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Sample records for glioma tumor volume

  1. The pathobiology of glioma tumors.

    PubMed

    Gladson, Candece L; Prayson, Richard A; Liu, Wei Michael

    2010-01-01

    The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled the development of rodent models for analysis of the molecular pathways underlying their proliferative and invasive behavior. Effective application of the targeted therapies that are now in development will depend on pathologists' ability to provide accurate information regarding the genetic alterations and the expression of key receptors and ligands in the tumors. Here we review the mechanisms that have been implicated in the pathogenesis of the gliomas and provide examples of the cooperative nature of the pathways involved, which may influence the initial therapeutic response and the potential for development of resistance.

  2. Serum levels of GFAP and EGFR in primary and recurrent high-grade gliomas: correlation to tumor volume, molecular markers, and progression-free survival.

    PubMed

    Kiviniemi, Aida; Gardberg, Maria; Frantzén, Janek; Parkkola, Riitta; Vuorinen, Ville; Pesola, Marko; Minn, Heikki

    2015-09-01

    Our aim was to study the association of two potential serum biomarkers glial fibrillary acidic protein (GFAP) and epidermal growth factor receptor (EGFR) with prognostic markers such as IDH1 mutation, tumor burden, and survival in patients with high-grade gliomas (HGG). Additionally, our objective was to evaluate the potential of serum EGFR as a surrogate marker for EGFR status in the tumor. Pre-operative serum samples were prospectively collected from patients with primary (n = 17) or recurrent (n = 10) HGG. Serum GFAP and EGFR levels were determined by ELISA and studied for correlation with molecular markers including EGFR amplification, tumor volume in contrast-enhanced T1-weighted MRI, and progression-free survival (PFS). Pre-operative serum GFAP level of ≥0.014 ng/ml was 86 % sensitive and 85 % specific for the diagnosis of glioblastoma. High GFAP was related to the lack of IDH1 mutation (P = 0.016), high Ki67 proliferation index (P < 0.001), and poor PFS (HR 5.9, CI 1.2-29.9, P = 0.032). Serum GFAP correlated with enhancing tumor volume in primary (r = 0.64 P = 0.005), but also in recurrent HGGs (r = 0.76 P = 0.011). In contrast, serum EGFR levels did not differ between HGG patients and 13 healthy controls, and were not related to EGFR status in the tumor. We conclude that high serum GFAP associates with IDH1 mutation-negative HGG, and poor PFS. Correlation with tumor burden in recurrent HGG implicates the potential of serum GFAP for detection of tumor recurrence. Our results suggest that circulating EGFR is not derived from glioma cells and cannot be used as a marker for EGFR status in the tumor.

  3. Evaluating changes in tumor volume using magnetic resonance imaging during the course of radiotherapy treatment of high-grade gliomas: Implications for conformal dose-escalation studies

    SciTech Connect

    Tsien, Christina . E-mail: ctsien@umich.edu; Gomez-Hassan, Diana; Haken, Randall K. ten; Tatro, Daniel C.; Junck, L.; Chenevert, T.L.; Lawrence, T.

    2005-06-01

    Objective: To determine whether changes in tumor volume occur during the course of conformal 3D radiotherapy of high-grade gliomas by use of magnetic resonance imaging (MRI) during treatment and whether these changes had an impact on tumor coverage. Methods and Materials: Between December 2000 and January 2004, 21 patients with WHO Grades 3 to 4 supratentorial malignant gliomas treated with 3D conformal radiotherapy (median dose, 70 Gy) were enrolled in a prospective clinical study. All patients underwent T1-weighted contrast-enhancing and T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging at approximately 1 to 2 weeks before radiotherapy, during radiotherapy (Weeks 1 and 3), and at routine intervals thereafter. All MRI scans were coregistered to the treatment-planning CT. Gross tumor volume (GTV Pre-Rx) was defined from a postoperative T1-weighted contrast-enhancing MRI performed 1 to 2 weeks before start of radiotherapy. A second GTV (GTV Week 3) was defined by use of an MRI performed during Week 3 of radiotherapy. A uniform 0.5 cm expansion of the respective GTV, PTV (Pre-Rx), and PTV (Week 3) was applied to the final boost plan. Dose-volume histograms (DVH) were used to analyze any potential adverse changes in tumor coverage based on Week 3 MRI. Results: All MRI scans were reviewed independently by a neuroradiologist (DGH). Two patients were noted to have multifocal disease at presentation and were excluded from analysis. In 19 cases, changes in the GTV based on MRI at Week 3 during radiotherapy were as follows: 2 cases had an objective decrease in GTV ({>=}50%); 12 cases revealed a slight decrease in the rim enhancement or changes in cystic appearance of the GTV; 2 cases showed no change in GTV; and 3 cases demonstrated an increase in tumor volume. Both cases with objective decreases in GTV during treatment were Grade 3 tumors. No cases of tumor progression were noted in Grade 3 tumors during treatment. In comparison, three of 12 Grade 4

  4. Rapid magnetic heating treatment by highly charged maghemite nanoparticles on Wistar rats exocranial glioma tumors at microliter volume

    PubMed Central

    Rabias, Ioannis; Tsitrouli, Danai; Karakosta, Eleni; Kehagias, Thomas; Diamantopoulos, Georgios; Fardis, Michael; Stamopoulos, Dimosthenis; Maris, Thomas G.; Falaras, Polykarpos; Zouridakis, Nikolaos; Diamantis, Nikolaos; Panayotou, Georgios; Verganelakis, Dimitrios A.; Drossopoulou, Garyfalia I.; Tsilibari, Effie C.; Papavassiliou, Georgios

    2010-01-01

    One of the most significant challenges implementing colloidal magnetic nanoparticles in medicine is the efficient heating of microliter quantities by applying a low frequency alternating magnetic field. The ultimate goal is to accomplish nonsurgically the treatment of millimeter size tumors. Here, we demonstrate the synthesis, characterization, and the in vitro as well as in vivo efficiency of a dextran coated maghemite (γ-Fe2O3) ferrofluid with an exceptional response to magnetic heating. The difference to previous synthetic attempts is the high charge of the dextran coating, which according to our study maintains the colloidal stability and good dispersion of the ferrofluid during the magnetic heating stage. Specifically, in vitro 2 μl of the ferrofluid gives an outstanding temperature rise of 33 °C within 10 min, while in vivo treatment, by infusing 150 μl of the ferrofluid in animal model (rat) glioma tumors, causes an impressive cancer tissue dissolution. PMID:20697578

  5. Glioma

    MedlinePlus

    ... cells are called mixed gliomas. Tumors such as “optic nerve glioma” and “brain stem glioma” are named ... Oligodendroglioma: Click here to learn more about oligodendroglioma. Optic Glioma: These tumors may involve any part of ...

  6. Residual Tumor Volume as Best Outcome Predictor in Low Grade Glioma – A Nine-Years Near-Randomized Survey of Surgery vs. Biopsy

    PubMed Central

    Roelz, Roland; Strohmaier, David; Jabbarli, Ramazan; Kraeutle, Rainer; Egger, Karl; Coenen, Volker A.; Weyerbrock, Astrid; Reinacher, Peter C.

    2016-01-01

    Diffuse low grade gliomas (DLGG) are continuously progressive primary brain neoplasms that lead to neurological deficits and death. Treatment strategies are controversial. Randomized trials establishing the prognostic value of surgery do not exist. Here, we report the results of a nine-year near-randomized patient distribution between resection and biopsy. Until 2012, the Department of Neurosurgery and the Department of Stereotactic Neurosurgery at the University Medical Center Freiburg were organized as separate administrative units both coordinating DLGG patient treatment independently. All consecutive adult patients with a new diagnosis of DLGG by either stereotactic biopsy or resection were included. Pre- and post-operative tumor volumetry was performed. 126 patients, 87 men (69%), 39 women (31%), median age 41 years, were included. 77 (61%) were initially managed by biopsy, 49 (39%) by resection. A significant survival benefit was found for patients with an initial management by resection (5-year OS 82% vs. 54%). The survival benefit of patients with initial resection was reserved to patients with a residual tumor volume of less than 15 cm3. Maximum safe resection is the first therapy of choice in DLGG patients if a near-complete tumor removal can be achieved. Accurate prediction of the extent-of-resection is required for selection of surgical candidates. PMID:27574036

  7. FIBULIN-3 IS UNIQUELY UPREGULATED IN MALIGNANT GLIOMAS AND PROMOTES TUMOR CELL MOTILITY AND INVASION

    PubMed Central

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

    2013-01-01

    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 to 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 pro-invasive role of fibulin-3, a mesenchymal matrix protein specifically upregulated in gliomas. Fibulin-3 is downregulated in peripheral tumors and 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 to controls. Tumors and cultured cells overexpressing fibulin-3 also showed elevated expression and activity of matrix metalloproteases, such as MMP-2/9 and ADAMTS-5. Taken together, our results suggest that fibulin-3 has a unique expression and pro-tumoral 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 dissemination of these tumors. PMID:19887559

  8. NDRG1 overexpressing gliomas are characterized by reduced tumor vascularization and resistance to antiangiogenic treatment.

    PubMed

    Broggini, Thomas; Wüstner, Marie; Harms, Christoph; Stange, Lena; Blaes, Jonas; Thomé, Carina; Harms, Ulrike; Mueller, Susanne; Weiler, Markus; Wick, Wolfgang; Vajkoczy, Peter; Czabanka, Marcus

    2016-10-01

    Hypoxia-regulated molecules play an important role in vascular resistance to antiangiogenic treatment. N-myc downstream-regulated-gene 1 (NDRG1) is significantly upregulated during hypoxia in glioma. It was the aim of the present study to analyze the role of NDRG1 on glioma angiogenesis and on antiangiogenic treatment. Orthotopically implanted NDRG1 glioma showed reduced tumor growth and vessel density compared to controls. RT-PCR gene array analysis revealed a 30-fold TNFSF15 increase in NDRG1 tumors. Consequently, the supernatant from NDRG1 transfected U87MG glioma cells resulted in reduced HUVEC proliferation, migration and angiogenic response in tube formation assays in vitro. This effect was provoked by increased TNFSF15 promoter activity in NDRG1 cells. Mutations in NF-κB and AP-1 promoter response elements suppressed TNFSF15 promoter activity. Moreover, U87MG glioma NDRG1 knockdown supernatant contained multiple proangiogenic proteins and increased HUVEC spheroid sprouting. Sunitinib treatment of orhotopically implanted mice reduced tumor volume and vessel density in controls; in NDRG1 overexpressing cells no reduction of tumor volume or vessel density was observed. NDRG1 overexpression leads to reduced tumor growth and angiogenesis in experimental glioma via upregulation of TNFSF15. In NDRG1 overexpressing glioma antiangiogenic treatment does not yield a therapeutic response.

  9. Brain tumor modeling: glioma growth and interaction with chemotherapy

    NASA Astrophysics Data System (ADS)

    Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood

    2011-10-01

    In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.

  10. Differential Glioma-Associated Tumor Antigen Expression Profiles of Human Glioma Cells Grown in Hypoxia

    PubMed Central

    Ge, Lisheng; Cornforth, Andrew N.; Hoa, Neil T.; Delgado, Christina; Chiou, Shiun Kwei; Zhou, Yi Hong; Jadus, Martin R.

    2012-01-01

    Human U251 and D54 glioma cells were tested for expression of 25 glioma-associated tumor antigen precursor proteins (TAPP) under hypoxic (1% O2) or normoxic (21% O2) conditions. Hypoxic glioma cell lines increased their mRNA expression for nine TAPP (Aim2, Art-4, EphA2, EZH2, Fosl1, PTH-rP, Sox 11, Whsc2 and YKL-40), as assessed by quantitative reverse transcriptase real-time/polymerase chain reaction (qRT-PCR). Increased differences with three hypoxic-induced TAPP: EZH2, Whsc2 and YKL-40 were shown at the protein levels by fluorescent antibody staining and quantitative electrophoretic analysis. Two TAPP (MRP3 and Trp1) were down-regulated by hypoxia in glioma cell lines. Growing the glioma cells under hypoxia for 13 days, followed by returning them back to normoxic conditions for 7 days, and restored the original normoxic TAPP profile. Thus, hypoxia was an environmental factor that stimulated the transient expression of these antigens. Intracranial xenografts grown in nude mice derived from U251 cells that had been cultured under neurosphere stem cell conditions showed increased expression of Whsc2 or YKL-40, demonstrating that these in vitro properties of glioma also occur in vivo. Whsc2-specific cytotoxic T lymphocytes killed the hypoxic U251 glioma cells better than normoxic glioma cells. The antigens expressed by hypoxic tumor cells may be a better source of starting tumor material for loading dendritic cells for novel immunotherapy of glioma using tumor-associated antigens. PMID:22957023

  11. Differential glioma-associated tumor antigen expression profiles of human glioma cells grown in hypoxia.

    PubMed

    Ge, Lisheng; Cornforth, Andrew N; Hoa, Neil T; Delgado, Christina; Chiou, Shiun Kwei; Zhou, Yi Hong; Jadus, Martin R

    2012-01-01

    Human U251 and D54 glioma cells were tested for expression of 25 glioma-associated tumor antigen precursor proteins (TAPP) under hypoxic (1% O(2)) or normoxic (21% O(2)) conditions. Hypoxic glioma cell lines increased their mRNA expression for nine TAPP (Aim2, Art-4, EphA2, EZH2, Fosl1, PTH-rP, Sox 11, Whsc2 and YKL-40), as assessed by quantitative reverse transcriptase real-time/polymerase chain reaction (qRT-PCR). Increased differences with three hypoxic-induced TAPP: EZH2, Whsc2 and YKL-40 were shown at the protein levels by fluorescent antibody staining and quantitative electrophoretic analysis. Two TAPP (MRP3 and Trp1) were down-regulated by hypoxia in glioma cell lines. Growing the glioma cells under hypoxia for 13 days, followed by returning them back to normoxic conditions for 7 days, and restored the original normoxic TAPP profile. Thus, hypoxia was an environmental factor that stimulated the transient expression of these antigens. Intracranial xenografts grown in nude mice derived from U251 cells that had been cultured under neurosphere stem cell conditions showed increased expression of Whsc2 or YKL-40, demonstrating that these in vitro properties of glioma also occur in vivo. Whsc2-specific cytotoxic T lymphocytes killed the hypoxic U251 glioma cells better than normoxic glioma cells. The antigens expressed by hypoxic tumor cells may be a better source of starting tumor material for loading dendritic cells for novel immunotherapy of glioma using tumor-associated antigens.

  12. Noscapine inhibits tumor growth in TMZ-resistant gliomas.

    PubMed

    Jhaveri, Niyati; Cho, Heeyeon; Torres, Shering; Wang, Weijun; Schönthal, Axel H; Petasis, Nicos A; Louie, Stan G; Hofman, Florence M; Chen, Thomas C

    2011-12-22

    Noscapine, a common oral antitussive agent, has been shown to have potent antitumor activity in a variety of cancers. Treatment of glioblastoma multiforme (GBM) with temozolomide (TMZ), its current standard of care, is problematic because the tumor generally recurs and is then resistant to this drug. We therefore investigated the effects of noscapine on human TMZ-resistant GBM tumors. We found that noscapine significantly decreased TMZ-resistant glioma cell growth and invasion. Using the intracranial xenograft model, we showed that noscapine increased survival of animals with TMZ-resistant gliomas. Thus noscapine can provide an alternative therapeutic approach for the treatment of TMZ-resistant gliomas.

  13. TRAIL conjugated to nanoparticles exhibits increased anti-tumor activities in glioma cells and glioma stem cells in vitro and in vivo

    PubMed Central

    Perlstein, Benny; Finniss, Susan A.; Miller, Cathie; Okhrimenko, Hana; Kazimirsky, Gila; Cazacu, Simona; Lee, Hae Kyung; Lemke, Nancy; Brodie, Shlomit; Umansky, Felix; Rempel, Sandra A.; Rosenblum, Mark; Mikklesen, Tom; Margel, Shlomo; Brodie, Chaya

    2013-01-01

    Glioblastomas (GBM) are characterized by resistance to chemotherapy and radiotherapy, and therefore, alternative therapeutic approaches are needed. TRAIL induces apoptosis in cancer but not in normal cells and is considered to be a promising anti-tumor agent. However, its short in vivo half-life and lack of efficient administration modes are serious impediments to its therapeutic efficacy. Nanoparticles (NP) have been used as effective delivery tools for various anticancer drugs. TRAIL was conjugated to magnetic ferric oxide NP by binding the TRAIL primary amino groups to activated double bonds on the surface of the NP. The effect of NP-TRAIL was examined on the apoptosis of glioma cells and self-renewal of glioma stem cells (GSCs). In addition, the ability of the NP-TRAIL to track U251 cell–derived glioma xenografts and to affect cell apoptosis, tumor volume, and survival among xenografted rats was also examined. Conjugation of TRAIL to NP increased its apoptotic activity against different human glioma cells and GSCs, as compared with free recombinant TRAIL. Combined treatment with NP-TRAIL and γ-radiation or bortezomib sensitized TRAIL-resistant GSCs to NP-TRAIL. Using rhodamine-labeled NP and U251 glioma cell–derived xenografts, we demonstrated that the NP-TRAIL were found in the tumor site and induced a significant increase in glioma cell apoptosis, a decrease in tumor volume, and increased animal survival. In summary, conjugation of TRAIL to NP increased its apoptotic activity both in vitro and in vivo. Therefore, NP-TRAIL represents a targeted anticancer agent with more efficient action for the treatment of GBM and the eradication of GSCs. PMID:23144078

  14. Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

    PubMed Central

    Sehm, Tina; Fan, Zheng; Ghoochani, Ali; Rauh, Manfred; Engelhorn, Tobias; Minakaki, Georgia; Dörfler, Arnd; Klucken, Jochen; Buchfelder, Michael

    2016-01-01

    The glutamate transporter xCT (SCL7a11, system Xc-, SXC) is an emerging key player in glutamate/cysteine/glutathione homeostasis in the brain and in cancer. xCT expression correlates with the grade of malignancy. Here, we report on the use of the U.S. Food and Drug Administration and EMA-approved xCT inhibitor, sulfasalazine (SAS) in gliomas. SAS does not affect cell viability in gliomas at concentrations below 200 μM. At higher concentrations SAS becomes gliomatoxic. Mechanistically SAS inhibits xCT and induces ferroptotic cell death in glioma cells. There is no evidence for impact on autophagic flux following SAS application. However, SAS can potentiate the efficacy of the standard chemotherapeutic and autophagy-inducing agent temozolomide (Temcat, Temodal or Temodar®). We also investigated SAS in non-transformed cellular constituents of the brain. Neurons and brain tissue are almost non-responding to SAS whereas isolated astrocytes are less sensitive towards SAS toxicity compared to gliomas. In vivo SAS treatment does not affect experimental tumor growth and treated animals revealed comparable tumor volume as untreated controls. However, SAS treatment resulted in reduced glioma-derived edema and, hence, total tumor volume burden as revealed by T2-weighted magnetic resonance imaging. Altogether, we show that SAS can be utilized for targeting the glutamate antiporter xCT activity as a tumor microenvironment-normalizing drug, while crucial cytotoxic effects in brain tumors are minor. PMID:27074570

  15. Angiopoietin-1 Promotes Tumor Angiogenesis in a Rat Glioma Model

    PubMed Central

    Machein, Marcia Regina; Knedla, Anette; Knoth, Rolf; Wagner, Shawn; Neuschl, Elvira; Plate, Karl H.

    2004-01-01

    Angiopoietins have been implicated in playing an important role in blood vessel formation, remodeling, maturation, and maintenance. However, the role of angiopoietins in tumor angiogenesis remains uncertain. In this study, expression of human angiopoietin-1 (hAng-1) and angiopoietin (hAng-2) was amplified in the rat glioma cell line GS9L by stable transfection using an inducible tet-off system. Transfected cells were implanted intracerebrally into syngenic Fischer 344 rats. We demonstrated by means of magnetic resonance imaging that increased hAng-1 expression promoted a significant in vivo growth of intracerebral gliomas in rats. Overexpression of hAng-1 resulted in more numerous, more highly branched vessels, which were covered by pericytes. On the other hand, tumors derived from hAng-2-overexpressing cells were smaller than empty-plasmid control tumors. The tumor vasculature in these tumors was composed of aberrant small vascular cords, which were associated with few mural cells. Our results indicate that in the presence of hAng-1, tumors induce a more functional vascular network, which led to better tumor perfusion and growth. On the other hand, overexpression of hAng-2 led to less intact tumor vessels, inhibited capillary sprouting, and impaired tumor growth. PMID:15509526

  16. Thermal imaging of brain tumors in a rat glioma model

    NASA Astrophysics Data System (ADS)

    Papaioannou, Thanassis; Thompson, Reid C.; Kateb, Babak; Sorokoumov, Oleg; Grundfest, Warren S.; Black, Keith L.

    2002-05-01

    We have explored the capability of thermal imaging for the detection of brain tumors in a rat glioma mode. Fourteen Wistar rats were injected stereotactically with 100,000 C6 glioma cells. Approximately one and two weeks post implantation, the rats underwent bilateral craniotomy and the exposed brain surface was imaged with a short wave thermal camera. Thermal images were obtained at both low (approximately 28.7 degree(s)C) and high (approximately 38 degree(s)C) core temperatures. Temperature gradients between the tumor site and the contralateral normal brain were calculated. Overall, the tumors appeared cooler than normal brain, for both high and low core temperatures. Average temperature difference between tumor and normal brain were maximal in more advanced tumors (two weeks) and at higher core temperatures. At one week (N equals 6), the average temperature gradient between tumor and normal sites was 0.1 degree(s)C and 0.2 degree(s)C at low and high core temperatures respectively (P(greater than)0.05). At two weeks (N equals 8), the average temperature gradient was 0.3 degree(s)C and 0.7 degree(s)C at low and high core temperatures respectively (P<0.05). We conclude that thermal imaging can detect temperature differences between tumor and normal brain tissue in this model, particularly in more advanced tumors. Thermal imaging may provide a novel means to identify brain tumors intraoperatively.

  17. Number of glioma polyploid giant cancer cells (PGCCs) associated with vasculogenic mimicry formation and tumor grade in human glioma

    PubMed Central

    2013-01-01

    Background Polyploid giant cancer cells (PGCCs) contribute to solid tumor heterogeneity. This study investigated the relationships among PGCCs numbers, vasculogenic mimicry (VM) formation, and tumor grades in glioma. Methods A total of 76 paraffin-embedded glioma tissue samples, including 28 cases of low grade and 48 cases of high grade gliomas, were performed with H&E and immunohistochemical staining for Ki-67 and hemoglobin. The size of PGCCs nuclei was measured by a micrometer using H&E section and defined as at least three times larger than the nuclei of regular diploid cancer cells. The number of PGCCs and different blood supply patterns were compared in different grade gliomas. Microcirculation patterns in tumors were assessed using CD31 immunohistochemical and PAS histochemical double staining. Human glioma cancer cell line C6 was injected into the chicken embryonating eggs to form xenografts, which was used to observe the PGCCs and microcirculation patterns. Results In human glioma, the number of PGCCs increased with the grade of tumors (χ2 = 4.781, P = 0.015). There were three kinds of microcirculation pattern in human glioma including VM, mosaic vessel (MV) and endothelium dependent vessel. PGCCs were able to generate erythrocytes via budding to form VM. The walls of VM were positive (or negative) for PAS staining and negative for CD31 staining. There were more VM and MVs in high grade gliomas than those in low grade gliomas. The differences have statistical significances for VM (t = 3.745, P = 0.000) and MVs (t = 4.789, P = 0.000). PGCCs, VM and MVs can also be observed in C6 chicken embryonating eggs xenografts. Conclusions The data demonstrated presence of PGCCs, VM and MVs in glioma and PGCCs generating erythrocytes contribute the formation of VM and MVs. PMID:24422894

  18. Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

    ClinicalTrials.gov

    2013-10-07

    Childhood High-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  19. Relationships between tumor grade and neurocognitive functioning in patients with glioma of the left temporal lobe prior to surgical resection

    PubMed Central

    Noll, Kyle R.; Sullaway, Catherine; Ziu, Mateo; Weinberg, Jeffrey S.; Wefel, Jeffrey S.

    2015-01-01

    Background Various tumor characteristics have been associated with neurocognitive functioning (NCF), though the role of tumor grade has not been adequately examined. Methods Seventy-two patients with histologically confirmed grade IV glioma (n = 37), grade III glioma (n = 20), and grade II glioma (n = 15) in the left temporal lobe completed preoperative neuropsychological assessment. Rates of impairment and mean test performances were compared by tumor grade with follow-up analysis of the influence of other tumor- and patient-related characteristics on NCF. Results NCF impairment was more frequent in patients with grade IV tumor compared with patients with lower-grade tumors in verbal learning, executive functioning, as well as language abilities. Mean performances significantly differed by tumor grade on measures of verbal learning, processing speed, executive functioning, and language, with the grade IV group exhibiting worse performances than patients with lower-grade tumors. Group differences in mean performances remained significant when controlling for T1-weighted and fluid attenuated inversion recovery MRI-based lesion volume. Performances did not differ by seizure status or antiepileptic and steroid use. Conclusions Compared with patients with grade II or III left temporal lobe glioma, patients with grade IV tumors exhibit greater difficulty with verbal learning, processing speed, executive functioning, and language. Differences in NCF associated with glioma grade were independent of lesion volume, seizure status, and antiepileptic or steroid use, lending support to the concept of “lesion momentum” as a primary contributor to deficits in NCF of newly diagnosed patients prior to surgery. PMID:25227126

  20. Association of carcinoid tumor and low grade glioma

    PubMed Central

    2012-01-01

    Background Lung carcinoid tumor and low grade glioma are two uncommon malignancies. Patients and methods We report the case of 24-year-old man who presented with respiratory disease. Imaging investigations showed a right lung tumor and histological analysis confirmed a typical carcinoid tumor. As part of initial staging, brain MRI revealed an asymptomatic right frontal lesion. First, a right pulmonary lobectomy was performed without adjuvant treatment. In second time, brain tumorectomy was performed. Histological examination confirmed the diagnosis of low grade glioma (LGG). The patient remained in complete remission 2.5 years after the initial diagnosis. Results This is the first case reporting the association between LGG and lung carcinoid tumor, while no association between LGG and a systemic tumor have been published to date. Association of lung carcinoid tumor with other malignant diseases has been reported but remained uncommon. Only minimal data support a potential molecular common origin. Conclusion This exceptional association may be fortuitous. However, their concomitant diagnoses suggest a potential association between both rare diseases. A genetic susceptibility remains possible. PMID:23137305

  1. Stereotactic brachytherapy of low-grade cerebral glioma after tumor resection.

    PubMed

    Suchorska, Bogdana; Ruge, Maximilian; Treuer, Harald; Sturm, Volker; Voges, Jürgen

    2011-10-01

    The purpose of this study was to assess the impact of stereotactic brachytherapy (SBT) on survival time and outcome when applied after resection of low-grade glioma (LGG) of World Health Organization grade II. From January 1982 through December 2006 we treated 1024 patients who had glioma with stereotactic implantation of iodine-125 seeds and SBT in accordance with a prospective protocol. For the present analysis, we selected 95 of 277 patients with LGG, in whom SBT was applied to treat progressive (43 patients) or recurrent (52 patients) tumor after resection. At 24 months after seed implantation, the tumor response rate was 35.9%, and the tumor control rate was 97.3%. The median progression-free-survival (PFS) duration after SBT was 52.7 ± 7.1 months. Five-year and 10-year PFS probabilities were 43.4% and 10.7%, respectively. Malignant tumor transformation, the diagnosis "astrocytoma," and tumor volume >20 mL were significantly associated with reduced PFS. Tumor progression or relapse after SBT (53 of 95 patients) was treated with tumor resection, a second SBT, chemotherapy, and/or radiotherapy. The median overall survival duration (from the first diagnosis of LGG until the patient's last contact) was 245.0 ± 4.9 months. Patients still under observation after seed implantation had a median follow-up time of 156.4 ± 55.7 months. Perioperative transient morbidity was 1.1%, and the frequency of permanent morbidity caused by SBT was 3.3%. In conclusion, SBT of recurrent or progressive LGG after resection located in functionally critical brain areas has high local efficacy and comparably low morbidity. Referred to individually adopted glioma treatment concepts SBT provides a reasonably long PFS, thus improving overall survival. In selected patients, SBT can lead to delays in the application of chemotherapy and/or radiotherapy.

  2. Senescence from glioma stem cell differentiation promotes tumor growth

    PubMed Central

    Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro; Nakano, Ichiro; Seimiya, Hiroyuki

    2016-01-01

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs’ role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. PMID:26775840

  3. Gas5 Exerts Tumor-suppressive Functions in Human Glioma Cells by Targeting miR-222

    PubMed Central

    Zhao, Xihe; Wang, Ping; Liu, Jing; Zheng, Jian; Liu, Yunhui; Chen, Jiajia; Xue, Yixue

    2015-01-01

    Aberrant expression of noncoding RNAs in glioma cells, including long noncoding RNAs (lncRNAs) and microRNAs, may participate in the progression of glioma. Encoded by Growth Arrest-Specific 5 (GAS5) gene, lncRNA Gas5 was reported to be a negative regulator for survival and proliferation of several cancers. Here, Gas5 is found to be downregulated in glioma specimens and U87 and U251 glioma cell lines. We showed that the introduction of Gas5 by plasmid transfection increased the expression of tumor suppressor Bcl-2-modifying factor (bmf) and Plexin C1 via directly targeting and reducing the expression of miR-222. Downregulated expression of miR-222 inhibited U87 and U251 cell proliferation and promoted the apoptosis by upregulating bmf. As downstream signaling molecules of bmf, Bcl-2 and Bax were involved in the process. Meanwhile, knockdown of miR-222 attenuated U87 and U251 cell migration and invasion by upregulating Plexin C1, and cofilin was a crucial regulator targeted by Plexin C1. Gas5 combined with the knockdown of miR-222 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. In summary, we show that Gas5 suppresses tumor malignancy by downregulating miR-222, which may serve as a promising therapy for glioma. PMID:26370254

  4. Gas5 Exerts Tumor-suppressive Functions in Human Glioma Cells by Targeting miR-222.

    PubMed

    Zhao, Xihe; Wang, Ping; Liu, Jing; Zheng, Jian; Liu, Yunhui; Chen, Jiajia; Xue, Yixue

    2015-12-01

    Aberrant expression of noncoding RNAs in glioma cells, including long noncoding RNAs (lncRNAs) and microRNAs, may participate in the progression of glioma. Encoded by Growth Arrest-Specific 5 (GAS5) gene, lncRNA Gas5 was reported to be a negative regulator for survival and proliferation of several cancers. Here, Gas5 is found to be downregulated in glioma specimens and U87 and U251 glioma cell lines. We showed that the introduction of Gas5 by plasmid transfection increased the expression of tumor suppressor Bcl-2-modifying factor (bmf) and Plexin C1 via directly targeting and reducing the expression of miR-222. Downregulated expression of miR-222 inhibited U87 and U251 cell proliferation and promoted the apoptosis by upregulating bmf. As downstream signaling molecules of bmf, Bcl-2 and Bax were involved in the process. Meanwhile, knockdown of miR-222 attenuated U87 and U251 cell migration and invasion by upregulating Plexin C1, and cofilin was a crucial regulator targeted by Plexin C1. Gas5 combined with the knockdown of miR-222 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. In summary, we show that Gas5 suppresses tumor malignancy by downregulating miR-222, which may serve as a promising therapy for glioma.

  5. Circulating tumor cell is a common property of brain glioma and promotes the monitoring system

    PubMed Central

    Gao, Faliang; Cui, Yong; Jiang, Haihui; Sui, Dali; Wang, Yonggang; Jiang, Zhongli; Zhao, Jizong; Lin, Song

    2016-01-01

    Brain glioma is the most common primary intracranial tumor characterized by dismal prognosis and frequent recurrence, yet a real-time and reliable biological approach to monitor tumor response and progression is still lacking. Recently, few studies have reported that circulating tumor cells (CTCs) could be detected in glioblastoma multiform (GBM), providing the possibility of its application in brain glioma monitoring system. But its application limits still exist, because the detection rate of CTCs is still low and was exclusively limited to high- grade gliomas. Here, we adopted an advanced integrated cellular and molecular approach of SE-iFISH to detect CTCs in the peripheral blood (PB) of patients with 7 different subtypes of brain glioma, uncovering the direct evidences of glioma migration. We identified CTCs in the PB from 24 of 31 (77%) patients with glioma in all 7 subtypes. No statistical difference of CTC incidence and count was observed in different pathological subtypes or WHO grades of glioma. Clinical data revealed that CTCs, to some extent, was superior to MRI in monitoring the treatment response and differentiating radionecrosis from recurrence of glioma. Conclusively, CTCs is a common property of brain gliomas of various pathological subtypes, which has provided an ultimate paradox for the hypothesis “soil and seed”. It can be used to monitor the microenvironment of gliomas dynamically, which will be a meaningful complement to radiographic imaging. PMID:27517490

  6. Anti-tumoral activity of native compound morelloflavone in glioma

    PubMed Central

    Li, Xianfeng; Ai, Hongyan; Sun, Deke; Wu, Tao; He, Jian; Xu, Zhai; Ding, Li; Wang, Ling

    2016-01-01

    The aim of the study was to investigate the anti-tumoral activity of morelloflavone substances with different structures. We also studied the possible link between morelloflavone structure and its function. Various types of chromatographic techniques were used to isolate and screen morelloflavone substances from the extracts of gambogic tree trunk and the morelloflavone structures were identified by analytical techniques such as high resolution mass spectrometry and nuclear magnetism. Anti-tumoral activities of different compounds were investigated and the link between the antitumor activity and the structure of compound was exaimed. Our results showed that the isolated morelloflavone substances demonstrated a certain level of antitumor activity. The compound no. 1 had the strongest effect to inhibit glioma U87 and C6 cells followed by compound no. 2 while compound no. 5 was the weakest among them. We conducted a preliminary analysis on the structure-function relationship through the structure comparison and we concluded that the antitumor effects of morelloflavone substances with different structures were significantly different from each other. Thus, the glucose chain in C4 position of biflavone structure can enhance the antitumor activity of the compound in glioma cells. Additionally, the formation of intramolecular hydrogen bonds in biflavone compounds may also play a role in enhancing the antitumor activity and inhibition rate. PMID:27900007

  7. IGFBP2 promotes glioma tumor stem cell expansion and survival

    SciTech Connect

    Hsieh, David; Hsieh, Antony; Stea, Baldassarre; Ellsworth, Ron

    2010-06-25

    IGFBP2 is overexpressed in the most common brain tumor, glioblastoma (GBM), and its expression is inversely correlated to GBM patient survival. Previous reports have demonstrated a role for IGFBP2 in glioma cell invasion and astrocytoma development. However, the function of IGFBP2 in the restricted, self-renewing, and tumorigenic GBM cell population comprised of tumor-initiating stem cells has yet to be determined. Herein we demonstrate that IGFBP2 is overexpressed within the stem cell compartment of GBMs and is integral for the clonal expansion and proliferative properties of glioma stem cells (GSCs). In addition, IGFBP2 inhibition reduced Akt-dependent GSC genotoxic and drug resistance. These results suggest that IGFBP2 is a selective malignant factor that may contribute significantly to GBM pathogenesis by enriching for GSCs and mediating their survival. Given the current dearth of selective molecular targets against GSCs, we anticipate our results to be of high therapeutic relevance in combating the rapid and lethal course of GBM.

  8. Malignant brainstem tumors in children, excluding diffuse intrinsic pontine gliomas.

    PubMed

    Klimo, Paul; Nesvick, Cody L; Broniscer, Alberto; Orr, Brent A; Choudhri, Asim F

    2016-01-01

    OBJECT Malignant tumors of the brainstem, excluding classic diffuse intrinsic pontine gliomas (DIPGs), are a very rare, heterogeneous group of neoplasms that have been infrequently described in the literature. In this paper, the authors present their experiences with treating these unique cancers. METHODS A retrospective chart review was conducted to identify eligible cases over a 15-year period. All tumors involving the pons were, by consensus, felt not to be DIPGs based on their neuroimaging features. Demographic information, pathological specimens, neuroimaging characteristics, surgical and nonsurgical management plans, and survival data were gathered for analysis. RESULTS Between January 2000 and December 2014, 29 patients were identified. The mean age at diagnosis was 8.4 years (range 2 months to 25 years), and 17 (59%) patients were male. The most common presenting signs and symptoms were cranial neuropathies (n = 24; 83%), hemiparesis (n = 12; 41%), and ataxia or gait disturbance (n = 10; 34%). There were 18 glial and 11 embryonal tumors. Of the glial tumors, 5 were radiation-induced and 1 was a malignant transformation of a previously known low-grade tumor. Surgical intervention consisted of biopsy alone in 12 patients and some degree of resection in another 15 patients. Two tumors were diagnosed postmortem. The median overall survival for all patients was 196 days (range 15 to 3999 days). There are currently 5 (17%) patients who are still alive: 1 with an anaplastic astrocytoma and the remaining with embryonal tumors. CONCLUSIONS In general, malignant non-DIPG tumors of the brainstem carry a poor prognosis. However, maximal cytoreductive surgery may be an option for select patients with focal tumors. Long-term survival is possible in patients with nonmetastatic embryonal tumors after multimodal treatment, most importantly maximal resection.

  9. HOXB1 Is a Tumor Suppressor Gene Regulated by miR-3175 in Glioma

    PubMed Central

    Han, Liang; Liu, Dehua; Li, Zhaohui; Tian, Nan; Han, Ziwu; Wang, Guang; Fu, Yao; Guo, Zhigang; Zhu, Zifeng

    2015-01-01

    The HOXB1 gene plays a critical role as an oncogene in diverse tumors. However, the functional role of HOXB1 and the mechanism regulating HOXB1 expression in glioma are not fully understood. A preliminary bioinformatics analysis showed that HOXB1 is ectopically expressed in glioma, and that HOXB1 is a possible target of miR-3175. In this study, we investigated the function of HOXB1 and the relationship between HOXB1 and miR-3175 in glioma. We show that HOXB1 expression is significantly downregulated in glioma tissues and cell lines, and that its expression may be closely associated with the degree of malignancy. Reduced HOXB1 expression promoted the proliferation and invasion of glioma cells, and inhibited their apoptosis in vitro, and the downregulation of HOXB1 was also associated with worse survival in glioma patients. More importantly, HOXB1 was shown experimentally to be a direct target of miR-3175 in this study. The downregulated expression of miR-3175 inhibited cell proliferation and invasion, and promoted apoptosis in glioma. The oncogenicity induced by low HOXB1 expression was prevented by an miR-3175 inhibitor in glioma cells. Our results suggest that HOXB1 functions as a tumor suppressor, regulated by miR-3175 in glioma. These results clarify the pathogenesis of glioma and offer a potential target for its treatment. PMID:26565624

  10. Epigenetic regulation of human hedgehog interacting protein in glioma cell lines and primary tumor samples

    PubMed Central

    Shahi, Mehdi H.; Zazpe, Idoya; Afzal, Mohammad; Sinha, Subrata; Rebhun, Robert B.; Meléndez, Bárbara; Rey, Juan A.

    2016-01-01

    Glioma constitutes one of the most common groups of brain tumors, and its prognosis is influenced by different genetic and epigenetic modulations. In this study, we demonstrated low or no expression of hedgehog interacting protein (HHIP) in most of the cell lines and primary glioma tumor samples. We further proceeded to promoter methylation study of this gene in the same cell lines and primary tumor samples and found 87 % (7/8) HHIP methylation in glioblastoma cell lines and 75 % (33/44) in primary tumor samples. These methylation pattern correlates with low or unexpressed HHIP in both cell lines and primary tumor samples. Our results suggest the possibility of epigenetic regulation of this gene in glioma, similarly to medulloblastoma, gastric, hepatic, and pancreatic cancers. Also, HHIP might be a diagnostic or prognostic marker in glioma and help to the detection of these tumors in early stages of disease. PMID:25416442

  11. Anti-tumor activity of phenoxybenzamine hydrochloride on malignant glioma cells.

    PubMed

    Lin, Xian-Bin; Jiang, Lei; Ding, Mao-Hua; Chen, Zhen-Hua; Bao, Yi; Chen, Yi; Sun, Wei; Zhang, Chen-Ran; Hu, Hong-Kang; Cai, Zhen; Lu, Cheng-Yin; Zhou, Jue-Yu; Qian, Jun; Wu, Xiao-Jun; Jin, Wei-Lin; Hu, Guo-Han

    2016-03-01

    Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells.

  12. Probing the Bi-directional Interaction Between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice.

    PubMed

    Gu, Rui; Zhang, Xu; Zhang, Ge; Tao, Tingting; Yu, Haibo; Liu, Lianqing; Dou, Ying; Li, Aiping; Qin, Jianhua

    2017-02-24

    It has been proven that microglia are involved in both early and late stages of glioma progression and contribute substantially to the tumor mass of gliomas. Because no appropriate in vitro or in vivo investigative approach is available, the dynamic interaction between microglia and gliomas during tumor formation remains unclear. In this study, three types of microfluidic assay were developed to examine the outcomes of the dynamic interaction between microglia and gliomas. Co-migration assay and two-dimensional cell co-culture assay have been used to show that microglial BV-2 cells migrate toward C6 glioma cells and inhibit tumor growth during the early stage of tumorigenesis. However, in three-dimensional cell spheres (three-dimensional cell co-culture assay) that contain a large amount of glioma cells, mimicking the late stage of glioma growth, the phagocytosis of microglia was suppressed, which suggests that glioma cells could reeducate classically activated microglia into a tumor-promoting state at some point during tumor progression. Notably, we found that microglia could contribute to tumor invasion and acquisition of the epithelial-mesenchymal transition phenotype in the glioma microenvironment during the early stage and the late stage of tumor progression. In conclusion, we have developed a potential quantitative method for in vitro study of glioma immunity and provided evidence for the duality of glioma-associated microglia.

  13. Standard of care therapy for malignant glioma and its effect on tumor and stromal cells.

    PubMed

    Jones, T S; Holland, E C

    2012-04-19

    Glioblastoma is the most common and deadly of the primary central nervous system tumors. Recent advances in molecular characterization have subdivided these tumors into at least three main groups. In addition, these tumors are cellularly complex with multiple stromal cell types contributing to the biology of the tumor and treatment response. Because essentially all glioma patients are treated with radiation, various chemotherapies and steroids, the tumor that finally kills them has been modified by these treatments. Most of the investigation of the effects of therapy on these tumors has focused on the glioma cells per se. However, despite the importance of the stromal cells in these tumors, little has been done to understand the effects of treatment on stromal cells and their contribution to disease. Understanding how current standard therapy affects the biology of the tumor and the tumor stroma may provide insight into the mechanisms that are important to the inhibition of tumor growth as well as the biology of recurrent tumors.

  14. Molecular Markers in Low-Grade Glioma-Toward Tumor Reclassification.

    PubMed

    Olar, Adriana; Sulman, Erik P

    2015-07-01

    Low-grade diffuse gliomas are a heterogeneous group of primary glial brain tumors with highly variable survival. Currently, patients with low-grade diffuse gliomas are stratified into risk subgroups by subjective histopathologic criteria with significant interobserver variability. Several key molecular signatures have emerged as diagnostic, prognostic, and predictor biomarkers for tumor classification and patient risk stratification. In this review, we discuss the effect of the most critical molecular alterations described in diffuse (IDH1/2, 1p/19q codeletion, ATRX, TERT, CIC, and FUBP1) and circumscribed (BRAF-KIAA1549, BRAF(V600E), and C11orf95-RELA fusion) gliomas. These molecular features reflect tumor heterogeneity and have specific associations with patient outcome that determine appropriate patient management. This has led to an important, fundamental shift toward developing a molecular classification of World Health Organization grade II-III diffuse glioma.

  15. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy12

    PubMed Central

    Baker, Gregory J.; Yadav, Viveka Nand; Motsch, Sebastien; Koschmann, Carl; Calinescu, Anda-Alexandra; Mineharu, Yohei; Camelo-Piragua, Sandra Ines; Orringer, Daniel; Bannykh, Serguei; Nichols, Wesley S.; deCarvalho, Ana C.; Mikkelsen, Tom; Castro, Maria G.; Lowenstein, Pedro R.

    2014-01-01

    As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients. PMID:25117977

  16. Gab3 overexpression in human glioma mediates Akt activation and tumor cell proliferation

    PubMed Central

    Gu, Weiting; Zhang, Weifeng

    2017-01-01

    This current study tested expression and potential biological functions of Gab3 in human glioma. Gab3 mRNA and protein expression was significantly elevated in human glioma tissues and glioma cells. Its level was however low in normal brain tissues and primary human astrocytes. In both established (U251MG cell line) and primary human glioma cells, Gab3 knockdown by shRNA/siRNA significantly inhibited Akt activation and cell proliferation. Reversely, forced Gab3 overexpression in U251MG cells promoted Akt activation and cell proliferation. In vivo, the growth of U251MG tumors in nude mice was inhibited following expressing Gab3 shRNA. Akt activation in cancer tissues was also suppressed by Gab3 shRNA. Together, we conclude that Gab3 overexpression in human glioma mediates Akt activation and cancer cell proliferation. PMID:28291820

  17. Functional Response of Tumor Vasculature to PaCO2: Determination of Total and Microvascular Blood Volume by MRI

    PubMed Central

    Packard, Scott D; Mandeville, Joseph B; Ichikawa, Tomotsugu; Ikeda, Keiro; Terada, Kinya; Niloff, Stephanie; Chiocca, E Antonio; Rosen, Bruce R; Marota, John J A

    2003-01-01

    Abstract In order to identify differences in functional activity, we compared the reactivity of glioma vasculature and the native cerebral vasculature to both dilate and constrict in response to altered PaCO2. Gliomas were generated by unilateral implantation of U87MGdEGFR human glioma tumor cells into the striatum of adult female athymic rats. Relative changes in total and microvascular cerebral blood volume were determined by steady state contrast agent-enhanced magnetic resonance imaging for transitions from normocarbia to hypercarbia and hypocarbia. Although hypercarbia induced a significant increase in both total and microvascular blood volume in normal brain and glioma, reactivity of glioma vasculature was significantly blunted in comparison to normal striatum; glioma total CBV increased by 0.6±0.1% / mm Hg CO2 whereas normal striatum increased by 1.5±0.2%/ mm Hg CO2, (P < .0001, group t-test). Reactivity of microvascular blood volume was also significantly blunted. In contrast, hypocarbia decreased both total and microvascular blood volumes more in glioma than in normal striatum. These results indicate that cerebral blood vessels derived by tumor-directed angiogenesis do retain reactivity to CO2. Furthermore, reduced reactivity of tumor vessels to a single physiological perturbation, such as hypercarbia, should not be construed as a generalized reduction of functional activity of the tumor vascular bed. PMID:14511404

  18. Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis.

    PubMed

    Shan, Shouqin; Hui, Guangyan; Hou, Fanggao; Shi, Hua; Zhou, Guoqing; Yan, Han; Wang, Lu; Liu, Jinfeng

    2015-10-01

    Glioma represents a disparate group of tumors characterized by high invasion ability, and therefore it is of clinical significance to identify molecular markers and therapeutic targets for better clinical management. Previously, metastasis-associated protein family (MTA) is considered to promote tumor cell invasion and metastasis of human malignancies. Recently, the newly identified MTA3 has been shown to play conflicting roles in human malignancies, while the expression pattern and potential clinical significance of MTA3 in human glioma have not been addressed yet. In the present study, we investigated the protein expression of MTA3 by immunohistochemistry assay and analyzed its association with glioma prognosis in 186 cases of patients. Results showed that MTA3 expression was decreased in glioma compared with that in normal brain (P < 0.05). In addition, tumors with high MTA3 expression were more likely to be of low WHO grade (P = 0.005) and reserve of body function (P = 0.014). Survival analysis showed that decreased MTA3 expression was independently associated with unfavorable overall survival of patients (P < 0.001). These results provide the first evidence that MTA3 expression was decreased in human glioma and negatively associated with prognosis of patients, suggesting that MTA3 may play a tumor suppressor role in glioma.

  19. Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes

    PubMed Central

    Zhao, Hua; Heimberger, Amy B.; Lu, Zhimin; Wu, Xifeng; Hodges, Tiffany R.; Song, Renduo; Shen, Jie

    2016-01-01

    Background Tumor-based molecular biomarkers have redefined in the classification gliomas. However, the association of systemic metabolomics with glioma phenotype has not been explored yet. Methods In this study, we conducted two-step (discovery and validation) metabolomic profiling in plasma samples from 87 glioma patients. The metabolomics data were tested for correlation with glioma grade (high vs low), glioblastoma (GBM) versus malignant gliomas, and IDH mutation status. Results Five metabolites, namely uracil, arginine, lactate, cystamine, and ornithine, significantly differed between high- and low-grade glioma patients in both the discovery and validation cohorts. When the discovery and validation cohorts were combined, we identified 29 significant metabolites with 18 remaining significant after adjusting for multiple comparisons. Those 18 significant metabolites separated high- from low-grade glioma patients with 91.1% accuracy. In the pathway analysis, a total of 18 significantly metabolic pathways were identified. Similarly, we identified 2 and 6 metabolites that significantly differed between GBM and non-GBM, and IDH mutation positive and negative patients after multiple comparison adjusting. Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy. Three pathways were identified to be associated with IDH mutation status. Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors. Conclusion Our findings identified metabolites and metabolic pathways that differentiated tumor phenotypes. These may be useful as host biomarker candidates to further help glioma molecular classification. PMID:26967252

  20. Lower expression of Nrdp1 in human glioma contributes tumor progression by reducing apoptosis.

    PubMed

    Shi, Hengliang; Du, Jin; Wang, Lei; Zheng, Bao; Gong, Hui; Wu, Yuxuan; Tang, Yuan; Gao, Yong; Yu, Rutong

    2014-10-01

    Ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) plays important roles in multiple physiological process because it can ubiquitinate various substrates such as ErbB3, BRUCE, MyD88, C/EBPβ, and Parkin, and so forth. In addition to the physiological function, it was also found to be involved in tumor progression. It has been shown that loss of Nrdp1 enhances breast cancer cell growth. Up to now, the role of Nrdp1 in glioma has not been elucidated. Here, we reported that Nrdp1 as well as cleaved caspase 3 was lower expressed in human glioma tissues comparing with the nontumorous. And then we found that the expression of Nrdp1 and cleaved caspase 3 was increased in the treatment of Temozolomide (TMZ), a drug for glioma chemotherapy. Further investigation indicated that transient transfection of Nrdp1 significantly promoted cell apoptosis by aggravating the degradation of BRUCE and activation of caspase 3. In addition, overexpression of Nrdp1 augmented TMZ induced apoptosis by evaluating the degradation of BRUCE and the activation of caspase 3, while silencing of Nrdp1 reduced the sensitivity to the TMZ by inhibiting the degradation of BRUCE and the activation of caspase 3 in human glioma cells. These observations show that Nrdp1 is a pro-apoptotic protein in human glioma and lower expression of Nrdp1 in human glioma may promote tumor progression by reducing apoptosis, suggesting that Nrdp1 may be an important regulator in the development of human glioma.

  1. Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression

    PubMed Central

    Miyauchi, Jeremy T.; Chen, Danling; Choi, Matthew; Nissen, Jillian C.; Shroyer, Kenneth R.; Djordevic, Snezana; Zachary, Ian C.; Selwood, David; Tsirka, Stella E.

    2016-01-01

    Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. PMID:26755653

  2. Taurine concentration in human gliomas and meningiomas: tumoral, peritumoral, and extratumoral tissue.

    PubMed

    Cubillos, Suzana; Obregón, Francisco; Vargas, María Fernanda; Salazar, Luis Antonio; Lima, Lucimey

    2006-01-01

    Taurine concentrations were determined in gliomas from 16 patients and in meningiomas from 15 patients. After imaging analysis and clinical evaluation to consider the level of functional deterioration by the scale of Karnosky, tissue was obtained by surgery. Tumoral, peritumoral and extratumoral samples were taken and analyzed by HPLC with fluorescence detector. The concentration of taurine (nmol/mg protein) was higher in tumoral and peritumoral tissues than in the extratumoral samples for gliomas. In the case of meningiomas, the taurine concentration was higher in tumoral than in peritumoral and extratumoral samples. These modifications might be due to specific functions of this amino acid, being either protective or involved in the proliferation of cells. The differential distribution in the two types of tumors could be related to the malignancy of them, which is higher in gliomas than in meningiomas.

  3. Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients.

    PubMed

    Mukasa, Akitake; Takayanagi, Shunsaku; Saito, Kuniaki; Shibahara, Junji; Tabei, Yusuke; Furuya, Kazuhide; Ide, Takafumi; Narita, Yoshitaka; Nishikawa, Ryo; Ueki, Keisuke; Saito, Nobuhito

    2012-03-01

    Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were an Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have either mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q co-deletion also had an IDH mutation, and these alterations were significantly correlated (P < 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas (P = 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 (P < 0.001) and grade 3 (P = 0.02) gliomas. IDH mutation and 1p/19q co-deletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q co-deletion, IDH mutation was strongly associated with increased progression-free survival (P < 0.0001) and overall survival (P < 0.0001), but no such marked correlation was observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most of these grade 3 gliomas.

  4. 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.

  5. 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

  6. 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.

  7. The Use of MR Perfusion Imaging in the Evaluation of Tumor Progression in Gliomas

    PubMed Central

    Snelling, Brian; Shah, Ashish H.; Buttrick, Simon; Benveniste, Ronald

    2017-01-01

    Objective Diagnosing tumor progression and pseudoprogression remains challenging for many clinicians. Accurate recognition of these findings remains paramount given necessity of prompt treatment. However, no consensus has been reached on the optimal technique to discriminate tumor progression. We sought to investigate the role of magnetic resonance perfusion (MRP) to evaluate tumor progression in glioma patients. Methods An institutional retrospective review of glioma patients undergoing MRP with concurrent clinical follow up visit was performed. MRP was evaluated in its ability to predict tumor progression, defined clinically or radiographically, at concurrent clinical visit and at follow up visit. The data was then analyzed based on glioma grade and subtype. Resusts A total of 337 scans and associated clinical visits were reviewed from 64 patients. Sensitivity, specificity, positive and negative predictive value were reported for each tumor subtype and grade. The sensitivity and specificity for high-grade glioma were 60.8% and 87.8% respectively, compared to low-grade glioma which were 85.7% and 89.0% respectively. The value of MRP to assess future tumor progression within 90 days was 46.9% (sensitivity) and 85.0% (specificity). Conclusion Based on our retrospective review, we concluded that adjunct imaging modalities such as MRP are necessary to help diagnose clinical disease progression. However, there is no clear role for stand-alone surveillance MRP imaging in glioma patients especially to predict future tumor progression. It is best used as an adjunctive measure in patients in whom progression is suspected either clinically or radiographically. PMID:28061488

  8. Overexpression of CAP1 and its significance in tumor cell proliferation, migration and invasion in glioma.

    PubMed

    Fan, Yue-Chao; Cui, Chen-Chen; Zhu, Yi-Shuo; Zhang, Lei; Shi, Meng; Yu, Jin-Song; Bai, Jin; Zheng, Jun-Nian

    2016-09-01

    Adenylate cyclase-associated protein 1 (CAP1), a protein related to the regulation of actin filaments and the Ras/cAMP pathway, is associated with tumor progression. Nevertheless, the expression level and effects of CAP1 in regards to glioma have not been reported. In the present study, we examined the expression of CAP1 in glioma and tumor adjacent normal brain tissues by tissue microarray and immunohistochemistry. Our results showed that CAP1 was overexpressed in glioma tissues in comparison with that noted in the tumor adjacent normal brain tissues and increased staining of CAP1 was found to be correlated with WHO stage. In addition, we discovered that knockdown of CAP1 by specific RNA interference markedly inhibited cell growth and caused downregulation of the proliferation markers, PCNA and cyclin A. We further demonstrated that knockdown of CAP1 inhibited cell metastatic abilities by downregulating N-cadherin and vimentin and upregulating E-cadherin. These findings revealed that CAP1 expression is markedly increased in human glioma and that downregulation of CAP1 in tumors may serve as a treatment for glioma patients.

  9. Effective Treatment of Established GL261 Murine Gliomas through Picornavirus Vaccination-Enhanced Tumor Antigen-Specific CD8+ T Cell Responses.

    PubMed

    Renner, Danielle N; Jin, Fang; Litterman, Adam J; Balgeman, Alexis J; Hanson, Lisa M; Gamez, Jeffrey D; Chae, Michael; Carlson, Brett L; Sarkaria, Jann N; Parney, Ian F; Ohlfest, John R; Pirko, Istvan; Pavelko, Kevin D; Johnson, Aaron J

    2015-01-01

    Glioblastoma (GBM) is among the most invasive and lethal of cancers, frequently infiltrating surrounding healthy tissue and giving rise to rapid recurrence. It is therefore critical to establish experimental model systems and develop therapeutic approaches that enhance anti-tumor immunity. In the current study, we have employed a newly developed murine glioma model to assess the efficacy of a novel picornavirus vaccination approach for the treatment of established tumors. The GL261-Quad system is a variation of the GL261 syngeneic glioma that has been engineered to expresses model T cell epitopes including OVA257-264. MRI revealed that both GL261 and GL261-Quad tumors display characteristic features of human gliomas such as heterogeneous gadolinium leakage and larger T2 weighted volumes. Analysis of brain-infiltrating immune cells demonstrated that GL261-Quad gliomas generate detectable CD8+ T cell responses toward the tumor-specific Kb:OVA257-264 antigen. Enhancing this response via a single intracranial or peripheral vaccination with picornavirus expressing the OVA257-264 antigen increased anti-tumor CD8+ T cells infiltrating the brain, attenuated progression of established tumors, and extended survival of treated mice. Importantly, the efficacy of the picornavirus vaccination is dependent on functional cytotoxic activity of CD8+ T cells, as the beneficial response was completely abrogated in mice lacking perforin expression. Therefore, we have developed a novel system for evaluating mechanisms of anti-tumor immunity in vivo, incorporating the GL261-Quad model, 3D volumetric MRI, and picornavirus vaccination to enhance tumor-specific cytotoxic CD8+ T cell responses and track their effectiveness at eradicating established gliomas in vivo.

  10. M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells

    PubMed Central

    Zhang, Lin; Xu, Yangyang; Sun, Jintang; Chen, Weiliang; Zhao, Lei; Ma, Chao; Wang, Qingjie; Sun, Jia; Huang, Bin; Zhang, Yun; Li, Xingang; Qu, Xun

    2017-01-01

    Vasculogenic mimicry (VM) has offered a new horizon for understanding tumor angiogenesis, but the mechanisms of VM in glioma progression have not been studied explicitly until now. As a significant component of immune infiltration in tumor microenvironment, macrophages have been demonstrated to play an important role in tumor growth and angiogenesis. However, whether macrophages could play a potential key role in glioma VM is still poorly understood. Herein we reported that both VM and CD163+ cells were associated with WHO grade and reduced patient survival, and VM channel counting was correlated to the number of infiltrated CD163+ cells in glioma specimens. In vitro studies of glioma cell lines implicated that M2-like macrophages (M2) promoted glioma VM. We found that conditional medium derived from M2 amplified IL-6 expression in glioma cells. Furthermore, our data indicated that IL-6 could promote glioma VM, as blocking IL-6 with neutralizing antibodies abrogated M2-mediated VM enhancement. In addition, the potent PKC inhibitor bisindolylmaleimide I could prevent M2-induced IL-6 upregulation and further inhibited glioma VM facilitation. Taken together, our results suggested that M2-like macrophages drove glioma VM through amplifying IL-6 secretion in glioma cells via PKC pathway. PMID:27903982

  11. DICER governs characteristics of glioma stem cells and the resulting tumors in xenograft mouse models of glioblastoma

    PubMed Central

    Alamsahebpour, Amir; Burrell, Kelly; Li, Mira; Karabork, Merve; Ekinci, Can; Koch, Elizabeth; Solaroglu, Ihsan; Chang, Jeffery T.; Wouters, Bradly; Aldape, Kenneth; Zadeh, Gelareh

    2016-01-01

    The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently decreased in a variety of malignancies. We characterized the role of DICER in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells (GSCs) to form tumors in a mouse model of GB. DICER silencing in GSCs reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER silencing enhances the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB. PMID:27421140

  12. Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells.

    PubMed

    Chen, Tunan; Yi, Liang; Li, Fei; Hu, Rong; Hu, Shengli; Yin, Yi; Lan, Chuan; Li, Zhao; Fu, Chuhua; Cao, Liu; Chen, Zhi; Xian, Jishu; Feng, Hua

    2015-04-01

    Glioma‑initiating cells are a small population of cells that have the ability to undergo self‑renewal and initiate tumorigenesis. In the present study, the potential role of salinomycin, a polyether antibiotic, on the suppression of glioma cell growth was investigated. GL261 glioma cells were maintained in a stem‑cell‑like status [GL261 neurospheres (GL261‑NS)] or induced for differentiation [GL261 adherent cells (GL261‑AC)]. It was demonstrated that salinomycin significantly reduced the cell viability of GL261‑NS and GL261‑AC cells in a dose‑dependent manner, with a more substantial inhibition of GL261‑NS proliferation (P<0.05). The inhibitory effect of salinomycin on cell growth was more effective than that of 1‑(4‑amino‑2‑methyl‑5‑pyrimid l)‑methyl‑3‑(2‑chloroethyl)‑3‑nitrosourea hydrochloride and vincristine (P<0.05). Salinomycin depleted GL261‑NS from tumorspheres and induced cell apoptosis. In addition, salinomycin prolonged the median survival time of glioma‑bearing mice (P<0.05). Therefore, the present study indicated that salinomycin may preferentially inhibit glioma‑initiated cell growth by inducing apoptosis, suggesting that salinomycin may provide a valuable therapeutic strategy for the treatment of malignant glioma.

  13. Differentiation between normal and tumor vasculature of animal and human glioma by FTIR imaging.

    PubMed

    Wehbe, Katia; Pineau, Raphael; Eimer, Sandrine; Vital, Anne; Loiseau, Hugues; Déléris, Gérard

    2010-12-01

    Malignant gliomas are very aggressive tumors, highly angiogenic and invading heterogeneously the surrounding brain parenchyma, making their resection very difficult. To overcome the limits of current diagnostic imaging techniques used for gliomas, we proposed using FTIR imaging, with a spatial resolution from 6 to 10 μm, to provide molecular information for their histological examination, based on discrimination between normal and tumor vasculature. Differentiation between normal and tumor blood vessel spectra by hierarchical cluster analysis was performed on tissue sections obtained from xenografted brain tumors of Rag-gamma mice 28 days after intracranial implantation of glioma cells, as well as for human brain tumors obtained in clinics. Classical pathological examination and immunohistochemistry were performed in parallel to the FTIR spectral imaging of brain tissues. First on the animal model, classification of FTIR spectra of blood vessels could be performed using spectral intervals based on fatty acyl (3050-2800 cm(-1)) and carbohydrate (1180-950 cm(-1)) absorptions, with the formation of two clusters corresponding to healthy and tumor parts of the tissue sections. Further data treatments on these two spectral intervals provided interpretable information about the molecular contents involved in the differentiation between normal and tumor blood vessels, the latter presenting a higher level of fatty acyl chain unsaturation and an unexpected loss of absorption from osidic residues. This classification method was further successfully tested on human glioma tissue sections. These findings demonstrate that FTIR imaging could highlight discriminant molecular markers to distinguish between normal and tumor vasculature, and help to delimitate areas of corresponding tissue.

