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Sample records for adult diffuse gliomas

  1. Moving toward molecular classification of diffuse gliomas in adults.

    PubMed

    Theeler, Brett J; Yung, W K Alfred; Fuller, Gregory N; De Groot, John F

    2012-10-30

    Diffuse gliomas are a heterogenous group of neoplasms traditionally classified as grades II to IV based on histologic features, and with prognosis determined mainly by histologic grade and pretreatment clinical factors. Our understanding of the molecular basis of glioma initiation, tumor progression, and treatment failure is rapidly evolving. A molecular profile of diffuse gliomas is emerging. Studies evaluating gene expression and DNA methylation profile have found multiple glioma subtypes and an association between subtype and survival. The recent discovery of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations in glioma has provided reproducible prognostic biomarkers and novel therapeutic targets. Glioblastomas that exhibit CpG island hypermethylator phenotype, proneural gene expression, or IDH1 mutation identify a subset of patients with markedly improved prognosis. Accumulated evidence supports the stratification of both low-grade and anaplastic diffuse gliomas into prognostic groups using 1p/19q codeletion and IDH mutation status. A classification scheme incorporating clinical, pathologic, and molecular information may facilitate improved prognostication for patients treated in the clinic, the development of more effective clinical trials, and rational testing of targeted therapeutics.

  2. KIAA1549-BRAF fusions and IDH mutations can coexist in diffuse gliomas of adults.

    PubMed

    Badiali, Manuela; Gleize, Vincent; Paris, Sophie; Moi, Loredana; Elhouadani, Selma; Arcella, Antonietta; Morace, Roberta; Antonelli, Manila; Buttarelli, Francesca Romana; Figarella-Branger, Dominique; Kim, Young-Ho; Ohgaki, Hiroko; Mokhtari, Karima; Sanson, Marc; Giangaspero, Felice

    2012-11-01

    KIAA1549-BRAF fusion gene and isocitrate dehydrogenase (IDH) mutations are considered two mutually exclusive genetic events in pilocytic astrocytomas and diffuse gliomas, respectively. We investigated the presence of the KIAA1549-BRAF fusion gene in conjunction with IDH mutations and 1p/19q loss in 185 adult diffuse gliomas. Moreover BRAF(v600E) mutation was also screened. The KIAA1549-BRAF fusion gene was evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and sequencing. We found IDH mutations in 125 out 175 cases (71.4%). There were KIAA1549-BRAF fusion gene in 17 out of 180 (9.4%) cases and BRAF(v600E) in 2 out of 133 (1.5%) cases. In 11 of these 17 cases, both IDH mutations and the KIAA1549-BRAF fusion were present, as independent molecular events. Moreover, 6 of 17 cases showed co-presence of 1p/19q loss, IDH mutations and KIAA1549-BRAF fusion. Among the 17 cases with KIAA1549-BRAF fusion gene 15 (88.2%) were oligodendroglial neoplasms. Similarly, the two cases with BRAF(v600E) mutation were both oligodendroglioma and one had IDH mutations and 1p/19q co-deletion. Our results suggest that in a small fraction of diffuse gliomas, KIAA1549-BRAF fusion gene and BRAF(v600E) mutation may be responsible for deregulation of the Ras-RAF-ERK signaling pathway. Such alterations are more frequent in oligodendroglial neoplasm and may be co-present with IDH mutations and 1p/19q loss.

  3. BRAF V600E-mutated diffuse glioma in an adult patient: a case report and review.

    PubMed

    Suzuki, Yuta; Takahashi-Fujigasaki, Junko; Akasaki, Yasuharu; Matsushima, Satoshi; Mori, Ryosuke; Karagiozov, Kostadin; Joki, Tatsuhiro; Ikeuchi, Satoshi; Ikegami, Masahiro; Manome, Yoshinobu; Murayama, Yuichi

    2016-01-01

    Recent advances in genomic technology and genome-wide analysis have identified key molecular alterations that are relevant to the diagnosis and prognosis of brain tumors. Molecular information such as mutations in isocitrate dehydrogenase (IDH) genes or 1p/19q co-deletion status will be more actively incorporated into the histological classification of diffuse gliomas. BRAF V600E mutations are found frequently in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E-GBM), a rare variant of GBM. This mutation is relatively rare in other types of diffuse gliomas, especially in adult onset cases. Here, we present an adult onset case of IDH wild-type/BRAF V600E-mutated diffuse glioma, evolving from grade III to grade IV. The tumor displayed atypical exophytic growth and had unusual histological features not fully compatible with, but indicative of PXA and E-GBM. We discuss differential diagnosis of the tumor, and review previously described diffuse gliomas with the BRAF V600E mutation.

  4. O8.04TEMOZOLOMIDE AFTER RADIOTHERAPY IN RECURRENT “LOW-GRADE” DIFFUSE BRAINSTEM GLIOMA IN ADULTS

    PubMed Central

    Reyes-Botero, G.; Laigle-Donadey, F.; Mokhtari, K.; Martin-Duverneuil, N.; Delattre, J.Y.

    2014-01-01

    INTRODUCTION: Diffuse brainstem glioma is a rare disease in adults. Radiotherapy (RT) is frequently used as initial treatment. However, only limited data is available concerning chemotherapy efficacy at relapse after RT. Temozolomide (TMZ) is frequently used in progressive supratentorial gliomas after RT, but its efficacy in diffuse brainstem gliomas in adults has not been reported. PATIENTS AND METHODS: We conducted a retrospective analysis including patients from our database with non-enhancing diffuse brainstem glioma (histological or MRI criteria compatible with low-grade glioma) who received TMZ at relapse after RT. Tumors localized in the pons, medulla oblongata or midbrain were analyzed excluding supratentorial or infratentorial tumors secondary infiltrating the brainstem. Clinical and radiological responses were assessed and progression-free survival (PFS) and overall survival (OS) time were estimated. RESULTS: In total, 15 adult patients (median age 34 years) were selected. Histological analysis was available in 5 cases showing grade II oligodendroglioma (2 cases), grade II oligoastrocytoma (2 cases), grade II astrocytoma (1 case). Ten patients were selected by MRI criteria only. All patients received RT as initial treatment obtaining a median PFS of 34.2 months (95% CI 24.1-44.2). Median KPS at the time of relapse after RT was 80. TMZ was administered orally at 150-200mg/m2 for 5 days every 28 days at progression disease after RT. Clinical improvement after TMZ was observed in 9 cases (60%) whereas radiological assessment detected 6 partial responses. Estimated median PFS after TMZ was 9.5 months (95% CI 7.9-11) and median OS was 14.4 months (95% CI 10.5-18.2). Grade 3 thrombocytopenia was observed in 26% of cases. CONCLUSIONS: TMZ could be useful in adult patients with progressive diffuse low-grade brainstem glioma after RT failure. Further studies are warranted to detect clinical and biological markers of response to TMZ.

  5. 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.

  6. Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma.

    PubMed

    Carceller, Fernando; Fowkes, Lucy A; Khabra, Komel; Moreno, Lucas; Saran, Frank; Burford, Anna; Mackay, Alan; Jones, David T W; Hovestadt, Volker; Marshall, Lynley V; Vaidya, Sucheta; Mandeville, Henry; Jerome, Neil; Bridges, Leslie R; Laxton, Ross; Al-Sarraj, Safa; Pfister, Stefan M; Leach, Martin O; Pearson, Andrew D J; Jones, Chris; Koh, Dow-Mu; Zacharoulis, Stergios

    2016-08-01

    Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1-21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2-20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168-1.803; p = 0.325) in HGG; and 0.308 (0.107-0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.

  7. Co-expression modules of NF1, PTEN and sprouty enable distinction of adult diffuse gliomas according to pathway activities of receptor tyrosine kinases

    PubMed Central

    Xue, Yang; Wu, Chenxing; Yao, Kun; Zhang, Chuanbao; Jin, Qiang; Huang, Rong; Li, Jiuyi; Sun, Yingyu; Su, Xiaodong; Jiang, Tao; Fan, Xiaolong

    2016-01-01

    Inter-individual variability causing elevated signaling of receptor tyrosine kinases (RTK) may have hampered the efficacy of targeted therapies. We developed a molecular signature for clustering adult diffuse gliomas based on the extent of RTK pathway activities. Glioma gene modules co-expressed with NF1 (NF1-M), Sprouty (SPRY-M) and PTEN (PTEN-M) were identified, their signatures enabled robust clustering of adult diffuse gliomas of WHO grades II-IV from five independent data sets into two subtypes with distinct activities of RAS-RAF-MEK-MAPK cascade and PI3K-AKT pathway (named RMPAhigh and RMPAlow subtypes) in a morphology-independent manner. The RMPAhigh gliomas were associated with poor prognosis compared to the RMPAlow gliomas. The RMPAhigh and RMPAlow glioma subtypes harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPAhigh gliomas were enriched in immature vessel cells and tumor associated macrophages, and both cell types expressed high levels of pro-angiogenic RTKs including MET, VEGFR1, KDR, EPHB4 and NRP1. In gliomas with major genomic lesions unrelated to RTK pathway, high RMPA signature was associated with short survival. Thus, the RMPA signatures capture RTK activities in both glioma cells and glioma microenvironment, and RTK signaling in the glioma microenvironment contributes to glioma progression. PMID:27385209

  8. 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.

  9. 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

  10. Immunohistochemistry on IDH 1/2, ATRX, p53 and Ki-67 substitute molecular genetic testing and predict patient prognosis in grade III adult diffuse gliomas.

    PubMed

    Takano, Shingo; Ishikawa, Eiichi; Sakamoto, Noriaki; Matsuda, Masahide; Akutsu, Hiroyoshi; Noguchi, Masayuki; Kato, Yukinari; Yamamoto, Tetsuya; Matsumura, Akira

    2016-04-01

    The molecular subgrouping of diffuse gliomas was recently found to stratify patients into prognostically distinct groups better than histological classification. Among several molecular parameters, the key molecules for the subtype diagnosis of diffuse gliomas are IDH mutation, 1p/19q co-deletion, and ATRX mutation; 1p/19q co-deletion is undetectable by immunohistochemistry, but is mutually exclusive with ATRX and p53 mutation in IDH mutant gliomas. Therefore, we applied ATRX and p53 immunohistochemistry instead of 1p/19q co-deletion analysis. The prognostic value of immunohistochemical diagnosis for Grade III gliomas was subsequently investigated. Then, the same immunohistochmical diagnostic approach was expanded for the evaluation of Grade II and IV diffuse glioma prognosis. The results indicate immunohistochemical analysis including IDH1/2, ATRX, p53, and Ki-67 index is valuable for the classification of diffuse gliomas, which is useful for the evaluation of prognosis, especially Grade III gliomas and lower-grade gliomas (i.e., Grade II and III).

  11. Patterns of diagnostic marker assessment in adult diffuse glioma: a survey of the European Confederation of Neuropathological Societies (Euro-CNS).

    PubMed

    Woehrer, Adelheid; Kristensen, Bjarne W; Vital, Anne; Hainfellner, Johannes A

    The 2016 update of the WHO classification has introduced an integrated diagnostic approach that incorporates both tumor morphology and molecular information. This conceptual change has far-reaching implications, especially for neuropathologists who are in the forefront of translating molecular markers to routine diagnostic use. Adult diffuse glioma is a prototypic example for a group of tumors that underwent substantial regrouping, and it represents a major workload for surgical neuropathologists. Hence, we conducted a survey among members of the European Confederation of Neuropathological Societies (Euro-CNS) in order to assess 1) the extent to which molecular markers have already been incorporated in glioma diagnoses, 2) which molecular techniques are in daily use, and 3) to set a baseline for future surveys in this field. Based on 130 responses from participants across 40 nations neuropathologists uniformly rate molecular marker testing as highly relevant and already incorporate molecular information in their diagnostic assessments. At the same time however, the survey documents substantial differences in access to crucial biomarkers and molecular techniques across geographic regions and within individual countries. Concerns are raised concerning the validity of test assays with MGMT, 1p19q, and ATRX; being perceived as most problematic. Neuropathologists advocate the need for international harmonization of standards and consensus guidelines, and the majority is willing to actively engage in interlaboratory trials aiming at quality control (Figure 1).
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  12. Patterns of diagnostic marker assessment in adult diffuse glioma: a survey of the European Confederation of Neuropathological Societies (Euro-CNS)

    PubMed Central

    Woehrer, Adelheid; Kristensen, Bjarne W.; Vital, Anne; Hainfellner, Johannes A.

    2017-01-01

    The 2016 update of the WHO classification has introduced an integrated diagnostic approach that incorporates both tumor morphology and molecular information. This conceptual change has far-reaching implications, especially for neuropathologists who are in the forefront of translating molecular markers to routine diagnostic use. Adult diffuse glioma is a prototypic example for a group of tumors that underwent substantial regrouping, and it represents a major workload for surgical neuropathologists. Hence, we conducted a survey among members of the European Confederation of Neuropathological Societies (Euro-CNS) in order to assess 1) the extent to which molecular markers have already been incorporated in glioma diagnoses, 2) which molecular techniques are in daily use, and 3) to set a baseline for future surveys in this field. Based on 130 responses from participants across 40 nations neuropathologists uniformly rate molecular marker testing as highly relevant and already incorporate molecular information in their diagnostic assessments. At the same time however, the survey documents substantial differences in access to crucial biomarkers and molecular techniques across geographic regions and within individual countries. Concerns are raised concerning the validity of test assays with MGMT, 1p19q, and ATRX; being perceived as most problematic. Neuropathologists advocate the need for international harmonization of standards and consensus guidelines, and the majority is willing to actively engage in interlaboratory trials aiming at quality control (Figure 1). PMID:27966427

  13. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

    PubMed Central

    2015-01-01

    BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q

  14. Clinicopathologic implications of NF1 gene alterations in diffuse gliomas.

    PubMed

    Vizcaíno, M Adelita; Shah, Smit; Eberhart, Charles G; Rodriguez, Fausto J

    2015-09-01

    Recent studies have identified somatic alterations in the gene encoding for neurofibromin (NF1) in a subset of glioblastoma (GBM), usually associated with the mesenchymal molecular subtype. To understand the significance of NF1 genetic alterations in diffuse gliomas in general, we evaluated public databases and tested for NF1 copy number alterations in a cohort using fluorescence in situ hybridization. NF1 genetic loss (homozygous NF1 deletions or mutations with predicted functional consequences) was present in 30 (of 281) (11%) GBM and 21 (of 286) (7%) lower-grade gliomas in The Cancer Genome Atlas data. Furthermore, NF1 loss was associated with worse overall and disease-specific survival in the lower-grade glioma, but not GBM, Group in The Cancer Genome Atlas cohort. IDH1 or 2 mutations co-existed in lower-grade gliomas with NF1 loss (36%) but not in GBM. In our cohort studied by fluorescence in situ hybridization, NF1/17q (n = 2) or whole Ch17 (n = 3) losses were only identified in the GBM group (5/86 [6%]). Tumors with NF1/Ch17 loss were predominantly adult GBM (4/5); lacked EGFR amplification (0/4), strong p53 immunolabeling (1/5), or IDH1 (R132H) protein expression (0/5); but expressed the mesenchymal marker podoplanin in 4/5. NF1 genetic loss occurs in a subset of diffuse gliomas, and its significance deserves further exploration.

  15. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

    PubMed

    Ceccarelli, Michele; Barthel, Floris P; Malta, Tathiane M; Sabedot, Thais S; Salama, Sofie R; Murray, Bradley A; Morozova, Olena; Newton, Yulia; Radenbaugh, Amie; Pagnotta, Stefano M; Anjum, Samreen; Wang, Jiguang; Manyam, Ganiraju; Zoppoli, Pietro; Ling, Shiyun; Rao, Arjun A; Grifford, Mia; Cherniack, Andrew D; Zhang, Hailei; Poisson, Laila; Carlotti, Carlos Gilberto; Tirapelli, Daniela Pretti da Cunha; Rao, Arvind; Mikkelsen, Tom; Lau, Ching C; Yung, W K Alfred; Rabadan, Raul; Huse, Jason; Brat, Daniel J; Lehman, Norman L; Barnholtz-Sloan, Jill S; Zheng, Siyuan; Hess, Kenneth; Rao, Ganesh; Meyerson, Matthew; Beroukhim, Rameen; Cooper, Lee; Akbani, Rehan; Wrensch, Margaret; Haussler, David; Aldape, Kenneth D; Laird, Peter W; Gutmann, David H; Noushmehr, Houtan; Iavarone, Antonio; Verhaak, Roel G W

    2016-01-28

    Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

  16. 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

  17. Sunitinib in Treating Patients With Recurrent Malignant Gliomas

    ClinicalTrials.gov

    2016-01-29

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

  18. 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.

  19. 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

  20. MRI in treatment of adult gliomas.

    PubMed

    Henson, John W; Gaviani, Paola; Gonzalez, R Gilberto

    2005-03-01

    Diffuse astrocytomas of the adult cerebral hemispheres are unique among tumours in human beings in the extent to which their imaging features are related to histopathological characteristics and clinical behaviour. However, understanding is still restricted about the value of imaging features in the measurement of response and of progression in these tumours. The present approach used in clinical trials, which consists of an anatomical measurement of the enhancing tumour on MRI, has many problems, and might not be acceptable as a surrogate endpoint for survival in patients with glioblastoma who are enrolled in clinical trials. Dynamic imaging techniques, such as capillary permeability mapping, are being used in studies of new drugs that target specific molecular features of gliomas; however, the validity of these techniques has not been elucidated. Diffusion imaging can be valuable for fibre-tract mapping to assist surgical planning and might become useful in measuring early response to treatment in densely cellular tumours. Functional imaging techniques can be used to localise motor, sensory, and language-control areas before surgery. Intraoperative MRI has produced improvements in the extent of tumour resection, and molecular imaging is another technique on the horizon, which could come to have a role in clinical trials in the near future. Thus, as a rapidly expanding sphere of investigation, brain-tumour imaging is producing great excitement. The aim of these new techniques is to aid the identification of more effective treatments.

  1. Supratotal resection of diffuse gliomas - an overview of its multifaceted implications.

    PubMed

    Yordanova, Y N; Duffau, H

    2017-02-06

    Successful management of diffuse low-grade and high-grade gliomas in adults is a challenge for neuro-oncologists. Indeed, due to their highly infiltrative feature, these diseases remain incurable despite therapeutic advances. Nevertheless, the elaboration of individualized therapeutic strategies has led to an improvement of both overall survival and quality of life. In particular, the impact of surgical resection on diffuse glioma survival has been extensively demonstrated. However, this impact is significant only when the resection is total (i.e., complete removal of the T2-hyperintensity in diffuse low-grade gliomas, or complete removal of the enhancement in high-grade gliomas), or at least subtotal. Interestingly, biopsy samples within and beyond the abnormalities, defined by magnetic resonance imaging, have shown that the actual spatial extent of gliomas was underestimated by this conventional imaging modality, since glioma cells were present outside the signal abnormalities. Thus, it was suggested that the removal of a margin around the tumor visible on magnetic resonance imaging, i.e. "supratotal resection", might improve the outcomes in diffuse gliomas. To achieve this type of supramaximal resection, while preserving the quality of life, a new concept is to switch from an image-guided surgery to a functional-guided surgery, i.e. to pursue the resection up to the eloquent neural networks using intraoperative direct electrical stimulation mapping in awake patients. The aim of this article was to review the recent data about supratotal resection, including both oncological and functional results. Favorable outcomes have recently opened the door to the principle of "preventive surgery" in incidentally discovered gliomas, and to the proposal of a medical screening.

  2. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma.

    PubMed

    Jones, Chris; Baker, Suzanne J

    2014-10-01

    Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for paediatric HGG ranges from 30%, for tumours arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation, as well as developmental signalling pathways. These new genetic findings give insights into disease pathogenesis and the challenges and opportunities for improving patient survival in these mostly incurable childhood brain tumours.

  3. Genomic Insights into Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Lapin, Danielle H.; Tsoli, Maria; Ziegler, David S.

    2017-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor with a peak incidence in middle childhood and a median survival of less than 1 year. The dismal prognosis associated with DIPG has been exacerbated by the failure of over 250 clinical trials to meaningfully improve survival compared with radiotherapy, the current standard of care. The traditional practice to not biopsy DIPG led to a scarcity in available tissue samples for laboratory analysis that till recently hindered therapeutic advances. Over the past few years, the acquisition of patient derived tumor samples through biopsy and autopsy protocols has led to distinct breakthroughs in the identification of key oncogenic drivers implicated in DIPG development. Aberrations have been discovered in critical genetic drivers including histone H3, ACVR1, TP53, PDGFRA, and Myc. Mutations, previously not identified in other malignancies, highlight DIPG as a distinct biological entity. Identification of novel markers has already greatly influenced the direction of preclinical investigations and offers the exciting possibility of establishing biologically targeted therapies. This review will outline the current knowledge of the genomic landscape related to DIPG, overview preclinical investigations, and reflect how biological advances have influenced the focus of clinical trials toward targeted therapies.

  4. 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.

  5. IDH-1R132H mutation status in diffuse glioma patients: implications for classification.

    PubMed

    Wang, Peng-Fei; Liu, Ning; Song, Hong-Wang; Yao, Kun; Jiang, Tao; Li, Shou-Wei; Yan, Chang-Xiang

    2016-05-24

    WHO2007 grading of diffuse gliomas in adults is well-established. However, IDH mutations make classification of gliomas according to the WHO2007 edition controversial. Here, we characterized IDH-1R132H mut status in a cohort of 670 adult patients with different WHO2007 grades of diffuse glioma. Patient characteristics, clinical data and prognoses were obtained from medical records. Patients with IDH-1R132H mut were younger and had better clinical outcomes than those without mutations. Differences in age among patients with astrocytomas of different WHO2007 grades were eliminated after patients were grouped based on IDH-1R132H status. IDH-1R132H mut was present more often in patients with lower Ki-67 and MGMT protein levels and higher mutant p53 levels. Ki-67 was also strongly associated with WHO2007 grade independently of IDH-1R132H mut status. Moreover, patients with Ki-67<30 survived longer than those with Ki-67≥30, regardless of IDH-1R132H mut status. Patients in the IDH-1R132H mut group with lower MGMT protein levels also had better clinical outcomes than those in other groups. Our results indicate that to better treat gliomas, IDH mutation status should be included when determining WHO2007 grade in glioma patients.

  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. 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

  8. 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.

  9. Season of Birth and Risk for Adult Onset Glioma

    PubMed Central

    Efird, Jimmy T.

    2010-01-01

    Adult onset glioma is a rare cancer which occurs more frequently in Caucasians than African Americans, and in men than women. The etiology of this disease is largely unknown. Exposure to ionizing radiation is the only well established environmental risk factor, and this factor explains only a small percentage of cases. Several recent studies have reported an association between season of birth and glioma risk. This paper reviews the plausibility of evidence focusing on the seasonal interrelation of farming, allergies, viruses, vitamin D, diet, birth weight, and handedness. To date, a convincing explanation for the occurrence of adult gliomas decades after a seasonal exposure at birth remains elusive. PMID:20623001

  10. 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

  11. 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.

  12. 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.

  13. Network Plasticity and Intraoperative Mapping for Personalized Multimodal Management of Diffuse Low-Grade Gliomas

    PubMed Central

    Ghinda, Cristina Diana; Duffau, Hugues

    2017-01-01

    Gliomas are the most frequent primary brain tumors and include a variety of different histological tumor types and malignancy grades. Recent achievements in terms of molecular and imaging fields have created an unprecedented opportunity to perform a comprehensive interdisciplinary assessment of the glioma pathophysiology, with direct implications in terms of the medical and surgical treatment strategies available for patients. The current paradigm shift considers glioma management in a comprehensive perspective that takes into account the intricate connectivity of the cerebral networks. This allowed significant improvement in the outcome of patients with lesions previously considered inoperable. The current review summarizes the current theoretical framework integrating the adult human brain plasticity and functional reorganization within a dynamic individualized treatment strategy for patients affected by diffuse low-grade gliomas. The concept of neuro-oncology as a brain network surgery has major implications in terms of the clinical management and ensuing outcomes, as indexed by the increased survival and quality of life of patients managed using such an approach. PMID:28197403

  14. Network Plasticity and Intraoperative Mapping for Personalized Multimodal Management of Diffuse Low-Grade Gliomas.

    PubMed

    Ghinda, Cristina Diana; Duffau, Hugues

    2017-01-01

    Gliomas are the most frequent primary brain tumors and include a variety of different histological tumor types and malignancy grades. Recent achievements in terms of molecular and imaging fields have created an unprecedented opportunity to perform a comprehensive interdisciplinary assessment of the glioma pathophysiology, with direct implications in terms of the medical and surgical treatment strategies available for patients. The current paradigm shift considers glioma management in a comprehensive perspective that takes into account the intricate connectivity of the cerebral networks. This allowed significant improvement in the outcome of patients with lesions previously considered inoperable. The current review summarizes the current theoretical framework integrating the adult human brain plasticity and functional reorganization within a dynamic individualized treatment strategy for patients affected by diffuse low-grade gliomas. The concept of neuro-oncology as a brain network surgery has major implications in terms of the clinical management and ensuing outcomes, as indexed by the increased survival and quality of life of patients managed using such an approach.

  15. 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

  16. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1

    PubMed Central

    Ramkissoon, Lori A.; Horowitz, Peleg M.; Craig, Justin M.; Ramkissoon, Shakti H.; Rich, Benjamin E.; Schumacher, Steven E.; McKenna, Aaron; Lawrence, Michael S.; Bergthold, Guillaume; Brastianos, Priscilla K.; Tabak, Barbara; Ducar, Matthew D.; Van Hummelen, Paul; MacConaill, Laura E.; Pouissant-Young, Tina; Cho, Yoon-Jae; Taha, Hala; Mahmoud, Madeha; Bowers, Daniel C.; Margraf, Linda; Tabori, Uri; Hawkins, Cynthia; Packer, Roger J.; Hill, D. Ashley; Pomeroy, Scott L.; Eberhart, Charles G.; Dunn, Ian F.; Goumnerova, Liliana; Getz, Gad; Chan, Jennifer A.; Santagata, Sandro; Hahn, William C.; Stiles, Charles D.; Ligon, Azra H.; Kieran, Mark W.; Beroukhim, Rameen; Ligon, Keith L.

    2013-01-01

    Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas. PMID:23633565

  17. Molecular classification of low-grade diffuse gliomas.

    PubMed

    Kim, Young-Ho; Nobusawa, Sumihito; Mittelbronn, Michel; Paulus, Werner; Brokinkel, Benjamin; Keyvani, Kathy; Sure, Ulrich; Wrede, Karsten; Nakazato, Yoichi; Tanaka, Yuko; Vital, Anne; Mariani, Luigi; Stawski, Robert; Watanabe, Takuya; De Girolami, Umberto; Kleihues, Paul; Ohgaki, Hiroko

    2010-12-01

    The current World Health Organization classification recognizes three histological types of grade II low-grade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ± IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ± IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P = 0.0037). Multivariate analysis with adjustment for age and treatment confirmed these results (P = 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P = 0.0005) and 1p/19q loss for longer survival (P = 0.0002), while IDH1/2 mutations are not prognostic (P = 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma.

  18. Fluorine F 18 Fluorodopa-Labeled PET Scan in Planning Surgery and Radiation Therapy in Treating Patients With Newly Diagnosed High- or Low-Grade Malignant Glioma

    ClinicalTrials.gov

    2016-10-10

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; 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 Subependymal Giant Cell Astrocytoma; Adult Subependymoma

  19. 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.

  20. Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment.

    PubMed

    Zhou, Zhiping; Singh, Ranjodh; Souweidane, Mark M

    2017-01-01

    Convection-enhanced delivery (CED) is a technique designed to deliver drugs directly into the brain or tumors. Its ability to bypass the blood-brain barrier (BBB), one of the major hurdles in delivering drugs to the brain, has made it a promising drug delivery method for the treatment of primary brain tumors. A number of clinical trials utilizing CED of various therapeutic agents have been conducted to treat patients with supratentorial high-grade gliomas. Significant responses have been observed in certain patients in all of these trials. However, the insufficient ability to monitor drug distribution and pharmacokinetics hampers CED from achieving its potentials on a larger scale. Brainstem CED for diffuse intrinsic pontine glioma (DIPG) treatment is appealing because this tumor is compact and has no definitive treatment. The safety of brainstem CED has been established in small and large animals, and recently in early stage clinical trials. There are a few current clinical trials of brainstem CED in treating DIPG patients using targeted macromolecules such as antibodies and immunotoxins. Future advances for CED in DIPG treatment will come from several directions including: choosing the right agents for infusion; developing better agents and regimen for DIPG infusion; improving instruments and technique for easier and accurate surgical targeting and for allowing multisession or prolonged infusion to implement optimal time sequence; and better understanding and control of drug distribution, clearance and time sequence. CED-based therapies for DIPG will continue to evolve with new understanding of the technique and the disease.

  1. 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 ...

  2. The evolving role of molecular markers in the diagnosis and management of diffuse glioma.

    PubMed

    Huse, Jason T; Aldape, Kenneth D

    2014-11-15

    While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management.

  3. Interhemispheric Difference Images from Postoperative Diffusion Tensor Imaging of Gliomas

    PubMed Central

    Kosztyla, Robert; Reinsberg, Stefan A; Moiseenko, Vitali; Toyota, Brian

    2016-01-01

    Introduction Determining the full extent of gliomas during radiotherapy planning can be challenging with conventional T1 and T2 magnetic resonance imaging (MRI). The purpose of this study was to develop a method to automatically calculate differences in the fractional anisotropy (FA) and mean diffusivity (MD) values in target volumes obtained with diffusion tensor imaging (DTI) by comparing with values from anatomically homologous voxels on the contralateral side of the brain. Methods Seven patients with a histologically confirmed glioma underwent postoperative radiotherapy planning with 1.5 T MRI and computed tomography. DTI was acquired using echo planar imaging for 20 noncolinear directions with b = 1000 s/mm2 and one additional image with b = 0, repeated four times for signal averaging. The distribution of FA and MD was calculated in the gross tumor volume (GTV), shells 0-5 mm, 5-10 mm, 10-15 mm, 15-20 mm, and 20-25 mm outside the GTV, and the GTV mirrored in the left-right direction (mirGTV). All images were aligned to a template image, and FA and MD interhemispheric difference images were calculated. The difference in mean FA and MD between the regions of interest was statistically tested using two-sided paired t-tests with α = 0.05. Results The mean FA in mirGTV was 0.20 ± 0.04, which was larger than the FA in the GTV (0.12 ± 0.03) and shells 0-5 mm (0.15 ± 0.03) and 5-10 mm (0.17 ± 0.03) outside the GTV. The mean MD (×10-3 mm2/s) in mirGTV was 0.93 ± 0.09, which was smaller than the MD in the GTV (1.48 ± 0.19) and the peritumoral shells. The distribution of FA and MD interhemispheric differences followed the same trends as FA and MD values. Conclusions This study successfully implemented a method for calculation of FA and MD differences by comparison of voxel values with anatomically homologous voxels on the contralateral side of the brain. Further research is warranted to determine if radiotherapy planning using these images can be used to improve

  4. Interhemispheric Difference Images from Postoperative Diffusion Tensor Imaging of Gliomas.

    PubMed

    Kosztyla, Robert; Reinsberg, Stefan A; Moiseenko, Vitali; Toyota, Brian; Nichol, Alan

    2016-10-05

    Introduction Determining the full extent of gliomas during radiotherapy planning can be challenging with conventional T1 and T2 magnetic resonance imaging (MRI). The purpose of this study was to develop a method to automatically calculate differences in the fractional anisotropy (FA) and mean diffusivity (MD) values in target volumes obtained with diffusion tensor imaging (DTI) by comparing with values from anatomically homologous voxels on the contralateral side of the brain. Methods Seven patients with a histologically confirmed glioma underwent postoperative radiotherapy planning with 1.5 T MRI and computed tomography. DTI was acquired using echo planar imaging for 20 noncolinear directions with b = 1000 s/mm(2) and one additional image with b = 0, repeated four times for signal averaging. The distribution of FA and MD was calculated in the gross tumor volume (GTV), shells 0-5 mm, 5-10 mm, 10-15 mm, 15-20 mm, and 20-25 mm outside the GTV, and the GTV mirrored in the left-right direction (mirGTV). All images were aligned to a template image, and FA and MD interhemispheric difference images were calculated. The difference in mean FA and MD between the regions of interest was statistically tested using two-sided paired t-tests with α = 0.05. Results The mean FA in mirGTV was 0.20 ± 0.04, which was larger than the FA in the GTV (0.12 ± 0.03) and shells 0-5 mm (0.15 ± 0.03) and 5-10 mm (0.17 ± 0.03) outside the GTV. The mean MD (×10(-3) mm(2)/s) in mirGTV was 0.93 ± 0.09, which was smaller than the MD in the GTV (1.48 ± 0.19) and the peritumoral shells. The distribution of FA and MD interhemispheric differences followed the same trends as FA and MD values. Conclusions This study successfully implemented a method for calculation of FA and MD differences by comparison of voxel values with anatomically homologous voxels on the contralateral side of the brain. Further research is warranted to determine if radiotherapy planning using these images can be used to

  5. Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases

    ClinicalTrials.gov

    2017-03-22

    Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Primary Melanocytic Lesion of Meninges; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma; Metastatic Malignant Neoplasm in the Brain; Multiple Sclerosis; Recurrent Adult Brain Neoplasm

  6. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.

    PubMed

    Taylor, Kathryn R; Mackay, Alan; Truffaux, Nathalène; Butterfield, Yaron S; Morozova, Olena; Philippe, Cathy; Castel, David; Grasso, Catherine S; Vinci, Maria; Carvalho, Diana; Carcaboso, Angel M; de Torres, Carmen; Cruz, Ofelia; Mora, Jaume; Entz-Werle, Natacha; Ingram, Wendy J; Monje, Michelle; Hargrave, Darren; Bullock, Alex N; Puget, Stéphanie; Yip, Stephen; Jones, Chris; Grill, Jacques

    2014-05-01

    Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.

  7. Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Paugh, Barbara S.; Broniscer, Alberto; Qu, Chunxu; Miller, Claudia P.; Zhang, Junyuan; Tatevossian, Ruth G.; Olson, James M.; Geyer, J. Russell; Chi, Susan N.; da Silva, Nasjla Saba; Onar-Thomas, Arzu; Baker, Justin N.; Gajjar, Amar; Ellison, David W.; Baker, Suzanne J.

    2011-01-01

    Purpose Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. Results Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase–Ras–phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. Conclusion DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG. PMID:21931021

  8. Voxel-based clustered imaging by multiparameter diffusion tensor images for glioma grading

    PubMed Central

    Inano, Rika; Oishi, Naoya; Kunieda, Takeharu; Arakawa, Yoshiki; Yamao, Yukihiro; Shibata, Sumiya; Kikuchi, Takayuki; Fukuyama, Hidenao; Miyamoto, Susumu

    2014-01-01

    Gliomas are the most common intra-axial primary brain tumour; therefore, predicting glioma grade would influence therapeutic strategies. Although several methods based on single or multiple parameters from diagnostic images exist, a definitive method for pre-operatively determining glioma grade remains unknown. We aimed to develop an unsupervised method using multiple parameters from pre-operative diffusion tensor images for obtaining a clustered image that could enable visual grading of gliomas. Fourteen patients with low-grade gliomas and 19 with high-grade gliomas underwent diffusion tensor imaging and three-dimensional T1-weighted magnetic resonance imaging before tumour resection. Seven features including diffusion-weighted imaging, fractional anisotropy, first eigenvalue, second eigenvalue, third eigenvalue, mean diffusivity and raw T2 signal with no diffusion weighting, were extracted as multiple parameters from diffusion tensor imaging. We developed a two-level clustering approach for a self-organizing map followed by the K-means algorithm to enable unsupervised clustering of a large number of input vectors with the seven features for the whole brain. The vectors were grouped by the self-organizing map as protoclusters, which were classified into the smaller number of clusters by K-means to make a voxel-based diffusion tensor-based clustered image. Furthermore, we also determined if the diffusion tensor-based clustered image was really helpful for predicting pre-operative glioma grade in a supervised manner. The ratio of each class in the diffusion tensor-based clustered images was calculated from the regions of interest manually traced on the diffusion tensor imaging space, and the common logarithmic ratio scales were calculated. We then applied support vector machine as a classifier for distinguishing between low- and high-grade gliomas. Consequently, the sensitivity, specificity, accuracy and area under the curve of receiver operating characteristic

  9. Determining optimal treatment strategy for diffuse glioma: the emerging role of IDH mutations.

    PubMed

    Juratli, Tareq A; Cahill, Daniel P; McCutcheon, Ian E

    2015-06-01

    The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes mutate frequently in gliomas, and it has become increasingly apparent that IDH mutation status accounts for much of the prognostic information previously rendered by histological grading. Most glioblastomas (90-95%) are IDH wild-type and most lower-grade diffuse gliomas (80%) are IDH-mutant. We examine here how IDH mutation status interacts with treatments known to influence survival (surgery, chemotherapy and radiotherapy) in patients with gliomas, and the impact of the IDH mutations on patients' survival after such treatments. IDH mutations is associated with more complete surgical resection of enhancing disease, and with a better response to RT. In addition, there is increasing clinical evidence that, in certain contexts, IDH mutations predict chemotherapeutic sensitivity. Mutations in IDH and other genes are beginning to drive decisions on therapy for diffuse gliomas and will likely allow tailoring of treatment by molecular profile in the future.

  10. Intravoxel incoherent motion diffusion-weighted MR imaging of gliomas: efficacy in preoperative grading.

    PubMed

    Hu, Yu-Chuan; Yan, Lin-Feng; Wu, Lang; Du, Pang; Chen, Bao-Ying; Wang, Liang; Wang, Shu-Mei; Han, Yu; Tian, Qiang; Yu, Ying; Xu, Tian-Yong; Wang, Wen; Cui, Guang-Bin

    2014-12-01

    The preoperative grading of gliomas, which is critical for guiding therapeutic strategies, remains unsatisfactory. We aimed to retrospectively assess the efficacy of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in the grading of gliomas. Forty-two newly diagnosed glioma patients underwent conventional MR imaging, DWI, and contrast-enhanced MR imaging. Parameters of apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), and fraction of fast ADC (f) were generated. They were tested for differences between low- and high-grade gliomas based on one-way ANOVA. Receiver-operating characteristic (ROC) analyses were conducted to determine the optimal thresholds as well as the sensitivity and specificity for grading. ADC, D, and f were higher in the low-grade gliomas, whereas D* tended to be lower (all P<0.05). The AUC, sensitivity, specificity and the cutoff value, respectively, for differentiating low- from high-grade gliomas for ADC, D and f, and differentiating high- from low-grade gliomas for D* were as follows: ADC, 0.926, 100%, 82.8%, and 0.7 × 10(-3) mm(2)/sec; D, 0.942, 92.3%, 86.2%, and 0.623 × 10(-3) mm(2)/sec; f, 0.902, 92.3%, 86.2%, and 35.3%; D*, 0.798, 79.3%, 84.6%, and 0.303 × 10(-3) mm(2)/sec. The IVIM DWI demonstrates efficacy in differentiating the low- from high-grade gliomas.