  14. MGMT promoter methylation in serum and cerebrospinal fluid as a tumor-specific biomarker of glioma.

    PubMed

    Wang, Zheng; Jiang, Wei; Wang, Yahong; Guo, Yang; Cong, Zheng; DU, Fangfang; Song, Bin

    2015-07-01

    O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a conventional technique to predict the prognosis or individualized treatment of glioma in tumor tissue following surgery or biopsy. However, the technique cannot be applied in those glioma patients with concomitant neurological dysfunctions or advanced age. The present study aimed to find a new minimally invasive and efficient alternative method for the detection of MGMT promoter methylation. The expression of MGMT promoter methylation was assessed in peripheral blood and cerebrospinal fluid (CSF), and compared to the corresponding tumor tissue from glioma patients. The 89 patients in the study [32 World Health Organization (WHO) grade II, 19 WHO grade III and 38 WHO grade IV) were pathologically-diagnosed glioma and received radiation therapy following sample collection. The resected glioma tumor tissue (89), corresponding serum (89) and CSF (78) samples were collected for the detection of MGMT promoter methylation using methylation-specific polymerase chain reaction. The sensitivity and specificity of detecting MGMT promoter methylation in CSF and serum were compared. Among the tumor tissue samples, 51/89 (57.3%) showed MGMT promoter methylation. The specificity of the detection in the CSF and serum samples reached 100%. The sensitivity of MGMT promoter methylation detection in CSF and serum were 26/40 (65.0%) and 19/51 (37.3%), respectively (P<0.05). In the WHO II, III and IV subgroups, the sensitivities of MGMT promoter methylation detection using CSF were 8/12 (66.7%), 11/18 (61.1%) and 7/10 (70.0%), respectively, which were significantly higher than the sensitivities using serum (7/21, 33.3%; 7/19, 36.8%; and 5/11, 45.5%, respectively P<0.05). Among patients with residual postoperative tumors, the sensitivities of detecting MGMT promoter methylation using CSF and serum were 18/25 (72.0%) and 10/24 (41.7%), respectively, both of which were significantly higher than the corresponding

  15. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

    PubMed

    Solga, Anne C; Pong, Winnie W; Kim, Keun-Young; Cimino, Patrick J; Toonen, Joseph A; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L; Ly, Amy; Ellisman, Mark H; Mardis, Elaine R; Gutmann, David H

    2015-10-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies.

  16. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor

    PubMed Central

    Hawkins-Daarud, Andrea; Rockne, Russell C.; Anderson, Alexander R. A.; Swanson, Kristin R.

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  17. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor.

    PubMed

    Hawkins-Daarud, Andrea; Rockne, Russell C; Anderson, Alexander R A; Swanson, Kristin R

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  18. Modeling and quantifying biochemical changes in C6 tumor gliomas by Fourier transform infrared imaging.

    PubMed

    Beljebbar, Abdelilah; Amharref, Nadia; Lévèques, Antoine; Dukic, Sylvain; Venteo, Lydie; Schneider, Laurence; Pluot, Michel; Manfait, Michel

    2008-11-15

    The purpose of the study was to investigate molecular changes associated with glioma tissues using FT-IR microspectroscopic imaging (FT-IRM). A multivariate statistical analysis allowed one to successfully discriminate between normal, tumoral, peri-tumoral, and necrotic tissue structures. Structural changes were mainly related to qualitative and quantitative changes in lipid content, proteins, and nucleic acids that can be used as spectroscopic markers for this pathology. We have developed a spectroscopic model of glioma to quantify these chemical changes. The model constructed includes individual FT-IR spectra of normal and glioma brain constituents such as lipids, DNA, and proteins (measured on delipidized tissue). Modeling of FT-IR spectra yielded fit coefficients reflecting the chemical changes associated with a tumor. Our results demonstrate the ability of FT-IRM to assess the importance and distribution of each individual constituent and its variation in normal brain structures as well as in the different pathological states of glioma. We demonstrated that (i) cholesterol and phosphatidylethanolamine contributions are highest in corpus callosum and anterior commissure but decrease gradually towards the cortex surface as well as in the tumor, (ii) phosphatidylcholine contribution is highest in the cortex and decreases in the tumor, (iii) galactocerebroside is localized only in white, but not in gray matter, and decreases in the vital tumor region while the necrosis area shows a higher concentration of this cerebroside, (iv) DNA and oleic acid increase in the tumor as compared to gray matter. This approach could, in the future, contribute to enhance diagnostic accuracy, improve the grading, prognosis, and play a vital role in therapeutic strategy and monitoring.

  19. 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

  20. Chlorotoxin: A Helpful Natural Scorpion Peptide to Diagnose Glioma and Fight Tumor Invasion

    PubMed Central

    Dardevet, Lucie; Rani, Dipti; Abd El Aziz, Tarek; Bazin, Ingrid; Sabatier, Jean-Marc; Fadl, Mahmoud; Brambilla, Elisabeth; De Waard, Michel

    2015-01-01

    Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma-specific chloride currents, it was soon discovered that chlorotoxin possesses targeting properties towards cancer cells including glioma, melanoma, small cell lung carcinoma, neuroblastoma and medulloblastoma. The investigation of the mechanism of action of chlorotoxin has been challenging because its cell surface receptor target remains under questioning since two other receptors have been claimed besides chloride channels. Efforts on chlorotoxin-based applications focused on producing analogues helpful for glioma diagnosis, imaging and treatment. These efforts are welcome since gliomas are very aggressive brain cancers, close to impossible to cure with the current therapeutic arsenal. Among all the chlorotoxin-based strategies, the most promising one to enhance patient mean survival time appears to be the use of chlorotoxin as a targeting agent for the delivery of anti-tumor agents. Finally, the discovery of chlorotoxin has led to the screening of other scorpion venoms to identify chlorotoxin-like peptides. So far several new candidates have been identified. Only detailed research and clinical investigations will tell us if they share the same anti-tumor potential as chlorotoxin. PMID:25826056

  1. Obesity and Risk for Brain/CNS Tumors, Gliomas and Meningiomas: A Meta-Analysis

    PubMed Central

    Sergentanis, Theodoros N.; Tsivgoulis, Georgios; Perlepe, Christina; Ntanasis-Stathopoulos, Ioannis; Tzanninis, Ioannis-Georgios; Sergentanis, Ioannis N.; Psaltopoulou, Theodora

    2015-01-01

    Objective This meta-analysis aims to examine the association between being overweight/obese and risk of meningiomas and gliomas as well as overall brain/central nervous system (CNS) tumors. Study Design Potentially eligible publications were sought in PubMed up to June 30, 2014. Random-effects meta-analysis and dose-response meta-regression analysis was conducted. Cochran Q statistic, I-squared and tau-squared were used for the assessment of between-study heterogeneity. The analysis was performed using Stata/SE version 13 statistical software. Results A total of 22 studies were eligible, namely 14 cohort studies (10,219 incident brain/CNS tumor cases, 1,319 meningioma and 2,418 glioma cases in a total cohort size of 10,143,803 subjects) and eight case-control studies (1,009 brain/CNS cases, 1,977 meningioma cases, 1,265 glioma cases and 8,316 controls). In females, overweight status/obesity was associated with increased risk for overall brain/CNS tumors (pooled RR = 1.12, 95%CI: 1.03–1.21, 10 study arms), meningiomas (pooled RR = 1.27, 95%CI: 1.13–1.43, 16 study arms) and gliomas (pooled RR = 1.17, 95%CI: 1.03–1.32, six arms). Obese (BMI>30 kg/m2) females seemed particularly aggravated in terms of brain/CNS tumor (pooled RR = 1.19, 95%CI: 1.05–1.36, six study arms) and meningioma risk (pooled RR = 1.48, 95%CI: 1.28–1.71, seven arms). In males, overweight/obesity status correlated with increased meningioma risk (pooled RR = 1.58, 95%CI: 1.22–2.04, nine study arms), whereas the respective association with overall brain/CNS tumor or glioma risk was not statistically significant. Dose-response meta-regression analysis further validated the findings. Conclusion Our findings highlight obesity as a risk factor for overall brain/CNS tumors, meningiomas and gliomas among females, as well as for meningiomas among males. PMID:26332834

  2. Photo-acoustic imaging of blue nanoparticle targeted brain tumor for intra-operative glioma delineation

    NASA Astrophysics Data System (ADS)

    Ray, Aniruddha; Wang, Xueding; Koo Lee, Yong-Eun; Hah, HoeJin; Kim, Gwangseong; Chen, Thomas; Orrienger, Daniel; Sagher, Oren; Kopelman, Raoul

    2011-07-01

    Distinguishing the tumor from the background neo-plastic tissue is challenging for cancer surgery such as surgical resection of glioma. Attempts have been made to use visible or fluorescent markers to delineate the tumors during surgery. However, the systemic injection of the dyes requires high dose, resulting in negative side effects. A novel method to delineate rat brain tumors intra-operatively, as well as post-operatively, using a highly sensitive photoacoustic imaging technique enhanced by tumor targeting blue nanoparticle as contrast agent is demonstrated. The nanoparticles are made of polyacrylamide (PAA) matrix with covalently linked Coomassie-Blue dye. They contain 7.0% dye and the average size is 80nm. Their surface was conjugated with F3 peptide for active tumor targeting. These nanoparticles are nontoxic, chemically inert and have long plasma circulation lifetime, making them suitable as nanodevices for imaging using photoacoustics. Experiments on phantoms and rat brains tumors ex-vivo demonstrate the high sensitivity of photoacoustic imaging in delineating the tumor, containing contrast agent at concentrations too low to be visualized by eye. The control tumors without nanoparticles did not show any enhanced signal. This study shows that photoacoustic imaging facilitated with the nanoparticle contrast agent could contribute to future surgical procedures for glioma.

  3. Updated therapeutic strategy for adult low-grade glioma stratified by resection and tumor subtype.

    PubMed

    Nitta, Masayuki; Muragaki, Yoshihiro; Maruyama, Takashi; Iseki, Hiroshi; Ikuta, Soko; Konishi, Yoshiyuki; Saito, Taichi; Tamura, Manabu; Chernov, Michael; Watanabe, Atsushi; Okamoto, Saori; Maebayashi, Katsuya; Mitsuhashi, Norio; Okada, Yoshikazu

    2013-01-01

    The importance of surgical resection for patients with supratentorial low-grade glioma (LGG) remains controversial. This retrospective study of patients (n = 153) treated between 2000 to 2010 at a single institution assessed whether increasing the extent of resection (EOR) was associated with improved progression-free survival (PFS) and overall survival (OS). Histological subtypes of World Health Organization grade II tumors were as follows: diffuse astrocytoma in 49 patients (32.0%), oligoastrocytoma in 45 patients (29.4%), and oligodendroglioma in 59 patients (38.6%). Median pre- and postoperative tumor volumes and median EOR were 29.0 cm(3) (range 0.7-162 cm(3)) and 1.7 cm(3) (range 0-135.7 cm(3)) and 95%, respectively. Five- and 10-year OS for all LGG patients were 95.1% and 85.4%, respectively. Eight-year OS for diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma were 70.7%, 91.2%, and 98.3%, respectively. Five-year PFS for diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma were 42.6%, 71.3%, and 62.7%, respectively. Patients were divided into two groups by EOR ≥90% and <90%, and OS and PFS were analyzed. Both OS and PFS were significantly longer in patients with ≥90% EOR. Increased EOR resulted in better PFS for diffuse astrocytoma but not for oligodendroglioma. Multivariate analysis identified age and EOR as parameters significantly associated with OS. The only parameter associated with PFS was EOR. Based on these findings, we established updated therapeutic strategies for LGG. If surgery resulted in EOR <90%, patients with astrocytoma will require second-look surgery, whereas patients with oligodendroglioma or oligoastrocytoma, which are sensitive to chemotherapy, will be treated with chemotherapy.

  4. Advanced MR imaging techniques in the evaluation of nonenhancing gliomas: perfusion-weighted imaging compared with proton magnetic resonance spectroscopy and tumor grade.

    PubMed

    Sahin, Neslin; Melhem, Elias R; Wang, Sumei; Krejza, Jaroslaw; Poptani, Harish; Chawla, Sanjeev; Verma, Gaurav

    2013-10-01

    A significant number of nonenhancing (NE) gliomas are reported to be malignant. The purpose of this study was to compare the value of advanced MR imaging techniques, including T2*-dynamic susceptibility contrast PWI (DSC-PWI) and proton magnetic resonance spectroscopy ((1)HMRS) in the evaluation of NE gliomas. Twenty patients with NE gliomas underwent MRI including DSC-PWI and (1)HMRS. The relative CBV (rCBV) measurements were obtained from regions of maximum perfusion. The peak ratios of choline/creatine (Cho/Cr) and myo-inositol/creatine (mIns/Cr) were measured at a TE of 30 ms. Demographic features, tumor volumes, and PWI- and (1)HMRS-derived measures were compared between low-grade gliomas (LGGs) and high-grade gliomas (HGGs). In addition, the association of initial rCBV ratio with tumor progression was evaluated in LGGs. No significant difference was noted in age, sex or tumor size between LGGs and HGGs. Cho/Cr ratios were significantly higher in HGGs (1.7±0.63) than in LGGs (1.2±0.38). The receiver operating characteristic analysis demonstrated that a Cho/Cr ratio with a cutoff value of 1.3 could differentiate between LGG and HGG with a specificity of 100% and a sensitivity of 71.4%. There was no significant difference in the rCBV ratio and the mIns/Cr ratio between LGG and HGG. However, higher rCBV ratios were observed with more rapid progressions in LGGs. The results imply that Cho/Cr ratios are useful in distinguishing NE LGG from HGG and can be helpful in preoperative grading and biopsy guidance. On the other hand, rCBV ratios do not help in the distinction.

  5. Photoradiation therapy causing selective tumor kill in a rat glioma model

    SciTech Connect

    Kaye, A.H.; Morstyn, G.

    1987-03-01

    We evaluated the effect of photoradiation therapy using the photosensitizer, hematoporphyrin derivative (HpD), and the argon-pumped rhodamine dye laser tuned to 630 nm in the rat C6 glioma model. Animal models of cerebral glioma were established by implanting 10(6) C6 glioma cells in adult Wistar rats, and craniotomies were performed on normal and tumor-bearing animals. HpD in doses of up to 80 mg/kg followed by craniotomy resulted in no damage to the normal brain, and laser light at doses of up to 1200 joules/cm2 without the prior administration of HpD produced no significant damage if the craniotomy site was irrigated with normal saline to prevent a temperature rise. Photoradiation caused no brain necrosis in non-tumor bearing animals if less than 20 mg of HpD per kg and 200 joules of red light per cm2 were used. At higher doses of HpD and light, cerebral necrosis did occur. The depth of necrosis depended on the dose of both HpD and light. Treatment with 40 mg of HpD per kg and 400 joules of light per cm2 resulted in cerebral necrosis in 50% of the treated animals. The mean depth of brain necrosis was 1.3 mm. Selective kill of a cerebral glioma with sparing of the normal brain was achieved with photoradiation therapy at doses of HpD of less than 20 mg/kg and light doses of less than 200 joules/cm2. At these doses, the mean depth of tumor kill was 4.5 mm. In 2 of 10 animals, the depth of tumor destruction was more than 6 mm.

  6. ADAM9 Expression Is Associate with Glioma Tumor Grade and Histological Type, and Acts as a Prognostic Factor in Lower-Grade Gliomas

    PubMed Central

    Fan, Xing; Wang, Yongheng; Zhang, Chuanbao; Liu, Li; Yang, Sen; Wang, Yinyan; Liu, Xing; Qian, Zenghui; Fang, Shengyu; Qiao, Hui; Jiang, Tao

    2016-01-01

    The A disintegrin and metalloproteinase 9 (ADAM9) protein has been suggested to promote carcinoma invasion and appears to be overexpressed in various human cancers. However, its role has rarely been investigated in gliomas and, thus, in the current study we have evaluated ADAM9 expression in gliomas and examined the relevance of its expression in the prognosis of glioma patients. Clinical characteristics, RNA sequence data, and the case follow-ups were reviewed for 303 patients who had histological, confirmed gliomas. The ADAM9 expression between lower-grade glioma (LGG) and glioblastoma (GBM) patients was compared and its association with progression-free survival (PFS) and overall survival (OS) was assessed to evaluate its prognostic value. Our data suggested that GBM patients had significantly higher expression of ADAM9 in comparison to LGG patients (p < 0.001, t-test). In addition, among the LGG patients, aggressive astrocytic tumors displayed significantly higher ADAM9 expression than oligodendroglial tumors (p < 0.001, t-test). Moreover, high ADAM9 expression also correlated with poor clinical outcome (p < 0.001 and p < 0.001, log-rank test, for PFS and OS, respectively) in LGG patients. Further, multivariate analysis suggested ADAM9 expression to be an independent marker of poor survival (p = 0.002 and p = 0.003, for PFS and OS, respectively). These results suggest that ADAM9 mRNA expression is associated with tumor grade and histological type in gliomas and can serve as an independent prognostic factor, specifically in LGG patients. PMID:27571068

  7. Radiation-associated gliomas: a report of four cases and analysis of postradiation tumors of the central nervous system

    SciTech Connect

    Liwnicz, B.H.; Berger, T.S.; Liwnicz, R.G.; Aron, B.S.

    1985-09-01

    Four cases of radiation-associated gliomas are described. All patients were white men, irradiated in childhood for craniopharyngioma, anaplastic ependymoma, retinoblastoma of the orbit, and Burkitt's lymphoma, respectively. The dose ranged from 1800 to 5900 rads, and the latency period was 5 to 25 years. All primary and secondary tumors were verified histologically, and no evidence of persistence of the primary tumors was found. All secondary tumors arose in the fields of irradiation. Ninety-six cases of radiation-induced tumors of the central nervous system have been reported in the literature to date. Twenty-four were gliomas and occurred mainly in young men.

  8. Toward Distinguishing Recurrent Tumor From Radiation Necrosis: DWI and MTC in a Gamma Knife–Irradiated Mouse Glioma Model

    SciTech Connect

    Perez-Torres, Carlos J.; Engelbach, John A.; Cates, Jeremy; Thotala, Dinesh; Yuan, Liya; Schmidt, Robert E.; Rich, Keith M.; Drzymala, Robert E.; Ackerman, Joseph J.H.; Garbow, Joel R.

    2014-10-01

    Purpose: Accurate noninvasive diagnosis is vital for effective treatment planning. Presently, standard anatomical magnetic resonance imaging (MRI) is incapable of differentiating recurring tumor from delayed radiation injury, as both lesions are hyperintense in both postcontrast T1- and T2-weighted images. Further studies are therefore necessary to identify an MRI paradigm that can differentially diagnose these pathologies. Mouse glioma and radiation injury models provide a powerful platform for this purpose. Methods and Materials: Two MRI contrasts that are widely used in the clinic were chosen for application to a glioma/radiation-injury model: diffusion weighted imaging, from which the apparent diffusion coefficient (ADC) is obtained, and magnetization transfer contrast, from which the magnetization transfer ratio (MTR) is obtained. These metrics were evaluated longitudinally, first in each lesion type alone–glioma versus irradiation – and then in a combined irradiated glioma model. Results: MTR was found to be consistently decreased in all lesions compared to nonlesion brain tissue (contralateral hemisphere), with limited specificity between lesion types. In contrast, ADC, though less sensitive to the presence of pathology, was increased in radiation injury and decreased in tumors. In the irradiated glioma model, ADC also increased immediately after irradiation, but decreased as the tumor regrew. Conclusions: ADC is a better metric than MTR for differentiating glioma from radiation injury. However, MTR was more sensitive to both tumor and radiation injury than ADC, suggesting a possible role in detecting lesions that do not enhance strongly on T1-weighted images.

  9. Induction of selective blood-tumor barrier permeability and macromolecular transport by a biostable kinin B1 receptor agonist in a glioma rat model.

    PubMed

    Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand

    2012-01-01

    Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg(9)BK (LDBK) and SarLys[dPhe(8)]desArg(9)BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T(1)-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.

  10. Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model

    PubMed Central

    Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand

    2012-01-01

    Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites. PMID:22629405

  11. Endothelial Differentiation of Adipose Tissue-Derived Mesenchymal Stromal Cells in Glioma Tumors: Implications for Cell-Based Therapy

    PubMed Central

    Bagó, Juli R; Alieva, Maria; Soler, Carolina; Rubio, Núria; Blanco, Jerónimo

    2013-01-01

    Multipotent human adipose tissue mesenchymal stromal cells (hAMSCs) are promising therapy vehicles with tumor-homing capacity that can be easily modified to deliver cytotoxicity activating systems in the proximity of tumors. In a previous work, we observed that hAMSCs are very effective delivering cytotoxicity to glioma tumors. However, these results were difficult to reconcile with the relatively few hAMSCs surviving implantation. We use a bioluminescence imaging (BLI) platform to analyze the behavior of bioluminescent hAMSCs expressing HSV-tTK in a U87 glioma model and gain insight into the therapeutic mechanisms. Tumor-implanted hAMSCs express the endothelial marker PECAM1(CD31), integrate in tumor vessels and associate with CD133-expressing glioma stem cells (GSC). Inhibition of endothelial lineage differentiation in hAMSCs by Notch1 shRNA had no effect on their tumor homing and growth-promoting capacity but abolished the association of hAMSCs with tumor vessels and CD133+ tumor cells and significantly reduced their tumor-killing capacity. The current strategy allowed the study of tumor/stroma interactions, showed that tumor promotion and tumor-killing capacities of hAMSCs are based on different mechanisms. Our data strongly suggest that the therapeutic effectiveness of hAMSCs results from their association with special tumor vascular structures that also contain GSCs. PMID:23760448

  12. Plasminogen kringle 5-engineered glioma cells block migration of tumor-associated macrophages and suppress tumor vascularization and progression.

    PubMed

    Perri, Sabrina R; Nalbantoglu, Josephine; Annabi, Borhane; Koty, Zafiro; Lejeune, Laurence; François, Moïra; Di Falco, Marcos R; Béliveau, Richard; Galipeau, Jacques

    2005-09-15

    Angiostatin, a well-characterized angiostatic agent, is a proteolytic cleavage product of human plasminogen encompassing the first four kringle structures. The fifth kringle domain (K5) of human plasminogen is distinct from angiostatin and has been shown, on its own, to act as a potent endothelial cell inhibitor. We propose that tumor-targeted K5 cDNA expression may act as an effective therapeutic intervention as part of a cancer gene therapy strategy. In this study, we provide evidence that eukaryotically expressed His-tagged human K5 cDNA (hK5His) is exported extracellularly and maintains predicted disulfide bridging conformation in solution. Functionally, hK5His protein produced by retrovirally engineered human U87MG glioma cells suppresses in vitro migration of both human umbilical vein endothelial cells and human macrophages. Subcutaneous implantation of Matrigel-embedded hK5His-producing glioma cells in nonobese diabetic/severe combined immunodeficient mice reveals that hK5His induces a marked reduction in blood vessel formation and significantly suppresses the recruitment of tumor-infiltrating CD45+ Mac3+ Gr1- macrophages. Therapeutically, we show in a nude mouse orthotopic brain cancer model that tumor-targeted K5 expression is capable of effectively suppressing glioma growth and promotes significant long-term survival (>120 days) of test animals. These data suggest that plasminogen K5 acts as a novel two-pronged anticancer agent, mediating its inhibitory effect via its action on host-derived endothelial cells and tumor-associated macrophages, resulting in a potent, clinically relevant antitumor effect.

  13. Intra-Tumor Distribution and Test-Retest Comparisons of Physiological Parameters quantified by Dynamic Contrast-Enhanced MRI in Rat U251 Glioma

    PubMed Central

    Aryal, Madhava P.; Nagaraja, Tavarekere N.; Brown, Stephen L.; Lu, Mei; Bagher-Ebadian, Hassan; Ding, Guangliang; Panda, Swayamprava; Keenan, Kelly; Cabral, Glauber; Mikkelsen, Tom; Ewing, James R.

    2014-01-01

    The distribution of dynamic contrast enhanced MRI (DCE-MRI) parametric estimates in a rat U251 glioma model was analyzed. Using Magnevist as contrast agent (CA), 17 nude rats implanted with U251 cerebral glioma were studied by DCE-MRI twice in a 24 h interval. A data-driven analysis selected one of three models to estimate either: 1) CA plasma volume (vp), 2) vp and forward volume transfer constant (Ktrans; or 3) vp, Ktrans, and interstitial volume fraction (ve), constituting Models 1, 2 and 3, respectively. CA interstitial distribution volume (VD) was estimated in Model 3 regions by Logan plots. Regions of interest (ROIs) were selected by model. In the Model 3 ROI, descriptors of parameter distributions – mean, median, variance and skewness – were calculated and compared between the two time points for repeatability. All distributions of parametric estimates in Model 3 ROIs were positively skewed. Test-retest differences between population summaries for any parameter were not significant (p≥0.10; Wilcoxon signed-rank and paired t tests). This and similar measures of parametric distribution and test-retest variance from other tumor models can be used to inform the choice of biomarkers that best summarize tumor status and treatment effects. PMID:25125367

  14. Targeting Glioma with a Dual Mode Optical and Paramagnetic Nanoprobe across the Blood-brain Tumor Barrier

    PubMed Central

    Karki, Kishor; Ewing, James R; Ali, Meser M

    2016-01-01

    In brain tumors, delivering nanoparticles across the blood-tumor barrier presents major hurdles. A clinically relevant MRI contrast agent, GdDOTA and a near-infrared (NIR) fluorescent dye, DL680 were conjugated to a G5 PAMAM dendrimer, thus producing a dual-mode MRI and NIR imaging agent. Systemic delivery of the subsequent nano-sized agent demonstrated glioma-specific accumulation, probably due to the enhanced permeability and retention effect. In vivo MRI detected the agent in glioma tissue, but not in normal contralateral tissue; this observation was validated with in vivo and ex vivo fluorescence imaging. A biodistribution study showed the agent to have accumulated in the glioma tumor and the liver, the latter being the excretion path for a G5 dendrimer-based agent. PMID:27695645

  15. Relationship between extracellular osmolarity, NaCl concentration and cell volume in rat glioma cells.

    PubMed

    Rouzaire-Dubois, Béatrice; Ouanounou, Gilles; Dubois, Jean Marc

    2011-06-01

    The cell volume, which controls numerous cellular functions, is theoretically linearly related with the inverse osmolarity. However, deviations from this law have often been observed. In order to clarify the origin of these deviations we electronically measured the mean cell volume of rat glioma cells under three different experimental conditions, namely: at different osmolarities and constant NaCl concentration; at different NaCl concentrations and constant osmolarity and at different osmolarities caused by changes in NaCl concentration. In each condition, the osmolarity was maintained constant or changed with NaCl or mannitol. We showed that the cell volume was dependent on both the extracellular osmolarity and the NaCl concentration. The relationship between cell volume, osmolarity and NaCl concentration could be described by a new equation that is the product of the Boyle-van't Hoff law and the Michaelis-Menten equation at a power of 4. Together, these results suggest that in hyponatriemia, the cell volume deviates from the Boyle-van't Hoff law because either the activity of aquaporin 1, expressed in glioma cells, is decreased or the reduced NaCl influx decreases the osmotically obliged influx of water.

  16. Tumor Volumes and Prognosis in Laryngeal Cancer

    PubMed Central

    Issa, Mohamad R.; Samuels, Stuart E.; Bellile, Emily; Shalabi, Firas L.; Eisbruch, Avraham; Wolf, Gregory

    2015-01-01

    Tumor staging systems for laryngeal cancer (LC) have been developed to assist in estimating prognosis after treatment and comparing treatment results across institutions. While the laryngeal TNM system has been shown to have prognostic information, varying cure rates in the literature have suggested concern about the accuracy and effectiveness of the T-classification in particular. To test the hypothesis that tumor volumes are more useful than T classification, we conducted a retrospective review of 78 patients with laryngeal cancer treated with radiation therapy at our institution. Using multivariable analysis, we demonstrate the significant prognostic value of anatomic volumes in patients with previously untreated laryngeal cancer. In this cohort, primary tumor volume (GTVP), composite nodal volumes (GTVN) and composite total volume (GTVP + GTVN = GTVC) had prognostic value in both univariate and multivariate cox model analysis. Interestingly, when anatomic volumes were measured from CT scans after a single cycle of induction chemotherapy, all significant prognosticating value for measured anatomic volumes was lost. Given the literature findings and the results of this study, the authors advocate the use of tumor anatomic volumes calculated from pretreatment scans to supplement the TNM staging system in subjects with untreated laryngeal cancer. The study found that tumor volume assessment after induction chemotherapy is not of prognostic significance. PMID:26569309

  17. Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model

    PubMed Central

    Huhndorf, Monika; Moussavi, Amir; Kramann, Nadine; Will, Olga; Hattermann, Kirsten; Stadelmann, Christine; Jansen, Olav

    2016-01-01

    Objectives Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization. Methods We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC) MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV) and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections. Results In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement) was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement) were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology. Conclusion Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development. PMID:28005983

  18. Reirradiation of Large-Volume Recurrent Glioma With Pulsed Reduced-Dose-Rate Radiotherapy

    SciTech Connect

    Adkison, Jarrod B.; Tome, Wolfgang; Seo, Songwon; Richards, Gregory M.; Robins, H. Ian; Rassmussen, Karl; Welsh, James S.; Mahler, Peter A.; Howard, Steven P.

    2011-03-01

    Purpose: Pulsed reduced-dose-rate radiotherapy (PRDR) is a reirradiation technique that reduces the effective dose rate and increases the treatment time, allowing sublethal damage repair during irradiation. Patients and Methods: A total of 103 patients with recurrent glioma underwent reirradiation using PRDR (86 considered to have Grade 4 at PRDR). PRDR was delivered using a series of 0.2-Gy pulses at 3-min intervals, creating an apparent dose rate of 0.0667 Gy/min to a median dose of 50 Gy (range, 20-60) delivered in 1.8-2.0-Gy fractions. The mean treatment volume was 403.5 {+-} 189.4 cm{sup 3} according to T{sub 2}-weighted magnetic resonance imaging and a 2-cm margin. Results: For the initial or upgraded Grade 4 cohort (n = 86), the median interval from the first irradiation to PRDR was 14 months. Patients undergoing PRDR within 14 months of the first irradiation (n = 43) had a median survival of 21 weeks. Those treated {>=}14 months after radiotherapy had a median survival of 28 weeks (n = 43; p = 0.004 and HR = 1.82 with a 95% CI ranging from 1.25 to 3.10). These data compared favorably to historical data sets, because only 16% of the patients were treated at first relapse (with 46% treated at the second relapse, 32% at the third or fourth relapse, and 4% at the fourth or fifth relapse). The median survival since diagnosis and retreatment was 6.3 years and 11.4 months for low-grade, 4.1 years and 5.6 months for Grade 3, and 1.6 years and 5.1 months for Grade 4 tumors, respectively, according to the initial histologic findings. Multivariate analysis revealed age at the initial diagnosis, initial low-grade disease, and Karnofsky performance score of {>=}80 to be significant predictors of survival after initiation of PRDR. Conclusion: PRDR allowed for safe retreatment of larger volumes to high doses with palliative benefit.

  19. Pc 4 photodynamic therapy of U87 (human glioma) orthotopic tumor in nude rat brain

    NASA Astrophysics Data System (ADS)

    Dean, David; George, John E., III; Ahmad, Yusra; Wolfe, Michael S.; Lilge, Lothar; Morris, Rachel L.; Peterson, Allyn; Lust, W. D.; Totonchi, Ali; Varghai, Davood; Li, Xiaolin; Hoppel, Charles L.; Sun, Jiayang; Oleinick, Nancy L.

    2005-04-01

    Introduction: Photodynamic therapy (PDT) for Barrett"s esophagus, advanced esophageal cancer, and both early and late inoperable lung carcinoma is now FDA-approved using the first generation photosensitizer PhotofrinTM (Axcan Pharma, Birmingham, AL). Photofrin-mediated PDT of glioma is now in Phase III clinical trials. A variety of second generation photosensitizers have been developed to provide improved: (1) specificity for the target tissue, (2) tumoricidal capability, and (3) rapid clearance the vascular compartment, skin, and eyes. The phthalocyanine Pc 4 is a second generation photosensitizer that is in early phase I clinical trials for skin cancer. We have undertaken a preclinical study that seeks to determine if Pc 4-mediated PDT can be of benefit for the intra-operative localization and treatment of glioma. Methods: Using a stereotactic frame, 250,000 U87 cells were injected via Hamilton syringe through a craniotomy, and the dura, 1-2 mm below the cortical surface of nude (athymic) rat brains (N=91). The craniotomy was filled with a piece of surgical PVC and the scalp closed. After two weeks of tumor growth, the animals received 0.5 mg/kg Pc 4 via tail vein injection. One day later the scalp was re-incised, and the PVC removed. The tumor was then illuminated with either 5 or 30 Joule/cm2 of 672-nm light from a diode laser at 50 mW/cm2. The animals were sacrificed one day later and the brain was cold-perfused with formaldehyde. Two thirds of the explanted brains are now being histologically surveyed for necrosis after staining with hematoxylin and eosin and for apoptosis via immunohistochemistry (i.e., TUNEL assay). The other third were analyzed by HPLC-mass spectrometry for the presence of drug in tumor, normal brain, and plasma at sacrifice. Initial histological results show PDT-induced apoptosis and necrosis confined to the growing (live) portion of the tumor. Preliminary analysis shows an average selectivity of Pc 4 uptake in the bulk tumor to be 3

  20. ATRX Loss Promotes Tumor Growth and Impairs Non-Homologous End Joining DNA Repair in Glioma

    PubMed Central

    Koschmann, Carl; Calinescu, Anda-Alexandra; Nunez, Felipe J.; Mackay, Alan; Fazal-Salom, Janet; Thomas, Daniel; Mendez, Flor; Kamran, Neha; Dzaman, Marta; Mulpuri, Lakshman; Krasinkiewicz, Johnathon; Doherty, Robert; Lemons, Rosemary; Brosnan-Cashman, Jackie A.; Li, Youping; Roh, Soyeon; Zhao, Lili; Appelman, Henry; Ferguson, David; Gorbunova, Vera; Meeker, Alan; Jones, Chris; Lowenstein, Pedro R.; Castro, Maria G.

    2017-01-01

    Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and show that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs non-homologous end joining (NHEJ) and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated, but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival. PMID:26936505

  1. Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model12

    PubMed Central

    Gabrusiewicz, Konrad; Hossain, Mohammad B.; Cortes-Santiago, Nahir; Fan, Xuejun; Kaminska, Bozena; Marini, Frank C.; Fueyo, Juan; Gomez-Manzano, Candelaria

    2015-01-01

    Monocytes/macrophages are an influential component of the glioma microenvironment. However, understanding their diversity and plasticity constitute one of the most challenging areas of research due to the paucity of models to study these cells' inherent complexity. Herein, we analyzed the role of monocytes/macrophages in glioma growth by using a transgenic model that allows for conditional ablation of this cell population. We modeled glioma using intracranial GL261-bearing CSF-1R–GFP+ macrophage Fas-induced apoptosis (MAFIA) transgenic mice. Conditional macrophage ablation was achieved by exposure to the dimerizer AP20187. Double immunofluorescence was used to characterize M1- and M2-like monocytes/macrophages during tumor growth and after conditional ablation. During glioma growth, the monocyte/macrophage population consisted predominantly of M2 macrophages. Conditional temporal depletion of macrophages reduced the number of GFP+ cells, targeting mainly the repopulation of M2-polarized cells, and altered the appearance of M1-like monocytes/macrophages, which suggested a shift in the M1/M2 macrophage balance. Of interest, compared with control-treated mice, macrophage-depleted mice had a lower tumor mitotic index, microvascular density, and reduced tumor growth. These results demonstrated the possibility of studying in vivo the role and phenotype of macrophages in gliomas and suggested that transitory depletion of CSF-1R+ population influences the reconstitutive phenotypic pool of these cells, ultimately suppressing tumor growth. The MAFIA model provides a much needed advance in defining the role of macrophages in gliomas. PMID:25925380

  2. hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells.

    PubMed

    Shi, Lei; Cheng, Zihao; Zhang, Junxia; Li, Rui; Zhao, Peng; Fu, Zhen; You, Yongping

    2008-10-21

    MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammal animals, their function mainly represses the target mRNAs transcripts via imperfectly complementary to the 3' UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some up-regulated miRNA, such as hsa-miR-21 and hsa-miR-221. However, here we reported that the down-regulated hsa-miR-181a and hsa-miR-181b of hsa-miR-181 family were also involved in oncogenesis of glioma. Our studies showed that hsa-miR-181a and hsa-miR-181b functioned as tumor suppressors which triggered growth inhibition, induced apoptosis and inhibited invasion in glioma cells. Furthermore, the tumor-suppressive effect of hsa-miR-181b in glioma cells was more apparent than the effect of hsa-miR-181a. These findings suggest aberrantly down-regulated hsa-miR-181a and hsa-miR-181b may be critical factors that contribute to malignant appearance in human gliomas.

  3. XuefuZhuyu Tang exerts antitumor effects by inhibiting glioma cell metastasis and invasion via regulating tumor microenvironment

    PubMed Central

    Liu, Jianmin; Zhang, Ji; Huang, Liangwen; Zhu, Xuhong; Chen, Wei; Hu, Peng

    2016-01-01

    Background XuefuZhuyu Tang (XZT) is a traditional Chinese herb used for destagnation and is currently being used for oncotherapy. This study was intended to assess the effects of XZT on glioma along with its anticancer mechanism. Materials and methods U251 cells were divided into five groups: CNC (cells were cultured with normal saline), TSC (cells were treated with TaohongSiwu Tang [TST]), XSC (cells were treated with XZT), THC (cells were treated with homogenate of TST), and XHC (cells were treated with homogenate of XZT). The mRNA and protein expression of VEGF/VEGFR, CXCR4/CXCL12, and TIMP1/MMP9/MMP2 were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. Moreover, MTT assay, transwell assay, wound-healing assay, and flow cytometry were conducted to assess the cell viability, cell migration and invasion, cell motility, and cell apoptosis of U251 cells, respectively. In vivo, three mice models (group CNM, gavaging saline; group TSM, gavaging TST; group XZM, gavaging XZT) were constructed after establishing xenograft mice models. Then, models were examined using hematoxylin and eosin staining, RT-PCR, and Western blotting. Results In vitro, XZT significantly upregulated TIMP1 expression and downregulated the expression of VEGF, VEGFR, CXCR4, CXCL12, MMP9, and MMP2 in U251 cells (all P<0.05). In addition, XZT inhibited cell proliferation, invasion, and migration and induced cell apoptosis. In vivo, the average expression level of VEGF, CXCL12, MMP9, and MMP2 was downregulated in the XZM group compared with the control and TSM groups (all P<0.05). Tumor volumes in the XZM group were significantly lower than those in the CNM and TSM groups (all P<0.05). Conclusion XZT may suppress glioma growth and decrease expression levels of VEGF, CXCL12, MMP9, and MMP2. We speculate that XZT may be a potential therapeutic herb for curing glioma. PMID:27382298

  4. Genetics of adult glioma.

    PubMed

    Goodenberger, McKinsey L; Jenkins, Robert B

    2012-12-01

    Gliomas make up approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Despite the frequency of gliomas, the etiology of these tumors remains largely unknown. Diffuse gliomas, including astrocytomas and oligodendrogliomas, belong to a single pathologic class but have very different histologies and molecular etiologies. Recent genomic studies have identified separate molecular subtypes within the glioma classification that appear to correlate with biological etiology, prognosis, and response to therapy. The discovery of these subtypes suggests that molecular genetic tests are and will be useful, beyond classical histology, for the clinical classification of gliomas. While a familial susceptibility to glioma has been identified, only a small percentage of gliomas are thought to be due to single-gene hereditary cancer syndromes. Through the use of linkage studies and genome-wide association studies, multiple germline variants have been identified that are beginning to define the genetic susceptibility to glioma.

  5. Tumor-specific Immunotherapy Targeting the EGFRvIII Mutation in Patients with Malignant Glioma

    PubMed Central

    Sampson, John H.; Archer, Gary E.; Mitchell, Duane A.; Heimberger, Amy B.; Bigner, Darell D.

    2008-01-01

    Conventional therapies for malignant gliomas (MGs) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by non-specific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in MGs and other neoplasms. This mutation encodes a constitutively active tyrosine kinase that enhances tumorgenicity and migration and confers radiation and chemotherapeutic resistance. This in-frame deletion mutation splits a codon resulting in the creation of a novel glycine at the fusion junction between normally distant parts of the molecule and producing a sequence rearrangement which creates a tumor-specific epitope for cellular or humoral immunotherapy in patients with MGs. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction is an efficacious immunotherapy in syngeneic murine models, but patients with MGs have a profound immunosuppression that may inhibit the ability of antigen presenting cells (APCs), even those generated ex vivo, to induce EGFRvIII-specific immune responses. In this report, we summarize our results in humans targeting this mutation in two consecutive and one multi-institutional Phase II immunotherapy trials. These trials demonstrated that vaccines targeting EGFRvIII are capable of inducing potent T- and B-cell immunity in these patients, and an unexpectedly long survival time. Most importantly, vaccines targeting EGFRvIII were universally successful at eliminating tumor cells expressing the targeted antigen without any evidence of symptomatic collateral toxicity. These studies establish the tumor-specific EGFRvIII mutation as a novel target for humoral- and cell-mediated immunotherapy in a variety of cancers. The recurrence of EGFRvIII-negative tumors in our patients, however, highlights the

  6. GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion.

    PubMed

    Shashidhar, Sumana; Lorente, Gustavo; Nagavarapu, Usha; Nelson, April; Kuo, Jane; Cummins, Jeramiah; Nikolich, Karoly; Urfer, Roman; Foehr, Erik D

    2005-03-03

    GPR56 (also known as TM7XN1) is a newly discovered orphan G-protein-coupled receptor (GPCR) of the secretin family that has a role in the development of neural progenitor cells and has been linked to developmental malformations of the human brain. GPR56 diverges from other secretin-like family members in that it has an extremely large N-terminal extracellular region (381 amino acids) and contains a novel feature among this new subclass, consisting of four cysteine residues that define a GPCR proteolytic site (GPS motif) located just before the first transmembrane spanning domain. The rest of the amino-terminal domain contains a large number of possible N- and O-linked glycosylation sites similar to mucin-like proteins. These features suggest a role in cell-cell, or cell-matrix interactions. Here, we demonstrate upregulation of GPR56 in glioblastoma multiforme tumors using functional genomics. Immunohistochemistry studies confirmed the expression of GPR56 protein in a majority of glioblastoma/astrocytoma tumor samples with undetectable levels of expression in normal adult brain tissue. Immunofluorescence analysis of human glioma cells using anti-GPR56 antibodies demonstrate that GPR56 is expressed on the leading edge of membrane filopodia and colocalizes with alpha-actinin. Purified recombinant GPR56 extracellular domain protein inhibits glioma cell adhesion and causes abnormal cytoskeletal morphology and cell rounding. These results indicate that the extracellular domain may compete for unidentified ligand(s), and block the normal function of GPR56 in cell attachment. In reporter assays, overexpression of GPR56 activates the NF-kappaB, PAI-1 and TCF transcriptional response elements. These pathways have been implicated in cytoskeletal signaling, adhesion and tumor biology. The above results indicate that GPR56 serves as an adhesion GPCR and is involved in adhesion signaling.

  7. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth1

    PubMed Central

    Solga, Anne C.; Pong, Winnie W.; Kim, Keun-Young; Cimino, Patrick J.; Toonen, Joseph A.; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L.; Ly, Amy; Ellisman, Mark H.; Mardis, Elaine R.; Gutmann, David H.

    2015-01-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233

  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. Expressions of glia maturation factor-β by tumor cells and endothelia correlate with neovascularization and poor prognosis in human glioma

    PubMed Central

    Chen, Cong; Su, Xiao-rui; Shi, Yu; Wu, Jin-rong; Zhang, Peng; Zhang, Xin-li; Cui, You-hong; Ping, Yi-fang; Bian, Xiu-wu

    2016-01-01

    Glia maturation factor-β (GMF-β) has been reported to promote glial differentiation, and act as a negative prognostic indicator in certain cancers. However, its roles in glioma progression remain unclear. Since neurogenesis and vasculogenesis were proved to share some common regulators during gliomagenesis, we aim to explore the potential impact of GMF-β on tumor neovascularization and patient survival in glioma. In this study, we first detected GMF-β expression not only in tumor cells but also in microvascular endothelia by double immunohistochemical staining. Both tumoral and endothelial GMF-β expression levels were positively correlated with tumor grade and microvessel density (MVD), while negatively associated with poor prognoses of the patients. Interestingly, multivariate analysis demonstrated that endothelial GMF-β expression level was the only independent predictor of progression-free and overall survival of glioma patients. The results of in vitro angiogenesis assay showed that GMF-β knockdown significantly inhibited tubulogenesis of human U87 glioblastoma cells. Furthermore, GMF-β knockdown suppressed tumor growth and the formation of human-CD31 positive (glioma cell-derived) microvessels in a mouse orthotopic U87 glioma model. Our results demonstrated that GMF-β is an important player in glioma progression via promoting neovascularization. GMF-β may therefore be a novel prognostic marker as well as a potential therapeutic target for glioma. PMID:26515590

  10. Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta.

    PubMed

    Nagai, Taku; Tanaka, Masashi; Tsuneyoshi, Yasuhiro; Xu, Baohui; Michie, Sara A; Hasui, Kazuhisa; Hirano, Hirofumi; Arita, Kazunori; Matsuyama, Takami

    2009-10-01

    Tumor-associated macrophages (TAMs) are frequently found in glioblastomas and a high degree of macrophage infiltration is associated with a poor prognosis for glioblastoma patients. However, it is unclear whether TAMs in glioblastomas promote tumor growth. In this study, we found that folate receptor beta (FR beta) was expressed on macrophages in human glioblastomas and a rat C6 glioma implanted subcutaneously in nude mice. To target FR beta-expressing TAMs, we produced a recombinant immunotoxin consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse FR beta monoclonal antibody and Pseudomonas exotoxin A. Injection of the immunotoxin into C6 glioma xenografts in nude mice significantly depleted TAMs and reduced tumor growth. The immunotoxin targeting FR beta-expressing macrophages will provide a therapeutic tool for human glioblastomas.

  11. Monitoring glioma growth and tumor necrosis with the U-SPECT-II/CT scanner by targeting integrin αvβ3.

    PubMed

    Shao, Guoqiang; Zhou, Yang; Wang, Feng; Liu, Shuang

    2013-01-01

    The purpose of this study was to validate (99m)Tc-3P-RGD(2) single-photon emission computed tomography/computed tomography (SPECT/CT) as an imaging tool to monitor α(v)β(3) expression and tumor necrosis. The animal model was established by subcutaneous injection of 5 × 10(6) U87MG cells into the shoulder flank of each mouse. Imaging was performed using the U-SPECT-II/CT scanner (Milabs, Utrecht, the Netherlands). Tumor volumes were determined, and the tumor uptake of (99m)Tc-3P-RGD(2) was calculated on the basis of SPECT/CT and compared to that from biodistribution. Immunohistochemistry was performed to determine CD31 and α(v)β(3) expression levels. We found that the tumor detection limit was ≈ 0.5 mm(3) by (99m)Tc-3P-RGD(2) SPECT/CT. The tumor uptake of (99m)Tc-3P-RGD(2) from SPECT/CT was almost identical to that from biodistribution. The α(v)β(3) was expressed mainly on blood vessels for the tumors of 0.2 to 0.5 cm(3). In larger tumors, tumor α(v)β(3) expression increased due to more contribution from glioma cells. When tumors were > 0.5 cm(3), the %ID/cm(3) uptake of (99m)Tc-3P-RGD(2) decreased because of necrosis. The overall relationship between the tumor size and %ID of (99m)Tc-3P-RGD(2) was modeled as a quadratic polynomial fitting curve, with R(2) being > .95. (99m)Tc-3P-RGD(2) SPECT/CT is excellent for monitoring α(v)β(3) expression and tumor necrosis during tumor growth and may become a screening tool for patient selection before anti-α(v)β(3) therapy.

  12. Impact of epidemiological characteristics of supratentorial gliomas in adults brought about by the 2016 world health organization classification of tumors of the central nervous system.

    PubMed

    Jiang, Haihui; Cui, Yong; Wang, Junmei; Lin, Song

    2016-11-24

    The latest World Health Organization (WHO) classification of tumors of the central nervous system (CNS) integrates both histological and molecular features in the definition of diagnostic entities. This new approach enrolls novel entities of gliomas. In this study, we aimed to reveal the epidemiological characteristics, including age at diagnosis, gender ratio, tumor distribution and survival, of these new entities. We retrospectively reclassified 1210 glioma samples according to the 2016 CNS WHO diagnostic criteria. In our cohort, glioblastoma multiforme (GBM) with wildtype isocitrate dehydrogenase (IDH) was the most common malignant tumor in the brain. Almost all gliomas were more prevalent in males, especially in the cluster of WHO grade III gliomas and IDH-wildtype GBM. Age at diagnosis was directly proportional to tumor grade. With respect to the distribution by histology, we found that gliomas concurrent with IDH-mutant and 1p/19q-codeleted or with single IDH-mutant were mainly distributed in frontal lobe, while those with IDH-wildtype were dominant in temporal lobe. Lesions located in insular lobe were more likely to be IDH-mutant astrocytoma. In summary, our results elucidated the epidemiological characteristics as well as the regional constituents of these new gliomas entities, which could bring insights into tumorigenesis and personalized treatment of Chinese glioma population.

  13. Dynamic contrast enhanced MRI parameters and tumor cellularity in a rat model of cerebral glioma at 7T

    NASA Astrophysics Data System (ADS)

    Aryal, Madhava Prasad

    This dissertation mainly focuses on establishing and evaluating a stable and reproducible procedure for assessing tumor microvasculature by measuring the tissue parameters: plasma volume (vp), forward transfer constant (Ktrans), interstitial volume (ve) and distribution volume (VD), utilizing T1-weighted dynamic contrast enhanced MRI (DCE-MRI) and examining their relationship with a histo measure, cell counting. In the first part of the work, two T1-weighted DCE-MRI studies at 24 hrs time interval, using a dual-echo gradient-echo pulse sequence, were performed in 18 athymic rats implanted with U251 cerebral glioma. Using the "standard," or "consensus" model, and a separate Logan graphical analysis, T1-weighted images before, during and after the injection of a gadolinium contrast agent were used to estimate the tissue parameters mentioned above. After MRI study rats were sacrificed, and sectioned brain tissues were stained with Hematoxylin and Eosin for cell counting. Measurements in a region where a model selection process demonstrates that it can be reliably shown that contrast agent leaks from the capillary into the interstitial space quickly enough, and a concentration sufficient to measure its back flux to the vasculature, especially for Ktrans and ve, showed a remarkable stability. The combined mean parameter values in this region were: vp = (0.79+/-0.36)%, Ktrans = (2.23+/-0.71) x10-2 min -1, ve = (6.99+/-2.14)%, and VD = (7.57+/-2.32)%. In the second part of this work, the Logan graphical approach, after establishing its stability in an untreated control group, was applied to investigate a cohort of animals in which a therapeutic dose of 20 Gy radiation had been administered. In this cohort, tissue normalization appeared to be the most effective at 8 h after irradiation; this implies that the 8 hrs post-treatment time might be an ideal combination time for optimized therapeutic outcome in combined modalities. The relationship between non-invasive DCE

  14. Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model.

    PubMed

    Caretti, Viola; Zondervan, Ilse; Meijer, Dimphna H; Idema, Sander; Vos, Wim; Hamans, Bob; Bugiani, Marianna; Hulleman, Esther; Wesseling, Pieter; Vandertop, W Peter; Noske, David P; Kaspers, Gertjan; Molthoff, Carla F M; Wurdinger, Thomas

    2011-07-01

    Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy because of its diffuse infiltrative growth pattern. Translational research suffers from the lack of a representative DIPG animal model. Hence, human E98 glioma cells were stereotactically injected into the pons of nude mice. The E98 DIPG tumors presented a strikingly similar histhopathology to autopsy material of a DIPG patient, including diffuse and perivascular growth, brainstem- and supratentorial invasiveness and leptomeningeal growth. Magnetic resonance imaging (MRI) was effectively employed to image the E98 DIPG tumor. [(18) F] 3'-deoxy-3'-[(18) F]fluorothymidine (FLT) positron emission tomography (PET) imaging was applied to assess the subcutaneous (s.c.) E98 tumor proliferation status but no orthotopic DIPG activity could be visualized. Next, E98 cells were cultured in vitro and engineered to express firefly luciferase and mCherry (E98-Fluc-mCherry). These cultured E98-Fluc-mCherry cells developed focal pontine glioma when injected into the pons directly. However, the diffuse E98 DIPG infiltrative phenotype was restored when cells were injected into the pons immediately after an intermediate s.c. passage. The diffuse E98-Fluc-mCherry model was subsequently used to test escalating doses of irradiation, applying the bioluminescent Fluc signal to monitor tumor recurrence over time. Altogether, we here describe an accurate DIPG mouse model that can be of clinical relevance for testing experimental therapeutics in vivo.

  15. BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 proteins are related to human glioma tumor grade: immunohistochemistry and public microarray data meta-analysis.

    PubMed

    Pelekanou, Vassiliki; Notas, George; Kampa, Marilena; Tsentelierou, Eleftheria; Stathopoulos, Efstathios N; Tsapis, Andreas; Castanas, Elias

    2013-01-01

    Gliomas are common and lethal tumors of the central nervous system (CNS). Genetic alterations, inflammatory and angiogenic processes have been identified throughout tumor progression; however, treatment still remains palliative for most cases. Biological research on parameters influencing cell survival, invasion and tumor heterogeneity identified several cytokines interfering in CNS inflammation, oxidative stress and malignant transformation, including TNF-superfamily (TNFSF) members. In this report we performed a meta-analysis of public gene-array data on the expression of a group of TNFSF ligands (BAFF, APRIL, TWEAK) and their receptors (BAFF-R, TACI, BCMA, Fn14) in gliomas. In addition, we investigated by immunohistochemistry (IHC) the tumor cells' expression of these ligands and receptors in a series of 56 gliomas of different grade. We show that in IHC, BAFF and APRIL as well as their cognate receptors (BCMA, TACI) and Fn14 expression correlate with tumor grade. This result was not evidenced in micro-arrays meta-analysis. Finally, we detected for the first time Fn14, BAFF, BCMA and TACI in glioma-related vascular endothelium. Our data, combined with our previous report in glioma cell lines, suggest a role for these receptors and ligands in glioma biology and advance these molecules as potential markers for the classification of these tumors to the proliferative, angiogenic or stem-like molecular subtype.

  16. Long Non-coding RNA TUSC7, a Target of miR-23b, Plays Tumor-Suppressing Roles in Human Gliomas

    PubMed Central

    Shang, Chao; Guo, Yan; Hong, Yang; Xue, Yi-xue

    2016-01-01

    Tumour suppressor candidate 7 (TUSC7) is a novel tumor suppressor gene generating long non-coding RNA (lncRNAs) in several types of human cancers. The expression and function of TUSC7 in human brain glioma has yet to be elucidated. In this study, TUSC7 was poorly expressed in tissues and cell lines of glioma, and the lower expression was correlated with glioma of the worse histological grade. Moreover, TUSC7 is a prognostic biomarker of glioma patients. Up-regulation of TUSC7 suppressed cellular proliferation and invasion of glioma cells, and accelerated cellular apoptosis. Bioinformatics analysis showed that TUSC7 specifically binds to miR-23b. MiR-23b was up-regulated in glioma and negatively correlated with the expression of TUSC7. The miR-23b expression was inhibited remarkably by the upregulation of TUSC7 and the reciprocal inhibition was determined between TUSC7 and miR-23b.RNA pull-down and luciferase reporter assays were used to validate the sequence-specific correlation between miR-23b and TUSC7. TUSC7 inhibited the proliferation, migration and invasion of glioma cells and promoted cellular apoptosis largely bypassing miR-23b. We conclude that the lncRNA TUSC7 acted as a tumor suppressor gene negatively regulated by miR-23b, suggesting a novel therapeutic strategy against gliomas. PMID:27766072

  17. Incidence of gliomas by anatomic location

    PubMed Central

    Larjavaara, Suvi; Mäntylä, Riitta; Salminen, Tiina; Haapasalo, Hannu; Raitanen, Jani; Jääskeläinen, Juha; Auvinen, Anssi

    2007-01-01

    The anatomic location of a glioma influences prognosis and treatment options. The aim of our study was to describe the distribution of gliomas in different anatomic areas of the brain. A representative population-based sample of 331 adults with glioma was used for preliminary analyses. The anatomic locations for 89 patients from a single center were analyzed in more detail from radiologic imaging and recorded on a three-dimensional 1 × 1 × 1– cm grid. The age-standardized incidence rate of gliomas was 4.7 per 100,000 person-years. The most frequent subtypes were glioblastoma (47%) and grade II–III astrocytoma (23%), followed by oligodendroglioma and mixed glioma. The gliomas were located in the frontal lobe in 40% of the cases, temporal in 29%, parietal in 14%, and occipital lobe in 3%, with 14% in the deeper structures. The difference in distribution between lobes remained after adjustment for their tissue volume: the tumor:volume ratio was 4.5 for frontal, 4.8 for temporal, and 2.3 for parietal relative to the occipital lobe. The area with the densest occurrence was the anterior subcortical brain. Statistically significant spatial clustering was found in the three-dimensional analysis. No differences in location were found among glioblastoma, diffuse astrocytoma, and oligodendroglioma. Our results demonstrate considerable heterogeneity in the anatomic distribution of gliomas within the brain. PMID:17522333

  18. Evaluation of nano-magnetic fluid on malignant glioma cells

    PubMed Central

    Xu, Hongsheng; Zong, Hailiang; Ma, Chong; Ming, Xing; Shang, Ming; Li, Kai; He, Xiaoguang; Cao, Lei

    2017-01-01

    The temperature variation rule of nano-magnetic fluid in the specific magnetic field and the effect on the treatment of malignant glioma were examined. The temperature variation of nano-magnetic fluid in the specific magnetic field was investigated by heating in vitro, and cell morphology was observed through optical microscopy and electron microscopy. MTT detection also was used to detect the effect of Fe3O4 nanometer magnetic fluid hyperthermia (MFH) on the proliferation of human U251 glioma cell line. The Fe3O4 nano MFH experiment was used to detect the inhibition rate of the tumor volume in nude mice with tumors. The results of the experiment showed that the heating ability of magnetic fluid was positively correlated with its concentration at the same intensity of the magnetic field. The results also indicated the prominent inhibitory effect of nanometer MFH on the proliferation of glioma cells, which was a dose-dependent relationship with nanometer magnetic fluid concentration. The hyperthermia experiment of nude mice with tumors displayed a significant inhibiting effect of Fe3O4 nanometer magnetic fluid in glioma volume. These results explain that iron (II, III) oxide (Fe3O4) nanometer MFH can inhibit the proliferation of U251 glioma cells, and has an obvious inhibitory effect on glioma volume, which plays a certain role in the treatment of brain glioma. PMID:28356945

  19. Evaluation of nano-magnetic fluid on malignant glioma cells.

    PubMed

    Xu, Hongsheng; Zong, Hailiang; Ma, Chong; Ming, Xing; Shang, Ming; Li, Kai; He, Xiaoguang; Cao, Lei

    2017-02-01

    The temperature variation rule of nano-magnetic fluid in the specific magnetic field and the effect on the treatment of malignant glioma were examined. The temperature variation of nano-magnetic fluid in the specific magnetic field was investigated by heating in vitro, and cell morphology was observed through optical microscopy and electron microscopy. MTT detection also was used to detect the effect of Fe3O4 nanometer magnetic fluid hyperthermia (MFH) on the proliferation of human U251 glioma cell line. The Fe3O4 nano MFH experiment was used to detect the inhibition rate of the tumor volume in nude mice with tumors. The results of the experiment showed that the heating ability of magnetic fluid was positively correlated with its concentration at the same intensity of the magnetic field. The results also indicated the prominent inhibitory effect of nanometer MFH on the proliferation of glioma cells, which was a dose-dependent relationship with nanometer magnetic fluid concentration. The hyperthermia experiment of nude mice with tumors displayed a significant inhibiting effect of Fe3O4 nanometer magnetic fluid in glioma volume. These results explain that iron (II, III) oxide (Fe3O4) nanometer MFH can inhibit the proliferation of U251 glioma cells, and has an obvious inhibitory effect on glioma volume, which plays a certain role in the treatment of brain glioma.

  20. Intratumoral oncolytic adenoviral treatment modulates the glioma microenvironment and facilitates systemic tumor-antigen-specific T cell therapy

    PubMed Central

    Qiao, Jian; Dey, Mahua; Chang, Alan L; Kim, Julius W; Miska, Jason; Ling, Alex; M Nettlebeck, Dirk; Han, Yu; Zhang, Lingjiao; Lesniak, Maciej S

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is associated with poor survival. Virotherapy is a promising candidate for the development of effective, novel treatments for GBM. Recent studies have underscored the potential of virotherapy in enhancing antitumor immunity despite the fact that its mechanisms remain largely unknown. Here, using a syngeneic GBM mouse model, we report that intratumoral virotherapy significantly modulates the tumor microenvironment. We found that intratumoral administration of an oncolytic adenovirus, AdCMVdelta24, decreased tumor-infiltrating CD4+ Foxp3+ regulatory T cells (Tregs) and increased IFNγ-producing CD8+ T cells in treated tumors, even in late stage disease in which a highly immunosuppressive tumor microenvironment is considered to be a significant barrier to immunotherapy. Importantly, intratumoral AdCMVdelta24 treatment augmented systemically transferred tumor-antigen-specific T cell therapy. Furthermore, mechanistic studies showed (1) downregulation of Foxp3 in Tregs that were incubated with media conditioned by virus-infected tumor cells, (2) downregulation of indoleamine 2,3 dioxygenase 1 (IDO) in glioma cells upon infection by AdCMVdelta24, and (3) reprograming of Tregs from an immunosuppressive to a stimulatory state. Taken together, our findings demonstrate the potency of intratumoral oncolytic adenoviral treatment in enhancing antitumor immunity through the regulation of multiple aspects of immune suppression in the context of glioma, supporting further clinical development of oncolytic adenovirus-based immune therapies for malignant brain cancer. PMID:26405578

  1. Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma

    PubMed Central

    Shankar, Adarsh; Borin, Thaiz F; Iskander, Asm; Varma, Nadimpalli RS; Achyut, Bhagelu R; Jain, Meenu; Mikkelsen, Tom; Guo, Austin M; Chwang, Wilson B; Ewing, James R; Bagher-Ebadian, Hassan; Arbab, Ali S

    2016-01-01

    Background Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N′-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis. The aims of the studies were to determine 1) whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2) whether the treatment schedule would have a crucial impact on controlling GBM. Methods U251 human glioma cells (4×105) were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8–21 days treatment) of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0–21 days treatment) was to mimic cases following radiation therapy or surgery. There were four different treatment groups: vehicle, vatalanib (oral treatment 50 mg/kg/d), HET0016 (intraperitoneal treatment 10 mg/kg/d), and combined (vatalanib and HET0016). Following scheduled treatments, all animals underwent magnetic resonance imaging on day 22, followed by euthanasia. Brain specimens were equally divided for immunohistochemistry and protein array analysis. Results Our results demonstrated a trend that HET0016, alone or in combination with vatalanib, is capable of controlling the tumor growth compared with that of vatalanib alone, indicating attenuation of the unwanted effect of vatalanib. When both vatalanib and HET0016 were administered together on the day of the tumor implantation (0–21 days treatment), tumor

  2. Handheld confocal laser endomicroscopic imaging utilizing tumor-specific fluorescent labeling to identify experimental glioma cells in vivo

    PubMed Central

    Martirosyan, Nikolay L.; Georges, Joseph; Kalani, M. Yashar S.; Nakaji, Peter; Spetzler, Robert F.; Feuerstein, Burt G.; Preul, Mark C.