  11. Radiation combined with temozolomide contraindicated for young adults diagnosed with anaplastic glioma

    PubMed Central

    Cai, Jinquan; You, Gan; Wang, Yinyan; Qiu, Xiaoguang; Li, Shouwei; Wu, Chenxing; Yao, Kun; Li, Wenbin; Peng, Xiaoxia; Zhang, Wei; Jiang, Tao

    2016-01-01

    Purpose Age is a major prognostic factor for malignant gliomas. However, few studies have investigated the management of gliomas in young adults. We determined the role of survival and treatment in young adults with advanced gliomas in a large population from the Chinese Glioma Genome Atlas (CGGA). Methods This study included 726 adults (age ≥ 18) with histologically proven anaplastic glioma or glioblastoma multiforme (GBM). The overall and progression-free survival was determined in young (age < 50) and older groups (age ≥ 50). Results The study included an older group (OP) of 264 patients and a younger group (YP) of 462patients. In the OP group with GBM and anaplastic glioma, patients treated with RT combined with temozolomide (TMZ) manifested significantly longer OS and PFS compared with patients assigned to RT alone (P < 0.05). In contrast, the YP group diagnosed with anaplastic glioma failed to show any survival advantage with RT plus TMZ compared with RT alone. Conclusions We observed no survival benefit in young adults (age < 50) with anaplastic glioma when treated with TMZ combined with RT. Our findings warrant further investigation of younger patients diagnosed with anaplastic glioma treated with radiotherapy plus TMZ chemotherapy. PMID:27590514

  12. Sexuality after surgery for diffuse low-grade glioma

    PubMed Central

    Surbeck, Werner; Herbet, Guillaume; Duffau, Hugues

    2015-01-01

    Background Although neurological and neurocognitive outcomes have previously been studied after resection of diffuse low-grade glioma (DLGG), the impact of surgery on sexual life has not been investigated. Our aim was to assess whether DLGG surgery could have consequences on sexual experience. Methods Anonymous standardized questionnaires concerning sexual functioning, including the Arizona Sexual Experiences Scale (ASEX) and a subjective statement, were completed by 32 patients who underwent surgery for DLGG. All patients returned to a normal social and professional life following resection, with neither neurological deficits nor depression. No radiotherapy was administered, and patients who received chemotherapy were without treatment for at least 1 year. Results Seventeen patients (53%) reported a postoperative sexual change, with subjective deterioration in 15 (88%) and improvement in 2 (12%). Sexual dysfunction according to ASEX affected 9 of 15 women (60%) and 5 of 17 men (29%). Right-sided resections were associated with more difficulties in reaching orgasm than left-sided resections (P < .02). Men with temporal lobe resection displayed more reduction in sexual drive (P < .003) and sexual arousal (P < .004) than women, resulting in significant higher overall ASEX scores for temporal lobe resections in men (P = .01). Men remaining on antiepileptic drugs who underwent right-sided resection displayed higher overall ASEX scores than women (P = .031). Conclusions This first evaluation of sexual life after surgery for DLGG suggests that sexual dysfunction is common in this population. Therefore, we suggest that sexual health should consistently be addressed during routine pre- and postoperative examination of patients with DLGG. PMID:25699682

  13. 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.

  14. P17.41CLINICAL MANAGEMENT AND OUTCOME OF HISTOLOGICALLY VERIFIED ADULT BRAINSTEM GLIOMAS IN SWITZERLAND: A RETROSPECTIVE ANALYSIS OF 21 PATIENTS

    PubMed Central

    Hundsberger, T.; Tonder, M.; Andreas, H.; Brügge, D.; Roelcke, U.; Putora, P.M.; Stupp, R.; Weller, M.

    2014-01-01

    BACKGROUND: Because of low incidence, mixed study populations and paucity of clinical and histological data, the management of adult brainstem gliomas remains non-standardized. We here describe characteristics, treatment and outcome of patients with exclusively histologically confirmed adult brainstem gliomas. METHODS: A retrospective chart review of adults (>age 18 years) was conducted. Brainstem glioma was defined as a glial tumor located in the midbrain, pons or medulla. Characteristics, management and outcome were analyzed. RESULTS: 21 patients (17 males; median age 41 years) were diagnosed between 2004 and 2012 by biopsy (n = 15), partial (n = 4) or complete resection (n = 2). Diagnoses were glioblastoma (WHO grade IV, n = 6), anaplastic astrocytoma (WHO grade III, n = 7), diffuse astrocytoma (WHO grade II, n = 6) and pilocytic astrocytoma (WHO grade I, n = 2). Diffuse gliomas were mainly located in the pons and frequently showed MRI contrast enhancement. Endophytic growth was common (16 versus 5). Postoperative therapy in low-grade (WHO grade I/II) and high-grade gliomas (WHO grade III/IV) consisted of radiotherapy alone (3 in each group), radiochemotherapy (2 versus 6), chemotherapy alone (0 versus 2) or no postoperative therapy (3 versus 1). Median PFS (24.1 versus 5.8 months; log-rank, p = 0.009) and mOS (30.5 versus 11.5 months; log-rank, p = 0.028) was significantly better in WHO grade II than in WHO grade III/IV tumors. Second-line therapy considerably varied. CONCLUSIONS: Histologically verification of adult brainstem glioma is feasible and has an impact on postoperative treatment. Low-grade gliomas can simple be followed or treated with radiotherapy alone. Radiochemotherapy with temozolomide can safely be prescribed for high-grade gliomas without additional CNS toxicities.

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

    ClinicalTrials.gov

    2015-09-28

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

  17. A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

    ClinicalTrials.gov

    2017-01-30

    Pilomyxoid Astrocytoma; Pilocytic Astrocytoma; Glioma, Astrocytic; Optic Nerve Glioma; Pleomorphic Xanthoastrocytoma; Glioblastoma Multiforme; Anaplastic Astrocytoma; Gliosarcoma; Diffuse Intrinsic Pontine Glioma; DIPG; Low-grade Glioma; Brainstem Glioma

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

    PubMed

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

    2014-10-07

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

  19. A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas.

    PubMed

    Hummel, Trent R; Salloum, Ralph; Drissi, Rachid; Kumar, Shiva; Sobo, Matthew; Goldman, Stewart; Pai, Ahna; Leach, James; Lane, Adam; Pruitt, David; Sutton, Mary; Chow, Lionel M; Grimme, Laurie; Doughman, Renee; Backus, Lori; Miles, Lili; Stevenson, Charles; Fouladi, Maryam; DeWire, Mariko

    2016-03-01

    Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG.

  20. Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.

    PubMed

    Sewing, A Charlotte P; Lagerweij, Tonny; van Vuurden, Dannis G; Meel, Michaël H; Veringa, Susanna J E; Carcaboso, Angel M; Gaillard, Pieter J; Peter Vandertop, W; Wesseling, Pieter; Noske, David; Kaspers, Gertjan J L; Hulleman, Esther

    2017-02-17

    OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic

  1. 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.

  2. Superselective intracerebral catheterization for administration of oncolytic virotherapy in a case of diffuse intrinsic pontine glioma.

    PubMed

    Carceller, Fernando; Aleu, Aitziber; Casasco, Alfredo; Guimaraens, Leopoldo; López-Pino, Migel A; Madero, Luís; Ramírez, Manuel

    2014-10-01

    New therapies are needed to improve current results in diffuse intrinsic pontine glioma. We present here the initial experience of administering Celyvir, autologous mesenchymal stem cells infected with ICOVIR-5, an oncolytic adenovirus that selectively replicates in cancer cells, by means of superselective intra-arterial delivery, in a patient diagnosed of diffuse intrinsic pontine glioma. Feasibility, safety, and morbidity rates of the superselective catheterization technique are comparable with those of diagnostic angiography. The intra-arterial approach warrants a greater contact of the mesenchymal stem cells with the tumor mass, and minimizes hemorrhages or vascular disruption. The tolerance to the 2 administrations was excellent, with no acute or delayed adverse effect, underscoring the feasibility of this technique for the delivery of virotherapies and/or cellular therapies in this location.

  3. Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

    DTIC Science & Technology

    2012-09-01

    CONTRACTING ORGANIZATION: Duke University REPORT DATE: TYPE OF REPORT: PREPARED FOR: U.S. Army Medical Research and Materiel...display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE Annual 3. DATES...ABSTRACT Diffuse Intrinsic Pontine Gliomas or DIPG, is a type of brain tumor that afflicts children and is the leading cause of death in pediatric

  4. Molecular Drug Imaging: 89Zr-bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma.

    PubMed

    Jansen, Marc; Veldhuijzen van Zanten, Sophie Em; Van Vuurden, Dannis G; Huisman, Marc; Vugts, Danielle J; Hoekstra, Otto S; van Dongen, Guus A M S; Kaspers, Gert-Jan Jl

    2016-10-20

    Predictive tools to guide therapy in children with brain tumors are urgently needed. We introduced molecular imaging to facilitate this. We investigated whether bevacizumab can reach the tumor in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of zirconium-89((89)Zr)-labeled bevacizumab by PET. In addition we evaluated the safety of the procedure in children and determined the optimal timing of imaging.

  5. Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort.

    PubMed

    Tabouret, Emeline; Nguyen, Anh Tuan; Dehais, Caroline; Carpentier, Catherine; Ducray, François; Idbaih, Ahmed; Mokhtari, Karima; Jouvet, Anne; Uro-Coste, Emmanuelle; Colin, Carole; Chinot, Olivier; Loiseau, Hugues; Moyal, Elisabeth; Maurage, Claude-Alain; Polivka, Marc; Lechapt-Zalcman, Emmanuèle; Desenclos, Christine; Meyronet, David; Delattre, Jean-Yves; Figarella-Branger, Dominique

    2016-10-01

    The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50.4 years (range 17.1-84.4). Based on the new histomolecular classification, diagnoses included anaplastic oligodendroglioma IDH mutant and 1p/19q-codeleted (32.5 %), anaplastic astrocytoma IDH mutant (IDH (mut)) (11.0 %), anaplastic astrocytoma IDH wild type (IDH (wt)) (5.3 %), glioblastoma IDH (mut) (17.1 %), and glioblastoma IDH (wt) (33.2 %). Ten patients presented with a diffuse midline tumor, H3 K27M mutant. The new WHO classification was prognostic for progression-free survival (PFS) and overall survival (OS) (p < 0.001). We did not find prognosis differences between grades III and IV for IDH (mut) 1p/19q intact and IDH (wt) gliomas in univariate and multivariate analyses. Among anaplastic astrocytoma IDH (wt), cases with chromosome arm 7p gain and 10q loss (55 %) had shorter PFS than the others (p = 0.027). In conclusion, the new WHO histomolecular classification of diffuse gliomas presented with high prognostic value. Grading was not discriminant between grade III and IV high-grade gliomas.

  6. Magnetic resonance spectroscopic detection of lactate is predictive of a poor prognosis in patients with diffuse intrinsic pontine glioma

    PubMed Central

    Yamasaki, Fumiyuki; Kurisu, Kaoru; Kajiwara, Yoshinori; Watanabe, Yosuke; Takayasu, Takeshi; Akiyama, Yuji; Saito, Taiichi; Hanaya, Ryosuke; Sugiyama, Kazuhiko

    2011-01-01

    Diffuse brainstem glioma has a poor prognosis, and there are few long-term survivors. We looked for clinical, conventional magnetic resonance (MR), and MR spectroscopic (MRS) findings predictive of the prognosis of patients with brainstem glioma. Our institutional review board approved this retrospective study of 23 patients with diffuse intrinsic pontine or diffuse medullary brainstem glioma treated during the period 2000–2009. To evaluate prognostic values, we performed a Kaplan-Meier survival analysis (log-rank test) that incorporated the patients’ age and sex, symptom duration, the presence or absence of cranial nerve palsy, long tract sign, ataxia, and cysts, the chemotherapeutic regimen, Gd enhancement, longitudinal and cerebellar extension, basilar artery encasement, and MRS parameters. Of the 23 diffuse brainstem gliomas, 19 were located at the pons (ratio of male to female patients, 1.1:1). The mean age of the 23 patients was 15.9 years (range, 4–50 years); 16 were aged <20 years. The duration of overall survival was 19.7 months; in patients with diffuse intrinsic pontine glioma, it was 16.6 months, and in patients aged <20 years, it was 11.8 months. Clinical and conventional MR findings at presentation were not predictive of the prognosis in children with diffuse intrinsic pontine glioma. In addition, a patient age <20 years and the detection of lactate by MRS were poor prognostic factors. The MRS detection of lactate is a prognostic factor in patients with diffuse intrinsic pontine glioma. Additional studies of larger patient populations using other imaging modalities are needed. PMID:21653595

  7. Prognostic and Predictive Biomarkers in Adult and Pediatric Gliomas: Toward Personalized Treatment

    PubMed Central

    Haynes, Harry R.; Camelo-Piragua, Sandra; Kurian, Kathreena M.

    2014-01-01

    It is increasingly clear that both adult and pediatric glial tumor entities represent collections of neoplastic lesions, each with individual pathological molecular events and treatment responses. In this review, we discuss the current prognostic biomarkers validated for clinical use or with future clinical validity for gliomas. Accurate prognostication is crucial for managing patients as treatments may be associated with high morbidity and the benefits of high risk interventions must be judged by the treating clinicians. We also review biomarkers with predictive validity, which may become clinically relevant with the development of targeted therapies for adult and pediatric gliomas. PMID:24716189

  8. In vivo molecular profiling of human glioma using diffusion kurtosis imaging.

    PubMed

    Hempel, Johann-Martin; Bisdas, Sotirios; Schittenhelm, Jens; Brendle, Cornelia; Bender, Benjamin; Wassmann, Henk; Skardelly, Marco; Tabatabai, Ghazaleh; Vega, Salvador Castaneda; Ernemann, Ulrike; Klose, Uwe

    2017-01-01

    The purpose of this study is to assess the diagnostic performance of diffusion kurtosis imaging (DKI) for in vivo molecular profiling of human glioma. Normalized mean kurtosis (MKn) and mean diffusivity (MDn) metrics from DKI were assessed in 50 patients with histopathologically confirmed glioma. The results were compared in regard to the WHO-based histological findings and molecular characteristics leading to integrated diagnosis (Haarlem Consensus): isocitrate-dehydrogenase (IDH1/2) mutation status, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression, chromosome 1p/19q loss of heterozygosity (LOH), and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. MKn was significantly lower in tumors with IDH1/2 mutation (0.43 ± 0.09) and ATRX loss of expression (0.41 ± 0.11) than in those with IDH1/2 wild type (0.57 ± 0.09, p < 0.001) and ATRX maintained expression (0.51 ± 0.10, p = 0.004), respectively. Regarding the integrated molecular diagnosis, MKn was significantly higher in primary glioblastoma (0.57 ± 0.10) than in astrocytoma (0.39 ± 0.11, p < 0.001) and oligodendroglioma (0.47 ± 0.05, p = 0.003). MK may be used to provide insight into the human glioma molecular profile regarding IDH1/2 mutation status and ATRX expression. Considering the diagnostic and prognostic significance of these molecular markers, MK appears to be a promising in vivo biomarker for glioma. The diagnostic performance of MK seems to fit more with the integrated molecular approach than the conventional histological findings of the current WHO 2007 classification.

  9. 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.

  10. Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

    PubMed Central

    Walsh, Kyle M.; Codd, Veryan; Rice, Terri; Nelson, Christopher P.; Smirnov, Ivan V.; McCoy, Lucie S.; Hansen, Helen M.; Elhauge, Edward; Ojha, Juhi; Francis, Stephen S.; Madsen, Nils R.; Bracci, Paige M.; Pico, Alexander R.; Molinaro, Annette M.; Tihan, Tarik; Berger, Mitchel S.; Chang, Susan M.; Prados, Michael D.; Jenkins, Robert B.; Wiemels, Joseph L.; Samani, Nilesh J.; Wiencke, John K.; Wrensch, Margaret R.

    2015-01-01

    Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82×10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48×10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83×10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis. PMID:26646793

  11. Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

    PubMed

    Walsh, Kyle M; Codd, Veryan; Rice, Terri; Nelson, Christopher P; Smirnov, Ivan V; McCoy, Lucie S; Hansen, Helen M; Elhauge, Edward; Ojha, Juhi; Francis, Stephen S; Madsen, Nils R; Bracci, Paige M; Pico, Alexander R; Molinaro, Annette M; Tihan, Tarik; Berger, Mitchel S; Chang, Susan M; Prados, Michael D; Jenkins, Robert B; Wiemels, Joseph L; Samani, Nilesh J; Wiencke, John K; Wrensch, Margaret R

    2015-12-15

    Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

  12. A Probabilistic Atlas of Diffuse WHO Grade II Glioma Locations in the Brain

    PubMed Central

    Baumann, Cédric; Zouaoui, Sonia; Yordanova, Yordanka; Blonski, Marie; Rigau, Valérie; Chemouny, Stéphane; Taillandier, Luc; Bauchet, Luc; Duffau, Hugues; Paragios, Nikos

    2016-01-01

    Diffuse WHO grade II gliomas are diffusively infiltrative brain tumors characterized by an unavoidable anaplastic transformation. Their management is strongly dependent on their location in the brain due to interactions with functional regions and potential differences in molecular biology. In this paper, we present the construction of a probabilistic atlas mapping the preferential locations of diffuse WHO grade II gliomas in the brain. This is carried out through a sparse graph whose nodes correspond to clusters of tumors clustered together based on their spatial proximity. The interest of such an atlas is illustrated via two applications. The first one correlates tumor location with the patient’s age via a statistical analysis, highlighting the interest of the atlas for studying the origins and behavior of the tumors. The second exploits the fact that the tumors have preferential locations for automatic segmentation. Through a coupled decomposed Markov Random Field model, the atlas guides the segmentation process, and characterizes which preferential location the tumor belongs to and consequently which behavior it could be associated to. Leave-one-out cross validation experiments on a large database highlight the robustness of the graph, and yield promising segmentation results. PMID:26751577

  13. A Probabilistic Atlas of Diffuse WHO Grade II Glioma Locations in the Brain.

    PubMed

    Parisot, Sarah; Darlix, Amélie; Baumann, Cédric; Zouaoui, Sonia; Yordanova, Yordanka; Blonski, Marie; Rigau, Valérie; Chemouny, Stéphane; Taillandier, Luc; Bauchet, Luc; Duffau, Hugues; Paragios, Nikos

    2016-01-01

    Diffuse WHO grade II gliomas are diffusively infiltrative brain tumors characterized by an unavoidable anaplastic transformation. Their management is strongly dependent on their location in the brain due to interactions with functional regions and potential differences in molecular biology. In this paper, we present the construction of a probabilistic atlas mapping the preferential locations of diffuse WHO grade II gliomas in the brain. This is carried out through a sparse graph whose nodes correspond to clusters of tumors clustered together based on their spatial proximity. The interest of such an atlas is illustrated via two applications. The first one correlates tumor location with the patient's age via a statistical analysis, highlighting the interest of the atlas for studying the origins and behavior of the tumors. The second exploits the fact that the tumors have preferential locations for automatic segmentation. Through a coupled decomposed Markov Random Field model, the atlas guides the segmentation process, and characterizes which preferential location the tumor belongs to and consequently which behavior it could be associated to. Leave-one-out cross validation experiments on a large database highlight the robustness of the graph, and yield promising segmentation results.

  14. Rapid and fulminant leptomeningeal spread following radiotherapy in diffuse intrinsic pontine glioma.

    PubMed

    Tinkle, Christopher L; Orr, Brent A; Lucas, John T; Klimo, Paul; Patay, Zoltan; Baker, Suzanne J; Broniscer, Alberto; Qaddoumi, Ibrahim

    2017-01-13

    A 4-year-old male presented with rapid-onset cranial nerve palsy and ataxia. Brain magnetic resonance imaging (MRI) revealed a pontine mass lesion with discordant conventional and advanced imaging. A stereotactic core biopsy revealed glioblastoma with immunostaining suggestive of histone H3K27M and TP53 mutation, consistent with diffuse intrinsic pontine glioma. MRI 3 months after radiotherapy revealed extensive new leptomeningeal metastatic disease involving both the supra- and infratentorial brain, as well as the imaged portion of the spine. Tissue procured at the time of needle biopsy has undergone striking in vivo expansion as an orthotopic xenograft.

  15. Pediatric and Adult High-Grade Glioma Stem Cell Culture Models Are Permissive to Lytic Infection with Parvovirus H-1

    PubMed Central

    Josupeit, Rafael; Bender, Sebastian; Kern, Sonja; Leuchs, Barbara; Hielscher, Thomas; Herold-Mende, Christel; Schlehofer, Jörg R.; Dinsart, Christiane; Witt, Olaf; Rommelaere, Jean; Lacroix, Jeannine

    2016-01-01

    Combining virus-induced cytotoxic and immunotherapeutic effects, oncolytic virotherapy represents a promising therapeutic approach for high-grade glioma (HGG). A clinical trial has recently provided evidence for the clinical safety of the oncolytic parvovirus H-1 (H-1PV) in adult glioblastoma relapse patients. The present study assesses the efficacy of H-1PV in eliminating HGG initiating cells. H-1PV was able to enter and to transduce all HGG neurosphere culture models (n = 6), including cultures derived from adult glioblastoma, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Cytotoxic effects induced by the virus have been observed in all HGG neurospheres at half maximal inhibitory concentration (IC50) doses of input virus between 1 and 10 plaque forming units per cell. H-1PV infection at this dose range was able to prevent tumorigenicity of NCH421k glioblastoma multiforme (GBM) “stem-like” cells in NOD/SCID mice. Interestingly NCH421R, an isogenic subclone with equal capacity of xenograft formation, but resistant to H-1PV infection could be isolated from the parental NCH421k culture. To reveal changes in gene expression associated with H-1PV resistance we performed a comparative gene expression analysis in these subclones. Several dysregulated genes encoding receptor proteins, endocytosis factors or regulators innate antiviral responses were identified and represent intriguing candidates for to further study molecular mechanisms of H-1PV resistance. PMID:27213425

  16. Pediatric and Adult High-Grade Glioma Stem Cell Culture Models Are Permissive to Lytic Infection with Parvovirus H-1.

    PubMed

    Josupeit, Rafael; Bender, Sebastian; Kern, Sonja; Leuchs, Barbara; Hielscher, Thomas; Herold-Mende, Christel; Schlehofer, Jörg R; Dinsart, Christiane; Witt, Olaf; Rommelaere, Jean; Lacroix, Jeannine

    2016-05-19

    Combining virus-induced cytotoxic and immunotherapeutic effects, oncolytic virotherapy represents a promising therapeutic approach for high-grade glioma (HGG). A clinical trial has recently provided evidence for the clinical safety of the oncolytic parvovirus H-1 (H-1PV) in adult glioblastoma relapse patients. The present study assesses the efficacy of H-1PV in eliminating HGG initiating cells. H-1PV was able to enter and to transduce all HGG neurosphere culture models (n = 6), including cultures derived from adult glioblastoma, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Cytotoxic effects induced by the virus have been observed in all HGG neurospheres at half maximal inhibitory concentration (IC50) doses of input virus between 1 and 10 plaque forming units per cell. H-1PV infection at this dose range was able to prevent tumorigenicity of NCH421k glioblastoma multiforme (GBM) "stem-like" cells in NOD/SCID mice. Interestingly NCH421R, an isogenic subclone with equal capacity of xenograft formation, but resistant to H-1PV infection could be isolated from the parental NCH421k culture. To reveal changes in gene expression associated with H-1PV resistance we performed a comparative gene expression analysis in these subclones. Several dysregulated genes encoding receptor proteins, endocytosis factors or regulators innate antiviral responses were identified and represent intriguing candidates for to further study molecular mechanisms of H-1PV resistance.

  17. 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

  18. Occupation and adult gliomas in the San Francisco Bay Area.

    PubMed

    Krishnan, Geetha; Felini, Martha; Carozza, Susan E; Miike, Rei; Chew, Terri; Wrensch, Margaret

    2003-06-01

    The etiology of gliomas is not well understood. Some jobs might involve sustained and elevated exposures to carcinogens. This study compares lifetime job histories of 879 glioma cases diagnosed between August 1991 to April 1994 and May 1997 to August 1999 in the San Francisco Bay Area and 864 controls. Logistic analyses compared longest and ever held occupations of 1 year or more for all astrocytic and nonastrocytic cases and controls overall with adjustment for age, gender, and ethnicity and separately for men and women. Two-fold or higher or statistically significant elevated odds ratios were found overall and in men among those with longest held occupations, as firefighters, physicians, material moving equipment operators, and janitors; such elevated odds ratios were also observed for longest-held occupations among male motor vehicle operators and personal service workers and female messengers, legal/social service workers, electronic equipment operators, painters, and food processors. Odds ratios of 0.50 or less, but not statistically significant, were found for those with longest held jobs as writers/journalists, biological scientists, paper workers, mechanics, chemists, and photographers/photoprocessors. This study supports previously observed occupational associations and is one of the few studies with sufficient numbers to separately analyze occupations by gender.

  19. The Role of Hypofractionation Radiotherapy for Diffuse Intrinsic Brainstem Glioma in Children: A Pilot Study

    SciTech Connect

    Janssens, Geert O.R.J. Gidding, Corrie E.M.; Lindert, Erik J. van; Oldenburger, Foppe R.; Erasmus, Corrie E.; Schouten-Meeteren, Antoinette Y.N.; Kaanders, Johannes H.A.M.

    2009-03-01

    Purpose: Most children with a diffuse intrinsic brainstem glioma will die within 1 year after diagnosis. To reduce patient burden, we investigated the feasibility of a radical hypofractionation radiotherapy schedule, given over 3 weeks, as an alternative to the standard regimen (30 fractions over 6 weeks). Methods and Materials: Nine children, ages 3-13, were treated by 13 fractions of 3 Gy (n = 8) or 6 fractions of 5.5 Gy (n = 1) given over 3 weeks. All patients had symptoms for {<=}3 months and {>=}2 signs of the neurologic triad (long tract signs, ataxia, cranial nerve deficit). Bilateral involvement of the pons (n = 8), encasement of the basilar artery (n = 7) and extension into the cerebellar peduncle (n = 6) was visible on magnetic resonance imaging. Results: Symptom improvement occurred in all patients within 2 weeks after start of radiotherapy. At a mean follow-up time of 15 months, 7 patients have died. Median time to progression and overall survival was 4.9 and 8.6 months, respectively. Median time to death after progression was 3.6 months. No Grade 3 or 4 toxicity was observed. In a recently published review of clinical trials, median time to progression, overall survival, and time between progression and death ranged from 5.0-8.8, 7.0-16, and 1.0-4.5 months, respectively, with more aggressive regimens. Conclusion: This radical hypofractionation radiotherapy regimen for children with diffuse intrinsic brainstem glioma is feasible and associated with no Grade 3 or 4 toxicities. With a minimal overall treatment time, it offers quick symptom relief and outcome results within the range of published data.

  20. Olig2 labeling index is correlated with histological and molecular classifications in low-grade diffuse gliomas.

    PubMed

    Suzuki, Aya; Nobusawa, Sumihito; Natsume, Atsushi; Suzuki, Hiromichi; Kim, Young-Ho; Yokoo, Hideaki; Nagaishi, Masaya; Ikota, Hayato; Nakazawa, Takuro; Wakabayashi, Toshihiko; Ohgaki, Hiroko; Nakazato, Yoichi

    2014-11-01

    Diagnosis of low-grade diffuse gliomas based on morphology is highly subjective and, therefore, is often difficult, with significant intra- and interobserver variability. Here, we investigated WHO grade II diffuse astrocytomas, oligoastrocytomas and oligodendrogliomas for immunohistochemical expression of Olig2, measuring its labeling index (LI), and evaluated the significance of Olig2 LI in the histological and molecular classifications. The means of Olig2 LI in glioma cells were 43.7 % in diffuse astrocytomas, 59.3 % in oligoastrocytomas and 76.1 % in oligodendrogliomas. There was a statistically significant difference between all pairs of histological types. The mean of Olig2 LI of gliomas with 1p/19q loss ± IDH1/2 mutation, the majority of them being oligodendrogliomas, was significantly higher than the means of those with TP53 mutation ± IDH1/2 mutation and IDH1/2 mutation only, the majority of which were diffuse astrocytomas (70.1 vs. 47.2 and 46.5 %, respectively). When categorized according to the classification of Jiao et al., Olig2 LI of I-CF gliomas (cases with IDH and one or more of CIC, FUBP1 or combined 1p/19q loss; mean 71.0 %) was significantly higher than that of I-A gliomas (cases with IDH and ATRX alterations; mean 45.3 %). These molecular classifications were reported to correlate well with clinical outcome. However, borderlines of Olig2 LI were broad and could not clearly distinguish genotypes in the molecular classifications. In conclusion, Olig2 LI cannot be taken as a complete surrogate marker for molecular genotype, but could possibly provide some ancillary information when molecular assay is not availabe.

  1. 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.

  2. 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.

  3. 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

  4. Diffusion Weighted MRI and MRS to Differentiate Radiation Necrosis and Recurrent Disease in Gliomas

    NASA Astrophysics Data System (ADS)

    Ewell, Lars

    2006-03-01

    A difficulty encountered in the diagnosis of patients with gliomas is the differentiation between recurrent disease and Radiation Induced Necrosis (RIN). Both can appear as ‘enhancing lesions’ on a typical T2 weighted MRI scan. Magnetic Resonance Spectroscopy (MRS) and Diffusion Weighted MRI (DWMRI) have the potential to be helpful regarding this differentiation. MRS has the ability to measure the concentration of brain metabolites, such as Choline, Creatin and N- Acetyl Aspartate, the ratios of which have been shown to discriminate between RIN and recurrent disease. DWMRI has been linked via a rise in the Apparent Diffusion Coefficient (ADC) to successful treatment of disease. Using both of these complimentary non-invasive imaging modalities, we intend to initiate an imaging protocol whereby we will study how best to combine metabolite ratios and ADC values to obtain the most useful information in the least amount of scan time. We will look for correlations over time between ADC values, and MRS, among different sized voxels.

  5. Microfoci of malignant progression in diffuse low-grade gliomas: towards the creation of an intermediate grade in glioma classification?

    PubMed

    Pedeutour-Braccini, Zoé; Burel-Vandenbos, Fanny; Gozé, Catherine; Roger, Coralie; Bazin, Audrey; Costes-Martineau, Valérie; Duffau, Hugues; Rigau, Valérie

    2015-04-01

    Low-grade gliomas (GII) inescapably progress to high-grade gliomas (GIII). The duration of this transition is highly variable between patients and reliable predictive markers do not exist. We noticed in a subset of cases of GII, obtained by awake neurosurgery, the presence of microfoci with high cellular density, high vascular density, or minimal endothelial proliferation, which we called GII+. Our aim was to investigate whether these foci display immunohistochemical and molecular characteristics similar to GIII and whether their presence is correlated to poor prognosis. We analyzed cell proliferation, hypoxia, vascularization, and alterations of tumorigenic pathways by immunohistochemistry (Ki-67, CD31, HIF-1-alpha, EGFR, P-AKT, P53, MDM2) and fluorescence in situ hybridization (EGFR, MDM2, PDGFRA) in the hypercellular foci of 16 GII+ cases. We compared overall survival between GII, GII+, and GIII. Ki-67, and CD31 expression was higher in the foci than in the tumor background in all cases. Aberrant expression of protein markers and genomic aberrations were also observed in some foci, distinct from the tumor background. Survival was shorter in GII+ than in GII cases. Our results suggest that these foci are the early histological hallmark of anaplastic transformation, which is supported by molecular aberrations. Our study is the first to demonstrate intratumoral morphological, immunohistochemical, and molecular heterogeneity in resection specimens of GII, the presence of which is correlated to shorter survival. Our findings question the discriminative capacity of the current glioma classification and provide arguments in favor of the creation of a grade intermediate between GII and GIII, to optimize the treatment strategy of GII.

  6. Distinction Between Recurrent Glioma and Radiation Injury Using Magnetic Resonance Spectroscopy in Combination With Diffusion-Weighted Imaging

    SciTech Connect

    Zeng, Q.-S. . E-mail: nanwushan@yahoo.com; Li, C.-F.; Liu Hong; Zhen, J.-H.; Feng, D.-C.

    2007-05-01

    Purpose: The aim of this study was to explore the diagnostic effectiveness of magnetic resonance (MR) spectroscopy with diffusion-weighted imaging on the evaluation of the recurrent contrast-enhancing areas at the site of treated gliomas. Methods and Materials: In 55 patients who had new contrast-enhancing lesions in the vicinity of the previously resected and irradiated high-grade gliomas, two-dimensional MR spectroscopy and diffusion-weighted imaging were performed. Spectral data for N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lipid (Lip), and lactate (Lac) were analyzed in conjunction with the apparent diffusion coefficient (ADC) in all patients. Diagnosis of these lesions was assigned by means of follow-up or histopathology. Results: The Cho/NAA and Cho/Cr ratios were significantly higher in recurrent tumor than in regions of radiation injury (p < 0.01). The ADC value and ADC ratios (ADC of contrast-enhancing lesion to matching structure in the contralateral hemisphere) were significantly higher in radiation injury regions than in recurrent tumor (p < 0.01). With MR spectroscopic data, two variables (Cho/NAA and Cho/Cr ratios) were shown to differentiate recurrent glioma from radiation injury, and 85.5% of total subjects were correctly classified into groups. However, with discriminant analysis of MR spectroscopy imaging plus diffusion-weighted imaging, three variables (Cho/NAA, Cho/Cr, and ADC ratio) were identified and 96.4% of total subjects were correctly classified. There was a significant difference between the diagnostic accuracy of the two discriminant analyses (Chi-square = 3.96, p = 0.046). Conclusion: Using discriminant analysis, this study found that MR spectroscopy in combination with ADC ratio, rather than ADC value, can improve the ability to differentiate recurrent glioma and radiation injury.

  7. A glioma classification scheme based on coexpression modules of EGFR and PDGFRA.

    PubMed

    Sun, Yingyu; Zhang, Wei; Chen, Dongfeng; Lv, Yuhong; Zheng, Junxiong; Lilljebjörn, Henrik; Ran, Liang; Bao, Zhaoshi; Soneson, Charlotte; Sjögren, Hans Olov; Salford, Leif G; Ji, Jianguang; French, Pim J; Fioretos, Thoas; Jiang, Tao; Fan, Xiaolong

    2014-03-04

    We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM(low)PM(low) gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM(low)PM(low) gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM(low)PM(low) gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtype-specific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.

  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. Natural history and management of brainstem gliomas in adults. A retrospective Italian study.

    PubMed

    Salmaggi, A; Fariselli, L; Milanesi, I; Lamperti, E; Silvani, A; Bizzi, A; Maccagnano, E; Trevisan, E; Laguzzi, E; Rudà, R; Boiardi, A; Soffietti, R

    2008-02-01

    Brainstem gliomas in adults are rare tumors, with heterogeneous clinical course; only a few studies in the MRI era describe the features in consistent groups of patients. In this retrospective study, we report clinical features at onset, imaging characteristics and subsequent course in a group of 34 adult patients with either histologically proven or clinico-radiologically diagnosed brainstem gliomas followed at two centers in Northern Italy. Of the patients 18 were male, 14 female, with a median age of 31. In 21 of the patients histology was obtained and in 20 it was informative (2 pilocytic astrocytoma, 9 low-grade astrocytoma, 8 anaplastic astrocytoma and 1 glioblastoma). Contrast enhancement at MRI was present in 14 patients. In all of the 9 patients who were investigated with MR spectroscopy, the Cho/NAA ratio was elevated at diagnosis. In 8 of the patients, an initial watch and wait policy was adopted, while 24 were treated shortly after diagnosis with either radiotherapy alone [4] or radiotherapy and chemotherapy [20] (mostly temozolomide). Only minor radiological responses were observed after treatments; in a significant proportion of patients (9 out of 15) clinical improvement during therapy occurred in the context of radiologically (MRI) stable disease. Grade III or IV myelotoxicity was observed in 6 patients. After a follow-up ranging from 9 to 180 months, all but 2 patients have progressed and 14 have died (12 for disease progression, 2 for pulmonary embolism). Median overall survival time was of 59 months. Investigation of putative prognostically relevant parameters showed that a short time between disease onset and diagnosis was related to a shorter survival. Compared with literature data, our study confirms the clinical and radiological heterogeneity of adult brainstem gliomas and underscores the need for multicenter trials in order to assess the efficacy of treatments in these tumors.

  10. Dual Receptor Recognizing Cell Penetrating Peptide for Selective Targeting, Efficient Intratumoral Diffusion and Synthesized Anti-Glioma Therapy

    PubMed Central

    Liu, Yayuan; Mei, Ling; Xu, Chaoqun; Yu, Qianwen; Shi, Kairong; Zhang, Li; Wang, Yang; Zhang, Qianyu; Gao, Huile; Zhang, Zhirong; He, Qin

    2016-01-01

    Cell penetrating peptides (CPPs) were widely used for drug delivery to tumor. However, the nonselective in vivo penetration greatly limited the application of CPPs-mediated drug delivery systems. And the treatment of malignant tumors is usually followed by poor prognosis and relapse due to the existence of extravascular core regions of tumor. Thus it is important to endue selective targeting and stronger intratumoral diffusion abilities to CPPs. In this study, an RGD reverse sequence dGR was conjugated to a CPP octa-arginine to form a CendR (R/KXXR/K) motif contained tandem peptide R8-dGR (RRRRRRRRdGR) which could bind to both integrin αvβ3 and neuropilin-1 receptors. The dual receptor recognizing peptide R8-dGR displayed increased cellular uptake and efficient penetration ability into glioma spheroids in vitro. The following in vivo studies indicated the active targeting and intratumoral diffusion capabilities of R8-dGR modified liposomes. When paclitaxel was loaded in the liposomes, PTX-R8-dGR-Lip induced the strongest anti-proliferation effect on both tumor cells and cancer stem cells, and inhibited the formation of vasculogenic mimicry channels in vitro. Finally, the R8-dGR liposomal drug delivery system prolonged the medium survival time of intracranial C6 bearing mice by 2.1-fold compared to the untreated group, and achieved an exhaustive anti-glioma therapy including anti-tumor cells, anti-vasculogenic mimicry and anti-brain cancer stem cells. To sum up, all the results demonstrated that R8-dGR was an ideal dual receptor recognizing CPP with selective glioma targeting and efficient intratumoral diffusion, which could be further used to equip drug delivery system for effective glioma therapy. PMID:26877777

  11. The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma

    PubMed Central

    Yadavilli, Sridevi; Scafidi, Joseph; Becher, Oren J.; Saratsis, Amanda M.; Hiner, Rebecca L.; Kambhampati, Madhuri; Mariarita, Santi; MacDonald, Tobey J.; Codispoti, Kari-Elise; Magge, Suresh N.; Jaiswal, Jyoti K.; Packer, Roger J.; Nazarian, Javad

    2015-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50). We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG primary tumor cells in vitro. NG2 expression is altered (symmetric segregation) in mitotic human DIPG and mouse tumor cells. These mitotic cells co-express oligodendrocyte (Olig2) and astrocyte (glial fibrillary acidic protein, GFAP) markers, indicating lack of terminal differentiation. NG2 knockdown retards cellular migration in vitro, while NG2 expressing neurospheres are highly tumorigenic in vivo, resulting in rapid growth of pontine tumors. NG2 expression is targetable in vivo using miR129-2 indicating a potential avenue for therapeutic interventions. This data implicates NG2 as a molecule of interest in DIPGs especially those with H3.3 mutation. PMID:25987129

  12. 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

  13. Diffuse low-grade glioma: a review on the new molecular classification, natural history and current management strategies.

    PubMed

    Delgado-López, P D; Corrales-García, E M; Martino, J; Lastra-Aras, E; Dueñas-Polo, M T

    2017-03-02

    The management of diffuse supratentorial WHO grade II glioma remains a challenge because of the infiltrative nature of the tumor, which precludes curative therapy after total or even supratotal resection. When possible, functional-guided resection is the preferred initial treatment. Total and subtotal resections correlate with increased overall survival. High-risk patients (age >40, partial resection), especially IDH-mutated and 1p19q-codeleted oligodendroglial lesions, benefit from surgery plus adjuvant chemoradiation. Under the new 2016 WHO brain tumor classification, which now incorporates molecular parameters, all diffusely infiltrating gliomas are grouped together since they share specific genetic mutations and prognostic factors. Although low-grade gliomas cannot be regarded as benign tumors, large observational studies have shown that median survival can actually be doubled if an early, aggressive, multi-stage and personalized therapy is applied, as compared to prior wait-and-see policy series. Patients need an honest long-term therapeutic strategy that should ideally anticipate neurological, cognitive and histopathologic worsening.

  14. A mechanically coupled reaction-diffusion model that incorporates intra-tumoural heterogeneity to predict in vivo glioma growth.

    PubMed

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

    2017-03-01

    While gliomas have been extensively modelled with a reaction-diffusion (RD) type equation it is most likely an oversimplification. In this study, three mathematical models of glioma growth are developed and systematically investigated to establish a framework for accurate prediction of changes in tumour volume as well as intra-tumoural heterogeneity. Tumour cell movement was described by coupling movement to tissue stress, leading to a mechanically coupled (MC) RD model. Intra-tumour heterogeneity was described by including a voxel-specific carrying capacity (CC) to the RD model. The MC and CC models were also combined in a third model. To evaluate these models, rats (n = 14) with C6 gliomas were imaged with diffusion-weighted magnetic resonance imaging over 10 days to estimate tumour cellularity. Model parameters were estimated from the first three imaging time points and then used to predict tumour growth at the remaining time points which were then directly compared to experimental data. The results in this work demonstrate that mechanical-biological effects are a necessary component of brain tissue tumour modelling efforts. The results are suggestive that a variable tissue carrying capacity is a needed model component to capture tumour heterogeneity. Lastly, the results advocate the need for additional effort towards capturing tumour-to-tissue infiltration.

  15. TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas.

    PubMed

    Zhang, Zhen-Yu; Chan, Aden Ka-Yin; Ding, Xiao-Jie; Qin, Zhi-Yong; Hong, Christopher S; Chen, Ling-Chao; Zhang, Xin; Zhao, Fang-Ping; Wang, Yin; Wang, Yang; Zhou, Liang-Fu; Zhuang, Zhengping; Ng, Ho-Keung; Yan, Hai; Yao, Yu; Mao, Ying

    2015-09-22

    IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery

  16. Fall of the Optical Wall: Freedom from the Tyranny of the Microscope Improves Glioma Risk Stratification.

    PubMed

    Ramaswamy, Vijay; Taylor, Michael D

    2016-02-08

    A recent study uses an integrated genomic approach to identify biologically defined subgroups of adult diffuse glioma. These results further lay the foundation for a pathological classification scheme for gliomas that incorporates both histology and molecular biomarkers, which appears far more robust than the current scheme, based solely on morphology.

  17. Amide Proton Transfer Imaging of Diffuse Gliomas: Effect of Saturation Pulse Length in Parallel Transmission-Based Technique

    PubMed Central

    Hiwatashi, Akio; Keupp, Jochen; Yamashita, Koji; Kikuchi, Kazufumi; Yoshiura, Takashi; Yoneyama, Masami; Kruiskamp, Marijn J.; Sagiyama, Koji; Takahashi, Masaya; Honda, Hiroshi

    2016-01-01

    In this study, we evaluated the dependence of saturation pulse length on APT imaging of diffuse gliomas using a parallel transmission-based technique. Twenty-two patients with diffuse gliomas (9 low-grade gliomas, LGGs, and 13 high-grade gliomas, HGGs) were included in the study. APT imaging was conducted at 3T with a 2-channel parallel transmission scheme using three different saturation pulse lengths (0.5 s, 1.0 s, 2.0 s). The 2D fast spin-echo sequence was used for imaging. Z-spectrum was obtained at 25 frequency offsets from -6 to +6 ppm (step 0.5 ppm). A point-by-point B0 correction was performed with a B0 map. Magnetization transfer ratio (MTRasym) and ΔMTRasym (contrast between tumor and normal white matter) at 3.5 ppm were compared among different saturation lengths. A significant increase in MTRasym (3.5 ppm) of HGG was found when the length of saturation pulse became longer (3.09 ± 0.54% at 0.5 s, 3.83 ± 0.67% at 1 s, 4.12 ± 0.97% at 2 s), but MTRasym (3.5 ppm) was not different among the saturation lengths in LGG. ΔMTRasym (3.5 ppm) increased with the length of saturation pulse in both LGG (0.48 ± 0.56% at 0.5 s, 1.28 ± 0.56% at 1 s, 1.88 ± 0.56% at 2 s and HGG (1.72 ± 0.54% at 0.5 s, 2.90 ± 0.49% at 1 s, 3.83 ± 0.88% at 2 s). In both LGG and HGG, APT-weighted contrast was enhanced with the use of longer saturation pulses. PMID:27227746

  18. Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22

    ClinicalTrials.gov

    2017-01-12

    Glioblastoma Multiforme; Fibrillary Astrocytoma of Brain; Glioma of Brainstem; Anaplastic Astrocytoma; Pilomyxoid Astrocytoma; Mixed Oligodendroglioma-Astrocytoma; Brain Stem Glioma; Diffuse Intrinsic Pontine Glioma

  19. Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas.

    PubMed

    Piunti, Andrea; Hashizume, Rintaro; Morgan, Marc A; Bartom, Elizabeth T; Horbinski, Craig M; Marshall, Stacy A; Rendleman, Emily J; Ma, Quanhong; Takahashi, Yoh-Hei; Woodfin, Ashley R; Misharin, Alexander V; Abshiru, Nebiyu A; Lulla, Rishi R; Saratsis, Amanda M; Kelleher, Neil L; James, C David; Shilatifard, Ali

    2017-02-27

    Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments in vivo with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.

  20. Single- and Multivoxel Proton Spectroscopy in Pediatric Patients With Diffuse Intrinsic Pontine Glioma

    SciTech Connect

    Steffen-Smith, Emilie A.; Venzon, David J.; Bent, Robyn S.; Hipp, Sean J.; Warren, Katherine E.

    2012-11-01

    Purpose: To determine the feasibility of two magnetic resonance spectroscopy (MRS) techniques for treating pediatric patients with diffuse intrinsic pontine gliomas (DIPGs) and to evaluate the relationship of metabolic profiles determined by each technique. Utility of each technique for improving patient management is also discussed. Methods and Materials: Children with DIPG (n = 36) were evaluated using single-voxel spectroscopy (SVS) and magnetic resonance spectroscopic imaging (MRSI) during the same imaging session. Patients were followed longitudinally (n = 150 total studies). Technical feasibility was defined by sufficient water and lipid suppression for detection of metabolites. Correlation of metabolic data obtained by SVS and MRSI was determined using the Spearman rank method. Metabolite ratios, including choline:N-acetyl-aspartate (Cho:NAA) and Cho:creatine (Cho:Cr), were obtained from SVS and MRSI. Results: SVS and MRSI acquisitions were feasible in >90% of studies. Maximum Cho:NAA and Cho:Cr from MRSI analysis were strongly associated with Cho:NAA and Cho:Cr obtained by SVS (r = 0.67 and 0.76, respectively). MRSI Cho:NAA values were more heterogeneous than Cho:Cr values within the same lesion, and a strong linear relationship between the range and maximum Cho:NAA values was observed. Conclusions: SVS and MRSI acquisitions were feasible, with a strong correlation in metabolic data. Both techniques may improve diagnostic evaluation and management of DIPG. SVS is recommended for global assessment of tumor metabolism before and after therapy. MRSI showed heterogeneous patterns of metabolic activity within these tumors and is recommended for planning and monitoring targeted therapies and evaluating nearby tissue for tumor invasion.

  1. Phase I Study of Vandetanib During and After Radiotherapy in Children With Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Broniscer, Alberto; Baker, Justin N.; Tagen, Michael; Onar-Thomas, Arzu; Gilbertson, Richard J.; Davidoff, Andrew M.; Panandiker, Atmaram Pai; Leung, Wing; Chin, Thomas K.; Stewart, Clinton F.; Kocak, Mehmet; Rowland, Christopher; Merchant, Thomas E.; Kaste, Sue C.; Gajjar, Amar

    2010-01-01

    Purpose To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. Patients and Methods Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy. Results Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m2 (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039). Conclusion The recommended phase II dose of vandetanib in children is 145 mg/m2 per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids. PMID:20921456

  2. Prospective Collection of Tissue Samples at Autopsy in Children with Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Broniscer, Alberto; Baker, Justin N.; Baker, Suzanne J.; Chi, Susan N.; Geyer, J. Russell; Morris, E. Brannon; Gajjar, Amar

    2010-01-01

    BACKGROUND Brain tissue obtained at autopsy has been used in research for non-oncological disorders. However, this tool has never been systematically used in large investigational studies for cancer. We conducted a prospective, multicenter study to assess the feasibility of tissue collection at autopsy and its suitability for molecular analyses in children with diffuse intrinsic pontine glioma. METHODS Tumor tissue was collected at diagnosis, if clinically indicated, or at autopsy. Normal brain tissue was also collected at autopsy. The integrity of DNA and RNA was evaluated in all samples. Logistical data about autopsies were recorded. The feasibility of tissue collection at autopsy was assessed for patients treated at a single institution over a 43-month period. RESULTS Tumor samples were collected at diagnosis (n=3) or at autopsy (n=38) at 29 centers across the US; samples were obtained at diagnosis and autopsy in two cases. The median interval from death to autopsy was 7.7 hours. DNA and RNA with minimal or partial degradation, which were suitable for genome-wide analysis, were obtained from 100% and 63% of tumor samples, respectively. At the coordinating institution, approximately 40% of parents consented to autopsy and 40% declined. During the study period, 12 autopsies were obtained from patients who did not receive therapy at the coordinating center. CONCLUSIONS Multicenter, biological studies based on tissue obtained at autopsy are feasible in children with brain cancer. Our experience established a new paradigm for brain tissue collection which may increase the potential for research studies in patients with cancer. PMID:20589749

  3. Immunohistochemical profiles of IDH1, MGMT and P53: practical significance for prognostication of patients with diffuse gliomas.

    PubMed

    Ogura, Ryosuke; Tsukamoto, Yoshihiro; Natsumeda, Manabu; Isogawa, Mizuho; Aoki, Hiroshi; Kobayashi, Tsutomu; Yoshida, Seiichi; Okamoto, Kouichiro; Takahashi, Hitoshi; Fujii, Yukihiko; Kakita, Akiyoshi

    2015-08-01

    Genetic and epigenetic status, including mutations of isocitrate dehydrogenase (IDH) and TP53 and methylation of O(6) -methylguanine-DNA methyltransferase (MGMT), are associated with the development of various types of glioma and are useful for prognostication. Here, using routinely available histology sections from 312 patients with diffuse gliomas, we performed immunohistochemistry using antibodies specific for IDH1 mutation, MGMT methylation status, and aberrant p53 expression to evaluate the possible prognostic significance of these features. With regard to overall survival (OS), univariate analysis indicated that an IDH1-positive profile in patients with glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligoastrocytoma and oligodendroglioma, or a MGMT-negative profile in patients with GBM and AA were significantly associated with a favorable outcome. Multivariate analysis revealed that both profiles were independent factors influencing prognosis. The OS of patients with IDH1-positive/MGMT-negative profiles was significantly longer than that of patients with negative/negative and negative/positive profiles. A p53 profile was not an independent prognostic factor. However, for GBM/AA patients with IDH1-negative/MGMT-negative profiles, p53 overexpression was significantly associated with an unfavorable outcome. Thus, the immunohistochemical profiles of IDH1 and MGMT are of considerable significance in gliomas, and a combination of IDH1, MGMT and p53 profiles may be useful for prognostication of GBM/AA.

  4. An inverse problem formulation for parameter estimation of a reaction-diffusion model of low grade gliomas

    PubMed Central

    Gholami, Amir; Mang, Andreas; Biros, George

    2015-01-01

    We present a numerical scheme for solving a parameter estimation problem for a model of low-grade glioma growth. Our goal is to estimate the spatial distribution of tumor concentration, as well as the magnitude of anisotropic tumor diffusion. We use a constrained optimization formulation with a reaction-diffusion model that results in a system of nonlinear partial differential equations (PDEs). In our formulation, we estimate the parameters using partially observed, noisy tumor concentration data at two different time instances, along with white matter fiber directions derived from diffusion tensor imaging (DTI). The optimization problem is solved with a Gauss-Newton reduced space algorithm. We present the formulation and outline the numerical algorithms for solving the resulting equations. We test the method using synthetic dataset and compute the reconstruction error for different noise levels and detection thresholds for monofocal and multifocal test cases. PMID:25963601

  5. 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

  6. The potential of theragnostic 124I-8H9 convection-enhanced delivery in diffuse intrinsic pontine glioma

    PubMed Central

    Luther, Neal; Zhou, Zhiping; Zanzonico, Pat; Cheung, Nai-Kong; Humm, John; Edgar, Mark A.; Souweidane, Mark M.

    2014-01-01

    Background Reasons for failure in prior human glioma convection-enhanced delivery (CED) clinical trials remain unclear. Concentration-dependent volume of distribution (Vd) measurement of CED-infused agents in the human brain is challenging and highlights a potential technical shortcoming. Activity of iodine isotope 124 (124I ) in tissue can be directly measured in vivo with high resolution via PET. With the potential therapeutic utility of radioimmunotherapy, we postulate 124I conjugated to the antiglioma monoclonal antibody 8H9 may serve as a “theragnostic” agent delivered via CED to diffuse intrinsic pontine glioma. Methods Fifteen rats underwent CED of 0.1–1.0 mCi of 131I-8H9 to the pons for toxicity evaluation. Six additional rats underwent CED of 10 µCi of 124I-8H9 to the pons for dosimetry, with serial microPET performed for 1 week. Two primates underwent CED of gadolinium-albumin and 1.0 mCi of 124I-8H9 to the pons for safety and dosimetry analysis. Serial postoperative PET, blood, and CSF radioactivity counts were performed. Results One rat (1.0 mCi 131I-8H9 infusion) suffered toxicity necessitating early sacrifice. PET analysis in rats yielded a pontine absorbed dose of 37 Gy/mCi. In primates, no toxicity was observed, and absorbed pontine dose was 3.8 Gy/mCi. Activity decreased 10-fold with 48 h following CED in both animal models. Mean Vd was 0.14 cc3 (volume of infusion [Vi] to Vd ratio = 14) in the rat and 6.2 cc3 (Vd/Vi = 9.5) in primate. Conclusion The safety and feasibility of 124I dosimetry following CED via PET is demonstrated, establishing a preclinical framework for a trial evaluating CED of 124I-8H9 for diffuse intrinsic pontine glioma. PMID:24526309

  7. Role of Early Postradiation Magnetic Resonance Imaging Scans in Children With Diffuse Intrinsic Pontine Glioma

    SciTech Connect

    Ko, Christine; Kaushal, Aradhana; Hammoud, Dima A.; Steffen-Smith, Emilie A.; Bent, Robyn; Citrin, Deborah; Camphausen, Kevin; Warren, Katherine E.

    2012-07-15

    Purpose: To determine optimal timing of assessing postradiation radiographic response on magnetic resonance imaging (MRI) scans in pediatric patients with diffuse intrinsic pontine glioma (DIPG). Methods and Materials: Patients were treated on a prospective study at the National Cancer Institute (Protocol no. 06-C-0219) evaluating the effects of radiotherapy (RT). Standard RT was administered in standard fractionation over 6 weeks. Postradiation MRI scans were performed at 2 and 6-8 weeks. Results: Eleven patients with DIPG were evaluated. Median age was 6 years (range, 4-13 years). Patients were treated with external-beam RT to 55.8 Gy (n = 10) or 54 Gy (n = 1), with a gross tumor volume to planning target volume expansion of 1.8-2.0 cm. All patients received prescribed dose and underwent posttreatment MRI scans at 2 and 6-8 weeks. Pretreatment imaging revealed compression of fourth ventricle (n = 11); basilar artery encasement (n = 9); tumor extension outside the pons (n = 11); and tumor hemorrhage (n = 2). At the 2-week scan, basilar artery encasement improved in 7 of 9 patients, and extent of tumor was reduced in 5 of 11 patients. Fourth ventricle compression improved in 6 of 11 patients but worsened in 3 of 11 patients. Presumed necrosis was observed in 5 of 11 patients at 2 weeks and in 1 additional patient at 6-8 weeks. There was no significant difference in mean anteroposterior and transverse diameters of tumor between the 2- and 6-8-week time points. Six of 11 patients had increasing ventricular size, with no evidence of obstruction. Conclusions: There is no significant difference in tumor size of DIPG patients who have received standard RT when measured at 2 weeks vs. 6-8 weeks after RT. The majority of patients had the largest change in tumor size at the 2-week post-RT scan, with evolving changes documented on the 6-8-week scan. Six of 11 patients had progressive ventriculomegaly without obstruction, suggestive of communicating hydrocephalus. To the best

  8. Detection of intracellular lactate with localized diffusion { 1H- 13C}-spectroscopy in rat glioma in vivo

    NASA Astrophysics Data System (ADS)

    Pfeuffer, Josef; Lin, Joseph C.; DelaBarre, Lance; Ugurbil, Kamil; Garwood, Michael

    2005-11-01

    The aim of this study was to compare the diffusion characteristic of lactate and alanine in a brain tumor model to that of normal brain metabolites known to be mainly intracellular such as N-acetylaspartate or creatine. The diffusion of 13C-labeled metabolites was measured in vivo with localized NMR spectroscopy at 9.4 T (400 MHz) using a previously described localization and editing pulse sequence known as ACED-STEAM ('adiabatic carbon editing and decoupling'). 13C-labeled glucose was administered and the apparent diffusion coefficients of the glycolytic products, { 1H- 13C}-lactate and { 1H- 13C}-alanine, were determined in rat intracerebral 9L glioma. To obtain insights into { 1H- 13C}-lactate compartmentation (intra- versus extracellular), the pulse sequence used very large diffusion weighting (50 ms/μm 2). Multi-exponential diffusion attenuation of the lactate metabolite signals was observed. The persistence of a lactate signal at very large diffusion weighting provided direct experimental evidence of significant intracellular lactate concentration. To investigate the spatial distribution of lactate and other metabolites, 1H spectroscopic images were also acquired. Lactate and choline-containing compounds were consistently elevated in tumor tissue, but not in necrotic regions and surrounding normal-appearing brain. Overall, these findings suggest that lactate is mainly associated with tumor tissue and that within the time-frame of these experiments at least some of the glycolytic product ([ 13C] lactate) originates from an intracellular compartment.

  9. Early Detection of Malignant Transformation in Resected WHO II Low-Grade Glioma Using Diffusion Tensor-Derived Quantitative Measures

    PubMed Central

    Freitag, Martin T.; Maier-Hein, Klaus H.; Binczyk, Francisczek; Laun, Frederik B.; Weber, Christian; Bonekamp, David; Tarnawski, Rafal; Bobek-Billewicz, Barbara; Polanska, Joanna; Majchrzak, Henryk; Stieltjes, Bram

    2016-01-01

    Objective Here, we retrospectively investigate the value of voxel-wisely plotted diffusion tensor-derived (DTI) axial, radial and mean diffusivity for the early detection of malignant transformation (MT) in WHO II glioma compared to contrast-enhanced images. Materials and Methods Forty-seven patients underwent brain magnetic resonance imaging follow-up between 2006–2014 after gross-tumor resection of intra-axial WHO II glioma. Axial/Mean/Radial diffusivity maps (AD/MD/RD) were generated from DTI data. ADmin/MDmin/RDmin values were quantified within tumor regions-of-interest generated by two independent readers including tumor contrast-to-noise (CNR). Sensitivity/specificity and area-under-the-curve (AUC) were calculated using receiver-operating-characteristic analysis. Inter-reader agreement was assessed (Cohen’s kappa). Results Eighteen patients demonstrated malignant transformation (MT) confirmed in 8/18 by histopathology and in 10/18 through imaging follow-up. Twelve of 18 patients (66.6%) with MT showed diffusion restriction timely coincidental with contrast-enhancement (CE). In the remaining six patients (33.3%), the diffusion restriction preceded the CE. The mean gain in detection time using DTI was (0.8±0.5 years, p = 0.028). Compared to MDmin and RDmin, ROC-analysis showed best diagnostic value for ADmin (sensitivity/specificity 94.94%/89.7%, AUC 0.96; p<0.0001) to detect MT. CNR was highest for AD (1.83±0.14), compared to MD (1.31±0.19; p<0.003) and RD (0.90±0.23; p<0.0001). Cohen’s Kappa was 0.77 for ADmin, 0.71 for MDmin and 0.65 for RDmin (p<0.0001, respectively). Conclusion MT is detectable at the same time point or earlier compared to T1w-CE by diffusion restriction in diffusion-tensor-derived maps. AD demonstrated highest sensitivity/specificity/tumor-contrast compared to radial or mean diffusivity (= apparent diffusion coefficient) to detect MT. PMID:27741525

  10. Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas

    PubMed Central

    Weston, Cody; Weston, Jennifer; Connor, James; Toms, Steven A.; Marko, Nicholas F.

    2016-01-01

    Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue. Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in cancer pathophysiology. We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with World Health Organization Grade II-III gliomas. Using a feature selection algorithm we identified a novel, optimized subset of eight iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, UROS, SLC11A2, and STEAP4) whose differential expression defines two phenotypic groups with median survival differences of 52.3 months for patients with grade II gliomas (25.9 vs. 78.2 months, p< 10−3), 43.5 months for patients with grade III gliomas (43.9 vs. 87.4 months, p = 0.025), and 54.0 months when considering both grade II and III gliomas (79.9 vs. 25.9 months, p < 10−5). PMID:27898674

  11. Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas.

    PubMed

    Weston, Cody; Klobusicky, Joe; Weston, Jennifer; Connor, James; Toms, Steven A; Marko, Nicholas F

    2016-01-01

    Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue. Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in cancer pathophysiology. We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with World Health Organization Grade II-III gliomas. Using a feature selection algorithm we identified a novel, optimized subset of eight iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, UROS, SLC11A2, and STEAP4) whose differential expression defines two phenotypic groups with median survival differences of 52.3 months for patients with grade II gliomas (25.9 vs. 78.2 months, p< 10-3), 43.5 months for patients with grade III gliomas (43.9 vs. 87.4 months, p = 0.025), and 54.0 months when considering both grade II and III gliomas (79.9 vs. 25.9 months, p < 10-5).

  12. 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

  13. 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.

  14. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT.

    PubMed

    Pekmezci, Melike; Rice, Terri; Molinaro, Annette M; Walsh, Kyle M; Decker, Paul A; Hansen, Helen; Sicotte, Hugues; Kollmeyer, Thomas M; McCoy, Lucie S; Sarkar, Gobinda; Perry, Arie; Giannini, Caterina; Tihan, Tarik; Berger, Mitchel S; Wiemels, Joseph L; Bracci, Paige M; Eckel-Passow, Jeanette E; Lachance, Daniel H; Clarke, Jennifer; Taylor, Jennie W; Luks, Tracy; Wiencke, John K; Jenkins, Robert B; Wrensch, Margaret R

    2017-03-02

    The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05-7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17-0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27-0.87), p = 0.02). Thus, we present evidence that in

  15. Involvement of the neural stem cell compartment by pediatric and adult gliomas: a retrospective review of 377 cases.

    PubMed

    Marsh, James C; Goldman, Stewart; Ziel, Ellis; Bregman, Corey; Diaz, Aidnag; Byrne, Richard; Fangusaro, Jason

    2015-03-01

    To assess frequency of neural stem cell compartment (NSC) involvement in adult and pediatric gliomas [World Health Organization (WHO) grades 1-4], and to assess whether NSC involvement at presentation impacts on survival, recurrence rates, and/or transformation from low grade (WHO grade 1-2) to high grade disease (WHO grades 3-4). Cranial MRIs for 154 pediatric and 223 adult glioma patients treated from 2000 to 2012 were reviewed. NSC involvement was documented. Tumors were stratified by age (adult vs. pediatric), histology, tumor grade, tumor location, and involvement of midline structures. Odds ratios (OR) for death were calculated based on NSC status at presentation. Rates of transformation and recurrence rates (ORR) were compared using Fisher's Exact Test. Time to recurrence (TTR) was calculated using student t test. Among recurrent and transformed tumors, we also assessed the rate of NSC involvement at time of recurrence or transformation. 74.8 % of tumors had NSC involvement. Higher rates of NSC involvement were seen among adult (p = .0001); high grade (p = .0001)); grade 2 versus grade 1 (p = .0001) and other grade 1 histologies (p = .0001) versus JPA (juvenile pilocytic astrocytoma) patients); grade 2-4 tumors (p = .0001); and supratentorial tumors (p < .0001). No transformation was noted among pediatric low grade tumors or adult grade 1 tumors. 22/119 (18.5 %) adult grade 2 tumors transformed. Rates of transformation were not impacted by NSC status (p = .47). ORR was 15.1 %, and was greater for NSC+ tumors at presentation (p = .05). 36/41 recurrences (87.8 %) involved NSC at time of recurrence. OR for death was 2.62 (1.16-5.9), p = .02 for NSC+ tumors at presentation. Adult and pediatric gliomas (all grades) frequently involve NSC at presentation, although rates are lower in pediatric JPA and all infratentorial tumors. NSC involvement at presentation increases OR death and reduces TTR for pediatric gliomas (all grades) and adult low grade gliomas, and

  16. 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)

  17. Therapeutic Targeting of Histone Modifications in Adult and Pediatric High-Grade Glioma

    PubMed Central

    Williams, Maria J.; Singleton, Will G. B.; Lowis, Stephen P.; Malik, Karim; Kurian, Kathreena M.

    2017-01-01

    Recent exciting work partly through The Cancer Genome Atlas has implicated epigenetic mechanisms including histone modifications in the development of both pediatric and adult high-grade glioma (HGG). Histone lysine methylation has emerged as an important player in regulating gene expression and chromatin function. Lysine (K) 27 (K27) is a critical residue in all seven histone 3 variants and the subject of posttranslational histone modifications, as it can be both methylated and acetylated. In pediatric HGG, two critical single-point mutations occur in the H3F3A gene encoding the regulatory histone variant H3.3. These mutations occur at lysine (K) 27 (K27M) and glycine (G) 34 (G34R/V), both of which are involved with key regulatory posttranscriptional modifications. Therefore, these mutations effect gene expression, cell differentiation, and telomere maintenance. In recent years, alterations in histone acetylation have provided novel opportunities to explore new pharmacological targeting, with histone deacetylase (HDAC) overexpression reported in high-grade, late-stage proliferative tumors. HDAC inhibitors have shown promising therapeutic potential in many malignancies. This review focuses on the epigenetic mechanisms propagating pediatric and adult HGGs, as well as summarizing the current advances in clinical trials using HDAC inhibitors.

  18. An image-driven parameter estimation problem for a reaction-diffusion glioma growth model with mass effects

    PubMed Central

    Hogea, Cosmina; Davatzikos, Christos; Biros, George

    2010-01-01

    We present a framework for modeling gliomas growth and their mechanical impact on the surrounding brain tissue (the so-called, mass-effect). We employ an Eulerian continuum approach that results in a strongly coupled system of nonlinear Partial Differential Equations (PDEs): a reaction-diffusion model for the tumor growth and a piecewise linearly elastic material for the background tissue. To estimate unknown model parameters and enable patient-specific simulations we formulate and solve a PDE-constrained optimization problem. Our two main goals are the following: (1) to improve the deformable registration from images of brain tumor patients to a common stereotactic space, thereby assisting in the construction of statistical anatomical atlases; and (2) to develop predictive capabilities for glioma growth, after the model parameters are estimated for a given patient. To our knowledge, this is the first attempt in the literature to introduce an adjoint-based, PDE-constrained optimization formulation in the context of image-driven modeling spatio-temporal tumor evolution. In this paper, we present the formulation, and the solution method and we conduct 1D numerical experiments for preliminary evaluation of the overall formulation/methodology. PMID:18026731

  19. New concepts in the management of diffuse low-grade glioma: Proposal of a multistage and individualized therapeutic approach

    PubMed Central

    Duffau, Hugues; Taillandier, Luc

    2015-01-01

    Diffuse low-grade glioma grows, migrates along white matter tracts, and progresses to high-grade glioma. Rather than a “wait and see” policy, an aggressive attitude is now recommended, with early surgery as the first therapy. Intraoperative mapping, with maximal resection according to functional boundaries, is associated with a longer overall survival (OS) while minimizing morbidity. However, most studies have investigated the role of only one specific treatment (surgery, radiotherapy, chemotherapy) without taking a global view of managing the cumulative time while preserving quality of life (QoL) versus time to anaplastic transformation. Our aim is to switch towards a more holistic concept based upon the anticipation of a personalized and long-term multistage therapeutic approach, with online adaptation of the strategy over the years using feedback from clinical, radiological, and histomolecular monitoring. This dynamic strategy challenges the traditional approach by proposing earlier therapy, by repeating treatments, and by reversing the classical order of therapies (eg, neoadjuvant chemotherapy when maximal resection is impossible, no early radiotherapy) to improve OS and QoL. New individualized management strategies should deal with the interactions between the course of this chronic disease, reaction brain remapping, and oncofunctional modulation elicited by serial treatments. This philosophy supports a personalized, functional, and preventive neuro-oncology. PMID:25087230

  20. Proceedings of the diffuse intrinsic pontine glioma (DIPG) Toronto Think Tank: advancing basic and translational research and cooperation in DIPG.

    PubMed

    Bartels, Ute; Hawkins, Cynthia; Vézina, Gilbert; Kun, Larry; Souweidane, Mark; Bouffet, Eric

    2011-10-01

    Diffuse intrinsic pontine glioma (DIPG) nearly exclusively affects children. The prognosis of DIPGs has remained grim despite more than three decades of clinical research and numerous clinical trials. More than 90% of the children with DIPG will succumb within 2 years of diagnosis. The tumor's incidence is still undefined, but data suggest 100-150 affected children annually in the US. The single proven effective treatment modality in DIPG remains radiation therapy. For the majority of patients however this treatment is only of transient effectiveness. Recent breakthroughs in the understanding of the molecular biology of DIPG have raised new hope and opened new avenues for therapeutic options. The advancement of basic and translational research and cooperation was the objective of the Toronto Think Tank, as new approaches are urgently needed.

  1. EPB41L3, TSP-1 and RASSF2 as new clinically relevant prognostic biomarkers in diffuse gliomas

    PubMed Central

    Perez-Janices, Noemi; Blanco-Luquin, Idoia; Tuñón, Maria Teresa; Barba-Ramos, Edurne; Ibáñez, Berta; Zazpe-Cenoz, Idoya; Martinez-Aguillo, Maria Teresa; Hernandez, Berta; Martínez-Lopez, Enrique; Fernández, Agustin F.; Mercado, Maria Roasario; Cabada, Teresa; Escors, David; Megias, Diego; Guerrero-Setas, David

    2015-01-01

    Hypermethylation of tumor suppressor genes is one of the hallmarks in the progression of brain tumors. Our objectives were to analyze the presence of the hypermethylation of EPB41L3, RASSF2 and TSP-1 genes in 132 diffuse gliomas (astrocytic and oligodendroglial tumors) and in 10 cases of normal brain, and to establish their association with the patients’ clinicopathological characteristics. Gene hypermethylation was analyzed by methylation-specific-PCR and confirmed by pyrosequencing (for EPB41L3 and TSP-1) and bisulfite-sequencing (for RASSF2). EPB41L3, RASSF2 and TSP-1 genes were hypermethylated only in tumors (29%, 10.6%, and 50%, respectively), confirming their cancer-specific role. Treatment of cells with the DNA-demethylating-agent 5-aza-2′-deoxycytidine restores their transcription, as confirmed by quantitative-reverse-transcription-PCR and immunofluorescence. Immunohistochemistry for EPB41L3, RASSF2 and TSP-1 was performed to analyze protein expression; p53, ki-67, and CD31 expression and 1p/19q co-deletion were considered to better characterize the tumors. EPB41L3 and TSP-1 hypermethylation was associated with worse (p = 0.047) and better (p = 0.037) prognosis, respectively. This observation was confirmed after adjusting the results for age and tumor grade, the role of TSP-1 being most pronounced in oligodendrogliomas (p = 0.001). We conclude that EPB41L3, RASSF2 and TSP-1 genes are involved in the pathogenesis of diffuse gliomas, and that EPB41L3 and TSP-1 hypermethylation are of prognostic significance. PMID:25621889

  2. Resecting diffuse low-grade gliomas to the boundaries of brain functions: a new concept in surgical neuro-oncology.

    PubMed

    Duffau, H

    2015-12-01

    The traditional dilemma making surgery for diffuse low-grade gliomas (DLGGs) challenging is underlain by the need to optimize tumor resection in order to significantly increase survival versus the risk of permanent neurological morbidity. Development of neuroimaging led neurosurgeons to achieve tumorectomy according to the oncological limits provided by preoperative or intraoperative structural and metabolic imaging. However, this principle is not coherent, neither with the infiltrative nature of DLGGs nor with the limited resolution of current neuroimaging. Indeed, despite technical advances, MRI still underestimates the actual spatial extent of gliomas, since tumoral cells are present several millimeters to centimeters beyond the area of signal abnormalities. Furthermore, cortical and subcortical structures may be still crucial for brain functions despite their invasion by this diffuse tumoral disease. Finally, the lack of reliability of functional MRI has also been demonstrated. Therefore, to talk about "maximal safe resection" based upon neuroimaging is a non-sense, because oncological MRI does not show the tumor and functional MRI does not show critical neural pathways. This review proposes an original concept in neuro-oncological surgery, i.e. to resect DLGG to the boundaries of brain functions, thanks to intraoperative electrical mapping performed in awake patients. This paradigmatic shift from image-guided resection to functional mapping-guided resection, based upon an accurate study of brain connectomics and neuroplasticity in each patient throughout tumor removal has permitted to solve the classical dilemma, by increasing both survival and quality of life in DLGG patients. With this in mind, brain surgeons should also be neuroscientists.

  3. The nature and timing of specific copy number changes in the course of molecular progression in diffuse gliomas: further elucidation of their genetic "life story".

    PubMed

    Jeuken, Judith W M; Sijben, Angelique; Bleeker, Fonnet E; Boots-Sprenger, Sandra H E; Rijntjes, Jos; Gijtenbeek, Johanna M M; Mueller, Wolf; Wesseling, Pieter

    2011-05-01

    Up till now, typing and grading of diffuse gliomas is based on histopathological features. However, more objective tools are needed to improve reliable assessment of their biological behavior. We evaluated 331 diffuse gliomas for copy number changes involving 1p, 19q, CDKN2A, PTEN and EGFR(vIII) by Multiplex Ligation-dependent Probe Amplification (MLPA®, Amsterdam, The Netherlands). Specifically based on the co-occurrence of these aberrations we built a model for the timing of the different events and their exact nature (hemi- → homozygous loss; low-level gain → (high-copy) amplification) in the course of molecular progression. The mutation status of IDH1 and TP53 was also evaluated and shown to correlate with the level of molecular progression. The relevance of the proposed model was confirmed by analysis of 36 sets of gliomas and their 39 recurrence(s) whereas survival analysis for anaplastic gliomas confirmed the actual prognostic relevance of detecting molecular malignancy. Moreover, based on our results, molecular diagnostic analysis of 1p/19q can be further improved as different aberrations were identified, some of them being indicative for advanced molecular malignancy rather than for favorable tumor behavior. In conclusion, identification of molecular malignancy as proposed will aid in establishing a risk profile for individual patients and thereby in therapeutic decision making.

  4. Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models

    PubMed Central

    Olaciregui, Nagore G.; Barton, Kelly L.; Ehteda, Anahid; Chitranjan, Arjanna; Chang, Cecilia; Gifford, Andrew J.; Tsoli, Maria; Ziegler, David S.; Carcaboso, Angel M.; Becher, Oren J.

    2017-01-01

    Background Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. Methods A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. Results In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Conclusion Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation. PMID

  5. Towards Building Computerized Image Analysis Framework for Nucleus Discrimination in Microscopy Images of Diffuse Glioma

    PubMed Central

    Kong, Jun; Cooper, Lee; Kurc, Tahsin; Brat, Daniel; Saltz, Joel

    2012-01-01

    As an effort to build an automated and objective system for pathologic image analysis, we present, in this paper, a computerized image processing method for identifying nuclei, a basic biological unit of diagnostic utility, in microscopy images of glioma tissue samples. The complete analysis includes multiple processing steps, involving mode detection with color and spatial information for pixel clustering, background normalization leveraging morphological operations, boundary refinement with deformable models, and clumped nuclei separation using watershed. In aggregate, our validation dataset includes 220 nuclei from 11 distinct tissue regions selected at random by an experienced neuropathologist. Computerized nuclei detection results are in good concordance with human markups by both visual appraisement and quantitative measures. We compare the performance of the proposed analysis algorithm with that of CellProfiler, a classical analysis software for cell image process, and present the superiority of our method to CellProfiler. PMID:22255853

  6. 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

  7. Treatment of Adult Lower-Grade Glioma in the Era of Genomic Medicine.

    PubMed

    Chang, Susan M; Cahill, Daniel P; Aldape, Kenneth D; Mehta, Minesh P

    2016-01-01

    By convention, gliomas are histopathologically classified into four grades by the World Health Organization (WHO) legacy criteria, in which increasing grade is associated with worse prognosis and grades also are subtyped by presumed cell of origin. This classification has prognostic value but is limited by wide variability of outcome within each grade, so the classification is rapidly undergoing dramatic re-evaluation in the context of a superior understanding of the biologic heterogeneity and molecular make-up of these tumors, such that we now recognize that some low-grade gliomas behave almost like malignant glioblastoma, whereas other anaplastic gliomas have outcomes comparable to favorable low-grade gliomas. This clinical spectrum is partly accounted for by the dispersion of several molecular genetic alterations inherent to clinical tumor behavior. These molecular biomarkers have become important not only as prognostic factors but also, more critically, as predictive markers to drive therapeutic decision making. Some of these, in the near future, will likely also serve as potential therapeutic targets. In this article, we summarize the key molecular features of clinical significance for WHO grades II and III gliomas and underscore how the therapeutic landscape is changing.

  8. Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era

    PubMed Central

    Perry, Christina; Agarwal, Devika; Abdel-Fatah, Tarek M.A.; Lourdusamy, Anbarasu; Grundy, Richard; Auer, Dorothee T.; Walker, David; Lakhani, Ravi; Scott, Ian S.; Chan, Stephen; Ball, Graham; Madhusudan, Srinivasan

    2014-01-01

    Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in ‘The Cancer Genome Atlas’ (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 and low PTEN remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas. PMID:25026297

  9. 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.

  10. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas.

    PubMed

    Olar, Adriana; Wani, Khalida M; Alfaro-Munoz, Kristin D; Heathcock, Lindsey E; van Thuijl, Hinke F; Gilbert, Mark R; Armstrong, Terri S; Sulman, Erik P; Cahill, Daniel P; Vera-Bolanos, Elizabeth; Yuan, Ying; Reijneveld, Jaap C; Ylstra, Bauke; Wesseling, Pieter; Aldape, Kenneth D

    2015-04-01

    Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II-III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91-1.61] compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95-3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p < 0.0001, HR = 4.41, 95 % CI = 2.55-7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.5157, HR = 1.10, 95 % CI = 0.80-1.51), and could demonstrate a statistical interaction (p < 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II-III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II-III gliomas as independent entities.

  11. Dietary factors and the risk of glioma in adults: results of a case-control study in Melbourne, Australia.

    PubMed

    Giles, G G; McNeil, J J; Donnan, G; Webley, C; Staples, M P; Ireland, P D; Hurley, S F; Salzberg, M

    1994-11-01

    In a population-based case-control study of 416 incident gliomas in adults carried out in Melbourne, Australia, between 1987 and 1991, 409 age-sex-matched case-control pairs (243 male and 166 female) had adequate data available to examine associations between the dietary intake of N-nitroso compounds, N-nitroso precursors, other nutrients including N-nitroso inhibitors, and the risk of glioma. Dietary intakes were based on the reported frequency of consumption of 59 food items. Increased odds ratio (OR) were observed in males who consumed high levels of bacon, corned meats, apples, melons and oil. OR less than unity were observed in men consuming cabbage and cola drinks, and in women who consumed wholegrain bread, pasta, corned meat, bananas, cauliflower, brocoli, cola drinks and nuts. Generally, N-nitroso associations were greater in men and micronutrient associations were greater in women. Elevated OR in men, but not women, were associated with the intake of N-nitroso dimethylamine (NDMA), retinol and vitamin E. The intake of nitrate (largely of vegetable origin) was protective in women but not in men. When analyzed using multiple logistic regression, the association with NDMA intake in males was not modified by dietary micronutrient intakes. In females, beta carotene alone, though not directly associated with risk, modified the effect of NDMA. On balance, this study added only limited support to the N-nitroso hypothesis of glial carcinogenesis.