    2016-01-01

    Background: We have reported that handheld confocal laser endomicroscopy (CLE) can be used with various nonspecific fluorescent dyes to improve the microscopic identification of brain tumor and its boundaries. Here, we show that CLE can be used experimentally with tumor-specific fluorescent labeling to define glioma margins in vivo. Methods: Thirteen rats underwent craniectomy and in vivo imaging 21 days after implantation with green fluorescent protein (GFP)-labeled U251 (n = 7) cells or epidermal growth factor receptor (EGFR) overexpressing F98 cells (n = 6). Fluorescein isothiocyanate (FITC) conjugated EGFR fluorescent antibody (FITC-EGFR) was applied for contrast in F98 tumors. Confocal images of normal brain, obvious tumor, and peritumoral zones were collected using the CLE system. Bench-top confocal microscopy and hematoxylin and eosin-stained sections were correlated with CLE images. Results: GFP and FITC-EGFR fluorescence of glioma cells were detected by in vivo visible-wavelength fluorescence CLE. CLE of GFP-labeled tumors revealed bright individual satellite tumor cells within peritumoral tissue, a definitive tumor border, and subcellular structures. Imaging with FITC-EGFR labeling provided weaker contrast in F98-EGFR tumors but was able to delineate tumor cells. Imaging with both methods in various tumor regions correlated with standard confocal imaging and clinical histology. Conclusions: These data suggest that in vivo CLE of selectively tagged neoplasms could allow specific interactive identification of tumoral areas. Imaging of GFP and FITC-EGFR provides real-time histologic information precisely related to the site of microscopic imaging of tumor. PMID:28144472

  3. ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma

    PubMed Central

    2009-01-01

    Background Cancer cells display widespread changes in DNA methylation that may lead to genetic instability by global hypomethylation and aberrant silencing of tumor suppressor genes by focal hypermethylation. In turn, altered DNA methylation patterns have been used to identify putative tumor suppressor genes. Methods In a methylation screening approach, we identified ECRG4 as a differentially methylated gene. We analyzed different cancer cells for ECRG4 promoter methylation by COBRA and bisulfite sequencing. Gene expression analysis was carried out by semi-quantitative RT-PCR. The ECRG4 coding region was cloned and transfected into colorectal carcinoma cells. Cell growth was assessed by MTT and BrdU assays. ECRG4 localization was analyzed by fluorescence microscopy and Western blotting after transfection of an ECRG4-eGFP fusion gene. Results We found a high frequency of ECRG4 promoter methylation in various cancer cell lines. Remarkably, aberrant methylation of ECRG4 was also found in primary human tumor tissues, including samples from colorectal carcinoma and from malignant gliomas. ECRG4 hypermethylation associated strongly with transcriptional silencing and its expression could be re-activated in vitro by demethylating treatment with 5-aza-2'-deoxycytidine. Overexpression of ECRG4 in colorectal carcinoma cells led to a significant decrease in cell growth. In transfected cells, ECRG4 protein was detectable within the Golgi secretion machinery as well as in the culture medium. Conclusions ECRG4 is silenced via promoter hypermethylation in different types of human cancer cells. Its gene product may act as inhibitor of cell proliferation in colorectal carcinoma cells and may play a role as extracellular signaling molecule. PMID:20017917

  4. NI-79RAPID ASSESSMENT OF LESION VOLUMES FOR PATIENTS WITH GLIOMA USING THE SMARTBRUSH SOFTWARE PACKAGE

    PubMed Central

    Vaziri, Sana; Lafontaine, Marisa; Olson, Beck; Crane, Jason C.; Chang, Susan; Lupo, Janine; Nelson, Sarah J.

    2014-01-01

    The increasing interest in enhancing the RANO criteria by using quantitative assessments of changes in lesion size and image intensities has highlighted the need for rapid, easy-to-use tools that provide DICOM compatible outputs for evaluation of patients with glioma. To evaluate the performance of the SmartBrush software (Brainlab AG), which provides computer-assisted definitions of regions of interest (ROIs), a cohort of 20 patients with glioma (equal number having high and low grade and treated and un-treated) were scanned using a 3T whole-body MR system prior to surgical resection. The T2-weighted FLAIR, pre- and post-contrast T1-weighted gradient echo DICOM images were pushed from the scanner to an offline workstation where analysis of lesion volumes was performed using SmartBrush. Volumes of the T2Ls ranged from 7.9 to 110.2cm3 and the volumes of the CELs was 0.1 to 28.5 cm3 with 19/20 of the subjects having CELs and all 20 having T2Ls. the computer-assisted analysis was performed rapidly and efficiently, with the mean time for defining both lesions per subject was 5.77 (range 3.5 to 7.5) minutes. Prior analysis of ROIS with the SLICER package (www.slicer.org) took approximately 30 minutes/subject. SmartBrush provides lesion volumes and cross-sectional diameter as a PDF report, which can be stored in DICOM. The ROIs were also saved as DICOM objects and transferred to other packages for performing histogram analysis from ADC or other functional parameter maps. Ongoing studies that will be reported in this presentation are performing a similar analysis with multiple users in order to compare the relative intra- and inter-operator variations in terms of both the speed of analysis and the ROIs that are identified. Acknowledgements: The authors would like to acknowledge Rowena Thomson and Natalie Wright from Brainlab for helping to set up this study.

  5. 18F-FDOPA PET/CT or PET/MRI in Measuring Tumors in Patients With Newly-Diagnosed or Recurrent Gliomas

    ClinicalTrials.gov

    2017-01-30

    Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Recurrent Adult Brain Tumor; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Diffuse Astrocytoma; Recurrent Childhood Fibrillary Astrocytoma; Recurrent Childhood Gemistocytic Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Oligoastrocytoma; Recurrent Childhood Oligodendroglioma; Recurrent Childhood Pilomyxoid Astrocytoma; Recurrent Childhood Protoplasmic Astrocytoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligoastrocytoma; Untreated Childhood Anaplastic Oligodendroglioma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Cerebellar Astrocytoma; Untreated Childhood Cerebral Astrocytoma; Untreated Childhood Diffuse Astrocytoma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Gemistocytic Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliomatosis Cerebri; Untreated Childhood Gliosarcoma; Untreated Childhood

  6. Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients.

    PubMed

    Sun, Boqian; Chu, Dake; Li, Wei; Chu, Xiaodan; Li, Yunming; Wei, Dun; Li, Haiping

    2009-09-01

    The aim of the study was to examine the expression of NDRG1 gene in glioma samples with different WHO grades and its association with survival. About 168 glioma specimens and 21 normal control tissues were collected. Immunochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of NDRG1 and Myc. Kaplan-Meier method and Cox's proportional hazards model were used in survival analysis. Immunohistochemistry showed that Ndrg1 expression was reduced in glioma. NDRG1 mRNA and protein levels were lower in glioma compared to control on real-time PCR and Western blot analysis (P < 0.001). Its expression levels increase from grade IV to grade I glioma on real-time PCR, immunohistochemistry analysis (P < 0.001) and Western blot. On the contrary, the expression of Myc by real-time PCR and Western blot showed the opposite trend of NDRG1. The survival rate of Ndrg1-negative patients was lower than that of Ndrg1-positive patients. We confirmed that the loss of NDRG1 expression was a significant and independent prognostic indicator in glioma by multivariate analysis. NDRG1 may play an inhibitory role during the development of glioma and may be a potential prognosis predictor of glioma.

  7. Proposed therapeutic strategy for adult low-grade glioma based on aggressive tumor resection.

    PubMed

    Nitta, Masayuki; Muragaki, Yoshihiro; Maruyama, Takashi; Ikuta, Soko; Komori, Takashi; Maebayashi, Katsuya; Iseki, Hiroshi; Tamura, Manabu; Saito, Taiichi; Okamoto, Saori; Chernov, Mikhail; Hayashi, Motohiro; Okada, Yoshikazu

    2015-01-01

    OBJECT There is no standard therapeutic strategy for low-grade glioma (LGG). The authors hypothesized that adjuvant therapy might not be necessary for LGG cases in which total radiological resection was achieved. Accordingly, they established a treatment strategy based on the extent of resection (EOR) and the MIB-1 index: patients with a high EOR and low MIB-1 index were observed without postoperative treatment, whereas those with a low EOR and/or high MIB-1 index received radiotherapy (RT) and/or chemotherapy. In the present retrospective study, the authors reviewed clinical data on patients with primarily diagnosed LGGs who had been treated according to the above-mentioned strategy, and they validated the treatment policy. Given their results, they will establish a new treatment strategy for LGGs stratified by EOR, histological subtype, and molecular status. METHODS One hundred fifty-three patients with diagnosed LGG who had undergone resection or biopsy at Tokyo Women's Medical University between January 2000 and August 2010 were analyzed. The patients consisted of 84 men and 69 women, all with ages ≥ 15 years. A total of 146 patients underwent surgical removal of the tumor, and 7 patients underwent biopsy. RESULTS Postoperative RT and nitrosourea-based chemotherapy were administered in 48 and 35 patients, respectively. Extent of resection was significantly associated with both overall survival (OS; p = 0.0096) and progression-free survival (PFS; p = 0.0007) in patients with diffuse astrocytoma but not in those with oligodendroglial subtypes. Chemotherapy significantly prolonged PFS, especially in patients with oligodendroglial subtypes (p = 0.0009). Patients with a mutant IDH1 gene had significantly longer OS (p = 0.034). Multivariate analysis did not identify MIB-1 index or RT as prognostic factors, but it did identify chemotherapy as a prognostic factor for PFS and EOR as a prognostic factor for OS and PFS. CONCLUSIONS The findings demonstrated that EOR was

  8. Molecular genetics of pediatric brain stem gliomas. Application of PCR techniques to small and archival brain tumor specimens

    SciTech Connect

    Louis, D.N.; Rubio, M.P.; Correa, K.M.; Gusella, J.F.; Deimling, A. von )

    1993-09-01

    Brain stem gliomas are pediatric astrocytomas that histologically resemble adult supratentorial astrocytomas such as gliobastomas multiforme (GBM). The molecular genetic studies have suggested that adult GBM can be divided into two genetic subsets: Tumors with p53 tumor suppressor gene mutations and chromosome 17p loss that occur more commonly in younger patients; and tumors with epidermal growth factor receptor (EGFR) gene amplification that occur more commonly in older patients. Brain stem gliomas have not been studied since biopsies of these tumors are rare and extremely small. The authors investigated the molecular genetic composition of seven brain stem glioblastomas (two small biopsies, five autopsies) using polymerase chain reaction (PCR) assays for chromosomal loss, gene mutation and gene amplification. Four cases lost portions of chromosome 17p that included the 53p gene. These four cases and one additional case had mutations in the p53 gene. None of the cases showed amplification of the EGFR gene. Allelic losses of the long arm of chromosome 10 were noted in four cases. These results suggest similarities between pediatric brain stem glioblastomas and those GBM that occur in younger adult patients, and confirm the utility of PCR-based means of studying small and archival brain tumor specimens. 47 refs., 7 figs., 2 tabs.

  9. Plasmacytoid dendritic cells in the tumor microenvironment: immune targets for glioma therapeutics.

    PubMed

    Candolfi, Marianela; King, Gwendalyn D; Yagiz, Kader; Curtin, James F; Mineharu, Yohei; Muhammad, A K M Ghulam; Foulad, David; Kroeger, Kurt M; Barnett, Nick; Josien, Regis; Lowenstein, Pedro R; Castro, Maria G

    2012-08-01

    Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.

  10. Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics12

    PubMed Central

    Candolfi, Marianela; King, Gwendalyn D; Yagiz, Kader; Curtin, James F; Mineharu, Yohei; Muhammad, AKM Ghulam; Foulad, David; Kroeger, Kurt M; Barnett, Nick; Josien, Regis; Lowenstein, Pedro R; Castro, Maria G

    2012-01-01

    Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM. PMID:22952428

  11. Potent tumor tropism of induced pluripotent stem cells and induced pluripotent stem cell-derived neural stem cells in the mouse intracerebral glioma model.

    PubMed

    Yamazoe, Tomohiro; Koizumi, Shinichiro; Yamasaki, Tomohiro; Amano, Shinji; Tokuyama, Tsutomu; Namba, Hiroki

    2015-01-01

    Although neural and mesenchymal stem cells have been well-known to have a strong glioma tropism, this activity in induced pluripotent stem cells (iPSCs) has not yet been fully studied. In the present study, we tested tumor tropic activity of mouse iPSCs and neural stem cells derived from the iPSC (iPS-NSCs) using in vitro Matrigel invasion chamber assay and in vivo mouse intracranial tumor model. Both iPSC and iPS-NSC had a similar potent in vitro tropism for glioma conditioned media. The migrated iPSCs to the gliomas kept expressing Nanog-GFP gene, suggesting no neuronal or glial differentiation. iPSCs or iPS-NSCs labeled with 5-bromo-2-deoxyuridine were intracranially implanted in the contralateral hemisphere to the GL261 glioma cell implantation in the allogeneic C57BL/6 mouse. Active migration of both stem cells was observed 7 days after implantation. Again, the iPSCs located in the tumor area expressed Nanog-GFP gene, suggesting that the migrated cells were still iPSCs. These findings demonstrated that both iPSCs and iPS-NSCs had potent glioma tropism and could be candidates as vehicles in stem cell-based glioma therapy.

  12. Efficacy of salvage stereotactic radiotherapy for recurrent glioma: impact of tumor morphology and method of target delineation on local control

    PubMed Central

    Ogura, Kengo; Mizowaki, Takashi; Arakawa, Yoshiki; Sakanaka, Katsuyuki; Miyamoto, Susumu; Hiraoka, Masahiro

    2013-01-01

    In this study, we assessed the efficacy of salvage stereotactic radiotherapy (SRT) for recurrent glioma. From August 2008 to December 2012, 30 patients with recurrent glioma underwent salvage SRT. The initial histological diagnoses were World Health Organization (WHO) grades II, III, and IV in 6, 9, and 15 patients, respectively. Morphologically, the type of recurrence was classified as diffuse or other. Two methods of clinical target delineation were used: A, a contrast-enhancing tumor; or B, a contrast-enhancing tumor with a 3–10-mm margin and/or surrounding fluid attenuation inversion recovery (FLAIR) high-intensity areas. The prescribed dose was 22.5–35 Gy delivered in five fractions at an isocenter using a dynamic conformal arc technique. The overall survival (OS) and local control probability (LCP) after SRT were calculated using the Kaplan–Meier method. A univariate analysis was used to test the effect of clinical variables on OS/LCP. The median follow-up period was 272 days after SRT. The OS and LCP were 83% and 56% at 6 months after SRT, respectively. Morphologically, the tumor type correlated significantly with both OS and LCP (P = 0.006 and <0.001, respectively). The method of target delineation also had a significant influence on LCP (P = 0.016). Grade 3 radiation necrosis was observed in two patients according to Common Terminology Criteria for Adverse Events, version 3. Salvage SRT was safe and effective for recurrent glioma, especially non-diffuse recurrences. Improved local control might be obtained by adding a margin to contrast-enhancing tumors or including increased FLAIR high-intensity areas. PMID:24403268

  13. A role for ion channels in perivascular glioma invasion

    PubMed Central

    Thompson, Emily G.

    2017-01-01

    Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuro-peptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials. PMID:27424110

  14. A role for ion channels in perivascular glioma invasion.

    PubMed

    Thompson, Emily G; Sontheimer, Harald

    2016-10-01

    Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuropeptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials.

  15. Molecular genetics of adult grade II gliomas: towards a comprehensive tumor classification system.

    PubMed

    Figarella-Branger, Dominique; Bouvier, Corinne; de Paula, André Maues; Mokhtari, Karima; Colin, Carole; Loundou, Anderson; Chinot, Olivier; Metellus, Philippe

    2012-11-01

    Adult grade II low-grade gliomas (LGG) are classified according to the WHO as astrocytomas, oligodendrogliomas or mixed gliomas. TP53 mutations and 1p19q codeletion are the main molecular abnormalities recorded, respectively, in astrocytomas and oligodendrogliomas and in mixed gliomas. Although IDH mutations (IDH1 or IDH2) are recorded in up to 85 % of low-grade gliomas, IDH negative gliomas do occur. We have searched for p53 expression, 1p19q codeletion and IDH status (immunohistochemical detection of the common R132H IDH1 mutation and IDH direct sequencing). Internexin alpha (INA) expression previously recorded to be associated with 1p19q codeletion (1p19q+) gliomas was also analysed. Low-grade gliomas were accurately classified into four groups: group 1, IDH+/p53-/1p19q-; group 2, IDH+/p53-/1p19q+; group 3, IDH+/p53+/1p19q-; and group 4, triple negative gliomas. In contrast to the WHO classification, this molecular classification predicts overall survival on uni- and multivariate analysis (P = 0.001 and P = 0.007, respectively). Group 4 carries the worst prognosis and group 2 the best. Interestingly, p53 +/INA- expression predicts lack of 1p19q codeletion (specificity 100 %, VPP 100 %). The combined use of these three molecular markers allow for an accurate prediction of survival in LGG. These findings could significantly modify LGG classification and may represent a new tool to guide patient-tailored therapy. Moreover, immunohistochemical detection of p53, INA and mR132H IDH1 expression could represent an interesting prescreening test to be performed before 1p19q codeletion, IDH1 minor mutation and IDH2 mutation detection.

  16. Altered Resting-State Functional Connectivity in the Hand Motor Network in Glioma Patients.

    PubMed

    Mallela, Arka N; Peck, Kyung K; Petrovich-Brennan, Nicole M; Zhang, Zhigang; Lou, William; Holodny, Andrei I

    2016-08-22

    To examine the functional connectivity of the primary and supplementary motor areas (SMA) in glioma patients using resting-state functional MRI (rfMRI). To correlate rfMRI data with tumor characteristics and clinical information to characterize functional reorganization of resting-state networks (RSN) and the limitations of this method. This study was IRB approved and in compliance with Health Insurance Portability and Accountability Act. Informed consent was waived in this retrospective study. We analyzed rfMRI in 24 glioma patients and 12 age- and sex-matched controls. We compared global activation, interhemispheric connectivity, and functional connectivity in the hand motor RSNs using hemispheric voxel counts, pairwise Pearson correlation, and pairwise total spectral coherence. We explored the relationship between tumor grade, volume, location, and the patient's clinical status to functional connectivity. Global network activation and interhemispheric connectivity were reduced in gliomas (p < 0.05). Functional connectivity between the bilateral motor cortices and the SMA was reduced in gliomas (p < 0.01). High-grade gliomas had lower functional connectivity than low-grade gliomas (p < 0.05). Tumor volume and distance to ipsilateral motor cortex demonstrated no association with functional connectivity loss. Functional connectivity loss is associated with motor deficits in low-grade gliomas, but not in high-grade gliomas. Global reduction in resting-state connectivity in areas distal to tumor suggests that radiological tumor boundaries underestimate areas affected by glioma. Association between motor deficits and rfMRI suggests that rfMRI may accurately reflect functional changes in low-grade gliomas. Lack of association between rfMRI and clinical motor deficits implies decreased sensitivity of rfMRI in high-grade gliomas, possibly due to neurovascular uncoupling.

  17. Molecular neuropathology of gliomas.

    PubMed

    Riemenschneider, Markus J; Reifenberger, Guido

    2009-01-01

    Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified according to the World Health Organization (WHO) classification of tumors of the nervous system. Over the past 20 years the cytogenetic and molecular genetic alterations associated with glioma formation and progression have been intensely studied and genetic profiles as additional aids to the definition of brain tumors have been incorporated in the WHO classification. In fact, first steps have been undertaken in supplementing classical histopathological diagnosis by the use of molecular tests, such as MGMT promoter hypermethylation in glioblastomas or detection of losses of chromosome arms 1p and 19q in oligodendroglial tumors. The tremendous progress that has been made in the use of array-based profiling techniques will likely contribute to a further molecular refinement of glioma classification and lead to the identification of glioma core pathways that can be specifically targeted by more individualized glioma therapies.

  18. Epidemiology of gliomas.

    PubMed

    Ostrom, Quinn T; Gittleman, Haley; Stetson, Lindsay; Virk, Selene M; Barnholtz-Sloan, Jill S

    2015-01-01

    Gliomas are the most common type of primary intracranial tumors. Some glioma subtypes cause significant mortality and morbidity that are disproportionate to their relatively rare incidence. A very small proportion of glioma cases can be attributed to inherited genetic disorders. Many potential risk factors for glioma have been studied to date, but few provide explanation for the number of brain tumors identified. The most significant of these factors includes increased risk due to exposure to ionizing radiation, and decreased risk with history of allergy or atopic disease. The potential effect of exposure to cellular phones has been studied extensively, but the results remain inconclusive. Recent genomic analyses, using the genome-wide association study (GWAS) design, have identified several inherited risk variants that are associated with increased glioma risk. The following chapter provides an overview of the current state of research in the epidemiology of intracranial glioma.

  19. Irradiation enhances the tumor tropism and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand-secreting human umbilical cord blood-derived mesenchymal stem cells in glioma therapy.

    PubMed

    Kim, Seong Muk; Oh, Ji Hyeon; Park, Soon A; Ryu, Chung Heon; Lim, Jung Yeon; Kim, Dal-Soo; Chang, Jong Wook; Oh, Wonil; Jeun, Sin-Soo

    2010-12-01

    Irradiation is a standard therapy for gliomas and many other cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for cancer gene therapy. Here, we show that tumor irradiation enhances the tumor tropism of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and the therapeutic effect of TRAIL delivered by UCB-MSCs. The sequential treatment with irradiation followed by TRAIL-secreting UCB-MSCs (MSC-TRAIL) synergistically enhanced apoptosis in either TRAIL-sensitive or TRAIL-resistant glioma cells by upregulating the death receptor 5 and by inducing caspase activation. Migration assays showed greater MSC migration toward irradiated glioma cells and the tumor site in glioma-bearing mice compared with unirradiated tumors. Irradiated glioma cells had increased expression of interleukin-8 (IL-8), which leads to the upregulation of the IL-8 receptor on MSCs. This upregulation, which is involved in the migratory capacity of UCB-MSCs, was confirmed by siRNA inhibition and an antibody-neutralizing assay. In vivo survival experiments in orthotopic xenografted mice showed that MSC-based TRAIL gene delivery to irradiated tumors had greater therapeutic efficacy than a single treatment. These results suggest that clinically relevant tumor irradiation increases the therapeutic efficacy of MSC-TRAIL by increasing tropism of MSCs and TRAIL-induced apoptosis, which may be a more useful strategy for cancer gene therapy.

  20. Acyl-coenzyme A: cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines.

    PubMed

    Bemlih, Sana; Poirier, Marie-Denise; El Andaloussi, Abdeljabar

    2010-06-15

    Glioblastoma is the most common primary brain tumor in adults and one of its hallmarks is resistance to apoptosis. Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular membrane-bound enzyme that uses cholesterol and long chain fatty acyl-CoA as substrates to produce cholesteryl esters. The presence of cholesteryl esters in glioblastoma may be related to vascular and/or cell neoplastic proliferation in the tumor mass, two prerequisites for tumor cell growth. ACAT activity has been detected in glioblastoma cell homogenates. The present study is the first report on the effect of Avasimibe, a specific inhibitor of ACAT, on glioma cell lines (U87, A172 and GL261). Our results showed that Avasimibe inhibited ACAT-1 expression and cholesterol ester synthesis in glioma cell lines. Moreover, Avasimibe inhibited the growth of the cells by inducing cell cycle arrest and induced apoptosis as a result of caspase-8 and caspase-3 activation. Also, Our findings provide proof of principle that targeting ACAT-1 with the inhibitor Avasimibe could be an efficient therapy in the treatment of glioblastoma.

  1. Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by suppressing miR-155 expression and activating FBXW7 function

    PubMed Central

    Cao, Shuanzhu; Wang, Yanzhou; Li, Jinquan; Lv, Mingliang; Niu, Haitao; Tian, Yong

    2016-01-01

    The human metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA associated with metastasis, and is a favorable prognostic factor for lung cancer. Recent studies have shown that MALAT1 plays an important role in many malignancies. However, little is known about the role of MALAT1 in glioma. In this study, we determined the expression of MALAT1 and explored its prognostic value in glioma. Further, we investigated the regulatory mechanism of MALAT1 in glioma progression. Our results showed that the expression of MALAT1 was significantly decreased in glioma specimens than in noncancerous brain tissues. In addition, MALAT1 expression was significantly correlated with tumor size, WHO grade and Karnofsky Performance Status (KPS), and was an independent prognostic factor for survival of glioma patients. The gain- and loss-of-function experiments revealed miR-155 down-regulation by MALAT1, resulting in reciprocal effects. Further, MALAT1 suppresses cell viability by down-regulating miR-155. FBXW7 mRNA was identified as a direct target of miR-155 in glioma. The miR-155-induced tumorigenesis is mediated through FBXW7 function. Finally, we found that MALAT1 positively regulated FBXW7 expression, which was responsible for glioma progression mediated by MALAT1-miR-155 pathway. In conclusion, our data demonstrated that MALAT1 may be a novel prognostic biomarker and therapeutic target in glioma. Restoration of MALAT1 levels represents a novel therapeutic strategy against glioma. PMID:27904771

  2. High-Grade Glioma Radiation Therapy Target Volumes and Patterns of Failure Obtained From Magnetic Resonance Imaging and {sup 18}F-FDOPA Positron Emission Tomography Delineations From Multiple Observers

    SciTech Connect

    Kosztyla, Robert; Chan, Elisa K.; Hsu, Fred; Wilson, Don; Ma, Roy; Cheung, Arthur; Zhang, Susan; Moiseenko, Vitali; Benard, Francois; Nichol, Alan

    2013-12-01

    Purpose: The objective of this study was to compare recurrent tumor locations after radiation therapy with pretreatment delineations of high-grade gliomas from magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[{sup 18}F]fluoro-L-phenylalanine ({sup 18}F-FDOPA) positron emission tomography (PET) using contours delineated by multiple observers. Methods and Materials: Nineteen patients with newly diagnosed high-grade gliomas underwent computed tomography (CT), gadolinium contrast-enhanced MRI, and {sup 18}F-FDOPA PET/CT. The image sets (CT, MRI, and PET/CT) were registered, and 5 observers contoured gross tumor volumes (GTVs) using MRI and PET. Consensus contours were obtained by simultaneous truth and performance level estimation (STAPLE). Interobserver variability was quantified by the percentage of volume overlap. Recurrent tumor locations after radiation therapy were contoured by each observer using CT or MRI. Consensus recurrence contours were obtained with STAPLE. Results: The mean interobserver volume overlap for PET GTVs (42% ± 22%) and MRI GTVs (41% ± 22%) was not significantly different (P=.67). The mean consensus volume was significantly larger for PET GTVs (58.6 ± 52.4 cm{sup 3}) than for MRI GTVs (30.8 ± 26.0 cm{sup 3}, P=.003). More than 95% of the consensus recurrence volume was within the 95% isodose surface for 11 of 12 (92%) cases with recurrent tumor imaging. Ten (91%) of these cases extended beyond the PET GTV, and 9 (82%) were contained within a 2-cm margin on the MRI GTV. One recurrence (8%) was located outside the 95% isodose surface. Conclusions: High-grade glioma contours obtained with {sup 18}F-FDOPA PET had similar interobserver agreement to volumes obtained with MRI. Although PET-based consensus target volumes were larger than MRI-based volumes, treatment planning using PET-based volumes may not have yielded better treatment outcomes, given that all but 1 recurrence extended beyond the PET GTV and most were contained by a 2-cm

  3. Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model

    PubMed Central

    Wu, Junjie; Waxman, David J.

    2014-01-01

    Metronomic cyclophosphamide (CPA) treatment activates robust innate anti-tumor immunity and induces major regression of large, implanted brain tumor xenografts when administered on an intermittent, every 6-day schedule, but not on a daily low-dose or a maximum-tolerated dose CPA schedule. Here, we used an implanted GL261 glioma model to compare five intermittent metronomic CPA schedules to elucidate the kinetics and schedule dependence of innate immune cell recruitment and tumor regression. Tumor-recruited natural killer cells induced by two every 6-day treatment cycles were significantly ablated one day after a third CPA treatment, but largely recovered several days later. Natural killer and other tumor-infiltrating innate immune cells peaked 12 days after the last CPA treatment on the every 6-day schedule, suggesting that drug-free intervals longer than 6 days may show increased efficacy. Metronomic CPA treatments spaced 9 or 12 days apart, or on an alternating 6 and 9 day schedule, induced extensive tumor regression, similar to the 6-day schedule, however, the tumor-infiltrating natural killer cell responses were not sustained, leading to rapid resumption of tumor regrowth after day 24, despite ongoing metronomic CPA treatment. Increasing the CPA dose prolonged the period of tumor regression on the every 9-day schedule, but natural killer cell activation was markedly decreased. Thus, while several intermittent metronomic CPA treatment schedules can activate innate immune cell recruitment leading to major tumor regression, sustained immune and anti-tumor responses are only achieved on the 6-day schedule. However, even with this schedule, some tumors eventually relapse, indicating a need for further improvements in immunogenic metronomic therapies. PMID:25069038

  4. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    PubMed Central

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-01-01

    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the “blood tumor barrier” (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced MRI (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and Definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg/kg. This chemotherapy agent was shown previously to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823±600, 1817±732 and 2432±448 ng/g) in the control tumors at 9, 14 and 17 days. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222±784, 3687±796 and 5658±821 ng/g) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (p<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can

  5. Matrix metalloproteinase triggered size-shrinkable gelatin-gold fabricated nanoparticles for tumor microenvironment sensitive penetration and diagnosis of glioma

    NASA Astrophysics Data System (ADS)

    Ruan, Shaobo; He, Qin; Gao, Huile

    2015-05-01

    To improve glioma targeting delivery efficiency and to monitor drug delivery and treatment outcome, a novel tumor microenvironment sensitive size-shrinkable theranostic system was constructed and evaluated. The G-AuNPs-DC-RRGD system was constructed by fabricating small sized gold nanoparticles (AuNPs) onto matrix metalloproteinase-2 (MMP-2) degradable gelatin nanoparticles (GNPs), doxorubicin (DOX) and Cy5.5 were decorated onto AuNPs through a hydrazone bond to enable the system with pH triggered cargoes release, and RRGD, a tandem peptide of RGD and octarginine was surface-modified onto the system to enable it with glioma active targeting ability. In vitro, the size of G-AuNPs-DC-RRGD could effectively shrink from 188.2 nm to 55.9 nm after incubation with MMP-2, while DOX and Cy5.5 were released in a pH dependent manner. Cellular uptake demonstrated that G-AuNPs-DC-RRGD could be effectively taken up by cells with higher intensity than G-AuNPs-DC-PEG. A study of tumor spheroids further demonstrated that the particles with smaller size showed better penetration ability, while RRGD modification could further improve permeability. In vivo, G-AuNPs-DC-RRGD displayed the best glioma targeting and accumulation efficiency, with good colocalization with neovessels. Cy5.5 also was colocalized well with DOX, indicating that Cy5.5 could be used for imaging of DOX delivery.To improve glioma targeting delivery efficiency and to monitor drug delivery and treatment outcome, a novel tumor microenvironment sensitive size-shrinkable theranostic system was constructed and evaluated. The G-AuNPs-DC-RRGD system was constructed by fabricating small sized gold nanoparticles (AuNPs) onto matrix metalloproteinase-2 (MMP-2) degradable gelatin nanoparticles (GNPs), doxorubicin (DOX) and Cy5.5 were decorated onto AuNPs through a hydrazone bond to enable the system with pH triggered cargoes release, and RRGD, a tandem peptide of RGD and octarginine was surface-modified onto the system to

  6. A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models.

    PubMed

    Bagci-Onder, Tugba; Wakimoto, Hiroaki; Anderegg, Maarten; Cameron, Cody; Shah, Khalid

    2011-01-01

    The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133(+) glioma-initiating cells and explored the potential of combining PI-103 with stem cell-delivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G(0)-G(1) arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell-delivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanism-based systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas.

  7. CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model.

    PubMed

    Jordan, Marie; Waxman, David J

    2016-04-01

    Cyclophosphamide administered on an intermittent metronomic schedule induces strong immune-dependent regression in several glioma models. Here we investigate whether this immunogenic chemotherapy can be potentiated by combination with the immune stimulatory TLR9 agonist CpG-1826. CpG-1826 treatment of GL261 gliomas implanted in immune competent mice induced tumor growth delay associated with increased tumor recruitment of macrophages and B cells. Anti-tumor responses varied between individuals, with CpG-1826 inducing robust tumor growth delay in ~50% of treated mice. Both high and low CpG-1826-responsive mice showed striking improvements when CpG-1826 was combined with cyclophosphamide treatment. Tumor-associated macrophages, B cells, dendritic cells, and cytotoxic T cells were increased, T regulatory cells were not induced, and long-term GL261 glioma regression with immune memory was achieved when CpG-1826 was combined with either single cyclophosphamide dosing (90 mg/kg) or metronomic cyclophosphamide treatment (two cycles at 45 mg/kg, spaced 12-days apart). B16F10 melanoma, a low immunogenic tumor model, also showed enhanced immune and anti-tumor responses to cyclophosphamide/CpG-1826 chemoimmunotherapy, but unlike GL261 tumors, did not regress. TLR9-based immunotherapy can thus be effectively combined with immunogenic cyclophosphamide treatment to enhance immune-based anti-tumor responses, even in poorly immunogenic cancer models.

  8. Secreted protein acidic and rich in cysteine promotes glioma invasion and delays tumor growth in vivo.

    PubMed

    Schultz, Chad; Lemke, Nancy; Ge, Shugang; Golembieski, William A; Rempel, Sandra A

    2002-11-01

    Secreted protein acidic and rich in cysteine (SPARC) is highly expressed in human astrocytomas, grades II-IV. We demonstrated previously that SPARC promotes invasion in vitro using the U87MG-derived clone U87T2 and U87T2-derived SPARC-transfected clones, A2b2, A2bi, and C2a4, in the spheroid confrontation assay. Additional in vitro studies demonstrated that SPARC delays growth, increases attachment, and modulates migration of tumor cells in extracellular matrix-specific and concentration-dependent manners. Therefore, we propose that SPARC functionally contributes to brain tumor invasion and delays tumor growth in vivo, and that the effects of SPARC are related to the level of SPARC secreted into the extracellular matrix. To test these hypotheses, we stereotactically injected these clones into nude rat brains (six animals were injected per clone). Animals were sacrificed on day 7 to assess growth and invasion for all clones at the same time in tumor development. To determine whether SPARC delayed but did not inhibit growth, rats were injected with U87T2 or clone A2b2, and the animals were sacrificed on days 9 (U87T2) and 20 (A2b2), when the animals demonstrated neurological deficit. Brains were removed, fixed, photographed, paraffin embedded, and sectioned. Sections were then serially stained with H&E for morphological assessment of invasion and to measure tumor volume, immunohistochemically stained to visualize SPARC, subjected to in situ hybridization with the human AluII DNA-binding probe to identify human cells, and immunohistochemically stained with MIB-1 to measure proliferation index. The results demonstrate that SPARC promotes invasion in vivo at day 7. Both the low (A2bi) and the high (A2b2) SPARC-secreting clones produced invasive tumors, invading with fingerlike projections and satellite masses into adjacent brain, as well as along the corpus collosum. The intermediate SPARC secreting clone (C2a4) primarily migrated as a bulk tumor along the corpus

  9. Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

    NASA Astrophysics Data System (ADS)

    Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A.

    2014-02-01

    Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

  10. Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

    PubMed

    Bielle, Franck; Ducray, François; Mokhtari, Karima; Dehais, Caroline; Adle-Biassette, Homa; Carpentier, Catherine; Chanut, Anaïs; Polivka, Marc; Poggioli, Sylvie; Rosenberg, Shai; Giry, Marine; Marie, Yannick; Duyckaerts, Charles; Sanson, Marc; Figarella-Branger, Dominique; Idbaih, Ahmed

    2016-08-20

    The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3(id) ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3(id) . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3(id) overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3(id) is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3(id) recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3(id) and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3(id) . A better understanding of spatial and temporal intratumor cell heterogeneity in O3(id) will open new therapeutic avenues overcoming resistance to current antitumor treatments.

  11. In vivo imaging of hypoxia-inducible factor regulation in a subcutaneous and orthotopic GL261 glioma tumor model using a reporter gene assay.

    PubMed

    Bürgi, Sandra; Seuwen, Aline; Keist, Ruth; Vom Berg, Johannes; Grandjean, Joanes; Rudin, Markus

    2014-01-01

    Intratumoral hypoxia changes the metabolism of gliomas, leading to a more aggressive phenotype with increased resistance to radio- and chemotherapy. Hypoxia triggers a signaling cascade with hypoxia-inducible factor (HIF) as a key regulator. We monitored activation of the HIF pathway longitudinally in murine glioma tumors. GL261 cells, stably transfected with a luciferase reporter driven under the control of a promoter comprising the HIF target gene motive hypoxia response element, were implanted either subcutaneously or orthotopically. In vivo experiments were carried out using bioluminescence imaging. Tumors were subsequently analyzed using immunofluorescence staining for hypoxia, endothelial cells, tumor perfusion, and glucose transporter expression. Transient upregulation of the HIF signaling was observed in both subcutaneous and orthotopic gliomas. Immunofluorescence staining confirmed hypoxic regions in subcutaneous and, to a lesser extent, intracranial tumors. Subcutaneous tumors showed substantial necrosis, which might contribute to the decreased bioluminescence output observed toward the end of the experiment. Orthotopic tumors were less hypoxic than subcutaneous ones and did not develop extensive necrotic areas. Although this may be the result of the overall smaller size of orthotopic tumors, it might also reflect differences in the local environment, such as the better intrinsic vascularization of brain tissue compared to the subcutaneous tissue compartment.

  12. Comparative permeability of different glioma models to horseradish peroxidase.

    PubMed

    Groothuis, D R; Fischer, J M; Vick, N A; Bigner, D D

    1981-01-01

    Seven different experimental glioma models were studied to determine their capillary permeability to horseradish peroxidase. The models were the autochthonous ASV-viral model, intracerebral (ic) and (sc) injections of rat 9L and RG-2 tumor cell lines, the sc rat S-69C15 tumor cell line, and human glioblastoma cell lines in nude mice. The ASV-viral model showed an average HRP permeability of 63% of tumor volume, the ic RG-2 tumors were 100% permeable, and the ic 9L tumors were 41% permeable. The permeability of the marginal zone (brain-tumor interface) showed similar variation from group to group. In contrast, all of the sc tumors were 100% permeable regardless of the cell line used to create the tumors. Our results show the variability between these glioma models, and suggest that RG-2 ic gliomas and all sc gliomas should be optimal to assess the tumoricidal effect of drugs, because access to the tumor compartment from the vascular compartment is complete.

  13. A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

    ClinicalTrials.gov

    2015-03-02

    Adult Anaplastic Astrocytoma; Recurrent Grade III Glioma; Recurrent Grade IV Glioma; Adult Anaplastic Oligodendroglioma; Adult Brain Tumor; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Adult Anaplastic Oligoastrocytoma; Recurrent High Grade Glioma

  14. Metallothinein 1E Enhances Glioma Invasion through Modulation Matrix Metalloproteinases-2 and 9 in U87MG Mouse Brain Tumor Model

    PubMed Central

    Hur, Hyuk; Ryu, Hyang-Hwa; Li, Chun-Hao; Kim, In Young; Jang, Woo-Youl

    2016-01-01

    Malignant glioma cells invading surrounding normal brain are inoperable and resistant to radio- and chemotherapy, and eventually lead to tumor regrowth. Identification of genes related to motility is important for understanding the molecular biological behavior of invasive gliomas. According to our previous studies, Metallothionein 1E (MT1E) was identified to enhance migration of human malignant glioma cells. The purpose of this study was to confirm that MT1E could modulate glioma invasion in vivo. Firstly we established 2 cell lines; MTS23, overexpressed by MT1E complementary DNA construct and pV12 as control. The expression of matrix metalloproteinases (MMP)-2, -9 and a disintegrin and metalloproteinase 17 were increased in MTS23 compared with pV12. Furthermore it was confirmed that MT1E could modulate MMPs secretion and translocation of NFkB p50 and B-cell lymphoma-3 through small interfering ribonucleic acid knocked U87MG cells. Then MTS23 and pV12 were injected into intracranial region of 5 week old male nude mouse. After 4 weeks, for brain tissues of these two groups, histological analysis, and immunohistochemical stain of MMP-2, 9 and Nestin were performed. As results, the group injected with MTS23 showed irregular margin and tumor cells infiltrating the surrounding normal brain, while that of pV12 (control) had round and clear margin. And regrowth of tumor cells in MTS23 group was observed in another site apart from tumor cell inoculation. MT1E could enhance tumor proliferation and invasion of malignant glioma through regulation of activation and expression of MMPs. PMID:27847566

  15. Tissue pO{sub 2} of Orthotopic 9L and C6 Gliomas and Tumor-Specific Response to Radiotherapy and Hyperoxygenation

    SciTech Connect

    Khan, Nadeem Li Hongbin; Hou, Huagang; Lariviere, Jean P.; Gladstone, David J.; Demidenko, Eugene; Swartz, Harold M.

    2009-03-01

    Purpose: Tumor hypoxia is a well-known therapeutic problem; however, a lack of methods for repeated measurements of glioma partial pressure of oxygen (pO{sub 2}) limits the ability to optimize the therapeutic approaches. We report the effects of 9.3 Gy of radiation and carbogen inhalation on orthotopic 9L and C6 gliomas and on the contralateral brain pO{sub 2} in rats using a new and potentially widely useful method, multisite in vivo electron paramagnetic resonance oximetry. Methods and Materials: Intracerebral 9L and C6 tumors were established in the left hemisphere of syngeneic rats, and electron paramagnetic resonance oximetry was successfully used for repeated tissue pO{sub 2} measurements after 9.3 Gy of radiation and during carbogen breathing for 5 consecutive days. Results: Intracerebral 9L gliomas had a pO{sub 2} of 30-32 mm Hg and C6 gliomas were relatively hypoxic, with a pO{sub 2} of 12-14 mm Hg (p < 0.05). The tissue pO{sub 2} of the contralateral brain was 40-45 mm Hg in rats with either 9L or C6 gliomas. Irradiation resulted in a significant increase in pO{sub 2} of the 9L gliomas only. A significant increase in the pO{sub 2} of the 9L and C6 gliomas was observed in rats breathing carbogen, but this effect decreased during 5 days of repeated experiments in the 9L gliomas. Conclusion: These results highlight the tumor-specific effect of radiation (9.3.Gy) on tissue pO{sub 2} and the different responses to carbogen inhalation. The ability of electron paramagnetic resonance oximetry to provide direct repeated measurements of tissue pO{sub 2} could have a vital role in understanding the dynamics of hypoxia during therapy that could then be optimized by scheduling doses at times of improved tumor oxygenation.

  16. Antroquinonol Targets FAK-Signaling Pathway Suppressed Cell Migration, Invasion, and Tumor Growth of C6 Glioma

    PubMed Central

    Thiyagarajan, Varadharajan; Tsai, May-Jywan; Weng, Ching-Feng

    2015-01-01

    Focal adhesion kinase (FAK) is a non-receptor protein tyrosine that is overexpressed in many types of tumors and plays a pivotal role in multiple cell signaling pathways involved in cell survival, migration, and proliferation. This study attempts to determine the effect of synthesized antroquinonol on the modulation of FAK signaling pathways and explore their underlying mechanisms. Antroquinonol significantly inhibits cell viability with an MTT assay in both N18 neuroblastoma and C6 glioma cell lines, which exhibits sub G1 phase cell cycle, and further induction of apoptosis is confirmed by a TUNEL assay. Antroquinonol decreases anti-apoptotic proteins, whereas it increases p53 and pro-apoptotic proteins. Alterations of cell morphology are observed after treatment by atomic force microscopy. Molecular docking results reveal that antroquinonol has an H-bond with the Arg 86 residue of FAK. The protein levels of Src, pSrc, FAK, pFAK, Rac1, and cdc42 are decreased after antroquinonol treatment. Additionally, antroquinonol also regulates the expression of epithelial to mesenchymal transition (EMT) proteins. Furthermore, antroquinonol suppresses the C6 glioma growth in xenograft studies. Together, these results suggest that antroquinonol is a potential anti-tumorigenesis and anti-metastasis inhibitor of FAK. PMID:26517117

  17. Histologic classification of gliomas.

    PubMed

    Perry, Arie; Wesseling, Pieter

    2016-01-01

    Gliomas form a heterogeneous group of tumors of the central nervous system (CNS) and are traditionally classified based on histologic type and malignancy grade. Most gliomas, the diffuse gliomas, show extensive infiltration in the CNS parenchyma. Diffuse gliomas can be further typed as astrocytic, oligodendroglial, or rare mixed oligodendroglial-astrocytic of World Health Organization (WHO) grade II (low grade), III (anaplastic), or IV (glioblastoma). Other gliomas generally have a more circumscribed growth pattern, with pilocytic astrocytomas (WHO grade I) and ependymal tumors (WHO grade I, II, or III) as the most frequent representatives. This chapter provides an overview of the histology of all glial neoplasms listed in the WHO 2016 classification, including the less frequent "nondiffuse" gliomas and mixed neuronal-glial tumors. For multiple decades the histologic diagnosis of these tumors formed a useful basis for assessment of prognosis and therapeutic management. However, it is now fully clear that information on the molecular underpinnings often allows for a more robust classification of (glial) neoplasms. Indeed, in the WHO 2016 classification, histologic and molecular findings are integrated in the definition of several gliomas. As such, this chapter and Chapter 6 are highly interrelated and neither should be considered in isolation.

  18. Deletion mapping of gliomas suggests the presence of two small regions for candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q

    SciTech Connect

    Albarosa, R.; Colombo, B.M.; Roz, L.

    1996-06-01

    The loss of genetic material on chromosome 10q is frequent in different tumors and particularly in malignant gliomas. We analyzed 90 of these tumors and found loss of heterozygosity (LOH) in > 90% of the informative loci in glioblastoma multiforme (GBM). Initial studies restricted the common LOH region to 10q24-qter. Subsequently, the study of a pediatric GBM suggested D10S221 and D10S209, respectively, as centromeric and telomeric markers of a 4-cM LOH region. It is interesting to note that, in one subset of cells from this tumor, locus D10S209 seems involved in the allelic imbalance of a larger region, with D10S214 as telomeric marker. This 17-cM region contains the D10S587-D10S216 interval of common deletion recently defined on another set of gliomas. 31 refs., 5 figs., 1 tab.

  19. Comparison of magnetic resonance spectroscopy and positron emission tomography in detection of tumor recurrence in posttreatment of glioma: A diagnostic meta-analysis.

    PubMed

    Wang, Xiaoyue; Hu, Xudong; Xie, Peng; Li, Wanhu; Li, Xiaoling; Ma, Li

    2015-06-01

    It is important to distinguish between tumor recurrence and treatment effects in posttreatment patients with high-grade gliomas. Several imaging modalities have been reported in differentiating between tumor recurrence and treatment effects. However, there were no consistent conclusions between different studies. We performed a meta-analysis of 23 studies that compared the diagnostic values of fluorine-18-fluorodeoxyglucose ((18)F-FDG) and (11)C-methionine ((11)C-MET) PET (positron emission tomography) or PET/CT (computed tomography) and magnetic resonance spectroscopy (MRS) in predicting tumor recurrence of gliomas. The pooled estimated sensitivity, specificity, positive likelihood ratios, negative likelihood ratios and summary receiver operating characteristic curves of (18)F-FDG and (11)C-MET PET or PET/CT and MRS in detecting tumor recurrence were calculated. In conclusion, MRS is highly sensitive in the detection of tumor recurrence in glioma.(18)F-FDG PET or PET/CT is highly specific in recurrence diagnosis. (11)C-MET does not have noticeable advantage over (18)F-FDG. The current evidence shows no statistical difference between MRS and PET on the accuracy.

  20. Effects of the nitric oxide donor JS-K on the blood-tumor barrier and on orthotopic U87 rat gliomas assessed by MRI.

    PubMed

    Weidensteiner, Claudia; Reichardt, Wilfried; Shami, Paul J; Saavedra, Joseph E; Keefer, Larry K; Baumer, Brunhilde; Werres, Anna; Jasinski, Robert; Osterberg, Nadja; Weyerbrock, Astrid

    2013-04-01

    Nitric oxide (NO) released from NO donors can be cytotoxic in tumor cells and can enhance the transport of drugs into brain tumors by altering blood-tumor barrier permeability. The NO donor JS-K [O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] releases NO upon enzymatic activation selectively in cells overexpressing glutathione-S-transferases (GSTs) such as gliomas. Thus, JS-K-dependent NO effects - especially on cell viability and vascular permeability - were investigated in U87 glioma cells in vitro and in an orthotopic U87 xenograft model in vivo by magnetic resonance imaging (MRI). In vitro experiments showed dose-dependent antiproliferative and cytotoxic effects in U87 cells. In addition, treatment of U87 cells with JS-K resulted in a dose-dependent activation of soluble guanylate cyclase and intracellular accumulation of cyclic guanosine monophosphate (cGMP) which was irreversibly inhibited by the selective inhibitor of soluble guanylate cyclase ODQ (1H-[1,2,4]oxadiazolo(4,3a)quinoxaline-1-one). Using dynamic contrast enhanced MRI (DCE-MRI) as a minimally invasive technique, we demonstrated for the first time a significant increase in the DCE-MRI read-out initial area under the concentration curve (iAUC60) indicating an acute increase in blood-tumor barrier permeability after i.v. treatment with JS-K. Repeated MR imaging of animals with intracranial U87 gliomas under treatment with JS-K (3.5 μmol/kg JS-K 3×/week) and of untreated controls on day 12 and 19 after tumor inoculation revealed no significant changes in tumor growth, edema formation or tumor perfusion. Immunohistochemical workup of the brains showed a significant antiproliferative effect of JS-K in the gliomas. Taken together, in vitro and in vivo data suggest that JS-K has antiproliferative effects in U87 gliomas and opens the blood-tumor barrier by activation of the NO/cGMP signaling pathway. This might be a novel approach to facilitate entry of therapeutic

  1. Brain tumor locating in 3D MR volume using symmetry

    NASA Astrophysics Data System (ADS)

    Dvorak, Pavel; Bartusek, Karel

    2014-03-01

    This work deals with the automatic determination of a brain tumor location in 3D magnetic resonance volumes. The aim of this work is not the precise segmentation of the tumor and its parts but only the detection of its location. This work is the first step in the tumor segmentation process, an important topic in neuro-image processing. The algorithm expects 3D magnetic resonance volumes of brain containing a tumor. The detection is based on locating the area that breaks the left-right symmetry of the brain. This is done by multi-resolution comparing of corresponding regions in left and right hemisphere. The output of the computation is the probabilistic map of the tumor location. The created algorithm was tested on 80 volumes from publicly available BRATS databases containing 3D brain volumes afflicted by a brain tumor. These pathological structures had various sizes and shapes and were located in various parts of the brain. The locating performance of the algorithm was 85% for T1-weighted volumes, 91% for T1-weighted contrast enhanced volumes, 96% for FLAIR and T2-wieghted volumes and 95% for their combinations.

  2. SHMT2 drives glioma cell survival in the tumor microenvironment but imposes a dependence on glycine clearance

    PubMed Central

    Kim, Dohoon; Fiske, Brian P.; Birsoy, Kivanc; Freinkman, Elizaveta; Kami, Kenjiro; Possemato, Richard; Chudnovsky, Yakov; Pacold, Michael E.; Chen, Walter W.; Cantor, Jason R.; Shelton, Laura M.; Gui, Dan Y.; Kwon, Manjae; Ramkissoon, Shakti H.; Ligon, Keith L.; Kang, Seong Woo; Snuderl, Matija; Heiden, Matthew G. Vander; Sabatini, David M.

    2015-01-01

    SUMMARY Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumor microenvironment1–3. Here, we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischemic zones of gliomas. In human glioblastoma multiforme (GBM), mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumor regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumor environment, but also renders these cells sensitive to glycine cleavage system inhibition. PMID:25855294

  3. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    NASA Astrophysics Data System (ADS)

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-03-01

    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P < 0.05, P < 0.01, and P < 0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222  ±  784, 3687  ±  796 and 5658  ±  821 ng g-1) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P < 0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are

  4. Anatomical location differences between mutated and wild-type isocitrate dehydrogenase 1 in low-grade gliomas.

    PubMed

    Yu, Jinhua; Shi, Zhifeng; Ji, Chunhong; Lian, Yuxi; Wang, Yuanyuan; Chen, Liang; Mao, Ying

    2017-01-06

    Anatomical location of gliomas has been considered as a factor implicating the contributions of a specific precursor cells during the tumor growth. Isocitrate dehydrogenase 1 (IDH1) is a pathognomonic biomarker with a significant impact on the development of gliomas and remarkable prognostic effect. The correlation between anatomical location of tumor and IDH1 states for low-grade gliomas was analyzed quantitatively in this study. Ninety-two patients diagnosed of low-grade glioma pathologically were recruited in this study, including 65 patients with IDH1-mutated glioma and 27 patients with wide-type IDH1. A convolutional neural network was designed to segment the tumor from three-dimensional magnetic resonance imaging images. Voxel-based lesion symptom mapping was then employed to study the tumor location distribution differences between gliomas with mutated and wild-type IDH1. In order to characterize the location differences quantitatively, the Automated Anatomical Labeling Atlas was used to partition the standard brain atlas into 116 anatomical volumes of interests (AVOIs). The percentages of tumors with different IDH1 states in 116 AVOIs were calculated and compared. Support vector machine and AdaBoost algorithms were used to estimate the IDH1 status based on the 116 location features of each patient. Experimental results proved that the quantitative tumor location measurement could be a very important group of imaging features in biomarker estimation based on radiomics analysis of glioma.

  5. Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes.

    PubMed

    Zhang, Chao; Chen, Wenliang; Zhang, Xin; Huang, Bin; Chen, Aanjing; He, Ying; Wang, Jian; Li, Xingang

    2016-03-15

    Gliomas are among the most lethal primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic mimicry. With suspension microarray technology and in vitro tube formation assays, we identified that astrocytes relied on TGF-β1 to enhance vasculogenic mimicry. We also found that vasculogenic mimicry was inhibited by galunisertib, a promising TGF-β1 inhibitor currently being studied in an ongoing trial in glioma patients. The inhibition was partially attributed to a decrease in autophagy after galunisertib treatment. Moreover, we observed a decrease in VE-cadherin and smooth muscle actin-α expression, as well as down-regulation of Akt and Flk phosphorylation in galunisertib-treated glioma cells. By comparing tumor weight and volume in a xenograft model, we acquired promising results to support our theory. This study expands our understanding of the role of astrocytes in gliomas and demonstrates that galunisertib inhibits glioma vasculogenic mimicry induced by astrocytes.

  6. Visualization of microvascular proliferation as a tumor infiltration structure in rat glioma specimens using the diffraction-enhanced imaging in-plane CT technique

    NASA Astrophysics Data System (ADS)

    Seo, Seung-Jun; Sunaguchi, Naoki; Yuasa, Tetsuya; Huo, Qingkai; Ando, Masami; Choi, Gi-Hwan; Kim, Hong-Tae; Kim, Ki-Hong; Jeong, Eun-Ju; Chang, Won-Seok; Kim, Jong-Ki

    2012-03-01

    In order to study potent microenvironments of malignant gliomas with a high- resolution x-ray imaging technique, an injection orthotopic glioma model was made using the Sprague-Dawley rat. Total brain tissue, taken out as an ex vivo model, was examined with diffraction-enhanced imaging (DEI) computed tomography (CT) acquired with a 35 keV monochromatic x-ray. In the convolution-reconstructed 2D/3D images with a spatial resolution of 12.5 × 12.5 × 25 µm, distinction among necrosis, typical ring-shaped viable tumors, edemas and healthy tissues was clearly observed near the frontal lobe in front of the rat's caudate nucleus. Multiple microvascular proliferations (MVPs) were observed surrounding peritumoral edemas as a tumor infiltration structure. Typical dimensions of tubular MVPs were 130 (diameter) ×250 (length) µm with a partial sprout structure revealed in the 3D reconstructed image. Hyperplasia of cells around vessel walls was revealed with tumor cell infiltration along the perivascular space in microscopic observations of mild MVP during histological analysis. In conclusion, DEI-CT is capable of imaging potent tumor-infiltrating MVP structures surrounding high-grade gliomas.

  7. TERT PROMOTER MUTATIONS OCCUR FREQUENTLY IN GLIOMAS AND A SUBSET OF TUMORS DERIVED FROM CELLS WITH LOW RATES OF SELF-RENEWAL

    PubMed Central

    Yan, Hai; Killela, P.J.; Reitman, Z.J.; Jiao, Y.; Bettegowda, C.; Agrawal, N.; Diaz, L.A.; Friedman, A.H.; Friedman, H.; Gallia, G.L.; Giovanella, B.C.; Grollman, A.P.; He, T.C.; He, Y.; Hruban, R.H.; Jallo, G.I.; Mandahl, N.; Meeker, A.K.; Mertens, F.; Netto, G.J.; Rasheed, B.A.; Riggins, G.J.; Rosenquist, T.A.; Schiffman, M.; Shih, IeM; Theodorescu, D.; Torbenson, M.S.; Velculescu, V.E.; Wang, T.L.; Wentzensen, N.; Wood, L.D.; Zhang, M.; Healy, P.; Yang, R.; Diplas, B.; Wang, Z.H.; Greer, P.; Zhu, H.S.; Wang, C.; Carpenter, A.; Herndon, J.E.; McLendon, R.E.; Kinzler, K.W.; Vogelstein, B.; Papadopoulos, N.; Bigner, D.D.

    2014-01-01

    BACKGROUND: Malignant cells must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas. METHODS: To further define the tumor types in which TERT plays a role, we surveyed 1,230 tumors of 60 different types. We also analyzed the relationship between median overall survival (OS) of patients with IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas with the hypothesis that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. RESULTS: We found that tumors could be divided into types with low and high frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas. TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of

  8. Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells.

    PubMed

    Yin, Jinlong; Park, Gunwoo; Kim, Tae Hoon; Hong, Jun Hee; Kim, Youn-Jae; Jin, Xiong; Kang, Sangjo; Jung, Ji-Eun; Kim, Jeong-Yub; Yun, Hyeongsun; Lee, Jeong Eun; Kim, Minkyung; Chung, Junho; Kim, Hyunggee; Nakano, Ichiro; Gwak, Ho-Shin; Yoo, Heon; Yoo, Byong Chul; Kim, Jong Heon; Hur, Eun-Mi; Lee, Jeongwu; Lee, Seung-Hoon; Park, Myung-Jin; Park, Jong Bae

    2015-05-01

    Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.

  9. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

    PubMed Central

    Stokum, Jesse A.; Schneider, Craig S.; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J.; Kim, Anthony J.; Simard, J. Marc; Winkles, Jeffrey A.; Holland, Eric C.; Woodworth, Graeme F.

    2017-01-01

    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  10. The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients' survival.

    PubMed

    Fogli, Anne; Chautard, Emmanuel; Vaurs-Barrière, Catherine; Pereira, Bruno; Müller-Barthélémy, Mélanie; Court, Franck; Biau, Julian; Pinto, Afonso Almeida; Kémény, Jean-Louis; Khalil, Toufic; Karayan-Tapon, Lucie; Verrelle, Pierre; Costa, Bruno Marques; Arnaud, Philippe

    2016-02-01

    Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ.

  11. Living T9 glioma cells expressing membrane macrophage colony-stimulating factor produce immediate tumor destruction by polymorphonuclear leukocytes and macrophages via a "paraptosis"-induced pathway that promotes systemic immunity against intracranial T9 gliomas.

    PubMed

    Chen, Yijun; Douglass, Thomas; Jeffes, Edward W B; Xu, Qingcheng; Williams, Christopher C; Arpajirakul, Neary; Delgado, Christina; Kleinman, Michael; Sanchez, Ramon; Dan, Qinghong; Kim, Ronald C; Wepsic, H Terry; Jadus, Martin R

    2002-08-15

    Cloned T9-C2 glioma cells transfected with membrane macrophage colony-stimulating factor (mM-CSF) never formed subcutaneous tumors when implanted into Fischer rats, whereas control T9 cells did. The T9-C2 cells were completely killed within 1 day through a mechanism that resembled paraptosis. Vacuolization of the T9-C2 cell's mitochondria and endoplasmic reticulum started within 4 hours after implantation. By 24 hours, the dead tumor cells were swollen and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive. Bcl2-transduced T9-C2 cells failed to form tumors in rats. Both T9 and T9-C2 cells produced cytokine-induced neutrophil chemoattractant that recruited the granulocytes into the tumor injection sites, where they interacted with the tumor cells. Freshly isolated macrophages killed the T9-C2 cells in vitro by a mechanism independent of phagocytosis. Nude athymic rats treated with antiasialo GM1 antibody formed T9-C2 tumors, whereas rats treated with a natural killer cell (NK)-specific antibody failed to form tumors. When treated with antipolymorphonuclear leukocyte (anti-PMN) and antimacrophage antibodies, 80% of nude rats formed tumors, whereas only 40% of the rats developed a tumor when a single antibody was used. This suggests that both PMNs and macrophages are involved in the killing of T9-C2 tumor cells. Immunocompetent rats that rejected the living T9-C2 cells were immune to the intracranial rechallenge with T9 cells. No vaccinating effect occurred if the T9-C2 cells were freeze-thawed, x-irradiated, or treated with mitomycin-C prior to injection. Optimal tumor immunization using mM-CSF-transduced T9 cells requires viable tumor cells. In this study optimal tumor immunization occurred when a strong inflammatory response at the injection of the tumor cells was induced.

  12. Increasing of Blood-Brain Tumor Barrier Permeability through Transcellular and Paracellular Pathways by Microbubble-Enhanced Diagnostic Ultrasound in a C6 Glioma Model

    PubMed Central

    Zhang, Jinlong; Liu, Heng; Du, Xuesong; Guo, Yu; Chen, Xiao; Wang, Shunan; Fang, Jingqin; Cao, Peng; Zhang, Bo; Liu, Zheng; Zhang, Weiguo

    2017-01-01

    Most of the anticancer agents cannot be efficiently delivered into the brain tumor because of the existence of blood-brain tumor barrier (BTB). The objective of this study was to explore the effect of microbubble-enhanced diagnostic ultrasound (MEUS) on the BTB permeability and the possible mechanism. Glioma-bearing rats were randomized into three groups as follows: the microbubble-enhanced continued diagnostic ultrasound (MECUS) group; the microbubble-enhanced intermittent diagnostic ultrasound (MEIUS) group and the control group. The gliomas were insonicated through the skull with a diagnostic ultrasound and injected with microbubbles through the tail veins. Evans Blue (EB) and dynamic contrast-enhanced-MRI were used to test changes in the BTB permeability. Confocal laser scanning microscopy was used to observe the deposition of the EB in the tumor tissues. The distribution and expression of junctional adhesion molecule-A (JAM-A) and calcium-activated potassium channels (KCa channels) were detected by a Western blot, qRT-PCR, and immunohistochemical staining. In the MEUS groups, the EB extravasation (11.0 ± 2.2 μg/g in MECUS group and 17.9 ± 2.3 μg/g in MEIUS group) exhibited a significant increase compared with the control group (5.3 ± 0.9 μg/g). The MEIUS group had more EB extravasation than the MECUS group. The Ktrans value of the dynamic contrast-enhanced-MRI in the MEUS groups was higher than that of the control group and correlated strongly with the EB extravasation in the tumor (R2 = 0.97). This showed that the Ktrans value might be a non-invasive method to evaluate the BTB permeability in rat glioma after microbubble-enhanced ultrasound treatment.Western blot, qRT-PCR and immunohistochemical staining revealed that MEUS increased the KCa channels expression and reduced JAM-A expression in glioma. This change was more obvious in the MEIUS group than in the MECUS group. The results demonstrated that MEUS effectively increased the BTB permeability in

  13. Unsupervised measurement of brain tumor volume on MR images.

    PubMed

    Velthuizen, R P; Clarke, L P; Phuphanich, S; Hall, L O; Bensaid, A M; Arrington, J A; Greenberg, H M; Silbiger, M L

    1995-01-01

    We examined unsupervised methods of segmentation of MR images of the brain for measuring tumor volume in response to treatment. Two clustering methods were used: fuzzy c-means and a nonfuzzy clustering algorithm. Results were compared with volume segmentations by two supervised methods, k-nearest neighbors and region growing, and all results were compared with manual labelings. Results of individual segmentations are presented as well as comparisons on the application of the different methods with 10 data sets of patients with brain tumors. Unsupervised segmentation is preferred for measuring tumor volumes in response to treatment, as it eliminates operator dependency and may be adequate for delineation of the target volume in radiation therapy. Some obstacles need to be overcome, in particular regarding the detection of anatomically relevant tissue classes. This study shows that these improvements are possible.

  14. Autophagy and the functional roles of Atg5 and beclin-1 in the anti-tumor effects of 3beta androstene 17alpha diol neuro-steroid on malignant glioma cells.

    PubMed

    Graf, Martin R; Jia, Wentao; Johnson, Ross S; Dent, Paul; Mitchell, Clint; Loria, Roger M

    2009-07-01

    In this study, we demonstrate that the anti-tumor activity of the neuro-steroid, 3beta androstene 17alpha diol (17alpha-AED) on malignant glioma cells is mediated by the induction of autophagy. 17alpha-AED can inhibit the proliferation an induce cell death of multiple, unrelated gliomas with an IC(50) between 8 and 25muM. 17alpha-AED treatment induced the formation of autophagosomes and acidic vesicular organelles in human malignant gliomas which was blocked by bafilomycin A1 or 3-methyladenine. Cleavage of microtubule-associated protein-light chain 3 (LC3), an essential step in autophagosome formation, was detected in human malignant glioma cells exposed to 17alpha-AED. In 17alpha-AED treated T98G glioma cells there was an increase in the autophagy related proteins Atg5 and beclin-1. Silencing of ATG5 or beclin-1 with small interfering RNA significantly reduced the incidence of autophagy in 17alpha-AED treated malignant gliomas and attenuated the cytotoxic effects of the neuro-steroid indicating that the induction of autophagy mediates the anti-glioma activity of 17alpha-AED rather than serving as a cyto-protective response. These results demonstrate that 17alpha-AED possesses significant anti-glioma activity when used at pharmacologically relevant concentrations in vitro and the cytotoxic effects are resultant from the induction of autophagy.

  15. Photochemical internalization (PCI) enhanced nonviral transfection of tumor suppressor and pro-drug activating genes; a potential treatment modality for gliomas

    NASA Astrophysics Data System (ADS)

    Wang, Frederick; Zamora, Genesis; Sun, Chung-Ho; Trinidad, Anthony; Berg, Kristian; Madsen, Steen; Kwon, Young Jik; Hirschberg, Henry

    2014-03-01

    The overall objective of the research is to investigate the utility of photochemical internalization for the enhanced nonviral transfection of genes into cells. We have examined, in detail, the evaluation of photochemical internalization (PCI) as a method for the non-viral introduction of the tumor suppressor gene PTEN and the PCI mediated transfection of the cytosine deaminase (CD) pro drug activating gene into glioma cell monolayers and multi-cell tumor spheroids. Expression of the CD gene within the target cell produces an enzyme that converts the nontoxic prodrug, 5-fluorocytosine (5-FC), to the toxic metabolite, 5-fluorouracil (5-FU).

  16. Comparison of CT and MRI brain tumor imaging using a canine glioma model.

    PubMed

    Whelan, H T; Clanton, J A; Wilson, R E; Tulipan, N B

    1988-01-01

    A canine gliosarcoma model was used to study the effectiveness of magnetic resonance imaging (MRI) with gadolinium contrast enhancement in defining the histologic margins of brain tumors. The effectiveness of this technique was compared to conventional computed tomography (CT) using iodinated contrast enhancement. Cultured canine gliosarcoma cells were injected into the left hemisphere of adult mongrel dogs. The dogs developed brain tumors and progressive clinical signs. Serial MRI with and without gadolinium diethylene triamine penta-acetic acid was compared to serial CT with and without sodium iothalamate obtained on the same days. After the final scans, animals were sacrificed; the brains were removed and processed for routine histopathologic study. All tumors were visualized with contrast-enhanced MRI which proved most sensitive. Gadolinium di-ethylene triamine penta-acetic acid caused bright enhancement of tumors in a distribution that consistently corresponded to areas of pathologically proved tumor infiltration. Gross and microscopic autopsy findings correlated better with MRI than with CT which tended to produce poorer resolution and underrepresent the size of viable tumor. Gadolinium-enhanced MRI is more accurate than unenhanced MRI, unenhanced CT, or enhanced CT in defining the histologic margins of tumors.

  17. Probing the infiltrating character of brain tumors: inhibition of RhoA/ROK-mediated CD44 cell surface shedding from glioma cells by the green tea catechin EGCg.

    PubMed

    Annabi, Borhane; Bouzeghrane, Mounia; Moumdjian, Robert; Moghrabi, Albert; Béliveau, Richard

    2005-08-01

    Glioma cell-surface binding to hyaluronan (HA), a major constituent of the brain extracellular matrix (ECM) environment, is regulated through a complex membrane type-1 matrix metalloproteinase (MT1-MMP)/CD44/caveolin interaction that takes place at the leading edges of invading cells. In the present study, intracellular transduction pathways required for the HA-mediated recognition by infiltrating glioma cells in brain was investigated. We show that the overexpression of the GTPase RhoA up-regulated MT1-MMP expression and triggered CD44 shedding from the U-87 glioma cell surface. This potential implication in cerebral metastatic processes was also observed in cells overexpressing the full-length recombinant MT1-MMP, while the overexpression of a cytoplasmic domain truncated from of MT1-MMP failed to do so. This suggests that the cytoplasmic domain of MT1-MMP transduces intracellular signaling leading to RhoA-mediated CD44 shedding. Treatment of glioma cells with the Rho-kinase (ROK) inhibitor Y27632, or with EGCg, a green tea catechin with anti-MMP and anti-angiogenesis activities, antagonized both RhoA- and MT1-MMP-induced CD44 shedding. Conversely, overexpression of recombinant ROK stimulated CD44 release. Taken together, our results suggest that RhoA/ROK intracellular signaling regulates MT1-MMP-mediated CD44 recognition of HA. These molecular processes may partly explain the diffuse brain-infiltrating character of glioma cells within the surrounding parenchyma and thus be a target for new approaches to anti-tumor therapy.

  18. Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model.

    PubMed

    Grasso, Carole; Fabre, Marie-Sophie; Collis, Sarah V; Castro, M Leticia; Field, Cameron S; Schleich, Nanette; McConnell, Melanie J; Herst, Patries M

    2014-01-01

    Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8-45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant.

  19. Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.

    PubMed

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

    2014-01-01

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

  20. Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1- 13C]pyruvate and 13C magnetic resonance spectroscopic imaging.

    PubMed

    Day, Sam E; Kettunen, Mikko I; Cherukuri, Murali Krishna; Mitchell, James B; Lizak, Martin J; Morris, H Douglas; Matsumoto, Shingo; Koretsky, Alan P; Brindle, Kevin M

    2011-02-01

    We show here that hyperpolarized [1-(13) C]pyruvate can be used to detect treatment response in a glioma tumor model; a tumor type where detection of response with (18) fluoro-2-deoxyglucose, using positron emission tomography, is limited by the high background signals from normal brain tissue. (13) C chemical shift images acquired following intravenous injection of hyperpolarized [1-(13) C]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but comparatively low levels in surrounding brain.Labeled pyruvate was observed at high levels in blood vessels above the brain and from other major vessels elsewhere but was detected at only low levels in tumor and brain.The ratio of hyperpolarized (13) C label in tumor lactate compared to the maximum pyruvate signal in the blood vessels was decreased from 0.38 ± 0.16 to 0.23 ± 0.13, (a reduction of 34%) by 72 h following whole brain irradiation with 15 Gy.

  1. Autologous tumor cell vaccination plus infusion of GM-CSF by a programmable pump in the treatment of recurrent malignant gliomas.

    PubMed

    Clavreul, Anne; Piard, Nicole; Tanguy, Jean-Yves; Gamelin, Eric; Rousselet, Marie-Christine; Leynia, Pierre; Menei, Philippe

    2010-07-01

    We report on the safety and feasibility of autologous tumor cell vaccination combined with infusion of granulocyte-macrophage colony-stimulating factor by a programmable pump in the treatment of recurrent malignant gliomas. The programmable pump is a promising tool used to infuse cytokines subcutaneously for vaccination. Our trial enrolled nine patients who had undergone surgery, radiation and had been successfully weaned off steroids. Unfortunately, only five patients completed the protocol and were monitored for side effects, local reactions, delayed-type hypersensitivity (DTH) responses and survival. The treatment was well tolerated. Two patients developed DTH reactions after vaccination and three patients had an unusually long survival without any other treatment. Despite the few patients treated, the results of this trial are encouraging. This study also highlights the specific difficulties encountered in vaccination programs for the treatment of glioma.

  2. Autocrine VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

    PubMed Central

    Hamerlik, Petra; Lathia, Justin D.; Rasmussen, Rikke; Wu, Qiulian; Bartkova, Jirina; Lee, MyungHee; Moudry, Pavel; Bartek, Jiri; Fischer, Walter; Lukas, Jiri

    2012-01-01

    Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133+ human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2–Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF–VEGFR2–NRP1, which is associated with VEGFR2–NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF–VEGFR2–NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach. PMID:22393126

  3. Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improves outcomes in a rat glioma model

    PubMed Central

    Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; Park, Juyoung; McDannold, Nathan

    2013-01-01

    The blood-brain-barrier (BBB) prevents the transport of most anticancer agents to the central nervous system and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels, along with several other factors, creates additional barriers for drug treatment for brain tumors. Focused ultrasound (FUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and the “blood-tumor barrier”. Here, we tested the impact of three weekly sessions of FUS and liposomal doxorubicin (DOX) in 9L rat glioma tumors. Animals that received FUS + DOX (N = 8) had a median survival time that was increased significantly (P < 0.001) compared to animals who received DOX only (N = 6), FUS only (N = 8), or no treatment (N = 7). Median survival for animals that received FUS + DOX was increased by 100% relative to untreated controls, whereas animals who received DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS + DOX group, and in two animals, only a few tumor cells were detected. Adverse events in the treatment group included skin toxicity, impaired activity, damage to surrounding brain tissue, and tissue loss at the tumor site. In one animal, intratumoral hemorrhage was observed. These events are largely consistent with known side effects of doxorubicin and with an extensive tumor burden. Overall this work demonstrates that multiple sessions using this FUS technique to enhance the delivery of liposomal doxorubicin has a pronounced therapeutic effect in this rat glioma model. PMID:23603615

  4. Liposome encapsulated of temozolomide for the treatment of glioma tumor: preparation, characterization and evaluation.

    PubMed

    Gao, Jinhua; Wang, Zhonglan; Liu, Honghai; Wang, Longmei; Huang, Guihua

    2015-06-01

    Temozolomide plays a critical role in curing glioma at present. The purpose of this work was to develop a suitable drug delivery system which could prolong the half-life, improve the brain targeting, and reduce the systemic effect of the drug. Temozolomide-liposomes were formulated by the method of proliposomes. They were found to be relatively uniform in size of 156.70 ± 11.40 nm with a narrow polydispersity index (PI) of 0.29 ± 0.04. The average drug entrapment efficiency and loading capacity were 35.45 ± 1.48% and 2.81 ± 0.20%, respectively. The pH of temozolomide-liposomes was 6.46. In vitro release studies were conducted by a dynamic dialysis. The results showed that temozolomide released slowly from liposomes compared with the solution group. The release behavior of temozolomide-liposomes was in line with First-order kinetics and Weibull equation. The pharmacokinetics study was evaluated by pharmacokinetics parameters. The t(1/2β) and MRT of temozolomide-liposomes were 3.57 times and 1.27 times greater than that of temozolomide solution. The Cmax and AUC values of temozolomide-liposomes were 1.10 times and 1.55 times greater than that of temozolomide solution. The results of pharmacokinetics study showed temozolomide-liposomes prolonged the in vivo circulation time and increased AUC. Furthermore, the biodistribution in mice showed that temozolomide-liposomes preferentially decreased the accumulation of temozolomide in heart and lung and increased the drug concentration in brain after i.v. injection, which implied that temozolomide-liposomes improved the therapeutic effect in the brain and reduced the toxicity in lung and heart.

  5. Progression of motor deficits in glioma-bearing mice: impact of CNF1 therapy at symptomatic stages.

    PubMed

    Vannini, Eleonora; Maltese, Federica; Olimpico, Francesco; Fabbri, Alessia; Costa, Mario; Caleo, Matteo; Baroncelli, Laura

    2017-02-15

    Glioblastoma (GBM) is the most aggressive type of brain tumor. In this context, animal models represent excellent tools for the early detection and longitudinal mapping of neuronal dysfunction, that are critical in the preclinical validation of new therapeutic strategies. In a mouse glioma model, we developed sensitive behavioral readouts that allow early recognizing and following neurological symptoms. We injected GL261 cells into the primary motor cortex of syngenic mice and we used a battery of behavioral tests to longitudinally monitor the dysfunction induced by tumor growth. Grip strength test revealed an early onset of functional deficit associated to the glioma growth, with a significant forelimb weakness appearing 9 days after tumor inoculation. A later deficit was observed in the rotarod and in the grid walk tasks. Using this model, we found reduced tumor growth and maintenance of behavioral functions following treatment with Cytotoxic Necrotizing Factor 1 (CNF1) at a symptomatic stage. Our data provide a detailed and precise examination of how tumor growth reverberates on the behavioral functions of glioma-bearing mice, providing normative data for the study of therapeutic strategies for glioma treatment. The reduced tumor volume and robust functional sparing observed in CNF1-treated, glioma-bearing mice strengthen the notion that CNF1 delivery is a promising strategy for glioma therapy.

  6. Single-session Gamma Knife radiosurgery for optic pathway/hypothalamic gliomas.

    PubMed

    El-Shehaby, Amr M N; Reda, Wael A; Abdel Karim, Khaled M; Emad Eldin, Reem M; Nabeel, Ahmed M

    2016-12-01

    OBJECTIVE Because of their critical and central location, it is deemed necessary to fractionate when considering irradiating optic pathway/hypothalamic gliomas. Stereotactic fractionated radiotherapy is considered safer when dealing with gliomas in this location. In this study, the safety and efficacy of single-session stereotactic radiosurgery for optic pathway/hypothalamic gliomas were reviewed. METHODS Between December 2004 and June 2014, 22 patients with optic pathway/hypothalamic gliomas were treated by single-session Gamma Knife radiosurgery. Twenty patients were available for follow-up for a minimum of 1 year after treatment. The patients were 5 to 43 years (median 16 years) of age. The tumor volume was 0.15 to 18.2 cm(3) (median 3.1 cm(3)). The prescription dose ranged from 8 to 14 Gy (median 11.5 Gy). RESULTS The mean follow-up period was 43 months. Five tumors involved the optic nerve only, and 15 tumors involved the chiasm/hypothalamus. Two patients died during the follow-up period. The tumors shrank in 12 cases, remained stable in 6 cases, and progressed in 2 cases, thereby making the tumor control rate 90%. Vision remained stable in 12 cases, improved in 6 cases, and worsened in 2 cases in which there was tumor progression. Progression-free survival was 83% at 3 years. CONCLUSIONS The initial results indicate that single-session Gamma Knife radiosurgery is a safe and effective treatment option for optic pathway/hypothalamic gliomas.

  7. 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

  8. 70-kDa heat shock protein coated magnetic nanocarriers as a nanovaccine for induction of anti-tumor immune response in experimental glioma.

    PubMed

    Shevtsov, Maxim A; Nikolaev, Boris P; Yakovleva, Liudmila Y; Parr, Marina A; Marchenko, Yaroslav Y; Eliseev, Igor; Yudenko, Anna; Dobrodumov, Anatolii V; Zlobina, Olga; Zhakhov, Alexander; Ischenko, Alexander M; Pitkin, Emil; Multhoff, Gabriele

    2015-12-28

    Nanovaccines based on superparamagnetic iron oxide nanoparticles (SPIONs) provide a novel approach to induce the humoral and cell-based immune system to fight cancer. Herein, we increased the immunostimulatory capacity of SPIONs by coating them with recombinant heat shock protein 70 (Hsp70) which is known to chaperone antigenic peptides. After binding, Hsp70-SPIONs deliver immunogenic peptides from tumor lysates to dendritiс cells (DCs) and thus stimulate a tumor-specific, CD8+ cytotoxic T cell response. We could show that binding activity of Hsp70-SPIONs to the substrate-binding domain (SBD) is highly dependent on the ATPase activity of its nucleotide-binding domain NBD), as shown by (31)P NMR spectroscopy. Immunization of C6 glioma-bearing rats with DCs pulsed with Hsp70-SPIONs and tumor lysates resulted in a delayed tumor progression (as measured by MRI) and an increased overall survival. In parallel an increased IFNγ secretion were detected in the serum of these animals and immunohistological analysis of subsequent cryosections of the glioma revealed an enhanced infiltration of memory CD45RO+ and cytotoxic CD8+ T cells. Taken together the study demonstrates that magnetic nanocarriers such as SPIONs coated with Hsp70 can be applied as a platform for boosting anti-cancer immune responses.

  9. Standard of care and future pharmacological treatment options for malignant glioma: an urgent need for screening and identification of novel tumor-specific antigens

    PubMed Central

    Batich, Kristen A

    2015-01-01

    Introduction Malignant gliomas (MGs) represent the most common primary brain tumors in adults, the most deadly of which is grade IV glioblastoma. Patients with glioblastoma undergoing current standard-of-care therapy have a median survival of 12 – 15 months. Areas covered Over the past 25 years, there have been modest advancements in the treatment of MGs. Assessment of therapeutic responses has continued to evolve to account for the increasing number of agents being tested in the clinic. Currently approved therapies for primary tumors have been extended for use in the setting of recurrent disease with modest efficacy. Agents initially approved for recurrent gliomas have begun to demonstrate efficacy against de novo tumors but will ultimately need to be evaluated in future studies for scheduling, timing and dosing relative to chemotherapy. Expert opinion Screening and identification of tumor-specific mutations is critical for the advancement of effective therapy that is both safe and precise for the patient. Two unique antigens found in glioblastoma are currently being employed as targets for immunotherapeutic vaccines, one of which has advanced to Phase III testing. Whole genome sequencing of MGs has yielded two other novel mutations that offer great promise for the development of molecular inhibitors. PMID:25139628

  10. Clinical investigation survival prediction in high-grade gliomas by MRI perfusion before and during early stage of RT

    SciTech Connect

    Cao Yue . E-mail: yuecao@med.umich.edu; Tsien, Christina I.; Nagesh, Vijaya; Junck, Larry; Haken, Randall ten; Ross, Brian D.; Chenevert, Thomas L.; Lawrence, Theodore S.

    2006-03-01

    Purpose: To determine whether cerebral blood volume (CBV) and cerebral blood flow can predict the response of high-grade gliomas to radiotherapy (RT) by taking into account spatial heterogeneity and temporal changes in perfusion. Methods and Materials: Twenty-three patients with high-grade gliomas underwent conformal RT, with magnetic resonance imaging perfusion before and at Weeks 1-2 and 3-4 during RT. Tumor perfusion was classified as high, medium, or low. The prognostic values of pre-RT perfusion and the changes during RT for early prediction of tumor response to RT were evaluated. Results: The fractional high-CBV tumor volume before RT and the fluid-attenuated inversion recovery imaging tumor volume were identified as predictors for survival (p = 0.01). Changes in tumor CBV during the early treatment course also predicted for survival. Better survival was predicted by a decrease in the fractional low-CBV tumor volume at Week 1 of RT vs. before RT, a decrease in the fractional high-CBV tumor volume at Week 3 vs. Week 1 of RT, and a smaller pre-RT fluid-attenuated inversion recovery imaging tumor volume (p = 0.01). Conclusion: Early temporal changes during RT in heterogeneous regions of high and low perfusion in gliomas might predict for different physiologic responses to RT. This might also open the opportunity to identify tumor subvolumes that are radioresistant and might benefit from intensified RT.

  11. Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth

    PubMed Central

    Kaul, Aparna; Toonen, Joseph A.; Cimino, Patrick J.; Gianino, Scott M.; Gutmann, David H.

    2015-01-01

    Background Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth. Methods Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma–bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction. Results Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma–associated retinal ganglion cell loss and nerve fiber layer thinning. Conclusion These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1–optic pathway glioma clinical trials. PMID:25534823

  12. A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702)

    PubMed Central

    Stokland, Tore; Liu, Jo-Fen; Ironside, James W.; Ellison, David W.; Taylor, Roger; Robinson, Kathryn J.; Picton, Susan V.; Walker, David A.

    2010-01-01

    The purpose of this study was to identify risk factors for the progression of low-grade glioma in children from a large population-based cohort. Patient and tumor details of a national cohort of children with low-grade glioma, recruited into an international multidisciplinary clinical strategy, were subjected to univariate and multivariate analyses of progression-free survival and overall survival. From the cohort of 798 patients, 639 patients were eligible, with a median age 6.71 years (0.26–16.75 years); 49% were males; 15.9% had neurofibromatosis type 1, 63.7% pilocytic astrocytoma, 5.9% fibrillary astrocytoma, 4.2% mixed neuronal-glial tumors, and 3.6% others; 21.1% were diagnosed clinically. Anatomically implicated were 31.6% cerebellum, 24.6% chiasma/hypothalamus, 16.0% cerebral hemispheres, 9.9% brain stem, 6.1% other supratentorial midline structures, 5.9% optic nerve only, 4.5% spinal cord, and 1.4% others. The 5-year overall survival and progression-free survival in the whole cohort were 94.6% and 69.4%, respectively. There was a significant association between age and site (P < .001) and extent of tumor resection and site (P < .001). Multivariate analysis identified young age, fibrillary astrocytoma, and extent of surgical resection as significant independent risk factors for progression. Hypothalamic/chiasmatic tumors demonstrated the most sustained tendency to progress. In conclusion, the influence of age and anatomical site upon the risk of tumor progression suggests that these factors strongly influence tumor behavior for the majority of pilocytic tumors. Age <1 year and 1–5 years, fibrillary histology, completeness of resection, and chiasmatic location are candidates for stratification in future studies. PMID:20861086

  13. Cognitive Rehabilitation in Patients with Gliomas and Other Brain Tumors: State of the Art

    PubMed Central

    Lombardi, G.; Pambuku, A.; Della Puppa, A.; Bellu, L.; D'Avella, D.; Zagonel, V.

    2016-01-01

    Disease prognosis is very poor in patients with brain tumors. Cognitive deficits due to disease or due to its treatment have an important weight on the quality of life of patients and caregivers. Studies often take into account quality of life as a fundamental element in the management of disease and interventions have been developed for cognitive rehabilitation of neuropsychological deficits with the aim of improving the quality of life and daily-life autonomy of patients. In this literature review, we will consider the published studies of cognitive rehabilitation over the past 20 years. PMID:27493954

  14. Molecular classification of gliomas.

    PubMed

    Masui, Kenta; Mischel, Paul S; Reifenberger, Guido

    2016-01-01

    The identification of distinct genetic and epigenetic profiles in different types of gliomas has revealed novel diagnostic, prognostic, and predictive molecular biomarkers for refinement of glioma classification and improved prediction of therapy response and outcome. Therefore, the new (2016) World Health Organization (WHO) classification of tumors of the central nervous system breaks with the traditional principle of diagnosis based on histologic criteria only and incorporates molecular markers. This will involve a multilayered approach combining histologic features and molecular information in an "integrated diagnosis". We review the current state of diagnostic molecular markers for gliomas, focusing on isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) gene mutation, α-thalassemia/mental retardation syndrome X-linked (ATRX) gene mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutation in adult tumors, as well as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and H3 histone family 3A (H3F3A) aberrations in pediatric gliomas. We also outline prognostic and predictive molecular markers, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and discuss the potential clinical relevance of biologic glioblastoma subtypes defined by integration of multiomics data. Commonly used methods for individual marker detection as well as novel large-scale DNA methylation profiling and next-generation sequencing approaches are discussed. Finally, we illustrate how advances in molecular diagnostics affect novel strategies of targeted therapy, thereby raising new challenges and identifying new leads for personalized treatment of glioma patients.

  15. Steroid requirements during radiotherapy for malignant gliomas.

    PubMed

    Marantidou, Athina; Levy, Christine; Duquesne, Alyette; Ursu, Renata; Bailon, Olivier; Coman, Irene; Belin, Catherine; Carpentier, Antoine F

    2010-10-01

    Radiotherapy (RT) is the standard treatment for high-grade gliomas. However, toxicity may develop during RT, such as brain edema or worsening of neurological symptoms. Surprisingly, no dedicated study had focused on steroid requirements during RT in adult patients with malignant gliomas. We evaluated prospectively all patients with malignant gliomas treated by RT in a single center from July 2006 to May 2009. Age, sex, initial Karnofsky performance status (KPS), tumor localization and histology, type of surgical resection, clinical target volume, total dose and duration of RT, concomitant treatment with temozolomide, and steroid dosage during RT and at 1 and 3 months after RT were recorded in all patients. Most of the 80 patients (70%) were already taking steroids before RT. Half of them (55%) required initiation or further steroids increase during RT. The median time to steroid increase was 8 days. Only 13% of patients remained free of steroids during RT, and the mean maximal dosage of prednisone was 55 ± 48 mg. At 3 months after RT, 29% of patients were free of steroids, and the mean prednisone dosage was 32 ± 50 mg. Unresected tumors and initial KPS ≤80% were the only variables associated with higher steroid requirements on multivariate analysis. In our series, almost all patients required steroids during RT. Poor initial KPS and biopsy were associated with higher steroid requirements.

  16. Pharmacological Doses of Daily Ascorbate Protect Tumors from Radiation Damage after a Single Dose of Radiation in an Intracranial Mouse Glioma Model

    PubMed Central

    Grasso, Carole; Fabre, Marie-Sophie; Collis, Sarah V.; Castro, M. Leticia; Field, Cameron S.; Schleich, Nanette; McConnell, Melanie J.; Herst, Patries M.

    2014-01-01

    Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8–45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant. PMID:25566497

  17. Inhibition of autophagy induced by quercetin at a late stage enhances cytotoxic effects on glioma cells.

    PubMed

    Bi, Yunke; Shen, Chen; Li, Chenguang; Liu, Yaohua; Gao, Dandan; Shi, Chen; Peng, Fei; Liu, Zhendong; Zhao, Boxian; Zheng, Zhixing; Wang, Xiaoxiong; Hou, Xu; Liu, Huailei; Wu, Jianing; Zou, Huichao; Wang, Kaikai; Zhong, Chen; Zhang, Jiakang; Shi, Changbin; Zhao, Shiguang

    2016-03-01

    Glioma is the most common primary brain tumor in the central nervous system (CNS) with high morbidity and mortality in adults. Although standardized comprehensive therapy has been adapted, the prognosis of glioma patients is still frustrating and thus novel therapeutic strategies are urgently in need. Quercetin (Quer), an important flavonoid compound found in many herbs, is shown to be effective in some tumor models including glioma. Recently, it is reported that adequate regulation of autophagy can strengthen cytotoxic effect of anticancer drugs. However, it is not yet fully clear how we should modulate autophagy to achieve a satisfactory therapeutic effect. 3-Methyladenine (3-MA) and Beclin1 short hairpin RNA (shRNA) were used to inhibit the early stage of autophage while chloroquine (CQ) to inhibit the late stage. MTT assay was implemented to determine cell viability. Transmission electron microscopy, western blot, and immunohistochemistry were adopted to evaluate autophagy. Western blot, flow cytometry, and immunohistochemistry were used to detect apoptosis. C6 glioma xenograft models were established to assess the therapeutic effect (the body weight change, the median survival time, and tumor volume) in vivo. Quercetin can inhibit cell viability and induce autophagy of U87 and U251 glioma cells in a dose-dependent manner. Inhibition of early-stage autophagy by 3-MA or shRNA against Beclin1 attenuated the quercetin-induced cytotoxicity. In contrast, suppression of autophagy at a late stage by CQ enhanced the anti-glioma efficiency of quercetin. Therapeutic effect of quercetin for malignant glioma can be strengthened by inhibition of autophagy at a late stage, not initial stage, which may provide a novel opportunity for glioma therapy.

  18. Targeted Next-Generation Sequencing in Molecular Subtyping of Lower-Grade Diffuse Gliomas: Application of the World Health Organization's 2016 Revised Criteria for Central Nervous System Tumors.

    PubMed

    Carter, Jamal H; McNulty, Samantha N; Cimino, Patrick J; Cottrell, Catherine E; Heusel, Jonathan W; Vigh-Conrad, Katinka A; Duncavage, Eric J

    2017-03-01

    The 2007 World Health Organization Classification of Tumours of the Central Nervous System classifies lower-grade gliomas [LGGs (grades II to III diffuse gliomas)] morphologically as astrocytomas or oligodendrogliomas, and tumors with unclear ambiguous morphology as oligoastrocytomas. The World Health Organization's newly released (2016) classification incorporates molecular data. A single, targeted next-generation sequencing (NGS) panel was used for detecting single-nucleotide variation and copy number variation in 50 LGG cases originally classified using the 2007 criteria, including 36 oligoastrocytomas, 11 oligodendrogliomas, 2 astrocytomas, and 1 LGG not otherwise specified. NGS results were compared with those from IHC analysis and fluorescence in situ hybridization to assess concordance and to categorize the tumors according to the 2016 criteria. NGS results were concordant with those from IHC analysis in all cases. In 3 cases, NGS was superior to fluorescence in situ hybridization in distinguishing segmental chromosomal losses from whole-arm deletions. The NGS approach was effective in reclassifying 36 oligoastrocytomas as 30 astrocytomas (20 IDH1/2 mutant and 10 IDH1/2 wild type) and 6 oligodendrogliomas, and 1 oligodendroglioma as an astrocytoma (IDH1/2 mutant). Here we show that a single, targeted NGS assay can serve as the sole testing modality for categorizing LGG according to the World Health Organization's 2016 diagnostic scheme. This modality affords greater accuracy and efficiency while reducing specimen tissue requirements compared with multimodal approaches.

  19. Pten signaling in gliomas.

    PubMed Central

    Knobbe, Christiane B.; Merlo, Adrian; Reifenberger, Guido

    2002-01-01

    In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas. PMID:12084351

  20. [Therapeutic strategies and prospects of gliomas].

    PubMed

    Taillibert, Sophie; Pedretti, Marta; Sanson, Marc

    2004-10-23

    The prognosis and the treatment of gliomas depend on age, performance status and histological grade. Symptomatic treatment relies on steroids against cerebral edema, anti-epileptic drugs for seizures and perioperatively, prevention of thrombo-embolism and digestive complications, physiotherapy. Specific therapies include surgery, radiotherapy and chemotherapy. Surgery is necessary for histological diagnosis. In low grade gliomas, it has a significant impact in terms of survival. In malignant gliomas, surgery provides symptomic relief without clearly improving survival. Radiation therapy has been shown to improve survival in malignant glioma, but not in asymptomatic low grade tumors. Chemotherapy has a modest efficacy in glioblastomas, whereas oligodendrogliomas with 1p 19q deletion are chemosensitive tumors.

  1. MiRNA-181b suppresses IGF-1R and functions as a tumor suppressor gene in gliomas.

    PubMed

    Shi, Zhu-Mei; Wang, Xie-Feng; Qian, Xu; Tao, Tao; Wang, Lin; Chen, Qiu-Dan; Wang, Xi-Rui; Cao, Lei; Wang, Ying-Yi; Zhang, Jun-Xia; Jiang, Tao; Kang, Chun-Sheng; Jiang, Bing-Hua; Liu, Ning; You, Yong-Ping

    2013-04-01

    MicroRNAs (miRNAs) are single-stranded, 18- to 23-nt RNA molecules that function as regulators of gene expression. Previous studies have shown that microRNAs play important roles in human cancers, including gliomas. Here, we found that expression levels of miR-181b were decreased in gliomas, and we identified IGF-1R as a novel direct target of miR-181b. MiR-181b overexpression inhibited cell proliferation, migration, invasion, and tumorigenesis by targeting IGF-1R and its downstream signaling pathways, PI3K/AKT and MAPK/ERK1/2. Overexpression of IGF-1R rescued the inhibitory effects of miR-181b. In clinical specimens, IGF-1R was overexpressed, and its protein levels were inversely correlated with miR-181b expression. Taken together, our results indicate that miR-181b functions in gliomas to suppress growth by targeting the IGF-1R oncogene and that miR-181b may serve as a novel therapeutic target for gliomas.

  2. Comprehensive management of head and neck tumors, volume 1

    SciTech Connect

    Thawley, S.E.; Panje, W.R.

    1987-01-01

    This book consists of 14 parts, each containing several papers. The parts are: General Considerations in the Management of Patients with Head and Neck Tumors, Tumors of the Ear, Tumors of the Nasal Cavity and Paranasal Sinuses, Tumors of the Oral Cavity, Tumors of the Pharynx, Tumors of the Larynx, Tumors of the Skin, Dental and Jaw Tumors, Tumors of the Thyroid and Parathyroid Glands, Tumors of the Trachea, Tumors of the Eye, Orbit, and Lacrimal Apparatus, and Special Topics.

  3. Circulating glioma biomarkers

    PubMed Central

    Kros, Johan M.; Mustafa, Dana M.; Dekker, Lennard J.M.; Sillevis Smitt, Peter A.E.; Luider, Theo M.; Zheng, Ping-Pin

    2015-01-01

    Validated biomarkers for patients suffering from gliomas are urgently needed for standardizing measurements of the effects of treatment in daily clinical practice and trials. Circulating body fluids offer easily accessible sources for such markers. This review highlights various categories of tumor-associated circulating biomarkers identified in blood and cerebrospinal fluid of glioma patients, including circulating tumor cells, exosomes, nucleic acids, proteins, and oncometabolites. The validation and potential clinical utility of these biomarkers is briefly discussed. Although many candidate circulating protein biomarkers were reported, none of these have reached the required validation to be introduced for clinical practice. Recent developments in tracing circulating tumor cells and their derivatives as exosomes and circulating nuclear acids may become more successful in providing useful biomarkers. It is to be expected that current technical developments will contribute to the finding and validation of circulating biomarkers. PMID:25253418

  4. The impact of coexisting genetic mutations on murine optic glioma biology

    PubMed Central

    Kaul, Aparna; Toonen, Joseph A.; Gianino, Scott M.; Gutmann, David H.

    2015-01-01

    Background Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology. Methods Nf1+/− mice were intercrossed with Nf1flox/flox mice, which were then crossed with Nf1flox/flox; GFAP-Cre mice, to generate Nf1flox/mut; GFAP-Cre (FMC) mice. These mice were additionally mated with conditional KIAA1549:BRAF knock-in or Ptenflox/wt mice to generate Nf1flox/mut; f-BRAF; GFAP-Cre (FMBC) mice or Nf1flox/mut; Ptenflox/wt; GFAP-Cre (FMPC) mice, respectively. The resulting optic gliomas were analyzed for changes in tumor volume, proliferation, and retinal ganglion cell loss. Results While KIAA1549:BRAF conferred no additional biological properties on Nf1 optic glioma, FMPC mice had larger optic gliomas with greater proliferative indices and microglial infiltration. In addition, all 3 Nf1 murine optic glioma strains exhibited reduced retinal ganglion cell survival and numbers; however, FMPC mice had greater retinal nerve fiber layer thinning near the optic head relative to FMC and FMBC mice. Conclusions Collectively, these experiments demonstrate genetic cooperativity between Nf1 loss and Pten heterozygosity relevant to optic glioma biology and further underscore the value of employing genetically engineered mouse strains to define the contribution of discovered molecular alterations to brain tumor pathogenesis. PMID:25246427

  5. Phenotypic Transition as a Survival Strategy of Glioma.

    PubMed

    Ichikawa, Tomotsugu; Otani, Yoshihiro; Kurozumi, Kazuhiko; Date, Isao

    2016-07-15

    Malignant glioma is characterized by rapid proliferation, invasion into surrounding central nervous system tissues, and aberrant vascularization. There is increasing evidence that shows gliomas are more complex than previously thought, as each tumor comprises considerable intratumoral heterogeneity with mixtures of genetically and phenotypically distinct subclones. Heterogeneity within and across tumors is recognized as a critical factor that limits therapeutic progress for malignant glioma. Recent genotyping and expression profiling of gliomas has allowed for the creation of classification schemes that assign tumors to subtypes based on similarity to defined expression signatures. Also, malignant gliomas frequently shift their biological features upon recurrence and progression. The ability of glioma cells to resist adverse conditions such as hypoxia and metabolic stress is necessary for sustained tumor growth and strongly influences tumor behaviors. In general, glioma cells are in one of two phenotypic categories: higher proliferative activity with angiogenesis, or higher migratory activity with attenuated proliferative ability. Further, they switch phenotypic categories depending on the situation. To date, a multidimensional approach has been employed to clarify the mechanisms of phenotypic shift of glioma. Various molecular and signaling pathways are involved in phenotypic shifts of glioma, possibly with crosstalk between them. In this review, we discuss molecular and phenotypic heterogeneity of glioma cells and mechanisms of phenotypic shifts in regard to the glioma proliferation, angiogenesis, and invasion. A better understanding of the molecular mechanisms that underlie phenotypic shifts of glioma may provide new insights into targeted therapeutic strategies.

  6. AngioMatrix, a signature of the tumor angiogenic switch-specific matrisome, correlates with poor prognosis for glioma and colorectal cancer patients

    PubMed Central

    Rupp, Tristan; Arnold, Christiane; van der Heyden, Michaël; Orend, Gertraud; Hussenet, Thomas

    2014-01-01

    Angiogenesis represents a rate-limiting step during tumor progression. Targeting angiogenesis is already applied in cancer treatment, yet limits of anti-angiogenic therapies have emerged, notably because tumors adapt and recur after treatment. Therefore, there is a strong need to better understand the molecular and cellular mechanisms underlying tumor angiogenesis. Using the RIP1-Tag2 transgenic murine model, we identified 298 genes that are deregulated during the angiogenic switch, revealing an ingression/expansion of specific stromal cell types including endothelial cells and pericytes, but also macrophages and perivascular mesenchymal cells. Canonical TGF-β signaling is up-regulated during the angiogenic switch, especially in tumor-associated macrophages and fibroblasts. The matrisome, comprising extracellular matrix (ECM) and ECM-associated molecules, is significantly enriched, which allowed us to define the AngioMatrix signature as the 110 matrisomal genes induced during the RIP1-Tag2 angiogenic switch. Several AngioMatrix molecules were validated at expression level. Ablation of tenascin-C, one of the most highly induced ECM molecules during the switch, resulted in reduced angiogenesis confirming its important role. In human glioma and colorectal samples, the AngioMatrix signature correlates with the expression of endothelial cell markers, is increased with tumor progression and finally correlates with poor prognosis demonstrating its diagnostic and therapeutic potential. PMID:25301723

  7. Proton Beam Radiation Therapy in Treating Patients With Low Grade Gliomas

    ClinicalTrials.gov

    2015-12-14

    Adult Brain Tumor; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Melanocytic Lesion; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma; Adult Pineocytoma; Recurrent Adult Brain Tumor

  8. Tumor response parameters for head and neck cancer derived from tumor-volume variation during radiation therapy

    SciTech Connect

    Chvetsov, Alexei V.

    2013-03-15

    Purpose: The main goal of this paper is to reconstruct a distribution of cell survival fractions from tumor-volume variation for a heterogeneous group of head and neck cancer patients and compare this distribution to the data from predictive assays. Methods: To characterize the tumor-volume variation during radiation therapy treatment, the authors use a two-level tumor-volume model of cell population that separates the entire tumor cell population into two subpopulations of viable cells and lethally damaged cells. This parameterized radiobiological model is integrated with a least squares objective function and a simulated annealing optimization algorithm to describe time-dependent tumor-volume variation rates in individual patients. Several constraints have been used in the optimization problem because tumor-volume variation during radiotherapy is described by a sum of exponentials; therefore, the problem of accurately fitting a model to measured data is ill-posed. The model was applied to measured tumor-volume variation curves from a clinical study on tumor-volume variation during radiotherapy for 14 head and neck cancer patients in which an integrated CT/linear particle accelerator (LINAC) system was used for tumor-volume measurements. Results: The two-level cell population tumor-volume modeling is capable of describing tumor-volume variation throughout the entire treatment for 11 of the 14 patients. For three patients, the tumor-volume variation was described only during the initial part of treatment, a fact that may be related to the neglected hypoxia in the two-level approximation. The predicted probability density distribution for the survival fractions agrees with the data obtained using in vitro studies with predictive assays. The mean value 0.35 of survival fraction obtained in this study is larger than the value 0.32 from in vitro studies, which could be expected because of greater repair in vivo. The mean half-life obtained in this study for the head

  9. SVM-based glioma grading: Optimization by feature reduction analysis.

    PubMed

    Zöllner, Frank G; Emblem, Kyrre E; Schad, Lothar R

    2012-09-01

    We investigated the predictive power of feature reduction analysis approaches in support vector machine (SVM)-based classification of glioma grade. In 101 untreated glioma patients, three analytic approaches were evaluated to derive an optimal reduction in features; (i) Pearson's correlation coefficients (PCC), (ii) principal component analysis (PCA) and (iii) independent component analysis (ICA). Tumor grading was performed using a previously reported SVM approach including whole-tumor cerebral blood volume (CBV) histograms and patient age. Best classification accuracy was found using PCA at 85% (sensitivity=89%, specificity=84%) when reducing the feature vector from 101 (100-bins rCBV histogram+age) to 3 principal components. In comparison, classification accuracy by PCC was 82% (89%, 77%, 2 dimensions) and 79% by ICA (87%, 75%, 9 dimensions). For improved speed (up to 30%) and simplicity, feature reduction by all three methods provided similar classification accuracy to literature values (∼87%) while reducing the number of features by up to 98%.

  10. Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data

    PubMed Central

    Wang, Zhaoming; Rajaraman, Preetha; Melin, Beatrice S.; Chung, Charles C.; Zhang, Weijia; McKean-Cowdin, Roberta; Michaud, Dominique; Yeager, Meredith; Ahlbom, Anders; Albanes, Demetrius; Andersson, Ulrika; Beane Freeman, Laura E.; Buring, Julie E.; Butler, Mary Ann; Carreón, Tania; Feychting, Maria; Gapstur, Susan M.; Gaziano, J. Michael; Giles, Graham G.; Hallmans, Goran; Henriksson, Roger; Hoffman-Bolton, Judith; Inskip, Peter D.; Kitahara, Cari M.; Le Marchand, Loic; Linet, Martha S.; Li, Shengchao; Peters, Ulrike; Purdue, Mark P.; Rothman, Nathaniel; Ruder, Avima M.; Sesso, Howard D.; Severi, Gianluca; Stampfer, Meir; Stevens, Victoria L.; Visvanathan, Kala; Wang, Sophia S.; White, Emily; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Fraumeni, Joseph F.; Chatterjee, Nilanjan; Hartge, Patricia; Chanock, Stephen J.

    2016-01-01

    We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10−11), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ~3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma. PMID:25907361

  11. Enhancement of blood-tumor barrier permeability by Sar-[D-Phe8]des-Arg9BK, a metabolically resistant bradykinin B1 agonist, in a rat C6 glioma model

    PubMed Central

    Cardoso, Ronie Cleverson; Lobão-Soares, Bruno; Bianchin, Marino Muxfeldt; Carlotti, Carlos Gilberto; Walz, Roger; Alvarez-Silva, Márcio; Trentin, Andréa Gonçalves; Nicolau, Mauro

    2004-01-01

    Background While it is well known that bradykinin B2 agonists increase plasma protein extravasation (PPE) in brain tumors, the bradykinin B1 agonists tested thus far are unable to produce this effect. Here we examine the effect of the selective B1 agonist bradykinin (BK) Sar-[D-Phe8]des-Arg9BK (SAR), a compound resistant to enzymatic degradation with prolonged activity on PPE in the blood circulation in the C6 rat glioma model. Results SAR administration significantly enhanced PPE in C6 rat brain glioma compared to saline or BK (p < 0.01). Pre-administration of the bradykinin B1 antagonist [Leu8]-des-Arg (100 nmol/Kg) blocked the SAR-induced PPE in the tumor area. Conclusions Our data suggest that the B1 receptor modulates PPE in the blood tumor barrier of C6 glioma. A possible role for the use of SAR in the chemotherapy of gliomas deserves further study. PMID:15458573

  12. Mutant IDH1 and thrombosis in gliomas.

    PubMed

    Unruh, Dusten; Schwarze, Steven R; Khoury, Laith; Thomas, Cheddhi; Wu, Meijing; Chen, Li; Chen, Rui; Liu, Yinxing; Schwartz, Margaret A; Amidei, Christina; Kumthekar, Priya; Benjamin, Carolina G; Song, Kristine; Dawson, Caleb; Rispoli, Joanne M; Fatterpekar, Girish; Golfinos, John G; Kondziolka, Douglas; Karajannis, Matthias; Pacione, Donato; Zagzag, David; McIntyre, Thomas; Snuderl, Matija; Horbinski, Craig

    2016-12-01

    Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

  13. Canine spontaneous glioma: a translational model system for convection-enhanced delivery.

    PubMed

    Dickinson, Peter J; LeCouteur, Richard A; Higgins, Robert J; Bringas, John R; Larson, Richard F; Yamashita, Yoji; Krauze, Michal T; Forsayeth, John; Noble, Charles O; Drummond, Daryl C; Kirpotin, Dmitri B; Park, John W; Berger, Mitchel S; Bankiewicz, Krystof S

    2010-09-01

    Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.

  14. Canine spontaneous glioma: A translational model system for convection-enhanced delivery

    PubMed Central

    Dickinson, Peter J.; LeCouteur, Richard A.; Higgins, Robert J.; Bringas, John R.; Larson, Richard F.; Yamashita, Yoji; Krauze, Michal T.; Forsayeth, John; Noble, Charles O.; Drummond, Daryl C.; Kirpotin, Dmitri B.; Park, John W.; Berger, Mitchel S.; Bankiewicz, Krystof S.

    2010-01-01

    Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes. PMID:20488958

  15. Endogenous GABAA receptor activity suppresses glioma growth.

    PubMed

    Blanchart, A; Fernando, R; Häring, M; Assaife-Lopes, N; Romanov, R A; Andäng, M; Harkany, T; Ernfors, P

    2017-02-09

    Although genome alterations driving glioma by fueling cell malignancy have largely been resolved, less is known of the impact of tumor environment on disease progression. Here, we demonstrate functional GABAA receptor-activated currents in human glioblastoma cells and show the existence of a continuous GABA signaling within the tumor cell mass that significantly affects tumor growth and survival expectancy in mouse models. Endogenous GABA released by tumor cells, attenuates proliferation of the glioma cells with enriched expression of stem/progenitor markers and with competence to seed growth of new tumors. Our results suggest that GABA levels rapidly increase in tumors impeding further growth. Thus, shunting chloride ions by a maintained local GABAA receptor activity within glioma cells has a significant impact on tumor development by attenuating proliferation, reducing tumor growth and prolonging survival, a mechanism that may have important impact on therapy resistance and recurrence following tumor resection.

  16. [Controversy on treatments for gliomas].

    PubMed

    Nomura, K

    1998-09-01

    Gliomas are representative primary malignant brain tumors, and with such tumors it is difficult to define the advanced stage. If the advanced stage indicates no curability by surgery alone, most gliomas would belong to this criterion because of their poor prognosis without any completely effective treatment. In this sense, no one could show a standard therapy to treat these unfortunate patients, for example, patients with glioblastoma, they could permit only 1 year survived even they had any applicable treatments to the lesions, these days. Treatment for low-grade gliomas has been most controversial for a long time, and no standard treatments have been determined so far. In this paper, as the treatment of low-grade gliomas it was intended to report what must be done for this patient and the present results of opinion survey for the treatment of gliomas which was done to professors of 80 institutes, from schools of medicine at all universities and medical colleges in Japan. For high-grade gliomas, some effectiveness of radiation therapy was disclosed as well as chemotherapy from recent papers. Gene therapy was also discussed briefly, its present status and future.

  17. A simple, quantitative method using alginate gel to determine rat colonic tumor volume in vivo.

    PubMed

    Irving, Amy A; Young, Lindsay B; Pleiman, Jennifer K; Konrath, Michael J; Marzella, Blake; Nonte, Michael; Cacciatore, Justin; Ford, Madeline R; Clipson, Linda; Amos-Landgraf, James M; Dove, William F

    2014-04-01

    Many studies of the response of colonic tumors to therapeutics use tumor multiplicity as the endpoint to determine the effectiveness of the agent. These studies can be greatly enhanced by accurate measurements of tumor volume. Here we present a quantitative method to easily and accurately determine colonic tumor volume. This approach uses a biocompatible alginate to create a negative mold of a tumor-bearing colon; this mold is then used to make positive casts of dental stone that replicate the shape of each original tumor. The weight of the dental stone cast correlates highly with the weight of the dissected tumors. After refinement of the technique, overall error in tumor volume was 16.9% ± 7.9% and includes error from both the alginate and dental stone procedures. Because this technique is limited to molding of tumors in the colon, we utilized the Apc(Pirc/+) rat, which has a propensity for developing colonic tumors that reflect the location of the majority of human intestinal tumors. We have successfully used the described method to determine tumor volumes ranging from 4 to 196 mm³. Alginate molding combined with dental stone casting is a facile method for determining tumor volume in vivo without costly equipment or knowledge of analytic software. This broadly accessible method creates the opportunity to objectively study colonic tumors over time in living animals in conjunction with other experiments and without transferring animals from the facility where they are maintained.

  18. A Simple, Quantitative Method Using Alginate Gel to Determine Rat Colonic Tumor Volume In Vivo

    PubMed Central

    Irving, Amy A; Young, Lindsay B; Pleiman, Jennifer K; Konrath, Michael J; Marzella, Blake; Nonte, Michael; Cacciatore, Justin; Ford, Madeline R; Clipson, Linda; Amos-Landgraf, James M; Dove, William F

    2014-01-01

    Many studies of the response of colonic tumors to therapeutics use tumor multiplicity as the endpoint to determine the effectiveness of the agent. These studies can be greatly enhanced by accurate measurements of tumor volume. Here we present a quantitative method to easily and accurately determine colonic tumor volume. This approach uses a biocompatible alginate to create a negative mold of a tumor-bearing colon; this mold is then used to make positive casts of dental stone that replicate the shape of each original tumor. The weight of the dental stone cast correlates highly with the weight of the dissected tumors. After refinement of the technique, overall error in tumor volume was 16.9% ± 7.9% and includes error from both the alginate and dental stone procedures. Because this technique is limited to molding of tumors in the colon, we utilized the ApcPirc/+ rat, which has a propensity for developing colonic tumors that reflect the location of the majority of human intestinal tumors. We have successfully used the described method to determine tumor volumes ranging from 4 to 196 mm3. Alginate molding combined with dental stone casting is a facile method for determining tumor volume in vivo without costly equipment or knowledge of analytic software. This broadly accessible method creates the opportunity to objectively study colonic tumors over time in living animals in conjunction with other experiments and without transferring animals from the facility where they are maintained. PMID:24674588

  19. The Art of Intraoperative Glioma Identification

    PubMed Central

    Zhang, Zoe Z.; Shields, Lisa B. E.; Sun, David A.; Zhang, Yi Ping; Hunt, Matthew A.; Shields, Christopher B.

    2015-01-01

    A major dilemma in brain-tumor surgery is the identification of tumor boundaries to maximize tumor excision and minimize postoperative neurological damage. Gliomas, especially low-grade tumors, and normal brain have a similar color and texture, which poses a challenge to the neurosurgeon. Advances in glioma resection techniques combine the experience of the neurosurgeon and various advanced technologies. Intraoperative methods to delineate gliomas from normal tissue consist of (1) image-based navigation, (2) intraoperative sampling, (3) electrophysiological monitoring, and (4) enhanced visual tumor demarcation. The advantages and disadvantages of each technique are discussed. A combination of these methods is becoming widely accepted in routine glioma surgery. Gross total resection in conjunction with radiation, chemotherapy, or immune/gene therapy may increase the rates of cure in this devastating disease. PMID:26284196

  20. 3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma.

    PubMed

    Anderson, David M G; Van de Plas, Raf; Rose, Kristie L; Hill, Salisha; Schey, Kevin L; Solga, Anne C; Gutmann, David H; Caprioli, Richard M

    2016-10-21

    Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions.

  1. Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade.

    PubMed

    Tao, Bang-Bao; He, Hua; Shi, Xiu-hua; Wang, Chun-lin; Li, Wei-qing; Li, Bing; Dong, Yan; Hu, Guo-Han; Hou, Li-Jun; Luo, Chun; Chen, Ju-xiang; Chen, Huai-rui; Yu, Yu-hong; Sun, Qing-fang; Lu, Yi-Cheng

    2013-05-01

    Gliomas are the most common neoplasms in the central nervous system. The lack of efficacy of glioma therapies necessitates in-depth studies of glioma pathology, especially of the underlying molecular mechanisms that transform normal glial cells into tumor cells. Here we report that a deubiquitinating enzyme, ubiquitin-specific protease 2a (USP2a), and its substrate, fatty acid synthase (FASN), are over-expressed in glioma tissue. Using real-time quantitative polymerase chain reaction (PCR), Western blot and immunohistochemistry, we examined the expression and cellular distribution of USP2a and FASN in human glioma tissues. The expression patterns of USP2a and FASN correlated with the pathologic and clinical characteristics of the patients. Real-time PCR analysis showed that the expression levels of USP2a and its substrate FASN were higher in high-grade (World Health Organization [WHO] grades III and IV) glioma tissues than in low-grade (WHO grades I and II) glioma tissues. Western blot analysis indicated that the average optical densitometry ratio of USP2a and its substrate FASN in high-grade gliomas was higher than in low-grade gliomas. Moreover, statistical analysis of grade-classified glioma samples showed that the level of USP2a and FASN expression increased with the elevation of the WHO grade of glioma. USP2a protein expression was detected in the nucleus of glioma tissues and an increase in expression was significantly associated with the elevation of the WHO grade of glioma by immunohistochemistry. These findings expand our understanding of the molecular profiling of glioma and could shed light on new diagnostic criteria for gliomas.

  2. Glutamine Metabolism in Gliomas.

    PubMed

    Szeliga, Monika; Albrecht, Jan

    2016-01-01

    By histological, morphological criteria, and malignancy, brain tumors are classified by WHO into grades I (most benign) to IV (highly malignant), and gliomas are the most frequently occurring class throughout the grades. Similar to peripheral tumors, the growth of glia-derived tumor cells largely depends on glutamine (Gln), which is vividly taken up by the cells, using mostly ASCT2 and SN1 as Gln carriers. Tumor growth-promoting effects of Gln are associated with its phosphate-activated glutaminase (GA) (specifically KGA)-mediated degradation to glutamate (Glu) and/or with its entry to the energy- and intermediate metabolite-generating pathways related to the tricarboxylic acid cycle. However, a subclass of liver-type GA are absent in glioma cells, a circumstance which allows phenotype manipulations upon their transfection to the cells. Gln-derived Glu plays a major role in promoting tumor proliferation and invasion. Glu is relatively inefficiently recycled to Gln and readily leaves the cells by exchange with the extracellular pool of the glutathione (GSH) precursor Cys mediated by xc- transporter. This results in (a) cell invasion-fostering interaction of Glu with ionotropic Glu receptors in the surrounding tissue, (b) intracellular accumulation of GSH which increases tumor resistance to radio- and chemotherapy.

  3. Convection-enhanced Delivery of Therapeutics for Malignant Gliomas

    PubMed Central

    SAITO, Ryuta; TOMINAGA, Teiji

    2017-01-01

    Convection-enhanced delivery (CED) circumvents the blood–brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future. PMID:27980285

  4. Tumor volume, luxury perfusion, and regional blood volume changes in man visualized by subtraction computerized tomography.

    PubMed

    Penn, R D; Walser, R; Kurtz, D; Ackerman, L

    1976-04-01

    Computer and photographic methods for producing subtractions of computerized axial tomographic (CAT) scans have been developed. By subtracting point for point a normal scan from one taken after intravenous infusion of contrast material, a picture of the contrast in the cerebral vessels is created. By this method, tumor size and degree of vascularity may be assessed. Furthermore, abnormalities in perfusion and changes in blood volume due to mass effects and edema may be detected. Subtracting scans should add to the diagnostic potential of CAT and provide a noninvasive way to study vascular changes in cerebral disease.

  5. Comparison of Cerebral Blood Volume and Plasma Volume in Untreated Intracranial Tumors

    PubMed Central

    Ramalho, Joana; Eldeniz, Cihat; An, Hongyu; Lee, Yueh Z.

    2016-01-01

    Purpose Plasma volume and blood volume are imaging-derived parameters that are often used to evaluation intracranial tumors. Physiologically, these parameters are directly related, but their two different methods of measurements, T1-dynamic contrast enhanced (DCE)- and T2-dynamic susceptibility contrast (DSC)-MR utilize different model assumptions and approaches. This poses the question of whether the interchangeable use of T1-DCE-MRI derived fractionated plasma volume (vp) and relative cerebral blood volume (rCBV) assessed using DSC-MRI, particularly in glioblastoma, is reliable, and if this relationship can be generalized to other types of brain tumors. Our goal was to examine the hypothetical correlation between these parameters in three most common intracranial tumor types. Methods Twenty-four newly diagnosed, treatment naïve brain tumor patients, who had undergone DCE- and DSC-MRI, were classified in three histologically proven groups: glioblastoma (n = 7), meningioma (n = 9), and intraparenchymal metastases (n = 8). The rCBV was obtained from DSC after normalization with the normal-appearing anatomically symmetrical contralateral white matter. Correlations between these parameters were evaluated using Pearson (r), Spearman's (ρ) and Kendall’s tau-b (τB) rank correlation coefficient. Results The Pearson, Spearman and Kendall’s correlation between vp with rCBV were r = 0.193, ρ = 0.253 and τB = 0.33 (p-Pearson = 0.326, p-Spearman = 0.814 and p-Kendall = 0.823) in glioblastoma, r = -0.007, ρ = 0.051 and τB = 0.135 (p-Pearson = 0.970, p-Spearman = 0.765 and p-Kendall = 0.358) in meningiomas, and r = 0.289, ρ = 0.228 and τB = 0.239 (p-Pearson = 0.109, p-Spearman = 0.210 and p-Kendall = 0.095) in metastasis. Conclusion Results indicate that no correlation exists between vp with rCBV in glioblastomas, meningiomas and intraparenchymal metastatic lesions. Consequently, these parameters, as calculated in this study, should not be used interchangeably in

  6. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults.

    PubMed

    Feng, Jie; Hao, Shuyu; Pan, Changcun; Wang, Yu; Wu, Zhen; Zhang, Junting; Yan, Hai; Zhang, Liwei; Wan, Hong

    2015-11-01

    Brainstem and thalamic gliomas are rare, and they are poorly understood in adults. Genetic aberrations that occur in these tumors are still unknown. In this study, we investigated whether thalamic gliomas have different genetic aberrations and clinical outcomes compared with brainstem gliomas in adults. Forty-three glioma samples were selected, including 28 brainstem and 15 thalamic gliomas. The frequency of the K27M mutation in adult midline gliomas was 58.1%. High-grade gliomas in the thalamus were statistically significantly more numerous than brainstem gliomas. Patients with K27M mutant brainstem gliomas had a significantly shorter overall survival than patients with wild-type tumors (P = .020) by Cox regression after adjustment for other independent risk factors. However, there was no statistical tendency toward a poorer overall survival in thalamic gliomas containing the K27M mutation compared with wild-type tumors. The presence of the K27M mutation significantly corresponded with mutations in TP53 in thalamic gliomas. Interestingly, the K27M mutation was mutually exclusive with mutations in IDH1, which was detected only in brainstem gliomas. The microarray data identified 86 differentially expressed genes between brainstem and thalamic gliomas with the K27M mutation. The cyclin-dependent kinase 6 (CDK6) gene, which plays an important role in cancer pathways, was found to be differentially expressed between brainstem and thalamic gliomas with K27M mutations. Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas. Brainstem gliomas may present different genetic aberrations from thalamic gliomas. These differences may provide guidance for therapeutic decisions for the treatment of adult brainstem and thalamic gliomas, which may have different molecular targets.