  12. Hypofractionation vs Conventional Radiation Therapy for Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Matched-Cohort Analysis

    SciTech Connect

    Janssens, Geert O.; Jansen, Marc H.; Nowak, Peter J.; Oldenburger, Foppe R.; Bouffet, Eric; Kamphuis-van Ulzen, Karin; Lindert, Erik J. van; Schieving, Jolanda H.; Boterberg, Tom; Kaspers, Gertjan J.; Gidding, Corrie E.; Hargrave, Darren

    2013-02-01

    Purpose: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. Methods and Materials: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptoms for {<=}3 months, {>=}2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. Results: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. Conclusions: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.

  13. Prospective Evaluation of Radiotherapy With Concurrent and Adjuvant Temozolomide in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

    SciTech Connect

    Jalali, Rakesh; Raut, Nirmal; Arora, Brijesh; Gupta, Tejpal; Dutta, Debnarayan; Munshi, Anusheel; Sarin, Rajiv; Kurkure, Purna

    2010-05-01

    Purpose: To present outcome data in a prospective study of radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ) in children with diffuse intrinsic pontine gliomas (DIPGs). Methods and Materials: Pediatric patients with newly diagnosed DIPGs were prospectively treated with focal RT to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m{sup 2}, Days 1-42). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m{sup 2}, Days 1-5) was given every 28 days to a maximum of 12 cycles. Response was evaluated clinically and radiologically with magnetic resonance imaging and positron emission tomography scans. Results: Between March 2005 and November 2006, 20 children (mean age, 8.3 years) were accrued. Eighteen patients have died from disease progression, one patient is alive with progressive disease, and one patient is alive with stable disease. Median overall survival and progression-free survival were 9.15 months and 6.9 months, respectively. Grade III/IV toxicity during the concurrent RT-TMZ phase included thrombocytopenia in 3 patients, leucopenia in 2, and vomiting in 7. Transient Grade II skin toxicity developed in the irradiated fields in 18 patients. During the adjuvant TMZ phase, Grade III/IV leucopenia developed in 2 patients and Grade IV thrombocytopenia in 1 patient. Patients with magnetic resonance imaging diagnosis of a high-grade tumor had worse survival than those with a low-grade tumor (p = 0.001). Patients with neurologic improvement after RT-TMZ had significantly better survival than those who did not (p = 0.048). Conclusions: TMZ with RT has not yielded any improvement in the outcome of DIPG compared with RT alone. Further clinical trials should explore novel treatment modalities.

  14. Two Unique Glioma Subtypes Revealed.

    PubMed

    Poh, Alissa

    2016-04-01

    A comprehensive analysis of 1,122 diffuse glioma samples from The Cancer Genome Atlas has revealed two new subtypes of this common brain cancer, with molecular and clinical features that diverge from the norm. The study findings also support the use of DNA methylation profiles to improve glioma classification and treatment.

  15. High-Grade Glioma of the Ventrolateral Medulla in an Adult: Case Presentation and Discussion of Surgical Considerations

    PubMed Central

    Spurgeon, Angela; Le, Viet; Konakondla, Sanjay; Miller, Douglas C.; Hopkins, Tamera; Litofsky, N. Scott

    2016-01-01

    Background. High-grade gliomas of the brainstem are rare in adults and are particularly rare in the anterolateral medulla. We describe an illustrative case and discuss the diagnostic and treatment issues associated with a tumor in this location, including differential diagnosis, anatomical considerations for options for surgical management, multimodality treatment, and prognosis. Case Description. A 69-year-old woman presented with a 3-week history of progressive right lower extremity weakness. She underwent an open biopsy via a far lateral approach with partial condylectomy, which revealed a glioblastoma. Concurrent temozolomide and radiation were completed; however, she elected to stop her chemotherapy after 5.5 weeks of treatment. She succumbed to her disease 11 months after diagnosis. Conclusions. Biopsy can be performed relatively safely to provide definitive diagnosis to guide treatment, but long-term prognosis is poor. PMID:27242937

  16. 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

  17. Parametric Response Mapping of Apparent Diffusion Coefficient (ADC) as an Imaging Biomarker to Distinguish Pseudoprogression from True Tumor Progression In Peptide-Based Vaccine Therapy for Pediatric Diffuse Instrinsic Pontine Glioma

    PubMed Central

    Ceschin, Rafael; Kurland, Brenda F.; Abberbock, Shira R.; Ellingson, Benjamin M.; Okada, Hideho; Jakacki, Regina I.; Pollack, Ian F.; Panigrahy, Ashok

    2015-01-01

    Background and Purpose Immune response to cancer therapy may result in pseudoprogression, which can only be identified retrospectively and which may disrupt an effective therapy. This study assesses whether serial parametric response mapping (PRM, a voxel-by-voxel method of image analysis also known as functional diffusion mapping) analysis of ADC measurements following peptide-based vaccination may help prospectively distinguish progression from pseudoprogression in pediatric patients with diffuse intrinsic pontine gliomas. Materials and Methods From 2009–2012, 21 children age 4–18 with diffuse intrinsic pontine gliomas were enrolled in a serial peptide-based vaccination protocol following radiotherapy. DWI was acquired before immunotherapy and at six week intervals during vaccine treatment. Pseudoprogression was identified retrospectively based on clinical and radiographic findings, excluding DWI. Parametric response mapping was used to analyze 96 scans, comparing ADC measures at multiple time points (from first vaccine to up to 12 weeks after the vaccine was halted) to pre-vaccine baseline values. Log-transformed fractional increased ADC (fiADC), fractional decreased ADC (fdADC), and parametric response mapping ratio (fiADC/fdADC) were compared between patients with and without pseudoprogression, using generalized estimating equations with inverse weighting by cluster size. Results Median survival was 13.1 months from diagnosis (range 6.4–24.9 months). Four of 21 children (19%) were assessed as experiencing pseudoprogression. Patients with pseudoprogression had higher fitted average log-transformed parametric response mapping ratios (p=0.01) and fiADCs (p=0.0004), compared to patients without pseudoprogression. Conclusion Serial parametric response mapping of ADC, performed at multiple time points of therapy, may distinguish pseudoprogression from true progression in patients with diffuse intrinsic pontine gliomas treated with peptide-based vaccination

  18. The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma.

    PubMed

    Michalski, Antony; Bouffet, Eric; Taylor, Roger E; Hargrave, Darren; Walker, David; Picton, Susan; Robinson, Kathryn; Pizer, Barry; Bujkiewicz, Sylwia

    2010-10-01

    The study aimed to examine the tolerability of the combination of radiotherapy and tamoxifen and the effect on median and event free survival as well as collecting data on the use of steroids in this population. 31 patients with diffuse intrinsic pontine glioma, diagnosed on clinical and radiological criteria, were treated with high-dose oral tamoxifen (120 mg/m(2)/day) given concomitantly with standard dose radiotherapy (54 Gy in 1.8 Gy fractions over 6 weeks). Results Tamoxifen was well tolerated with no grade 3 or 4 CTC toxicity reported. At 1 year, the progression free and event free survival were 3.2% (95% CI: 0.2-14.1%), and at 6 months 19.4% (CI: 7.9% to 34.6%). The overall survival at 1 year was 16.1% (CI: 5.9-30.9%) with median survival 6.32 months. In this study, in which tamoxifen was used in conjunction with radiotherapy, progression free survival was shown to be less good when compared with historical data HR = 3.1 (CI: 1.7-5.7). There was no significant reduction in overall survival. The addition of high-dose tamoxifen, although well tolerated, confers no clinical benefit to patients treated with diffuse intrinsic pontine glioma treated with standard radiotherapy.

  19. Recovery of functional connectivity of the sensorimotor network after surgery for diffuse low-grade gliomas involving the supplementary motor area.

    PubMed

    Vassal, Matthieu; Charroud, Céline; Deverdun, Jérémy; Le Bars, Emmanuelle; Molino, François; Bonnetblanc, Francois; Boyer, Anthony; Dutta, Anirban; Herbet, Guillaume; Moritz-Gasser, Sylvie; Bonafé, Alain; Duffau, Hugues; de Champfleur, Nicolas Menjot

    2017-04-01

    OBJECTIVE The supplementary motor area (SMA) syndrome is a well-studied lesional model of brain plasticity involving the sensorimotor network. Patients with diffuse low-grade gliomas in the SMA may exhibit this syndrome after resective surgery. They experience a temporary loss of motor function, which completely resolves within 3 months. The authors used functional MRI (fMRI) resting state analysis of the sensorimotor network to investigate large-scale brain plasticity between the immediate postoperative period and 3 months' follow-up. METHODS Resting state fMRI was performed preoperatively, during the immediate postoperative period, and 3 months postoperatively in 6 patients with diffuse low-grade gliomas who underwent partial surgical excision of the SMA. Correlation analysis within the sensorimotor network was carried out on those 3 time points to study modifications of its functional connectivity. RESULTS The results showed a large-scale reorganization of the sensorimotor network. Interhemispheric connectivity was decreased in the postoperative period, and increased again during the recovery process. Connectivity between the lesion side motor area and the contralateral SMA rose to higher values than in the preoperative period. Intrahemispheric connectivity was decreased during the immediate postoperative period and had returned to preoperative values at 3 months after surgery. CONCLUSIONS These results confirm the findings reported in the existing literature on the plasticity of the SMA, showing large-scale modifications of the sensorimotor network, at both inter- and intrahemispheric levels. They suggest that interhemispheric connectivity might be a correlate of SMA syndrome recovery.

  20. 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

  1. Prognostic significance of IDH mutation in adult low-grade gliomas: a meta-analysis.

    PubMed

    Sun, Hairui; Yin, Lianhu; Li, Showwei; Han, Song; Song, Guangrong; Liu, Ning; Yan, Changxiang

    2013-06-01

    Mutations in the gene encoding isocitrate dehydrogenase (IDH) have been identified in approximately 65-90 % of low-grade gliomas (LGGs). Various studies examining the relationship between IDH mutation with the clinical outcome in patients with LGGs have yielded inconclusive results. The purpose of the present meta-analysis of literature is to determine this effect. We conducted a meta-analysis of 10 studies (937 patients) that evaluated the correlation between IDH mutation and overall survival (OS). For the quantitative aggregation of the survival results, the IDH mutation effect was measured by hazard ratio (HR). Overall, the pooled HR was 0.585 (95 % CI, 0.376-0.911, p = 0.025, random effect model) for patients with IDH mutation vs patients without IDH mutation. IDH mutation was associated with better overall survival of LGGs. At least this trend was observed in our analysis.

  2. Reference values for pulmonary diffusing capacity for adult native Finns.

    PubMed

    Kainu, Annette; Toikka, Jyri; Vanninen, Esko; Timonen, Kirsi L

    2017-04-01

    Measurement standards for pulmonary diffusing capacity were updated in 2005 by the ATS/ERS Task Force. However, in Finland reference values published in 1982 by Viljanen et al. have been used to date. The main aim of this study was to produce updated reference models for single-breath diffusing capacity for carbon monoxide for Finnish adults. Single-breath diffusing capacity for carbon monoxide was measured in 631 healthy non-smoking volunteers (41.5% male). Reference values for diffusing capacity (DLCO), alveolar volume (VA), diffusing capacity per unit of lung volume (DLCO/VA), and lung volumes were calculated using a linear regression model. Previously used Finnish reference values were found to produce too low predicted values, with mean predicted DLCO 111.0 and 104.4%, and DLCO/VA of 103.5 and 102.7% in males and females, respectively. With the European Coalition for Steel and Coal (ECSC) reference values there was a significant sex difference in DLCO/VA with mean predicted 105.4% in males and 92.8% in females (p < .001). New reference values for DLCO, DLCO/VA, VA, vital capacity (VC), inspiratory vital capacity (IVC), and inspiratory capacity (IC) are suggested for clinical use to replace technically outdated reference values for clinical applications.

  3. 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.

  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. Primary Gliosarcoma of the Optic Nerve: A Unique Adult Optic Pathway Glioma.

    PubMed

    Cimino, Patrick J; Sychev, Yevgeniy V; Gonzalez-Cuyar, Luis F; Mudumbai, Raghu C; Keene, C Dirk

    2016-10-11

    A 90-year-old woman presented with 1-year history of right-sided progressive proptosis, neovascular glaucoma, blindness, and worsening ocular pain. No funduscopic examination was possible because of a corneal opacity. Head CT scan without contrast demonstrated a heterogeneous 4.1 cm (anterior-posterior) by 1.7 cm (transverse) cylindrical mass arising in the right optic nerve and extending from the retrobulbar globe to the optic canal. She underwent palliative enucleation with subtotal resection of the orbital optic nerve and tumor. Pathological examination showed effacement of the optic nerve by an infiltrative high-grade glial neoplasm with biphasic sarcomeric differentiation. Invasion into the uvea and retina was present. The neoplasm was negative for melan-A, HMB45, tyrosinase, synaptophysin, smooth muscle actin, and epithelial membrane antigen. The glioma had strongly intense, but patchy immunopositivity for glial fibrillary acidic protein. Multiple foci of neoplastic cells had pericellular reticulin staining. The overall features were diagnostic of a gliosarcoma (World Health Organization grade IV) of the optic nerve. Postoperative MRI demonstrated postsurgical changes and residual gliosarcoma with extension into the optic chiasm. The patient died 2 and a half months after her enucleation surgery at her nursing home. Autopsy was unavailable due to the caregiver wishes, making a definitive cause of death unknown. Gliosarcoma is a rare variant of glioblastoma, and this is the first documented case presenting as a primary neoplasm of the optic nerve.

  6. 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

  7. Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives.

    PubMed

    Marlow, Megan M; Shah, Sumedh S; Véliz, Eduardo A; Ivan, Michael E; Graham, Regina M

    2017-01-01

    Resistance mechanisms employed by high-grade gliomas allow them to successfully evade current standard treatment of chemotherapy and radiation treatment. Withaferin A (WA), utilized in Ayurvedic medicine for centuries, is attracting attention for its antitumor capabilities. Here we review pertinent literature on WA as a high-grade glioma treatment, and discuss the cancerous mechanisms it affects. WA is relatively nontoxic and has shown potential in crossing the blood-brain barrier. WA prevents p53 alterations and inactivates overexpressed MDM2 through ARF and ROS production. Furthermore, WA upregulates Bax, inducing mitochondrial death cascades, inhibits mutated Akt, mTOR, and NF-κB pathways, and inhibits angiogenesis in tumors. Therapy with WA for high-grade gliomas is supported through the literature. Further investigation is warranted and encouraged to fully unearth its abilities against malignant gliomas.

  8. 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.

  9. Extension of diffuse low-grade gliomas beyond radiological borders as shown by the coregistration of histopathological and magnetic resonance imaging data.

    PubMed

    Zetterling, Maria; Roodakker, Kenney R; Berntsson, Shala Ghaderi; Edqvist, Per-Henrik; Latini, Francesco; Landtblom, Anne-Marie; Pontén, Fredrik; Alafuzoff, Irina; Larsson, Elna-Marie; Smits, Anja

    2016-11-01

    OBJECTIVE Magnetic resonance imaging tends to underestimate the extent of diffuse low-grade gliomas (DLGGs). With the aim of studying the presence of tumor cells outside the radiological border, the authors developed a method of correlating MRI findings with histological data in patients with suspected DLGGs in whom en bloc resections were performed. METHODS Five patients with suspected DLGG suitable for en bloc resection were recruited from an ongoing prospective study. Sections of the entire tumor were immunostained with antibodies against mutated IDH1 protein (IDH1-R132H). Magnetic resonance images were coregistered with corresponding IDH1 images. The growth pattern of tumor cells in white and gray matter was assessed in comparison with signal changes on corresponding MRI slices. RESULTS Neuropathological assessment revealed DLGG in 4 patients and progression to WHO Grade III glioma in 1 patient. The tumor core consisted of a high density of IDH1-R132H-positive tumor cells and was located in both gray and white matter. Tumor cells infiltrated along the peripheral fibers of the white matter tracts. In all cases, tumor cells were found outside the radiological tumor border delineated on T2-FLAIR MRI sequences. CONCLUSIONS The authors present a new method for the coregistration of histological and radiological characteristics of en bloc-removed infiltrative brain tumors that discloses tumor invasion at the radiological tumor borders. This technique can be applied to evaluate the sensitivity of alternative imaging methods to detect scattered tumor cells at tumor borders. Accurate methods for detection of infiltrative tumor cells will improve the possibility of performing radical tumor resection. In future studies, the method could also be used for in vivo studies of tumor invasion.

  10. Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas: a clinicopathological study.

    PubMed

    You, Gan; Sha, Zhi-Yi; Yan, Wei; Zhang, Wei; Wang, Yong-Zhi; Li, Shao-Wu; Sang, Lin; Wang, Zi; Li, Gui-Lin; Li, Shou-Wei; Song, Yi-Jun; Kang, Chun-Sheng; Jiang, Tao

    2012-02-01

    Seizure is a common presenting manifestation and plays an important role in the clinical presentation and quality of life for patients with low-grade gliomas (LGGs). The authors set out to identify factors that influence preoperative seizure characteristics and postoperative seizure control. Cases involving adult patients who had undergone initial surgery for LGGs in a single institution between 2005 and 2009 were retrospectively reviewed. Univariate and multivariate logistic regression analyses were used to identify factors associated with preoperative seizures and postoperative seizure control. Of the 508 patients in the series, 350 (68.9%) presented with seizures. Age less than 38 years and cortical involvement of tumor were more likely to be associated with seizures (P = .003 and .001, respectively, multivariate logistic analysis). For the cohort of 350 patients with seizures, Engel classification was used to evaluate 6- and 12-month outcome after surgery: completely seizure free (Engel class I), 65.3% and 62.5%; not seizure free (Engel classes II, III, IV), 34.7% and 37.5%. After multivariate logistic analysis, favorable seizure prognosis was more common in patients with secondary generalized seizure (P = .006) and with calcification on MRI (.031). With respect to treatment-related variables, patients achieved much better seizure control after gross total resection than after subtotal resection (P < .0001). Ki67 was an independent molecular marker predicting poor seizure control in the patients with a history of seizure if overexpressed but was not a predictor for those without preoperative seizures. These factors may provide insight into developing effective treatment strategies aimed at prolonging patients' survival.

  11. Circulating levels of the innate and humoral immune regulators CD14 and CD23 are associated with adult glioma.

    PubMed

    Zhou, Mi; Wiemels, Joseph L; Bracci, Paige M; Wrensch, Margaret R; McCoy, Lucie S; Rice, Terri; Sison, Jennette D; Patoka, Joseph S; Wiencke, John K

    2010-10-01

    Allergy history has been consistently inversely associated with glioma risk. Two serologic markers, soluble CD23 (sCD23) and soluble CD14 (sCD14), are part of the innate and adaptive humoral immune systems and modulate allergic responses in opposite directions, with sCD23 enhancing and sCD14 blunting inflammatory responses. We measured sCD23 and sCD14 in serum from blood that was drawn at a single time point from 1,079 glioma patients postdiagnosis and 736 healthy controls. Glioma was strongly associated with high sCD14 [highest versus lowest quartile odds ratio (OR), 3.94; 95% confidence interval (95% CI), 2.98-5.21] and low sCD23 (lowest versus highest quartile OR, 2.5; 95% CI, 1.89-3.23). Results were consistent across glioma histologic types and grades, but were strongest for glioblastoma. Whereas temozolomide treatment was not associated with either sCD14 or sCD23 levels among cases, those taking dexamethasone had somewhat lower sCD23 levels than those not taking dexamethasone. However, sCD23 was associated with case status regardless of dexamethasone treatment. These results augment the long-observed association between allergies and glioma and support a role for the innate and adaptive humoral functions of the immune system, in particular immunoregulatory proteins, in gliomagenesis.

  12. Vorinostat and Radiation Therapy Followed by Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

    ClinicalTrials.gov

    2017-04-05

    Childhood Glioblastoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligoastrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Gliosarcoma

  13. Efficacy of 68Ga-DOTATOC Positron Emission Tomography (PET) CT in Children and Young Adults With Brain Tumors

    ClinicalTrials.gov

    2016-09-07

    Acoustic Schwannoma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Supratentorial Ependymoma; Meningeal Melanocytoma; Newly Diagnosed Childhood Ependymoma; 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 Ependymoma; 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 Medulloblastoma; Recurrent Childhood

  14. Synthesis and anti-glioma activity of 25(R)-spirostan-3beta,5alpha,6beta,19-tetrol.

    PubMed

    Leng, TianDong; Zhang, JingXia; Xie, Jun; Zhou, ShuJia; Huang, YiJun; Zhou, YueHan; Zhu, WenBo; Yan, GuangMei

    2010-03-01

    Malignant gliomas are common and aggressive brain tumours in adults. The rapid proliferation and diffuse brain migration are the main obstacles to successful treatment. Here, we show 25(R)-spirostan-3beta,5alpha,6beta,19-tetrol, a polyhydroxy steroid, is capable of suppressing proliferation and migration of C6 malignant glioma cells in a concentration-dependent manner. The compound 25(R)-spirostan-3beta,5alpha,6beta,19-tetrol was synthesised by seven steps starting from diosgenin in 8.55% overall yield. The structures of the synthetic compounds were characterised by infrared (IR), (1)H nuclear magnetic resonance (NMR), (13)C NMR spectra and EA.

  15. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04).

    PubMed

    Bailey, S; Howman, A; Wheatley, K; Wherton, D; Boota, N; Pizer, B; Fisher, D; Kearns, P; Picton, S; Saran, F; Gibson, M; Glaser, A; Connolly, D J A; Hargrave, D

    2013-12-01

    Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8 years (2-20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10-100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5-11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.

  16. State of affairs in use of steroids in diffuse intrinsic pontine glioma: an international survey and a review of the literature.

    PubMed

    Veldhuijzen van Zanten, Sophie E M; Cruz, Ofelia; Kaspers, Gertjan J L; Hargrave, Darren R; van Vuurden, Dannis G

    2016-07-01

    Children diagnosed with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with severe neurologic deterioration and inevitable death at a median of 9 months from diagnosis. Steroids are widely prescribed as supportive or palliative treatment although they are known to cause severe side effects that may reduce the quality of life. This study aims to review the current knowledge on, and use of, steroids in DIPG patients. A global questionnaire-study among health care professionals was performed to ascertain information on the current (multi-)institutional and (multi-)national use of steroids, the availability of clinical guidelines, and the need for improvements in prescribing steroids to DIPG patients. In addition, an extensive literature search was performed to review studies investigating steroids in pediatric brain tumor patients. From 150 responding health care professionals, only 7 % had clinical guidelines. The use of steroids was heterogeneous and over 85 % of respondents reported serious side effects. Fourteen articles, with low level of evidence, described the use of steroids in pediatric brain tumor patients. Clinical trials investigating optimal dose or regimen were lacking. This study is a first inventory of the availability of evidence-based information and clinical guidelines, and the current attitude towards the use of steroids in DIPG patients. To date, the risk-benefit ratio of steroids in this disease is yet to be determined. We emphasize the need for clinical trials resulting in guidelines on steroids, and possibly alternative drugs, to optimize the quality of care and quality of life of DIPG patients.

  17. Molecular neuropathology of low-grade gliomas and its clinical impact.

    PubMed

    Riemenschneider, M J; Reifenberger, G

    2010-01-01

    The term "low-grade glioma" refers to a heterogeneous group of slowly growing glial tumors corresponding histologically to World Health Organization (WHO) grade I or II. This group includes astrocytic, oligodendroglial, oligoastrocytic and ependymal tumor entities, most of which preferentially manifest in children and young adults. Depending on histological type and WHO grade, growth patterns of low-grade gliomas are quite variable, with some tumors diffusely infiltrating the surrounding central nervous system tissue and others showing well demarcated growth. Furthermore, some entities tend to recur and show spontaneous malignant progression while others remain stable for many years. This review provides a condensed overview concerning the molecular genetics of different glioma entities subsumed under the umbrella of low-grade glioma. For a better understanding the cardinal epidemiological, histological and immunohistochemical features of each entity are shortly outlined. Multiple cytogenetic, chromosomal and genetic alterations have been identified in low-grade gliomas to date, with distinct genetic patterns being associated with the individual tumor subtypes. Some of these molecular alterations may serve as a diagnostic adjunct for tumor classification in cases with ambiguous histological features. However, to date only few molecular changes have been associated with clinical outcome, such as the combined losses of chromosome arms 1p and 19q as a favorable prognostic marker in patients with oligodendroglial tumors.

  18. Preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas: Final results of BSG 98 prospective trial

    PubMed Central

    Frappaz, Didier; Schell, Matthias; Thiesse, Philippe; Marec-Bérard, Perrine; Mottolese, Carmine; Perol, David; Bergeron, Christophe; Philip, Thierry; Ricci, Anne Claire; Galand-Desme, Sophie; Szathmari, Alexandru; Carrie, Christian

    2008-01-01

    Radiation therapy remains the only treatment that provides clinical benefit to children with diffuse brainstem tumors. Their median survival, however, rarely exceeds 9 months. The authors report a prospective trial of front-line chemotherapy aimed at delaying radiation until time of clinical progression. The aim was to investigate the possibility that radiotherapy would maintain its activity in children whose disease progressed after chemotherapy. Twenty-three patients took part in this protocol, the BSG 98 protocol, which consisted of frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules. Each cycle included three courses delivered monthly; the first course was 1,3-bis(2-chloroethyl)-1-nitrosourea– cisplatin, and the second and third were high-dose methotrexate. Three patients underwent one cycle; 5 patients each, two and three cycles; and 10 patients, four cycles. Twenty of the 23 patients eventually received local radiation therapy. A historical cohort of 14 patients who received at least local radiation therapy served as controls. Four patients experienced severe iatrogenic infections, and 11 patients required platelet transfusions. Median survival increased significantly in patients participating in the protocol compared to that in the historical controls (17 months, 95% confidence interval [CI], 10–23 months, vs. 9 months, 95% CI, 8–10 months; p = 0.022), though hospitalization was prolonged (57 vs. 25 days, p = 0.001). Although frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules significantly increases overall median survival, its cost from infection and hospitalization deserves honest discussion with the children and their parents. PMID:18577561

  19. 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

  20. Children Are Not like Older Adults: A Diffusion Model Analysis of Developmental Changes in Speeded Responses

    ERIC Educational Resources Information Center

    Ratcliff, Roger; Love, Jessica; Thompson, Clarissa A.; Opfer, John E.

    2012-01-01

    Children (n = 130; M[subscript age] = 8.51-15.68 years) and college-aged adults (n = 72; M[subscript age] = 20.50 years) completed numerosity discrimination and lexical decision tasks. Children produced longer response times (RTs) than adults. R. Ratcliff's (1978) diffusion model, which divides processing into components (e.g., quality of…

  1. Disseminating Competency-Based Adult Education through the National Diffusion Network.

    ERIC Educational Resources Information Center

    Shelton, Elaine

    1980-01-01

    Defines competency-based adult education; provides a brief history of the Adult Performance Level (APL) Curriculum and Competency-Based High School Diploma program; explains the National Diffusion Network; examines how the APL staff offers training and technical assistance; and focuses on nontraditional APL program implementation. (CT)

  2. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.

    PubMed

    Weller, Michael; Weber, Ruthild G; Willscher, Edith; Riehmer, Vera; Hentschel, Bettina; Kreuz, Markus; Felsberg, Jörg; Beyer, Ulrike; Löffler-Wirth, Henry; Kaulich, Kerstin; Steinbach, Joachim P; Hartmann, Christian; Gramatzki, Dorothee; Schramm, Johannes; Westphal, Manfred; Schackert, Gabriele; Simon, Matthias; Martens, Tobias; Boström, Jan; Hagel, Christian; Sabel, Michael; Krex, Dietmar; Tonn, Jörg C; Wick, Wolfgang; Noell, Susan; Schlegel, Uwe; Radlwimmer, Bernhard; Pietsch, Torsten; Loeffler, Markus; von Deimling, Andreas; Binder, Hans; Reifenberger, Guido

    2015-05-01

    Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression

  3. Quantitative longitudinal evaluation of diaschisis-related cerebellar perfusion and diffusion parameters in patients with supratentorial hemispheric high-grade gliomas after surgery.

    PubMed

    Patay, Zoltan; Parra, Carlos; Hawk, Harris; George, Arun; Li, Yimei; Scoggins, Matthew; Broniscer, Alberto; Ogg, Robert J

    2014-10-01

    Decreased cerebral blood volume (CBV) in contralateral cerebellar gray matter (cGM) in conjunction with cerebellar white matter (cWM) damage, consistent with crossed cerebro-cerebellar diaschisis (cCCD) develop following supratentorial hemispheric stroke. In this study, we investigated the longitudinal evolution of diaschisis-related cerebellar perfusion and diffusion tensor-imaging (DTI) changes in patients after surgery for supratentorial brain tumors. Eight patients (M:F 5:3, age 8-22 years) who received surgery for supratentorial high-grade gliomas were evaluated. Initial MRI studies were performed 19-54 days postoperatively, with follow-ups at 2- to 3-month intervals. For each study, parametric maps of the cerebellum were generated and coregistered to T1-weighted images that had been previously segmented for cGM and cWM. Aggregate mean values of CBV, cerebral blood flow (CBF), and fractional anisotropy (FA) were obtained separately for cGM and cWM, and asymmetry indices (AIs) were calculated. Hemodynamic changes were more robust in cGM than in cWM. Seven patients showed decreased perfusion within cGM contralateral to the supratentorial lesion on the first postoperative study, and asymmetry was significant for both CBV (p = 0.008) and CBF (p < 0.01). For CBV, follow-up studies showed a significant trend towards recovery (p < 0.02). DTI changes were more pronounced in cWM. FA values suggested a "paradoxical" increase at initial follow-up, but steadily declined thereafter (p = 0.0003), without evidence of subsequent recovery. Diaschisis-related hemodynamic alterations within cGM appear on early postoperative studies, but CBV recovers over time. Conversely, cWM DTI changes are delayed and progressive. Although the clinical correlates of cCCD are yet to be elucidated, better understanding of longitudinal structural and hemodynamic changes within brain remote from the area of primary insult could have implications in research and clinical

  4. Discrete or diffuse intramedullary tumor? Contrast-enhanced intraoperative ultrasound in a case of intramedullary cervicothoracic hemangioblastomas mimicking a diffuse infiltrative glioma: technical note and case report.

    PubMed

    Vetrano, Ignazio G; Prada, Francesco; Nataloni, Ilaria F; Bene, Massimiliano Del; Dimeco, Francesco; Valentini, Laura G

    2015-08-01

    Hemangioblastomas are benign, highly vascularized intramedullary lesions that may also extend into the intradural space. Surgery represents the standard therapy, with the goal of obtaining complete resection even at the risk of neurological morbidity. MRI is the gold standard for diagnosis and assessment of intramedullary tumors. Nevertheless, sometimes MRI may not accurately differentiate between different types of intramedullary tumors, in particular if they are associated with syringes or intra- and peritumoral cysts. This could subsequently affect surgical strategies. Intraoperative ultrasound (ioUS) has become in the last few years a very useful tool for use during neurosurgical procedures. Various ioUS modalities such as B-mode and Doppler have been applied during neurosurgical procedures. On the other hand, the use of contrast-enhanced ultrasound (CEUS) is not yet well defined and standardized in this field. We report a case of a young patient harboring a cervicothoracic intramedullary tumor, for which the preoperative neuroradiologi-cal diagnosis was in favor of a diffuse astrocytoma with nodular components whereas ioUS demonstrated 3 distinct intramedullary nodules. CEUS showed highly vascularized lesions, compatible with hemangioblastomas. These findings, particularly those obtained with CEUS, allowed better definition of the lesions for diagnosis, enhanced understanding of the physiopathological aspects, and permitted the localization of all 3 nodules, thus limiting spinal cord manipulation and allowing complete resection of the lesions, with an uneventful postoperative neurological course. To the best of our knowledge, this is the first report of the use of intraoperative CEUS in a case of intramedullary hemangioblastoma.

  5. Insight from uncertainty: bootstrap-derived diffusion metrics differentially predict memory function among older adults.

    PubMed

    Vorburger, Robert S; Habeck, Christian G; Narkhede, Atul; Guzman, Vanessa A; Manly, Jennifer J; Brickman, Adam M

    2016-01-01

    Diffusion tensor imaging suffers from an intrinsic low signal-to-noise ratio. Bootstrap algorithms have been introduced to provide a non-parametric method to estimate the uncertainty of the measured diffusion parameters. To quantify the variability of the principal diffusion direction, bootstrap-derived metrics such as the cone of uncertainty have been proposed. However, bootstrap-derived metrics are not independent of the underlying diffusion profile. A higher mean diffusivity causes a smaller signal-to-noise ratio and, thus, increases the measurement uncertainty. Moreover, the goodness of the tensor model, which relies strongly on the complexity of the underlying diffusion profile, influences bootstrap-derived metrics as well. The presented simulations clearly depict the cone of uncertainty as a function of the underlying diffusion profile. Since the relationship of the cone of uncertainty and common diffusion parameters, such as the mean diffusivity and the fractional anisotropy, is not linear, the cone of uncertainty has a different sensitivity. In vivo analysis of the fornix reveals the cone of uncertainty to be a predictor of memory function among older adults. No significant correlation occurs with the common diffusion parameters. The present work not only demonstrates the cone of uncertainty as a function of the actual diffusion profile, but also discloses the cone of uncertainty as a sensitive predictor of memory function. Future studies should incorporate bootstrap-derived metrics to provide more comprehensive analysis.

  6. 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

  7. A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method.

    PubMed

    Walker, David A; Liu, JoFen; Kieran, Mark; Jabado, Nada; Picton, Susan; Packer, Roger; St Rose, Christian

    2013-04-01

    Astrocytic tumors account for 42% of childhood brain tumors, arising in all anatomical regions and associated with neurofibromatosis type 1 (NF1) in 15%. Anatomical site determines the degree and risk of resectability; the more complete resection, the better the survival rates. New biological markers and modern radiotherapy techniques are altering the risk assessments of clinical decisions for tumor resection and biopsy. The increasingly distinct pediatric neuro-oncology multidisciplinary team (PNMDT) is developing a distinct evidence base. A multidisciplinary consensus conference on pediatric neurosurgery was held in February 2011, where 92 invited participants reviewed evidence for clinical management of hypothalamic chiasmatic glioma (HCLGG), diffuse intrinsic pontine glioma (DIPG), and high-grade glioma (HGG). Twenty-seven statements were drafted and subjected to online Delphi consensus voting by participants, seeking >70% agreement from >60% of respondents; where <70% consensus occurred, the statement was modified and resubmitted for voting. Twenty-seven statements meeting consensus criteria are reported. For HCLGG, statements describing overall therapeutic purpose and indications for biopsy, observation, or treatment aimed at limiting the risk of visual damage and the need for on-going clinical trials were made. Primary surgical resection was not recommended. For DIPG, biopsy was recommended to ascertain biological characteristics to enhance understanding and targeting of treatments, especially in clinical trials. For HGG, biopsy is essential, the World Health Organization classification was recommended; selection of surgical strategy to achieve gross total resection in a single or multistep process should be discussed with the PNMDT and integrated with trials based drug strategies for adjuvant therapies.

  8. 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.

  9. Altered myelination and axonal integrity in adults with childhood lead exposure: a diffusion tensor imaging study.

    PubMed

    Brubaker, Christopher J; Schmithorst, Vincent J; Haynes, Erin N; Dietrich, Kim N; Egelhoff, John C; Lindquist, Diana M; Lanphear, Bruce P; Cecil, Kim M

    2009-11-01

    Childhood lead exposure is associated with adverse cognitive, neurobehavioral and motor outcomes, suggesting altered brain structure and function. The purpose of this work was to assess the long-term impact of childhood lead exposure on white matter integrity in young adults. We hypothesized that childhood lead exposure would alter adult white matter architecture via deficits in axonal integrity and myelin organization. Adults (22.9+/-1.5 years, range 20.0-26.1 years) from the Cincinnati Lead Study were recruited to undergo a study employing diffusion tensor imaging (DTI). The anatomic regions of association between water diffusion characteristics in white matter and mean childhood blood lead level were determined for 91 participants (52 female). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured on an exploratory voxel-wise basis. In adjusted analyses, mean childhood blood lead levels were associated with decreased FA throughout white matter. Regions of the corona radiata demonstrated highly significant lead-associated decreases in FA and AD and increases in MD and RD. The genu, body, and splenium of the corpus callosum demonstrated highly significant lead-associated decreases in RD, smaller and less significant decreases in MD, and small areas with increases in AD. The results of this analysis suggest multiple insults appear as distinct patterns of white matter diffusion abnormalities in the adult brain. Neurotoxic insults from the significant lead burden the participants experienced throughout childhood affect neural elements differently and may be related to the developmental stage of myelination at periods of exposure. This study indicates that childhood lead exposure is associated with a significant and persistent impact on white matter microstructure as quantified with diffusivity changes suggestive of altered myelination and axonal integrity.

  10. Task Inhibition and Response Inhibition in Older vs. Younger Adults: A Diffusion Model Analysis

    PubMed Central

    Schuch, Stefanie

    2016-01-01

    Differences in inhibitory ability between older (64–79 years, N = 24) and younger adults (18–26 years, N = 24) were investigated using a diffusion model analysis. Participants performed a task-switching paradigm that allows assessing n−2 task repetition costs, reflecting inhibitory control on the level of tasks, as well as n−1 response-repetition costs, reflecting inhibitory control on the level of responses. N−2 task repetition costs were of similar size in both age groups. Diffusion model analysis revealed that for both younger and older adults, drift rate parameters were smaller in the inhibition condition relative to the control condition, consistent with the idea that persisting task inhibition slows down response selection. Moreover, there was preliminary evidence for task inhibition effects in threshold separation and non-decision time in the older, but not the younger adults, suggesting that older adults might apply different strategies when dealing with persisting task inhibition. N−1 response-repetition costs in mean RT were larger in older than younger adults, but in mean error rates tended to be larger in younger than older adults. Diffusion-model analysis revealed longer non-decision times in response repetitions than response switches in both age groups, consistent with the idea that motor processes take longer in response repetitions than response switches due to persisting response inhibition of a previously executed response. The data also revealed age-related differences in overall performance: Older adults responded more slowly and more accurately than young adults, which was reflected by a higher threshold separation parameter in diffusion model analysis. Moreover, older adults showed larger non-decision times and higher variability in non-decision time than young adults, possibly reflecting slower and more variable motor processes. In contrast, overall drift rate did not differ between older and younger adults. Taken together

  11. 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.