  7. Plerixafor After Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed High Grade Glioma

    ClinicalTrials.gov

    2016-11-08

    Adult Ependymoblastoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglial Tumors; Adult Pineoblastoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET)

  8. Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model.

    PubMed

    Hanihara, Mitsuto; Kawataki, Tomoyuki; Oh-Oka, Kyoko; Mitsuka, Kentaro; Nakao, Atsuhito; Kinouchi, Hiroyuki

    2016-06-01

    OBJECT Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor-derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. METHODS Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. RESULTS In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). CONCLUSIONS These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO

  9. Canine spinal cord glioma.

    PubMed

    Rissi, Daniel R; Barber, Renee; Burnum, Annabelle; Miller, Andrew D

    2017-01-01

    Spinal cord glioma is uncommonly reported in dogs. We describe the clinicopathologic and diagnostic features of 7 cases of canine spinal cord glioma and briefly review the veterinary literature on this topic. The median age at presentation was 7.2 y. Six females and 1 male were affected and 4 dogs were brachycephalic. The clinical course lasted from 3 d to 12 wk, and clinical signs were progressive and associated with multiple suspected neuroanatomic locations in the spinal cord. Magnetic resonance imaging of 6 cases revealed T2-weighted hyperintense lesions with variable contrast enhancement in the spinal cord. All dogs had a presumptive clinical diagnosis of intraparenchymal neoplasia or myelitis based on history, advanced imaging, and cerebrospinal fluid analysis. Euthanasia was elected in all cases because of poor outcome despite anti-inflammatory or immunosuppressive treatment or because of poor prognosis at the time of diagnosis. Tumor location during autopsy ranged from C1 to L6, with no clear predilection for a specific spinal cord segment. The diagnosis was based on histopathology and the immunohistochemistry expression of glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, neuron-specific enolase, synaptophysin, and Ki-67. Diagnoses consisted of 4 cases of oligodendroglioma, 2 cases of gliomatosis cerebri, and 1 astrocytoma. This case series further defines the clinicopathologic features of canine spinal glioma and highlights the need for comprehensive immunohistochemistry in addition to routine histopathology to confirm the diagnosis of these tumors.

  10. Terahertz reflectometry imaging for low and high grade gliomas

    NASA Astrophysics Data System (ADS)

    Ji, Young Bin; Oh, Seung Jae; Kang, Seok-Gu; Heo, Jung; Kim, Sang-Hoon; Choi, Yuna; Song, Seungri; Son, Hye Young; Kim, Se Hoon; Lee, Ji Hyun; Haam, Seung Joo; Huh, Yong Min; Chang, Jong Hee; Joo, Chulmin; Suh, Jin-Suck

    2016-10-01

    Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes.

  11. Terahertz reflectometry imaging for low and high grade gliomas

    PubMed Central

    Ji, Young Bin; Oh, Seung Jae; Kang, Seok-Gu; Heo, Jung; Kim, Sang-Hoon; Choi, Yuna; Song, Seungri; Son, Hye Young; Kim, Se Hoon; Lee, Ji Hyun; Haam, Seung Joo; Huh, Yong Min; Chang, Jong Hee; Joo, Chulmin; Suh, Jin-Suck

    2016-01-01

    Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes. PMID:27782153

  12. Sensitivity Analysis of the MGMT-STP27 Model and Impact of Genetic and Epigenetic Context to Predict the MGMT Methylation Status in Gliomas and Other Tumors.

    PubMed

    Bady, Pierre; Delorenzi, Mauro; Hegi, Monika E

    2016-05-01

    The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Our model MGMT-STP27 allows prediction of the methylation status of the MGMT promoter using data from the Illumina's Human Methylation BeadChips (HM-27K and HM-450K) that is publically available for many cancer data sets. Here, we investigate the impact of the context of genetic and epigenetic alterations and tumor type on the classification and report on technical aspects, such as robustness of cutoff definition and preprocessing of the data. The association between gene copy number variation, predicted MGMT methylation, and MGMT expression revealed a gene dosage effect on MGMT expression in lower grade glioma (World Health Organization grade II/III) that in contrast to glioblastoma usually carry two copies of chromosome 10 on which MGMT resides (10q26.3). This implies some MGMT expression, potentially conferring residual repair function blunting the therapeutic effect of alkylating agents. A sensitivity analyses corroborated the performance of the original cutoff for various optimization criteria and for most data preprocessing methods. Finally, we propose an R package mgmtstp27 that allows prediction of the methylation status of the MGMT promoter and calculation of appropriate confidence and/or prediction intervals. Overall, MGMT-STP27 is a robust model for MGMT classification that is independent of tumor type and is adapted for single sample prediction.

  13. SU-E-J-79: Internal Tumor Volume Motion and Volume Size Assessment Using 4D CT Lung Data

    SciTech Connect

    Jurkovic, I; Stathakis, S; Li, Y; Patel, A; Vincent, J; Papanikolaou, N; Mavroidis, P

    2014-06-01

    Purpose: To assess internal tumor volume change through breathing cycle and associated tumor motion using the 4DCT data. Methods: Respiration induced volume change through breathing cycle and associated motion was analyzed for nine patients that were scanned during the different respiratory phases. The examined datasets were the maximum and average intensity projections (MIP and AIP) and the 10 phases of the respiratory cycle. The internal target volume (ITV) was delineated on each of the phases and the planning target volume (PTV) was then created by adding setup margins to the ITV. Tumor motion through the phases was assessed using the acquired 4DCT dataset, which was then used to determine if the margins used for the ITV creation successfully encompassed the tumor in three dimensions. Results: Results showed that GTV motion along the superior inferior axes was the largest in all the cases independent of the tumor location and/or size or the use of abdomen compression. The extent of the tumor motion was found to be connected with the size of the GTV. The smallest GTVs exhibited largest motion vector independent of the tumor location. The motion vector size varied through the phases depending on the tumor size and location and it was smallest for phases 20 and 30. The smaller the volume of the delineated GTV, the greater its volume difference through the different respiratory phases was. The average GTV volume change was largest for the phases 60 and 70. Conclusion: Even if GTV is delineated using both AIP and MIP datasets, its motion extent will exceed the used margins especially for the very small GTV volumes. When the GTV size is less than 10 cc it is recommended to use fusion of the GTVs through all the phases to create the planning ITV.

  14. Impact of [18F]-fluoro-ethyl-tyrosine PET imaging on target definition for radiation therapy of high-grade glioma

    PubMed Central

    Munck af Rosenschold, Per; Costa, Junia; Engelholm, Svend Aage; Lundemann, Michael J.; Law, Ian; Ohlhues, Lars; Engelholm, Silke

    2015-01-01

    Background We sought to assess the impact of amino-acid 18F-fluoro-ethyl-tyrosine (FET) positron emission tomography (PET) on the volumetric target definition for radiation therapy of high-grade glioma versus the current standard using MRI alone. Specifically, we investigated the influence of tumor grade, MR-defined tumor volume, and the extent of surgical resection on PET positivity. Methods Fifty-four consecutive high-grade glioma patients (World Health Organization grades III–IV) with confirmed histology were scanned using FET-PET/CT and T1 and T2/fluid attenuated inversion recovery MRI. Gross tumor volume and clinical target volumes (CTVs) were defined in a blinded fashion based on MRI and subsequently PET, and volumetric analysis was performed. The extent of the surgical resection was reviewed using postoperative MRI. Results Overall, for ∼90% of the patients, the PET-positive volumes were encompassed by T1 MRI with contrast-defined tumor plus a 20-mm margin. The tumor volume defined by PET was larger for glioma grade IV (P < .001) and smaller for patients with more extensive surgical resection (P = .004). The margin required to be added to the MRI-defined tumor in order to fully encompass the FET-PET positive volume tended to be larger for grade IV tumors (P = .018). Conclusion With an unchanged CTV margin and by including FET-PET for gross tumor volume definition, the CTV will increase moderately for most patients, and quite substantially for a minority of patients. Patients with grade IV glioma were found to be the primary candidates for PET-guided radiation therapy planning. PMID:25537018

  15. Statistical evaluation of manual segmentation of a diffuse low-grade glioma MRI dataset.

    PubMed

    Ben Abdallah, Meriem; Blonski, Marie; Wantz-Mezieres, Sophie; Gaudeau, Yann; Taillandier, Luc; Moureaux, Jean-Marie

    2016-08-01

    Software-based manual segmentation is critical to the supervision of diffuse low-grade glioma patients and to the optimal treatment's choice. However, manual segmentation being time-consuming, it is difficult to include it in the clinical routine. An alternative to circumvent the time cost of manual segmentation could be to share the task among different practitioners, providing it can be reproduced. The goal of our work is to assess diffuse low-grade gliomas' manual segmentation's reproducibility on MRI scans, with regard to practitioners, their experience and field of expertise. A panel of 13 experts manually segmented 12 diffuse low-grade glioma clinical MRI datasets using the OSIRIX software. A statistical analysis gave promising results, as the practitioner factor, the medical specialty and the years of experience seem to have no significant impact on the average values of the tumor volume variable.

  16. Predicting in vivo glioma growth with the reaction diffusion equation constrained by quantitative magnetic resonance imaging data

    NASA Astrophysics Data System (ADS)

    Hormuth, David A., II; Weis, Jared A.; Barnes, Stephanie L.; Miga, Michael I.; Rericha, Erin C.; Quaranta, Vito; Yankeelov, Thomas E.

    2015-07-01

    Reaction-diffusion models have been widely used to model glioma growth. However, it has not been shown how accurately this model can predict future tumor status using model parameters (i.e., tumor cell diffusion and proliferation) estimated from quantitative in vivo imaging data. To this end, we used in silico studies to develop the methods needed to accurately estimate tumor specific reaction-diffusion model parameters, and then tested the accuracy with which these parameters can predict future growth. The analogous study was then performed in a murine model of glioma growth. The parameter estimation approach was tested using an in silico tumor ‘grown’ for ten days as dictated by the reaction-diffusion equation. Parameters were estimated from early time points and used to predict subsequent growth. Prediction accuracy was assessed at global (total volume and Dice value) and local (concordance correlation coefficient, CCC) levels. Guided by the in silico study, rats (n = 9) with C6 gliomas, imaged with diffusion weighted magnetic resonance imaging, were used to evaluate the model’s accuracy for predicting in vivo tumor growth. The in silico study resulted in low global (tumor volume error <8.8%, Dice >0.92) and local (CCC values >0.80) level errors for predictions up to six days into the future. The in vivo study showed higher global (tumor volume error >11.7%, Dice <0.81) and higher local (CCC <0.33) level errors over the same time period. The in silico study shows that model parameters can be accurately estimated and used to accurately predict future tumor growth at both the global and local scale. However, the poor predictive accuracy in the experimental study suggests the reaction-diffusion equation is an incomplete description of in vivo C6 glioma biology and may require further modeling of intra-tumor interactions including segmentation of (for example) proliferative and necrotic regions.

  17. Tumor Volume Reduction Rate After Preoperative Chemoradiotherapy as a Prognostic Factor in Locally Advanced Rectal Cancer

    SciTech Connect

    Yeo, Seung-Gu; Kim, Dae Yong; Park, Ji Won; Oh, Jae Hwan; Kim, Sun Young; Chang, Hee Jin; Kim, Tae Hyun; Kim, Byung Chang; Sohn, Dae Kyung; Kim, Min Ju

    2012-02-01

    Purpose: To investigate the prognostic significance of tumor volume reduction rate (TVRR) after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). Methods and Materials: In total, 430 primary LARC (cT3-4) patients who were treated with preoperative CRT and curative radical surgery between May 2002 and March 2008 were analyzed retrospectively. Pre- and post-CRT tumor volumes were measured using three-dimensional region-of-interest MR volumetry. Tumor volume reduction rate was determined using the equation TVRR (%) = (pre-CRT tumor volume - post-CRT tumor volume) Multiplication-Sign 100/pre-CRT tumor volume. The median follow-up period was 64 months (range, 27-99 months) for survivors. Endpoints were disease-free survival (DFS) and overall survival (OS). Results: The median TVRR was 70.2% (mean, 64.7% {+-} 22.6%; range, 0-100%). Downstaging (ypT0-2N0M0) occurred in 183 patients (42.6%). The 5-year DFS and OS rates were 77.7% and 86.3%, respectively. In the analysis that included pre-CRT and post-CRT tumor volumes and TVRR as continuous variables, only TVRR was an independent prognostic factor. Tumor volume reduction rate was categorized according to a cutoff value of 45% and included with clinicopathologic factors in the multivariate analysis; ypN status, circumferential resection margin, and TVRR were significant prognostic factors for both DFS and OS. Conclusions: Tumor volume reduction rate was a significant prognostic factor in LARC patients receiving preoperative CRT. Tumor volume reduction rate data may be useful for tailoring surgery and postoperative adjuvant therapy after preoperative CRT.

  18. Evaluation of an Automatic Registration-Based Algorithm for Direct Measurement of Volume Change in Tumors

    SciTech Connect

    Sarkar, Saradwata; Johnson, Timothy D.; Ma, Bing; Chenevert, Thomas L.; Bland, Peyton H.; Park, Hyunjin; Schott, Anne F.; Ross, Brian D.; Meyer, Charles R.

    2012-07-01

    Purpose: Assuming that early tumor volume change is a biomarker for response to therapy, accurate quantification of early volume changes could aid in adapting an individual patient's therapy and lead to shorter clinical trials. We investigated an image registration-based approach for tumor volume change quantification that may more reliably detect smaller changes that occur in shorter intervals than can be detected by existing algorithms. Methods and Materials: Variance and bias of the registration-based approach were evaluated using retrospective, in vivo, very-short-interval diffusion magnetic resonance imaging scans where true zero tumor volume change is unequivocally known and synthetic data, respectively. The interval scans were nonlinearly registered using two similarity measures: mutual information (MI) and normalized cross-correlation (NCC). Results: The 95% confidence interval of the percentage volume change error was (-8.93% to 10.49%) for MI-based and (-7.69%, 8.83%) for NCC-based registrations. Linear mixed-effects models demonstrated that error in measuring volume change increased with increase in tumor volume and decreased with the increase in the tumor's normalized mutual information, even when NCC was the similarity measure being optimized during registration. The 95% confidence interval of the relative volume change error for the synthetic examinations with known changes over {+-}80% of reference tumor volume was (-3.02% to 3.86%). Statistically significant bias was not demonstrated. Conclusion: A low-noise, low-bias tumor volume change measurement algorithm using nonlinear registration is described. Errors in change measurement were a function of tumor volume and the normalized mutual information content of the tumor.

  19. Occupation and adult gliomas.

    PubMed

    Carozza, S E; Wrensch, M; Miike, R; Newman, B; Olshan, A F; Savitz, D A; Yost, M; Lee, M

    2000-11-01

    Lifetime job histories from a population-based, case-control study of gliomas diagnosed among adults in the San Francisco Bay area between August 1991 and April 1994 were evaluated to assess occupational risk factors. Occupational data for 476 cases and 462 controls were analyzed, with adjustment for age, gender, education, and race. Imprecise increased risks were observed for physicians and surgeons (odds ratio (OR) = 3.5, 95% confidence interval (CI): 0.7, 17.6), artists (OR = 1.9, 95% CI: 0.5, 6.5), foundry and smelter workers (OR = 2.6, 95% CI: 0.5, 13.1), petroleum and gas workers (OR = 4.9, 95% CI: 0.6, 42.2), and painters (OR = 1.6, 95% CI: 0.5, 4.9). Legal and social service workers, shippers, janitors, motor vehicle operators, and aircraft operators had increased odds ratios only with longer duration of employment. Physicians and surgeons, foundry and smelter workers, petroleum and gas workers, and painters showed increased risk for both astrocytic and nonastrocytic tumors. Artists and firemen had increased risk for astrocytic tumors only, while messengers, textile workers, aircraft operators, and vehicle manufacturing workers showed increased risk only for nonastrocytic tumors. Despite study limitations, including small numbers for many of the occupational groups, a high percentage of proxy respondents among cases, and lack of specific exposure information, associations were observed for several occupations previously reported to be at higher risk for brain tumors generally and gliomas specifically.

  20. Acute Temporal Changes of MRI-Tracked Tumor Vascular Parameters after Combined Anti-angiogenic and Radiation Treatments in a Rat Glioma Model: Identifying Signatures of Synergism.

    PubMed

    Elmghirbi, Rasha; Nagaraja, Tavarekere N; Brown, Stephen L; Panda, Swayamprava; Aryal, Madhava P; Keenan, Kelly A; Bagher-Ebadian, Hassan; Cabral, Glauber; Ewing, James R

    2017-01-01

    In this study we used magnetic resonance imaging (MRI) biomarkers to monitor the acute temporal changes in tumor vascular physiology with the aim of identifying the vascular signatures that predict response to combined anti-angiogenic and radiation treatments. Forty-three athymic rats implanted with orthotopic U-251 glioma cells were studied for approximately 21 days after implantation. Two MRI studies were performed on each animal, pre- and post-treatment, to measure tumor vascular parameters. Two animal groups received treatment comprised of Cilengitide, an anti-angiogenic agent and radiation. The first group received a subcurative regimen of Cilengitide 1 h before irradiation, while the second group received a curative regimen of Cilengitide 8 h before irradiation. Cilengitide was given as a single dose (4 mg/kg; intraperitoneal) after the pretreatment MRI study and before receiving a 20 Gy radiation dose. After irradiation, the post-treatment MRI study was performed at selected time points: 2, 4, 8 and 12 h (n = ≥5 per time point). Significant changes in vascular parameters were observed at early time points after combined treatments in both treatment groups (1 and 8 h). The temporal changes in vascular parameters in the first group (treated 1 h before exposure) resembled a previously reported pattern associated with radiation exposure alone. Conversely, in the second group (treated 8 h before exposure), all vascular parameters showed an initial response at 2-4 h postirradiation, followed by an apparent lack of response at later time points. The signature time point to define the "synergy" of Cilengitide and radiation was 4 h postirradiation. For example, 4 h after combined treatments using a 1 h separation (which followed the subcurative regimen), tumor blood flow was significantly decreased, nearly 50% below baseline (P = 0.007), whereas 4 h after combined treatments using an 8 h separation (which followed the curative regimen), tumor blood flow was only 10

  1. Magnetic Resonance Imaging Protocol Optimization for Delineation of Gross Tumor Volume in Hypopharyngeal and Laryngeal Tumors

    SciTech Connect

    Verduijn, Gerda M.; Bartels, Lambertus W. Ph.D.; Pameijer, Frank A.

    2009-06-01

    Purpose: To optimize the use of MRI for delineation of gross tumor volume for radiotherapy treatment planning purposes in hypopharyngeal and laryngeal tumors. Methods and Materials: Magnetic resonance images (T1 weighted and T2 weighted) of a healthy volunteer were acquired using a 1.5 T and 3.0 T MR scanner. Various receiver coils were investigated that were compatible with the immobilization mask needed for reliable coregistration with computed tomography data. For the optimal receiver coil, the influence of resolution, slice thickness, and strength of magnetic field on the signal-to-noise ratio (SNR) was studied. Feasibility of the definitive protocol was tested on patients with hypopharyngeal (n = 19) and laryngeal (n = 42) carcinoma. Results: Large differences in SNR were obtained for the various coils. The SNR values obtained using surface coils that were compatible with the immobilization mask were three times higher than those obtained using a standard head-and-neck coil and five times higher than those obtained using a body coil. High-resolution images (0.4 x 0.4 x 4 mm{sup 3}) showed superior anatomic detail and resulted in a 4-min scan time. Image quality at 3.0 T was not significantly better compared with 1.5 T. In 3 patients the MR study could not be performed; for 5 patients images were severely deteriorated by motion artefacts. High-quality MR images were obtained in 53 patients. Conclusions: High-resolution MR images of the hypopharynx and larynx can be obtained in the majority of patients using surface receiver coils in combination with the radiotherapy mask. These MR images can be successfully used for tumor delineation in radiotherapy.

  2. Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes.

    PubMed

    Gao, Jian-Qing; Lv, Qing; Li, Li-Ming; Tang, Xin-Jiang; Li, Fan-Zhu; Hu, Yu-Lan; Han, Min

    2013-07-01

    Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy.

  3. Assessment of interpatient heterogeneity in tumor radiosensitivity for nonsmall cell lung cancer using tumor-volume variation data

    SciTech Connect

    Chvetsov, Alexei V. Schwartz, Jeffrey L.; Mayr, Nina; Yartsev, Slav

    2014-06-15

    Purpose: In our previous work, the authors showed that a distribution of cell surviving fractionsS{sub 2} in a heterogeneous group of patients could be derived from tumor-volume variation curves during radiotherapy for head and neck cancer. In this research study, the authors show that this algorithm can be applied to other tumors, specifically in nonsmall cell lung cancer. This new application includes larger patient volumes and includes comparison of data sets obtained at independent institutions. Methods: Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancer with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage computed tomography. Statistical distributions of cell surviving fractionsS{sub 2} and clearance half-lives of lethally damaged cells T{sub 1/2} have been reconstructed in each patient group by using a version of the two-level cell population model of tumor response and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Results: Nonsmall cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractionsS{sub 2} for nonsmall cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S{sub 2} reconstructed from tumor volume variation agree with the PDF measured in vitro. Conclusions: The data obtained

  4. Microglia-glioma cross-talk: a two way approach to new strategies against glioma.

    PubMed

    Arcuri, Cataldo; Fioretti, Bernard; Bianchi, Roberta; Mecca, Carmen; Tubaro, Claudia; Beccari, Tommaso; Franciolini, Fabio; Giambanco, Ileana; Donato, Rosario

    2017-01-01

    Glioblastoma (GBM) is the most malignant and aggressive among primary brain tumors, characterized by very low life expectancy. In vivo, glioma and glioblastoma in particular contain large numbers of immune cells (myeloid cells) such as microglia and tumour-infiltrating macrophages (or glioma associated macrophages). These glioma-infiltrating myeloid cells comprise up to 30% of total tumor mass and have been suggested to play several roles in glioma progression including proliferation, survival, motility and immunosuppression. Although tumor microglia and macrophages can acquire proinflammatory (M1) phenotype being capable of releasing proinflammatory cytokines, phagocytosing and presenting antigens, their effector immune function in gliomas appears to be suppressed by the acquisition of an anti-inflammatory (M2) phenotype. In the present work we review the microglia-glioma interactions to highlight the close relationship between the two cell types and the factors that can influence their properties (chemokines, cytokines, S100B protein). A future therapeutic possibility might be to simultaneously targeting, for example with nanomedicine, glioma cells and microglia to push the microglia towards an antitumor phenotype (M1) and/or prevent glioma cells from "conditioning" by microglia.

  5. Inherited predisposition to glioma

    PubMed Central

    Kyritsis, Athanassios P.; Bondy, Melissa L.; Rao, Jasti S.; Sioka, Chrissa

    2010-01-01

    In gliomas, germline gene alterations play a significant role during malignant transformation of progenitor glial cells, at least for families with occurrence of multiple cancers or with specific hereditary cancer syndromes. Scientific evidence during the last few years has revealed several constitutive genetic abnormalities that may influence glioma formation. These germline abnormalities are manifested as either gene polymorphisms or hemizygous mutations of key regulatory genes that are involved either in DNA repair or in apoptosis. Such changes, among others, include hemizygous alterations of the neurofibromatosis 1 (NF1) and p53 genes that are involved in apoptotic pathways, and alterations in multiple DNA repair genes such as mismatch repair (MMR) genes, x-ray cross-complementary genes (XRCC), and O6-methylguanine-DNA methyltransferase (MGMT) genes. Subsequent cellular changes include somatic mutations in cell cycle regulatory genes and genes involved in angiogenesis and invasion, leading eventually to tumor formation in various stages. Future molecular diagnosis may identify new genomic regions that could harbor genes important for glioma predisposition and aid in the early diagnosis of these patients and genetic counseling of their families. PMID:20150373

  6. Antiproliferative effect of thalidomide alone and combined with carmustine against C6 rat glioma

    PubMed Central

    Arrieta, Oscar; Guevara, Patricia; Tamariz, Joaquín; Rembao, Daniel; Rivera, Erika; Sotelo, Julio

    2002-01-01

    Thalidomide could have therapeutic applications in neoplasms and in other diseases, particularly those of autoimmune origin. The objective of this study was to investigate the effect of various doses of thalidomide on the growth of C6 glioma in rats, and to determine its effects on parameters of cell proliferation and angiogenesis. Additionally, we investigated a potential enhancement of the antitumoral action of thalidomide when combined with a low dose of the antineoplastic carmustine. C6 glioma cells were implanted subcutaneously in Wistar rats. A highly malignant glioma developed in 80% of animals. When the tumour reached 2.0 cm diameter thalidomide was administered at doses of 100, 200 or 400 mg/kg/day. When given at a dose of 400 mg/kg/day thalidomide significantly reduced the tumour volume, the mitotic index and cell proliferation but not the vascular density. The combination of thalidomide plus carmustine increased the inhibitory effect on tumoral growth. Our results indicate that thalidomide is effective against malignant glioma; apparently by an antiproliferative effect, rather than by inhibition of angiogenesis; when combined with carmustine it could increase the response of glioma to antineoplastic treatment. PMID:12084046

  7. Impact of the coxsackie and adenovirus receptor (CAR) on glioma cell growth and invasion: requirement for the C-terminal domain.

    PubMed

    Huang, Kuo-Cheng; Altinoz, Meric; Wosik, Karolina; Larochelle, Nancy; Koty, Zafiro; Zhu, Lixia; Holland, Paul C; Nalbantoglu, Josephine

    2005-02-20

    Expression of the coxsackie and adenovirus receptor (CAR) is downregulated in malignant glioma cell lines and is barely detectable in high-grade primary astrocytoma (glioblastoma multiforme). We determined the effect of forced CAR expression on the invasion and growth of the human glioma cell line U87-MG, which does not express any CAR. Although retrovirally mediated expression of full-length CAR in U87-MG cells did not affect monolayer growth in vitro, it did reduce glioma cell invasion in a 3-dimensional spheroid model. Furthermore, in xenograft experiments, intracerebral implantation of glioma cells expressing full-length CAR resulted in tumors with a significantly reduced volume compared to tumors generated by control vector-transduced U87-MG cells. In contrast, U87-MG cells expressing transmembrane CAR with a deletion of the entire cytoplasmic domain (except for the first 2 intracellular juxtamembrane cysteine amino acids) had rates of invasion and tumor growth that were similar to those of the control cells. This difference in behavior between the 2 forms of CAR was not due to improper cell surface localization of the cytoplasmically deleted CAR as determined by comparable immunostaining of unpermeabilized cells, equivalent adenoviral transduction of the cells and similar extent of fractionation into lipid-rich domains. Taken together, these results suggest that the decrease or loss of CAR expression in malignant glioma may confer a selective advantage in growth and invasion to these tumors.

  8. Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel.

    PubMed

    Zacher, Angela; Kaulich, Kerstin; Stepanow, Stefanie; Wolter, Marietta; Köhrer, Karl; Felsberg, Jörg; Malzkorn, Bastian; Reifenberger, Guido

    2017-03-01

    Current classification of gliomas is based on histological criteria according to the World Health Organization (WHO) classification of tumors of the central nervous system. Over the past years, characteristic genetic profiles have been identified in various glioma types. These can refine tumor diagnostics and provide important prognostic and predictive information. We report on the establishment and validation of gene panel next generation sequencing (NGS) for the molecular diagnostics of gliomas. We designed a glioma-tailored gene panel covering 660 amplicons derived from 20 genes frequently aberrant in different glioma types. Sensitivity and specificity of glioma gene panel NGS for detection of DNA sequence variants and copy number changes were validated by single gene analyses. NGS-based mutation detection was optimized for application on formalin-fixed paraffin-embedded tissue specimens including small stereotactic biopsy samples. NGS data obtained in a retrospective analysis of 121 gliomas allowed for their molecular classification into distinct biological groups, including (i) isocitrate dehydrogenase gene (IDH) 1 or 2 mutant astrocytic gliomas with frequent α-thalassemia/mental retardation syndrome X-linked (ATRX) and tumor protein p53 (TP53) gene mutations, (ii) IDH mutant oligodendroglial tumors with 1p/19q codeletion, telomerase reverse transcriptase (TERT) promoter mutation and frequent Drosophila homolog of capicua (CIC) gene mutation, as well as (iii) IDH wildtype glioblastomas with frequent TERT promoter mutation, phosphatase and tensin homolog (PTEN) mutation and/or epidermal growth factor receptor (EGFR) amplification. Oligoastrocytic gliomas were genetically assigned to either of these groups. Our findings implicate gene panel NGS as a promising diagnostic technique that may facilitate integrated histological and molecular glioma classification.

  9. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.

    PubMed

    Melin, Beatrice S; Barnholtz-Sloan, Jill S; Wrensch, Margaret R; Johansen, Christoffer; Il'yasova, Dora; Kinnersley, Ben; Ostrom, Quinn T; Labreche, Karim; Chen, Yanwen; Armstrong, Georgina; Liu, Yanhong; Eckel-Passow, Jeanette E; Decker, Paul A; Labussière, Marianne; Idbaih, Ahmed; Hoang-Xuan, Khe; Di Stefano, Anna-Luisa; Mokhtari, Karima; Delattre, Jean-Yves; Broderick, Peter; Galan, Pilar; Gousias, Konstantinos; Schramm, Johannes; Schoemaker, Minouk J; Fleming, Sarah J; Herms, Stefan; Heilmann, Stefanie; Nöthen, Markus M; Wichmann, Heinz-Erich; Schreiber, Stefan; Swerdlow, Anthony; Lathrop, Mark; Simon, Matthias; Sanson, Marc; Andersson, Ulrika; Rajaraman, Preetha; Chanock, Stephen; Linet, Martha; Wang, Zhaoming; Yeager, Meredith; Wiencke, John K; Hansen, Helen; McCoy, Lucie; Rice, Terri; Kosel, Matthew L; Sicotte, Hugues; Amos, Christopher I; Bernstein, Jonine L; Davis, Faith; Lachance, Dan; Lau, Ching; Merrell, Ryan T; Shildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Scheurer, Michael; Shete, Sanjay; Lai, Rose K; Claus, Elizabeth B; Olson, Sara H; Jenkins, Robert B; Houlston, Richard S; Bondy, Melissa L

    2017-03-27

    Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10(-9), odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10(-10), OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10(-8), OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10(-11), OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10(-10), OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10(-9), OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10(-10), OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10(-10), OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10(-9), OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10(-8), OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10(-10), OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10(-11), OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10(-9), OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  10. The Effect of Antitumor Glycosides on Glioma Cells and Tissues as Studied by Proton HR-MAS NMR Spectroscopy

    PubMed Central

    García-Álvarez, Isabel; Garrido, Leoncio; Romero-Ramírez, Lorenzo; Nieto-Sampedro, Manuel; Fernández-Mayoralas, Alfonso; Campos-Olivas, Ramón

    2013-01-01

    The effect of the treatment with glycolipid derivatives on the metabolic profile of intact glioma cells and tumor tissues, investigated using proton high resolution magic angle spinning (1H HR-MAS) nuclear magnetic resonance (NMR) spectroscopy, is reported here. Two compounds were used, a glycoside and its thioglycoside analogue, both showing anti-proliferative activity on glioma C6 cell cultures; however, only the thioglycoside exhibited antitumor activity in vivo. At the drug concentrations showing anti-proliferative activity in cell culture (20 and 40 µM), significant increases in choline containing metabolites were observed in the 1H NMR spectra of the same intact cells. In vivo experiments in nude mice bearing tumors derived from implanted C6 glioma cells, showed that reduction of tumor volume was associated with significant changes in the metabolic profile of the same intact tumor tissues; and were similar to those observed in cell culture. Specifically, the activity of the compounds is mainly associated with an increase in choline and phosphocholine, in both the cell cultures and tumoral tissues. Taurine, a metabolite that has been considered a biomarker of apoptosis, correlated with the reduction of tumor volume. Thus, the results indicate that the mode of action of the glycoside involves, at least in part, alteration of phospholipid metabolism, resulting in cell death. PMID:24194925

  11. Targeting different types of human meningioma and glioma cells using a novel adenoviral vector expressing GFP-TRAIL fusion protein from hTERT promoter

    PubMed Central

    2011-01-01

    Objective The objective of this study was to evaluate the anti-tumor effects of Ad/gTRAIL (an adenoviral vector in which expression of GFP and TRAIL is driven by a human telomerase reverse transcriptase promoter, hTERT) on malignant meningiomas and gliomas. Background Gliomas and meningiomas are the two most common types of human brain tumors. Currently there is no effective cure for recurrent malignant meningiomas or for gliomas. Ad/gTRAIL has been shown to be effective in killing selected lung, colon and breast cancer cells, but there have been no studies reporting its antitumor effects on malignant meningiomas. Therefore, we tested the antitumor effect of Ad/gTRAIL for the first time in human malignant meningioma and glioma cell lines, and in intracranial M6 and U87 xenografts. Methods Materials and Methods: Human malignant meningioma and glioma cells were infected with adenoviruses, Ad/gTRAIL and Ad/CMV-GFP. Cell viability was determined by proliferation assay. FACS analysis and quantification of TRAIL were used to measure apoptosis in these cells. We injected Ad/gTRAIL viruses in intracranial M6 and U87 xenografts, and measured the brain tumor volume, quantified apoptosis by TUNEL assay in the brain tumor tissue. Results Our studies demonstrate that in vitro/in vivo treatment with Ad/gTRAIL virus resulted in significant increase of TRAIL activity, and elicited a greater tumor cell apoptosis in malignant brain tumor cells as compared to treatment with the control, Ad/CMV-GFP virus without TRAIL activity. Conclusions We showed for the first time that adenovirus Ad/gTRAIL had significant antitumor effects against high grade malignant meningiomas as well as gliomas. Although more work needs to be done, our data suggests that Ad/gTRAIL has the potential to be useful as a tool against malignant brain tumors. PMID:22035360

  12. Glial Progenitors as Targets for Transformation in Glioma

    PubMed Central

    Ilkanizadeh, Shirin; Lau, Jasmine; Huang, Miller; Foster, Daniel J.; Wong, Robyn; Frantz, Aaron; Wang, Susan; Weiss, William A.; Persson, Anders I.

    2014-01-01

    Glioma is the most common primary malignant brain tumor and arises throughout the central nervous system (CNS). Recent focus on stem-like glioma cells has implicated neural stem cells (NSCs), a minor precursor population restricted to germinal zones, as a potential source of gliomas. In this review, we will focus on the relationship between oligodendrocyte progenitor cells (OPCs), the largest population of cycling glial progenitors in the postnatal brain, and gliomas. Recent studies suggest that OPCs can give rise to gliomas. Furthermore, signaling pathways often associated with NSCs also play key roles during OPC lineage development. Recent advances suggesting that gliomas can undergo a switch from progenitor- to stem-like phenotype after therapy, implicating that an OPC-origin is more likely than previously recognized. Future in-depth studies of OPC biology may shed light on the etiology of OPC-derived gliomas and reveal new therapeutic avenues. PMID:24889528

  13. Enhanced detection and comprehensive in situ phenotypic characterization of circulating and disseminated heteroploid epithelial and glioma tumor cells

    PubMed Central

    Wang, Daisy Dandan; Li, Linda; Lin, Peter Ping

    2015-01-01

    Conventional strategy of anti-EpCAM capture and immunostaining of cytokeratins (CKs) to detect circulating tumor cells (CTCs) is limited by highly heterogeneous and dynamic expression or absence of EpCAM and/or CKs in CTCs. In this study, a novel integrated cellular and molecular approach of subtraction enrichment (SE) and immunostaining-FISH (iFISH) was successfully developed. Both large or small size CTCs and circulating tumor microemboli (CTM) in various biofluid samples including cerebrospinal fluid (CSF) of cancer patients and patient-derived-xenograft (PDX) mouse models were efficiently enriched and comprehensively identified and characterized by SE-iFISH. Non-hematopoietic CTCs with heteroploid chromosome 8 were detected in 87–92% of lung, esophageal and gastric cancer patients. Characterization of CTCs performed by CK18-iFISH showed that CK18, the dual epithelial marker and tumor biomarker, was strong positive in only 14% of lung and 24% of esophageal CTCs, respectively. Unlike conventional methodologies restricted only to the large and/or both EpCAM and CK positive CTCs, SE-iFISH enables efficient enrichment and performing in situ phenotypic and karyotypic identification and characterization of the highly heterogeneous CTC subtypes classified by both chromosome ploidy and the expression of various tumor biomarkers. Each CTC subtype may possess distinct clinical significance relative to tumor metastasis, relapse, therapeutic drug sensitivity or resistance, etc. PMID:26267323

  14. Rehabilitation of patients with glioma.

    PubMed

    Vargo, Mary; Henriksson, Roger; Salander, Pär

    2016-01-01

    Disabling sequelae occur in a majority of patients diagnosed with brain tumor, including glioma, such as cognitive deficits, weakness, and visual perceptual changes. Often, multiple impairments are present concurrently. Healthcare staff must be aware of the "biographic disruption" the patient with glioma has experienced. While prognostic considerations factor into rehabilitation goals and expectations, regardless of prognosis the treatment team must offer cohesive support, facilitating hope, function, and quality of life. Awareness of family and caregiver concerns plays an important role in the overall care. Inpatient rehabilitation, especially after surgical resection, has been shown to result in functional improvement and homegoing rates on a par with individuals with other neurologic conditions, such as stroke or traumatic brain injury. Community integration comprises a significant element of life satisfaction, as has been shown in childhood glioma survivors. Employment is often affected by the glioma diagnosis, but may be ameliorated, when appropriate, by addressing modifiable factors such as depression, fatigue, or sleep disturbance, or by workplace accommodations. Further research is needed into many facets of rehabilitation in the setting of glioma, including establishing better care models for consistently identifying and addressing functional limitations in this population, measuring outcomes of various levels of rehabilitation care, identifying optimal physical activity strategies, delineating the long-term effects of rehabilitation interventions, and exploring impact of rehabilitation interventions on caregiver burden. The effective elements of cognitive rehabilitation, including transition of cognitive strategies to everyday living, need to be better defined.

  15. Tumor volume of resectable gastric adenocarcinoma on multidetector computed tomography: association with N categories

    PubMed Central

    Li, Hang; Chen, Xiao-li; Li, Jun-ru; Li, Zhen-lin; Chen, Tian-wu; Pu, Hong; Yin, Long-lin; Xu, Guo-hui; Li, Zhen-wen; Reng, Jing; Zhou, Peng; Cheng, Zhu-zhong; Cao, Ying

    2016-01-01

    OBJECTIVE: To determine whether the gross tumor volume of resectable gastric adenocarcinoma on multidetector computed tomography could predict the presence of regional lymph node metastasis and could determine N categories. MATERIALS AND METHODS: A total of 202 consecutive patients with gastric adenocarcinoma who had undergone gastrectomy 1 week after contrast-enhanced multidetector computed tomography were retrospectively identified. The gross tumor volume was evaluated on multidetector computed tomography images. Univariate and multivariate analyses were performed to determine whether the gross tumor volume could predict regional lymph node metastasis, and the Mann-Whitney U test was performed to compare the gross tumor volume among N categories. Additionally, a receiver operating characteristic analysis was performed to identify the accuracy of the gross tumor volume in differentiating N categories. RESULTS: The gross tumor volume could predict regional lymph node metastasis (p<0.0001) in the univariate analysis, and the multivariate analyses indicated that the gross tumor volume was an independent risk factor for regional lymph node metastasis (p=0.005, odds ratio=1.364). The Mann-Whitney U test showed that the gross tumor volume could distinguish N0 from the N1-N3 categories, N0-N1 from N2-N3, and N0-N2 from N3 (all p<0.0001). In the T1-T4a categories, the gross tumor volume could differentiate N0 from the N1-N3 categories (cutoff, 12.3 cm3), N0-N1 from N2-N3 (cutoff, 16.6 cm3), and N0-N2 from N3 (cutoff, 24.6 cm3). In the T4a category, the gross tumor volume could differentiate N0 from the N1-N3 categories (cutoff, 15.8 cm3), N0-N1 from N2-N3 (cutoff, 17.8 cm3), and N0-N2 from N3 (cutoff, 24 cm3). CONCLUSION: The gross tumor volume of resectable gastric adenocarcinoma on multidetector computed tomography could predict regional lymph node metastasis and N categories. PMID:27166769

  16. Targeting immune checkpoints in malignant glioma

    PubMed Central

    Li, Tete; Liu, Yong-Jun; Chen, Wei; Chen, Jingtao

    2017-01-01

    Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the bodys anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered immune privileged and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma. PMID:27756892

  17. Surgical management of low-grade gliomas.

    PubMed

    Gerard, Carter S; Straus, David; Byrne, Richard W

    2014-08-01

    Low-grade gliomas represent a wide spectrum of intra-axial brain tumors with diverse presentations, radiographic and surgical appearances, and prognoses. While there remains a role for biopsy, a growing body of evidence shows that aggressive surgical resection of low-grade gliomas may improve symptoms, extend progression-free survival (PFS), and even cure a select few patients. With the application of preoperative functional imaging, intraoperative navigation, and cortical stimulation, neurosurgeons are able to perform more complete resections while limiting the risk to patients. In this article, we describe the surgical management and current operative techniques used in the treatment of low-grade gliomas.

  18. Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells

    PubMed Central

    Li, Xue-tao; Tang, Wei; Jiang, Ying; Wang, Xiao-min; Wang, Yan-hong; Cheng, Lan; Meng, Xian-sheng

    2016-01-01

    Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood–brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma. PMID:27029055

  19. Mutations in chromatin machinery and pediatric high-grade glioma

    PubMed Central

    Lulla, Rishi R.; Saratsis, Amanda Muhs; Hashizume, Rintaro

    2016-01-01

    Pediatric central nervous system tumors are the most common solid tumor of childhood. Of these, approximately one-third are gliomas that exhibit diverse biological behaviors in the unique context of the developing nervous system. Although low-grade gliomas predominate and have favorable outcomes, up to 20% of pediatric gliomas are high-grade. These tumors are a major contributor to cancer-related morbidity and mortality in infants, children, and adolescents, with long-term survival rates of only 10 to 15%. The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. We review the current perspective on pediatric high-grade glioma genetics and epigenetics, and discuss the emerging and experimental therapeutics targeting the unique molecular abnormalities present in these deadly childhood brain tumors. PMID:27034984

  20. Depot delivery of dexamethasone and cediranib for the treatment of brain tumor associated edema in an intracranial rat glioma model.

    PubMed

    Ong, Qunya; Hochberg, Fred H; Cima, Michael J

    2015-11-10

    Treatments of brain tumor associated edema with systemically delivered dexamethasone, the standard of care, and cediranib, a novel anti-edema agent, are associated with systemic toxicities in brain tumor patients. A tunable, reservoir-based drug delivery device was developed to investigate the effects of delivering dexamethasone and cediranib locally in the brain in an intracranial 9L gliosarcoma rat model. Reproducible, sustained releases of both dexamethasone and solid dispersion of cediranib in polyvinylpyrrolidone (AZD/PVP) from these devices were achieved. The water-soluble AZD/PVP, which exhibited similar bioactivity as cediranib, was developed to enhance the release of cediranib from the device. Local and systemic administration of both dexamethasone and cediranib was equally efficacious in alleviating edema but had no effect on tumor growth. Edema reduction led to modest but significant improvement in survival. Local delivery of dexamethasone prevented dexamethasone-induced weight loss, an adverse effect seen in animals treated with systemic dexamethasone. Local deliveries of dexamethasone and cediranib via these devices used only 2.36% and 0.21% of the systemic doses respectively, but achieved similar efficacy as systemic drug deliveries without the side effects associated with systemic administration. Other therapeutic agents targeting brain tumor can be delivered locally in the brain to provide similar improved treatment outcomes.

  1. Receptor-Mediated Drug Delivery Systems Targeting to Glioma

    PubMed Central

    Wang, Shanshan; Meng, Ying; Li, Chengyi; Qian, Min; Huang, Rongqin

    2015-01-01

    Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications.

  2. Oncolytic adenoviruses: A thorny path to glioma cure

    PubMed Central

    Ulasov, I.V.; Borovjagin, A.V.; Schroeder, B.A.; Baryshnikov, A.Y.

    2014-01-01

    Glioblastoma Multiforme (GBM) is a rapidly progressing brain tumor. Despite the relatively low percentage of cancer patients with glioma diagnoses, recent statistics indicate that the number of glioma patients may have increased over the past decade. Current therapeutic options for glioma patients include tumor resection, chemotherapy, and concomitant radiation therapy with an average survival of approximately 16 months. The rapid progression of gliomas has spurred the development of novel treatment options, such as cancer gene therapy and oncolytic virotherapy. Preclinical testing of oncolytic adenoviruses using glioma models revealed both positive and negative sides of the virotherapy approach. Here we present a detailed overview of the glioma virotherapy field and discuss auxiliary therapeutic strategies with the potential for augmenting clinical efficacy of GBM virotherapy treatment. PMID:25685829

  3. Iterative volume morphing and learning for mobile tumor based on 4DCT

    NASA Astrophysics Data System (ADS)

    Mao, Songan; Wu, Huanmei; Sandison, George; Fang, Shiaofen

    2017-02-01

    During image-guided cancer radiation treatment, three-dimensional (3D) tumor volumetric information is important for treatment success. However, it is typically not feasible to image a patient’s 3D tumor continuously in real time during treatment due to concern over excessive patient radiation dose. We present a new iterative morphing algorithm to predict the real-time 3D tumor volume based on time-resolved computed tomography (4DCT) acquired before treatment. An offline iterative learning process has been designed to derive a target volumetric deformation function from one breathing phase to another. Real-time volumetric prediction is performed to derive the target 3D volume during treatment delivery. The proposed iterative deformable approach for tumor volume morphing and prediction based on 4DCT is innovative because it makes three major contributions: (1) a novel approach to landmark selection on 3D tumor surfaces using a minimum bounding box; (2) an iterative morphing algorithm to generate the 3D tumor volume using mapped landmarks; and (3) an online tumor volume prediction strategy based on previously trained deformation functions utilizing 4DCT. The experimental performance showed that the maximum morphing deviations are 0.27% and 1.25% for original patient data and artificially generated data, which is promising. This newly developed algorithm and implementation will have important applications for treatment planning, dose calculation and treatment validation in cancer radiation treatment.

  4. Iterative volume morphing and learning for mobile tumor based on 4DCT.

    PubMed

    Mao, Songan; Wu, Huanmei; Sandison, George; Fang, Shiaofen

    2017-02-21

    During image-guided cancer radiation treatment, three-dimensional (3D) tumor volumetric information is important for treatment success. However, it is typically not feasible to image a patient's 3D tumor continuously in real time during treatment due to concern over excessive patient radiation dose. We present a new iterative morphing algorithm to predict the real-time 3D tumor volume based on time-resolved computed tomography (4DCT) acquired before treatment. An offline iterative learning process has been designed to derive a target volumetric deformation function from one breathing phase to another. Real-time volumetric prediction is performed to derive the target 3D volume during treatment delivery. The proposed iterative deformable approach for tumor volume morphing and prediction based on 4DCT is innovative because it makes three major contributions: (1) a novel approach to landmark selection on 3D tumor surfaces using a minimum bounding box; (2) an iterative morphing algorithm to generate the 3D tumor volume using mapped landmarks; and (3) an online tumor volume prediction strategy based on previously trained deformation functions utilizing 4DCT. The experimental performance showed that the maximum morphing deviations are 0.27% and 1.25% for original patient data and artificially generated data, which is promising. This newly developed algorithm and implementation will have important applications for treatment planning, dose calculation and treatment validation in cancer radiation treatment.

  5. White Matter Change Revealed by Diffusion Tensor Imaging in Gliomas

    PubMed Central

    Won, Young Il; Kim, Chi Heon; Park, Chul-Kee; Koo, Bang-Bon; Lee, Jong-Min; Jung, Hee-Won

    2016-01-01

    Background Tumor-related white matter change is detected at late stages with magnetic resonance imaging (MRI), when mass effect or prominent edema is present. We analyzed if diffusion tensor imaging (DTI) white matter change earlier than conventional MRI. Methods Twenty-six patients with gliomas (World Health Organization grade II, 5; grade III, 12; and grade IV, 9) within 2 cm from the posterior limb of the internal capsule (IC) were studied. Fifteen normal adults were enrolled as controls. Fluid attenuation inversion recovery MRI showed a high signal change at the posterior limb of the IC (HSIC) in 9 patients with grade III or IV gliomas. We classified the gliomas as WHO grade II (gliomas II), grade III or IV without HSIC [gliomas III/IV(-)] and grade III or IV with HSIC [gliomas III/IV(+)], as an indicator of the increase in the severity of the white matter changes. Fractional anisotropy (FA) and apparent diffusion coefficients (ADC) were calculated for the pyramidal tract. Tumor progression along pyramidal tract was evaluated by follow-up MRI in 16 patients at 40±18 months. Results FA showed no significant difference between gliomas II and control (p=0.694), but was lower in gliomas III/IV(-) and gliomas III/IV(+) (p<0.001). ADCs were higher in gliomas II, gliomas III/IV(-) and gliomas III/IV(+) than control (p<0.001). Tumor progression was detected in 2/16 patients. Conclusion DTI detected white matter changes that appeared to be normal in MRI. ADC changed even in low grade glioma, indicating ADC may be a better parameter for the early detection of white matter change. PMID:27867919

  6. Stochastic modeling of the tumor volume assessment and growth patterns in hepatocellular carcinoma.

    PubMed

    Sãftoiu, Adrian; Ciurea, Tudorel; Gorunescu, Florin; Rogoveanu, Ion; Georgescu, Claudia

    2004-06-01

    The growth pattern of hepatocellular carcinoma (HCC) arising from cirrhosis is variable and depends on the degree of differentiation and vascularization. Because growth is not constant in the natural history of HCC, prediction of subsequent growth rate based on tumor volume doubling time and correlation with histological and ultrasonographical characteristics at the moment of initial diagnosis are usually unreliable. The aim of our study was to assess the growth patterns of HCC with the aid of stochastic modeling. Thus, we included in our study 27 patients with histologically proven HCC, which had multiple (more than three)follow-up ultrasound studies in a six months interval. The patients did not receive any treatment during the observation period. HCC was visualized by computer aided ultrasound imaging, obtaining both the primary size quantification and the edge-detection enhancement. By a bi-cubic B-spline interpolation of points on the edges (3-D Bezier approximation) we approximated the surfaces shapes, and using the hit or miss Monte Carlo method we accurately estimate the tumor volume. Starting from the previous tumor volumes time series recorded during the first six months of evolution we applied both a linear, exponential and logarithmic smoothing to forecast the future size of the HCC tumor in the next six months. Our conclusion was that a dynamic forecasting model of HCC volumes could be very accurate for the assessment of tumor volume doubling time usually obtained by two discrete volume measurements of the tumor.

  7. Targeted Radiolabeled Compounds in Glioma Therapy.

    PubMed

    Cordier, Dominik; Krolicki, Leszek; Morgenstern, Alfred; Merlo, Adrian

    2016-05-01

    Malignant gliomas of World Health Organization (WHO) grades II-IV represent the largest entity within the group of intrinsic brain tumors and are graded according to their pathophysiological features with survival times between more than 10 years (WHO II) and only several months (WHO IV). Gliomas arise from astrocytic or oligodendrocytic precursor cells and exhibit an infiltrative growth pattern lacking a clearly identifiable tumor border. The development of effective treatment strategies of the invasive tumor cell front represents the main challenge in glioma therapy. The therapeutic standard consists of surgical resection and, depending on the extent of resection and WHO grade, adjuvant external beam radiotherapy or systemic chemotherapy. Within the last decades, there has been no major improvement of the prognosis of patients with glioma. The consistent overexpression of neurokinin type 1 receptors in gliomas WHO grades II-IV has been used to develop a therapeutic substance P-based targeting system. A substance P-analogue conjugated to the DOTA or DOTAGA chelator has been labeled with different alpha-particle or beta-particle emitting radionuclides for targeted glioma therapy. The radiopharmaceutical has been locally injected into the tumors or the resection cavity. In several clinical studies, the methodology has been examined in adjuvant and neoadjuvant clinical settings. Although no large controlled series have so far been generated, the results of radiolabeled substance P-based targeted glioma therapy compare favorably with standard therapy. Recently, labeling with the alpha particle emitting Bi-213 has been found to be promising due to the high linear energy transfer and the very short tissue range of 0.08 mm. Further development needs to focus on the improvement of the stability of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within the prognostically critical

  8. Use of EF5 to Measure the Oxygen Level in Tumor Cells of Patients Undergoing Surgery or Biopsy for Newly Diagnosed Supratentorial Malignant Glioma

    ClinicalTrials.gov

    2013-01-15

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymoma

  9. Tumor Volume Is a Prognostic Factor in Non-Small-Cell Lung Cancer Treated With Chemoradiotherapy

    SciTech Connect

    Alexander, Brian M.; Othus, Megan; Caglar, Hale B.

    2011-04-01

    Purpose: To investigate whether primary tumor and nodal volumes defined on radiotherapy planning scans are correlated with outcome (survival and recurrence) after combined-modality treatment. Methods and Materials: A retrospective review of patients with Stage III non-small-cell lung cancer treated with chemoradiation at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2000 to 2006 was performed. Tumor and nodal volume measurements, as computed by Eclipse (Varian, Palo Alto, CA), were used as independent variables, along with existing clinical factors, in univariate and multivariate analyses for association with outcomes. Results: For patients treated with definitive chemoradiotherapy, both nodal volume (hazard ratio [HR], 1.09; p < 0.01) and tumor volume (HR, 1.03; p < 0.01) were associated with overall survival on multivariate analysis. Both nodal volume (HR, 1.10; p < 0.01) and tumor volume (HR, 1.04; p < 0.01) were also associated with local control but not distant metastases. Conclusions: In addition to traditional surgical staging variables, disease burden, measured by primary tumor and nodal metastases volume, provides information that may be helpful in determining prognosis and identifying groups of patients for which more aggressive local therapy is warranted.

  10. Characteristics of gliomas in patients with somatic IDH mosaicism.

    PubMed

    Bonnet, Charlotte; Thomas, Laure; Psimaras, Dimitri; Bielle, Franck; Vauléon, Elodie; Loiseau, Hugues; Cartalat-Carel, Stéphanie; Meyronet, David; Dehais, Caroline; Honnorat, Jérôme; Sanson, Marc; Ducray, François

    2016-03-31

    IDH mutations are found in the majority of adult, diffuse, low-grade and anaplastic gliomas and are also frequently found in cartilaginous tumors. Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to post-zygotic acquisition of IDH mutations. In addition to skeletal tumors, enchondromatosis patients sometimes develop gliomas. The aim of the present study was to determine whether gliomas in enchondromatosis patients might also result from somatic IDH mosaicism and whether their characteristics are similar to those of sporadic IDH-mutated gliomas. For this purpose, we analyzed the characteristics of 6 newly diagnosed and 32 previously reported cases of enchondromatosis patients who developed gliomas and compared them to those of a consecutive series of 159 patients with sporadic IDH-mutated gliomas. As was the case with sporadic IDH mutated gliomas, enchondromatosis gliomas were frequently located in the frontal lobe (54 %) and consisted of diffuse low-grade (73 %) or anaplastic gliomas (21 %). However, they were diagnosed at an earlier age (25.6 years versus 44 years, p < 0.001) and were more frequently multicentric (32 % versus 1 %, p < 0.001) and more frequently located within the brainstem than sporadic IDH mutated gliomas (21 % versus 1 %, p < 0.001). Their molecular profile was characterized by IDH mutations and loss of ATRX expression. In two patients, the same IDH mutation was demonstrated in the glioma and in a cartilaginous tumor. In contrast to sporadic IDH mutated gliomas, no enchondromatosis glioma harbored a 1p/19q co-deletion (0/6 versus 59/123, p = 0.03). The characteristics of gliomas in patients with enchondromatosis suggest that these tumors, as cartilaginous tumors, result from somatic IDH mosaicism and that the timing of IDH mutation acquisition might affect the location and molecular characteristics of gliomas. Early

  11. Correlation between tumor regression grade and rectal volume in neoadjuvant concurrent chemoradiotherapy for rectal cancer

    PubMed Central

    Lee, Hong Seok; Choi, Doo Ho; Park, Hee Chul; Park, Won; Yu, Jeong Il; Chung, Kwangzoo

    2016-01-01

    Purpose To determine whether large rectal volume on planning computed tomography (CT) results in lower tumor regression grade (TRG) after neoadjuvant concurrent chemoradiotherapy (CCRT) in rectal cancer patients. Materials and Methods We reviewed medical records of 113 patients treated with surgery following neoadjuvant CCRT for rectal cancer between January and December 2012. Rectal volume was contoured on axial images in which gross tumor volume was included. Average axial rectal area (ARA) was defined as rectal volume divided by longitudinal tumor length. The impact of rectal volume and ARA on TRG was assessed. Results Average rectal volume and ARA were 11.3 mL and 2.9 cm². After completion of neoadjuvant CCRT in 113 patients, pathologic results revealed total regression (TRG 4) in 28 patients (25%), good regression (TRG 3) in 25 patients (22%), moderate regression (TRG 2) in 34 patients (30%), minor regression (TRG 1) in 24 patients (21%), and no regression (TRG0) in 2 patients (2%). No difference of rectal volume and ARA was found between each TRG groups. Linear correlation existed between rectal volume and TRG (p = 0.036) but not between ARA and TRG (p = 0.058). Conclusion Rectal volume on planning CT has no significance on TRG in patients receiving neoadjuvant CCRT for rectal cancer. These results indicate that maintaining minimal rectal volume before each treatment may not be necessary. PMID:27592514

  12. Enhanced and selective delivery of enzyme therapy to 9L-glioma tumor via magnetic targeting of PEG-modified, β-glucosidase-conjugated iron oxide nanoparticles

    PubMed Central

    Zhou, Jie; Zhang, Jian; Gao, Wenxi

    2014-01-01

    The stability of enzyme-conjugated magnetic iron oxide nanoparticles in plasma is of great importance for in vivo delivery of the conjugated enzyme. In this study, β-glucosidase was conjugated on aminated magnetic iron oxide nanoparticles using the glutaraldehyde method (β-Glu-MNP), and further PEGylated via N-hydroxysuccinimide chemistry. The PEG-modified, β-glucosidase-immobilized magnetic iron oxide nanoparticles (PEG-β-Glu-MNPs) were characterized by hydrodynamic diameter distribution, zeta potential, Fourier transform infrared spectroscopy, transmission electron microscopy, and a superconducting quantum interference device. The results showed that the multidomain structure and magnetization properties of these nanoparticles were conserved well throughout the synthesis steps, with an expected diameter increase and zeta potential shifts. The Michaelis constant was calculated to evaluate the activity of conjugated β-glucosidase on the magnetic iron oxide nanoparticles, indicating 73.0% and 65.4% of enzyme activity remaining for β-Glu-MNP and PEG-β-Glu-MNP, respectively. Both magnetophoretic mobility analysis and pharmacokinetics showed improved in vitro/in vivo stability of PEG-β-Glu-MNP compared with β-Glu-MNP. In vivo magnetic targeting of PEG-β-Glu-MNP was confirmed by magnetic resonance imaging and electron spin resonance analysis in a mouse model of subcutaneous 9L-glioma. Satisfactory accumulation of PEG-β-Glu-MNP in tumor tissue was successfully achieved, with an iron content of 627±45 nmol Fe/g tissue and β-glucosidase activity of 32.2±8.0 mU/g tissue. PMID:24959078

  13. Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

    SciTech Connect

    Dai, Bin; Hu, Zhiqiang; Huang, Hui; Zhu, Guangtong; Xiao, Zhiyong; Wan, Weiqing; Zhang, Peng; Jia, Wang; Zhang, Liwei

    2014-11-07

    Highlights: • KDM5B is overexpressed in glioma samples. • KDM5B stimulated proliferation of glioma cells. • Inhibition of p21contributes to KDM5B-induced proliferation. - Abstract: Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Upregulation of lysine (K)-specific demethylase 5B (KDM5B) has been reported in a variety of malignant tumors. However, the impact of KDM5B in glioma remains unclear. The objective of this study was to investigate the expression and prognostic value of KDM5B in glioma. In clinical glioma samples, we found that KDM5B expression was significantly upregulated in cancer lesions compared with normal brain tissues. Kaplan–Meier analysis showed that patients with glioma and higher KDM5B expression tend to have shorter overall survival time. By silencing or overexpressing KDM5B in glioma cells, we found that KDM5B could promote cell growth both in vitro and in vivo. Moreover, we demonstrated that KDM5B promoted glioma proliferation partly via regulation of the expression of p21. Our study provided evidence that KDM5B functions as a novel tumor oncogene in glioma and may be a potential therapeutic target for glioma management.

  14. A neurocentric perspective on glioma invasion

    PubMed Central

    Cuddapah, Vishnu Anand; Robel, Stefanie; Watkins, Stacey; Sontheimer, Harald

    2017-01-01

    Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood-brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease. PMID:24946761

  15. Experimental therapy of human glioma by means of a genetically engineered virus mutant

    SciTech Connect

    Martuza, R.L.; Malick, A.; Markert, J.M.; Ruffner, K.L.; Coen, D.M. )

    1991-05-10

    Malignant gliomas are the most common malignant brain tumors and are almost always fatal. A thymidine kinase-negative mutant of herpes simplex virus-1 (dlsptk) that is attenuated for neurovirulence was tested as a possible treatment for gliomas. In cell culture, dlsptk killed two long-term human glioma lines and three short-term human glioma cell populations. In nude mice with implanted subcutaneous and subrenal U87 human gliomas, intraneoplastic inoculation of dlsptk caused growth inhibition. In nude mice with intracranial U87 gliomas, intraneoplastic inoculation of dlsptk prolonged survival. Genetically engineered viruses such as dlsptk merit further evaluation as novel antineoplastic agents.

  16. Treatment Planning and Volumetric Response Assessment for Yttrium-90 Radioembolization: Semiautomated Determination of Liver Volume and Volume of Tumor Necrosis in Patients with Hepatic Malignancy

    SciTech Connect

    Monsky, Wayne L.; Garza, Armando S.; Kim, Isaac; Loh, Shaun; Lin, Tzu-Chun; Li Chinshang; Fisher, Jerron; Sandhu, Parmbir; Sidhar, Vishal; Chaudhari, Abhijit J.; Lin, Frank; Deutsch, Larry-Stuart; Badawi, Ramsey D.