  12. Identity Diffusion as a Function of Sex-Roles in Adult Women.

    ERIC Educational Resources Information Center

    Jabury, Donald Eugene

    This study sought to demonstrate that the relative degree of adult female identity diffusion, as well as certain personality correlates, would be a function of specific sex roles and their combinations. Three groups of 32 women each were selected as married and noncareer, married and career, or unmarried and career women. They were administered a…

  13. PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas

    PubMed Central

    Nakae, Shunsuke; Sasaki, Hikaru; Hayashi, Saeko; Hattori, Natsuki; Kumon, Masanobu; Nishiyama, Yuya; Adachi, Kazuhide; Nagahisa, Shinya; Hayashi, Takuro; Inamasu, Joji; Abe, Masato; Hasegawa, Mitsuhiro; Hirose, Yuichi

    2015-01-01

    Genetic subgrouping of gliomas has been emphasized recently, particularly after the finding of isocitrate dehydrogenase 1 (IDH1) mutations. In a previous study, we investigated whole-chromosome copy number aberrations (CNAs) of gliomas and have described genetic subgrouping based on CNAs and IDH1 mutations. Subsequently, we classified gliomas using simple polymerase chain reaction (PCR)-based methods to improve the availability of genetic subgrouping. We selected IDH1/2 and TP53 as markers and analyzed 237 adult supratentorial gliomas using Sanger sequencing. Using these markers, we classified gliomas into three subgroups that were strongly associated with patient prognoses. These included IDH mutant gliomas without TP53 mutations, IDH mutant gliomas with TP53 mutations, and IDH wild-type gliomas. IDH mutant gliomas without TP53 mutations, which mostly corresponded to gliomas carrying 1p19q co-deletions, showed lower recurrence rates than the other 2 groups. In the other high-recurrence groups, the median progression-free survival (PFS) and overall survival (OS) of patients with IDH mutant gliomas with TP53 mutations were significantly longer than those of patients with IDH wild-type gliomas. Notably, most IDH mutant gliomas with TP53 mutations had at least one of the CNAs +7q, +8q, −9p, and −11p. Moreover, IDH mutant gliomas with at least one of these CNAs had a significantly worse prognosis than did other IDH mutant gliomas. PCR-based mutation analyses of IDH and TP53 were sufficient for simple genetic diagnosis of glioma that were strongly associated with prognosis of patients and enabled us to detect negative CNAs in IDH mutant gliomas. PMID:26558387

  14. PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas.

    PubMed

    Nakae, Shunsuke; Sasaki, Hikaru; Hayashi, Saeko; Hattori, Natsuki; Kumon, Masanobu; Nishiyama, Yuya; Adachi, Kazuhide; Nagahisa, Shinya; Hayashi, Takuro; Inamasu, Joji; Abe, Masato; Hasegawa, Mitsuhiro; Hirose, Yuichi

    2015-01-01

    Genetic subgrouping of gliomas has been emphasized recently, particularly after the finding of isocitrate dehydrogenase 1 (IDH1) mutations. In a previous study, we investigated whole-chromosome copy number aberrations (CNAs) of gliomas and have described genetic subgrouping based on CNAs and IDH1 mutations. Subsequently, we classified gliomas using simple polymerase chain reaction (PCR)-based methods to improve the availability of genetic subgrouping. We selected IDH1/2 and TP53 as markers and analyzed 237 adult supratentorial gliomas using Sanger sequencing. Using these markers, we classified gliomas into three subgroups that were strongly associated with patient prognoses. These included IDH mutant gliomas without TP53 mutations, IDH mutant gliomas with TP53 mutations, and IDH wild-type gliomas. IDH mutant gliomas without TP53 mutations, which mostly corresponded to gliomas carrying 1p19q co-deletions, showed lower recurrence rates than the other 2 groups. In the other high-recurrence groups, the median progression-free survival (PFS) and overall survival (OS) of patients with IDH mutant gliomas with TP53 mutations were significantly longer than those of patients with IDH wild-type gliomas. Notably, most IDH mutant gliomas with TP53 mutations had at least one of the CNAs +7q, +8q, -9p, and -11p. Moreover, IDH mutant gliomas with at least one of these CNAs had a significantly worse prognosis than did other IDH mutant gliomas. PCR-based mutation analyses of IDH and TP53 were sufficient for simple genetic diagnosis of glioma that were strongly associated with prognosis of patients and enabled us to detect negative CNAs in IDH mutant gliomas.

  15. White matter alterations in adults with probable developmental coordination disorder: an MRI diffusion tensor imaging study.

    PubMed

    Williams, Jacqueline; Kashuk, Saman R; Wilson, Peter H; Thorpe, Graham; Egan, Gary F

    2017-01-18

    Movement skill difficulties in children [or developmental coordination disorder (DCD)] often persist into adulthood (in up to 70% of cases). The suggestion of white matter microstructure alterations in children with DCD raises the question of whether similar alterations are present in adults with probable DCD (pDCD). Twelve adults with pDCD and 11 adults without pDCD underwent diffusion tensor imaging. The results showed that the pDCD group had significantly lower fractional anisotropy in the corticospinal tract and superior longitudinal fasciculus and lower mean diffusivity in the internal capsule and inferior longitudinal fasciculus. This suggests reduced white matter integrity in parietofrontal and corticospinal tracts, with possible compensatory increases in white matter integrity along the visual ventral stream and front-occipital networks. These findings support recent neuroimaging studies in children with DCD and suggest persistent neurobiological alterations along white matter tracts that are known to support motor planning, cognition and their association.

  16. Validation of EORTC Prognostic Factors for Adults With Low-Grade Glioma: A Report Using Intergroup 86-72-51

    SciTech Connect

    Daniels, Thomas B.; Brown, Paul D.; Felten, Sara J.; Wu, Wenting; Buckner, Jan C.; Arusell, Robert M.; Curran, Walter J.; Abrams, Ross A.; Schiff, David; Shaw, Edward G.

    2011-09-01

    Purpose: A prognostic index for survival was constructed and validated from patient data from two European Organisation for Research and Treatment of Cancer (EORTC) radiation trials for low-grade glioma (LGG). We sought to independently validate this prognostic index with a separate prospectively collected data set (Intergroup 86-72-51). Methods and Materials: Two hundred three patients were treated in a North Central Cancer Treatment Group-led trial that randomized patients with supratentorial LGG to 50.4 or 64.8 Gy. Risk factors from the EORTC prognostic index were analyzed for prognostic value: histology, tumor size, neurologic deficit, age, and tumor crossing the midline. The high-risk group was defined as patients with more than two risk factors. In addition, the Mini Mental Status Examination (MMSE) score, extent of surgical resection, and 1p19q status were also analyzed for prognostic value. Results: On univariate analysis, the following were statistically significant (p < 0.05) detrimental factors for both progression-free survival (PFS) and overall survival (OS): astrocytoma histology, tumor size, and less than total resection. A Mini Mental Status Examination score of more than 26 was a favorable prognostic factor. Multivariate analysis showed that tumor size and MMSE score were significant predictors of OS whereas tumor size, astrocytoma histology, and MMSE score were significant predictors of PFS. Analyzing by the EORTC risk groups, we found that the low-risk group had significantly better median OS (10.8 years vs. 3.9 years, p < 0.0001) and PFS (6.2 years vs. 1.9 years, p < 0.0001) than the high-risk group. The 1p19q status was available in 66 patients. Co-deletion of 1p19q was a favorable prognostic factor for OS vs. one or no deletion (median OS, 12.6 years vs. 7.2 years; p = 0.03). Conclusions: Although the low-risk group as defined by EORTC criteria had a superior PFS and OS to the high-risk group, this is primarily because of the influence of

  17. Intracellular tortuosity underlies slow cAMP diffusion in adult ventricular myocytes

    PubMed Central

    Richards, Mark; Lomas, Oliver; Jalink, Kees; Ford, Kerrie L.; Vaughan-Jones, Richard D.; Lefkimmiatis, Konstantinos; Swietach, Pawel

    2016-01-01

    Aims 3′,5′-Cyclic adenosine monophosphate (cAMP) signals in the heart are often confined to concentration microdomains shaped by cAMP diffusion and enzymatic degradation. While the importance of phosphodiesterases (degradative enzymes) in sculpting cAMP microdomains is well established in cardiomyocytes, less is known about cAMP diffusivity (DcAMP) and factors affecting it. Many earlier studies have reported fast diffusivity, which argues against sharply defined microdomains. Methods and results [cAMP] dynamics in the cytoplasm of adult rat ventricular myocytes were imaged using a fourth generation genetically encoded FRET-based sensor. The [cAMP]-response to the addition and removal of isoproterenol (β-adrenoceptor agonist) quantified the rates of cAMP synthesis and degradation. To obtain a read out of DcAMP, a stable [cAMP] gradient was generated using a microfluidic device which delivered agonist to one half of the myocyte only. After accounting for phosphodiesterase activity, DcAMP was calculated to be 32 µm2/s; an order of magnitude lower than in water. Diffusivity was independent of the amount of cAMP produced. Saturating cAMP-binding sites with the analogue 6-Bnz-cAMP did not accelerate DcAMP, arguing against a role of buffering in restricting cAMP mobility. cAMP diffused at a comparable rate to chemically unrelated but similar sized molecules, arguing for a common physical cause of restricted diffusivity. Lower mitochondrial density and order in neonatal cardiac myocytes allowed for faster diffusion, demonstrating the importance of mitochondria as physical barriers to cAMP mobility. Conclusion In adult cardiac myocytes, tortuosity due to physical barriers, notably mitochondria, restricts cAMP diffusion to levels that are more compatible with microdomain signalling. PMID:27089919

  18. The interface between glial progenitors and gliomas

    PubMed Central

    Canoll, Peter

    2009-01-01

    The mammalian brain and spinal cord contain heterogeneous populations of cycling, immature cells. These include cells with stem cell-like properties as well as progenitors in various stages of early glial differentiation. This latter population is distributed widely throughout gray and white matter and numerically represents an extremely large cell pool. In this review, we discuss the possibility that the glial progenitors that populate the adult CNS are one source of gliomas. Indeed, the marker phenotypes, morphologies, and migratory properties of cells in gliomas strongly resemble glial progenitors in many ways. We review briefly some salient features of normal glial development and then examine the similarities and differences between normal progenitors and cells in gliomas, focusing on the phenotypic plasticity of glial progenitors and the responses to growth factors in promoting proliferation and migration of normal and glioma cells, and discussing known mutational changes in gliomas in the context of how these might affect the proliferative and migratory behaviors of progenitors. Finally, we will discuss the “cancer stem cell” hypothesis in light of the possibility that glial progenitors can generate gliomas. PMID:18784926

  19. A Diffusion Model Analysis of Adult Age Differences in Episodic and Semantic Long-Term Memory Retrieval

    ERIC Educational Resources Information Center

    Spaniol, Julia; Madden, David J.; Voss, Andreas

    2006-01-01

    Two experiments investigated adult age differences in episodic and semantic long-term memory tasks, as a test of the hypothesis of specific age-related decline in context memory. Older adults were slower and exhibited lower episodic accuracy than younger adults. Fits of the diffusion model (R. Ratcliff, 1978) revealed age-related increases in…

  20. In vivo evaluation of optic nerve aging in adult rhesus monkey by diffusion tensor imaging

    PubMed Central

    Yan, Yumei; Li, Longchuan; Preuss, Todd M.; Hu, Xiaoping; Herndon, James G.

    2014-01-01

    Aging of the optic nerve can result in reduced visual sensitivity or vision loss. Normal optic nerve aging has been investigated previously in tissue specimens but poorly explored in vivo. In the present study, the normal aging of optic nerve was evaluated by diffusion tensor imaging (DTI) in non-human primates. Adult female rhesus monkeys at the ages of 9 to 13 years old (young group, n=8) and 21 to 27 years old (old group, n=7) were studied using parallel-imaging-based DTI on a clinical 3T scanner. Compared to young adults, the old monkeys showed 26% lower fractional anisotropy (P<0.01), and 44% greater radial diffusivity, although the latter difference was of marginal statistical significance (P=0.058). These MRI findings are largely consistent with published results of light and electron microscopic studies of optic nerve aging in macaque monkeys, which indicate a loss of fibers and degenerative changes in myelin sheaths. PMID:24649434

  1. 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.

  2. Diffuse Infantile Hepatic Hemangioendothelioma With Early Central Enhancement in an Adult

    PubMed Central

    Dong, Aisheng; Dong, Hui; Zuo, Changjing; He, Tianlin

    2015-01-01

    Abstract Infantile hepatic hemangioendothelioma (IHH) is the most common vascular tumor of the liver in infancy. Adult with IHH is extremely rare. We presented a diffuse IHH in an adult patient with computed tomography (CT) and magnetic resonance image (MRI) findings. A 39-year-old man was admitted to our hospital because of a 2-year history of abnormal liver function tests and a 7-day history of jaundice. Physical examination revealed enlarged liver. Unenhanced abdominal CT showed enlargement of the liver with diffuse hypodensity. Enhanced CT on the arterial phase revealed multiple centrally enhanced lesions diffusely involved the enlarged liver. The enhanced areas of the lesions became larger on the portal phase and all the lesions became homogeneous enhanced on the delayed phase. These lesions showed heterogeneously hyperintense on T2-weighted image, hypointense on T1-weighted image, and early centrally enhanced on dynamic gadolinium-enhanced MRI, with complete tumor enhancement after 180 s. The patient underwent orthotopic liver transplantation. IHH type 2 was confirmed by pathology. The patient died of tumor recurrence in the liver 4 months after transplantation. Unlike the previously described imaging appearances of IHH, this case showed diffuse nodules with early central enhancement on CT and MRI. Considering the importance of the ability to differentiate IHH from other hepatic tumors, radiologists should be aware of these imaging appearances to establish knowledge of the entire spectrum of IHH. PMID:26705232

  3. 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.

  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. Investigating task inhibition in children versus adults: A diffusion model analysis.

    PubMed

    Schuch, Stefanie; Konrad, Kerstin

    2017-04-01

    One can take n-2 task repetition costs as a measure of inhibition on the level of task sets. When switching back to a Task A after only one intermediate trial (ABA task sequence), Task A is thought to still be inhibited, leading to performance costs relative to task sequences where switching back to Task A is preceded by at least two intermediary trials (CBA). The current study investigated differences in inhibitory ability between children and adults by comparing n-2 task repetition costs in children (9-11years of age, N=32) and young adults (21-30years of age, N=32). The mean reaction times and error rate differences between ABA and CBA sequences did not differ between the two age groups. However, diffusion model analysis revealed that different cognitive processes contribute to the inhibition effect in the two age groups: The adults, but not the children, showed a smaller drift rate in ABA than in CBA, suggesting that persisting task inhibition is associated with slower response selection in adults. In children, non-decision time was longer in ABA than in CBA, possibly reflecting longer task preparation in ABA than in CBA. In addition, Ex-Gaussian functions were fitted to the distributions of correct reaction times. In adults, the ABA-CBA difference was reflected in the exponential parameter of the distribution; in children, the ABA-CBA difference was found in the Gaussian mu parameter. Hence, Ex-Gaussian analysis, although noisier, was generally in line with diffusion model analysis. Taken together, the data suggest that the task inhibition effect found in mean performance is mediated by different cognitive processes in children versus adults.

  6. Regional age differences in gray matter diffusivity among healthy older adults

    PubMed Central

    Salminen, Lauren E.; Conturo, Thomas E.; Laidlaw, David H.; Cabeen, Ryan P.; Akbudak, Erbil; Lane, Elizabeth M.; Heaps, Jodi M.; Bolzenius, Jacob D.; Baker, Laurie M.; Cooley, Sarah; Scott, Staci; Cagle, Lee M.; Phillips, Sarah; Paul, Robert H.

    2015-01-01

    Aging is associated with microstructural changes in brain tissue that can be visualized using diffusion tensor imaging (DTI). While previous studies have established age-related changes in white matter (WM) diffusion using DTI, the impact of age on gray matter (GM) diffusion remains unclear. The present study utilized DTI metrics of mean diffusivity (MD) to identify age differences in GM/WM micro-structure in a sample of healthy older adults (N=60). A secondary aim was to determine the functional significance of whole-brain GM/WM MD on global cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Participants were divided into three age brackets (ages 50–59, 60–69, and 70+) to examine differences in MD and cognition by decade. MD was examined bilaterally in the frontal, temporal, parietal, and occipital lobes for the primary analyses and an aggregate measure of whole-brain MD was used to test relationships with cognition. Significantly higher MD was observed in bilateral GM of the temporal and parietal lobes, and in right hemisphere WM of the frontal and temporal lobes of older individuals. The most robust differences in MD were between the 50–59 and 70+ age groups. Higher whole-brain GM MD was associated with poorer RBANS performance in the 60–69 age group. Results suggest that aging has a significant and differential impact on GM/WM diffusion in healthy older adults, which may explain a modest degree of cognitive variability at specific time points during older adulthood. PMID:25864197

  7. Diffusely adherent Escherichia coli strains isolated from children and adults constitute two different populations

    PubMed Central

    2013-01-01

    Background Diffusely adherent Escherichia coli (DAEC) have been considered a diarrheagenic category of E. coli for which several potential virulence factors have been described in the last few years. Despite this, epidemiological studies involving DAEC have shown inconsistent results. In this work, two different collections of DAEC possessing Afa/Dr genes, from children and adults, were studied regarding characteristics potentially associated to virulence. Results DAEC strains were recovered in similar frequencies from diarrheic and asymptomatic children, and more frequently from adults with diarrhea (P < 0.01) than from asymptomatic adults. Association with diarrhea (P < 0.05) was found for SAT-positive strains recovered from children and for curli-positive strains recovered from adults. Mixed biofilms involving DAEC and a Citrobacter freundii strain have shown an improved ability to form biofilms in relation to the monocultures. Control strains have shown a greater diversity of Afa/Dr adhesins and higher frequencies of cellulose, TTSS, biofilm formation and induction of IL-8 secretion than strains from cases of diarrhea in children. Conclusions DAEC strains possessing Afa/Dr genes isolated from children and adults represent two different bacterial populations. DAEC strains carrying genes associated to virulence can be found as part of the normal microbiota present in asymptomatic children. PMID:23374248

  8. Corpus callosum size and diffusion tensor anisotropy in adolescents and adults with schizophrenia.

    PubMed

    Balevich, Emily C; Haznedar, M Mehmet; Wang, Eugene; Newmark, Randall E; Bloom, Rachel; Schneiderman, Jason S; Aronowitz, Jonathan; Tang, Cheuk Y; Chu, King-Wai; Byne, William; Buchsbaum, Monte S; Hazlett, Erin A

    2015-03-30

    The corpus callosum has been implicated as a region of dysfunctional connectivity in schizophrenia, but the association between age and callosal pathology is unclear. Magnetic resonance imaging (MRI) and diffusion-tensor imaging (DTI) were performed on adults (n=34) and adolescents (n=17) with schizophrenia and adult (n=33) and adolescent (n=15) age- and sex-matched healthy controls. The corpus callosum was manually traced on each participant׳s MRI, and the DTI scan was co-registered to the MRI. The corpus callosum was divided into five anteroposterior segments. Area and anisotropy were calculated for each segment. Both patient groups demonstrated reduced callosal anisotropy; however, the adolescents exhibited reductions mostly in anterior regions while the reductions were more prominent in posterior regions of the adults. The adolescent patients showed greater decreases in absolute area as compared with the adult patients, particularly in the anterior segments. However, the adults showed greater reductions when area was considered relative to whole brain white matter volume. Our results suggest that the initial stages of the illness are characterized by deficiencies in frontal connections, and the chronic phase is characterized by deficits in the posterior corpus callosum; or, alternatively, adolescent-onset schizophrenia may represent a different or more severe form of the illness.

  9. 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.

  10. 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.

  11. [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.

  12. Cardiorespiratory fitness and brain diffusion tensor imaging in adults over 80 years of age.

    PubMed

    Tian, Qu; Simonsick, Eleanor M; Erickson, Kirk I; Aizenstein, Howard J; Glynn, Nancy W; Boudreau, Robert M; Newman, Anne B; Kritchevsky, Stephen B; Yaffe, Kristine; Harris, Tamara; Rosano, Caterina

    2014-11-07

    A positive association between cardiorespiratory fitness (CRF) and white matter integrity has been consistently reported in older adults. However, it is unknown whether this association exists in adults over 80 with a range of chronic disease conditions and low physical activity participation, which can influence both CRF and brain health. This study examined whether higher CRF was associated with greater microstructural integrity of gray and white matter in areas related to memory and information processing in adults over 80 and examined moderating effects of chronic diseases and physical activity. CRF was measured as time to walk 400 m as quickly as possible with concurrent 3T diffusion tensor imaging in 164 participants (57.1% female, 40.3% black). Fractional anisotropy (FA) was computed for cingulum, uncinate and superior longitudinal fasciculi. Mean diffusivity (MD) was computed for dorsolateral prefrontal cortex, hippocampus, parahippocampus, and entorhinal cortex. Moderating effects were tested using hierarchical regression models. Higher CRF was associated with higher FA in cingulum and lower MD in hippocampus and entorhinal cortex (β, sex-adjusted p: -0.182, 0.019; 0.165, 0.035; and 0.220, 0.006, respectively). Hypertension attenuated the association with MD in entorhinal cortex. Moderating effects of chronic diseases and physical activity in walking and climbing stairs on these associations were not significant. The association of higher CRF with greater microstructural integrity in selected subcortical areas appears robust, even among very old adults with a range of chronic diseases. Intervention studies should investigate whether increasing CRF can preserve memory and information processing by improving microstructure and potential effects of hypertension management.

  13. Amplifying diffusion of health information in low-literate populations through adult education health literacy classes.

    PubMed

    Freedman, Ariela M; Miner, Kathleen R; Echt, Katharina V; Parker, Ruth; Cooper, Hannah L F

    2011-01-01

    Over the next decade, as literacy rates are predicted to decline, the health care sector faces increasing challenges to effective communication with low-literate groups. Considering the rising costs of health care and the forthcoming changes in the American health care system, it is imperative to find nontraditional avenues through which to impart health knowledge and functional skills. This article draws on classroom observations and qualitative interviews with 21 students and 3 teachers in an adult education health literacy class to explore the efficacy of using adult education courses to teach functional health literacy skills to low-literate populations. Data were analyzed using a combination of thematic and content analyses. Results describe the motivation of students to share information within the classroom and with friends and family outside the classroom. This article also provides several recommendations to help ensure accuracy of diffused information both within and outside of the classroom. Ultimately, this study suggests that the adult education system is in a prime position to impart functional health literacy skills to low-literate populations in the classroom. Significantly, this study demonstrates that adult education students themselves may be a powerful vehicle for health communication beyond the walls of the classroom.

  14. Molecular alterations of KIT oncogene in gliomas.

    PubMed

    Gomes, Ana L; Reis-Filho, Jorge S; Lopes, José M; Martinho, Olga; Lambros, Maryou B K; Martins, Albino; Schmitt, Fernando; Pardal, Fernando; Reis, Rui M

    2007-01-01

    Gliomas are the most common and devastating primary brain tumours. Despite therapeutic advances, the majority of gliomas do not respond either to chemo or radiotherapy. KIT, a class III receptor tyrosine kinase (RTK), is frequently involved in tumourigenic processes. Currently, KIT constitutes an attractive therapeutic target. In the present study we assessed the frequency of KIT overexpression in gliomas and investigated the genetic mechanisms underlying KIT overexpression. KIT (CD117) immunohistochemistry was performed in a series of 179 gliomas of various grades. KIT activating gene mutations (exons 9, 11, 13 and 17) and gene amplification analysis, as defined by chromogenic in situ hybridization (CISH) and quantitative real-time PCR (qRT-PCR) were performed in CD117 positive cases. Tumour cell immunopositivity was detected in 15.6% (28/179) of cases, namely in 25% (1/4) of pilocytic astrocytomas, 25% (5/20) of diffuse astrocytomas, 20% (1/5) of anaplastic astrocytomas, 19.5% (15/77) of glioblastomas and one third (3/9) of anaplastic oligoastrocytomas. Only 5.7% (2/35) of anaplastic oligodendrogliomas showed CD117 immunoreactivity. No association was found between tumour CD117 overexpression and patient survival. In addition, we also observed CD117 overexpression in endothelial cells, which varied from 0-22.2% of cases, being more frequent in high-grade lesions. No KIT activating mutations were identified. Interestingly, CISH and/or qRT-PCR analysis revealed the presence of KIT gene amplification in 6 glioblastomas and 2 anaplastic oligoastrocytomas, corresponding to 33% (8/24) of CD117 positive cases. In conclusion, our results demonstrate that KIT gene amplification rather than gene mutation is a common genetic mechanism underlying KIT expression in subset of malignant gliomas. Further studies are warranted to determine whether glioma patients exhibiting KIT overexpression and KIT gene amplification may benefit from therapy with anti-KIT RTK inhibitors.

  15. Applications of hybrid diffuse optics for clinical management of adults after brain injury

    NASA Astrophysics Data System (ADS)

    Kim, Meeri Nam

    Information about cerebral blood flow (CBF) is valuable for clinical management of patients after severe brain injury. Unfortunately, current modalities for monitoring brain are often limited by hurdles that include high cost, low throughput, exposure to ionizing radiation, probe invasiveness, and increased risk to critically ill patients when transportation out of their room or unit is required. A further limitation of current technologies is an inability to provide continuous bedside measurements that are often desirable for unstable patients. Here we explore the clinical utility of diffuse correlation spectroscopy (DCS) as an alternative approach for bedside CBF monitoring. DCS uses the rapid intensity fluctuations of near-infrared light to derive a continuous measure of changes in blood flow without ionizing radiation or invasive probing. Concurrently, we employ another optical technique, called diffuse optical spectroscopy (DOS), to derive changes in cerebral oxyhemoglobin ( HbO2) and deoxyhemoglobin (Hb) concentrations. Our clinical studies integrate DCS with DOS into a single hybrid instrument that simultaneously monitors CBF and HbO2/Hb in the injured adult brain. The first parts of this dissertation present the motivations for monitoring blood flow in injured brain, as well as the theory underlying diffuse optics technology. The next section elaborates on details of the hybrid instrumentation. The final chapters describe four human subject studies carried out with these methods. Each of these studies investigates an aspect of the potential of the hybrid monitor in clinical applications involving adult brain. The studies include: (1) validation of DCS-measured CBF against xenon-enhanced computed tomography in brain-injured adults; (2) a study of the effects of age and gender on posture-change-induced CBF variation in healthy subjects; (3) a study of the efficacy of DCS/DOS for monitoring neurocritical care patients during various medical interventions such

  16. 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.

  17. Subjective Quality of Life in Persons with Low-Grade Glioma and Their Next of Kin

    ERIC Educational Resources Information Center

    Edvardsson, Tanja I.; Ahlstrom, Gerd I.

    2009-01-01

    Patients with low-grade glioma have a longer survival than patients with highly malignant glioma, and for this reason questions of quality of life (QoL) are of particular importance to such patients as well as to their next of kin. No studies have been found in which both adult patients with low-grade glioma and their next of kin have estimated…

  18. Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas

    PubMed Central

    Paugh, Barbara S.; Zhu, Xiaoyan; Qu, Chunxu; Endersby, Raelene; Diaz, Alexander K.; Zhang, Junyuan; Bax, Dorine A.; Carvalho, Diana; Reis, Rui M.; Onar-Thomas, Arzu; Broniscer, Alberto; Wetmore, Cynthia; Zhang, Jinghui; Jones, Chris; Ellison, David W.; Baker, Suzanne J.

    2013-01-01

    The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10–30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 non-brainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. PMID:23970477

  19. Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use

    PubMed Central

    Cervellione, Kelly; Cottone, John; Ardekani, Babak A.; Kumra, Sanjiv

    2012-01-01

    Background There is growing evidence that adolescence is a key period for neuronal maturation. Despite the high prevalence of marijuana use among adolescents and young adults in the United States and internationally, very little is known about its impact on the developing brain. Based on neuroimaging literature on normal brain developmental during adolescence, we hypothesized that individuals with heavy cannabis use (HCU) would have brain structure abnormalities in similar brain regions that undergo development during late adolescence, particularly the fronto-temporal connection. Method Fourteen young adult males in residential treatment for cannabis dependence and 14 age-matched healthy male control subjects were recruited. Patients had a history of HCU throughout adolescence; 5 had concurrent alcohol abuse. Subjects underwent structural and diffusion tensor magnetic resonance imaging. White matter integrity was compared between subject groups using voxelwise and fiber tractography analysis. Results Voxelwise and tractography analyses revealed that adolescents with HCU had reduced fractional anisotropy, increased radial diffusivity, and increased trace in the homologous areas known to be involved in ongoing development during late adolescence, particularly in the fronto-temporal connection via arcuate fasciculus. Conclusions Our results support the hypothesis that heavy cannabis use during adolescence may affect the trajectory of normal brain maturation. Due to concurrent alcohol consumption in five HCU subjects, conclusions from this study should be considered preliminary, as the DTI findings reported here may be reflective of the combination of alcohol and marijuana use. Further research in larger samples, longitudinal in nature, and controlling for alcohol consumption is needed to better understand the pathophysiology of the effect of cannabis on the developing brain. PMID:19111160

  20. 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

  1. 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

  2. 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.

  3. Adult age differences in interference from a prospective-memory task: a diffusion model analysis.

    PubMed

    Horn, Sebastian S; Bayen, Ute J; Smith, Rebekah E

    2013-12-01

    People often slow down their ongoing activities when they must remember an intended action, known as the cost or interference effect of prospective memory (PM). Only a few studies have examined adult age differences in PM interference, and the specific reasons underlying such differences are not well understood. The authors used a model-based approach to reveal processes underlying PM interference and age differences in these processes. Older and younger adults first performed a block of an ongoing lexical decision task alone. An embedded event-based PM task was added in a second block. Simultaneously accounting for the changes in response time distributions and error rates induced by the PM task, Ratcliff's (Psychological Review 85:59-108, 1978) diffusion model was used to decompose the nonlinear combination of speed and accuracy into psychologically meaningful components. Remembering an intention not only reduced processing efficiency in both age groups, but also prolonged peripheral nondecision times and induced response cautiousness. Overall, the findings suggest that there are multiple, but qualitatively similar factors underlying PM task interference in both age groups.

  4. 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

  5. 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

  6. [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

  7. Human immunoglobulin G levels of viruses and associated glioma risk.

    PubMed

    Sjöström, Sara; Hjalmars, Ulf; Juto, Per; Wadell, Göran; Hallmans, Göran; Tjönneland, Anne; Halkjaer, Jytte; Manjer, Jonas; Almquist, Martin; Melin, Beatrice S

    2011-09-01

    Few consistent etiological factors have been identified for primary brain tumors. Inverse associations to asthma and low levels of varicella-zoster virus, immunoglobulin (Ig) levels in prevalent cases have indicted a role for the immune system in the development of glioma. Because samples from prevalent cases of glioma could be influenced by treatments such as steroids and chemotherapy, we investigated pre-diagnostic samples from three large Scandinavian cohorts. To test the hypothesis that immune response levels to these viruses are associated etiologically with glioma risk, we investigated pre-diagnostic immunoglobulin levels for cytomegalovirus (CMV), varicella-zoster virus (VZV), adenovirus (Ad), and Epstein-Barr virus (EBV) including the nuclear antigen (EBNA1) using plasma samples from 197 cases of adult glioma and 394 controls collected from population-based cohorts in Sweden and Denmark. Low VZV IgG levels were marginally significantly more common in glioma cases than the controls (odds ratio (OR) = 0.68, 95% CI 0.41-1.13) for the fourth compared with the first quartile (p = 0.06 for trend). These results were more prominent when analyzing cases with blood sampling at least 2 years before diagnosis (OR = 0.63, 95% CI 0.37-1.08) (p = 0.03). No association with glioma risk was observed for CMV, EBV, and adenovirus.

  8. 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

  9. Gliomas Genomics and Epigenomics: Arriving at the Start and Knowing It for the First Time.

    PubMed

    Filbin, Mariella G; Suvà, Mario L

    2016-05-23

    Gliomas are the most common primary human brain tumors and occur in both adults and children. Over the past few years, systematic large-scale genomic and epigenomic profiling has provided unprecedented insight into their pathogenesis, uncovering alterations in an unanticipated number of genes and regulatory elements. In this review, we discuss recent discoveries about the genomics and epigenomics of adult and pediatric gliomas and highlight how some of the founding genetic mutations reshape the cancer epigenome. These studies provide an in-depth view of the molecular routes leading to glioma development, offer insight into the cancer stem cell model, help refine classifications, and should lay the foundation for improved clinical care.

  10. Progressive Gender Differences of Structural Brain Networks in Healthy Adults: A Longitudinal, Diffusion Tensor Imaging Study

    PubMed Central

    Sun, Yu; Lee, Renick; Chen, Yu; Collinson, Simon; Thakor, Nitish; Bezerianos, Anastasios; Sim, Kang

    2015-01-01

    Sexual dimorphism in the brain maturation during childhood and adolescence has been repeatedly documented, which may underlie the differences in behaviors and cognitive performance. However, our understanding of how gender modulates the development of structural connectome in healthy adults is still not entirely clear. Here we utilized graph theoretical analysis of longitudinal diffusion tensor imaging data over a five-year period to investigate the progressive gender differences of brain network topology. The brain networks of both genders showed prominent economical “small-world” architecture (high local clustering and short paths between nodes). Additional analysis revealed a more economical “small-world” architecture in females as well as a greater global efficiency in males regardless of scan time point. At the regional level, both increased and decreased efficiency were found across the cerebral cortex for both males and females, indicating a compensation mechanism of cortical network reorganization over time. Furthermore, we found that weighted clustering coefficient exhibited significant gender-time interactions, implying different development trends between males and females. Moreover, several specific brain regions (e.g., insula, superior temporal gyrus, cuneus, putamen, and parahippocampal gyrus) exhibited different development trajectories between males and females. Our findings further prove the presence of sexual dimorphism in brain structures that may underlie gender differences in behavioral and cognitive functioning. The sex-specific progress trajectories in brain connectome revealed in this work provide an important foundation to delineate the gender related pathophysiological mechanisms in various neuropsychiatric disorders, which may potentially guide the development of sex-specific treatments for these devastating brain disorders. PMID:25742013

  11. Diffuse Infantile Hepatic Hemangioendothelioma With Early Central Enhancement in an Adult: A Case Report of CT and MRI Findings.

    PubMed

    Dong, Aisheng; Dong, Hui; Zuo, Changjing; He, Tianlin

    2015-12-01

    Infantile hepatic hemangioendothelioma (IHH) is the most common vascular tumor of the liver in infancy. Adult with IHH is extremely rare. We presented a diffuse IHH in an adult patient with computed tomography (CT) and magnetic resonance image (MRI) findings.A 39-year-old man was admitted to our hospital because of a 2-year history of abnormal liver function tests and a 7-day history of jaundice. Physical examination revealed enlarged liver. Unenhanced abdominal CT showed enlargement of the liver with diffuse hypodensity. Enhanced CT on the arterial phase revealed multiple centrally enhanced lesions diffusely involved the enlarged liver. The enhanced areas of the lesions became larger on the portal phase and all the lesions became homogeneous enhanced on the delayed phase. These lesions showed heterogeneously hyperintense on T2-weighted image, hypointense on T1-weighted image, and early centrally enhanced on dynamic gadolinium-enhanced MRI, with complete tumor enhancement after 180 s. The patient underwent orthotopic liver transplantation. IHH type 2 was confirmed by pathology. The patient died of tumor recurrence in the liver 4 months after transplantation.Unlike the previously described imaging appearances of IHH, this case showed diffuse nodules with early central enhancement on CT and MRI. Considering the importance of the ability to differentiate IHH from other hepatic tumors, radiologists should be aware of these imaging appearances to establish knowledge of the entire spectrum of IHH.

  12. 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.

  13. Stimulation of glioma cell motility by expression, proteolysis, and release of the L1 neural cell recognition molecule

    PubMed Central

    Yang, Muhua; Adla, Shalini; Temburni, Murali K; Patel, Vivek P; Lagow, Errin L; Brady, Owen A; Tian, Jing; Boulos, Magdy I; Galileo, Deni S

    2009-01-01

    Background Malignant glioma cells are particularly motile and can travel diffusely through the brain parenchyma, apparently without following anatomical structures to guide their migration. The neural adhesion/recognition protein L1 (L1CAM; CD171) has been implicated in contributing to stimulation of motility and metastasis of several non-neural cancer types. We explored the expression and function of L1 protein as a stimulator of glioma cell motility using human high-grade glioma surgical specimens and established rat and human glioma cell lines. Results L1 protein expression was found in 17 out of 18 human high-grade glioma surgical specimens by western blotting. L1 mRNA was found to be present in human U-87/LacZ and rat C6 and 9L glioma cell lines. The glioma cell lines were negative for surface full length L1 by flow cytometry and high resolution immunocytochemistry of live cells. However, fixed and permeablized cells exhibited positive staining as numerous intracellular puncta. Western blots of cell line extracts revealed L1 proteolysis into a large soluble ectodomain (~180 kDa) and a smaller transmembrane proteolytic fragment (~32 kDa). Exosomal vesicles released by the glioma cell lines were purified and contained both full-length L1 and the proteolyzed transmembrane fragment. Glioma cell lines expressed L1-binding αvβ5 integrin cell surface receptors. Quantitative time-lapse analyses showed that motility was reduced significantly in glioma cell lines by 1) infection with an antisense-L1 retroviral vector and 2) L1 ectodomain-binding antibodies. Conclusion Our novel results support a model of autocrine/paracrine stimulation of cell motility in glioma cells by a cleaved L1 ectodomain and/or released exosomal vesicles containing L1. This mechanism could explain the diffuse migratory behavior of high-grade glioma cancer cells within the brain. PMID:19874583

  14. 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

  15. Serum proteomics of glioma: methods and applications.

    PubMed

    Somasundaram, Kumaravel; Nijaguna, Mamatha B; Kumar, Durairaj Mohan

    2009-10-01

    The prognosis of patients with glioblastoma, the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation and chemotherapy. Genetic heterogeneity of glioblastoma warrants extensive studies in order to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. Serum biomarkers have the potential to revolutionize the process of cancer diagnosis, grading, prognostication and treatment response monitoring. Besides having the advantage that serum can be obtained through a less invasive procedure, it contains molecules at an extraordinary dynamic range of ten orders of magnitude in terms of their concentrations. While the conventional methods, such as 2DE, have been in use for many years, the ability to identify the proteins through mass spectrometry techniques such as MALDI-TOF led to an explosion of interest in proteomics. Relatively new high-throughput proteomics methods such as SELDI-TOF and protein microarrays are expected to hasten the process of serum biomarker discovery. This review will highlight the recent advances in the proteomics platform in discovering serum biomarkers and the current status of glioma serum markers. We aim to provide the principles and potential of the latest proteomic approaches and their applications in the biomarker discovery process. Besides providing a comprehensive list of available serum biomarkers of glioma, we will also propose how these markers will revolutionize the clinical management of glioma patients.

  16. Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk.

    PubMed

    Safaeian, Mahboobeh; Rajaraman, Preetha; Hartge, Patricia; Yeager, Meredith; Linet, Martha; Butler, Mary Ann; Ruder, Avima M; Purdue, Mark P; Hsing, Ann; Beane-Freeman, Laura; Hoppin, Jane A; Albanes, Demetrius; Weinstein, Stephanie J; Inskip, Peter D; Brenner, Alina; Rothman, Nathaniel; Chatterjee, Nilanjan; Gillanders, Elizabeth M; Chanock, Stephen J; Wang, Sophia S

    2013-10-01

    Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the 'at-risk' variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55-0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47-0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma.

  17. 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

  18. 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.

  19. The role of drebrin in glioma migration and invasion

    SciTech Connect

    Terakawa, Yuzo; Agnihotri, Sameer; Golbourn, Brian; Nadi, Mustafa; Sabha, Nesrin; Smith, Christian A.; Croul, Sidney E.; Rutka, James T.