    2011-04-15

    Purpose: The primary purpose of this study was to demonstrate intraobserver/interobserver reproducibility for novel semiautomated measurements of hepatic volume used for Yttrium-90 dose calculations as well as whole-liver and necrotic-liver (hypodense/nonenhancing) tumor volume after radioembolization. The secondary aim was to provide initial comparisons of tumor volumetric measurements with linear measurements, as defined by Response Evaluation Criteria in Solid Tumors criteria, and survival outcomes. Methods: Between 2006 and 2009, 23 consecutive radioembolization procedures were performed for 14 cases of hepatocellular carcinoma and 9 cases of hepatic metastases. Baseline and follow-up computed tomography obtained 1 month after treatment were retrospectively analyzed. Three observers measured liver, whole-tumor, and tumor-necrosis volumes twice using semiautomated software. Results: Good intraobserver/interobserver reproducibility was demonstrated (intraclass correlation [ICC] > 0.9) for tumor and liver volumes. Semiautomated measurements of liver volumes were statistically similar to those obtained with manual tracing (ICC = 0.868), but they required significantly less time to perform (p < 0.0001, ICC = 0.088). There was a positive association between change in linear tumor measurements and whole-tumor volume (p < 0.0001). However, linear measurements did not correlate with volume of necrosis (p > 0.05). Dose, change in tumor diameters, tumor volume, and necrotic volume did not correlate with survival (p > 0.05 in all instances). However, Kaplan-Meier curves suggest that a >10% increase in necrotic volume correlated with survival (p = 0.0472). Conclusion: Semiautomated volumetric analysis of liver, whole-tumor, and tumor-necrosis volume can be performed with good intraobserver/interobserver reproducibility. In this small retrospective study, measurements of tumor necrosis were suggested to correlate with survival.

  17. Expression of the galectin-9-Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma.

    PubMed

    Liu, Zengjin; Han, Huamin; He, Xin; Li, Shouwei; Wu, Chenxing; Yu, Chunjiang; Wang, Shengdian

    2016-03-01

    Glioma is known to induce local and systemic immunosuppression, which inhibits antitumor T cell responses. The galectin-9-Tim-3-pathway negatively regulates T cell pathways in the tumor immunosuppressive environment. The present study assessed the expression of Tim-3 and galectin-9 in glioma patients, and evaluated the association between the expression of Tim-3 and galectin-9 with clinical characteristics. The present study identified that Tim-3 expression was significantly increased in peripheral blood T cells of glioma patients compared with those of healthy controls, and was additionally increased on tumor-infiltrating T cells. The expression of Tim-3 on tumor-infiltrating T cells was associated with the World Health Organization (WHO) grade of glioma, but negatively correlated with the Karnofsky Performance Status score of the glioma patients. Immunohistochemical analysis revealed that the expression of galectin-9 in tumor tissues was associated with Tim-3 expression on tumor-infiltrating T cells and the WHO grade of glioma. These findings suggest that the galectin-9-Tim-3 pathway may be critical in the immunoevasion of glioma and may be a potent target for immunotherapy in glioma patients.

  18. Stem cell-mediated delivery of therapies in the treatment of glioma.

    PubMed

    Frosina, G

    2011-06-01

    High grade gliomas can be seldom controlled, due to the infiltrative nature of these tumors and the presence of cell populations resistant to radio- and chemotherapy. Current research aims to develop novel therapeutic approaches to track and eliminate the disseminated glioma-driving cells. Selected delivery of therapeutic agents taking advantage of the tropism of normal stem cells for glioma cells might be one.

  19. [Blood DNA Radiosensitivity May Be Predictive Marker for Efficacy of Radiation Therapy in Glioma Tumorbearing Individuals].

    PubMed

    Ivanov, S D; Korytova, L I; Yamshanov, V A; Zhabina, R M; Semenov, A L; Krasnikova, V G

    2015-01-01

    Animal and clinical studies were conducted to evaluate the association between the blood DNA radiosensitivity, assessed by determining the original S-index ex vivo, and the response of gliomas to irradiation in vivo. Possible modifications of the latter after administration of iron-containing water (ICW) in rats were also explored. The study was performed on the rats with subcutaneously implanted experimental glioma-35. The tumors were locally X-irradiated with a single 15 Gy dose as a radiation therapy (RT). ICW (60-63 mg · Fe 2+/l) was administered as a drinking water for 3 days before treatment. The animals underwent blood sampling for analysis of the DNA concentration and leukocyte count. The DNA index was estimated 24 h after RT. The S-index was evaluated within 4 h before RT. The mean initial S-index in the blood samples of glioma-bearing rats was 0.73 ± 0.05. Addition of ICW ex vivo resulted in a significantly increased S-index in a half of the samples. In general, the irradiated rats, which had been given pretreatment with ICW and demonstrated an ex vivo increase of the S-index to > 1.0, showed the most marked inhibition of tumor progression and the smallest tumor volume 25 days after irradiation. They also exhibited the lowest rate of growth and the longest survival. Determination of the biochemical S-index and evaluation of its changes ex vivo caused by ICW may be predictive of the response of experimental glioma to irradiation with radiomodification. The S-index may serve as a predictive indicator in clinic of the efficient evaluation of RT in patients with glioma.

  20. Sequential imaging and volumetric analysis of an intracerebral C6 glioma by means of a clinical MRI system.

    PubMed

    Raila, F A; Bowles, A P; Perkins, E; Terrell, A

    1999-05-01

    In this study, using high resolution coils; implanted growing rat brain tumors were imaged sequentially with 3-D volume measurements generated by means of a clinical magnetic resonance imaging system (CMRI) and commercially available wrist coil. Ten female Sprague-Dawley rats were used, eight were implanted with C6 rat glioma cells and two served as controls. The images that were used for the three-dimensional (3-D) measurements were obtained from T1 weighted post contrast sequences. A commercially available computer work station with 3-D image analysis software was used to generate the tumor volumes. In addition to the rat studies a mouse was included to see if the resolution would be adequate for imaging very small brains. Six rats had brain tumor growth after transplantation and two rats did not have any tumor growth, however, their images were similar to the controls animals. Tumor volumes varied widely among the implanted rats. The number of implanted tumor cells had no direct relationship to developing tumor volumes. This study demonstrates that high resolution images of a rat brain tumor can be obtained from a CMRI system using a commercially available wrist coil which is capable of imaging two rats at the same time or even a mouse brain. A commercially available computer work station was able to generate the tumor volumes. The ability to image brain tumor and generate volume measurements over time has potential for animal research.

  1. Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology.

    PubMed

    Toonen, Joseph A; Solga, Anne C; Ma, Yu; Gutmann, David H

    2017-01-01

    Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice. We demonstrate that female Nf1-OPG mice exhibit greater retinal ganglion cell (RGC) loss and only females have retinal nerve fiber layer (RNFL) thinning, despite mice of both sexes harboring tumors of identical volumes and proliferation. Female gonadal sex hormones are responsible for this sexual dimorphism, as ovariectomy, but not castration, of Nf1-OPG mice normalizes RGC survival and RNFL thickness. In addition, female Nf1-OPG mice have threefold more microglia than their male counterparts, and minocycline inhibition of microglia corrects the retinal pathology. Moreover, pharmacologic inhibition of microglial estrogen receptor-β (ERβ) function corrects the retinal abnormalities in female Nf1-OPG mice. Collectively, these studies establish that female gonadal sex hormones underlie the sexual dimorphic differences in Nf1 optic glioma-induced retinal dysfunction by operating at the level of tumor-associated microglial activation.

  2. Cystoid angiocentric glioma: A case report and literature review

    PubMed Central

    Cheng, Sainan; Lü, Yubo; Xu, Shangchen; Liu, Qiang; Lee, Pearlene

    2015-01-01

    Angiocentric glioma is a rare subtype of neuroepithelial tumor that is associated with a history of epilepsy. We report a case of cystoid angiocentric glioma associated with an area of calcification. This 25 year old male patient presented with tonic clonic spasm. He underwent craniotomy with complete resection of the lesion. Pathologic specimen showed monomorphous bipolar cells with angiocentric growth pattern. PMID:26629293

  3. Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells.

    PubMed

    Lee, Yean-Jang; Kuo, Hsing-Chun; Chu, Chia-Yih; Wang, Chau-Jong; Lin, Wan-Chyi; Tseng, Tsui-Hwa

    2003-12-15

    Caffeic acid phenethyl ester (CAPE), an active component of propolis, has many biological and pharmacological activities including antioxidant, anti-inflammation, antiviral action, and anticancer effect. Our previous studies showed that CAPE exhibited significant cytotoxicity in oral cancer cells. Herein we further investigated the cytotoxicity potential of CAPE and the mechanism of its action in C6 glioma cells. The data exhibited that C6 glioma cells underwent internucleosomal DNA fragmentation 24 hr after the treatment of CAPE (50 microM). The proportion of C6 glioma cells with hypodiploid nuclei was increased to 24% at 36 hr after the exposure. Further results showed that CAPE induced the release of cytochrome c from mitochondria into cytosol, and the activation of CPP32. CAPE application also enhanced the expression of p53, Bax, and Bak. Finally, the potential signaling components underlying CAPE induction of apoptosis were elucidated. We found that CAPE activated extracellular signal-regulated kinase (ERKs) and p38 mitogen-activated protein kinase (p38 MAPK) in C6 glioma cells. More importantly, p38 kinase formed a complex with p53 after the treatment of CAPE for 0.5 hr. The expression of p53, phospho-serine 15 of p53, and Bax, and inactivate form of CPP32 was suppressed by a pretreatment of a specific p38 MAPK inhibitor, SB203580. The resultant data suggest that p38 MAPK mediated the CAPE-induced p53-dependent apoptosis in C6 glioma cells.

  4. Multigene sets for clinical application in glioma.

    PubMed

    de Groot, John F; Sulman, Erik P; Aldape, Kenneth D

    2011-04-01

    Diffuse gliomas are a heterogeneous group of malignancies with highly variable outcomes, and diagnosis is largely based on histologic appearance. Tumor classification according to cell type and grade provides some prognostic information. However, significant clinical and biologic heterogeneity exists in glioma, even after accounting for known clinicopathologic variables. Significant advances in knowledge of the molecular genetics of brain tumors have occurred in the past decade, largely because of the availability of high-throughput profiling techniques, including new sequencing methodologies and multidimensional profiling by The Cancer Genome Atlas project. The large amount of data generated from these efforts has enabled the identification of prognostic and predictive factors and helped to identify pathways driving tumor growth. Implementing these signatures into the clinic to personalize therapy presents a new challenge. Identification of relevant biomarkers, especially when coupled with clinical trials of newer targeted therapies, will enable better patient stratification and individualization of treatment for patients with glioma.

  5. EFEMP2 is upregulated in gliomas and promotes glioma cell proliferation and invasion

    PubMed Central

    Wang, Long; Chen, Qianxue; Chen, Zhibiao; Tian, Daofeng; Xu, Haitao; Cai, Qiang; Liu, Baohui; Deng, Gang

    2015-01-01

    Gliomas are the most common and aggressive form of primary brain tumor. Although EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2), an extracellular matrix (ECM) glycoprotein, is regarded as a candidate oncogene, little is known about the association of EFEMP2 and gliomas. Here, the expression of EFEMP2 was significantly increased in glioma tissues (n=60) compared to non-tumorous brain tissues (n=25). Silencing of EFEMP2 expression through RNA interference in two glioma cell lines (U87 and U373) remarkably inhibited cell proliferation and G1/S transition. More importantly, EFEMP2 silencing significantly induced cell apoptosis via increasing the ratio of Bax and Bcl-2. Additionally, knockdown of EFEMP2 significantly inhibited the invasive ability of both glioma cells, which was associated with the downregulated expression of metalloproteinase-2 (MMP-2) and MMP-9. In conclusion, expression of EFEMP2 was associated with the oncogenic potential of gliomas and silencing of its expression can suppress cancer cell growth and metastasis. Inhibition of EFEMP2 may be a therapeutic strategy for gliomas. PMID:26617746

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

    ClinicalTrials.gov

    2017-02-20

    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

  7. Volume changes and whole cell membrane currents activated during gradual osmolarity decrease in C6 glioma cells: contribution of two types of K+ channels.

    PubMed

    Ordaz, B; Vaca, L; Franco, R; Pasantes-Morales, H

    2004-06-01

    Volume changes and whole cell ionic currents activated by gradual osmolarity reductions (GOR) of 1.8 mosM/min were characterized in C6 glioma cells. Cells swell less in GOR than after sudden osmolarity reductions (SOR), the extent of swelling being partly Ca(2+) dependent. In nominally Ca(2+)-free conditions, GOR activated predominantly whole cell outward currents. Cells depolarized from the initial -79 mV to a steady state of -54 mV reached at 18% osmolarity reduction [hyposmolarity of -18% (H-18%)]. Recordings of Cl(-) and K(+) currents showed activation at H-3% of an outwardly rectifying Cl(-) current, with conductance of 1.6 nS, sensitive to niflumic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid, followed at H-18% by an outwardly rectifying K(+) current with conductance of 4.1 nS, inhibited by clofilium but insensitive to the typical K(+) channel blockers. With 200 nM Ca(2+) in the patch pipette, whole cell currents activated at H-3% and at H-13% cells depolarized from -77 to -63 mV. A K(+) current activated at H-1%, showing a rapid increase in conductance, suppressed by charybdotoxin and insensitive to clofilium. These results show the operation of two different K(+) channels in response to GOR in the same cell type, activated by Ca(2+) and osmolarity and with different osmolarity activation thresholds. Taurine and glutamate efflux, monitored by labeled tracers, showed delayed osmolarity thresholds of H-39 and H-33%, respectively. This observation clearly separates the Cl(-) and amino acid osmosensitive pathways. The delayed amino acid efflux may contribute to counteract swelling at more stringent osmolarity reductions.

  8. IGFBP2 expression predicts IDH-mutant glioma patient survival.

    PubMed

    Huang, Lin Eric; Cohen, Adam L; Colman, Howard; Jensen, Randy L; Fults, Daniel W; Couldwell, William T

    2017-01-03

    Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas. Furthermore, each of these genes is prognostic in overall gliomas; however, within the IDH-mutant group, none remains prognostic except IGFBP2 (encodinginsulin-like growth factor binding protein 2). Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients. These observations hold true across different histological and molecular subtypes of lower-grade glioma. We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2.

  9. Progress on molecular biomarkers and classification of malignant gliomas.

    PubMed

    Zhang, Chuanbao; Bao, Zhaoshi; Zhang, Wei; Jiang, Tao

    2013-06-01

    Gliomas are the most common primary intracranial tumors in adults. Anaplastic gliomas (WHO grade III) and glioblastomas (WHO grade IV) represent the major groups of malignant gliomas in the brain. Several diagnostic, predictive, and prognostic biomarkers for malignant gliomas have been reported over the last few decades, and these markers have made great contributions to the accuracy of diagnosis, therapeutic decision making, and prognosis of patients. However, heterogeneity in patient outcomes may still be observed, which highlights the insufficiency of a classification system based purely on histopathology. Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment. In this review, we summarize three distinctive biomarkers, three most commonly altered pathways, and three classifications based on microarray data in malignant gliomas.

  10. A mathematical model of pre-diagnostic glioma growth

    PubMed Central

    Sturrock, Marc; Hao, Wenrui; Schwartzbaum, Judith; Rempala, Grzegorz A.

    2015-01-01

    Due to their location, the malignant gliomas of the brain in humans are very difficult to treat in advanced stages. Blood-based biomarkers for glioma are needed for more accurate evaluation of treatment response as well as early diagnosis. However, biomarker research in primary brain tumors is challenging given their relative rarity and genetic diversity. It is further complicated by variations in the permeability of the blood brain barrier that affects the amount of marker released into the bloodstream. Inspired by recent temporal data indicating a possible decrease in serum glucose levels in patients with gliomas yet to be diagnosed, we present an ordinary differential equation model to capture early stage glioma growth. The model contains glioma-glucose-immune interactions and poses a potential mechanism by which this glucose drop can be explained. We present numerical simulations, parameter sensitivity analysis, linear stability analysis and a numerical experiment whereby we show how a dormant glioma can become malignant. PMID:26073722

  11. Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice.

    PubMed

    Ricard, Clement; Fernandez, Manuel; Requardt, Herwig; Wion, Didier; Vial, Jean Claude; Segebarth, Christoph; van der Sanden, Boudewijn

    2013-09-01

    Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.

  12. Revealing the potential pathogenesis of glioma by utilizing a glioma associated protein-protein interaction network.

    PubMed

    Pan, Weiran; Li, Gang; Yang, Xiaoxiao; Miao, Jinming

    2015-04-01

    This study aims to explore the potential mechanism of glioma through bioinformatic approaches. The gene expression profile (GSE4290) of glioma tumor and non-tumor samples was downloaded from Gene Expression Omnibus database. A total of 180 samples were available, including 23 non-tumor and 157 tumor samples. Then the raw data were preprocessed using robust multiarray analysis, and 8,890 differentially expressed genes (DEGs) were identified by using t-test (false discovery rate < 0.0005). Furthermore, 16 known glioma related genes were abstracted from Genetic Association Database. After mapping 8,890 DEGs and 16 known glioma related genes to Human Protein Reference Database, a glioma associated protein-protein interaction network (GAPN) was constructed. In addition, 51 sub-networks in GAPN were screened out through Molecular Complex Detection (score ≥ 1), and sub-network 1 was found to have the closest interaction (score = 3). What' more, for the top 10 sub-networks, Gene Ontology (GO) enrichment analysis (p value < 0.05) was performed, and DEGs involved in sub-network 1 and 2, such as BRMS1L and CCNA1, were predicted to regulate cell growth, cell cycle, and DNA replication via interacting with known glioma related genes. Finally, the overlaps of DEGs and human essential, housekeeping, tissue-specific genes were calculated (p value = 1.0, 1.0, and 0.00014, respectively) and visualized by Venn Diagram package in R. About 61% of human tissue-specific genes were DEGs as well. This research shed new light on the pathogenesis of glioma based on DEGs and GAPN, and our findings might provide potential targets for clinical glioma treatment.

  13. Lymphoid Cell-Glioma Cell Interaction Enhances Cell Coat Production by Human Gliomas: Novel Suppressor Mechanism

    NASA Astrophysics Data System (ADS)

    Dick, Steven J.; Macchi, Beatrice; Papazoglou, Savvas; Oldfield, Edward H.; Kornblith, Paul L.; Smith, Barry H.; Gately, Maurice K.

    1983-05-01

    Certain human glioma lines produce mucopolysaccharide coats that impair the generation of cytolytic lymphocytes in response to these lines in vitro. Coat production is substantially enhanced by the interaction of glioma cells with a macromolecular factor released by human peripheral blood mononuclear cells in culture. This interaction thus constitutes an unusual mechanism by which inflammatory cells may nonspecifically suppress the cellular immune response to at least one class of solid tumors in humans.

  14. Tumor Volume Reduction Rate Measured by Magnetic Resonance Volumetry Correlated With Pathologic Tumor Response of Preoperative Chemoradiotherapy for Rectal Cancer

    SciTech Connect

    Yeo, Seung-Gu; Kim, Dae Yong; Kim, Tae Hyun; Jung, Kyung Hae; Hong, Yong Sang; Chang, Hee Jin; Park, Ji Won; Lim, Seok-Byung; Choi, Hyo Seong; Jeong, Seung-Yong

    2010-09-01

    Purpose: To determine whether the tumor volume reduction rate (TVRR) measured using three-dimensional region-of-interest magnetic resonance volumetry correlates with the pathologic tumor response after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Methods and Materials: The study included 405 patients with locally advanced rectal cancer (cT3-T4) who had undergone preoperative CRT and radical proctectomy. The tumor volume was measured using three-dimensional region-of-interest magnetic resonance volumetry before and after CRT but before surgery. We analyzed the correlation between the TVRR and the pathologic tumor response in terms of downstaging and tumor regression grade (TRG). Downstaging was defined as ypStage 0-I (ypT0-T2N0M0), and the TRG proposed by Dworak et al. was used. Results: The mean TVRR was 65.0% {+-} 22.3%. Downstaging and complete regression occurred in 167 (41.2%) and 58 (14.3%) patients, respectively. The TVRRs according to ypT classification (ypT0-T2 vs. ypT3-T4), ypN classification (ypN0 vs. ypN1-N2), downstaging (ypStage 0-I vs. ypStage II-III), good regression (TRG 3-4 vs. TRG 1-2), and complete regression (TRG 4 vs. TRG 1-3) were all significantly different (p <.05). When the TVRR was categorized into three groups (<60%, 60-80%, and >80%), the rates of ypT0-T2, ypN0, downstaging, and good regression were all significantly greater for patients with a TVRR of {>=}60%, as was the complete regression rate for patients with a TVRR >80% (p <.05). Conclusion: The TVRR measured using three-dimensional region-of-interest magnetic resonance volumetry correlated significantly with the pathologic tumor response in terms of downstaging and TRG after preoperative CRT for locally advanced rectal cancer.

  15. Temporal Lung Tumor Volume Changes in Small-Cell Lung Cancer Patients Undergoing Chemoradiotherapy

    SciTech Connect

    Yee, Don; Rathee, Satyapal; Robinson, Don; Murray, Brad

    2011-05-01

    Purpose: Small-cell lung cancer is considered to be relatively chemosensitive and radiosensitive. Small-cell tumor volume changes during concurrent chemoradiotherapy have not been quantified. The purpose of this work is to quantify small-cell lung tumor volume variations in limited-stage patients undergoing chemoradiotherapy. Methods and Materials: Eligible patients had pathologically confirmed limited-stage small-cell lung cancer, underwent concurrent chemoradiotherapy, and signed study-specific consent forms. Patients underwent serial chest computed tomography (CT) scans on a CT simulator with images acquired at the same phase of patients' respiratory cycle. Computed tomography scans were obtained at the time of planning CT scan and 3 times a week during radiotherapy (RT). Gross tumor volumes (GTVs) were contoured on each CT scan. Gross tumor volumes defined on each CT scan were analyzed for volume changes relative to pre-RT scans. Results: We obtained 104 CT scans (median, 11.5 scans per patient). The median tumor dose was 50 Gy. The median pre-RT GTV was 98.9 cm{sup 3} (range, 57.8-412.4 cm{sup 3}). The median GTV at the final serial CT scan was 10.0 cm{sup 3} (range, 4.2-81.6 cm{sup 3}). The mean GTV relative to pre-RT volume at the end of each RT week was 53.0% for Week 1, 29.8% for Week 2, 22.9% for Week 3, 19.5% for Week 4, and 12.4% for Week 5. Conclusions: Dramatic shrinkage of small-cell lung tumors occurred in patients undergoing chemoradiotherapy in this trial. Most of the observed GTV shrinkage occurred during the first week of RT.

  16. Tumor Volume Estimation and Quasi-Continuous Administration for Most Effective Bevacizumab Therapy

    PubMed Central

    Sápi, Johanna; Kovács, Levente; Drexler, Dániel András; Kocsis, Pál; Gajári, Dávid; Sápi, Zoltán

    2015-01-01

    Background Bevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. Several studies have investigated the effectiveness of bevacizumab therapy according to different cancer types but these days there is an intense debate on its utility. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol. Materials and Methods We have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma. In both cases, three groups were compared in the experiments. The first group did not receive therapy, the second group received one 200 μg bevacizumab dose for a treatment period (protocol-based therapy), and the third group received 1.1 μg bevacizumab every day (quasi-continuous therapy). Tumor volume measurement was performed by digital caliper and small animal MRI. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. The effectiveness of bevacizumab administration was examined by statistical analysis. Results In the case of C38 adenocarcinoma, protocol-based treatment did not result in significantly smaller tumor volume compared to the no treatment group; however, there was a significant difference between untreated mice and mice who received quasi-continuous therapy (p = 0.002). In the case of HT-29 adenocarcinoma, the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment (p = 0.038). When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two

  17. Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema

    SciTech Connect

    Binkley, Michael S.; Shrager, Joseph B.; Leung, Ann N.; Popat, Rita; Trakul, Nicholas; Atwood, Todd F.; Chaudhuri, Aadel; Maxim, Peter G.; Diehn, Maximilian; Loo, Billy W.

    2014-09-01

    Purpose: Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema. Methods and Materials: We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3). Results: 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, −0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, −3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r{sup 2}=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r{sup 2}=0.47, P<.0001). Conclusions: We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across

  18. Glutamine Addiction In Gliomas.

    PubMed

    Márquez, Javier; Alonso, Francisco J; Matés, José M; Segura, Juan A; Martín-Rufián, Mercedes; Campos-Sandoval, José A

    2017-03-09

    Cancer cells develop and succeed by shifting to different metabolic programs compared with their normal cell counterparts. One of the classical hallmarks of cancer cells is their higher glycolysis rate and lactate production even in the presence of abundant O2 (Warburg effect). Another common metabolic feature of cancer cells is a high rate of glutamine (Gln) consumption normally exceeding their biosynthetic and energetic needs. The term Gln addiction is now widely used to reflect the strong dependence shown by most cancer cells for this essential nitrogen substrate after metabolic reprogramming. A Gln/glutamate (Glu) cycle occurs between host tissues and the tumor in order to maximize its growth and proliferation rates. The mechanistic basis for this deregulated tumor metabolism and how these changes are connected to oncogenic and tumor suppressor pathways are becoming increasingly understood. Based on these advances, new avenues of research have been initiated to find novel therapeutic targets and to explore strategies that interfere with glutamine metabolism as anticancer therapies. In this review, we provided an updated overview of glutamine addiction in glioma, the most prevalent type of brain tumor.

  19. SU-E-I-84: Accuracy Comparison of Multi-Modality Image-Based Volumes of Rodent Solid Tumors Using In-Air Micro-CT Image Volume

    SciTech Connect

    Lee, Y; Fullerton, G; Goins, B

    2015-06-15

    Purpose: Tumor volume is considered as a better predictor for therapy response monitoring and tumor staging over Response Evaluation Criteria In Solid Tumors (RECIST) or World Health Organization (WHO) criteria. In this study, the accuracy of subcutaneous rodent tumor volumes using preclinical magnetic resonance imaging (MRI), micro-computed tomography (micro-CT) and ultrasound (US) equipment and with an external caliper was compared using in-air micro-CT image volume of excised tumors determined as reference tumor volume in our prior study. Methods: MR, US and micro-CT images of subcutaneous SCC4 head and neck tumor xenografts were acquired 4, 6, 9, 11 and 13 days after tumor cell inoculation. Before MR and US scans, caliper measurements were made. After tumors were excised, in-air micro-CT imaging and ex vivo caliper measurements were performed. Tumor volumes were calculated using formula V = (π/6)*a*b*c where a, b and c are the maximum diameters in three perpendicular dimensions determined by the three image modalities and caliper, and compared with reference tumor volume by linear regression analysis as well as Bland-Altman plots. A one-way Analysis of Variance (ANOVA) test was also performed to compare volumes among caliper measurements. Results: The correlation coefficients (R2) of the regression lines for tumor volumes measured by the three imaging modalities and caliper were 0.9939, 0.9669, 0.9806, 0.9274, 0.9619 and 0.9819 for MRI, US and micro-CT, caliperbeforeMRI, caliperbeforeUS and ex vivo caliper respectively. In Bland-Altman plots, the average of tumor volume difference from reference tumor volume (bias) was significant for caliper and micro- CT, but not for MRI and US. Comparison of caliper measurements showed a significant difference (p < 0.05). Conclusion: Using the in-air micro-CT image volume, tumor volume measured by MRI was the most accurate among the three imaging modalities. In vivo caliper volume measurements showed unreliability while ex

  20. Intraoperative detection of glioma invasion beyond MRI enhancement with Raman spectroscopy in humans

    NASA Astrophysics Data System (ADS)

    Jermyn, Michael; Mok, Kelvin; Mercier, Jeanne; Desroches, Joannie; Pichette, Julien; Saint-Arnaud, Karl; Guiot, Marie-Christine; Petrecca, Kevin; Leblond, Frédéric

    2015-03-01

    Cancer tissue is frequently impossible to distinguish from normal brain during surgery. Gliomas are a class of brain cancer which invade into the normal brain. If left unresected, these invasive cancer cells are the source of glioma recurrence. Moreover, these invasion areas do not show up on standard-of-care pre-operative Magnetic Resonance Imaging (MRI). This inability to fully visualize invasive brain cancers results in subtotal surgical resections, negatively impacting patient survival. To address this issue, we have demonstrated the efficacy of single-point in vivo Raman spectroscopy using a contact hand-held fiber optic probe for rapid detection of cancer invasion in 8 patients with low and high grade gliomas. Using a supervised machine learning algorithm to analyze the Raman spectra obtained in vivo, we were able to distinguish normal brain from the presence of cancer cells with sensitivity and specificity greater than 90%. Moreover, by correlating these results with pre-operative MRI we demonstrate the ability to detect low density cancer invasion up to 1.5cm beyond the cancer extent visible using MRI. This represents the potential for significant improvements in progression-free and overall patient survival, by identifying previously undetectable residual cancer cell populations and preventing the resection of normal brain tissue. While the importance of maximizing the volume of tumor resection is important for all grades of gliomas, the impact for low grade gliomas can be dramatic because surgery can even be curative. This convenient technology can rapidly classify cancer invasion in real-time, making it ideal for intraoperative use in brain tumor resection.

  1. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1.

    PubMed

    Toonen, Joseph A; Anastasaki, Corina; Smithson, Laura J; Gianino, Scott M; Li, Kairong; Kesterson, Robert A; Gutmann, David H

    2016-05-01

    Neurofibromatosis type 1 (NF1) is a common neurogenetic condition characterized by significant clinical heterogeneity. A major barrier to developing precision medicine approaches for NF1 is an incomplete understanding of the factors that underlie its inherent variability. To determine the impact of the germline NF1 gene mutation on the optic gliomas frequently encountered in children with NF1, we developed genetically engineered mice harboring two representative NF1-patient-derived Nf1 gene mutations (c.2542G>C;p.G848R and c.2041C>T;p.R681X). We found that each germline Nf1 gene mutation resulted in different levels of neurofibromin expression. Importantly, only R681X(CKO) but not G848R(CKO), mice develop optic gliomas with increased optic nerve volumes, glial fibrillary acid protein immunoreactivity, proliferation and retinal ganglion cell death, similar to Nf1 conditional knockout mice harboring a neomycin insertion (neo) as the germline Nf1 gene mutation. These differences in optic glioma phenotypes reflect both cell-autonomous and stromal effects of the germline Nf1 gene mutation. In this regard, primary astrocytes harboring the R681X germline Nf1 gene mutation exhibit increased basal astrocyte proliferation (BrdU incorporation) indistinguishable from neo(CKO) astrocytes, whereas astrocytes with the G848R mutation have lower levels of proliferation. Evidence for paracrine effects from the tumor microenvironment were revealed when R681X(CKO) mice were compared with conventional neo(CKO) mice. Relative to neo(CKO) mice, the optic gliomas from R681X(CKO) mice had more microglia infiltration and JNK(Thr183/Tyr185) activation, microglia-produced Ccl5, and glial AKT(Thr308) activation. Collectively, these studies establish that the germline Nf1 gene mutation is a major determinant of optic glioma development and growth through by both tumor cell-intrinsic and stromal effects.

  2. Computer Simulation of Glioma Growth and Morphology

    PubMed Central

    Frieboes, Hermann B.; Lowengrub, John S.; Wise, S.; Zheng, X.; Macklin, Paul; Bearer, Elaine; Cristini, Vittorio

    2007-01-01

    Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in-vitro and in-vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g. from histopathology or intra-operative analysis, this model can be used for disease diagnosis

  3. Resection Probability Maps for Quality Assessment of Glioma Surgery without Brain Location Bias

    PubMed Central

    De Witt Hamer, Philip C.; Hendriks, Eef J.; Mandonnet, Emmanuel; Barkhof, Frederik; Zwinderman, Aeilko H.; Duffau, Hugues

    2013-01-01

    Background Intraoperative brain stimulation mapping reduces permanent postoperative deficits and extends tumor removal in resective surgery for glioma patients. Successful functional mapping is assumed to depend on the surgical team's expertise. In this study, glioma resection results are quantified and compared using a novel approach, so-called resection probability maps (RPM), exemplified by a surgical team comparison, here with long and short experience in mapping. Methods Adult patients with glioma were included by two centers with two and fifteen years of mapping experience. Resective surgery was targeted at non-enhanced MRI extension and was limited by functional boundaries. Neurological outcome was compared. To compare resection results, we applied RPMs to quantify and compare the resection probability throughout the brain at 1 mm resolution. Considerations for spatial dependence and multiple comparisons were taken into account. Results The senior surgical team contributed 56, and the junior team 52 patients. The patient cohorts were comparable in age, preoperative tumor volume, lateralization, and lobe localization. Neurological outcome was similar between teams. The resection probability on the RPMs was very similar, with none (0%) of 703,967 voxels in left-sided tumors being differentially resected, and 124 (0.02%) of 644,153 voxels in right-sided tumors. Conclusion RPMs provide a quantitative volumetric method to compare resection results, which we present as standard for quality assessment of resective glioma surgery because brain location bias is avoided. Stimulation mapping is a robust surgical technique, because the neurological outcome and functional-based resection results using stimulation mapping are independent of surgical experience, supporting wider implementation. PMID:24039922

  4. Extracts from Glioma Tissues following Cryoablation Have Proapoptosis, Antiproliferation, and Anti-Invasion Effects on Glioma Cells

    PubMed Central

    Liu, Tianzhu; Wang, Xin; Yin, Zhilin; Pan, Jun; Guo, Hongbo; Zhang, Shizhong

    2014-01-01

    Objective. This study is to investigate the in vivo apoptotic processes in glioma tissues following cryoablation and the effects of glioma tissue extracts on GL261 glioma cells in vitro. Methods. TUNEL and flow cytometry analysis were performed to detect the apoptotic processes in the glioma tissues following cryoablation and in the GL261 cells treated with cryoablated tumor extracts. The scratch assay, the transwell assay, and Western blot analysis were carried out to evaluate the effects of cryoablated tumor extracts on the migration, invasion, and proliferation of tumor cells. Results. Our in vivo results indicated that the rapid-onset apoptosis was induced via the intrinsic pathway and the delayed apoptosis was triggered through the extrinsic pathway. The in vitro results showed that extracts from glioma tissues following cryoablation induced apoptosis via extrinsic pathways in GL261 glioma cells. Furthermore, cryoablated tumor extracts significantly inhibited the migration and proliferation of these cells, which would be related to the inhibition of ERK1/2 pathway and the activation of P38 pathway. Conclusion. Glioma cells surviving in cryoablation undergo intrinsic or extrinsic apoptosis. Augmenting the induction of apoptosis or enhancing the cryosensitization of tumor cells by coupling cryoablation with specific chemotherapy effectively increases the efficiency of this therapeutic treatment. PMID:24818132

  5. An Interindividual Comparison of O-(2- [{sup 18}F]Fluoroethyl)-L-Tyrosine (FET)- and L-[Methyl-{sup 11}C]Methionine (MET)-PET in Patients With Brain Gliomas and Metastases

    SciTech Connect

    Grosu, Anca-Ligia; Astner, Sabrina T.; Riedel, Eva; Nieder, Carsten; Wiedenmann, Nicole; Heinemann, Felix; Schwaiger, Markus; and others

    2011-11-15

    Purpose: L-[methyl-{sup 11}C]methionine (MET)-positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of {sup 11}C (20 minutes) limits the use of MET-PET to institutions with onsite cyclotron. O-(2- [{sup 18}F]fluoroethyl)-L-tyrosine (FET) is labeled with {sup 18}F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI). Methods and Materials: We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion-to-gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up. Results: There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 (p = 0.001) and r = 0.84 (p < 0.001), respectively. Image contrast was similar for MET- and FET-PET (lesion-to-gray matter ratios of 2.36 {+-} 1.01 and 2.33 {+-} 0.77, respectively). Mean GTV in 17 glioma patients was not significantly different on MET- and FET-PET. Both MET- and FET-PET delineated tumor tissue outside of MRI changes. Both tracers provided differentiated tumor tissue and treatment-related changes with a sensitivity of 91% at a specificity of 100%. Conclusions: O-(2- [{sup 18}F]fluoroethyl)-L-tyrosine-PET and MET-PET provide comparable diagnostic

  6. 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

  7. Comparison of supervised MRI segmentation methods for tumor volume determination during therapy.

    PubMed

    Vaidyanathan, M; Clarke, L P; Velthuizen, R P; Phuphanich, S; Bensaid, A M; Hall, L O; Bezdek, J C; Greenberg, H; Trotti, A; Silbiger, M

    1995-01-01

    Two different multispectral pattern recognition methods are used to segment magnetic resonance images (MRI) of the brain for quantitative estimation of tumor volume and volume changes with therapy. A supervised k-nearest neighbor (kNN) rule and a semi-supervised fuzzy c-means (SFCM) method are used to segment MRI slice data. Tumor volumes as determined by the kNN and SFCM segmentation methods are compared with two reference methods, based on image grey scale, as a basis for an estimation of ground truth, namely: (a) a commonly used seed growing method that is applied to the contrast enhanced T1-weighted image, and (b) a manual segmentation method using a custom-designed graphical user interface applied to the same raw image (T1-weighted) dataset. Emphasis is placed on measurement of intra and inter observer reproducibility using the proposed methods. Intra- and interobserver variation for the kNN method was 9% and 5%, respectively. The results for the SFCM method was a little better at 6% and 4%, respectively. For the seed growing method, the intra-observer variation was 6% and the interobserver variation was 17%, significantly larger when compared with the multispectral methods. The absolute tumor volume determined by the multispectral segmentation methods was consistently smaller than that observed for the reference methods. The results of this study are found to be very patient case-dependent. The results for SFCM suggest that it should be useful for relative measurements of tumor volume during therapy, but further studies are required. This work demonstrates the need for minimally supervised or unsupervised methods for tumor volume measurements.

  8. Targeting Pediatric Glioma with Apoptosis and Autophagy Manipulation

    DTIC Science & Technology

    2014-10-01

    13. SUPPLEMENTARY NOTES 14. ABSTRACT Gliomas are the most common and most deadly solid tumors that affect children . Treatment options are limited and...Gliomas are the most common and most deadly solid tumors that affect children . Treatment options are limited and cure rates are dismal. My laboratory has...tyrosine kinase inhibition. Society for Neuro- Oncology International Meetings Poster Presentation. November 2013. -Pierce AM, Keating AK. TAM Receptor

  9. SU-E-J-12: A New Stereological Method for Tumor Volume Evaluation for Esophageal Cancer

    SciTech Connect

    Feng, Y; Pan, R; Lin, W; Sa, Y; Wang, P; Yang, C

    2014-06-01

    Purpose: Stereological method used to obtain three dimensional quantitative information from two dimensional images is a widely used tool in the study of cells and pathology. But the feasibility of the method for quantitative evaluation of volumes with 3D image data sets for radiotherapy clinical application has not been explored. On the other hand, a quick, easy-to-use and reliable method is highly desired in image-guided-radiotherapy(IGRT) for tumor volume measurement for the assessment of response to treatment. To meet this need, a stereological method for evaluating tumor volumes for esophageal cancer is presented in this abstract. Methods: The stereology method was optimized by selecting the appropriate grid point distances and sample types. 7 patients with esophageal cancer were selected retrospectively for this study, each having pre and post treatment computed tomography (CT) scans. Stereological measurements were performed for evaluating the gross tumor volume (GTV) changes after radiotherapy and the results was compared with the ones by planimetric measurements. Two independent observers evaluated the reproducibility for volume measurement using the new stereological technique. Results: The intraobserver variation in the GTV volume estimation was 3.42±1.68cm3 (the Wilcoxon matched-pairs test Resultwas Z=−1.726,P=0.084>0.05); the interobserver variation in the GTV volume estimation was 22.40±7.23 cm3 (Z=−3.296,P=0.083>0.05), which showed the consistency in GTV volume calculation with the new method for the same and different users. The agreement level between the results from the two techniques was also evaluated. Difference between the measured GTVs was 20.10±5.35 cm3 (Z=−3.101,P=0.089>0.05). Variation of the measurement results using the two techniques was low and clinically acceptable. Conclusion: The good agreement between stereological and planimetric techniques proves the reliability of the stereological tumor volume estimations. The

  10. Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling.

    PubMed

    a Dzaye, Omar Dildar; Hu, Feng; Derkow, Katja; Haage, Verena; Euskirchen, Philipp; Harms, Christoph; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne A; Kettenmann, Helmut

    2016-05-01

    Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.

  11. Assessment of Tumor Volumes in Skull Base Glomus Tumors Using Gluc-Lys[{sup 18}F]-TOCA Positron Emission Tomography

    SciTech Connect

    Astner, Sabrina T.; Bundschuh, Ralph A.; Beer, Ambros J.; Ziegler, Sibylle I.; Krause, Bernd J.; Schwaiger, Markus; Molls, Michael; Grosu, Anca L.; Essler, Markus

    2009-03-15

    Purpose: To assess a threshold for Gluc-Lys[{sup 18}F]-TOCA positron emission tomography (PET) in target volume delineation of glomus tumors in the skull base and to compare with MRI-based target volume delineation. Methods and Materials: The threshold for volume segmentation in the PET images was determined by a phantom study. Nine patients with a total of 11 glomus tumors underwent PET either with Gluc-Lys[{sup 18}F]-TOCA or with {sup 68}Ga-DOTATOC (in 1 case). All patients were additionally scanned by MRI. Positron emission tomography and MR images were transferred to a treatment-planning system; MR images were analyzed for lesion volume by two observers, and PET images were analyzed by a semiautomated thresholding algorithm. Results: Our phantom study revealed that 32% of the maximum standardized uptake value is an appropriate threshold for tumor segmentation in PET-based target volume delineation of gross tumors. Target volume delineation by MRI was characterized by high interobserver variability. In contrast, interobserver variability was minimal if fused PET/MRI images were used. The gross tumor volumes (GTVs) determined by PET (GTV-PET) showed a statistically significant correlation with the GTVs determined by MRI (GTV-MRI) in primary tumors; in recurrent tumors higher differences were found. The mean GTV-MRI was significantly higher than mean GTV-PET. The increase added by MRI to the common volume was due to scar tissue with strong signal enhancement on MRI. Conclusions: In patients with glomus tumors, Gluc-Lys[{sup 18}F]-TOCA PET helps to reduce interobserver variability if an appropriate threshold for tumor segmentation has been determined for institutional conditions. Especially in patients with recurrent tumors after surgery, Gluc-Lys[{sup 18}F]-TOCA PET improves the accuracy of GTV delineation.

  12. Radiosurgical boost for primary high-grade gliomas.

    PubMed

    Prisco, Flavio E; Weltman, Eduardo; de Hanriot, Rodrigo M; Brandt, Reynaldo A

    2002-04-01

    The purpose of this study was to retrospectively evaluate the survival of patients with high-grade gliomas treated with external beam radiotherapy with or without radiosurgical boost. From July 1993 to April 1998, 32 patients were selected, 15 of which received radiosurgery. Inclusion criteria were age > 18 years, histological confirmation of high-grade glioma, primary tumor treatment with curative intent, unifocal tumor and supratentorial location. All patients were found to be in classes III-VI, according to the recursive partitioning analysis proposed by the Radiation Therapy Oncology Group. The median interval between radiotherapy and radiosurgery was 5 weeks (range 1-13). Treatment volumes ranged from 2.9 to 70.3 cc (median 15.0 cc). Prescribed radiosurgery doses varied from 8.0 to 12.5 Gy (median 10.0 Gy). Radiosurgery and control groups were well balanced with respect to prognostic factor distributions. Median actuarial survival time in radiosurgery and control groups was 21.4 months and 11.6 months, respectively (p = 0.0254). Among patients with KPS > 80, median survival time was 11.0 months and 53.9 months in the control and radiosurgery groups, respectively (p = 0.0103). Radiosurgery was the single factor correlated with survival on Cox model analysis (p = 0.0362) and was associated with a 2.76 relative reduction in the risk of cancer death (95% confidence interval (CI) 1.07-7.13). Our results suggest that radiosurgery may confer a survival advantage for patients in RPA classes III-VI, especially for those with Karnofsky performance status >80. The definitive role of radiosurgical boost for patients with high-grade gliomas awaits the results of randomized trials.

  13. Malignant glioma: lessons from genomics, mouse models, and stem cells.

    PubMed

    Chen, Jian; McKay, Renée M; Parada, Luis F

    2012-03-30

    Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent sequencing studies are identifying unexpected drivers of gliomagenesis, including mutations in isocitrate dehydrogenase 1 and the NF-κB pathway, and how genome-wide analyses are reshaping the classification schemes for tumors and enhancing prognostic value of molecular markers. We discuss the controversies surrounding glioma stem cells and explore how the integration of new molecular data allows for the generation of more informative animal models to advance our knowledge of glioma's origin, progression, and treatment.

  14. A Gaussian mixture model for definition of lung tumor volumes in positron emission tomography.

    PubMed

    Aristophanous, Michalis; Penney, Bill C; Martel, Mary K; Pelizzari, Charles A

    2007-11-01

    The increased interest in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in radiation treatment planning in the past five years necessitated the independent and accurate segmentation of gross tumor volume (GTV) from FDG-PET scans. In some studies the radiation oncologist contours the GTV based on a computed tomography scan, while incorporating pertinent data from the PET images. Alternatively, a simple threshold, typically 40% of the maximum intensity, has been employed to differentiate tumor from normal tissue, while other researchers have developed algorithms to aid the PET based GTV definition. None of these methods, however, results in reliable PET tumor segmentation that can be used for more sophisticated treatment plans. For this reason, we developed a Gaussian mixture model (GMM) based segmentation technique on selected PET tumor regions from non-small cell lung cancer patients. The purpose of this study was to investigate the feasibility of using a GMM-based tumor volume definition in a robust, reliable and reproducible way. A GMM relies on the idea that any distribution, in our case a distribution of image intensities, can be expressed as a mixture of Gaussian densities representing different classes. According to our implementation, each class belongs to one of three regions in the image; the background (B), the uncertain (U) and the target (T), and from these regions we can obtain the tumor volume. User interaction in the implementation is required, but is limited to the initialization of the model parameters and the selection of an "analysis region" to which the modeling is restricted. The segmentation was developed on three and tested on another four clinical cases to ensure robustness against differences observed in the clinic. It also compared favorably with thresholding at 40% of the maximum intensity and a threshold determination function based on tumor to background image intensities proposed in a recent paper. The parts of the

  15. A Gaussian mixture model for definition of lung tumor volumes in positron emission tomography

    SciTech Connect

    Aristophanous, Michalis; Penney, Bill C.; Martel, Mary K.; Pelizzari, Charles A.

    2007-11-15

    The increased interest in {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in radiation treatment planning in the past five years necessitated the independent and accurate segmentation of gross tumor volume (GTV) from FDG-PET scans. In some studies the radiation oncologist contours the GTV based on a computed tomography scan, while incorporating pertinent data from the PET images. Alternatively, a simple threshold, typically 40% of the maximum intensity, has been employed to differentiate tumor from normal tissue, while other researchers have developed algorithms to aid the PET based GTV definition. None of these methods, however, results in reliable PET tumor segmentation that can be used for more sophisticated treatment plans. For this reason, we developed a Gaussian mixture model (GMM) based segmentation technique on selected PET tumor regions from non-small cell lung cancer patients. The purpose of this study was to investigate the feasibility of using a GMM-based tumor volume definition in a robust, reliable and reproducible way. A GMM relies on the idea that any distribution, in our case a distribution of image intensities, can be expressed as a mixture of Gaussian densities representing different classes. According to our implementation, each class belongs to one of three regions in the image; the background (B), the uncertain (U) and the target (T), and from these regions we can obtain the tumor volume. User interaction in the implementation is required, but is limited to the initialization of the model parameters and the selection of an 'analysis region' to which the modeling is restricted. The segmentation was developed on three and tested on another four clinical cases to ensure robustness against differences observed in the clinic. It also compared favorably with thresholding at 40% of the maximum intensity and a threshold determination function based on tumor to background image intensities proposed in a recent paper. The parts of

  16. Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes.

    PubMed

    Li, Aiguo; Walling, Jennifer; Ahn, Susie; Kotliarov, Yuri; Su, Qin; Quezado, Martha; Oberholtzer, J Carl; Park, John; Zenklusen, Jean C; Fine, Howard A

    2009-03-01

    Gliomas are the most common type of primary brain tumors in adults and a significant cause of cancer-related mortality. Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications based on gene expression data have been attempted in the past with varying success and with only some concordance between studies, possibly due to inherent bias that can be introduced through the use of analytic methodologies that make a priori selection of genes before classification. To overcome this potential source of bias, we have applied two unsupervised machine learning methods to genome-wide gene expression profiles of 159 gliomas, thereby establishing a robust glioma classification model relying only on the molecular data. The model predicts for two major groups of gliomas (oligodendroglioma-rich and glioblastoma-rich groups) separable into six hierarchically nested subtypes. We then identified six sets of classifiers that can be used to assign any given glioma to the corresponding subtype and validated these classifiers using both internal (189 additional independent samples) and two external data sets (341 patients). Application of the classification system to the external glioma data sets allowed us to identify previously unrecognized prognostic groups within previously published data and within The Cancer Genome Atlas glioblastoma samples and the different biological pathways associated with the different glioma subtypes offering a potential clue to the pathogenesis and possibly therapeutic targets for tumors within each subtype.

  17. Tumor delineation using PET in head and neck cancers: Threshold contouring and lesion volumes

    SciTech Connect

    Ford, Eric C.; Kinahan, Paul E.; Hanlon, Lorraine; Alessio, Adam; Rajendran, Joseph; Schwartz, David L.; Phillips, Mark

    2006-11-15

    Tumor boundary delineation using positron emission tomography (PET) is a promising tool for radiation therapy applications. In this study we quantify the uncertainties in tumor boundary delineation as a function of the reconstruction method, smoothing, and lesion size in head and neck cancer patients using FDG-PET images and evaluate the dosimetric impact on radiotherapy plans. FDG-PET images were acquired for eight patients with a GE Advance PET scanner. In addition, a 20 cm diameter cylindrical phantom with six FDG-filled spheres with volumes of 1.2 to 26.5 cm{sup 3} was imaged. PET emission scans were reconstructed with the OSEM and FBP algorithms with different smoothing parameters. PET-based tumor regions were delineated using an automatic contouring function set at progressively higher threshold contour levels and the resulting volumes were calculated. CT-based tumor volumes were also contoured by a physician on coregistered PET/CT patient images. The intensity value of the threshold contour level that returns 100% of the actual volume, I{sub V100}, was measured. We generated intensity-modulated radiotherapy (IMRT) plans for an example head and neck patient, treating 66 Gy to CT-based gross disease and 54 Gy to nodal regions at risk, followed by a boost to the FDG-PET-based tumor. The volumes of PET-based tumors are a sensitive function of threshold contour level for all patients and phantom datasets. A 5% change in threshold contour level can translate into a 200% increase in volume. Phantom data indicate that I{sub V100} can be set as a fraction, f, of the maximum measured uptake. Fractional threshold values in the cylindrical water phantom range from 0.23 to 0.51. Both the fractional threshold and the threshold-volume curve are dependent on lesion size, with lesions smaller than approximately 5 cm{sup 3} displaying a more pronounced sensitivity and larger fractional threshold values. The threshold-volume curves and fractional threshold values also depend

  18. Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma

    PubMed Central

    Lobo, Merryl R.; Kukino, Ayaka; Tran, Huong; Schabel, Matthias C.; Springer, Charles S.; Gillespie, G. Yancey; Grafe, Marjorie R.; Woltjer, Randall L.; Pike, Martin M.

    2015-01-01

    Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the

  19. Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma.

    PubMed

    Choi, Changho; Raisanen, Jack M; Ganji, Sandeep K; Zhang, Song; McNeil, Sarah S; An, Zhongxu; Madan, Akshay; Hatanpaa, Kimmo J; Vemireddy, Vamsidhara; Sheppard, Christie A; Oliver, Dwight; Hulsey, Keith M; Tiwari, Vivek; Mashimo, Tomoyuki; Battiste, James; Barnett, Samuel; Madden, Christopher J; Patel, Toral R; Pan, Edward; Malloy, Craig R; Mickey, Bruce E; Bachoo, Robert M; Maher, Elizabeth A

    2016-11-20

    Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

  20. SU-F-207-06: CT-Based Assessment of Tumor Volume in Malignant Pleural Mesothelioma

    SciTech Connect

    Qayyum, F; Armato, S; Straus, C; Husain, A; Vigneswaran, W; Kindler, H

    2015-06-15

    Purpose: To determine the potential utility of computed tomography (CT) scans in the assessment of physical tumor bulk in malignant pleural mesothelioma patients. Methods: Twenty-eight patients with malignant pleural mesothelioma were used for this study. A CT scan was acquired for each patient prior to surgical resection of the tumor (median time between scan and surgery: 27 days). After surgery, the ex-vivo tumor volume was measured by a pathologist using a water displacement method. Separately, a radiologist identified and outlined the tumor boundary on each CT section that demonstrated tumor. These outlines then were analyzed to determine the total volume of disease present, the number of sections with outlines, and the mean volume of disease per outlined section. Subsets of the initial patient cohort were defined based on these parameters, i.e. cases with at least 30 sections of disease with a mean disease volume of at least 3mL per section. For each subset, the R- squared correlation between CT-based tumor volume and physical ex-vivo tumor volume was calculated. Results: The full cohort of 28 patients yielded a modest correlation between CT-based tumor volume and the ex-vivo tumor volume with an R-squared value of 0.66. In general, as the mean tumor volume per section increased, the correlation of CT-based volume with the physical tumor volume improved substantially. For example, when cases with at least 40 CT sections presenting a mean of at least 2mL of disease per section were evaluated (n=20) the R-squared correlation increased to 0.79. Conclusion: While image-based volumetry for mesothelioma may not generally capture physical tumor volume as accurately as one might expect, there exists a set of conditions in which CT-based volume is highly correlated with the physical tumor volume. SGA receives royalties and licensing fees through the University of Chicago for computer-aided diagnosis technology.

  1. Cognition and resective surgery for diffuse infiltrative glioma: an overview.

    PubMed

    Klein, Martin; Duffau, Hugues; De Witt Hamer, Philip C

    2012-06-01

    Compared to classical oncological outcome measures such as time to progression and survival, the importance of cognitive functioning in patients with diffuse infiltrative brain tumors has only recently been recognized. Apart from the relatively low incidence and the invariably fatal outcome of gliomas, the general assumption that cognitive assessment is time-consuming and burdensome contributes to this notion. Our understanding of the effects of brain surgery on cognition, for instance, is largely based on studies in surgical patients with refractory epilepsy, with only a limited number of studies in surgical patients with gliomas. The impact of other factors affecting cognition in glioma patients such as direct tumor effects, radiotherapy and chemotherapy, and medical treatment, including anti-epileptic drugs and steroids, have been studied more extensively. The purpose of this paper is to provide an overview of cognition in patients with diffuse infiltrative gliomas and the impact of resective surgery as well as other tumor and treatment-related factors.

  2. Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors

    ClinicalTrials.gov

    2017-02-10

    Diffuse Intrinsic Pontine Glioma; Brain Tumor, Recurrent; Solid Tumor, Recurrent; Neuroblastoma, Recurrent, Refractory; Ewing Sarcoma, Recurrent, Refractory; Rhabdomyosarcoma, Recurrent, Refractory; Osteosarcoma, Recurrent, Refractory; Rhabdoid Tumor, Recurrent, Refractory

  3. Perspectives in Intraoperative Diagnostics of Human Gliomas

    PubMed Central

    Tyurikova, O.; Dembitskaya, Y.; Yashin, K.; Mishchenko, M.; Vedunova, M.; Medyanik, I.; Kazantsev, V.

    2015-01-01

    Amongst large a variety of oncological diseases, malignant gliomas represent one of the most severe types of tumors. They are also the most common type of the brain tumors and account for over half of the astrocytic tumors. According to different sources, the average life expectancy of patients with various glioblastomas varies between 10 and 12 months and that of patients with anaplastic astrocytic tumors between 20 and 24 months. Therefore, studies of the physiology of transformed glial cells are critical for the development of treatment methods. Modern medical approaches offer complex procedures, including the microsurgical tumor removal, radiotherapy, and chemotherapy, supplemented with photodynamic therapy and immunotherapy. The most radical of them is surgical resection, which allows removing the largest part of the tumor, reduces the intracranial hypertension, and minimizes the degree of neurological deficit. However, complete removal of the tumor remains impossible. The main limitations are insufficient visualization of glioma boundaries, due to its infiltrative growth, and the necessity to preserve healthy tissue. This review is devoted to the description of advantages and disadvantages of modern intraoperative diagnostics of human gliomas and highlights potential perspectives for development of their treatment. PMID:26543495

  4. An immuno-wall microdevice exhibits rapid and sensitive detection of IDH1-R132H mutation specific to grade II and III gliomas

    PubMed Central

    Yamamichi, Akane; Kasama, Toshihiro; Ohka, Fumiharu; Suzuki, Hiromichi; Kato, Akira; Motomura, Kazuya; Hirano, Masaki; Ranjit, Melissa; Chalise, Lushun; Kurimoto, Michihiro; Kondo, Goro; Aoki, Kosuke; Kaji, Noritada; Tokeshi, Manabu; Matsubara, Toshio; Senga, Takeshi; Kaneko, Mika K.; Suzuki, Hidenori; Hara, Masahito; Wakabayashi, Toshihiko; Baba, Yoshinobu; Kato, Yukinari; Natsume, Atsushi

    2016-01-01

    Abstract World Health Organization grade II and III gliomas most frequently occur in the central nervous system (CNS) in adults. Gliomas are not circumscribed; tumor edges are irregular and consist of tumor cells, normal brain tissue, and hyperplastic reactive glial cells. Therefore, the tumors are not fully resectable, resulting in recurrence, malignant progression, and eventual death. Approximately 69–80% of grade II and III gliomas harbor mutations in the isocitrate dehydrogenase 1 gene (IDH1), of which 83–90% are found to be the IDH1-R132H mutation. Detection of the IDH1-R132H mutation should help in the differential diagnosis of grade II and III gliomas from other types of CNS tumors and help determine the boundary between the tumor and normal brain tissue. In this study, we established a highly sensitive antibody-based device, referred to as the immuno-wall, to detect the IDH1-R132H mutation in gliomas. The immuno-wall causes an immunoreaction in microchannels fabricated using a photo-polymerizing polymer. This microdevice enables the analysis of the IDH1 status with a small sample within 15 min with substantially high sensitivity. Our results suggested that 10% content of the IDH1-R132H mutation in a sample of 0.33 μl volume, with 500 ng protein, or from 500 cells is theoretically sufficient for the analysis. The immuno-wall device will enable the rapid and highly sensitive detection of the IDH1-R132H mutation in routine clinical practice. PMID:27877908

  5. 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

  6. 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.

  7. Hypothalamic tumor

    MedlinePlus

    ... occur at any age. They are often more aggressive in adults than in children. In adults, tumors ... The treatment depends on how aggressive the tumor is, and whether it is a glioma or another type of cancer. Treatment may involve combinations of surgery, radiation , ...

  8. Effects of CCN1 and Macrophage Content on Glioma Virotherapy: A Mathematical Model.

    PubMed

    Jacobsen, Karly; Russell, Luke; Kaur, Balveen; Friedman, Avner

    2015-06-01

    Oncolytic virus (OV) is a genetically engineered virus that can selectively replicate in and kill tumor cells while not harming normal cells. OV therapy has been explored as a treatment for numerous cancers including glioblastoma, an aggressive and devastating brain tumor. Experiments show that extracellular matrix protein CCN1 limits OV therapy of glioma by orchestrating an antiviral response and enhancing the proinflammatory activation and migration of macrophages. Neutralizing CCN1 by antibody has been demonstrated to improve OV spread and tends to increase the time to disease progression. In this paper, we develop a mathematical model to investigate the effects of CCN1 on the treatment of glioma with oncolytic herpes simplex virus. We show that numerical simulations of the model are in agreement with the experimental results and then use the model to explore the anti-tumor effects of combining antibodies with OV therapy. Model simulations suggest that the macrophage content of the tumor is a critical factor to the success of OV therapy and to the reduction in tumor volume gained with the CCN1 antibody.

  9. Feasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma

    SciTech Connect

    Narayana, Ashwatha Golfinos, John G.; Fischer, Ingeborg; Raza, Shahzad; Kelly, Patrick M.D.; Parker, Erik; Knopp, Edmond A.; Medabalmi, Praveen; Zagzag, David; Eagan, Patricia; Gruber, Michael L.

    2008-10-01

    Introduction: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has shown promise in the treatment of patients with recurrent high-grade glioma. The purpose of this study is to test the feasibility of using bevacizumab with chemoradiation in the primary management of high-grade glioma. Methods and Materials: Fifteen patients with high-grade glioma were treated with involved field radiation therapy to a dose of 59.4 Gy at 1.8 Gy/fraction with bevacizumab 10 mg/kg on Days 14 and 28 and temozolomide 75 mg/m{sup 2}. Subsequently, bevacizumab 10 mg/kg was continued every 2 weeks with temozolomide 150 mg/m{sup 2} for 12 months. Changes in relative cerebral blood volume, perfusion-permeability index, and tumor volume measurement were measured to assess the therapeutic response. Immunohistochemistry for phosphorylated VEGF receptor 2 (pVEGFR2) was performed. Results: Thirteen patients (86.6%) completed the planned bevacizumab and chemoradiation therapy. Four Grade III/IV nonhematologic toxicities were seen. Radiographic responses were noted in 13 of 14 assessable patients (92.8%). The pVEGFR2 staining was seen in 7 of 8 patients (87.5%) at the time of initial diagnosis. Six patients have experienced relapse, 3 at the primary site and 3 as diffuse disease. One patient showed loss of pVEGFR2 expression at relapse. One-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively. Conclusion: Use of antiangiogenic therapy with radiation and temozolomide in the primary management of high-grade glioma is feasible. Perfusion imaging with relative cerebral blood volume, perfusion-permeability index, and pVEGFR2 expression may be used as a potential predictor of therapeutic response. Toxicities and patterns of relapse need to be monitored closely.

  10. [Genetics and brain gliomas].

    PubMed

    Alentorn, Agusti; Labussière, Marianne; Sanson, Marc; Delattre, Jean-Yves; Hoang-Xuan, Khê; Idbaih, Ahmed

    2013-05-01

    Chromosome arms 1p and 19q codeletion, corresponding to an unbalanced reciprocal translocation t(1;19)(q10;p10), is seen in oligodendroglial tumours and is associated with better prognosis and better chemosensitivity. BRAF abnormalities are observed in pilocytic astrocytomas (tandem duplication-rearrangement) and in pleomorphic xanthoastrocytomas (BRAF V600E mutation). The vast majority of primary or de novo glioblastomas exhibit genetic abnormalities disrupting the intracellular signaling pathways of: transmembrane tyrosine kinase receptors to growth factors and their downstream signaling pathways (i.e. NF1-RAS-RAF-MAPK and PTEN-PI3K-AKT-TSC-mTOR); RB and; TP53. IDH1 and IDH2 mutations are frequent in diffuse grade II and grade III gliomas and in secondary glioblastomas. They are diagnostic and favorable independent prognostic biomarkers. In contrast, they are rare in primary or de novo glioblastomas and not reported in pilocytic astrocytomas. Germlin mutations in MSH2/MLH1/PMS2/MSH6, CDKN2A, TSC1/TSC2, PTEN, TP53 and NF1/NF2 predispose to glial tumors in the setting of hereditary cancer predisposition syndromes. Single nucleotide polymorphisms in TERT,CCDC26, CDKN2A/CDKN2B, RTEL, EGFR and PHLDB1 confer an inherited susceptibility to glial tumors.