    2013-02-15

    Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite current advances in therapy consisting of surgery followed by chemotherapy and radiation, the overall survival rate still remains poor. Therapeutic failures are partly attributable to the highly infiltrative nature of tumor adjacent to normal brain parenchyma. Recently, evidence is mounting to suggest that actin cytoskeleton dynamics are critical components of the cell invasion process. Drebrin is an actin-binding protein involved in the regulation of actin filament organization, and plays a significant role in cell motility; however, the role of drebrin in glioma cell invasiveness has not yet been fully elucidated. Therefore, this study was aimed to clarify the role of drebrin in glioma cell morphology and cell motility. Here we show that drebrin is expressed in glioma cell lines and in operative specimens of GBM. We demonstrate that stable overexpression of drebrin in U87 cells leads to alterations in cell morphology, and induces increased invasiveness in vitro while knockdown of drebrin in U87 cells by small interfering RNA (siRNA) decreases invasion and migration. In addition, we show that depletion of drebrin by siRNA alters glioma cell morphology in A172 GBM cell line. Our results suggest that drebrin contributes to the maintenance of cell shape, and may play an important role in glioma cell motility. - Highlights: ► Drebrin is an actin-binding protein aberrantly expressed in several cancers. ► Role of drebrin in glioma cell morphology and motility is previously unknown. ► We demonstrate that drebrin is expressed in 40% of glioblastoma specimens. ► Drebrin plays a significant role in modulating glioma cell migration and invasion.

  20. Hyperbaric oxygen promotes malignant glioma cell growth and inhibits cell apoptosis.

    PubMed

    Wang, Yong-Gang; Zhan, Yi-Ping; Pan, Shu-Yi; Wang, Hai-Dong; Zhang, Dun-Xiao; Gao, Kai; Qi, Xue-Ling; Yu, Chun-Jiang

    2015-07-01

    Glioblastoma multiforme (GBM) is the most frequently diagnosed intracranial malignant tumor in adults. Clinical studies have indicated that hyperbaric oxygen may improve the prognosis and reduce complications in glioma patients; however, the specific mechanism by which this occurs remains unknown. The present study investigated the direct effects of hyperbaric oxygen stimulation on glioma by constructing an intracranial transplanted glioma model in congenic C57BL/6J mice. Bioluminescent imaging (BLI) was used to assess the growth of intracranial transplanted GL261-Luc glioma cells in vivo, while flow cytometric and immunohistochemical assays were used to detect and compare the expression of the biomarkers, Ki-67, CD34 and TUNEL, reflecting the cell cycle, apoptosis and angiogenesis. BLI demonstrated that hyperbaric oxygen promoted the growth of intracranially transplanted GL261-Luc glioma cells in vivo. Flow cytometric analysis indicated that hyperbaric oxygen promoted GL261-Luc glioma cell proliferation and also prevented cell cycle arrest. In addition, hyperbaric oxygen inhibited the apoptosis of the transplanted glioma cells. Immunohistochemical analysis also indicated that hyperbaric oxygen increased positive staining for Ki-67 and CD34, while reducing staining for TUNEL (a marker of apoptosis). The microvessel density was significantly increased in the hyperbaric oxygen treatment group compared with the control group. In conclusion, hyperbaric oxygen treatment promoted the growth of transplanted malignant glioma cells in vivo and also inhibited the apoptosis of these cells.

  1. Noninvasive amide proton transfer magnetic resonance imaging in evaluating the grading and cellularity of gliomas

    PubMed Central

    Zhang, Wei; Kong, Lingfei; Wang, Lifu; Zuo, Panli; Vallines, Ignacio; Schmitt, Benjamin; Tian, Jie; Song, Xiaolei; Zhou, Jinyuan; Wang, Meiyun

    2017-01-01

    Using noninvasive magnetic resonance imaging techniques to accurately evaluate the grading and cellularity of gliomas is beneficial for improving the patient outcomes. Amide proton transfer imaging is a noninvasive molecular magnetic resonance imaging technique based on chemical exchange saturation transfer mechanism that detects endogenous mobile proteins and peptides in biological tissues. Between August 2012 and November 2015, a total number of 44 patients with pathologically proven gliomas were included in this study. We compared the capability of amide proton transfer magnetic resonance imaging with that of noninvasive diffusion-weighted imaging and noninvasive 3-dimensional pseudo-continuous arterial spin imaging in evaluating the grading and cellularity of gliomas. Our results reveal that amide proton transfer magnetic resonance imaging is a superior imaging technique to diffusion-weighted imaging and 3-dimensional pseudo-continuous arterial spin imaging in the grading of gliomas. In addition, our results showed that the Ki-67 index correlated better with the amide proton transfer-weighted signal intensity than with the apparent diffusion coefficient value or the cerebral blood flow value in the gliomas. Amide proton transfer magnetic resonance imaging is a promising method for predicting the grading and cellularity of gliomas. PMID:27992380

  2. Noninvasive amide proton transfer magnetic resonance imaging in evaluating the grading and cellularity of gliomas.

    PubMed

    Bai, Yan; Lin, Yusong; Zhang, Wei; Kong, Lingfei; Wang, Lifu; Zuo, Panli; Vallines, Ignacio; Schmitt, Benjamin; Tian, Jie; Song, Xiaolei; Zhou, Jinyuan; Wang, Meiyun

    2017-01-24

    Using noninvasive magnetic resonance imaging techniques to accurately evaluate the grading and cellularity of gliomas is beneficial for improving the patient outcomes. Amide proton transfer imaging is a noninvasive molecular magnetic resonance imaging technique based on chemical exchange saturation transfer mechanism that detects endogenous mobile proteins and peptides in biological tissues. Between August 2012 and November 2015, a total number of 44 patients with pathologically proven gliomas were included in this study. We compared the capability of amide proton transfer magnetic resonance imaging with that of noninvasive diffusion-weighted imaging and noninvasive 3-dimensional pseudo-continuous arterial spin imaging in evaluating the grading and cellularity of gliomas. Our results reveal that amide proton transfer magnetic resonance imaging is a superior imaging technique to diffusion-weighted imaging and 3-dimensional pseudo-continuous arterial spin imaging in the grading of gliomas. In addition, our results showed that the Ki-67 index correlated better with the amide proton transfer-weighted signal intensity than with the apparent diffusion coefficient value or the cerebral blood flow value in the gliomas. Amide proton transfer magnetic resonance imaging is a promising method for predicting the grading and cellularity of gliomas.

  3. Participation and diffusion effects of a peer-intervention for HIV prevention among adults in rural Malawi.

    PubMed

    Crittenden, Kathleen S; Kaponda, Chrissie P N; Jere, Diana L; McCreary, Linda L; Norr, Kathleen F

    2015-05-01

    This paper examines whether a peer group intervention that reduced self-reported risky behaviors for rural adults in Malawi also had impacts on non-participants in the same communities. We randomly assigned two districts to the intervention and control conditions, and conducted surveys at baseline and 18 months post-intervention using unmatched independent random samples of intervention and control communities in 2003-2006. The six-session peer group intervention was offered to same-gender groups by trained volunteers. In this analysis, we divided the post-intervention sample into three exposure groups: 243 participants and 170 non-participants from the intervention district (total n = 415) and 413 control individuals. Controlling for demographics and participation, there were significant favorable diffusion effects on five partially overlapping behavioral outcomes: partner communication, ever used condoms, unprotected sex, recent HIV test, and a community HIV prevention index. Non-participants in the intervention district had more favorable outcomes on these behaviors than survey respondents in the control district. One behavioral outcome, community HIV prevention, showed both participation and diffusion effects. Participating in the intervention had a significant effect on six psychosocial outcomes: HIV knowledge (two measures), hope, condom attitudes, and self-efficacy for community HIV prevention and for safer sex; there were no diffusion effects. This pattern of results suggests that the behavioral changes promoted in the intervention spread to others in the same community, most likely through direct contact between participants and non-participants. These findings support the idea that diffusion of HIV-related behavior changes can occur for peer group interventions in communities, adding to the body of research supporting diffusion of innovations theory as a robust approach to accelerating change. If diffusion occurs, peer group intervention may be more

  4. 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

  5. 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.

  6. 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.

  7. Diffusion of Technology: Frequency of Use for Younger and Older Adults.

    PubMed

    Olson, Katherine E; O'Brien, Marita A; Rogers, Wendy A; Charness, Neil

    2011-03-01

    OBJECTIVES: When we think of technology-savvy consumers, older adults are typically not the first persons that come to mind. The common misconception is that older adults do not want to use or cannot use technology. But for an increasing number of older adults, this is not true (Pew Internet and American Life Project, 2003). Older adults do use technologies similar to their younger counterparts, but perhaps at different usage rates. Previous research has identified that there may be subgroups of older adults, "Silver Surfers", whose adoption patterns mimic younger adults (Pew Internet and American Life Project, 2003). Much of the previous research on age-related differences in technology usage has only investigated usage broadly -- from a "used" or "not used" standpoint. The present study investigated age-related differences in overall usage of technologies, as well as frequency of technology usage (i.e., never, occasional, or frequent). METHODS: The data were gathered through a questionnaire from younger adults (N=430) and older adults (N=251) in three geographically separate and ethnically diverse areas of the United States. RESULTS: We found that younger adults use a greater breadth of technologies than older adults. However, age-related differences in usage and the frequency of use depend on the technology domain. CONCLUSION: This paper presents technology usage and frequency data to highlight age-related differences and similarities. The results provide insights into older and younger adults' technology-use patterns, which in turn provide a basis for expectations about knowledge differences. Designers and trainers can benefit from understanding experience and knowledge differences.

  8. Carfilzomib, Rituximab, and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2017-03-07

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  9. Microscopic DTI accurately identifies early glioma cell migration: correlation with multimodal imaging in a new glioma stem cell model.

    PubMed

    Gimenez, Ulysse; Perles-Barbacaru, Adriana-T; Millet, Arnaud; Appaix, Florence; El-Atifi, Michele; Pernet-Gallay, Karin; van der Sanden, Boudewijn; Berger, François; Lahrech, Hana

    2016-11-01

    Monitoring glioma cell infiltration in the brain is critical for diagnosis and therapy. Using a new glioma Glio6 mouse model derived from human stem cells we show how diffusion tensor imaging (DTI) may predict glioma cell migration/invasion. In vivo multiparametric MRI was performed at one, two and three months of Glio6 glioma growth (Glio6 (n = 6), sham (n = 3)). This longitudinal study reveals the existence of a time window to study glioma cell/migration/invasion selectively. Indeed, at two months only Glio6 cell invasion was detected, while tumor mass formation, edema, blood-brain barrier leakage and tumor angiogenesis were detected later, at three months. To robustly confirm the potential of DTI for detecting glioma cell migration/invasion, a microscopic 3D-DTI (80 μm isotropic spatial resolution) technique was developed and applied to fixed mouse brains (Glio6 (n = 6), sham (n = 3)). DTI changes were predominant in the corpus callosum (CC), a known path of cell migration. Fractional anisotropy (FA) and perpendicular diffusivity (D⊥ ) changes derived from ex vivo microscopic 3D-DTI were significant at two months of tumor growth. In the caudate putamen an FA increase of +38% (p < 0.001) was observed, while in the CC a - 28% decrease in FA (p < 0.005) and a + 95% increase in D⊥ (p < 0.005) were observed. In the CC, DTI changes and fluorescent Glio6 cell density obtained by two-photon microscopy in the same brains were correlated (p < 0.001, r = 0.69), validating FA and D⊥ as early quantitative biomarkers to detect glioma cell migration/invasion. The origin of DTI changes was assessed by electron microscopy of the same tract, showing axon bundle disorganization. During the first two months, Glio6 cells display a migratory phenotype without being associated with the constitution of a brain tumor mass. This offers a unique opportunity to apply microscopic 3D-DTI and to validate DTI parameters FA and D⊥ as biomarkers for glioma cell

  10. Complete remission of diffuse hepatocellular carcinoma in a young adult after GSP-TACE: a case report.

    PubMed

    Liu, Song; Zhang, Yuewei; Zhao, Guangsheng; Liu, Ying

    2014-09-25

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. It mostly occurs in older age groups (usually those 50 to 60 years old), and rarely in young adults. The survival rate of these young HCC patients is usually very low. The authors report a case of a 22-year old man with diffuse-type HCC who successfully achieved complete remission for 46 months after second transcatheter arterial chemoembolization using gelatin sponge particles (Eric Kang Pharmaceutical Technology Co., Ltd. Hangzhou, China) combined with pirarubicin.

  11. [18F]-fluoro-l-thymidine PET and advanced MRI for preoperative grading of gliomas

    PubMed Central

    Collet, S.; Valable, S.; Constans, J.M.; Lechapt-Zalcman, E.; Roussel, S.; Delcroix, N.; Abbas, A.; Ibazizene, M.; Bernaudin, M.; Barré, L.; Derlon, J.M.; Guillamo, J.S.

    2015-01-01

    Purpose Conventional MRI based on contrast enhancement is often not sufficient in differentiating grade II from grade III and grade III from grade IV diffuse gliomas. We assessed advanced MRI, MR spectroscopy and [18F]-fluoro-l-thymidine ([18F]-FLT) PET as tools to overcome these limitations. Methods In this prospective study, thirty-nine patients with diffuse gliomas of grades II, III or IV underwent conventional MRI, perfusion, diffusion, proton MR spectroscopy (1H-MRS) and [18F]-FLT-PET imaging before surgery. Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), Cho/Cr, NAA/Cr, Cho/NAA and FLT-SUV were compared between grades. Results Cho/Cr showed significant differences between grade II and grade III gliomas (p = 0.03). To discriminate grade II from grade IV and grade III from grade IV gliomas, the most relevant parameter was the maximum value of [18F]-FLT uptake FLTmax (respectively, p < 0.001 and p < 0.0001). The parameter showing the best correlation with the grade was the mean value of [18F]-FLT uptake FLTmean (R2 = 0.36, p < 0.0001) and FLTmax (R2 = 0.5, p < 0.0001). Conclusion Whereas advanced MRI parameters give indications for the grading of gliomas, the addition of [18F]-FLT-PET could be of interest for the accurate preoperative classification of diffuse gliomas, particularly for identification of doubtful grade III and IV gliomas. PMID:26106569

  12. Diffusion of Technology: Frequency of Use for Younger and Older Adults

    PubMed Central

    Olson, Katherine E.; O’Brien, Marita A.; Rogers, Wendy A.; Charness, Neil

    2012-01-01

    Objectives When we think of technology-savvy consumers, older adults are typically not the first persons that come to mind. The common misconception is that older adults do not want to use or cannot use technology. But for an increasing number of older adults, this is not true (Pew Internet and American Life Project, 2003). Older adults do use technologies similar to their younger counterparts, but perhaps at different usage rates. Previous research has identified that there may be subgroups of older adults, “Silver Surfers”, whose adoption patterns mimic younger adults (Pew Internet and American Life Project, 2003). Much of the previous research on age-related differences in technology usage has only investigated usage broadly -- from a “used” or “not used” standpoint. The present study investigated age-related differences in overall usage of technologies, as well as frequency of technology usage (i.e., never, occasional, or frequent). Methods The data were gathered through a questionnaire from younger adults (N=430) and older adults (N=251) in three geographically separate and ethnically diverse areas of the United States. Results We found that younger adults use a greater breadth of technologies than older adults. However, age-related differences in usage and the frequency of use depend on the technology domain. Conclusion This paper presents technology usage and frequency data to highlight age-related differences and similarities. The results provide insights into older and younger adults’ technology-use patterns, which in turn provide a basis for expectations about knowledge differences. Designers and trainers can benefit from understanding experience and knowledge differences. PMID:22685360

  13. Central nervous system involvement in adult patients with diffuse large B-cell lymphoma: Influence of rituximab

    PubMed Central

    CAO, BING; ZHOU, XIAOYAN; JI, DONGMEI; CAO, JUNNING; GUO, YE; ZHANG, QUNLING; WU, XIANGHUA; LI, JUNMIN; WANG, JIANMIN; CHEN, FANGYUAN; WANG, CHUN; ZOU, SHANHUA; HONG, XIAONAN

    2012-01-01

    CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy, in combination with rituximab (R-CHOP-like), improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to investigate the impact of rituximab on central nervous system (CNS) disease in adult patients. We studied 315 patients (aged 18–60 years old) from six hospitals between July 2003 and May 2008. All patients received CHOP-like (n=165) or R-CHOP-like (n=150) regimen every 3 weeks. With a median follow-up of 3.69 years, 10 patients (3.17%) developed CNS disease. The cumulative risk of CNS occurrence was not significantly different between the two treatment groups (P=0.871). We conclude that the addition of rituximab did not reduce the risk of CNS disease in adult patients with DLBCL. PMID:22970053

  14. Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas

    PubMed Central

    2014-01-01

    Background Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers. Methods We searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas. Results FLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients’ sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC. Conclusions The present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study

  15. Melatonergic system-based two-gene index is prognostic in human gliomas.

    PubMed

    Kinker, Gabriela S; Oba-Shinjo, Sueli M; Carvalho-Sousa, Claudia E; Muxel, Sandra M; Marie, Suely K N; Markus, Regina P; Fernandes, Pedro A

    2016-01-01

    Gliomas, the most common primary brain tumors in adults, are classified into four malignancy grades according to morphological features. Recent studies have shown that melatonin treatment induces cytotoxicity in glioma-initiating cells and reduces the invasion and migration of glioma cell lines, inhibiting the nuclear factor κB (NFκB) oncopathway. Given that C6 rat glioma cells produce melatonin, we investigated the correlation between the capacity of gliomas to synthesize/metabolize melatonin and their overall malignancy. We first characterized the melatonergic system of human gliomas cell lines with different grades of aggressiveness (HOG, T98G, and U87MG) and demonstrated that glioma-synthesized melatonin exerts an autocrine antiproliferative effect. Accordingly, the sensitivity to exogenous melatonin was higher for the most aggressive cell line, U87MG, which synthesized/accumulated less melatonin. Using The Cancer Genome Atlas RNAseq data of 351 glioma patients, we designed a predictive model of the content of melatonin in the tumor microenvironment, the ASMT:CYP1B1 index, combining the gene expression levels of melatonin synthesis and metabolism enzymes. The ASMT:CYP1B1 index negatively correlated with tumor grade, as well as with the expression of pro-proliferation and anti-apoptotic NFκB target genes. More importantly, the index was a grade- and histological type-independent prognostic factor. Even when considering only high-grade glioma patients, a low ASMT:CYP1B1 value, which suggests decreased melatonin and enhanced aggressiveness, was strongly associated with poor survival. Overall, our data reveal the prognostic value of the melatonergic system of gliomas and provide insights into the therapeutic role of melatonin.

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

    PubMed

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

    1984-03-01

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

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

    PubMed Central

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

    1984-01-01

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

  18. Association of BCL2-938C>A genetic polymorphism with glioma risk in Chinese Han population.

    PubMed

    Li, Wei; Qian, Chunfa; Wang, Linxiong; Teng, Hong; Zhang, Li

    2014-03-01

    Glioma is the most common type of primary brain malignancy in adults. The anti-apoptotic protein B-cell lymphoma 2 (BCL2) has been implicated in the pathogenesis of glioma. This study aimed to evaluate the potential association between BCL2-938C>A genetic polymorphism and glioma susceptibility. This case-control study was conducted in Chinese Han populations consisting of 248 glioma cases and 252 cancer-free controls. The BCL2-938C>A genetic polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and verified using DNA sequencing methods. Our data suggested that the genotype/allele of BCL2-938C>A polymorphism were statistically associated with the increased risk of glioma where the risk of glioma for genotype AA or allele A is significantly higher than wild genotype CC (odds ratio (OR) = 2.23, 95% confidence interval (CI) 1.21-4.10, p = 0.009) or allele C (OR = 1.39, 95% CI 1.06-1.82, p = 0.016), respectively. In addition, the BCL2-938AA genotype was significantly more common in patients with glioblastoma and in patients with grade IV glioma. Our findings indicate that the BCL2-938C>A polymorphism is associated with the susceptibility to glioma in Chinese Han populations and might be used as molecular markers for evaluating glioma risk.

  19. 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.

  20. Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas.

    PubMed

    Patel, Y T; Daryani, V M; Patel, P; Zhou, D; Fangusaro, J; Carlile, D J; Martin, P D; Aarons, L; Stewart, C F

    2017-03-22

    Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately. A sequential zero- and first-order absorption with lag time with a two-compartment model for selumetinib and a two-compartment model for N-desmethyl-selumetinib best described the concentration-time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body-surface area based dosing should be used in pediatric patients.

  1. Childhood Brain Stem Glioma Treatment

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood brain stem gliomas may cause ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...

  2. Gene expression profiling of gliomas: merging genomic and histopathological classification for personalised therapy.

    PubMed

    Vitucci, M; Hayes, D N; Miller, C R

    2011-02-15

    The development of DNA microarray technologies over the past decade has revolutionised translational cancer research. These technologies were originally hailed as more objective, comprehensive replacements for traditional histopathological cancer classification systems, based on microscopic morphology. Although DNA microarray-based gene expression profiling (GEP) remains unlikely in the near term to completely replace morphological classification of primary brain tumours, specifically the diffuse gliomas, GEP has confirmed that significant molecular heterogeneity exists within the various morphologically defined gliomas, particularly glioblastoma (GBM). Herein, we provide a 10-year progress report on human glioma GEP, with focus on development of clinical diagnostic tests to identify molecular subtypes, uniquely responsive to adjuvant therapies. Such progress may lead to a more precise classification system that accurately reflects the cellular, genetic, and molecular basis of gliomagenesis, a prerequisite for identifying subsets uniquely responsive to specific adjuvant therapies, and ultimately in achieving individualised clinical care of glioma patients.

  3. Positron Spectroscopy Investigation of Normal Brain Section and Brain Section with Glioma Derived from a Rat Glioma Model

    NASA Astrophysics Data System (ADS)

    Yang, SH.; Ballmann, C.; Quarles, C. A.

    2009-03-01

    The application of positron annihilation lifetime spectroscopy (PALS) and Doppler broadening spectroscopy (DBS) to the study of animal or human tissue has only recently been reported [G. Liu, et al. phys. stat. sol. (C) 4, Nos. 10, 3912-3915 (2007)]. We have initiated a study of normal brain section and brain section with glioma derived from a rat glioma model. For the rat glioma model, 200,000 C6 cells were implanted in the basal ganglion of adult Sprague Dawley rats. The rats were sacrificed at 21 days after implantation. The brains were harvested, sliced into 2 mm thick coronal sections, and fixed in 4% formalin. PALS lifetime runs were made with the samples soaked in formalin, and there was not significant evaporation of formalin during the runs. The lifetime spectra were analyzed into two lifetime components. While early results suggested a small decrease in ortho-Positronium (o-Ps) pickoff lifetime between the normal brain section and brain section with glioma, further runs with additional samples have showed no statistically significant difference between the normal and tumor tissue for this type of tumor. The o-Ps lifetime in formalin alone was lower than either the normal tissue or glioma sample. So annihilation in the formalin absorbed in the samples would lower the o-Ps lifetime and this may have masked any difference due to the glioma itself. DBS was also used to investigate the difference in positronium formation between tumor and normal tissue. Tissue samples are heterogeneous and this needs to be carefully considered if PALS and DBS are to become useful tools in distinguishing tissue samples.

  4. Positron Spectroscopy Investigation of Normal Brain Section and Brain Section with Glioma Derived from a Rat Glioma Model

    SciTech Connect

    Yang, SH.; Ballmann, C.; Quarles, C. A.

    2009-03-10

    The application of positron annihilation lifetime spectroscopy (PALS) and Doppler broadening spectroscopy (DBS) to the study of animal or human tissue has only recently been reported [G. Liu, et al. phys. stat. sol. (C) 4, Nos. 10, 3912-3915 (2007)]. We have initiated a study of normal brain section and brain section with glioma derived from a rat glioma model. For the rat glioma model, 200,000 C6 cells were implanted in the basal ganglion of adult Sprague Dawley rats. The rats were sacrificed at 21 days after implantation. The brains were harvested, sliced into 2 mm thick coronal sections, and fixed in 4% formalin. PALS lifetime runs were made with the samples soaked in formalin, and there was not significant evaporation of formalin during the runs. The lifetime spectra were analyzed into two lifetime components. While early results suggested a small decrease in ortho-Positronium (o-Ps) pickoff lifetime between the normal brain section and brain section with glioma, further runs with additional samples have showed no statistically significant difference between the normal and tumor tissue for this type of tumor. The o-Ps lifetime in formalin alone was lower than either the normal tissue or glioma sample. So annihilation in the formalin absorbed in the samples would lower the o-Ps lifetime and this may have masked any difference due to the glioma itself. DBS was also used to investigate the difference in positronium formation between tumor and normal tissue. Tissue samples are heterogeneous and this needs to be carefully considered if PALS and DBS are to become useful tools in distinguishing tissue samples.

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

    PubMed

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

    2013-01-01

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

  6. Overexpression of FZD7 promotes glioma cell proliferation by upregulating TAZ

    PubMed Central

    Tian, Tian

    2016-01-01

    Gliomas are the most prevalent type of primary brain tumors in adults, accounting for more than 40% of neoplasm in the central nervous system. Frizzled-7 (FZD7) is a seven-pass trans-membrane Wnt receptor that plays a critical role in the development of various tumors. In this study, we detected high-level FZD7 expression in glioma and its overexpression was associated with advanced tumor stage. In vitro functional assays showed that forced overexpression of FZD7 promoted proliferation of gliomas cells, whereas knockdown of endogenous FZD7 significantly suppressed proliferation ability of these cells. In a xenograft assay, FZD7 was also found to promote the growth of glioma cells. We further found that FZD7 could activate transcriptional coactivator with PDZ-binding motif (TAZ), and TAZ was required for FZD7 to promote cell proliferation in glioma. Furthermore, the univariate analysis of survival shows that glioma patients with high FZD7 expression have a shorter survival. In conclusion, our findings demonstrate that FZD7 may promote glioma cell proliferation via upregulation of TAZ. PMID:27852064

  7. Critical Neural Networks in Awake Surgery for Gliomas

    PubMed Central

    KINOSHITA, Masashi; MIYASHITA, Katsuyoshi; TSUTSUI, Taishi; FURUTA, Takuya; NAKADA, Mitsutoshi

    2016-01-01

    From the embarrassing character commonly infiltrating eloquent brain regions, the surgical resection of glioma remains challenging. Owing to the recent development of in vivo visualization techniques for the human brain, white matter regions can be delineated using diffusion tensor imaging (DTI) as a routine clinical practice in neurosurgery. In confirmation of the results of DTI tractography, a direct electrical stimulation (DES) substantially influences the investigation of cortico-subcortical networks, which can be identified via specific symptoms elicited in the concerned white matter tracts (eg., the arcuate fascicle, superior longitudinal fascicles, inferior fronto-occipital fascicle, inferior longitudinal fascicle, frontal aslant tract, sensori-motor tracts, optic radiation, and so forth). During awake surgery for glioma using DES, it is important to identify the anatomo-functional structure of white matter tracts to identify the surgical boundaries of brain regions not only to achieve maximal resection of the glioma but also to maximally preserve quality of life. However, the risk exists that neurosurgeons may be misled by the inability of DTI to visualize the actual anatomy of the white matter fibers, resulting in inappropriate decisions regarding surgical boundaries. This review article provides information of the critical neuronal network that is necessary to identify and understand in awake surgery for glioma, with special references to white matter tracts and the author’s experiences. PMID:27250817

  8. [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.

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

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

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

  10. [Molecular Genetics as Best Evidence in Glioma Diagnostics].

    PubMed

    Masui, Kenta; Komori, Takashi

    2016-03-01

    The development of a genomic landscape of gliomas has led to the internally consistent, molecularly-based classifiers. However, development of a biologically insightful classification to guide therapy is still ongoing. Further, tumors are heterogeneous, and they change and adapt in response to drugs. The challenge of developing molecular classifiers that provide meaningful ways to stratify patients for therapy remains a major challenge for the field. Therefore, by incorporating molecular markers into the new World Health Organization (WHO) classification of tumors of the central nervous system, the traditional principle of diagnosis based on histologic criteria will be replaced by a multilayered approach combining histologic features and molecular information in an "integrated diagnosis", to define tumor entities as narrowly as possible. We herein review the current status of diagnostic molecular markers for gliomas, focusing on IDH mutation, ATRX mutation, 1p/19q co-deletion, and TERT promoter mutation in adult tumors, as well as BRAF and H3F3A aberrations in pediatric gliomas, the combination of which will be a promising endeavor to render molecular genetics as a best evidence in the glioma diagnositics.

  11. Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain.

    PubMed

    Morita, Shoko; Furube, Eriko; Mannari, Tetsuya; Okuda, Hiroaki; Tatsumi, Kouko; Wanaka, Akio; Miyata, Seiji

    2016-02-01

    Fenestrated capillaries of the sensory circumventricular organs (CVOs), including the organum vasculosum of the lamina terminalis, the subfornical organ and the area postrema, lack completeness of the blood-brain barrier (BBB) to sense a variety of blood-derived molecules and to convey the information into other brain regions. We examine the vascular permeability of blood-derived molecules and the expression of tight-junction proteins in sensory CVOs. The present tracer assays revealed that blood-derived dextran 10 k (Dex10k) having a molecular weight (MW) of 10,000 remained in the perivascular space between the inner and outer basement membranes, but fluorescein isothiocyanate (FITC; MW: 389) and Dex3k (MW: 3000) diffused into the parenchyma. The vascular permeability of FITC was higher at central subdivisions than at distal subdivisions. Neither FITC nor Dex3k diffused beyond the dense network of glial fibrillar acidic protein (GFAP)-positive astrocytes/tanycytes. The expression of tight-junction proteins such as occludin, claudin-5 and zonula occludens-1 (ZO-1) was undetectable at the central subdivisions of the sensory CVOs but some was expressed at the distal subdivisions. Electron microscopic observation showed that capillaries were surrounded with numerous layers of astrocyte processes and dendrites. The expression of occludin and ZO-1 was also observed as puncta on GFAP-positive astrocytes/tanycytes of the sensory CVOs. Our study thus demonstrates the heterogeneity of vascular permeability and expression of tight-junction proteins and indicates that the outer basement membrane and dense astrocyte/tanycyte connection are possible alternative mechanisms for a diffusion barrier of blood-derived molecules, instead of the BBB.

  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. Gene therapy for malignant glioma.

    PubMed

    Okura, Hidehiro; Smith, Christian A; Rutka, James T

    2014-01-01

    Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.

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

    PubMed Central

    Pisapia, David; Greenfield, Jeffrey P

    2016-01-01

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

  16. 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.

  17. Isocitrate dehydrogenase mutations in gliomas

    PubMed Central

    Waitkus, Matthew S.; Diplas, Bill H.; Yan, Hai

    2016-01-01

    Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg132 of IDH1 and Arg172 of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2 mutations on molecular classification and glioma therapy. PMID:26188014

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

    PubMed Central

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

    2014-01-01

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

  19. Advanced Image Coregistration within the Leksell Workstation for the Planning of Glioma Surgery: Initial Experience.

    PubMed

    Tamura, Manabu; Hayashi, Motohiro; Konishi, Yoshiyuki; Tamura, Noriko; Regis, Jean; Mangin, Jean François; Taira, Takaomi; Okada, Yoshikazu; Muragaki, Yoshihiro; Iseki, Hiroshi

    2013-12-01

    Background Leksell GammaPlan (LGP) and SurgiPlan (ELEKTA Instruments AB, Stockholm, Sweden) may be used effectively for the detailed evaluation of regional neuroanatomy before open neurosurgical procedures. We report our initial experience in the cases of cerebral gliomas. Methods LGP v.8.3 was used before the surgical resection of cerebral gliomas for (1) the delineation of subdural grid electrodes and a detailed evaluation of their position relatively to cortical structures, and (2) for the fusion of structural magnetic resonance imaging and diffusion tensor imaging (DTI) for a detailed visualization of the corticospinal tract (CST) and optic radiation. Results Delineation of the subdural grid within LGP in a patient with seizures caused by left parietal glioma permitted a detailed assessment of the location of electrodes relative to the cortical gyri and sulci and significantly facilitated interpretation of brain mapping before tumor resection. In another patient with parieto-occipital glioma, simultaneous three-dimensional visualization of the tumor, CST, and optic radiation with the use of LGP permitted us to perform tumor resection without postoperative neurologic complications. Finally, incorporation of DTI into SurgiPlan resulted in precise planning of stereotactic biopsy for bilateral thalamic glioma. Conclusion The possibility for detailed evaluation of regional neuroanatomy based on various images within LGP and SurgiPlan may facilitate effective and safe surgical management of intracranial gliomas.

  20. Trends in Fluorescence Image-guided Surgery for Gliomas

    PubMed Central

    Liu, Jonathan T.C.; Meza, Daphne; Sanai, Nader

    2014-01-01

    Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low-grade and high-grade glioma patients. However, radiographically complete resections are not often achieved in many cases due to the lack of sensitivity and specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins. Here, we provide a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care. PMID:24618801

  1. Differential response of glioma cells to FOXO1-directed therapy.

    PubMed

    Lau, Cara J; Koty, Zaf; Nalbantoglu, Josephine

    2009-07-01

    Gliomas are the most common adult primary brain tumors, and the most malignant form, glioblastoma multiforme, is invariably fatal. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is altered in most glioblastoma multiforme. PTEN, an important negative regulator of the PI3K-Akt pathway, is also commonly mutated in glioma, leading to constitutive activation of Akt. One ultimate consequence is phosphorylation and inactivation of FOXO forkhead transcription factors that regulate genes involved in apoptosis, cell cycle arrest, nutrient availability, DNA repair, stress, and angiogenesis. We tested the ability of a mutant FOXO1 factor that is not subject to Akt phosphorylation to overcome dysregulated PI3K-Akt signaling in two PTEN-null glioma cell lines, U87 and U251. Adenovirus-mediated gene transfer of the mutant FOXO1 successfully restored cell cycle arrest and induced cell death in vitro and prolonged survival in vivo in xenograft models of human glioma (33% survival at 1 year of animals bearing U251 tumors). However, U87 were much more resistant than U251 to mutant FOXO1-induced death, showing evidence of increased nuclear export and Akt-independent phosphorylation of FOXO1 at S249. A cyclin-dependent kinase 2 inhibitor decreased phosphorylation of S249 and rendered U87 cells significantly more susceptible to mutant FOXO1-induced death. Our results indicate that targeting FOXO1, which is at the convergence point of several growth factor receptor tyrosine kinase pathways, can effectively induce glioma cell death and inhibit tumor growth. They also highlight the importance of Akt-independent phosphorylation events in the nuclear export of FOXO1.

  2. Meat and haem iron intake in relation to glioma in the European Prospective Investigation into Cancer and Nutrition study.

    PubMed

    Ward, Heather A; Gayle, Alicia; Jakszyn, Paula; Merritt, Melissa; Melin, Beatrice; Freisling, Heinz; Weiderpass, Elisabete; Tjonneland, Anne; Olsen, Anja; Dahm, Christina C; Overvad, Kim; Katzke, Verena; Kühn, Tilman; Boeing, Heiner; Trichopoulou, Antonia; Lagiou, Pagona; Kyrozis, Andreas; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Ricceri, Fulvio; Mattiello, Amalia; Bueno-de-Mesquita, Bas; Peeters, Petra H; Quirós, José Ramón; Agudo, Antonio; Rodriguez-Barranco, Miguel; Larrañaga, Nerea; Huerta, José M; Barricarte, Aurelio; Sonestedt, Emily; Drake, Isabel; Sandström, Maria; Travis, Ruth C; Ferrari, Pietro; Riboli, Elio; Cross, Amanda J

    2016-11-11

    Diets high in red or processed meat have been associated positively with some cancers, and several possible underlying mechanisms have been proposed, including iron-related pathways. However, the role of meat intake in adult glioma risk has yielded conflicting findings because of small sample sizes and heterogeneous tumour classifications. The aim of this study was to examine red meat, processed meat and iron intake in relation to glioma risk in the European Prospective Investigation into Cancer and Nutrition study. In this prospective cohort study, 408 751 individuals from nine European countries completed demographic and dietary questionnaires at recruitment. Multivariable Cox proportional hazards models were used to examine intake of red meat, processed meat, total dietary iron and haem iron in relation to incident glioma. During an average follow-up of 14.1 years, 688 incident glioma cases were diagnosed. There was no evidence that any of the meat variables (red, processed meat or subtypes of meat) or iron (total or haem) were associated with glioma; results were unchanged when the first 2 years of follow-up were excluded. This study suggests that there is no association between meat or iron intake and adult glioma. This is the largest prospective analysis of meat and iron in relation to glioma and as such provides a substantial contribution to a limited and inconsistent literature.

  3. 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.

  4. Molecular signalling pathways in canine gliomas.

    PubMed

    Boudreau, C E; York, D; Higgins, R J; LeCouteur, R A; Dickinson, P J

    2017-03-01

    In this study, we determined the expression of key signalling pathway proteins TP53, MDM2, P21, AKT, PTEN, RB1, P16, MTOR and MAPK in canine gliomas using western blotting. Protein expression was defined in three canine astrocytic glioma cell lines treated with CCNU, temozolamide or CPT-11 and was further evaluated in 22 spontaneous gliomas including high and low grade astrocytomas, high grade oligodendrogliomas and mixed oligoastrocytomas. Response to chemotherapeutic agents and cell survival were similar to that reported in human glioma cell lines. Alterations in expression of key human gliomagenesis pathway proteins were common in canine glioma tumour samples and segregated between oligodendroglial and astrocytic tumour types for some pathways. Both similarities and differences in protein expression were defined for canine gliomas compared to those reported in human tumour counterparts. The findings may inform more defined assessment of specific signalling pathways for targeted therapy of canine gliomas.

  5. ATRX immunostaining predicts IDH and H3F3A status in gliomas.

    PubMed

    Ebrahimi, Azadeh; Skardelly, Marco; Bonzheim, Irina; Ott, Ines; Mühleisen, Helmut; Eckert, Franziska; Tabatabai, Ghazaleh; Schittenhelm, Jens

    2016-06-16

    Gliomas are the most frequent intraaxial CNS neoplasms with a heterogeneous molecular background. Recent studies on diffuse gliomas have shown frequent alterations in the genes involved in chromatin remodelling pathways such as α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX). Yet, the reliability of ATRX in predicting isocitrate dehydrogenase (IDH) and H3 histone, family 3A (H3F3A) mutations in gliomas, is unclear.We analysed the ATRX expression status by immunohistochemistry, in a large series of 1064 gliomas and analysed the results in correlation to IDH, H3F3A and loss of heterozygosity (LOH) 1p/19q status in these tumors. We also investigated the prognostic potential of ATRX concerning the clinical outcome of patients with diffuse gliomas.According to our results, loss of nuclear ATRX expression was accompanied with an astrocytic tumor lineage and a younger age of onset. ATRX loss in astrocytomas was also strongly associated with IDH1/2 and H3F3A mutation (p < 0.0001). Among 196 glial tumors with nuclear ATRX loss, 173 (89 %) had an IDH1 or IDH2 mutation. Among the remaining 23 cases (11 %) with ATRX loss and IDH wild type status, 7 cases had a H3F3A G34R mutation (3 %) and 2 cases had a H3F3A K27M mutation (1 %). ATRX retention in IDH1/2 mutant tumors was strongly associated with LOH 1p/19q and oligodendroglioma histology (p < 0.0001). We also confirmed the significant prognostic role of ATRX. Diffuse gliomas with ATRX loss (n = 137, median 1413 days, 95 % CI: 1065-1860 days) revealed a significantly better clinical outcome compared with tumors with ATRX retention (n = 335, median: 609, 95 % CI: 539-760 days, HR = 1.81, p < 0.0001).In conclusion, ATRX is a potential marker for prediction of IDH/H3F3A mutations and substratification of diffuse gliomas into survival relevant tumor groups. Such classification is of great importance for further clinical decision making especially concerning the therapeutic options

  6. Adherence to the Dietary Approaches to Stop Hypertension-style diet in relation to glioma: a case-control study.

    PubMed

    Benisi-Kohansal, Sanaz; Shayanfar, Mehdi; Mohammad-Shirazi, Minoo; Tabibi, Hadi; Sharifi, Giuve; Saneei, Parvane; Esmaillzadeh, Ahmad

    2016-03-28

    Data on the association of adherence to the Dietary Approaches to Stop Hypertension (DASH)-style and glioma are scarce. We aimed to examine the association between adherence to the DASH-style diet and glioma in Iranian adults. In this study, 128 pathologically confirmed cases of glioma were recruited from hospitals and 256 age- and sex-matched controls were enrolled from other wards of the hospital. Dietary intakes were assessed using a 126-item validated FFQ. Adherence to the DASH-style diet was followed considering the healthy and non-healthy foods emphasised in the DASH dietary pattern. After controlling for potential confounders, individuals with the greatest adherence to the DASH diet were 72 % less likely to have glioma compared with those with the lowest adherence (OR 0·28; 95 % CI 0·13, 0·57). Individuals with the highest consumption of fruits had lower odds for having glioma compared with those with the lowest intake (OR 0·31; 95 % CI 0·14, 0·68). A protective association was also observed between consumption of legumes and nuts and risk of glioma (OR 0·23; 95 % CI 0·10, 0·53). We found a significant positive association between red and processed meat (OR 2·60; 95 % CI 1·16, 5·81) and salt intakes (OR 2·87; 95 % CI 1·30, 6·34) and risk of glioma, after taking all potential confounders into account. Adherence to the DASH-style dietary pattern was inversely associated with glioma. In addition, some components of the DASH diet, including red meats and salt intakes, were positively associated with glioma. Consumption of nuts and legumes as well as fruits was inversely associated with glioma. Prospective cohort studies are required to confirm our findings.

  7. 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.

  8. KIAA0247 suppresses the proliferation, angiogenesis and promote apoptosis of human glioma through inactivation of the AKT and Stat3 signaling pathway

    PubMed Central

    Tan, Ying; Huang, Ning; Zhang, Xiang; Hu, Jiangang; Cheng, Si; Pi, Li; Cheng, Yuan

    2016-01-01

    Gliomas are the most common and aggressive type of primary adult brain tumors. Although KIAA0247 previously is a speculated target of the tumor suppressor gene, little is known about the association between KIAA0247 and glioma. In this study, we clearly demonstrate that KIAA0247 expression is decreased in glioma and was negatively correlated with the histologic grade. Overexpression of KIAA0247 in glioma cells inhibits proliferation, angiogenesis and promoted apoptosis of human glioma cells in vitro. In contrast, knockdown of KIAA0247 increases the proliferation, angiogenesis and decreases apoptosis of these cells. In a tumor xenograft model, overexpression of KIAA0247 suppresses tumor growth of glioma cells in vivo, while KIAA0247 knockdown promotes the tumor growth. Mechanistically, overexpression of KIAA0247 is able to inhibit phosphorylation of AKT and Stat3 in glioma cells, resulting in inactivation of the AKT and Stat3 signaling pathways, this ultimately decreases the expression of PCNA, CyclinD1, Bcl2 and VEGF. Collectively, these data indicate that KIAA0247 may work as a tumor suppressor gene in glioma and a promising therapeutic target for gliomas. PMID:27893430

  9. A Pilot Cost-Effectiveness Analysis of Treatments in Newly Diagnosed High-Grade Gliomas: The Example of 5-Aminolevulinic Acid Compared With White-Light Surgery

    PubMed Central

    Alves, Marta; Castel-Branco, Marta; Stummer, Walter

    2015-01-01

    BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratios are below €10 000 in all evaluated outcomes, being around €9100 per quality-adjusted life-year gained, €6700 per life-year gained, and €8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of €20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on

  10. Rituximab and Combination Chemotherapy in Treating Patients With Previously Untreated High- or High-Intermediate-Risk Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2016-03-01

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  11. Oblimersen Sodium and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage I, Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2012-10-11

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  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. Time-resolved diffuse reflectance measurement carried out on the head of an adult at large source-detector separation.

    PubMed

    Liebert, Adam; Sawosz, Piotr; Kacprzak, Michal; Weigl, Wojciech; Botwicz, Marcin; Maniewski, Roman

    2010-01-01

    Multichannel time-resolved optical monitoring system was constructed for measurements of diffuse reflectance in optically turbid medium at very large source-detector separation up to 9 cm. The system is based on femtosecond TiSa laser and sensitive photomultiplier tube detector. The laser light of 300mW of power was delivered to the surface of the head with the use of an optical fiber. A beam expander was applied in order to distribute the laser light on a large spot which allowed to avoid energetic stimulation of the tissue. The photomultiplier tube detector was positioned directly on the surface of the medium at the distance of 9cm from the center of the source position. In this paper we report results of an in-vivo experiment carried out on the head of an adult healthy volunteer. The time-resolved system was applied during intravenous injection of an optical contrast agent (indocyanine green - ICG) and the distributions of times of flight of photons were successfully acquired showing inflow and washout of the dye to the tissue. Time-courses of the moments of distributions of times of flight of photons are presented and compared with the results obtained simultaneously at shorter source-detector separations (3 cm, 4 cm and 5 cm).

  14. Assessment of a multi-layered diffuse correlation spectroscopy method for monitoring cerebral blood flow in adults

    PubMed Central

    Verdecchia, Kyle; Diop, Mamadou; Lee, Albert; Morrison, Laura B.; Lee, Ting-Yim; St. Lawrence, Keith

    2016-01-01

    Diffuse correlation spectroscopy (DCS) is a promising technique for brain monitoring as it can provide a continuous signal that is directly related to cerebral blood flow (CBF); however, signal contamination from extracerebral tissue can cause flow underestimations. The goal of this study was to investigate whether a multi-layered (ML) model that accounts for light propagation through the different tissue layers could successfully separate scalp and brain flow when applied to DCS data acquired at multiple source-detector distances. The method was first validated with phantom experiments. Next, experiments were conducted in a pig model of the adult head with a mean extracerebral tissue thickness of 9.8 ± 0.4 mm. Reductions in CBF were measured by ML DCS and computed tomography perfusion for validation; excellent agreement was observed by a mean difference of 1.2 ± 4.6% (CI95%: −31.1 and 28.6) between the two modalities, which was not significantly different. PMID:27699127

  15. 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.

  16. Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma.

    PubMed

    Raghunathan, Aditya; Olar, Adriana; Vogel, Hannes; Parker, John R; Coventry, Susan C; Debski, Robert; Albarracin, Constance T; Aldape, Kenneth D; Cahill, Daniel P; Powell, Suzanne Z; Fuller, Gregory N

    2012-08-01

    Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild-type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG

  17. Pneumopathie interstitielle diffuse révélant la leucémie-lymphome à cellules T de l’adulte HTLV1+

    PubMed Central

    Bouanani, Nouama; Lamchahab, Mouna

    2016-01-01

    La leucémie/lymphome à cellules T de l'adulte est une prolifération tumorale de cellules lymphoïdes T matures activées, dont l'agent étiologique est le rétrovirus humain T cell-leukemia virus type 1, ce virus entraine rarement des désordres inflammatoires bronchioloalveolaires. Nous rapportons l'observation d'un patient hospitalisé pour une pneumopathie interstitielle diffuse et dont le bilan étiologique a révélé une leucémie lymphome à cellules T de l'adulte HTLV1+. PMID:28292112

  18. [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.

  19. Practical molecular pathologic diagnosis of infiltrating gliomas.

    PubMed

    Pekmezci, Melike; Perry, Arie

    2015-03-01

    Recent advances in molecular diagnostics have led to better understanding of glioma tumorigenesis and biology. Numerous glioma biomarkers with diagnostic, prognostic, and predictive value have been identified. Although some of these markers are already part of the routine clinical management of glioma patients, data regarding others are limited and difficult to apply routinely. In addition, multiple methods for molecular subclassification have been proposed either together with or as an alternative to the current morphologic classification and grading scheme. This article reviews the literature regarding glioma biomarkers and offers a few practical suggestions.

  20. Myeloid-derived suppressor cells in gliomas

    PubMed Central

    Kaminska, Bozena

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of early myeloid progenitors and precursors at different stages of differentiation into granulocytes, macrophages, and dendritic cells. Blockade of their differentiation into mature myeloid cells in cancer results in an expansion of this population. High-grade gliomas are the most common malignant tumours of the central nervous system (CNS), with a poor prognosis despite intensive radiation and chemotherapy. Histopathological and flow cytometry analyses of human and rodent experimental gliomas revealed the extensive heterogeneity of immune cells infiltrating gliomas and their microenvironment. Immune cell infiltrates consist of: resident (microglia) and peripheral macrophages, granulocytes, myeloid-derived suppressor cells, and T lymphocytes. Intratumoural density of glioma-associated MDSCs correlates positively with the histological grade of gliomas and patient’s survival. MDSCs have the ability to attract T regulatory lymphocytes to the tumour, but block the activation of tumour-reactive CD4+ T helper cells and cytotoxic CD8+ T cells. Immunomodulatory mechanisms employed by malignant gliomas pose an appalling challenge to brain tumour immunotherapy. In this mini-review we describe phenotypic and functional characteristics of MDSCs in humans and rodents, and their occurrence and potential roles in glioma progression. While understanding the complexity of immune cell interactions in the glioma microenvironment is far from being accomplished, there is significant progress that may lead to the development of immunotherapy for gliomas. PMID:28373814

  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. Genetic therapy in gliomas: historical analysis and future perspectives.

    PubMed

    Mattei, Tobias Alécio; Ramina, Ricardo; Miura, Flavio Key; Aguiar, Paulo Henrique; Valiengo, Leandro da Costa

    2005-03-01

    High-grade gliomas are relatively frequent in adults, and consist of the most malignant kind of primary brain tumor. Being resistant to standard treatment modalities such as surgery, radiation, and chemotherapy, it is fatal within 1 to 2 years of onset of symptoms. Although several gene therapy systems proved to be efficient in controlling or eradicating these tumors in animal models, the clinical studies performed so far were not equally successful. Most clinical studies showed that methodologies that increase tumor infection/transduction and, consequently confer more permanent activity against the tumor, will lead to enhanced therapeutic results. Due to the promising practical clinical benefits that can be expected for the near future, an exposition to the practicing neurosurgeon about the basic issues in genetic therapy of gliomas seems convenient. Among the main topics, we shall discuss anti-tumoral mechanisms of various genes that can be transfected, the advantages and drawbacks of the different vectors utilized, the possibilities of tumor targeting by modifications in the native tropism of virus vectors, as well as the different physical methods for vector delivery to the tumors. Along with the exposition we will also review of the history of the genetic therapy for gliomas, with special focus on the main problems found during the advancement of scientific discoveries in this area. A general analysis is also made of the present state of this promising therapeutic modality, with reference to the problems that still must be solved and the new paradigms for future research in this area.

  3. Progress in the application of molecular biomarkers in gliomas.

    PubMed

    Wang, Jing; Su, Hong-kai; Zhao, Hua-fu; Chen, Zhong-ping; To, Shing-shun Tony

    2015-09-11

    Gliomas are a common adult central nervous system tumor, and glioblastoma (GBM), which has a poor prognosis, is the most lethal of all gliomas. The overall survival of GBM patients is only 12-14 months after diagnosis. With progress in the precision of personal medication, therapeutic options for various tumors have become gradually dependent on the molecular profiles of patients. GBM is one of the tumors in which treatment response relies largely on the molecular characteristics of the tumor. Therefore, awareness of the genetic background of each patient will help decision-making regarding the best treatment strategy to use. In this review, a novel molecular classification of gliomas based on recent findings of their genetic characteristics is introduced. Representative molecular markers, such as IDH1 mutation, 1p19q co-deletion, MGMT promoter methylation and EGFRvIII amplification, are described. Furthermore, the development of non-coding RNAs and omics studies of GBM are briefly discussed. Finally, a novel concept for non-invasive detection that could facilitate both diagnosis and treatment monitoring is presented. There is no doubt that the use of molecular profiling by biomarkers will indeed improve the overall survival and quality of life of GBM patients.

  4. ASYMMETRIC CELL DIVISION: IMPLICATIONS FOR GLIOMA DEVELOPMENT AND TREATMENT.

    PubMed

    Lewis, Kate Marie; Petritsch, Claudia

    2013-12-01

    Glioma is a heterogeneous disease process with differential histology and treatment response. It was previously thought that the histological features of glial tumors indicated their cell of origin. However, the discovery of continuous neuro-gliogenesis in the normal adult brain and the identification of brain tumor stem cells within glioma have led to the hypothesis that these brain tumors originate from multipotent neural stem or progenitor cells, which primarily divide asymmetrically during the postnatal period. Asymmetric cell division allows these cell types to concurrently self-renew whilst also producing cells for the differentiation pathway. It has recently been shown that increased symmetrical cell division, favoring the self-renewal pathway, leads to oligodendroglioma formation from oligodendrocyte progenitor cells. In contrast, there is some evidence that asymmetric cell division maintenance in tumor stem-like cells within astrocytoma may lead to acquisition of treatment resistance. Therefore cell division mode in normal brain stem and progenitor cells may play a role in setting tumorigenic potential and the type of tumor formed. Moreover, heterogeneous tumor cell populations and their respective cell division mode may confer differential sensitivity to therapy. This review aims to shed light on the controllers of cell division mode which may be therapeutically targeted to prevent glioma formation and improve treatment response.

  5. Diffusion tensor imaging (DTI) findings in adult civilian, military, and sport-related mild traumatic brain injury (mTBI): a systematic critical review.

    PubMed

    Asken, Breton Michael; DeKosky, Steven T; Clugston, James R; Jaffee, Michael S; Bauer, Russell M

    2017-03-24

    This review seeks to summarize diffusion tensor imaging (DTI) studies that have evaluated structural changes attributed to the mechanisms of mild traumatic brain injury (mTBI) in adult civilian, military, and athlete populations. Articles from 2002 to 2016 were retrieved from PubMed/MEDLINE, EBSCOhost, and Google Scholar, using a Boolean search string containing the following terms: "diffusion tensor imaging", "diffusion imaging", "DTI", "white matter", "concussion", "mild traumatic brain injury", "mTBI", "traumatic brain injury", and "TBI". We added studies not identified by this method that were found via manually-searched reference lists. We identified 86 eligible studies from English-language journals using, adult, human samples. Studies were evaluated based on duration between injury and DTI assessment, categorized as acute, subacute/chronic, remote mTBI, and repetitive brain trauma considerations. Since changes in brain structure after mTBI can also be affected by other co-occurring medical and demographic factors, we also briefly review DTI studies that have addressed socioeconomic status factors (SES), major depressive disorder (MDD), and attention-deficit hyperactivity disorder (ADHD). The review describes population-specific risks and the complications of clinical versus pathophysiological outcomes of mTBI. We had anticipated that the distinct population groups (civilian, military, and athlete) would require separate consideration, and various aspects of the study characteristics supported this. In general, study results suggested widespread but inconsistent differences in white matter diffusion metrics (primarily fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) following mTBI/concussion. Inspection of study designs and results revealed potential explanations for discrepant DTI findings, such as control group variability, analytic techniques, the manner in which regional differences were reported, and

  6. Molecular classification defines 4 prognostically distinct glioma groups irrespective of diagnosis and grade.

    PubMed

    Mur, Pilar; Mollejo, Manuela; Hernández-Iglesias, Teresa; de Lope, Ángel Rodríguez; Castresana, Javier S; García, Juan F; Fiaño, Concepción; Ribalta, Teresa; Rey, Juan A; Meléndez, Barbara

    2015-03-01

    According to World Health Organization criteria, diffuse gliomas are divided into several histological subtypes, including astrocytomas, oligodendrogliomas, and oligoastrocytomas, and 4 malignancy grades (I-IV). Molecular alterations, such as the isocitrate dehydrogenase gene (IDH) mutation or 1p/19q loss, are found in these tumors but are not included in the current classification system. Recently, mutation of α thalassemia/mental retardation syndrome X-linked (ATRX) gene and its loss of expression have been reported in infiltrating gliomas. We evaluated ATRX protein expression in 272 gliomas and its association with molecular and clinical features. Loss of ATRX expression was more common in tumors with an astrocytic component (astrocytomas II/III, 46.4%; oligoastrocytomas, 47.5%) but was uncommon in oligodendrogliomas (7.3%) and glioblastomas (0.9%). In astrocytic tumors, loss of ATRX expression was significantly associated with longer overall survival. Remarkably, on the basis of IDH mutation, 1p/19q codeletion, and ATRX expression, our study defined 4 molecularly and prognostically different groups of gliomas, showing the relevance of ATRX expression as a new marker for refining the molecular classification of gliomas and for distinguishing clinically distinct prognostic subgroups of patients.

  7. 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.

  8. Interaction of allergy history and antibodies to specific varicella-zoster virus proteins on glioma risk.

    PubMed

    Lee, Seung-Tae; Bracci, Paige; Zhou, Mi; Rice, Terri; Wiencke, John; Wrensch, Margaret; Wiemels, Joseph

    2014-05-01

    Glioma is the most common cancer of the central nervous system but with few confirmed risk factors. It has been inversely associated with chicken pox, shingles and seroreactivity to varicella virus (VZV), as well as to allergies and allergy-associated IgE. The role of antibody reactivity against individual VZV antigens has not been assessed. Ten VZV-related proteins, selected for high immunogenicity or known function, were synthesized and used as targets for antibody measurements in the sera of 143 glioma cases and 131 healthy controls selected from the San Francisco Bay Area Adult Glioma Study. Glioma cases exhibited significantly reduced seroreactivity compared to controls for six antigens, including proteins IE63 [odds ratio (OR) = 0.26, 95% confidence interval (CI): 0.12-0.58, comparing lowest quartile to highest) and the VZV-unique protein ORF2p (OR = 0.44, 95% CI: 0.21-0.96, lowest quartile to highest). When stratifying the study population into those with low and high self-reported allergy history, VZV protein seroreactivity was only associated inversely with glioma among individuals self-reporting more than two allergies. The data provide insight into both allergy and VZV effects on glioma: strong anti-VZV reactions in highly allergic individuals are associated with reduced occurrence of glioma. This result suggests a role for specificity in the anti-VZV immunity in brain tumor suppression for both individual VZV antigens and in the fine-tuning of the immune response by allergy. Anti-VZV reactions may also be a biomarker of effective CNS immunosurveillance owing to the tropism of the virus.

  9. TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways.

    PubMed

    Liu, Mingli; Inoue, Koichi; Leng, Tiandong; Guo, Shanchun; Xiong, Zhi-gang

    2014-12-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults with median survival time of 14.6 months. A small fraction of cancer stem cells (CSC) initiate and maintain tumors thus driving glioma tumorigenesis and being responsible for resistance to classical chemo- and radio-therapies. It is desirable to identify signaling pathways related to CSC to develop novel therapies to selectively target them. Transient receptor potential cation channel, subfamily M, member 7, also known as TRPM7 is a ubiquitous, Ca(2+) and Mg(2+) permeable ion channels that are special in being both an ion channel and a serine/threonine kinase. In studies of glioma cells silenced for TRPM7, we demonstrated that Notch (Notch1, JAG1, Hey2, and Survivin) and STAT3 pathways are down regulated in glioma cells grown in monolayer. Furthermore, phospho-STAT3, Notch target genes and CSC markers (ALDH1 and CD133) were significantly higher in spheroid glioma CSCs when compared with monolayer cultures. The results further show that tyrosine-phosphorylated STAT3 binds and activates the ALDH1 promoters in glioma cells. We found that TRMP7-induced upregulation of ALDH1 expression is associated with increases in ALDH1 activity and is detectable in stem-like cells when expanded as spheroid CSCs. Finally, TRPM7 promotes proliferation, migration and invasion of glioma cells. These demonstrate that TRPM7 activates JAK2/STAT3 and/or Notch signaling pathways and leads to increased cell proliferation and migration. These findings for the first time demonstrates that TRPM7 (1) activates a previously unrecognized STAT3→ALDH1 pathway, and (2) promotes the induction of ALDH1 activity in glioma cells.

  10. Plexin-B1 indirectly affects glioma invasiveness and angiogenesis by regulating the RhoA/αvβ3 signaling pathway and SRPK1.

    PubMed

    Chang, Yingwei; Li, Li; Zhang, Luping; Guo, Xuyan; Feng, Zhuoying; Zhou, Junchen; Zhou, Shuai; Feng, Guoying; Han, Fengchan; Huang, Wenhua; Yang, Jun; Huang, Fei

    2016-08-01

    Gliomas are one of the most common primary brain tumors in adults. They display aggressive invasiveness, are highly vascular, and have a poor prognosis. Plexin-B1 is involved in numerous cellular processes, especially cellular migration and angiogenesis. However, the role and regulatory mechanisms of Plexin-B1 in gliomas are not understood and were thus investigated in this study. By using multiple and diverse experimental techniques, we investigated cell apoptosis, mitochondrial membrane potential, cell migration and invasion, angiogenesis, PI3K and Akt phosphorylation, and also the levels of SRPK1 and αvβ3 in glioma cells and animal glioma tissues. The results indicated that Plexin-B1 expression in glioma cell lines is increased compared to normal human astrocytes. Plexin-B1 mediates RhoA/integrin αvβ3 involved in the PI3K/Akt pathway and SRPK1 to influence the growth of glioma cell, angiogenesis, and motility in vitro and in vivo. Thus, Plexin-B1 signaling regulates the Rho/αvβ3/PI3K/Akt pathway and SRPK1, which are involved in glioma invasiveness and angiogenesis. Therefore, the new drug research should focus on Plexin-B1 as a target for the treatment of glioma invasion and angiogenesis.

  11. Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326

    PubMed Central

    Ke, Jing; Yao, Yi-long; Zheng, Jian; Wang, Ping; Liu, Yun-hui; Ma, Jun; Li, Zhen; Liu, Xiao-bai; Li, Zhi-qing; Wang, Zhen-hua; Xue, Yi-xue

    2015-01-01

    Glioma is the most common and aggressive primary adult brain tumor. Long non-coding RNAs (lncRNAs) have important roles in a variety of biological properties of cancers. Here, we elucidated the function and the possible molecular mechanisms of lncRNA HOTAIR in human glioma U87 and U251 cell lines. Quantitative RT-PCR demonstrated that HOTAIR expression was up-regulated in glioma tissues and cell lines. Knockdown of HOTAIR exerted tumor-suppressive function in glioma cells. Further, HOTAIR was confirmed to be the target of miR-326 and miR-326 mediated the tumor-suppressive effects of HOTAIR knockdown on glioma cell lines. Moreover, over-expressed miR-326 reduced the FGF1 expression which played an oncogenic role in glioma by activating PI3K/AKT and MEK 1/2 pathways. In addition, the in vivo studies also supported the above findings. Taken together, knockdown of HOTAIR up-regulated miR-326 expression, and further inducing the decreased expression of FGF1, these results provided a comprehensive analysis of HOTAIR-miR-326-FGF1 axis in human glioma and provided a new potential therapeutic strategy for glioma treatment. PMID:26183397

  12. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas

    PubMed Central

    Okada, Hideho; Lieberman, Frank S; Walter, Kevin A; Lunsford, L Dade; Kondziolka, Douglas S; Bejjani, Ghassan K; Hamilton, Ronald L; Torres-Trejo, Alejandro; Kalinski, Pawel; Cai, Quan; Mabold, Jennifer L; Edington, Howard D; Butterfield, Lisa H; Whiteside, Theresa L; Potter, Douglas M; Schold, S Clifford; Pollack, Ian F

    2007-01-01

    Background The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts. Methods In University of Pittsburgh Cancer Institute (UPCI) protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) received gross total resection (GTR) of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC) loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging. Results and Discussion In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4+ as well as CD8+ T cells. Interferon (IFN)-γ Enzyme-Linked Immuno-SPOT (ELISPOT) assay in another human leukocyte antigen (HLA)-A2+ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA) epitope EphA2883–891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants received scheduled

  13. Intrinsic protective mechanisms of the neuron-glia network against glioma invasion.

    PubMed

    Iwadate, Yasuo; Fukuda, Kazumasa; Matsutani, Tomoo; Saeki, Naokatsu

    2016-04-01

    Gliomas arising in the brain parenchyma infiltrate into the surrounding brain and break down established complex neuron-glia networks. However, mounting evidence suggests that initially the network microenvironment of the adult central nervous system (CNS) is innately non-permissive to glioma cell invasion. The main players are inhibitory molecules in CNS myelin, as well as proteoglycans associated with astrocytes. Neural stem cells, and neurons themselves, possess inhibitory functions against neighboring tumor cells. These mechanisms have evolved to protect the established neuron-glia network, which is necessary for brain function. Greater insight into the interaction between glioma cells and the surrounding neuron-glia network is crucial for developing new therapies for treating these devastating tumors while preserving the important and complex neural functions of patients.

  14. Interferon-α/β enhances temozolomide activity against MGMT-positive glioma stem-like cells.

    PubMed

    Shen, Dong; Guo, Cheng-Cheng; Wang, Jing; Qiu, Zhi-Kun; Sai, Ke; Yang, Qun-Ying; Chen, Yin-Sheng; Chen, Fu-Rong; Wang, Jie; Panasci, Lawrence; Chen, Zhong-Ping

    2015-11-01

    Glioma is one of the most common primary tumors of the central nervous system in adults. Glioblastoma (GBM) is the most lethal type of glioma, whose 5-year survival is 9.8% at best. Glioma stem-like cells (GSCs) play an important role in recurrence and treatment resistance. MGMT is a DNA repair protein that removes DNA adducts and therefore attenuates treatment efficiency. It has been reported that interferon-α/β (IFN-α/β) downregulates the level of MGMT and sensitizes glioma cells to temozolomide. In the present study, we assessed whether IFN-α/β is able to sensitize GSCs to temozolomide by modulating MGMT expression. Upon the treatment of IFN-α/β, the efficacy of temozolomide against MGMT‑positive GSCs was markedly enhanced by combination treatment with IFN-α/β when compared with the temozolomide single agent group, and MGMT expression was markedly decreased at the same time. Further mechanistic study showed that IFN-α/β suppressed the NF-κB activity, which further mediated the sensitization of MGMT‑positive GSCs to temozolomide. Our data therefore demonstrated that the application of IFN-α/β is a promising agent with which to enhance temozolomide efficiency and reduce drug resistance, and our findings shed light on improving clinical outcomes and prolonging the survival of patients with malignant gliomas.

  15. Methods to Differentiate Radiation Necrosis and Recurrent Disease in Gliomas

    NASA Astrophysics Data System (ADS)

    Ewell, Lars

    2007-03-01

    Given the difficulty in differentiating Radiation Induced Necrosis (RIN) and recurrent disease in glioma patients using conventional techniques (CT scans, MRI scans), researchers have looked for different imaging modalities. Among these different modalities are Diffusion Weighted Magnetic Resonance Imaging (DWMRI) and Magnetic Resonance Spectroscopy (MRS). In DWMRI, an Apparent Diffusion Coefficient (ADC) is calculated for a Region Of Interest (ROI), and then monitored over time (longitudinally). In the brain, different anatomical features can complicate the interpretation of ADCs. In particular, the density and spatial variation of the cerebral spinal fluid filled fissures known as sulci can influence how a change in an ADC is explained. We have used the covariance of pixel intensity in T1 weighted MRI scans to study how intra-patient and inter-patient sulci density varies, and will present these results. MRS uses the shift in the MR signal due to the local chemical environment to determine the concentration of brain metabolites like choline and creatin. The ratio of metabolites such as these has been shown to have the power to discriminate between RIN and recurrent disease in glioma patients. At our institution, we have initiated a protocol whereby we will use DWMRI and MRS to study how best to utilize these complimentary forms of imaging.

  16. Associations of High-Grade Glioma With Glioma Risk Alleles and Histories of Allergy and Smoking

    PubMed Central

    Lachance, Daniel H.; Yang, Ping; Johnson, Derek R.; Decker, Paul A.; Kollmeyer, Thomas M.; McCoy, Lucie S.; Rice, Terri; Xiao, Yuanyuan; Ali-Osman, Francis; Wang, Frances; Stoddard, Shawn M.; Sprau, Debra J.; Kosel, Matthew L.; Wiencke, John K.; Wiemels, Joseph L.; Patoka, Joseph S.; Davis, Faith; McCarthy, Bridget; Rynearson, Amanda L.; Worra, Joel B.; Fridley, Brooke L.; O’Neill, Brian Patrick; Buckner, Jan C.; Il’yasova, Dora; Jenkins, Robert B.; Wrensch, Margaret R.

    2011-01-01

    Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. Data from 855 high-grade glioma cases and 1,160 controls from 4 geographic regions of the United States during 1997–2008 were analyzed for interactions between allergy and smoking histories and inherited variants in 5 established glioma risk regions: 5p15.3 (TERT), 8q24.21 (CCDC26/MLZE), 9p21.3 (CDKN2B), 11q23.3 (PHLDB1/DDX6), and 20q13.3 (RTEL1). The inverse relation between allergy and glioma was stronger among those who did not (odds ratioallergy-glioma = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratioallergy-glioma = 0.76, 95% confidence interval: 0.59, 0.97; Pinteraction = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratioallergy-glioma = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratioallergy-glioma = 0.68, 95% confidence interval: 0.54, 0.86) the 20q13.3 glioma risk allele, but this interaction was not statistically significant (P = 0.14). No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. The authors’ observations are consistent with a recent report that the inherited glioma risk variants in chromosome regions 9p21.3 and 20q13.3 may modify the inverse association of allergy and glioma. PMID:21742680

  17. Retinoids in the treatment of glioma: a new perspective

    PubMed Central

    Mawson, Anthony R

    2012-01-01

    Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners) in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α (RARα) and reduced expression of retinoic acid receptor-β (RARβ). This suggests a potential new treatment strategy for gliomas, possibly even at a late stage of the disease, ie, to combine the use of a RARα antagonist and a RARβ agonist. According to this hypothesis, the RARα antagonist would be expected to inhibit RAR

  18. Tubulin nitration in human gliomas.

    PubMed

    Fiore, Gabriella; Di Cristo, Carlo; Monti, Gianluca; Amoresano, Angela; Columbano, Laura; Pucci, Pietro; Cioffi, Fernando A; Di Cosmo, Anna; Palumbo, Anna; d'Ischia, Marco

    2006-02-06

    Immunohistochemical and biochemical investigations showed that significant protein nitration occurs in human gliomas, especially in grade IV glioblastomas at the level of astrocytes and oligodendrocytes and neurones. Enhanced alpha-tubulin immunoreactivity was co-present in the same elements in the glioblastomas. Proteomic methodologies were employed to identify a nitrated protein band at 55 kDa as alpha-tubulin. Peptide mass fingerprinting procedures demonstrated that tubulin is nitrated at Tyr224 in grade IV tumour samples but is unmodified in grade I samples and in non-cancerous brain tissue. These results provide the first characterisation of endogenously nitrated tubulin from human tumour samples.

  19. Combination Chemo, Rituximab, and Bevacizumab in Older Patients With Stage II-IV Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2014-05-06

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

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

    PubMed

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

    2011-05-01

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

  1. PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo

    PubMed Central

    Auvergne, R; Wu, C; Connell, A; Au, S; Cornwell, A; Osipovitch, M; Benraiss, A; Dangelmajer, S; Guerrero-Cazares, H; Quinones-Hinojosa, A; Goldman, SA

    2016-01-01

    Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5+ TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5+ TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas. PMID:26616854

  2. Diffusion tensor imaging reveals adolescent binge ethanol-induced brain structural integrity alterations in adult rats that correlate with behavioral dysfunction.

    PubMed

    Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz; Crews, Fulton T

    2016-07-01

    Adolescence is characterized by considerable brain maturation that coincides with the development of adult behavior. Binge drinking is common during adolescence and can have deleterious effects on brain maturation because of the heightened neuroplasticity of the adolescent brain. Using an animal model of adolescent intermittent ethanol [AIE; 5.0 g/kg, intragastric, 20 percent EtOH w/v; 2 days on/2 days off from postnatal day (P)25 to P55], we assessed the adult brain structural volumes and integrity on P80 and P220 using diffusion tensor imaging (DTI). While we did not observe a long-term effect of AIE on structural volumes, AIE did reduce axial diffusivity (AD) in the cerebellum, hippocampus and neocortex. Radial diffusivity (RD) was reduced in the hippocampus and neocortex of AIE-treated animals. Prior AIE treatment did not affect fractional anisotropy (FA), but did lead to long-term reductions of mean diffusivity (MD) in both the cerebellum and corpus callosum. AIE resulted in increased anxiety-like behavior and diminished object recognition memory, the latter of which was positively correlated with DTI measures. Across aging, whole brain volumes increased, as did volumes of the corpus callosum and neocortex. This was accompanied by age-associated AD reductions in the cerebellum and neocortex as well as RD and MD reductions in the cerebellum. Further, we found that FA increased in both the cerebellum and corpus callosum as rats aged from P80 to P220. Thus, both age and AIE treatment caused long-term changes to brain structural integrity that could contribute to cognitive dysfunction.

  3. Early presentation of de novo high grade glioma with epileptic seizures: electroclinical and neuroimaging findings.

    PubMed

    Rossi, Rosario; Figus, Andrea; Corraine, Simona

    2010-10-01

    We report the clinical, EEG and neuroradiologic findings from three adult patients who developed new-onset seizure disorders as early clinical manifestations of de novo high grade glioma. The malignancies could not be recognised at the time of the first epileptic seizure because of minimal non-specific brain abnormalities, which showed no signs of necrosis or significant contrast enhancement on computed tomography and magnetic resonance imaging. Focal EEG abnormalities were recorded in all cases and appeared consistent with the neuroradiologic findings. The patients regained normal neurological status after the first seizure but rapidly developed space-occupying necrotic lesions. Two patients underwent surgery and received histological diagnoses of the tumours. Another patient was finally diagnosed with a malignant glioma based on the neuroradiologic picture and rapid progression of the cerebral lesion. It should be noted that in adult patients, new-onset epileptic seizures might reveal the presence of malignant gliomas at a very early stage in the tumour formation process. This report indicates that typical anatomoradiologic features of de novo high grade glioma, such as necrosis and rim-contrast enhancement, could be absent at the time of the first epileptic seizure but become clear within a short period after clinical presentation.

  4. 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.

  5. A report on radiation-induced gliomas

    SciTech Connect

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

    1991-01-15

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

  6. Treatment of paediatric pontine glioma with oral trophosphamide and etoposide

    PubMed Central

    Wolff, J E A; Westphal, S; Mölenkamp, G; Gnekow, A; Warmuth-Metz, M; Rating, D; Kuehl, J

    2002-01-01

    To evaluate the overall survival of paediatric patients with pontine gliomas treated with oral trophosphamide and etoposide. Patients between 3 and 17 years of age with either typical diffuse pontine glioma on MRI or histologically proven anaplastic astrocytoma/glioblastoma multiforme located in the pons, were eligible. Treatment consisted of oral trophosphamide 100 mg m−2 day−1 combined with oral etoposide at 25 mg m−2 day−1 starting simultaneously with conventional radiation. Twenty patients were enrolled (median age 6 years, male : female=9 : 11). Surgical procedures included: no surgery: five, open biopsy: three, stereotactic biopsy: six, partial resection: three, and sub-total resection: three. Histological diagnoses included pilocytic astrocytoma: one, astrocytoma with no other specification: three, anaplastic astrocytoma: three, glioblastoma multiforme: eight, no histology: five. The most frequent side effects were haematologic and gastrointestinal. There was no toxic death. The response to combined treatment in 12 evaluable patients was: complete response: 0, partial response: three, stable disease: four, and progressive disease: five. All tumours progressed locally and all patients died. The overall median survival was 8 months. The overall survival rates at 1 and 4 years were: 0.4 and 0.05 respectively. This was not different from a control group of patients documented in the same population. Oral trophosphamide in combination with etoposide did not improve survival of pontine glioma patients. The treatment was well tolerated and should be evaluated for more chemoresponsive paediatric malignancies. British Journal of Cancer (2002) 87, 945–949. doi:10.1038/sj.bjc.6600552 www.bjcancer.com © 2002 Cancer Research UK PMID:12434281

  7. 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

  8. 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

  9. Photochemical internalization of bleomycin for glioma treatment

    PubMed Central

    Mathews, Marlon S.; Blickenstaff, Joseph W.; Shih, En-Chung; Zamora, Genesis; Vo, Van; Sun, Chung-Ho; Hirschberg, Henry; Madsen, Steen J.

    2012-01-01

    Abstract. We study the use of photochemical internalization (PCI) for enhancing chemotherapeutic response to malignant glioma cells in vitro. Two models are studied: monolayers consisting of F98 rat glioma cells and human glioma spheroids established from biopsy-derived glioma cells. In both cases, the cytotoxicity of aluminum phthalocyanine disulfonate (AlPcS2a)-based PCI of bleomycin was compared to AlPcS2a-photodynamic therapy (PDT) and chemotherapy alone. Monolayers and spheroids were incubated with AlPcS2a (PDT effect), bleomycin (chemotherapy effect), or AlPcS2a+bleomycin (PCI effect) and were illuminated (670 nm). Toxicity was evaluated using colony formation assays or spheroid growth kinetics. F98 cells in monolayer/spheroids were not particularly sensitive to the effects of low radiant exposure (1.5  J/cm2 @ 5  mW/cm2) AlPcS2a-PDT. Bleomycin was moderately toxic to F98 cells in monolayer at relatively low concentrations—incubation of F98 cells in 0.1  μg/ml for 4 h resulted in 80% survival, but less toxic in human glioma spheroids respectively. In both in vitro systems investigated, a significant PCI effect is seen. PCI using 1.5  J/cm2 together with 0.25  μg/ml bleomycin resulted in approximately 20% and 18% survival of F98 rat glioma cells and human glioma spheroids, respectively. These results show that AlPcS2a-mediated PCI can be used to enhance the efficacy of chemotherapeutic agents such as bleomycin in malignant gliomas. PMID:22612148

  10. 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

  11. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.

    PubMed

    Munson, Jennifer M; Fried, Levi; Rowson, Sydney A; Bonner, Michael Y; Karumbaiah, Lohitash; Diaz, Begoña; Courtneidge, Sara A; Knaus, Ulla G; Brat, Daniel J; Arbiser, Jack L; Bellamkonda, Ravi V

    2012-03-28

    The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB-mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.

  12. Alpha-aminoisobutyric acid transport into human glia and glioma cells in culture.

    PubMed

    Ronquist, G; Agren, G; Ponten, J; Westermark, B

    1976-11-01

    The AIB transport into human glia and glioma cells in culture has been studied. Because of the high affinity of AIB to the plastic culture dishes, a special washing technique had to be developed. With this technique, it was possible to perform transport experiments in a single plate containing about one million cells. The cells were viable, intact and adhered to the supporting medium throughout the experiment. The AIB transport into both types of cells was Na+-dependent and showed saturation kinetics when the small component of the transport due to diffusion had been subtracted. The AIB transport capacity of neoplastic glioma cells was 3.6 times higher than that of glia cells. This difference was related to the Vmax-values for the two types of cells. The apparent Km-values were the same. Inhibition experiments with other amino acids support the view that AIB is transported via System A in both glia and glioma cells. Sulfhydryl reagents (ethacrynic acid and NEM) and cytochalasin B clearly inhibited the AIB transport into glia cells whereas the effect on glioma cells was minimal.

  13. Bevacizumab as Therapy for Radiation Necrosis in Four Children With Pontine Gliomas

    SciTech Connect

    Liu, Arthur K.; Macy, Margaret E.; Foreman, Nicholas K.

    2009-11-15

    Purpose: Diffuse pontine gliomas are a pediatric brain tumor that is fatal in nearly all patients. Given the poor prognosis for patients with this tumor, their quality of life is very important. Radiation therapy provides some palliation, but can result in radiation necrosis and associated neurologic decline. The typical treatment for this necrosis is steroid therapy. Although the steroids are effective, they have numerous side effects that can often significantly compromise quality of life. Bevacizumab, an antibody against vascular endothelial growth factor, has been suggested as a treatment for radiation necrosis. We report on our initial experience with bevacizumab therapy for radiation necrosis in pediatric pontine gliomas. Materials and Methods: Four children with pontine gliomas treated at the Children's Hospital in Denver and the University of Colorado Denver developed evidence of radiation necrosis both clinically and on imaging. Those 4 children then received bevacizumab as a treatment for the radiation necrosis. We reviewed the clinical outcome and imaging findings. Results: After bevacizumab therapy, 3 children had significant clinical improvement and were able to discontinue steroid use. One child continued to decline, and, in retrospect, had disease progression, not radiation necrosis. In all cases, bevacizumab was well tolerated. Conclusions: In children with pontine gliomas, bevacizumab may provide both therapeutic benefit and diagnostic information. More formal evaluation of bevacizumab in these children is needed.