  11. Androglobin knockdown inhibits growth of glioma cell lines

    PubMed Central

    Huang, Bo; Lu, Yi-Sheng; Li, Xia; Zhu, Zhi-Chuan; Li, Kui; Liu, Ji-Wei; Zheng, Jing; Hu, Ze-Lan

    2014-01-01

    Globin family was famous for oxygen supply function of its members such as hemoglobin and myoglobin. With the progress of research, several members of this protein family have been proven to play roles in tumors including glioma. Androglobin (ADGB) is a recently identified member of globin family with very few studies about its function. In the present study, we show that ADGB plays an oncogene role in glioma. Lentiviral vector mediated ADGB knockdown inhibited the proliferation of glioma cell lines determined by MTT assay and colony formation assay. ADGB knockdown also increased the apoptosis of glioma cell line U251 assessed by flow cytometry. In addition, western blot showed that ADGB knockdown altered levels of several proteins related to proliferation, survival or apoptosis in U251 cells. These findings suggest ADGB is involved in the progression of glioma in vitro. PMID:24966926

  12. Mitochondrial Lon is over-expressed in high-grade gliomas, and mediates hypoxic adaptation: potential role of Lon as a therapeutic target in glioma

    PubMed Central

    Di, Kaijun; Lomeli, Naomi; Wood, Spencer D.; Vanderwal, Christopher D.; Bota, Daniela A.

    2016-01-01

    Mitochondrial dysfunction is a hallmark of cancer biology. Tumor mitochondrial metabolism is characterized by an abnormal ability to function in scarce oxygen conditions through glycolysis (the Warburg effect), and accumulation of mitochondrial DNA defects are present in both hereditary neoplasia and sporadic cancers. Mitochondrial Lon is a major regulator of mitochondrial metabolism and the mitochondrial response to free radical damage, and plays an essential role in the maintenance and repair of mitochondrial DNA. Despite these critical cellular functions of Lon, very little has been reported regarding its role in glioma. Lon expression in gliomas and its relevance with patient survival was examined using published databases and human tissue sections. The effect of Lon in glioma biology was investigated through siRNA targeting Lon. We also tested the in vitro antitumor activity of Lon inhibitor, CC4, in the glioma cell lines D-54 and U-251. High Lon expression was associated with high glioma tumor grade and poor patient survival. While Lon expression was elevated in response to a variety of stimuli, Lon knockdown in glioma cell lines decreased cell viability under normal conditions, and dramatically impaired glioma cell survival under hypoxic conditions. Furthermore, the Lon inhibitor, CC4, efficiently prohibited glioma cell proliferation and synergistically enhanced the therapeutic efficacy of the chemotherapeutic agents, temozolomide (TMZ) and cisplatin. We demonstrate that Lon plays a key role in glioma cell hypoxic survival and mitochondrial respiration, and propose Lon as a promising therapeutic target in the treatment of malignant gliomas. PMID:27764809

  13. Bafetinib in Treating Patients With Recurrent High-Grade Glioma or Brain Metastases

    ClinicalTrials.gov

    2013-03-18

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Tumors Metastatic to Brain; Adult Anaplastic Oligoastrocytoma

  14. [Arteriovenous malformation-glioma association: study of four cases].

    PubMed

    Borges, Lia Raquel R; Malheiros, Suzana M F; Pelaez, Maria Paula; Stávale, João Norberto; Santos, Adrialdo J; Carrete, Henrique; Nogueira, Roberto Gomes; Ferraz, Fernando A P; Gabbai, Alberto A

    2003-06-01

    We reviewed the clinical presentation, imaging and histopathologic findings in 4 patients with the diagnosis of arteriovenous malformation associated with glioma that were operated on from 1991 to 2000 in our institution. Four patients (2 males; age between 15 and 52 years) presented with progressive headache with clinical evidence of intracranial hypertension (in 3) and partial seizures (in 1). CT scan showed a brain tumor without any detectable pathologic vessels. Histologic examination revealed astrocytic tumors associated with arteriovenous malformation. No patient presented the vascular component intermixed with the tumor. The arteriovenous-glioma association is rare and must be identified by a clear demarcation between the malformation and the tumor.

  15. Automatic delineation of tumor volumes by co-segmentation of combined PET/MR data

    NASA Astrophysics Data System (ADS)

    Leibfarth, S.; Eckert, F.; Welz, S.; Siegel, C.; Schmidt, H.; Schwenzer, N.; Zips, D.; Thorwarth, D.

    2015-07-01

    Combined PET/MRI may be highly beneficial for radiotherapy treatment planning in terms of tumor delineation and characterization. To standardize tumor volume delineation, an automatic algorithm for the co-segmentation of head and neck (HN) tumors based on PET/MR data was developed. Ten HN patient datasets acquired in a combined PET/MR system were available for this study. The proposed algorithm uses both the anatomical T2-weighted MR and FDG-PET data. For both imaging modalities tumor probability maps were derived, assigning each voxel a probability of being cancerous based on its signal intensity. A combination of these maps was subsequently segmented using a threshold level set algorithm. To validate the method, tumor delineations from three radiation oncologists were available. Inter-observer variabilities and variabilities between the algorithm and each observer were quantified by means of the Dice similarity index and a distance measure. Inter-observer variabilities and variabilities between observers and algorithm were found to be comparable, suggesting that the proposed algorithm is adequate for PET/MR co-segmentation. Moreover, taking into account combined PET/MR data resulted in more consistent tumor delineations compared to MR information only.

  16. The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium

    PubMed Central

    Amirian, E. Susan; Armstrong, Georgina N.; Zhou, Renke; Lau, Ching C.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill S.; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S.; Jenkins, Robert B.; Lachance, Daniel; Olson, Sara H.; Bernstein, Jonine L.; Merrell, Ryan T.; Wrensch, Margaret R.; Davis, Faith G.; Lai, Rose; Shete, Sanjay; Amos, Christopher I.; Scheurer, Michael E.; Aldape, Kenneth; Alafuzoff, Irina; Brännström, Thomas; Broholm, Helle; Collins, Peter; Giannini, Caterina; Rosenblum, Marc; Tihan, Tarik; Melin, Beatrice S.; Bondy, Melissa L.

    2016-01-01

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010–2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions. PMID:26656478

  17. MYB-QKI rearrangements in Angiocentric Glioma drive tumorigenicity through a tripartite mechanism

    PubMed Central

    Bandopadhayay, Pratiti; Ramkissoon, Lori A.; Jain, Payal; Bergthold, Guillaume; Wala, Jeremiah; Zeid, Rhamy; Schumacher, Steven E.; Urbanski, Laura; O’Rourke, Ryan; Gibson, William J.; Pelton, Kristine; Ramkissoon, Shakti H.; Han, Harry J.; Zhu, Yuankun; Choudhari, Namrata; Silva, Amanda; Boucher, Katie; Henn, Rosemary E.; Kang, Yun Jee; Knoff, David; Paolella, Brenton R.; Gladden-Young, Adrianne; Varlet, Pascale; Pages, Melanie; Horowitz, Peleg M.; Federation, Alexander; Malkin, Hayley; Tracy, Adam; Seepo, Sara; Ducar, Matthew; Hummelen, Paul Van; Santi, Mariarita; Buccoliero, Anna Maria; Scagnet, Mirko; Bowers, Daniel C.; Giannini, Caterina; Puget, Stephanie; Hawkins, Cynthia; Tabori, Uri; Klekner, Almos; Bognar, Laszlo; Burger, Peter C.; Eberhart, Charles; Rodriguez, Fausto J.; Hill, D. Ashley; Mueller, Sabine; Haas-Kogan, Daphne A.; Phillips, Joanna J.; Santagata, Sandro; Stiles, Charles D.; Bradner, James E.; Jabado, Nada; Goren, Alon; Grill, Jacques; Ligon, Azra H.; Goumnerova, Liliana; Waanders, Angela J.; Storm, Phillip B.; Kieran, Mark W.; Ligon, Keith L.; Beroukhim, Rameen; Resnick, Adam C.

    2016-01-01

    Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs including 19 Angiocentric Gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in Angiocentric Gliomas. In vitro and in vivo functional studies show MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. This represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor. PMID:26829751

  18. Bionanotechnology and the Future of Glioma

    PubMed Central

    Chiarelli, Peter A.; Kievit, Forrest M.; Zhang, Miqin; Ellenbogen, Richard G.

    2015-01-01

    Designer nanoscaled materials have the potential to revolutionize diagnosis and treatment for glioma. This review summarizes current progress in nanoparticle-based therapies for glioma treatment including targeting, drug delivery, gene delivery, and direct tumor ablation. Preclinical and current human clinical trials are discussed. Although progress in the field has been significant over the past decade, many successful strategies demonstrated in the laboratory have yet to be implemented in human clinical trials. Looking forward, we provide examples of combined treatment strategies, which harness the potential for nanoparticles to interact with their biochemical environment, and simultaneously with externally applied photons or magnetic fields. We present our notion of the “ideal” nanoparticle for glioma, a concept that may soon be realized. PMID:25722933

  19. Synthesis and photophysical characterization of quasi push-pull dicyanodibenzodioxins and their anti-tumor activity against glioma cell line C6.

    PubMed

    Banerjee, Subhadeep; Chattopadhyay, Anjan; Banerjee, Arnab; Haridas, Meera; Saini, Praveen; Das, Moitreyi; Majik, Mahesh S; Maurya, Yogesh Kr

    2015-02-15

    Dibenzodioxins bearing multiple electron withdrawing groups were synthesized using a simple one-step methodology including examples of molecules possessing electron acceptor groups in both ends. As a consequence internal charge delocalization occurs and the optical spectra are found to be bathochromically shifted compared to similar examples known thus far. A theoretical analysis of the molecular orbitals reveals the origin of the peaks in the dibenzodioxin optical spectra. Select examples exhibit in vitro neuro-cytotoxicity against glioma cell line C6, a finding which enhances existing knowledge about the pharmacologically relevant structural motifs in dibenzodioxins.

  20. Aberrant CpG Islands Hypermethylation Profiles in Malignant Gliomas

    PubMed Central

    Kim, Kwang Ryeol; Kim, Ealmaan

    2014-01-01

    Background The authors analyzed whether the promoter hypermethylation of cancer-related genes was involved in the tumorigenesis of malignant gliomas. Methods A total of 29 patients received surgery and histologically confirmed to have malignant gliomas from January 2000 to December 2006. The promoter methylation status of several genes, which were reported to be frequently methylated in malignant gliomas, was investigated using methylation-specific polymerase chain reaction. Results All cases of malignant gliomas represented the promoter hypermethylation in at least 2 or more genes tested. Of 29 tumors, 28 (96.55%) showed concurrent hypermethylation of 3 or more genes. Ras association domain family member 1, epithelial cadherin, O-6 methyl guanine DNA methyltransferase, thrombospondin 1, p14 and adenomatous polyposis coli were frequently methylated in high grade gliomas including glioblastomas, anaplastic astrocytomas, and anaplastic oligodendrogliomas. Conclusion Aberrant hypermethylation profile was closely related with malignant gliomas suggesting that epigenetic change may play a role in the development of malignant gliomas. Two or three target genes may provide useful clues to the development of the useful prognostic as well as diagnostic assays for malignant gliomas. PMID:24926469

  1. [Histological and molecular classification of gliomas].

    PubMed

    Figarella-Branger, D; Colin, C; Coulibaly, B; Quilichini, B; Maues De Paula, A; Fernandez, C; Bouvier, C

    2008-01-01

    Gliomas are the most frequent tumors of the central nervous system. The WHO classification, based on the presumed cell origin, distinguishes astrocytic, oligodendrocytic and mixed gliomas. A grading system is based on the presence of the following criteria: increased cellular density, nuclear atypias, mitosis, vascular proliferation and necrosis. The main histological subtype of grade I gliomas are pilocytic astrocytomas, which are benign. Diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas are low-grade (II) or high-grade (III and IV) tumors. Glioblastomas correspond to grade IV astrocytomas. C. Daumas-Duport et al. have proposed another classification based on histology and imaging data, which distinguishes oligodendrogliomas and mixed gliomas of grade A (without endothelial proliferation and/or contrast enhancement), oligodendrogliomas and mixed gliomas of grade B (with endothelial proliferation or contrast enhancement), glioblastomas and glioneuronal malignant tumors. Both classifications lack reproducibility. Many studies have searched for a molecular classification. Recurrent abnormalities in gliomas have been found. They encompassed recurrent chromosomal alterations, such as lost of chromosome 10, gain of chromosome 7, deletion of chromosome 1p and 19q, but also activation of the Akt pathway (amplification of EGFR), dysregulation of the cell cycle (deletion of p16, p53). These studies have enabled the description of two molecular subtypes for glioblastomas. De novo glioblastomas, which occur in young patients without of a prior history of brain tumor and harbor frequent amplification of EGFR, deletion of p16 and mutation of PTEN while mutation of p53 is infrequent. Secondary glioblastomas occur in the context of a preexisting low-grade glioma and are characterized by more frequent mutation of p53. On the other side, combined complete deletion of 1p and 19q as the result of the translocation t(1;19)(q10;p10) is highly specific of oligodendrogliomas

  2. Diffusion-weighted imaging-based probabilistic segmentation of high- and low-proliferative areas in high-grade gliomas

    PubMed Central

    Fritzsche, Klaus H.; Thieke, Christian; Klein, Jan; Parzer, Peter; Weber, Marc-André; Stieltjes, Bram

    2012-01-01

    Abstract The apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) correlates inversely with tumor proliferation rates. High-grade gliomas are typically heterogeneous and the delineation of areas of high and low proliferation is impeded by partial volume effects and blurred borders. Commonly used manual delineation is further impeded by potential overlap with cerebrospinal fluid and necrosis. Here we present an algorithm to reproducibly delineate and probabilistically quantify the ADC in areas of high and low proliferation in heterogeneous gliomas, resulting in a reproducible quantification in regions of tissue inhomogeneity. We used an expectation maximization (EM) clustering algorithm, applied on a Gaussian mixture model, consisting of pure superpositions of Gaussian distributions. Soundness and reproducibility of this approach were evaluated in 10 patients with glioma. High- and low-proliferating areas found using the clustering correspond well with conservative regions of interest drawn using all available imaging data. Systematic placement of model initialization seeds shows good reproducibility of the method. Moreover, we illustrate an automatic initialization approach that completely removes user-induced variability. In conclusion, we present a rapid, reproducible and automatic method to separate and quantify heterogeneous regions in gliomas. PMID:22487677

  3. Hugl-1 inhibits glioma cell growth in intracranial model.

    PubMed

    Liu, Xuejiao; Lu, Dong; Ma, Peng; Liu, Huaqiang; Cao, Yuewen; Sang, Ben; Zhu, Xianlong; Shi, Qiong; Hu, Jinxia; Yu, Rutong; Zhou, Xiuping

    2015-10-01

    Drosophila lethal (2) giant larvae (lgl) has been reported as a tumor suppressor and could regulate the Drosophila hippo signaling. Human giant larvae-1(Hugl-1), one human homologue of Drosophila lgl, also has been reported to be involved in the development of some human cancers. However, whether Hugl-1 is associated with the pathogenesis of malignant gliomas remains poorly understood. In the present work, we examined the effect of Hugl-1 on glioma cell growth both in vitro and in vivo. Firstly, we found that Hugl-1 protein levels decreased in the human glioma tissues, suggesting that Hugl-1 is involved in glioma progression. Unfortunately, either stably or transiently over-expressing Hugl-1 did not affect glioma cell proliferation in vitro. In addition, Hugl-1 over-expression did not regulate hippo signaling pathway. Interestingly, over-expression of Hugl-1 not only inhibited gliomagenesis but also markedly inhibited cell proliferation and promoted the apoptosis of U251 cells in an orthotopic model of nude mice. Taken together, this study provides the evidence that Hugl-1 inhibits glioma cell growth in intracranial model of nude mice, suggesting that Hugl-1 might be a potential tumor target for glioma therapy.

  4. Understanding inherited genetic risk of adult glioma – a review

    PubMed Central

    Rice, Terri; Lachance, Daniel H.; Molinaro, Annette M.; Eckel-Passow, Jeanette E.; Walsh, Kyle M.; Barnholtz-Sloan, Jill; Ostrom, Quinn T.; Francis, Stephen S.; Wiemels, Joseph; Jenkins, Robert B.; Wiencke, John K.; Wrensch, Margaret R.

    2016-01-01

    During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families. PMID:26941959

  5. Understanding inherited genetic risk of adult glioma - a review.

    PubMed

    Rice, Terri; Lachance, Daniel H; Molinaro, Annette M; Eckel-Passow, Jeanette E; Walsh, Kyle M; Barnholtz-Sloan, Jill; Ostrom, Quinn T; Francis, Stephen S; Wiemels, Joseph; Jenkins, Robert B; Wiencke, John K; Wrensch, Margaret R

    2016-03-01

    During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families.

  6. Telomere maintenance and the etiology of adult glioma.

    PubMed

    Walsh, Kyle M; Wiencke, John K; Lachance, Daniel H; Wiemels, Joseph L; Molinaro, Annette M; Eckel-Passow, Jeanette E; Jenkins, Robert B; Wrensch, Margaret R

    2015-11-01

    A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.

  7. Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma.

    PubMed

    Bredlau, Amy Lee; Dixit, Suraj; Chen, Chao; Broome, Ann-Marie

    2017-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs. Multiple nanoparticle formulations are currently being investigated for the treatment of DIPGs. Nanoparticles based upon stable elements, polymer nanoparticles, and organic nanoparticles are under development for the treatment of brain tumors, including DIPGs. Targeting of nanoparticles is now possible as delivery techniques that address the difficulty in crossing the blood brain barrier (BBB) are developed. Theranostic nanoparticles, a combination of therapeutics and diagnostic nanoparticles, improve imaging of the cancerous tissue while delivering therapy to the local region. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG.

  8. Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model.

    PubMed

    Prins, Robert M; Odesa, Sylvia K; Liau, Linda M

    2003-12-01

    Immune-based treatments for central nervous system gliomas have traditionally lagged behind those of more immunogenic tumors such as melanoma. The relative paucity of defined glioma-associated antigens that can be targeted by the immune system may partially account for this situation. Antigens present on melanomas have been extensively characterized, both in humans and in murine preclinical models. Melanocytes and astrocytes are both derived embryologically from the neural ectoderm. Their neoplastic counterparts, malignant melanomas and gliomas, have been shown in humans to share common antigens at the RNA level. However, little is known concerning whether gliomas can be targeted by immune-based strategies that prime T cells to epitopes from melanoma-associated antigens (MAAs). In this study, we provide evidence that two common murine glioma cell lines (GL26 and GL261) express the melanoma antigens gp100 and tyrosinase-related protein 2 (TRP-2). To understand the immunogenicity of murine gliomas to CD8(+) T cells, we examined the ability of a MAA-specific CTL cell line to lyse the glioma cells, as well as the in vivo expansion of MAA-specific CD8(+) T cells in animals harboring gliomas. Both glioma cell lines were lysed by a human gp100-specific CTL cell line in vitro. Mice harboring s.c. GL26 gliomas possessed TRP-2-specific CD8(+) T cells, providing further evidence that these gliomas express the protein products in the context of MHC class I. Furthermore, MAA peptide-pulsed dendritic cells could prime T cells that specifically recognize GL26 glioma cells in vitro. Lastly, mice that were prevaccinated with human gp100 and TRP-2 peptide-pulsed dendritic cells had significantly extended survival when challenged with tumor cells in the brain, resulting in >50% long-term survival. These results suggest that shared MAAs on gliomas can be targeted immunotherapeutically, pointing the way to a new potential treatment option for patients with malignant gliomas.

  9. Metabolism of human gliomas: Assessment with H-1 MR spectroscopy and F-18 fluorodeoxyglucose PET

    SciTech Connect

    Alger, J.R.; Frank, J.A.; Bizzi, A.; Fulham, M.J.; DeSouza, B.X.; Duhaney, M.O.; Inscoe, S.W.; Black, J.L.; van Zijl, P.C.; Moonen, C.T. , Bethesda, MD )

    1990-12-01

    Localized hydrogen-1 magnetic resonance (MR) spectroscopy and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) were employed to obtain metabolic information from intracranial gliomas. Advantages and difficulties associated with comparison of results from the two modalities were realized. Forty patients were studied with H-1 MR spectroscopy. MR signal intensities from lactate, N-acetylaspartate (NAA), choline, and creatine from a volume of interest containing the tumor and a contralateral volume were obtained and evaluated. NAA signal intensities were generally decreased in the tumor spectra, and choline signal intensities were elevated. H-1 MR spectroscopy was unsuccessful in eight patients, and FDG PET scans were not obtained in four of the patients with successful MR spectroscopic examinations. Lactate signal intensity was detected in 10 of the 28 patients who had successful H-1 MR spectroscopic and FDG PET studies. Lactate signal intensities were observed in lesions shown at FDG PET to be hypermetabolic, as well as in lesions found to be hypometabolic.

  10. Ectopic expression of AP-2α transcription factor suppresses glioma progression.

    PubMed

    Su, Wenjing; Xia, Juan; Chen, Xueqin; Xu, Miao; Nie, Ling; Chen, Ni; Gong, Jing; Li, Xinglan; Zhou, Qiao

    2014-01-01

    The transcriptional factor AP-2α is a tumor suppressor gene and is downregulated in various neoplasms including glioma. Although the level of AP-2α is negatively associated with the grade of human glioma, the specific functions of AP-2α in glioma are still unknown. In this study, we experimentally showed that artificial overexpression of AP-2α in glioma T98G and U251 cells significantly downregulated the mRNA levels of Bcl-xl, Bcl-2, c-IAP2 and survivin, together with upregulation of the Hrk mRNA levels. Reintroduction of AP-2α also induced downregulation of the protein levels of survivin and VEGF in glioma cells. In biological assays with T98G and U251 cells, AP-2α reduced tumor cell growth, increased cell death, attenuated cell migration and endothelial tube formation. The AP-2α transcription factor may play an important role in suppressing glioma progression.

  11. Automatic estimation of extent of resection and residual tumor volume of patients with glioblastoma.

    PubMed

    Meier, Raphael; Porz, Nicole; Knecht, Urspeter; Loosli, Tina; Schucht, Philippe; Beck, Jürgen; Slotboom, Johannes; Wiest, Roland; Reyes, Mauricio

    2017-01-06

    OBJECTIVE In the treatment of glioblastoma, residual tumor burden is the only prognostic factor that can be actively influenced by therapy. Therefore, an accurate, reproducible, and objective measurement of residual tumor burden is necessary. This study aimed to evaluate the use of a fully automatic segmentation method-brain tumor image analysis (BraTumIA)-for estimating the extent of resection (EOR) and residual tumor volume (RTV) of contrast-enhancing tumor after surgery. METHODS The imaging data of 19 patients who underwent primary resection of histologically confirmed supratentorial glioblastoma were retrospectively reviewed. Contrast-enhancing tumors apparent on structural preoperative and immediate postoperative MR imaging in this patient cohort were segmented by 4 different raters and the automatic segmentation BraTumIA software. The manual and automatic results were quantitatively compared. RESULTS First, the interrater variabilities in the estimates of EOR and RTV were assessed for all human raters. Interrater agreement in terms of the coefficient of concordance (W) was higher for RTV (W = 0.812; p < 0.001) than for EOR (W = 0.775; p < 0.001). Second, the volumetric estimates of BraTumIA for all 19 patients were compared with the estimates of the human raters, which showed that for both EOR (W = 0.713; p < 0.001) and RTV (W = 0.693; p < 0.001) the estimates of BraTumIA were generally located close to or between the estimates of the human raters. No statistically significant differences were detected between the manual and automatic estimates. BraTumIA showed a tendency to overestimate contrast-enhancing tumors, leading to moderate agreement with expert raters with respect to the literature-based, survival-relevant threshold values for EOR. CONCLUSIONS BraTumIA can generate volumetric estimates of EOR and RTV, in a fully automatic fashion, which are comparable to the estimates of human experts. However, automated analysis showed a tendency to overestimate

  12. Tumor-Volume Simulation During Radiotherapy for Head-and-Neck Cancer Using a Four-Level Cell Population Model

    SciTech Connect

    Chvetsov, Alexei V. Dong Lei; Palta, Jantinder R.; Amdur, Robert J.

    2009-10-01

    Purpose: To develop a fast computational radiobiologic model for quantitative analysis of tumor volume during fractionated radiotherapy. The tumor-volume model can be useful for optimizing image-guidance protocols and four-dimensional treatment simulations in proton therapy that is highly sensitive to physiologic changes. Methods: The analysis is performed using two approximations: (1) tumor volume is a linear function of total cell number and (2) tumor-cell population is separated into four subpopulations: oxygenated viable cells, oxygenated lethally damaged cells, hypoxic viable cells, and hypoxic lethally damaged cells. An exponential decay model is used for disintegration and removal of oxygenated lethally damaged cells from the tumor. Results: We tested our model on daily volumetric imaging data available for 14 head-and-neck cancer patients treated with an integrated computed tomography/linear accelerator system. A simulation based on the averaged values of radiobiologic parameters was able to describe eight cases during the entire treatment and four cases partially (50% of treatment time) with a maximum 20% error. The largest discrepancies between the model and clinical data were obtained for small tumors, which may be explained by larger errors in the manual tumor volume delineation procedure. Conclusions: Our results indicate that the change in gross tumor volume for head-and-neck cancer can be adequately described by a relatively simple radiobiologic model. In future research, we propose to study the variation of model parameters by fitting to clinical data for a cohort of patients with head-and-neck cancer and other tumors. The potential impact of other processes, like concurrent chemotherapy, on tumor volume should be evaluated.

  13. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells

    PubMed Central

    Lin, Hua; Patel, Shaan; Affleck, Valerie S.; Wilson, Ian; Turnbull, Douglass M.; Joshi, Abhijit R.; Maxwell, Ross

    2017-01-01

    Background. Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells. Methods. We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention. Results. We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma. Conclusions. Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice. PMID:27365097

  14. Diffusion kurtosis imaging can efficiently assess the glioma grade and cellular proliferation.

    PubMed

    Jiang, Rifeng; Jiang, Jingjing; Zhao, Lingyun; Zhang, Jiaxuan; Zhang, Shun; Yao, Yihao; Yang, Shiqi; Shi, Jingjing; Shen, Nanxi; Su, Changliang; Zhang, Ju; Zhu, Wenzhen

    2015-12-08

    Conventional diffusion imaging techniques are not sufficiently accurate for evaluating glioma grade and cellular proliferation, which are critical for guiding glioma treatment. Diffusion kurtosis imaging (DKI), an advanced non-Gaussian diffusion imaging technique, has shown potential in grading glioma; however, its applications in this tumor have not been fully elucidated. In this study, DKI and diffusion weighted imaging (DWI) were performed on 74 consecutive patients with histopathologically confirmed glioma. The kurtosis and conventional diffusion metric values of the tumor were semi-automatically obtained. The relationships of these metrics with the glioma grade and Ki-67 expression were evaluated. The diagnostic efficiency of these metrics in grading was further compared. It was demonstrated that compared with the conventional diffusion metrics, the kurtosis metrics were more promising imaging markers in distinguishing high-grade from low-grade gliomas and distinguishing among grade II, III and IV gliomas; the kurtosis metrics also showed great potential in the prediction of Ki-67 expression. To our best knowledge, we are the first to reveal the ability of DKI to assess the cellular proliferation of gliomas, and to employ the semi-automatic method for the accurate measurement of gliomas. These results could have a significant impact on the diagnosis and subsequent therapy of glioma.

  15. Post-Radiation Metabolic Tumor Volume Predicts Outcome in Head-and-Neck Cancer

    PubMed Central

    Murphy, James D; La, Trang H.; Chu, Karen; Quon, Andrew; Fischbein, Nancy J.; Maxim, Peter G.; Graves, Edward E.; Loo, Billy W.; Le, Quynh-Thu

    2010-01-01

    Purpose To explore the prognostic value of metabolic tumor volume measured on post-radiation 18F-fluorodeoxyglucose positron emission tomography (PET) imaging in head-and-neck cancer patients. Methods and Materials Forty-seven head-and-neck cancer patients who received pre- and post-treatment PET/CT imaging along with definitive chemoradiotherapy were included in this study. PET/CT parameters evaluated include the maximum standardized uptake value, metabolic tumor volume (MTV2.0-MTV4.0; where MTV2.0 refers to the volume above an SUV threshold of 2.0), and integrated tumor volume. Kaplan-Meier and Cox-regression models were used to test for association between PET endpoints and disease-free survival (DFS) and overall survival (OS). Results Multiple post-radiation PET endpoints correlated significantly with outcome, however the most robust predictor of disease progression and death was MTV2.0. An increase in MTV2.0 of 21cm3 (difference between 75th and 25th percentile) was associated with an increased risk of disease progression (hazard ratio [HR]=2.5, p=0.0001) and death (HR=2.0, p=0.003). In patients with non-nasopharyngeal carcinoma (non-NPC) histology (n=34), MTV2.0<18cm3 and MTV2.0≥18cm3 yielded 2-year DFS rates of 100% and 63%, respectively (p=0.006) and 2-year OS rates of 100% and 81%, respectively (p=0.009). There was no correlation between MTV2.0 and DFS or OS with NPC histology (n=13). On multivariate analysis only post-radiation MTV2.0 was predictive of DFS (HR=2.47, p=0.0001) and OS (HR=1.98, p=0.003). Conclusions Post-radiation metabolic tumor volume is an adverse prognostic factor in head-and-neck cancer. Biomarkers such as MTV are important for risk stratification, and will be valuable in the future with risk-adapted therapies. PMID:20646870

  16. Loss of heterozygosity of chromosome 10p in human gliomas

    SciTech Connect

    Kimmelman, A.C.; Liang, B.C.; Ross, D.A.

    1996-06-01

    Molecular loss of heterozygosity studies on human gliomas have shown several regions on chromosome 10 frequently deleted in higher grade tumors, suggesting that chromosome 10 may contain several tumor suppressor genes. We assessed loss of heterozygosity with microsatellite markers in 20 gliomas, consisting of various grades and containing two chromosome 10 copies. The locus that exhibited the most loss (69%) was the region bordered by D10S249 and D10S558 and inclusive of D10S594, with a linkage distance of 3 cM. This region was noted to be deleted in various grades of tumor, including low- and high-grade tumors. These results suggest that chromosome region 10p15 is involved in human gliomas of diverse grades and that this region may harbor genes important in the development of and progression to the malignant phenotype. 20 refs., 4 figs., 1 tab.

  17. [Classification of gliomas. Current progress and perspectives].

    PubMed

    Capper, D; Reifenberger, G

    2015-06-01

    The diagnostic subdivision of gliomas is traditionally based on histological features as defined by the World Health Organization (WHO) classification of tumors of the central nervous system. In recent years molecular studies have identified a number of genetic and epigenetic markers that could contribute to an improved tumor classification and better prediction of response to therapy and prognosis in the individual patient. The most important molecular tests with differential diagnostic relevance in patients with astrocytic and oligodendroglial tumors include the detection of genetic mutations in the isocitrate dehydrogenase 1 (IDH1), IDH2, alpha thalassemia/mental retardation syndrome X-linked (ATRX), histone H3.3 (H3F3A) and v-raf murine sarcoma viral oncogene homolog B (BRAF) genes as well as the demonstration of codeletions of chromosomal arms 1p and 19q. Important predictive markers that have been linked to the response to alkylating chemotherapy are O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients and 1p/19q codel status in anaplastic glioma patients. Oncogenic c11orf95/RELA fusion gene formation is characteristic for a subgroup of patients with supratentorial ependymoma. In addition to diagnostic testing of individual genes, novel microarray and next generation sequencing (NGS) techniques show promising perspectives in glioma diagnostics. The assessment of DNA methylation profiles using DNA methylation arrays representing 450,000 CpG dinucleotides distributed throughout the human genome (450 k array test) now allows the robust molecular classification of gliomas into clinically relevant entities and variants. Moreover, glioma-associated gene panel NGS promises the timely parallel sequencing of relevant diagnostic and predictive marker genes in a single test. It will now be a major task to integrate these novel results and techniques into the conventional histological procedures in the up-coming revision of the

  18. Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation

    PubMed Central

    Li, Jiejing; Qu, Jiagui; Shi, Yu; Perfetto, Mark; Ping, Zhuxian; Christian, Laura; Niu, Hua; Mei, Shuting; Zhang, Qin; Yang, Xiangcai; Wei, Shuo

    2017-01-01

    Malignant glioma is a formidable disease that commonly leads to death, mainly due to the invasion of tumor cells into neighboring tissues. Therefore, inhibition of tumor cell invasion may provide an effective therapy for malignant glioma. Here we report that nicotinic acid (NA), an essential vitamin, inhibits glioma cell invasion in vitro and in vivo. Treatment of the U251 glioma cells with NA in vitro results in reduced invasion, which is accompanied by a loss of mesenchymal phenotype and an increase in cell-cell adhesion. At the molecular level, transcription of the adherens junction protein E-cadherin is upregulated, leading to accumulation of E-cadherin protein at the cell-cell boundary. This can be attributed to NA’s ability to facilitate the ubiquitination and degradation of Snail1, a transcription factor that represses E-cadherin expression. Similarly, NA transiently inhibits neural crest migration in Xenopus embryos in a Snail1-dependent manner, indicating that the mechanism of action for NA in cell migration is evolutionarily conserved. We further show that NA injection blocks the infiltration of tumor cells into the adjacent brain tissues and improves animal survival in a rat model of glioma. These results suggest that NA treatment may be developed into a potential therapy for malignant glioma. PMID:28256591

  19. Tumor Volume as an Alternative Response Measurement for Imatinib Treated GIST Patients

    PubMed Central

    Schiavon, Gaia; Ruggiero, Alessandro; Schöffski, Patrick; van der Holt, Bronno; Bekers, Dave J.; Eechoute, Karel; Vandecaveye, Vincent; Krestin, Gabriel P.; Verweij, Jaap; Sleijfer, Stefan; Mathijssen, Ron H. J.

    2012-01-01

    Background Assessment of tumor size changes is crucial in clinical trials and patient care. We compared imatinib-induced volume changes of liver metastases (LM) from gastro-intestinal stromal tumors (GIST) to RECIST and Choi criteria and their association with overall survival (OS). Methods LM from 84 GIST patients (training and validation set) were evaluated using manual and semi-automated Computed Tomography measurements at baseline, after 3, 6 and 12 months of imatinib. The ability of uni-dimensional (1D) and three-dimensional (3D) measurements to detect size changes (increase/decrease) ≥20% was evaluated. Volumetric response cut-offs were derived from minimally relevant changes (+20/−30%) by RECIST, considering lesions as spherical or ellipsoidal. Results 3D measurements detected size changes ≥20% more frequently than 1D at every time-point (P≤0.008). 3D and Choi criteria registered more responses than RECIST at 3 and 6 months for 3D-spheres (P≤0.03) and at all time-points for 3D-ellipsoids and Choi criteria (P<0.001). Progressive disease by 3D criteria seems to better correlate to OS at late time-points than other criteria. Conclusion Volume criteria (especially ellipsoids) classify a higher number of patients as imatinib-responders than RECIST. Volume discriminates size changes better than diameter in GIST and constitutes a feasible and robust method to evaluate response and predict patient benefit. PMID:23133631

  20. High-definition fiber tractography for the evaluation of perilesional white matter tracts in high-grade glioma surgery.

    PubMed

    Abhinav, Kumar; Yeh, Fang-Cheng; Mansouri, Alireza; Zadeh, Gelareh; Fernandez-Miranda, Juan C

    2015-09-01

    Conventional white matter (WM) imaging approaches, such as diffusion tensor imaging (DTI), have been used to preoperatively identify the location of affected WM tracts in patients with intracranial tumors in order to maximize the extent of resection and potentially reduce postoperative morbidity. DTI, however, has limitations that include its inability to resolve multiple crossing fibers and its susceptibility to partial volume effects. Therefore, recent focus has shifted to more advanced WM imaging techniques such as high-definition fiber tractography (HDFT). In this paper, we illustrate the application of HDFT, which in our preliminary experience has enabled accurate depiction of perilesional tracts in a 3-dimensional manner in multiple anatomical compartments including edematous zones around high-grade gliomas. This has facilitated accurate surgical planning. This is illustrated by using case examples of patients with glioblastoma multiforme. We also discuss future directions in the role of these techniques in surgery for gliomas.

  1. Total tumor volume predicts survival following liver resection in patients with hepatocellular carcinoma.

    PubMed

    Li, Mu-Xing; Zhao, Hong; Bi, Xin-Yu; Li, Zhi-Yu; Huang, Zhen; Han, Yue; Zhou, Jian-Guo; Zhao, Jian-Jun; Zhang, Ye-Fan; Wei, Wen-Qiang; Zhao, Dong-Bin; Cai, Jian-Qiang

    2016-07-01

    Assessing the prognosis of patients with hepatocellular carcinoma (HCC) by the number and size of tumors is sometimes difficult. The main purpose of the study was to evaluate the prognostic value of total tumor volume (TTV), which combines the two factors, in patients with HCC who underwent liver resection. We retrospectively reviewed 521 HCC patients from January 2001 to December 2008 in our center. Patients were categorized using the tertiles of TTV. The prognostic value of TTV was assessed. With a median follow-up of 116 months, the 1-, 3-, and 5-year overall survival (OS) rates of the patients were 93.1 , 69.9, and 46.3 %, respectively. OS was significantly differed by TTV tertile groups, and higher TTV was associated with shorter OS (P < 0.001). Multivariate analysis revealed that TTV was an independent prognostic factor for OS. Larger TTV was significantly associated with higher alpha-fetoprotein level, presence of macrovascular invasion, multiple tumor lesions, larger tumor size, and advanced tumor stages (all P < 0.05). Within the first and second tertiles of TTV (TTV ≤ 73.5 cm(3)), no significant differences in OS were detected in patients within and beyond Milan criteria (P = 0.183). TTV-based Cancer of the Liver Italian Program (CLIP) score gained the lowest Akaike information criterion value, the highest χ (2) value of likelihood ratio test, and the highest C-index among the tested staging systems. Our results suggested that TTV is a good indicator of tumor burden in patients with HCC. Further studies are warranted to validate the prognostic value of TTV.

  2. IGFBP2 expression predicts IDH-mutant glioma patient survival

    PubMed Central

    Huang, Lin Eric; Cohen, Adam L.; Colman, Howard; Jensen, Randy L.; Fults, Daniel W.; Couldwell, William T.

    2017-01-01

    Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas. Furthermore, each of these genes is prognostic in overall gliomas; however, within the IDH-mutant group, none remains prognostic except IGFBP2 (encodinginsulin-like growth factor binding protein 2). Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients. These observations hold true across different histological and molecular subtypes of lower-grade glioma. We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2. PMID:27852048

  3. Surgical benefits of combined awake craniotomy and intraoperative magnetic resonance imaging for gliomas associated with eloquent areas.

    PubMed

    Motomura, Kazuya; Natsume, Atsushi; Iijima, Kentaro; Kuramitsu, Shunichiro; Fujii, Masazumi; Yamamoto, Takashi; Maesawa, Satoshi; Sugiura, Junko; Wakabayashi, Toshihiko

    2017-01-06

    OBJECTIVE Maximum extent of resection (EOR) for lower-grade and high-grade gliomas can increase survival rates of patients. However, these infiltrative gliomas are often observed near or within eloquent regions of the brain. Awake surgery is of known benefit for the treatment of gliomas associated with eloquent regions in that brain function can be preserved. On the other hand, intraoperative MRI (iMRI) has been successfully used to maximize the resection of tumors, which can detect small amounts of residual tumors. Therefore, the authors assessed the value of combining awake craniotomy and iMRI for the resection of brain tumors in eloquent areas of the brain. METHODS The authors retrospectively reviewed the records of 33 consecutive patients with glial tumors in the eloquent brain areas who underwent awake surgery using iMRI. Volumetric analysis of MRI studies was performed. The pre-, intra-, and postoperative tumor volumes were measured in all cases using MRI studies obtained before, during, and after tumor resection. RESULTS Intraoperative MRI was performed to check for the presence of residual tumor during awake surgery in a total of 25 patients. Initial iMRI confirmed no further tumor resection in 9 patients (36%) because all observable tumors had already been removed. In contrast, intraoperative confirmation of residual tumor during awake surgery led to further tumor resection in 16 cases (64%) and eventually an EOR of more than 90% in 8 of 16 cases (50%). Furthermore, EOR benefiting from iMRI by more than 15% was found in 7 of 16 cases (43.8%). Interestingly, the increase in EOR as a result of iMRI for tumors associated mainly with the insular lobe was significantly greater, at 15.1%, than it was for the other tumors, which was 8.0% (p = 0.001). CONCLUSIONS This study revealed that combining awake surgery with iMRI was associated with a favorable surgical outcome for intrinsic brain tumors associated with eloquent areas. In particular, these benefits were

  4. The molecular biology of WHO grade II gliomas.

    PubMed

    Marko, Nicholas F; Weil, Robert J

    2013-02-01

    The WHO grading scheme for glial neoplasms assigns Grade II to 5 distinct tumors of astrocytic or oligodendroglial lineage: diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, and pilomyxoid astrocytoma. Although commonly referred to collectively as among the "low-grade gliomas," these 5 tumors represent molecularly and clinically unique entities. Each is the subject of active basic research aimed at developing a more complete understanding of its molecular biology, and the pace of such research continues to accelerate. Additionally, because managing and predicting the course of these tumors has historically proven challenging, translational research regarding Grade II gliomas continues in the hopes of identifying novel molecular features that can better inform diagnostic, prognostic, and therapeutic strategies. Unfortunately, the basic and translational literature regarding the molecular biology of WHO Grade II gliomas remains nebulous. The authors' goal for this review was to present a comprehensive discussion of current knowledge regarding the molecular characteristics of these 5 WHO Grade II tumors on the chromosomal, genomic, and epigenomic levels. Additionally, they discuss the emerging evidence suggesting molecular differences between adult and pediatric Grade II gliomas. Finally, they present an overview of current strategies for using molecular data to classify low-grade gliomas into clinically relevant categories based on tumor biology.

  5. Raman spectroscopy of gliomas: an exploratory study

    NASA Astrophysics Data System (ADS)

    Shenoy, Mahesh; Hole, Arti R.; Shridhar, E.; Moiyadi, Aliasgar V.; Krishna, C. Murali

    2014-03-01

    Gliomas are extremely infiltrative type of brain cancers, the borders of which are difficult to locate. Gliomas largely consist of tumors of astrocytic or oligodendroglial lineage. Usually stereotactic surgery is performed to obtain tumor tissue sample. Complete excision of these tumors with preservation of uninvolved normal areas is important during brain tumor surgeries. The present study was undertaken to explore feasibility of classifying abnormal and normal glioma tissues with Raman spectroscopy (RS). RS is a nondestructive vibrational spectroscopic technique, which provides information about molecular composition, molecular structures and molecular interactions in tissue. Postoperated 33 (20-abnormal and 13-normal) gliomas tissue samples of different grades were collected under clinical supervision. Five micron section from tissue sample was used for confirmatory histopathological diagnosis while the remaining tissue was placed on CaF2 window and spectra were acquired using a fiberoptic-probe-coupled HE-785 Raman-spectrometer. Spectral acquisition parameters were laser power-80mW, integration-20s and averaged over 3 accumulations. Spectra were pre-processed and subjected to unsupervised Principal-Component Analysis (PCA) to identify trends of classification. Supervised PC-LDA (Principal-Component-Linear-Discriminant Analysis) was used to develop standard-models using spectra of 12 normal and abnormal specimens each. Leave-one-out crossvalidation yielded classification-efficiency of 90% and 80% for normal and abnormal conditions, respectively. Evaluation with an independent-test data-set comprising of 135 spectra of 9 samples provided sensitivity of 100% and specificity of 70%. Findings of this preliminary study may pave way for objective tumor margin assessment during brain surgery.

  6. Neurodevelopmental Outcomes of Children with Low-Grade Gliomas

    ERIC Educational Resources Information Center

    Ris, M. Douglas; Beebe, Dean W.

    2008-01-01

    As a group, children with low-grade gliomas (LGGs) enjoy a high rate of long-term survival and do not require the intensity of neurotoxic treatments used with higher risk pediatric brain tumors. Because they are generally considered to have favorable neurobehavioral outcomes, they have not been studied as thoroughly as higher-grade brain tumors by…

  7. Assessment of the intrinsic radiosensitivity of glioma cells and monitoring of metabolite ratio changes after irradiation by 14.7-T high-resolution ¹H MRS.

    PubMed

    Zhang, Zhaotao; Zeng, Qingshi; Liu, Yun; Li, Chuanfu; Feng, Dechao; Wang, Jianzheng

    2014-05-01

    Gliomas are the most common type of primary brain tumor. Radiation therapy (RT) is the primary adjuvant treatment to eliminate residual tumor tissue after surgery. However, the current RT guided by conventional imaging is unsatisfactory. A fundamental question is whether it is possible to further enhance the effectiveness and efficiency of RT based on individual radiosensitivity. In this research, to probe the correlation between radiosensitivity and the metabolite characteristics of glioma cells in vitro, a perchloric acid (PCA) extracting method was used to obtain water-soluble metabolites [such as N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and succinate (Suc)]. Spectral patterns from these processed water-soluble metabolite samples were acquired by in vitro 14.7-T high-resolution ¹H MRS. Survival fraction analysis was performed to test the intrinsic radiosensitivity of glioma cell lines. Good ¹H MRS of PCA extracts from glioma cells was obtained. The radiosensitivity of glioma cells correlated positively with the Cho/Cr and Cho/NAA ratios, but negatively with the Suc/Cr ratio. Irradiation of the C6 cell line at different X-ray dosages led to changes in metabolite ratios and apoptotic rates. A plateau phase of metabolite ratio change and a decrease in apoptotic rate were found in the C6 cell line. We conclude that in vitro high-resolution ¹H MRS possesses the sensitivity required to detect subtle biochemical changes at the cellular level. ¹H MRS may aid in the assessment of the individual radiosensitivity of brain tumors, which is pivotal in the identification of the biological target volume.

  8. Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors

    ClinicalTrials.gov

    2016-04-11

    Ewing's Sarcoma; Osteosarcoma; Astrocytoma; Atypical Teratoid/Rhabdoid Tumor; Ependymoma; Germ Cell Tumor; Glioma; Medulloblastoma; Rhabdoid Tumor; Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Rhabdomyosarcoma

  9. Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells

    PubMed Central

    Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang; Han, Zhaozhong

    2012-01-01

    Background Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR. Methodology/Principal Findings Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR. Conclusions/Significance This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy. PMID:23028987

  10. Impact Factors for Microinvasion in Patients With Hepatocellular Carcinoma: Possible Application to the Definition of Clinical Tumor Volume

    SciTech Connect

    Wang Minhua; Ji Yuan; Zeng Zhaochong; Tang Zhaoyou; Fan Jia; Zhou Jian; Zeng Mengsu; Bi Aihong; Tan Yunshan

    2010-02-01

    Purpose: To evaluate the degree of invasion of hepatocellular carcinoma (HCC) microscopically that will provide a potential application for gross tumor volume to clinical tumor volume (GTV-to-CTV) expansion. Methods and Materials: From January 2002 to January 2006, 149 HCC patients were selected from those who had undergone surgical resection. Pathology slides and clinical data of all patients were reviewed, including platelet counts, serum alpha-fetoprotein (AFP) levels, degree of liver cirrhosis, tumor size, capsular status, portal vein invasion, TNM stage, and histologic tumor grade. The distance between the tumor margin (or fibrous capsule) and the invasive lesions was measured by senior pathologists. Results: Of these 149 patients, 79 (53.0%) patients presented with tumor microinvasion between 0.5 and 4 mm. This degree of microinvasion was inversely correlated with lower platelet counts and positively correlated with higher AFP levels, larger tumor sizes, portal vein invasion, and advanced TNM stage. Microinvasion distances less than or equal to 2 mm were found in 96.1% of patients (74/77) with tumor dimensions less than or equal to 5 cm and in 94.5% of patients (85/90) with AFP levels less than 400 mug/l. Conclusions: Based on our study findings, GTV-to-CTV expansions of 4 mm for HCC are required to conceal the gross tumor and any microscopic disease with 100% accuracy. Tumor size and AFP levels are the simplest indicators for determining the GTV-to-CTV distance for HCC.

  11. Impact of meriolins, a new class of cyclin-dependent kinase inhibitors, on malignant glioma proliferation and neo-angiogenesis

    PubMed Central

    Jarry, Marie; Lecointre, Céline; Malleval, Céline; Desrues, Laurence; Schouft, Marie-Thérèse; Lejoncour, Vadim; Liger, François; Lyvinec, Gildas; Joseph, Benoît; Loaëc, Nadège; Meijer, Laurent; Honnorat, Jérôme; Gandolfo, Pierrick; Castel, Hélène

    2014-01-01

    Background Glioblastomas are the most frequent and most aggressive primary brain tumors in adults. The median overall survival is limited to a few months despite surgery, radiotherapy, and chemotherapy. It is now clearly established that hyperactivity of cyclin-dependent kinases (CDKs) is one of the processes underlying hyperproliferation and tumoral growth. The marine natural products meridianins and variolins, characterized as CDK inhibitors, display a kinase-inhibitory activity associated with cytotoxic effects. In order to improve selectivity and efficiency of these CDK inhibitors, a series of hybrid compounds called meriolins have been synthesized. Methods The potential antitumoral activity of meriolins was investigated in vitro on glioma cell lines (SW1088 and U87), native neural cells, and a human endothelial cell line (HUV-EC-C). The impact of intraperitoneal or intratumoral administrations of meriolin 15 was evaluated in vivo on 2 different nude mice-xenografted glioma models. Results Meriolins 3, 5, and 15 exhibited antiproliferative properties with nanomolar IC50 and induced cell-cycle arrest and CDK inhibition associated with apoptotic events in human glioma cell lines. These meriolins blocked the proliferation rate of HUV-EC-C through cell cycle arrest and apoptosis. In vivo, meriolin 15 provoked a robust reduction in tumor volume in spite of toxicity for highest doses, associated with inhibition of cell division, activation of caspase 3, reduction of CD133 cells, and modifications of the vascular architecture. Conclusion Meriolins, and meriolin 15 in particular, exhibit antiproliferative and proapoptotic activities on both glioma and intratumoral endothelial cells, constituting key promising therapeutic lead compounds for the treatment of glioblastoma. PMID:24891448

  12. Automatic segmentation of tumor-laden lung volumes from the LIDC database

    NASA Astrophysics Data System (ADS)

    O'Dell, Walter G.

    2012-03-01

    The segmentation of the lung parenchyma is often a critical pre-processing step prior to application of computer-aided detection of lung nodules. Segmentation of the lung volume can dramatically decrease computation time and reduce the number of false positive detections by excluding from consideration extra-pulmonary tissue. However, while many algorithms are capable of adequately segmenting the healthy lung, none have been demonstrated to work reliably well on tumor-laden lungs. Of particular challenge is to preserve tumorous masses attached to the chest wall, mediastinum or major vessels. In this role, lung volume segmentation comprises an important computational step that can adversely affect the performance of the overall CAD algorithm. An automated lung volume segmentation algorithm has been developed with the goals to maximally exclude extra-pulmonary tissue while retaining all true nodules. The algorithm comprises a series of tasks including intensity thresholding, 2-D and 3-D morphological operations, 2-D and 3-D floodfilling, and snake-based clipping of nodules attached to the chest wall. It features the ability to (1) exclude trachea and bowels, (2) snip large attached nodules using snakes, (3) snip small attached nodules using dilation, (4) preserve large masses fully internal to lung volume, (5) account for basal aspects of the lung where in a 2-D slice the lower sections appear to be disconnected from main lung, and (6) achieve separation of the right and left hemi-lungs. The algorithm was developed and trained to on the first 100 datasets of the LIDC image database.

  13. Pathophysiology of glioma cyst formation.

    PubMed

    Adn, Mahmoudreza; Saikali, Stephan; Guegan, Yvon; Hamlat, Abderrahmane

    2006-01-01

    Fluid filled cystic cavities are accompaniments of some cerebral gliomas. These tumoural cysts together with peritumoural vasogenic brain oedema add to the morbid effects of the gliomas in terms of mass effect and increased intracranial pressure. Although different mechanisms have been suggested as to the pathogenesis of glioma-associated cysts, it is still unclear why these cysts appear in only a limited number of cerebral gliomas while brain oedema, a probable precursor of glioma cysts, is a usual accompaniment of most gliomas. Here, the authors present a two-hit hypothesis of brain glioma cyst formation. We suggest that after the formation of vasogenic tumoural brain oedema, microvascular phenomena may lead to the formation of microcysts, which might later become confluent and grow to form macroscopic cysts. Progress in the understanding of pathogenesis of cerebral glioma cysts might set targets for treatment of brain edema and glioma cysts.

  14. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    PubMed Central

    Massi, Paola; Valenti, Marta; Solinas, Marta; Parolaro, Daniela

    2010-01-01

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells. PMID:24281104

  15. Atlas-Based Semiautomatic Target Volume Definition (CTV) for Head-and-Neck Tumors

    SciTech Connect

    Strassmann, Gerd; Abdellaoui, Soulimane; Richter, Detlef; Bekkaoui, Fayzal; Haderlein, Marlene; Fokas, Emmanouil; Timmesfeld, Nina; Vogel, Birgitt M.D.; Henzel, Martin; Engenhart-Cabillic, Rita

    2010-11-15

    Purpose: To develop a new semiautomatic method to improve target delineation in head-and-neck cancer. Methods and Materials: We implemented an atlas-based software program using fourteen anatomic landmarks as well as the most superior and inferior computerd tomography slices for automatic target delineation, using an advanced laryngeal carcinoma as an example. Registration was made by an affine transformation. Evaluation was performed with manually drawn contours for comparison. Three physicians sampled and further applied a target volume atlas to ten other computer tomography data sets. In addition, a rapid three-dimensional (3D) correction program was developed. Results: The mean time to the first semiautomatic target delineation proposal was 2.7 minutes. Manual contouring required 20.2 minutes per target, whereas semiautomatic target volume definition with the rapid 3D correction was completed in only 9.7 minutes. The net calculation time for image registration of the target volume atlas was negligible (approximately 0.6 seconds). Our method depicted a sufficient adaptation of the target volume atlas on the new data sets, with a mean similarity index of 77.2%. The similarity index increased up to 85% after 3D correction performed by the physicians. Conclusions: We have developed a new, feasible method for semiautomatic contouring that saves a significant amount (51.8%) of target delineation time for head-and-neck cancer patients. This approach uses a target volume atlas and a landmark model. The software was evaluated by means of laryngeal cancer but has important implications for various tumor types whereby target volumes remain constant in form and do not move with respiration.

  16. Validation that Metabolic Tumor Volume Predicts Outcome in Head and Neck Cancer

    PubMed Central

    Tang, Chad; Murphy, James D.; Khong, Brian; La, Trang H.; Kong, Christina; Fischbein, Nancy J.; Colevas, A. Dimitrios; Iagaru, Andrei H.; Graves, Edward E.; Loo, Billy W.; Le, Quynh-Thu

    2011-01-01

    Purpose We have previously reported that metabolic tumor volume (MTV) obtained from pre-treatment FDG PET/CT predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study is to validate these results on an independent dataset, determine if the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16INK4a status as a surrogate marker for HPV. Methods and Materials The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan prior to definitive radiotherapy. MTV and SUVmax were calculated for the primary tumor, involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor versus nodal MTV. Results Similar to our prior findings, an increase in total MTV of 17 cm3 (difference between 75th and 25th percentile) was associated with a 2.1 fold increase in the risk of disease progression (p=0.0002), and a 2.0 fold increase in the risk of death (p=0.0048). SUVmax was not associated with either outcome. Primary tumor MTV predicted progression-free (HR=1.94; p<0.0001) and overall (HR=1.57; p<0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR=4.23; p<0.0001) and overall (HR=3.21; p=0.0029) survival in patients with p16INK4a positive oropharyngeal cancer. Conclusions This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk stratifying biomarker in future studies of HNC. PMID:22270174

  17. PRG3 induces Ras-dependent oncogenic cooperation in gliomas

    PubMed Central

    Yakubov, Eduard; Chen, Daishi; Broggini, Thomas; Sehm, Tina; Majernik, Gökce Hatipoglu; Hock, Stefan W.; Schwarz, Marc; Engelhorn, Tobias; Doerfler, Arnd; Buchfelder, Michael; Eyupoglu, Ilker Y.; Savaskan, Nicolai E.

    2016-01-01

    Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas. PMID:27058420

  18. Intra-rater variability in low-grade glioma segmentation.

    PubMed

    Bø, Hans Kristian; Solheim, Ole; Jakola, Asgeir Store; Kvistad, Kjell-Arne; Reinertsen, Ingerid; Berntsen, Erik Magnus

    2017-01-01

    Assessment of size and growth are key radiological factors in low-grade gliomas (LGGs), both for prognostication and treatment evaluation, but the reliability of LGG-segmentation is scarcely studied. With a diffuse and invasive growth pattern, usually without contrast enhancement, these tumors can be difficult to delineate. The aim of this study was to investigate the intra-observer variability in LGG-segmentation for a radiologist without prior segmentation experience. Pre-operative 3D FLAIR images of 23 LGGs were segmented three times in the software 3D Slicer. Tumor volumes were calculated, together with the absolute and relative difference between the segmentations. To quantify the intra-rater variability, we used the Jaccard coefficient comparing both two (J2) and three (J3) segmentations as well as the Hausdorff Distance (HD). The variability measured with J2 improved significantly between the two last segmentations compared to the two first, going from 0.87 to 0.90 (p = 0.04). Between the last two segmentations, larger tumors showed a tendency towards smaller relative volume difference (p = 0.07), while tumors with well-defined borders had significantly less variability measured with both J2 (p = 0.04) and HD (p < 0.01). We found no significant relationship between variability and histological sub-types or Apparent Diffusion Coefficients (ADC). We found that the intra-rater variability can be considerable in serial LGG-segmentation, but the variability seems to decrease with experience and higher grade of border conspicuity. Our findings highlight that some criteria defining tumor borders and progression in 3D volumetric segmentation is needed, if moving from 2D to 3D assessment of size and growth of LGGs.

  19. Microcomputer-based technique for 3-D reconstruction and volume measurement of computed tomographic images. Part 2: Anaplastic primary brain tumors.

    PubMed

    Albright, R E; Fram, E K

    1988-12-01

    Serial computed tomography (CT) plays an integral part in monitoring effects of therapy for primary anaplastic brain tumors. Despite advances in CT technology, clinicians often cannot obtain accurate quantitative volume information to complement the qualitative assessment of tumor change. This paper presents a microcomputer-based method that provides both quantitative volume measurements and 3-D reconstructions of primary anaplastic brain tumors based on their hard copy CT or magnetic resonance imaging studies. The findings of this study demonstrate that planimetry is feasible for routine clinical use and is superior in accuracy to the spherical geometric model, which is shown to significantly overestimate tumor volume. The findings of 62 quantitative tumor studies (17 patients) showed a direct relationship between the total tumor volume and the volume of the hypodense intratumor core. There was no evidence of a relationship between the total tumor volume and the amount of peritumor low density (edema).

  20. Anaplastic glioma: current treatment and management.

    PubMed

    Le Rhun, Emilie; Taillibert, Sophie; Chamberlain, Marc C

    2015-06-01

    Anaplastic glioma (AG) is divided into three morphology-based groups (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma) as well as three molecular groups (glioma-CpG island methylation phenotype [G-CIMP] negative, G-CIMP positive non-1p19q codeleted tumors and G-CIMP positive codeleted tumors). The RTOG 9402 and EORTC 26951 trials established radiotherapy plus (procarbazine, lomustine, vincristine) chemotherapy as the standard of care in 1p/19q codeleted AG. Uni- or non-codeleted AG are currently best treated with radiotherapy only or alkylator-based chemotherapy only as determined by the NOA-04 trial. Maturation of NOA-04 and results of the currently accruing studies, CODEL (for codeleted AG) and CATNON (for uni or non-codeleted AG), will likely refine current up-front treatment recommendations for AG.

  1. Alisertib and Fractionated Stereotactic Radiosurgery in Treating Patients With Recurrent High Grade Gliomas

    ClinicalTrials.gov

    2016-10-19

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

  2. Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study

    PubMed Central

    Buck, Jason R.; McKinley, Eliot T.; Fu, Allie; Abel, Ty W.; Thompson, Reid C.; Chambless, Lola; Watchmaker, Jennifer M.; Harty, James P.; Cooper, Michael K.; Manning, H. Charles

    2015-01-01

    Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes. PMID:26517124

  3. Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma

    PubMed Central

    McFarland, Braden C.; Marks, Margaret P.; Rowse, Amber L.; Fehling, Samuel C.; Gerigk, Magda; Qin, Hongwei; Benveniste, Etty N.

    2016-01-01

    In glioma, microglia and macrophages are the largest population of tumor-infiltrating cells, referred to as glioma associated macrophages (GAMs). Herein, we sought to determine the role of Suppressor of Cytokine Signaling 3 (SOCS3), a negative regulator of Signal Transducer and Activator of Transcription 3 (STAT3), in GAM functionality in glioma. We utilized a conditional model in which SOCS3 deletion is restricted to the myeloid cell population. We found that SOCS3-deficient bone marrow-derived macrophages display enhanced and prolonged expression of pro-inflammatory M1 cytokines when exposed to glioma tumor cell conditioned medium in vitro. Moreover, we found that deletion of SOCS3 in the myeloid cell population delays intracranial tumor growth and increases survival of mice bearing orthotopic glioma tumors in vivo. Although intracranial tumors from mice with SOCS3-deficient myeloid cells appear histologically similar to control mice, we observed that loss of SOCS3 in myeloid cells results in decreased M2 polarized macrophage infiltration in the tumors. Furthermore, loss of SOCS3 in myeloid cells results in increased CD8+ T-cell and decreased regulatory T-cell infiltration in the tumors. These findings demonstrate a beneficial effect of M1 polarized macrophages on suppressing glioma tumor growth, and highlight the importance of immune cells in the tumor microenvironment. PMID:26967393

  4. Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies

    SciTech Connect

    Williams, J.A.; Wessels, B.W.; Wharam, M.D.; Order, S.E.; Wanek, P.M.; Poggenburg, J.K.; Klein, J.L. )

    1990-06-01

    Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein, and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively.

  5. Maximum-Intensity Volumes for Fast Contouring of Lung Tumors Including Respiratory Motion in 4DCT Planning

    SciTech Connect

    Rietzel, Eike Liu, Arthur K.; Chen, George T.Y.; Choi, Noah C.

    2008-07-15

    Purpose: To assess the accuracy of maximum-intensity volumes (MIV) for fast contouring of lung tumors including respiratory motion. Methods and Materials: Four-dimensional computed tomography (4DCT) data of 10 patients were acquired. Maximum-intensity volumes were constructed by assigning the maximum Hounsfield unit in all CT volumes per geometric voxel to a new, synthetic volume. Gross tumor volumes (GTVs) were contoured on all CT volumes, and their union was constructed. The GTV with all its respiratory motion was contoured on the MIV as well. Union GTVs and GTVs including motion were compared visually. Furthermore, planning target volumes (PTVs) were constructed for the union of GTVs and the GTV on MIV. These PTVs were compared by centroid position, volume, geometric extent, and surface distance. Results: Visual comparison of GTVs demonstrated failure of the MIV technique for 5 of 10 patients. For adequate GTV{sub MIV}s, differences between PTVs were <1.0 mm in centroid position, 5% in volume, {+-}5 mm in geometric extent, and {+-}0.5 {+-} 2.0 mm in surface distance. These values represent the uncertainties for successful MIV contouring. Conclusion: Maximum-intensity volumes are a good first estimate for target volume definition including respiratory motion. However, it seems mandatory to validate each individual MIV by overlaying it on a movie loop displaying the 4DCT data and editing it for possible inadequate coverage of GTVs on additional 4DCT motion states.

  6. 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.

  7. Epo is involved in angiogenesis in human glioma.

    PubMed

    Nico, Beatrice; Annese, Tiziana; Guidolin, Diego; Finato, Nicoletta; Crivellato, Enrico; Ribatti, Domenico

    2011-03-01

    In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.

  8. Increasing the efficacy of antitumor glioma vaccines by photodynamic therapy and local injection of allogeneic glioma cells

    NASA Astrophysics Data System (ADS)

    Christie, Catherine E.; Peng, Qian; Madsen, Steen J.; Uzal, Francisco A.; Hirschberg, Henry

    2016-03-01

    Immunotherapy of brain tumors involves the stimulation of an antitumor immune response. This type of therapy can be targeted specifically to tumor cells thus sparing surrounding normal brain. Due to the presence of the blood-brain barrier, the brain is relatively isolated from the systemic circulation and, as such, the initiation of significant immune responses is more limited than other types of cancers. The purpose of this study was to show that the efficacy of tumor primed antigen presenting macrophage vaccines could be increased by: (1) PDT of the priming tumor cells, and (2) injection of allogeneic glioma cells directly into brain tumors. Experiments were conducted in an in vivo brain tumor model using Fisher rats and BT4C (allogeneic) and F98 (syngeneic) glioma cells. Preliminary results showed that vaccination alone had significantly less inhibitory effect on F98 tumor growth compared to the combination of vaccination and allogeneic cell (BT4C) injection.

  9. Adhesion molecules and the extracellular matrix as drug targets for glioma.

    PubMed

    Shimizu, Toshihiko; Kurozumi, Kazuhiko; Ishida, Joji; Ichikawa, Tomotsugu; Date, Isao

    2016-04-01

    The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.

  10. Prognostic factors for survival in stage III non-small-cell lung cancer treated with definitive radiation therapy: Impact of tumor volume

    SciTech Connect

    Basaki, Kiyoshi . E-mail: basaki-rad@umin.ac.jp; Abe, Yoshinao; Aoki, Masahiko; Kondo, Hidehiro; Hatayama, Yoshiomi; Nakaji, Shigeyuki

    2006-02-01

    Purpose: To investigate the impact of tumor volume on overall survival in patients with Stage III non-small-cell lung cancer (NSCLC) treated with definitive radiation therapy (RT). Methods and Materials: Between May 1997 and February 2003, 71 patients with Stage III NSCLC were treated with radiation therapy of 60 Gy or more. The total target dose was between 60 and 77 Gy (average, 66.3 Gy). Chemotherapy was used in 45 cases. The primary tumor and nodal volume were identified in pretreatment computed tomography scans. Univariate and multivariate analyses were used to evaluate the impact of tumor volume on survival after RT. Results: The overall 2-year survival rate was 23%, with a median survival time of 14 months. The median survival times were 10 months and 19 months with large primary tumor volume more than median volume and smaller primary tumor volume, respectively. At a univariate analysis, the total tumor volume (TTV) (p < 0.0003) and the primary tumor volume (p < 0.00008) were significant and the nodal volume was not. At multivariate analyses, both the TTV and the primary tumor volume were significant prognostic factors. Conclusion: The primary tumor volume as well as TTV is a significant prognostic factor on survival in patients with Stage III NSCLC treated with RT and should be recorded in clinical results when the survivals are compared among clinical studies.

  11. Boldine: a potential new antiproliferative drug against glioma cell lines.

    PubMed

    Gerhardt, Daniéli; Horn, Ana Paula; Gaelzer, Mariana Maier; Frozza, Rudimar Luiz; Delgado-Cañedo, Andrés; Pelegrini, Alessandra Luiza; Henriques, Amélia T; Lenz, Guido; Salbego, Christianne

    2009-12-01

    Malignant gliomas are the most common and devastating primary tumors of the central nervous system. Currently no efficient treatment is available. This study evaluated the effect and underlying mechanisms of boldine, an aporphine alkaloid of Peumus boldus, on glioma proliferation and cell death. Boldine decreased the cell number of U138-MG, U87-MG and C6 glioma lines at concentrations of 80, 250 and 500 muM. We observed that cell death caused by boldine was cell-type specific and dose-dependent. Exposure to boldine for 24 h did not activate key mediators of apoptosis. However, it induced alterations in the cell cycle suggesting a G(2)/M arrest in U138-MG cells. Boldine had no toxic effect on non-tumor cells when used at the same concentrations as those used on tumor cells. Based on these results, we speculate that boldine may be a promising compound for evaluation as an anti-cancer agent.

  12. Double Blockade of Glioma Cell Proliferation and Migration by Temozolomide Conjugated with NPPB, a Chloride Channel Blocker.

    PubMed

    Park, Miri; Song, Chiman; Yoon, Hojong; Choi, Kee-Hyun

    2016-03-16

    Glioblastoma is the most common and aggressive primary malignant brain tumor. Temozolomide (TMZ), a chemotherapeutic agent combined with radiation therapy, is used as a standard treatment. The infiltrative nature of glioblastoma, however, interrupts effective treatment with TMZ and increases the tendency to relapse. Voltage-gated chloride channels have been identified as crucial regulators of glioma cell migration and invasion by mediating cell shape and volume change. Accordingly, chloride current inhibition by 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), a chloride channel blocker, suppresses cell movement by diminishing the osmotic cell volume regulation. In this study, we developed a novel compound, TMZ conjugated with NPPB (TMZ-NPPB), as a potential anticancer drug. TMZ-NPPB blocked chloride currents in U373MG, a severely invasive human glioma cell line, and suppressed migration and invasion of U373MG cells. Moreover, TMZ-NPPB exhibited DNA modification activity similar to that of TMZ, and surprisingly showed remarkably enhanced cytotoxicity relative to TMZ by inducing apoptotic cell death via DNA damage. These findings indicate that TMZ-NPPB has a dual function in blocking both proliferation and migration of human glioma cells, thereby suggesting its potential to overcome challenges in current glioblastoma therapy.

  13. Tumor Volume Reduction Rate during Adaptive Radiation Therapy as a Prognosticator for Nasopharyngeal Cancer

    PubMed Central

    Lee, Hyebin; Ahn, Yong Chan; Oh, Dongryul; Nam, Heerim; Noh, Jae Myoung; Park, Su Yeon

    2016-01-01

    Purpose The purpose of this study is to evaluate the prognostic significance of the tumor volume reduction rate (TVRR) measured during adaptive definitive radiation therapy (RT) for nasopharyngeal cancer (NPC). Materials and Methods We reviewed the RT records of 159 NPC patients treated with definitive RT with or without concurrent chemotherapy between January 2006 and February 2013. Adaptive re-planning was performed in all patients at the third week of RT. The pre- and mid-RT gross tumor volumes (GTVs) of the primary tumor and the metastatic lymph nodes were measured and analyzed for prognostic implications. Results After a median follow-up period of 41.5 months (range, 11.2 to 91.8 months) for survivors, there were 43 treatment failures. The overall survival and progression-free survival (PFS) rates at 5 years were 89.6% and 69.7%, respectively. The mean pre-RT GTV, mid-RT GTV, and TVRR were 45.9 cm3 (range, 1.5 to 185.3 cm3), 26.7 cm3 (1.0 to 113.8 cm3), and –41.9% (range, –87% to 78%), respectively. Patients without recurrence had higher TVRR than those with recurrence (44.3% in the no recurrence group vs. 34.0% in the recurrence group, p=0.004), and those with TVRR > 35% achieved a significantly higher rate of PFS at 5 years (79.2% in TVRR > 35% vs. 53.2% in TVRR ≤ 35%; p < 0.001). In multivariate analysis, TVRR was a significant factor affecting PFS (hazard ratio, 2.877; 95% confidence interval, 1.555 to 5.326; p=0.001). Conclusion TVRR proved to be a significant prognostic factor in NPC patients treated with definitive RT, and could be used as a potential indicator for early therapeutic modification during the RT course. PMID:26194371

  14. MiRNA expression profiling in human gliomas: upregulated miR-363 increases cell survival and proliferation.

    PubMed

    Conti, Alfredo; Romeo, Sara G; Cama, Annamaria; La Torre, Domenico; Barresi, Valeria; Pezzino, Gaetana; Tomasello, Chiara; Cardali, Salvatore; Angileri, Filippo F; Polito, Francesca; Ferlazzo, Guido; Di Giorgio, Rosamaria; Germanò, Antonino; Aguennouz, M'hammed

    2016-10-01

    The role of microRNAs (miRNAs) in glioma biology is increasingly recognized. To investigate the regulatory mechanisms governing the malignant signature of gliomas with different grades of malignancy, we analyzed miRNA expression profiles in human grade I-IV tumor samples and primary glioma cell cultures. Multiplex real-time PCR was used to profile miRNA expression in a set of World Health Organization (WHO) grade I (pilocytic astrocytoma), II (diffuse fibrillary astrocytoma), and IV (glioblastoma multiforme) astrocytic tumors and primary glioma cell cultures. Primary glioma cell cultures were used to evaluate the effect of transfection of specific miRNAs and miRNA inhibitors. miRNA microarray showed that a set of miRNAs was consistently upregulated in all glioma samples. miR-363 was upregulated in all tumor specimens and cell lines, and its expression correlated with tumor grading. The transfection of glioma cells with the specific inhibitor of miR-363 increased the expression level of tumor suppressor growth-associated protein 43 (GAP-43). Transfection of miR-363 induced cell survival, while inhibition of miR-363 significantly reduced glioma cell viability. Furthermore, miRNA-363 inhibition induced the downregulation of AKT, cyclin-D1, matrix metalloproteinase (MMP)-2, MMP-9, and Bcl-2 and upregulation of caspase 3. Together, these data suggest that the upregulation of miR-363 may play a role in malignant glioma signature.

  15. Alpinetin targets glioma stem cells by suppressing Notch pathway.

    PubMed

    Wang, Jianpeng; Yan, Zhiyong; Liu, Xia; Che, Shusheng; Wang, Chao; Yao, Weicheng

    2016-07-01

    Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti-tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy.

  16. MEF promotes stemness in the pathogenesis of gliomas

    PubMed Central

    Bazzoli, Elena; Pulvirenti, Teodoro; Oberstadt, Moritz C.; Perna, Fabiana; Wee, Boyoung; Schultz, Nikolaus; Huse, Jason T.; Fomchenko, Elena I.; Voza, Francesca; Tabar, Viviane; Brennan, Cameron W.; DeAngelis, Lisa M.; Nimer, Stephen D.; Holland, Eric C.; Squatrito, Massimo

    2013-01-01

    Summary High-grade gliomas are aggressive and uniformly fatal tumors, composed of a heterogeneous population of cells that include many with stem cell-like properties. The acquisition of stem-like traits might contribute to glioma initiation, growth and recurrence. Here we investigated the role of the transcription factor myeloid Elf-1 like factor (MEF, also known as ELF4) in glioma. We found that MEF is highly expressed in both human and mouse GBMs and its absence impairs gliomagenesis in a PDGF-driven glioma mouse model. We show that modulation of MEF levels in both mouse neural stem cells and human glioblastoma cells, has a significant impact on neurosphere formation. Moreover, we identify Sox2 as a direct downstream target of MEF. Taken together, our studies implicate MEF as a previously unrecognized gatekeeper gene in gliomagenesis by promoting stem cell characteristics through Sox2 activation. PMID:23217424

  17. MEF promotes stemness in the pathogenesis of gliomas.

    PubMed

    Bazzoli, Elena; Pulvirenti, Teodoro; Oberstadt, Moritz C; Perna, Fabiana; Wee, Boyoung; Schultz, Nikolaus; Huse, Jason T; Fomchenko, Elena I; Voza, Francesca; Tabar, Viviane; Brennan, Cameron W; DeAngelis, Lisa M; Nimer, Stephen D; Holland, Eric C; Squatrito, Massimo

    2012-12-07

    High-grade gliomas are aggressive and uniformly fatal tumors, composed of a heterogeneous population of cells that include many with stem-cell-like properties. The acquisition of stem-like traits might contribute to glioma initiation, growth, and recurrence. Here we investigated the role of the transcription factor myeloid Elf-1 like factor (MEF, also known as ELF4) in gliomas. We found that MEF is highly expressed in both human and mouse glioblastomas and its absence impairs gliomagenesis in a PDGF-driven glioma mouse model. We show that modulation of MEF levels in both mouse neural stem cells and human glioblastoma cells has a significant impact on neurosphere formation. Moreover, we identify Sox2 as a direct downstream target of MEF. Taken together, our studies implicate MEF as a previously unrecognized gatekeeper gene in gliomagenesis that promotes stem cell characteristics through Sox2 activation.

  18. Low-grade gliomas: introduction and overview.

    PubMed

    Piepmeier, J M; Christopher, S

    1997-08-01

    This issue of the Journal of Neuro-Oncology is devoted to recent investigations of low-grade gliomas. The purpose of this issue is not to debate the relative merits and liabilities of different management strategies for low-grade gliomas, but to present new data concerning novel and innovative approaches to evaluating these lesions. The common theme of many of these reports represents a departure from grading systems that primarily depend on a morphology-based analysis from light microscopy to classify these tumors. The purpose of this review is to present the reasoning behind the selection of authors for this issue of the Journal of Neuro-Oncology and to provide a format for presentation of new ideas concerning these interesting tumors. It is clear that standard classification systems that address only the morphological characteristics of tumor cells can not adequately represent the wide variation in biological activity that is found with these lesions. It is hoped that these articles will stimulate further interest and research into low-grade gliomas that will one day lead to more effective therapy.

  19. Intensity-modulated radiotherapy in high-grade gliomas: Clinical and dosimetric results

    SciTech Connect

    Narayana, Ashwatha . E-mail: narayana@mskcc.org; Yamada, Josh; Berry, Sean; Shah, Priti B.S.; Hunt, Margie; Gutin, Philip H.; Leibel, Steven A.

    2006-03-01

    Purpose: To report preliminary clinical and dosimetric data from intensity-modulated radiotherapy (IMRT) for malignant gliomas. Methods and Materials: Fifty-eight consecutive high-grade gliomas were treated between January 2001 and December 2003 with dynamic multileaf collimator IMRT, planned with the inverse approach. A dose of 59.4-60 Gy at 1.8-2.0 Gy per fraction was delivered. A total of three to five noncoplanar beams were used to cover at least 95% of the target volume with the prescription isodose line. Glioblastoma accounted for 70% of the cases, and anaplastic oligodendroglioma histology (pure or mixed) was seen in 15% of the cases. Surgery consisted of biopsy only in 26% of the patients, and 80% received adjuvant chemotherapy. Results: With a median follow-up of 24 months, 85% of the patients have relapsed. The median progression-free survival time for anaplastic astrocytoma and glioblastoma histology was 5.6 and 2.5 months, respectively. The overall survival time for anaplastic glioma and glioblastoma was 36 and 9 months, respectively. Ninety-six percent of the recurrences were local. No Grade IV/V late neurologic toxicities were noted. A comparative dosimetric analysis revealed that regardless of tumor location, IMRT did not significantly improve target coverage compared with three-dimensional planning. However, IMRT resulted in a decreased maximum dose to the spinal cord, optic nerves, and eye by 16%, 7%, and 15%, respectively, owing to its improved dose conformality. The mean brainstem dose also decreased by 7%. Intensity-modulated radiotherapy delivered with a limited number of beams did not result in an increased dose to the normal brain. Conclusions: It is unlikely that IMRT will improve local control in high-grade gliomas without further dose escalation compared with conventional radiotherapy. However, it might result in decreased late toxicities associated with radiotherapy.

  20. Accurate tracking of tumor volume change during radiotherapy by CT-CBCT registration with intensity correction

    NASA Astrophysics Data System (ADS)

    Park, Seyoun; Robinson, Adam; Quon, Harry; Kiess, Ana P.; Shen, Colette; Wong, John; Plishker, William; Shekhar, Raj; Lee, Junghoon

    2016-03-01

    In this paper, we propose a CT-CBCT registration method to accurately predict the tumor volume change based on daily cone-beam CTs (CBCTs) during radiotherapy. CBCT is commonly used to reduce patient setup error during radiotherapy, but its poor image quality impedes accurate monitoring of anatomical changes. Although physician's contours drawn on the planning CT can be automatically propagated to daily CBCTs by deformable image registration (DIR), artifacts in CBCT often cause undesirable errors. To improve the accuracy of the registration-based segmentation, we developed a DIR method that iteratively corrects CBCT intensities by local histogram matching. Three popular DIR algorithms (B-spline, demons, and optical flow) with the intensity correction were implemented on a graphics processing unit for efficient computation. We evaluated their performances on six head and neck (HN) cancer cases. For each case, four trained scientists manually contoured the nodal gross tumor volume (GTV) on the planning CT and every other fraction CBCTs to which the propagated GTV contours by DIR were compared. The performance was also compared with commercial image registration software based on conventional mutual information (MI), VelocityAI (Varian Medical Systems Inc.). The volume differences (mean±std in cc) between the average of the manual segmentations and automatic segmentations are 3.70+/-2.30 (B-spline), 1.25+/-1.78 (demons), 0.93+/-1.14 (optical flow), and 4.39+/-3.86 (VelocityAI). The proposed method significantly reduced the estimation error by 9% (B-spline), 38% (demons), and 51% (optical flow) over the results using VelocityAI. Although demonstrated only on HN nodal GTVs, the results imply that the proposed method can produce improved segmentation of other critical structures over conventional methods.

  1. An integrated transcriptomic and computational analysis for biomarker identification in human glioma.

    PubMed

    Xing, Wenli; Zeng, Chun

    2016-06-01

    Malignant glioma is one of the most common primary brain tumors and is among the deadliest of human cancers. The molecular mechanism for human glioma is poorly understood. Early prognosis of this disease and early treatment are vital. Thus, it is crucial to target the key genes controlling pathogenesis in the early stage of glioma. In this study, differentially expressed genes in human glioma and paired peritumoral tissues were detected by transcriptome microarray analysis. Following gene microarray analysis, the gene expression profile in the differential grade glioma was further validated by bioinformatic analyses, co-expression network construction. Microarray analysis revealed that 1725 genes were differentially expressed and classified into different glioma stage. The analysis revealed 14 genes that were significantly associated with survival with a false discovery rate. Among these genes, macrophage capping protein (CAPG), a member of the actin-regulatory protein, was the key gene in a 20-gene network that modulates cell motility by interacting with the cytoskeleton. Furthermore, the prognostic impact of CAPG was validated by use of quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry on human glioma tissue. CAPG protein was significantly upregulated in clinical high-grade glioblastoma as compared with normal brain tissues. Overexpression of CAPG levels also predict shorter overall survival of glioma patients. These data demonstrated CAPG protein expression in human glioma was associated with tumorigenesis and may be a biomarker for identification of the pathological grade of glioma.

  2. Alphaxalone inhibits growth, migration and invasion of rat C6 malignant glioma cells.

    PubMed

    Sun, Huawei; Zheng, Xiaoke; Zhou, Yuehan; Zhu, Wenbo; Ou, Yanqiu; Shu, Minfeng; Gao, Xiuren; Leng, Tiandong; Qiu, Pengxin; Yan, Guangmei

    2013-10-01

    Malignant gliomas are the most devastating and aggressive brain tumors affecting the central nervous system. The insidious growth and infiltration are the most prominent characteristics of malignant gliomas, which render the current therapies for malignant gliomas including surgery, radiation and chemotherapy unsuccessful. Inhibition of infiltration as well as proliferation in combination with surgery might be more effective in the treatment of malignant gliomas. In the current study, we demonstrate the alphaxalone (3-hydroxypregnane-11,20-dione) could effectively inhibit the proliferation of C6 glioma cells in a concentration dependent manner. Moreover, this compound could also suppress the migration and invasion of C6 glioma cells at a concentration without causing significant cytotoxicity. Except the in vitro anti-glioma activity, alphaxalone effectively delayed the growth of rat C6 malignant glioma xenografts in vivo. Together, these findings suggest alphaxalone might be a promising candidate for the treatment of malignant gliomas and may also provide helpful clues for anti-glioma drugs development in future.

  3. Overexpressed homeobox B9 regulates oncogenic activities by transforming growth factor-β1 in gliomas

    SciTech Connect

    Fang, Liping; Xu, Yinghui; Zou, Lijuan

    2014-03-28

    Highlights: • HOXB9 is overexpressed in gliomas. • HOXB9 over expression had shorter survival time than down expression in gliomas. • HOXB9 stimulated the proliferation, migration and sphere formation of glioma cells. • Activation of TGF-β1 contributed to HOXB9-induced oncogenic activities. - Abstract: Glioma is the leading cause of deaths related to tumors in the central nervous system. The mechanisms of gliomagenesis remain elusive to date. Homeobox B9 (HOXB9) has a crucial function in the regulation of gene expression and cell survival, but its functions in glioma formation and development have yet to be elucidated. This study showed that HOXB9 expression in glioma tissues was significantly higher than that in nontumor tissues. Higher HOXB9 expression was also significantly associated with advanced clinical stage in glioma patients. HOXB9 overexpression stimulated the proliferation, migration, and sphere formation of glioma cells, whereas HOXB9 knockdown elicited an opposite effect. HOXB9 overexpression also increased the tumorigenicity of glioma cells in vivo. Moreover, the activation of transforming growth factor-β1 contributed to HOXB9-induced oncogenic activities. HOXB9 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in glioma for diagnosis or prognosis.

  4. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

    PubMed

    Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

    2015-12-08

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

  5. The transglutaminase 2 gene is aberrantly hypermethylated in glioma

    PubMed Central

    Dyer, Lisa M.; Schooler, Kevin P.; Ai, Lingbao; Klop, Corinne; Qiu, Jingxin; Robertson, Keith D.

    2010-01-01

    Transglutaminase 2 (TG2) is a ubiquitously expressed protein that catalyzes protein/protein crosslinking. Because extracellular TG2 crosslinks components of the extracellular matrix, TG2 is thought to function as a suppressor of cellular invasion. We have recently uncovered that the TG2 gene (TGM2) is a target for epigenetic silencing in breast cancer, highlighting a molecular mechanism that drives reduced TG2 expression, and this aberrant molecular event may contribute to invasiveness in this tumor type. Because tumor invasiveness is a primary determinant of brain tumor aggressiveness, we sought to determine if TGM2 is targeted for epigenetic silencing in glioma. Analysis of TGM2 gene methylation in a panel of cultured human glioma cells indicated that the 5′ flanking region of the TGM2 gene is hypermethylated and that this feature is associated with reduced TG2 expression as judged by immunoblotting. Further, culturing glioma cells in the presence of the global DNA demethylating agent 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor Trichostatin A resulted in re-expression of TG2 in these lines. In primary brain tumors we observed that the TGM2 promoter is commonly hypermethylated and that this feature is a cancer-associated phenomenon. Using publically available databases, TG2 expression in gliomas was found to vary widely, with many tumors showing overexpression or underexpression of this gene. Since overexpression of TG2 leads to resistance to doxorubicin through the ectopic activation of NFκB, we sought to examine the effects of recombinant TG2 expression in glioma cells treated with commonly used brain tumor therapeutics. We observed that in addition to doxorubicin, TG2 expression drove resistance to CCNU; however, TG2 expression did not alter sensitivity to other drugs tested. Finally, a catalytically null mutant of TG2 was also able to support doxorubicin resistance in glioma cells indicating that transglutaminase activity is not necessary

  6. Automated localization and segmentation of lung tumor from PET-CT thorax volumes based on image feature analysis.

    PubMed

    Cui, Hui; Wang, Xiuying; Feng, Dagan

    2012-01-01

    Positron emission tomography - computed tomography (PET-CT) plays an essential role in early tumor detection, diagnosis, staging and treatment. Automated and more accurate lung tumor detection and delineation from PET-CT is challenging. In this paper, on the basis of quantitative analysis of contrast feature of PET volume in SUV (standardized uptake value), our method firstly automatically localized the lung tumor. Then based on analysing the surrounding CT features of the initial tumor definition, our decision strategy determines the tumor segmentation from CT or from PET. The algorithm has been validated on 20 PET-CT studies involving non-small cell lung cancer (NSCLC). Experimental results demonstrated that our method was able to segment the tumor when adjacent to mediastinum or chest wall, and the algorithm outperformed the other five lung segmentation methods in terms of overlapping measure.

  7. Correlation of (18)F-FDG PET and MR Apparent Diffusion Coefficient (ADC) Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium.

    PubMed

    Zukotynski, Katherine; Vajapeyam, Sridhar; Fahey, Frederic H; Kocak, Mehmet; Brown, Douglas; Ricci, Kelsey; Onar-Thomas, Arzu; Fouladi, Maryam; Poussaint, Tina Young

    2017-03-30

    Rationale: To describe baseline (18)F-labeled 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) voxel characteristics in pediatric diffuse intrinsic pontine glioma (DIPG) and to correlate these metrics with baseline magnetic resonance (MR) apparent diffusion coefficient (ADC) histogram metrics, progression-free survival (PFS) and overall survival (OS). Methods: Baseline brain FDG-PET and MR scans were obtained in 33 children from Pediatric Brain Tumor Consortium (PBTC) clinical DIPG trials. FDG-PET, post-gadolinium (PG) and ADC images were registered to baseline fluid attenuation inversion recovery (FLAIR) images. Three-dimensional regions of interest on FLAIR and PG images and FDG-PET and ADC histograms were generated. Metrics evaluated included peak number, skewness and kurtosis. Correlation between PET and ADC histogram metrics was evaluated. PET pixel values within the ROI for each tumor were plotted against ADC values. Association of these imaging markers with survival was described. Results: PET histograms were almost always unimodal (94% vs. 6% bimodal). None of the PET histogram parameters (skewness or kurtosis) had a significant association with PFS, although a higher PET PG skewness tended towards less favorable PFS (Hazard Ratio (95% CI)=3.48 (0.75, 16.28); P = 0.11). There was a significant association of higher ADC PG skewness with shorter PFS (Hazard Ratio (95% CI)=2.56 (1.11, 5.91); P = 0.028) and the suggestion that this also led to shorter OS (Hazard Ratio (95% CI)=2.18 (0.95, 5.04); P = 0.067). Higher ADC PG kurtosis tended towards shorter PFS (Hazard Ratio (95% CI)=1.30 (0.98, 1.74); P = 0.073). In a number of cases, PET and ADC pixel values were negatively correlated using the Pearson correlation coefficient. Further, the level of PET and ADC correlation was significantly positively associated with PFS; tumors with higher values of ADC-PET correlation had more favorable PFS (Hazard Ratio (95% CI)=0.17 (0.03, 0.89), P = 0

  8. Subgroup characteristics of insular low-grade glioma based on clinical and molecular analysis of 42 cases.

    PubMed

    Tang, Chao; Zhang, Zhen-yu; Chen, Ling-chao; Sun, Zelin; Zhang, Yi; Qin, Zhiyong; Yao, Yu; Zhou, Liang-fu

    2016-02-01

    Although the classification of insular glioma has been established based on the anatomical location in order to facilitate personalized surgical resection, the diagnosis based on anatomical and functional characteristics becomes more complex when insular tumors extend into either the frontobasal brain region and/or the temporal lobe, as part of the limbic system. Moreover, prognosis of insular tumor resection is still controversial. Further analysis of subgroup characteristics of insular grade II gliomas based on clinical and molecular analysis is required to reliably determine patients' survival rates. In this retrospective study 20 purely insular grade II gliomas patients and 22 paralimbic grade II gliomas that involved frontal and/or temporal lobes were compared with regard to epidemiological and clinical characteristics. The molecular profiles including Isocitrate dehydrogenase 1 (IDH1), telomerase reverse transcriptase (TERT) promoter, and P53 mutations, 1p19q co-deletion were analyzed, and microRNA profiles were assessed by microarray and bioinformatics analysis. Purely insular grade II gliomas displayed a high frequency of IDH1 mutations with favorable outcome. IDH1 mutated paralimbic glioma shared many parameters with the purely insular glioma in respect to growth patterns, survival, and microRNA profile, but differed significantly from the IDH1 wild type paralimbic gliomas. Our findings suggest that IDH1 mutations can define subpopulations of insular gliomas with distinct disease entities regardless of tumor extension patterns. These findings could be useful to develop a customized treatment strategy for insular glioma patients.

  9. Decreased Expression of MiRNA-204-5p Contributes to Glioma Progression and Promotes Glioma Cell Growth, Migration and Invasion

    PubMed Central

    Xia, Zhiqiang; Liu, Fang; Zhang, Jian; Liu, Li

    2015-01-01

    Gliomas are the most common malignant primary brain tumors in adults and exhibit a spectrum of aberrantly aggressive phenotype. Although increasing evidence indicated that the deregulation of microRNAs (miRNAs) contributes to tumorigenesis and invasion, little is known about the roles of miR-204-5p in human gliomas. In the present study, the expression of miR-204-5p in clinical glioma tissues was measured by qRT-PCR. The effects of miR-204-5p on glioma cell growth and metastasis were examined by overexpressing or inhibiting miR-204-5p. We found that the expression level of miR-204-5p was significantly reduced in clinical glioma tissues compared with normal brain tissues. Moreover, we revealed that the introduction of miR-204-5p dramatically suppressed glioma cell growth, migration and invasion. Furthermore, mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in gliomas. In vivo, restoring miR-204-5p expression in glioma cells suppressed tumorigenesis and increased overall host survival. Our findings suggest that miR-204-5p is a cancer suppressor miRNA and overexpression of miR-204-5p is a novel glioma treatment strategy. PMID:26134825

  10. Monochromatic Minibeams Radiotherapy: From Healthy Tissue-Sparing Effect Studies Toward First Experimental Glioma Bearing Rats Therapy

    SciTech Connect

    Deman, Pierre; Vautrin, Mathias; Edouard, Magali; Stupar, Vasile; Bobyk, Laure; Farion, Regine; Elleaume, Helene; Remy, Chantal; Barbier, Emmanuel L.; Esteve, Francois; Adam, Jean-Francois

    2012-03-15

    Purpose: The purpose of this study was to evaluate high-dose single fraction delivered with monochromatic X-rays minibeams for the radiotherapy of primary brain tumors in rats. Methods and Materials: Two groups of healthy rats were irradiated with one anteroposterior minibeam incidence (four minibeams, 123 Gy prescribed dose at 1 cm depth in the brain) or two interleaved incidences (54 Gy prescribed dose in a 5 Multiplication-Sign 5 Multiplication-Sign 4.8 mm{sup 3} volume centered in the right hemisphere), respectively. Magnetic resonance imaging (MRI) follow-up was performed over 1 year. T2-weighted (T2w) images, apparent diffusion coefficient (ADC), and blood vessel permeability maps were acquired. F98 tumor bearing rats were also irradiated with interleaved minibeams to achieve a homogeneous dose of 54 Gy delivered to an 8 Multiplication-Sign 8 Multiplication-Sign 7.8 mm{sup 3} volume centered on the tumor. Anatomic and functional MRI follow-up was performed every 10 days after irradiation. T2w images, ADC, and perfusion maps were acquired. Results: All healthy rats were euthanized 1 year after irradiation without any clinical alteration visible by simple examination. T2w and ADC measurements remain stable for the single incidence irradiation group. Localized Gd-DOTA permeability, however, was observed 9 months after irradiation for the interleaved incidences group. The survival time of irradiated glioma bearing rats was significantly longer than that of untreated animals (49 {+-} 12.5 days versus 23.3 {+-} 2 days, p < 0.001). The tumoral cerebral blood flow and blood volume tend to decrease after irradiation. Conclusions: This study demonstrates the sparing effect of minibeams on healthy tissue. The increased life span achieved for irradiated glioma bearing rats was similar to the one obtained with other radiotherapy techniques. This experimental tumor therapy study shows the feasibility of using X-ray minibeams with high doses in brain tumor radiotherapy.

  11. Evaluation of potential internal target volume of liver tumors using cine-MRI

    SciTech Connect

    Akino, Yuichi; Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko

    2014-11-01

    Purpose: Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. Methods: The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas–Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV {sub Potential}). The concordance between ITV {sub Potential} and ITV estimated with 4DCT (ITV {sub 4DCT}) was evaluated using the Dice’s similarity coefficient (DSC). Results

  12. Gliomas and the vascular fragility of the blood brain barrier

    PubMed Central

    Dubois, Luiz Gustavo; Campanati, Loraine; Righy, Cassia; D’Andrea-Meira, Isabella; Spohr, Tania Cristina Leite de Sampaio e; Porto-Carreiro, Isabel; Pereira, Claudia Maria; Balça-Silva, Joana; Kahn, Suzana Assad; DosSantos, Marcos F.; Oliveira, Marcela de Almeida Rabello; Ximenes-da-Silva, Adriana; Lopes, Maria Celeste; Faveret, Eduardo; Gasparetto, Emerson Leandro; Moura-Neto, Vivaldo

    2014-01-01

    Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected. PMID:25565956

  13. Exploiting macrophages as targeted carrier to guide nanoparticles into glioma

    PubMed Central

    Pang, Liang; Qin, Jing; Han, Limei; Zhao, Wenjie; Liang, Jianming; Xie, Zhongyi; Yang, Pei; Wang, Jianxin

    2016-01-01

    The restriction of anti-cancer drugs entry to tumor sites in the brain is a major impediment to the development of new strategies for the treatment of glioma. Based on the finding that macrophages possess an intrinsic homing property enabling them to migrate to tumor sites across the endothelial barriers in response to the excretion of cytokines/chemokines in the diseased tissues, we exploited macrophages as ‘Trojan horses’ to carry drug-loading nanoparticles (NPs), pass through barriers, and offload them into brain tumor sites. Anticancer drugs were encapsulated in nanoparticles to avoid their damage to the cells. Drug loading NPs was then incubated with RAW264.7 cells in vitro to prepare macrophage-NPs (M-NPs). The release of NPs from M-NPs was very slow in medium of DMEM and 10% FBS and significantly accelerated when LPS and IFN-γ were added to mimic tumor inflammation microenvironment. The viability of macrophages was not affected when the concentration of doxorubicin lower than 25 μg/ml. The improvement of cellular uptake and penetration into the core of glioma spheroids of M-NPs compared with NPs was verified in in vitro studies. The tumor-targeting efficiency of NPs was also significantly enhanced after loading into macrophages in nude mice bearing intracranial U87 glioma. Our results provided great potential of macrophages as an active biocarrier to deliver anticancer drugs to the tumor sites in the brain and improve therapeutic effects of glioma. PMID:27213597

  14. Advances in Oncolytic Virus Therapy for Glioma

    PubMed Central

    Haseley, Amy; Alvarez-Breckenridge, Christopher; Chaudhury, Abhik Ray; Kaur, Balveen

    2009-01-01

    The World Health Organization grossly classifies the various types of astrocytomas using a grade system with grade IV gliomas having the worst prognosis. Oncolytic virus therapy is a novel treatment option for GBM patients. Several patents describe various oncolytic viruses used in preclinical and clinical trials to evaluate safety and efficacy. These viruses are natural or genetically engineered from different viruses such as HSV-1, Adenovirus, Reovirus, and New Castle Disease Virus. While several anecdotal studies have indicated therapeutic advantage, recent clinical trials have revealed the safety of their usage, but demonstration of significant efficacy remains to be established. Oncolytic viruses are being redesigned with an interest in combating the tumor microenvironment in addition to defeating the cancerous cells. Several patents describe the inclusion of tumor microenvironment modulating genes within the viral backbone and in particular those which attack the tumor angiotome. The very innovative approaches being used to improve therapeutic efficacy include: design of viruses which can express cytokines to activate a systemic antitumor immune response, inclusion of angiostatic genes to combat tumor vasculature, and also enzymes capable of digesting tumor extra cellular matrix (ECM) to enhance viral spread through solid tumors. As increasingly more novel viruses are being tested and patented, the future battle against glioma looks promising. PMID:19149710

  15. Wild-Type Reovirus in Combination With Sargramostim in Treating Younger Patients With High-Grade Relapsed or Refractory Brain Tumors

    ClinicalTrials.gov

    2016-11-09

    Childhood Astrocytoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Diffuse Intrinsic Pontine Glioma; Glioma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Glioblastoma; Recurrent Childhood Medulloblastoma; Recurrent Primitive Neuroectodermal Tumor; Refractory Brain Neoplasm

  16. IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging in human glioma.

    PubMed

    Kickingereder, Philipp; Sahm, Felix; Radbruch, Alexander; Wick, Wolfgang; Heiland, Sabine; Deimling, Andreas von; Bendszus, Martin; Wiestler, Benedikt

    2015-11-05

    The recent identification of IDH mutations in gliomas and several other cancers suggests that this pathway is involved in oncogenesis; however effector functions are complex and yet incompletely understood. To study the regulatory effects of IDH on hypoxia-inducible-factor 1-alpha (HIF1A), a driving force in hypoxia-initiated angiogenesis, we analyzed mRNA expression profiles of 288 glioma patients and show decreased expression of HIF1A targets on a single-gene and pathway level, strong inhibition of upstream regulators such as HIF1A and downstream biological functions such as angio- and vasculogenesis in IDH mutant tumors. Genotype/imaging phenotype correlation analysis with relative cerebral blood volume (rCBV) MRI - a robust and non-invasive estimate of tumor angiogenesis - in 73 treatment-naive patients with low-grade and anaplastic gliomas showed that a one-unit increase in rCBV corresponded to a two-third decrease in the odds for an IDH mutation and correctly predicted IDH mutation status in 88% of patients. Together, these findings (1) show that IDH mutation status is associated with a distinct angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging and (2) highlight the potential future of radiogenomics (i.e. the correlation between cancer imaging and genomic features) towards a more accurate diagnostic workup of brain tumors.

  17. The epidemiology of glioma in adults: a "state of the science" review.

    PubMed

    Ostrom, Quinn T; Bauchet, Luc; Davis, Faith G; Deltour, Isabelle; Fisher, James L; Langer, Chelsea Eastman; Pekmezci, Melike; Schwartzbaum, Judith A; Turner, Michelle C; Walsh, Kyle M; Wrensch, Margaret R; Barnholtz-Sloan, Jill S

    2014-07-01

    Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O⁶-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults.

  18. Caveolin-1 expression is variably displayed in astroglial-derived tumors and absent in oligodendrogliomas: concrete premises for a new reliable diagnostic marker in gliomas.

    PubMed

    Cassoni, Paola; Senetta, Rebecca; Castellano, Isabella; Ortolan, Erika; Bosco, Martino; Magnani, Ivana; Ducati, Alessandro

    2007-05-01

    Caveolins are basic constituents of flask-shaped cell membrane microdomains (caveolae), which are involved in many cell functions, including signalling, trafficking, and cellular growth control. The distribution of caveolae within the normal brain and in brain tumors is controversial. In the present study, we describe the expression of caveolin-1 (cav-1) in 64 brain tumors of different grade, of either astroglial or oligodendroglial origin. All studied astrocitomas of any grade (from II to IV) were cav-1 positive, displaying staining patterns and intensity specifically associated to the different tumor grades. In all glioblastomas and gliosarcomas, cav-1 staining was extremely intense, typically localized at the cell membrane and recognized a variable percentage of cells, including the majority of spindle cells and palisade-oriented perinecrotic cells. In anaplastic astrocytomas, a less intense membrane staining or a cytoplasmic dotlike immunoreactivity were present, the latter being almost the exclusive pattern observed in diffuse astrocitomas grade II. In contrast to astroglial tumors, the striking totality of grade II oligodendrogliomas and the large majority of grade III were lacking cav-1 expression. Interestingly, a cav-1 distribution overlapping the pattern described in tissues was observed also in primary cell cultures of human glioblastomas and astrocytomas, and also in one established glioblastoma cell line (U251 MG), analyzed by means of confocal microscopy and flow cytometry. In conclusion, among astroglial tumors cav-1 expression varies in distribution, pattern, and intensity specifically according to tumor types and grades. The association between tumor progression and a more structured membranous pattern of cav-1 expression could suggest the hypothesis of a neoplastic shift towards a mesenchymal phenotype, whose behavioral and biologic significance worth further studies. Finally, the lack of cav-1 immunoreactivity in oligodendrogliomas suggests its

  19. Residual Tumor After Neoadjuvant Chemoradiation Outside the Radiation Therapy Target Volume: A New Prognostic Factor for Survival in Esophageal Cancer

    SciTech Connect

    Muijs, Christina; Smit, Justin; Karrenbeld, Arend; Beukema, Jannet; Mul, Veronique; Dam, Go van; Hospers, Geke; Kluin, Phillip; Langendijk, Johannes; Plukker, John

    2014-03-15

    Purpose/Objective(s): The aim of this study was to analyze the accuracy of gross tumor volume (GTV) delineation and clinical target volume (CTV) margins for neoadjuvant chemoradiation therapy (neo-CRT) in esophageal carcinoma at pathologic examination and to determine the impact on survival. Methods and Materials: The study population consisted of 63 esophageal cancer patients treated with neo-CRT. GTV and CTV borders were demarcated in situ during surgery on the esophagus, using anatomical reference points to provide accurate information regarding tumor location at pathologic evaluation. To identify prognostic factors for disease-free survival (DFS) and overall survival (OS), a Cox regression analysis was performed. Results: After resection, macroscopic residual tumor was found outside the GTV in 7 patients (11%). Microscopic residual tumor was located outside the CTV in 9 patients (14%). The median follow-up was 15.6 months. With multivariate analysis, only microscopic tumor outside the CTV (hazard ratio [HR], 4.96; 95% confidence interval [CI], 1.03-15.36), and perineural growth (HR, 5.77; 95% CI, 1.27-26.13) were identified as independent prognostic factors for OS. The 1-year OS was 20% for patients with tumor outside the CTV and 86% for those without (P<.01). For DFS, microscopic tumor outside the CTV (HR, 5.92; 95% CI, 1.89-18.54) and ypN+ (HR, 3.36; 95% CI, 1.33-8.48) were identified as independent adverse prognostic factors. The 1-year DFS was 23% versus 77% for patients with or without tumor outside the CTV (P<.01). Conclusions: Microscopic tumor outside the CTV is associated with markedly worse OS after neo-CRT. This may either stress the importance of accurate tumor delineation or reflect aggressive tumor behavior requiring new adjuvant treatment modalities.

  20. Silencing of WNK2 is associated with upregulation of MMP2 and JNK in gliomas

    PubMed Central

    Costa, Angela Margarida; Pinto, Filipe; Martinho, Olga; Oliveira, Maria José; Jordan, Peter; Reis, Rui Manuel

    2015-01-01

    Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM), thus assisting invasion. Upregulation of MMPs, frequently reported in gliomas, is associated with aggressive behavior. WNK2 is a tumor suppressor gene expressed in normal brain, and silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis, and its downregulation was associated with increased glioma cell invasion. Here we showed that MMP2 expression and activity are increased in glioma cell lines that do not express WNK2. Also, WNK2 inhibited JNK, a process associated with decreasing levels of MMP2. Thus, WNK2 promoter methylation and silencing in gliomas is associated with increased JNK activation and MMP2 expression and activity, thus explaining in part tumor cell invasion potential. PMID:25596741

  1. MAb 806 Enhances the Efficacy of Ionizing Radiation in Glioma Xenografts Expressing the de2-7 Epidermal Growth Factor Receptor

    SciTech Connect

    Johns, Terrance G.; McKay, Michael J.; Cvrljevic, Anna N.; Gan, Hui K.; Taylor, Caitlin; Xu Huiling; Smyth, Fiona E.; Scott, Andrew M.

    2010-10-01

    Purpose: Mutations of the epidermal growth factor receptor (EGFR) are common in glioma. The most frequent mutation, de2-7 EGFR/EGFRvIII, occurs in approximately 40% of high-grade gliomas and confers resistance to ionizing radiation (IR). We have previously shown that mAb 806, a novel EGFR-specific antibody, is able to inhibit the growth of U87MG.{Delta}2-7 glioma xenografts expressing the de2-7 EGFR and may have potential as a therapeutic. Methods and Materials: Nude mice bearing U87MG.{Delta}2-7 xenografts were treated with mAb 806 and/or IR. Comparison of tumor volumes, the effect of treatment on angiogenesis as determined by mean vessel density, and expression changes in prosurvival protein pAkt between treatment groups were undertaken. Results: Treatment of mice bearing U87MG.{Delta}2-7 xenografts with mAb 806 and IR resulted in schedule-dependent radiosensitization. Maximal benefit was obtained when antibody treatment was given before irradiation, with the greatest inhibition of both tumor angiogenesis and tumor growth. Combination treatment mediated radiosensitization by selectively blocking the phosphorylation of the prosurvival protein Akt at serine 473, a process that is independent of DNA-dependent protein kinase catalytic subunit. Conclusions: Our results provide a rationale for the use of mAb 806 in combination with IR for the treatment of glioma and potentially other solid tumors bearing the de2-7 EGFR.

  2. Validation that Metabolic Tumor Volume Predicts Outcome in Head-and-Neck Cancer

    SciTech Connect

    Tang, Chad; Murphy, James D.; Khong, Brian; La, Trang H.; Kong, Christina; Fischbein, Nancy J.; Colevas, A. Dimitrios; Iagaru, Andrei H.; Graves, Edward E.; Loo, Billy W.; Le, Quynh-Thu

    2012-08-01

    Purpose: We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment {sup 18}F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16{sup INK4a} status as a surrogate marker for human papillomavirus (HPV). Methods and Materials: The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV{sub max}) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV. Results: Similarly to our prior findings, an increase in total MTV of 17 cm{sup 3} (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV{sub max} was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16{sup INK4a}-positive oropharyngeal cancer. Conclusions: This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

  3. SU-E-T-429: Uncertainties of Cell Surviving Fractions Derived From Tumor-Volume Variation Curves

    SciTech Connect

    Chvetsov, A

    2014-06-01

    Purpose: To evaluate uncertainties of cell surviving fraction reconstructed from tumor-volume variation curves during radiation therapy using sensitivity analysis based on linear perturbation theory. Methods: The time dependent tumor-volume functions V(t) have been calculated using a twolevel cell population model which is based on the separation of entire tumor cell population in two subpopulations: oxygenated viable and lethally damaged cells. The sensitivity function is defined as S(t)=[δV(t)/V(t)]/[δx/x] where δV(t)/V(t) is the time dependent relative variation of the volume V(t) and δx/x is the relative variation of the radiobiological parameter x. The sensitivity analysis was performed using direct perturbation method where the radiobiological parameter x was changed by a certain error and the tumor-volume was recalculated to evaluate the corresponding tumor-volume variation. Tumor volume variation curves and sensitivity functions have been computed for different values of cell surviving fractions from the practically important interval S{sub 2}=0.1-0.7 using the two-level cell population model. Results: The sensitivity functions of tumor-volume to cell surviving fractions achieved a relatively large value of 2.7 for S{sub 2}=0.7 and then approached zero as S{sub 2} is approaching zero Assuming a systematic error of 3-4% we obtain that the relative error in S{sub 2} is less that 20% in the range S2=0.4-0.7. This Resultis important because the large values of S{sub 2} are associated with poor treatment outcome should be measured with relatively small uncertainties. For the very small values of S2<0.3, the relative error can be larger than 20%; however, the absolute error does not increase significantly. Conclusion: Tumor-volume curves measured during radiotherapy can be used for evaluation of cell surviving fractions usually observed in radiation therapy with conventional fractionation.

  4. Implementation of image-guided brachytherapy (IGBT) for patients with uterine cervix cancer: a tumor volume kinetics approach

    PubMed Central

    Mendez, Lucas Castro; Stuart, Silvia Radwanski; Guimarães, Roger Guilherme Rodrigues; Ramos, Clarissa Cerchi Angotti; de Paula, Lucas Assad; de Sales, Camila Pessoa; Chen, André Tsin Chih; Blasbalg, Roberto; Baroni, Ronaldo Hueb

    2016-01-01

    Purpose To evaluate tumor shrinking kinetics in order to implement image-guided brachytherapy (IGBT) for the treatment of patients with cervix cancer. Material and methods This study has prospectively evaluated tumor shrinking kinetics of thirteen patients with uterine cervix cancer treated with combined chemoradiation. Four high dose rate brachytherapy fractions were delivered during the course of pelvic external beam radiation therapy (EBRT). Magnetic resonance imaging (MRI) exams were acquired at diagnosis (D), first (B1), and third (B3) brachytherapy fractions. Target volumes (GTV and HR-CTV) were calculated by both the ellipsoid formula (VE) and MRI contouring (VC), which were defined by a consensus between at least two radiation oncologists and a pelvic expert radiologist. Results Most enrolled patients had squamous cell carcinoma and FIGO stage IIB disease, and initiated brachytherapy after the third week of pelvic external beam radiation. Gross tumor volume volume reduction from diagnostic MRI to B1 represented 61.9% and 75.2% of the initial volume, when measured by VE and VC, respectively. Only a modest volume reduction (15-20%) was observed from B1 to B3. Conclusions The most expressive tumor shrinking occurred in the first three weeks of oncological treatment and was in accordance with gynecological examination. These findings may help in IGBT implementation. PMID:27648083

  5. Induction of the fibrinolytic system by cartilage extract mediates its antiangiogenic effect in mouse glioma.

    PubMed

    Simard, Bryan; Bouamrani, Ali; Jourdes, Peggy; Pernod, Gilles; Dimitriadou, Violetta; Berger, François

    2011-07-01

    Both the antiangiogenic and antitumoral activity of shark cartilage extracts (SCE) have been demonstrated in animal models and clinical trials. Studies reported that SCE induces the expression of tissue plasminogen activator gene (PLAT) in endothelial cells and increases the activity of the protein (t-PA) in vitro. The aim of this study was to demonstrate the crucial role of t-PA induction in the antiangiogenic and antitumor activity of SCE in experimental glioma. This study showed antiangiogenic and antitumoral effects of SCE in three mice glioma models (C6, HGD and GL26). Histological examination suggested perivascular proteolysis and edema as well as important intratumoral necrosis, which artefactually increased the tumor volume at high doses. Thus, the antiangiogenic effect of SCE correlated with the presence of t-PA and angiostatin in degenerating vessels. Functional in vivo experiments were conducted to modulate the plasminogen pathway. No antiangiogenic effect was observed on tumors overexpressing the plasminogen activator inhibitor-1 (PAI-1). Moreover, therapeutical effects were neutralized in mice that were cotreated with ε-aminocaproic acid (EACA, 120 mg/kg p.o.), an inhibitor that blocks the high-affinity lysine binding sites of both plasminogen and plasmin. In contrast, cotreatment with N-acetylcysteine (NAC, 7,5mg/kg i.p.), a sulfhydril donor that reduces plasmin into angiostatin or other antiangiogenic fragments, increased the benefit of SCE on mice survival. In subcutaneous models, NAC prevented the increase in tumor volume caused by high doses of cartilage extract. In conclusion, this study indicates that induction of t-PA by shark cartilage extract plays an essential role in its antiangiogenic activity, but that control of excessive proteolysis by a plasmin reductor could prevent edema and uncover the full benefit of shark cartilage extract in the treatment of intracranial tumors.

  6. 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

  7. Smoking and Glioma Risk

    PubMed Central

    Shao, Chuan; Zhao, Wei; Qi, Zhenyu; He, Jiaquan

    2016-01-01

    Abstract To systematically assess the relationship between smoking and glioma risk. A dose–response meta-analysis of case–control and cohort studies was performed. Pertinent studies were identified by searching database and reference lists. Random-effects model was employed to pool the estimates of the relative risks (RRs) with corresponding 95% confidence intervals (CIs). A total of 19 case–control and 6 cohort studies were included. Overall, compared with those who never smoked, the pooled RR and 95% CI was 0.98 (0.92–1.05) for ever smoker. The subgroups were not significantly different regarding risk of glioma except the group of age at start smoking (RR = 1.17, 95% CI: 0.93–1.48 for age < 20; RR = 1.25, 95% CI: 1.02–1.52 for age ≥ 20). Dose–response analysis also suggested no significant association between smoking and the risk of glioma, although some evidence for a linear relationship between smoking and glioma risk was observed. In conclusion, this meta-analysis provides little support for a causal relationship between smoking and risk of glioma. PMID:26765433

  8. KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages

    PubMed Central

    Grimaldi, A; D'Alessandro, G; Golia, M T; Grössinger, E M; Di Angelantonio, S; Ragozzino, D; Santoro, A; Esposito, V; Wulff, H; Catalano, M; Limatola, C

    2016-01-01

    Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca2+-activated K+ channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma. PMID:27054329

  9. Intraoperative radiation therapy in malignant glioma: early clinical results.

    PubMed

    Ortiz de Urbina, D; Santos, M; Garcia-Berrocal, I; Bustos, J C; Samblas, J; Gutierrez-Diaz, J A; Delgado, J M; Donckaster, G; Calvo, F A

    1995-08-01

    Intraoperative radiation therapy (IORT) with high energy electron beams is a treatment modality that has been included in multimodal programs in oncology to improve local tumor control. From August 1991 to December 1993, 17 patients with primary (8) or recurrent (9) high grade malignant gliomas, anaplastic astrocytoma (4), anaplastic oligodendroglioma (6) and glioblastoma multiforme (7), underwent surgical resection and a single dose of 10-20 Gy intraoperative radiation therapy was delivered in tumor bed. Fourteen patients received either pre-operative (8) or post-operative (6) external beam radiation therapy. Primary gliomas: 18-months actuarial survival rate has been 56% (range: 1-21+ months) and the median survival time has not yet been achieved. Four patients developed tumor progression (median time to tumor progression: 9 months). Recurrent gliomas: 18-months actuarial survival rate and median survival time has been 47% and 13 months (range: 6-32+ months) respectively. The median time to tumor progression was 11 months. No IORT related mortality has been observed. IORT is an attractive, tolerable and feasible treatment modality as antitumoral intensification procedure in high grade malignant gliomas.

  10. A Novel Technique for Endovascular Removal of Large Volume Right Atrial Tumor Thrombus.

    PubMed

    Nickel, Barbara; McClure, Timothy; Moriarty, John

    2015-08-01

    Venous thromboembolic disease is a significant cause of morbidity and mortality, particularly in the setting of large volume pulmonary embolism. Thrombolytic therapy has been shown to be a successful treatment modality; however, its use somewhat limited due to the risk of hemorrhage and potential for distal embolization in the setting of large mobile thrombi. In patients where either thrombolysis is contraindicated or unsuccessful, and conventional therapies prove inadequate, surgical thrombectomy may be considered. We present a case of percutaneous endovascular extraction of a large mobile mass extending from the inferior vena cava into the right atrium using the Angiovac device, a venovenous bypass system designed for high-volume aspiration of undesired endovascular material. Standard endovascular methods for removal of cancer-associated thrombus, such as catheter-directed lysis, maceration, and exclusion, may prove inadequate in the setting of underlying tumor thrombus. Where conventional endovascular methods either fail or are unsuitable, endovascular thrombectomy with the Angiovac device may be a useful and safe minimally invasive alternative to open resection.

  11. A Novel Technique for Endovascular Removal of Large Volume Right Atrial Tumor Thrombus

    SciTech Connect

    Nickel, Barbara; McClure, Timothy Moriarty, John

    2015-08-15

    Venous thromboembolic disease is a significant cause of morbidity and mortality, particularly in the setting of large volume pulmonary embolism. Thrombolytic therapy has been shown to be a successful treatment modality; however, its use somewhat limited due to the risk of hemorrhage and potential for distal embolization in the setting of large mobile thrombi. In patients where either thrombolysis is contraindicated or unsuccessful, and conventional therapies prove inadequate, surgical thrombectomy may be considered. We present a case of percutaneous endovascular extraction of a large mobile mass extending from the inferior vena cava into the right atrium using the Angiovac device, a venovenous bypass system designed for high-volume aspiration of undesired endovascular material. Standard endovascular methods for removal of cancer-associated thrombus, such as catheter-directed lysis, maceration, and exclusion, may prove inadequate in the setting of underlying tumor thrombus. Where conventional endovascular methods either fail or are unsuitable, endovascular thrombectomy with the Angiovac device may be a useful and safe minimally invasive alternative to open resection.

  12. Gene therapy and targeted toxins for glioma.

    PubMed

    Castro, Maria G; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D; Curtin, James F; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Ghulam Muhammad, A K M; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R

    2011-06-01

    The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of 15-18 months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.

  13. Gene Therapy and Targeted Toxins for Glioma

    PubMed Central

    Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

    2011-01-01

    The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

  14. AT-57LONG-TERM CLINICAL RESULTS OF EXTENSIVE TUMOR REMOVAL FOLLOWED BY ACNU-BASED CHEMORADIOTHERAPY FOR 147 ANAPLASTIC GLIOMAS

    PubMed Central

    Takayuki, Yasuda; Masayuki, Nitta; Takashi, Maruyama; Taichi, Saito; Satoko, Ikuta; Yoshikazu, Okada; Hiroshi, Iseki; Yoshihiro, Muragaki

    2014-01-01

    INTRODUCTION: Recent randomized trials showed that highly extent of resection (EOR) and PCV chemoradiotherapy had therapeutic long-term efficacy to anaplastic glioma (AG). From 2000, we have consistently enforced extensive removal and ACNU-based chemoradiotherapy for AG. We report retrospective clinical results of a single institution. METHODS: We reviewed 147 cases of primary AG between 2000 and 2011 (Male : Female = 94:53, average age; 43.9 year-old). 69 were anaplastic astrocytoma (41%), 43 were anaplastic oligoastrocytoma (29%), and 44 were anaplastic oligodendroglioma (30%). The intraoperative MRI was performed in 133 cases (90%), and awake surgery was performed in 58 cases (39%). Gross-total removal was 46 (31%), partial removal was 89 (61%), and biopsy was 12 (8%) (average; 83%, median; 95%). After resection, 60 Gy radiotherapy and ACNU or PAV chemotherapy were performed. The average Mib-1 index was 15%. The mean observation periods were 57 months and 95% follow-up rate. RESULTS: Overall survival (OS) wasn't reached median. The 3y-OS was 82%, 5y-OSs was 72%, and 10y-OS was 66%. There was no statistical significance among AA, AOA, AO (5y-OS; 64%, 79%, 77%). The each 5 years survival rate of gross-total resection, partial resection, and biopsy were 83%, 70%, 39%, and there was statistical significance (P = 0.0024). Extent of resection (EOR) correlated OS in AA (P = 0.02) but not in oligodendroglial subtypes (P = 0.6). Statistical significant factors were EOR (P = 0.0024) and Mib-1 index (P = 0.013). The significant factors in multi variable analysis were EOR (more than 95% or not, HR 2.5) and Mib-1 index (more than 13% or not, HR 2.3). The median PFS was 8.3, and 5y-PFS was 59%,and 10y-PFS was 45%. CONCLUSION: Our long-term clinical results of AG treated with extensive resection and ACNU-based chemoradiotherapy were better than previous reports. The EOR contributed better prognosis especially for AA.

  15. Adoptive cell transfer therapy for malignant gliomas.

    PubMed

    Ishikawa, Eiichi; Takano, Shingo; Ohno, Tadao; Tsuboi, Koji

    2012-01-01

    To date, various adoptive immunotherapies have been attempted for treatment of malignant gliomas using nonspecific and/or specific effector cells. Since the late 1980s, with the development of rIL-2, the efficacy of lymphokine-activated killer (LAK) cell therapy with or without rIL-2 for malignant gliomas had been tested with some modifications in therapeutic protocols. With advancements in technology, ex vivo expanded tumor specific cytotoxic T-lymphocytes (CTL) or those lineages were used in clinical trials with higher tumor response rates. In addition, combinations of those adoptive cell transfer using LAK cells, CTLs or natural killer (NK) cells with autologous tumor vaccine (ATV) therapy were attempted. Also, a strategy of high-dose (or lymphodepleting) chemotherapy followed by adoptive cell transfer has been drawing attentions recently. The most important role of these clinical studies using cell therapy was to prove that these ex vivo expanded effector cells could kill tumor cells in vivo. Although recent clinical results could demonstrate radiologic tumor shrinkage in a number of cases, cell transfer therapy alone has been utilized less frequently, because of the high cost of ex vivo cell expansion, the short duration of antitumor activity in vivo, and the recent shift of interest to vaccine immunotherapy. Nevertheless, NK cell therapy using specific feeder cells or allergenic NK cell lines have potentials to be a good choice of treatment because of easy ex vivo expansion and their efficacy especially when combined with vaccine therapy as they are complementary to each other. Also, further studies are expected to clarify the efficacy of the high-dose chemotherapy followed by a large scale cell transfer therapy as a new therapeutic strategy for malignant gliomas.

  16. [Gliomas – What I Have to Know in ten Questions].

    PubMed

    Gulden-Sala, Wiebke; Roth, Patrick; Brown, Michelle; Andratschke, Nicolaus; Weller, Michael; Stupp, Roger

    2016-03-16

    Gliomas are the most common primary tumors involving the central nervous system. They can manifest with diverse and non-specific general and neurological symptoms. The diagnostic gold standard is cerebral magnetic resonance imaging and subsequent histological confirmation of the diagnosis. Steroids, especially dexamethasone, are used in case of focal symptoms and of symptoms caused by increased intracranial pressure, and antiepileptic drugs are used to manage epileptic seizures. Non-enzyme-inducing antiepileptic drugs are preferable. Glioma patients have an inherently elevated thromboembolic risk, and therapeutic anticoagulation is indicated following a thromboembolic event. Surgery, radiotherapy and systemic therapy are used as tumor-specific therapy modalities in gliomas. Molecular markers play an increasing role in the prognosis and selection of therapy in daily oncological routine.

  17. Partial volume correction of PET-imaged tumor heterogeneity using expectation maximization with a spatially varying point spread function

    PubMed Central

    Barbee, David L; Flynn, Ryan T; Holden, James E; Nickles, Robert J; Jeraj, Robert

    2010-01-01

    Tumor heterogeneities observed in positron emission tomography (PET) imaging are frequently compromised of partial volume effects which may affe