  14. Evaluating the effects of diffused lavender in an adult day care center for patients with dementia in an effort to decrease behavioral issues: a pilot study

    PubMed Central

    Moorman Li, Robin; Gilbert, Brian; Orman, Anna; Aldridge, Petra; Leger-Krall, Sue; Anderson, Clare; Hincapie Castillo, Juan

    2017-01-01

    Abstract Objectives: To evaluate the effects of diffused lavender on the frequency of behavioral issues [BIs], defined as a composite of restlessness/wandering [RW], agitation [AGT], anger [ANG], and anxiety [ANX] in an adult day care center. Secondary objectives evaluate systematic differences on the frequency of BIs between age cohorts, gender, and individual behaviors. Design: Pre-post quasi-experimental study. Setting: Private nonprofit adult day care center for patients with dementia. Participants: Elderly patients older than 65 years of age with a clinical diagnosis of dementia, who require daytime monitoring. Intervention: Lavender aromatherapy twice a day for 20 min during a two-month period during active clinic days. Measurements: Behavioral issues were recorded using the behavior/intervention monthly flow record during the pre- and post-intervention periods. Results: There was no significant difference on frequency of BIs between pre-intervention and post-intervention periods (p = .06). There was a significant difference between pre-intervention and post-intervention total number of AGT occurrences (129 vs. 25; p value < .01). There was no significant difference between age cohorts for computed difference of RW, ANG, and ANX issues. There was a significant difference between age cohorts for computed difference of AGT (p value = .04) as the 70–85 age cohort showed less agitation compared to the 85–100 age cohort. Conclusion: The use of diffused lavender twice daily has shown to reduce the frequency of agitation in elderly patients with dementia, especially in the 70–85 age cohort. Though diffused lavender did not show statistical differences in the frequency of other behaviors (restlessness/wander, anger, anxiety), the study population may have been too small to find a difference. PMID:28265482

  15. 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

  16. 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.

  17. Language outcomes after resection of dominant inferior parietal lobule gliomas.

    PubMed

    Southwell, Derek G; Riva, Marco; Jordan, Kesshi; Caverzasi, Eduardo; Li, Jing; Perry, David W; Henry, Roland G; Berger, Mitchel S

    2017-01-06

    difference was not statistically significant (p = 0.46). Additionally, patients with long-term language deficits were older than those without deficits (p < 0.05). CONCLUSIONS In a small number of patients with preoperative language deficits, IPL glioma resection resulted in improved language function. However, in patients with intact preoperative language function, resection of IPL gliomas may result in new language deficits, especially if the tumors are diffuse, high-grade lesions. Thus, language-dominant IPL glioma resection is not risk-free, yet it is safe and its morbidity can be reduced by the use of cortical and subcortical stimulation mapping.

  18. Novel paracrine modulation of Notch-DLL4 signaling by fibulin-3 promotes angiogenesis in high-grade gliomas

    PubMed Central

    Cole, Susan E.; Erdreich-Epstein, Anat; Rodriguez-Gil, Diego J.; Viapiano, Mariano S.

    2014-01-01

    High-grade gliomas are characterized by exuberant vascularization, diffuse invasion and significant chemoresistance, resulting in a recurrent phenotype that makes them impossible to eradicate in the long-term. Targeting pro-tumoral signals in the glioma microenvironment could have significant impact against tumor cells and the supporting niche that facilitates their growth. Fibulin-3 is a protein secreted by glioma cells, but absent in normal brain, that promotes tumor invasion and survival. We show here that fibulin-3 is a paracrine activator of Notch signaling in endothelial cells and promotes glioma angiogenesis. Fibulin-3 overexpression increased tumor VEGF levels, microvascular density, and vessel permeability, while fibulin-3 knockdown reduced vessel density in xenograft models of glioma. Fibulin-3 localization in human glioblastomas showed dense fiber-like condensations around tumor blood vessels, which were absent in normal brain, suggesting a remarkable association of this protein with tumor endothelium. At the cellular level, fibulin-3 enhanced endothelial cell motility and association to glioma cells, reduced endothelial cell sprouting, and increased formation of endothelial tubules, in a VEGF-independent and Notch-dependent manner. Fibulin-3 increased ADAM10/17 activity in endothelial cells by inhibiting the metalloprotease inhibitor TIMP3; this resulted in increased Notch cleavage and increased expression of DLL4 independently of VEGF signaling. Inhibition of ADAM10/17 or knockdown of DLL4 reduced the pro-angiogenic effects of fibulin-3 in culture. Taken together, these results reveal a novel, pro-angiogenic role of fibulin-3 in gliomas, highlighting the relevance of this protein as an important molecular target in the tumor microenvironment. PMID:25139440

  19. 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.

  20. Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights

    NASA Astrophysics Data System (ADS)

    Alfonso, J. C. L.; Köhn-Luque, A.; Stylianopoulos, T.; Feuerhake, F.; Deutsch, A.; Hatzikirou, H.

    2016-11-01

    Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates.

  1. Functional assessment of glioma pathogenesis by in vivo multi-parametric magnetic resonance imaging and in vitro analyses

    PubMed Central

    Yao, Nai-Wei; Chang, Chen; Lin, Hsiu-Ting; Yen, Chen-Tung; Chen, Jeou-Yuan

    2016-01-01

    Gliomas are aggressive brain tumors with poor prognosis. In this study, we report a novel approach combining both in vivo multi-parametric MRI and in vitro cell culture assessments to evaluate the pathogenic development of gliomas. Osteopontin (OPN), a pleiotropic factor, has been implicated in the formation and progression of various human cancers, including gliomas, through its functions in regulating cell proliferation, survival, angiogenesis, and migration. Using rat C6 glioma model, the combined approach successfully monitors the acquisition and decrease of cancer hallmarks. We show that knockdown of the expression of OPN reduces C6 cell proliferation, survival, viability and clonogenicity in vitro, and reduces tumor burden and prolongs animal survival in syngeneic rats. OPN depletion is associated with reduced tumor growth, decreased angiogenesis, and an increase of tumor-associated metabolites, as revealed by T2-weighted images, diffusion-weighted images, Ktrans maps, and 1H-MRS, respectively. These strategies allow us to define an important role of OPN in conferring cancer hallmarks, which can be further applied to assess the functional roles of other candidate genes in glioma. In particular, the non-invasive multi-parametric MRI measurement of cancer hallmarks related to proliferation, angiogenesis and altered metabolism may serve as a useful tool for diagnosis and for patient management. PMID:27198662

  2. Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights

    PubMed Central

    Alfonso, J. C. L.; Köhn-Luque, A.; Stylianopoulos, T.; Feuerhake, F.; Deutsch, A.; Hatzikirou, H.

    2016-01-01

    Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates. PMID:27876890

  3. A Case of Angiocentric Glioma with Unusual Clinical and Radiological Features

    PubMed Central

    Rho, Gyung-Jun; Kim, Hyoung-Ihl; Ju, Myoung-Jin

    2011-01-01

    Angiocentric glioma was recently recognized as a distinct clinicopathological entity in the 2007 World Health Organization classification of tumors of the central nervous system. Typically, it presents with seizure in children and young adults. However, our patient did not have a history of seizure. Seizure did not occur up to 6 months after operation. Although it usually does not have calcification brain magnetic resonance imaging in our patient showed T1-hyperintense and T2-hypointense signals with calcification. PMID:21887397

  4. Analysis of SOX2-Regulated Transcriptome in Glioma Stem Cells

    PubMed Central

    Acanda de la Rocha, Arlet M.; López-Bertoni, Hernando; Guruceaga, Elizabeth; González-Huarriz, Marisol; Martínez-Vélez, Naiara; Xipell, Enric; Fueyo, Juan; Gomez-Manzano, Candelaria

    2016-01-01

    Introduction Glioblastoma is the most malignant brain tumor in adults and is associated with poor survival despite multimodal treatments. Glioma stem-like cells (GSCs) are cells functionally defined by their self-renewal potential and the ability to reconstitute the original tumor upon orthotopic implantation. They have been postulated to be the culprit of glioma chemo- and radio-resistance ultimately leading to relapse. Understanding the molecular circuits governing the GSC compartment is essential. SOX2, a critical transcription regulator of embryonic and neural stem cell function, is deregulated in GSCs however; the precise molecular pathways regulated by this gene in GSCs remain poorly understood. Results We performed a genome-wide analysis of SOX2-regulated transcripts in GSCs, using a microarray. We identified a total of 2048 differentially expressed coding transcripts and 261 non-coding transcripts. Cell adhesion and cell-cell signaling are among the most enriched terms using Gene Ontology (GO) classification. The pathways altered after SOX2 down-modulation includes multiple cellular processes such as amino-acid metabolism and intercellular signaling cascades. We also defined and classified the set of non-coding transcripts differentially expressed regulated by SOX2 in GSCs, and validated two of them. Conclusions We present a comprehensive analysis of the transcriptome controlled by SOX2 in GSCs, gaining insights in the understanding of the potential roles of SOX2 in glioblastoma. PMID:27669421

  5. Vorinostat, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2016-09-08

    Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  6. S0349 Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone With or Without Oblimersen in Treating Patients With Advanced Diffuse Large B-Cell Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2013-01-04

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  7. Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium

    PubMed Central

    Shete, Sanjay; Lau, Ching C; Houlston, Richard S; Claus, Elizabeth B; Barnholtz-Sloan, Jill; Lai, Rose; Il’yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Johansen, Christoffer; Bernstein, Jonine L; Olson, Sara H; Jenkins, Robert B; Yang, Ping; Vick, Nicholas A; Wrensch, Margaret; Davis, Faith G; McCarthy, Bridget J; Leung, Eastwood Hon-chiu; Davis, Caleb; Cheng, Rita; Hosking, Fay J; Armstrong, Georgina N; Liu, Yanhong; Yu, Robert K; Henriksson, Roger; Consortium, The Gliogene; Melin, Beatrice S; Bondy, Melissa L

    2011-01-01

    Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have demonstrated that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P=0.0005) at 17q12–21.32 and the Z-score of 4.20 (P=0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P=0.008) and the Z-score of 1.47 (P=0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P=0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. PMID:22037877

  8. 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.

  9. Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma

    PubMed Central

    Chen, Li; Voronovich, Zoya; Clark, Kenneth; Hands, Isaac; Mannas, Jonathan; Walsh, Meggen; Nikiforova, Marina N.; Durbin, Eric B.; Weiss, Heidi; Horbinski, Craig

    2014-01-01

    Background Several variables are associated with the likelihood of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation in gliomas, though no guidelines yet exist for when testing is warranted, especially when an R132H IDH1 immunostain is negative. Methods A cohort of 89 patients was used to build IDH1/2 mutation prediction models in World Health Organization grades II–IV gliomas, and an external cohort of 100 patients was used for validation. Logistic regression and backward model selection with the Akaike information criterion were used to develop prediction models. Results A multivariable model, incorporating patient age, glioblastoma multiforme diagnosis, and prior history of grade II or III glioma, was developed to predict IDH1/2 mutation probability. This model generated an area under the curve (AUC) of 0.934 (95% CI: 0.878, 0.978) in the external validation cohort and 0.941 (95% CI: 0.918, 0.962) in the cohort of The Cancer Genome Atlas. When R132H IDH1 immunostain information was added, AUC increased to 0.986 (95% CI: 0.967, 0.998). This model had an AUC of 0.947 (95% CI: 0.891, 0.995) in predicting whether an R132H IDH1 immunonegative case harbored a less common IDH1 or IDH2 mutation. The models were also 94% accurate in predicting IDH1/2 mutation status in gliomas from The Cancer Genome Atlas. An interactive web-based application for calculating the probability of an IDH1/2 mutation is now available using these models. Conclusions We have integrated multiple variables to generate a probability of an IDH1/2 mutation. The associated web-based application can help triage diffuse gliomas that would benefit from mutation testing in both clinical and research settings. PMID:24860178

  10. 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

  11. Resistance to DNA Damaging Agents Produced Invasive Phenotype of Rat Glioma Cells-Characterization of a New in Vivo Model.

    PubMed

    Stojković, Sonja; Podolski-Renić, Ana; Dinić, Jelena; Pavković, Željko; Ayuso, Jose M; Fernández, Luis J; Ochoa, Ignacio; Pérez-García, Victor M; Pešić, Vesna; Pešić, Milica

    2016-06-27

    Chemoresistance and invasion properties are severe limitations to efficient glioma therapy. Therefore, development of glioma in vivo models that more accurately resemble the situation observed in patients emerges. Previously, we established RC6 rat glioma cell line resistant to DNA damaging agents including antiglioma approved therapies such as 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ). Herein, we evaluated the invasiveness of RC6 cells in vitro and in a new orthotopic animal model. For comparison, we used C6 cells from which RC6 cells originated. Differences in cell growth properties were assessed by real-time cell analyzer. Cells' invasive potential in vitro was studied in fluorescently labeled gelatin and by formation of multicellular spheroids in hydrogel. For animal studies, fluorescently labeled cells were inoculated into adult male Wistar rat brains. Consecutive coronal and sagittal brain sections were analyzed 10 and 25 days post-inoculation, while rats' behavior was recorded during three days in the open field test starting from 25th day post-inoculation. We demonstrated that development of chemoresistance induced invasive phenotype of RC6 cells with significant behavioral impediments implying usefulness of orthotopic RC6 glioma allograft in preclinical studies for the examination of new approaches to counteract both chemoresistance and invasion of glioma cells.

  12. The human glia maturation factor-gamma gene: genomic structure and mutation analysis in gliomas with chromosome 19q loss.

    PubMed

    Peters, N; Smith, J S; Tachibana, I; Lee, H K; Pohl, U; Portier, B P; Louis, D N; Jenkins, R B

    1999-09-01

    Human glia maturation factor-gamma (hGMF-gamma) is a recently identified gene that may be involved in glial differentiation, neural regeneration, and inhibition of tumor cell proliferation. The gene maps to the long arm of chromosome 19 at band q13.2, a region that is frequently deleted in human malignant gliomas and is thus suspected to harbor a glioma tumor suppressor gene. Given the putative role of hGMF-gamma in cell differentiation and proliferation and its localization to chromosome 19q13, this gene is an interesting candidate for the chromosome 19q glioma tumor suppressor gene. To evaluate this possibility, we determined the genomic structure of human hGMF-gamma and performed mutation screening in a series of 41 gliomas with and without allelic loss of chromosome 19q. Mutations were not detected, which suggests that hGMF-gamma is not the chromosome 19q glioma suppressor gene. However, the elucidation of the genomic structure of hGMF-gamma may prove useful in future investigations of hGMF-gamma in the normal adult and developing human nervous system.

  13. 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

  14. 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.

  15. Positron Emission Tomography Using Fluorine F 18 EF5 to Find Oxygen in Tumor Cells of Patients Who Are Undergoing Surgery or Biopsy for Newly Diagnosed Brain Tumors

    ClinicalTrials.gov

    2013-01-15

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Meningeal Melanocytoma

  16. Change in Pattern of Relapse After Antiangiogenic Therapy in High-Grade Glioma

    SciTech Connect

    Narayana, Ashwatha; Kunnakkat, Saroj D.; Medabalmi, Praveen; Golfinos, John; Parker, Erik; Knopp, Edmond; Zagzag, David; Eagan, Patricia; Gruber, Deborah; Gruber, Michael L.

    2012-01-01

    Purpose: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. Methods and Materials: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. Results: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R{sup 2} = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). Conclusion: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials.

  17. Naming performance in two bilinguals with frontal vs. temporal glioma.

    PubMed

    Gatignol, Peggy; Duffau, Hugues; Capelle, Laurent; Plaza, Monique

    2009-12-01

    Two bilingual patients had World Health Organization Grade II Gliomas removed from a language area, one in the left mesiofronto-cingular region and one in the left postero-temporal region. They performed a picture naming task in their two languages before their surgery and afterwards. Both patients showed slowness in naming in their first language but different patterns of naming performance across their first and second language. Their patterns depended upon the site of their lesion and their language experience. These data, from brain-damaged, bilingual adult patients, contribute to the neuropsychological literature on brain organization and plasticity, and highlight the importance of assessing naming speed to obtain a better understanding of impairment and recovery mechanisms.

  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. 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.

  20. Structural organization of the prefrontal white matter pathways in the adult and aging brain measured by diffusion tensor imaging.

    PubMed

    Malykhin, Nikolai; Vahidy, Sana; Michielse, Stijn; Coupland, Nick; Camicioli, Richard; Seres, Peter; Carter, Rawle

    2011-11-01

    Previous diffusion tensor imaging (DTI) studies confirmed the vulnerability of frontal callosal fibers to normal aging. The present study extended this examination systematically to other prefrontal white matter regions. Structural magnetic resonance imaging and DTI datasets were acquired from 69 healthy subjects aged 22-84 years. The prefrontal white matter was parcellated into several anatomical sub-regions: medial and lateral orbitofrontal white matter, dorsolateral prefrontal white matter, and medial prefrontal white matter, using reliable DTI-tractography protocols. Tract-specific characteristics were calculated using Matlab. Regression models were used to determine the relationship between age and structural integrity of white matter tracts. The results of our study demonstrate regional age-related changes in the prefrontal white matter tracts of the human brain. This study was cross-sectional and therefore additional longitudinal studies are needed to confirm our findings.

  1. Automated voxel classification used with atlas-guided diffuse optical tomography for assessment of functional brain networks in young and older adults.

    PubMed

    Li, Lin; Cazzell, Mary; Babawale, Olajide; Liu, Hanli

    2016-10-01

    Atlas-guided diffuse optical tomography (atlas-DOT) is a computational means to image changes in cortical hemodynamic signals during human brain activities. Graph theory analysis (GTA) is a network analysis tool commonly used in functional neuroimaging to study brain networks. Atlas-DOT has not been analyzed with GTA to derive large-scale brain connectivity/networks based on near-infrared spectroscopy (NIRS) measurements. We introduced an automated voxel classification (AVC) method that facilitated the use of GTA with atlas-DOT images by grouping unequal-sized finite element voxels into anatomically meaningful regions of interest within the human brain. The overall approach included volume segmentation, AVC, and cross-correlation. To demonstrate the usefulness of AVC, we applied reproducibility analysis to resting-state functional connectivity measurements conducted from 15 young adults in a two-week period. We also quantified and compared changes in several brain network metrics between young and older adults, which were in agreement with those reported by a previous positron emission tomography study. Overall, this study demonstrated that AVC is a useful means for facilitating integration or combination of atlas-DOT with GTA and thus for quantifying NIRS-based, voxel-wise resting-state functional brain networks.

  2. Atypical white-matter microstructure in congenitally deaf adults: A region of interest and tractography study using diffusion-tensor imaging.

    PubMed

    Karns, Christina M; Stevens, Courtney; Dow, Mark W; Schorr, Emily M; Neville, Helen J

    2017-01-01

    Considerable research documents the cross-modal reorganization of auditory cortices as a consequence of congenital deafness, with remapped functions that include visual and somatosensory processing of both linguistic and nonlinguistic information. Structural changes accompany this cross-modal neuroplasticity, but precisely which specific structural changes accompany congenital and early deafness and whether there are group differences in hemispheric asymmetries remain to be established. Here, we used diffusion tensor imaging (DTI) to examine microstructural white matter changes accompanying cross-modal reorganization in 23 deaf adults who were genetically, profoundly, and congenitally deaf, having learned sign language from infancy with 26 hearing controls who participated in our previous fMRI studies of cross-modal neuroplasticity. In contrast to prior literature using a whole-brain approach, we introduce a semiautomatic method for demarcating auditory regions in which regions of interest (ROIs) are defined on the normalized white matter skeleton for all participants, projected into each participants native space, and manually constrained to anatomical boundaries. White-matter ROIs were left and right Heschl's gyrus (HG), left and right anterior superior temporal gyrus (aSTG), left and right posterior superior temporal gyrus (pSTG), as well as one tractography-defined region in the splenium of the corpus callosum connecting homologous left and right superior temporal regions (pCC). Within these regions, we measured fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and white-matter volume. Congenitally deaf adults had reduced FA and volume in white matter structures underlying bilateral HG, aSTG, pSTG, and reduced FA in pCC. In HG and pCC, this reduction in FA corresponded with increased RD, but differences in aSTG and pSTG could not be localized to alterations in RD or AD. Direct statistical tests of hemispheric asymmetries in these

  3. Detecting the Effects of Fabry Disease in the Adult Human Brain with Diffusion Tensor Imaging and Fast Bound-Pool Fraction Imaging

    PubMed Central

    Underhill, Hunter R.; Golden-Grant, Katie; Garrett, Lauren T.; Uhrich, Stefanie; Zielinski, Brandon A.; Scott, C. Ronald

    2015-01-01

    Purpose To identify quantitative MRI parameters associated with diffusion tensor imaging (DTI) and fast bound-pool fraction imaging (FBFI) that may detect alterations in gray matter and/or white matter in adults with Fabry disease, a lysosomal storage disorder. Materials and Methods Twelve healthy controls (mean age ± standard deviation: 48.0±12.4 years) and ten participants with Fabry disease (46.7±12.9 years) were imaged at 3.0 T. Whole-brain parametric maps of diffusion tensor metrics (apparent diffusion coefficient (ADC) and fractional anisotropy (FA)) and the bound-pool fraction (f) were acquired. Mean voxel values of parametric maps from regions-of-interest within gray and white matter structures were compared between cases and controls using the independent t-test. Spearman’s rho was used to identify associations between parametric maps and age. Results Compared to controls, the left thalamus of Fabry participants had an increase in FA (0.29±0.02 vs. 0.33±0.05, respectively; p=0.030) and a trend towards an increase in ADC (0.73±00.02 vs. 0.76±0.03 μm2/s, respectively; p=0.082). The left posterior white matter demonstrated a reduction in f (10.45±0.37 vs. 9.00±1.84 %, respectively; p=0.035), an increase in ADC (0.78±0.04 vs. 0.94±0.19 μm2/s, respectively; p=0.024), and a trend towards a reduction in FA (0.42±0.07 vs. 0.36±0.08, respectively; p=0.052). Amongst all parameters, only f measured in the left posterior white matter was significantly associated with age in Fabry participants (rho= −0.71, p=0.022). Conclusions Parameters derived from DTI and FBFI detect Fabry-related changes in the adult human brain, particularly in the posterior white matter where reductions in myelin density as measured by FBFI appear age related. PMID:26018987

  4. 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

  5. Choroid plexus cyst and chordoid glioma. Report of two cases.

    PubMed

    Hanbali, F; Fuller, G N; Leeds, N E; Sawaya, R

    2001-06-15

    confusion. Three weeks later he died of a massive myocardial infarction. These two patients represent the sixth case of an adult with a choroid plexus cyst in the anterior lateral ventricle and the 19th case of an adult with a chordoid glioma of the third ventricle, respectively.

  6. Brain stem glioma: two case studies.

    PubMed

    Rosenblum, Ruth K

    2005-01-01

    The paths taken by each family in coming to terms with the dismal prognosis associated with brain stem glioma can be quite different. The case studies of 2 school-age girls diagnosed with a brain stem glioma within weeks of each other are presented. The multi-disciplinary team response to each family was individualized at each stage of diagnosis, treatment, and end-of-life care, as expected. The ultimate chronologic union of these 2 families as each child neared death was somewhat uncanny. The experience of each family, and their relationship with the team through this process, was an intense challenge and learning experience.

  7. [Guidelines for the radiotherapy of gliomas].

    PubMed

    Feuvret, L; Antoni, D; Biau, J; Truc, G; Noël, G; Mazeron, J-J

    2016-09-01

    Gliomas are the most frequent primary brain tumours. Treating these tumours is difficult because of the proximity of organs at risk, infiltrating nature, and radioresistance. Clinical prognostic factors such as age, Karnofsky performance status, tumour location, and treatments such as surgery, radiation therapy, and chemotherapy have long been recognized in the management of patients with gliomas. Molecular biomarkers are increasingly evolving as additional factors that facilitate diagnosis and therapeutic decision-making. These practice guidelines aim at helping in choosing the best treatment, in particular radiation therapy.

  8. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

    PubMed

    Patil, Abhijit A; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D; Roylance, Anthony; Kriplani, Deepti H; Myers, Katie N; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A; Collis, Spencer J

    2014-08-15

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

  9. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

    PubMed Central

    Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

    2014-01-01

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

  10. Extent of resection of peritumoral diffusion tensor imaging-detected abnormality as a predictor of survival in adult glioblastoma patients.

    PubMed

    Yan, Jiun-Lin; van der Hoorn, Anouk; Larkin, Timothy J; Boonzaier, Natalie R; Matys, Tomasz; Price, Stephen J

    2017-01-01

    OBJECTIVE Diffusion tensor imaging (DTI) has been shown to detect tumor invasion in glioblastoma patients and has been applied in surgical planning. However, the clinical value of the extent of resection based on DTI is unclear. Therefore, the correlation between the extent of resection of DTI abnormalities and patients' outcome was retrospectively reviewed. METHODS A review was conducted of 31 patients with newly diagnosed supratentorial glioblastoma who underwent standard 5-aminolevulinic acid-aided surgery with the aim of maximal resection of the enhancing tumor component. All patients underwent presurgical MRI, including volumetric postcontrast T1-weighted imaging, DTI, and FLAIR. Postsurgical anatomical MR images were obtained within 72 hours of resection. The diffusion tensor was split into an isotropic (p) and anisotropic (q) component. The extent of resection was measured for the abnormal area on the p, q, FLAIR, and postcontrast T1-weighted images. Data were analyzed in relation to patients' outcome using univariate and multivariate Cox regression models controlling for possible confounding factors including age, O(6)-methylguanine-DNA-methyltrans-ferase methylation status, and isocitrate dehydrogenase-1 mutation. RESULTS Complete resection of the enhanced tumor shown on the postcontrast T1-weighted images was achieved in 24 of 31 patients (77%). The mean extent of resection of the abnormal p, q, and FLAIR areas was 57%, 83%, and 59%, respectively. Increased resection of the abnormal p and q areas correlated positively with progression-free survival (p = 0.009 and p = 0.006, respectively). Additionally, a larger, residual, abnormal q volume predicted significantly shorter time to progression (p = 0.008). More extensive resection of the abnormal q and contrast-enhanced area improved overall survival (p = 0.041 and 0.050, respectively). CONCLUSIONS Longer progression-free survival and overall survival were seen in glioblastoma patients in whom more DTI

  11. Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

    PubMed Central

    Elsherbiny, Marwa E.; Emara, Marwan; Godbout, Roseline

    2015-01-01

    Malignant gliomas are the most common adult brain cancers. In spite of aggressive treatment, recurrence occurs in the great majority of patients and is invariably fatal. Polyunsaturated fatty acids are abundant in brain, particularly ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Although the levels of ω-6 and ω-3 polyunsaturated fatty acids are tightly regulated in brain, the ω-6:ω-3 ratio is dramatically increased in malignant glioma, suggesting deregulation of fundamental lipid homeostasis in brain tumor tissue. The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA-rich medium. This fatty acid-dependent effect on cell migration is dependent on expression of the brain fatty acid binding protein (FABP7) previously shown to bind DHA and AA. Increased levels of enzymes involved in eicosanoid production in FABP7-positive malignant glioma cells suggest that FABP7 is an important modulator of AA metabolism. We provide evidence that increased production of eicosanoids in FABP7-positive malignant glioma growing in an AA-rich environment contributes to tumor infiltration in the brain. We discuss pathways and molecules that may underlie FABP7/AA-mediated promotion of cell migration and FABP7/DHA-mediated inhibition of cell migration in malignant glioma. PMID:23981365

  12. Long Noncoding RNA MEG3 Suppresses Glioma Cell Proliferation, Migration, and Invasion By Acting As Competing Endogenous RNA of MiR-19a.

    PubMed

    Tong, Gui-Feng; Qin, Nan; Sun, Li-Wei; Xu, Xiao-Lin

    2017-03-08

    Glioma, with varying malignancy grades and histological subtypes, is the commonest primary brain tumor in adults. Longnon-coding RNAs (lncRNAs) are non-protein-coding transcripts and have been proven to play important roles in tumorigenesis. Our study aims to elucidate the combined effect of lncRNA MEG3 and microRNA-19a in human glioma U87 and U251 cell lines. Real time PCR revealed that MEG3 was down-regulated and miR-19a was up-regulated in malignant glioma tissues and cell lines. Bioinformatics analyses (TargetScan, miRanda and starBase V2.0) showed that PTEN is a target of miR-19a with complementary binding sites in the 3'-UTR. As expected, luciferase results verify the putative target site and also reveal the complementary binding between miR-19a and MEG3. MiR-19a represses the expression of PTEN and promotes glioma cell proliferation, migration and invasion. However, MEG3 could directly bind to miR-19a and effectively act as a competing endogenous RNA (ceRNA) for miR-19a to suppress tumorigenesis. Our data firstly demonstrates that lncRNA MEG3 suppresses glioma cell proliferation, migration and invasion via acting as competing endogenous RNA (ceRNA) of miR-19a, which provides a novel insight about the pathogenesis of glioma.

  13. 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.

  14. 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.

  15. A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma.

    PubMed

    Turner, Kathryn L; Honasoge, Avinash; Robert, Stephanie M; McFerrin, Michael M; Sontheimer, Harald

    2014-06-01

    Glioblastoma multiforme are highly motile primary brain tumors. Diffuse tissue invasion hampers surgical resection leading to poor patient prognosis. Recent studies suggest that intracellular Ca(2+) acts as a master regulator for cell motility and engages a number of downstream signals including Ca(2+) -activated ion channels. Querying the REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT), an annotated patient gene database maintained by the National Cancer Institute, we identified the intermediate conductance Ca(2+) -activated K(+) channels, KCa3.1, being overexpressed in 32% of glioma patients where protein expression significantly correlated with poor patient survival. To mechanistically link KCa3.1 expression to glioma invasion, we selected patient gliomas that, when propagated as xenolines in vivo, present with either high or low KCa3.1 expression. In addition, we generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression. Subjecting these cells to a combination of in vitro and in situ invasion assays, we demonstrate that KCa3.1 expression significantly enhances glioma invasion and that either specific pharmacological inhibition with TRAM-34 or elimination of the channel impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA resulted in a significant reduction in tumor invasion into surrounding brain in vivo. These results show that KCa3.1 confers an invasive phenotype that significantly worsens a patient's outlook, and suggests that KCa3.1 represents a viable therapeutic target to reduce glioma invasion.

  16. Immunotherapy for high-grade glioma: how to go beyond Phase I/II clinical trials.

    PubMed

    van Gool, Stefaan

    2013-10-01

    Evaluation of: Lasky JL 3rd, Panosyan EH, Plant A et al. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 33, 2047-2056 (2013). Immunotherapy for children and adults with high-grade glioma (HGG) is an emerging innovative treatment approach, which aims at stimulating the body's own immune system against HGG by using autologous dendritic cells pulsed with autologous tumor lysate as a therapeutic vaccine. This is the third report on immunotherapy for HGG in children, bringing additional knowledge and experience to the scientific community. However, at the same time, this and other manuscripts urge for the next step in treatment development.

  17. Assessment of quality of life in patients treated for low-grade glioma: a preliminary report.

    PubMed Central

    Taphoorn, M J; Heimans, J J; Snoek, F J; Lindeboom, J; Oosterink, B; Wolbers, J G; Karim, A B

    1992-01-01

    In this pilot study quality of life was assessed in fourteen adult patients who were treated for a low-grade glioma with surgery and radiotherapy at least one year previously. Apart from widely used parameters, such as the neurological and functional status, the patients' cognitive functioning and actual affective status were determined. In addition the patients were interviewed to evaluate various aspects of quality of life. Generally no serious focal neurological deficits were found, although psychological examination showed serious cognitive and affective disturbances in most cases. Self report measures concerning cognitive functioning were not in all cases in accordance with objective test results. When the results of treatment in glioma patients are evaluated assessment of quality of life, including neuropsychological functioning, should be performed, especially as new therapeutic strategies are being developed. PMID:1602310

  18. Photodynamic therapy of supratentorial gliomas

    NASA Astrophysics Data System (ADS)

    Muller, Paul J.; Wilson, Brian C.

    1997-05-01

    We are reporting the results form intraoperative intracavitary PDT treatment in 56 patients with recurrent supratentorial gliomas who had failed previous surgery and radiotherapy. These patients received 2mg/kg Photofin iv. 12-36 hours prior to surgical resection of their tumor or tumor cyst drainage. The median survival times in weeks for glioblastoma (GBM), malignant astrocytoma (MA), malignant mixed astrocytoma-oligodendroglioma and ependymoma were 30, 40, >56 and >174 weeks, respectively. Eight patients with recurrent GBM who received >60 J/cm2 had a median survival of 58 weeks and 24 patients who received <60 J/cm2 survived 29 weeks. The survival of patients with recurrent glioblastoma who undergo surgical treatment alone is only 20 weeks. We are also reporting the results of PDT treatment in 20 patients with newly diagnosed MA or GBM treated with intracavitary Photofin-PDT at the time of their initial craniotomy. The median survival of the whole cohort was 44 weeks with a 1 and 2 year survival of 40 percent and 15 percent, respectively. The median survival of patients with GBM was 37 weeks with a 1 and 2 year actuarial survival of 35 percent and 0 percent, respectively. The median survival of patients with MA as 48 weeks with a 1 and 2 year actuarial survival of 44 percent and 33 percent, respectively. Six patients with a Karnofsky score of >70 who received a light dose of >1260J had a median survival of 92 weeks with a 1 and 2 year survival of 83 percent and 33 percent, respectively. The mortality rate in our total series of 93 PDT treatments or brain tumor is 3 percent. The combined serious mortality-morbidity rate is 8 percent.

  19. Gliomas and exposure to wood preservatives.

    PubMed

    Cordier, S; Poisson, M; Gerin, M; Varin, J; Conso, F; Hemon, D

    1988-10-01

    A case-referent study was undertaken to look for occupational risk factors among patients with glioma treated in a neurological hospital in Paris between 1975 and 1984. In the study group were 125 men with gliomas (aged less than or equal to 65) and 238 patients (also less than or equal to 65) admitted for non-neoplastic, non-malformative vascular diseases in the same department during the same period constituting the reference group. All diagnoses were confirmed by tomodensitometry. Information on occupational history was obtained from a postal questionnaire and from medical records. Comparison of cases and referents showed a significant excess risk among teachers (OR = 4.1) and a raised risk among wood workers (OR = 1.6). Four of nine cases of glioma who had been employed as wood workers reported that a colleague had suffered from glioma (those reports were confirmed by hospital records). None were reported among 11 referent wood workers. Using a complementary questionnaire on wood work, exposure assessment to wood preservatives and solvents showed that frequent exposure to organochlorine wood preservatives and to organic solvents occurred more often among cases than referent wood workers (p less than 0.10).

  20. The Effects of Thermal Preconditioning on Oncogenic and Intraspinal Cord Growth Features of Human Glioma Cells.

    PubMed

    Zeng, Xiang; Han, Inbo; Abd-El-Barr, Muhammad; Aljuboori, Zaid; Anderson, Jamie E; Chi, John H; Zafonte, Ross D; Teng, Yang D

    2016-12-13

    The adult rodent spinal cord presents an inhibitory environment for donor cell survival, impeding efficiency for xenograft-based modeling of gliomas. We postulated that mild thermal preconditioning may influence the fate of the implanted tumor cells. To test this hypothesis, high-grade human astrocytoma G55 and U87 cells were cultured under 37C and 38.5C to mimic regular experimental or core body temperatures of rodents, respectively. In vitro, the 38.5C-conditioned cells, relative to 37C, grew slightly faster. Compared to U87 cells, G55 cells demonstrated a greater response to the temperature difference. Hyperthermal culture markedly increased production of Hsp27 in most G55 cells, but only promoted transient expression of cancer stem cell marker CD133 in a small cell subpopulation. We subsequently transplanted G55 cells following 37C or 38.5C culture into the C2 or T10 spinal cord of adult female immunodeficient rats (3 rats/each locus/per temperature; total: 12 rats). Systematic analyses revealed that 38.5C-preconditioned G55 cells grew more malignantly at either C2 or T10 as determined by tumor size, outgrowth profile, resistance to bolus intratumor administration of 5-fluorouracil (0.1 mol), and posttumor survival (p0.05; n=6/group). Therefore, thermal preconditioning of glioma cells may be an effective way to influence the in vitro and in vivo oncological contour of glioma cells. Future studies are needed for assessing the potential oncogenic modifying effect of hyperthermia regimens on glioma cells.

  1. Mapping the connectome in awake surgery for gliomas: an update.

    PubMed

    Duffau, Hugues

    2017-03-06

    The traditional principle underlying oncological neurosurgery is to remove a tumor mass displacing the brain in order to increase survival. Recently, advances in connectomics enabled an improved understanding of cerebral processing, and led to a paradigmatic shift in tumor surgery based upon interactions between neurooncology and cognitive neurosciences. First, glioma is not a focal tumor invaginated within the parenchyma but a diffuse neoplastic disease migrating in the brain. This concept resulted in a new surgical ideology, i.e., to maximally resect the invaded nervous system on the condition that eloquent neural networks are spared. Second, this led to determine what structures are crucial to preserve the quality of life (QoL) versus those that can be compensated by means of neuroplasticity. Because limitations of functional remodelling are mainly represented by the subcortical connectivity, mapping the connectome during surgery is a priority. Neurosurgeons have to switch from an image-guided surgery to a functional mapping-guided resection, namely, from a technological guidance into the operating theater to a philosophy based on the investigation of the dynamics of delocalized neural circuits throughout resection. Indeed, awake mapping with real-time monitoring of sensorimotor, visuospatial, language, executive and behavioral functions allowed an optimization of the onco-functional balance. Third, surgery should not be seen in isolation, but integrated in a global multistep therapeutic management, especially in low- grade gliomas, opening the window to repeat resections thanks to the potential of remapping over years. Such a "cognitive neurooncological surgery" which aims to improve both QoL and survival must become a "connectomal neurosurgery".

  2. Predictive and Prognostic Roles of Abnormal Expression of Tissue miR-125b, miR-221, and miR-222 in Glioma.

    PubMed

    Li, Xinxing; Zheng, Jihui; Chen, Liangyu; Diao, Hongyu; Liu, Yunhui

    2016-01-01

    Glioma is the most prevalent primary brain tumors in adults. In addition to the high incidence and mortality rate, the 5-year survival rate of glioma is also extremely low. MicroRNAs (miRNAs), as a class of small non-coding RNAs, may play an important role in carcinogenesis. It was also proposed that miRNAs might also be associated with glioma diagnosis and prognosis. In this study, we aimed at investigating the predictive and prognostic values of miR-125b, miR-221, and miR-222 in glioma and, hopefully, to provide some evidence for novel therapy of glioma. Tissue specimens were obtained from tumor tissue and adjacent non-tumor tissue. RNA was extracted and qRT-PCR was performed with U6 being the internal control. Receiver-operating characteristic (ROC) curves were constructed, and the area under the ROC curves (AUC) was calculated to evaluate the significance of candidate miRNAs in distinguishing glioma tumor tissues and adjacent normal tissues. Survival curves of Kaplan-Meier method were constructed for both high expression group and low expression group, and the difference between curves was evaluated by log-rank test. All the statistical analyses were performed using Stata version 12.0 software, and graphs were generated by GraphPad Prism 5.0. The significance of miR-125b, miR-221, and miR-222 expression level in distinguishing glioma tumor from adjacent non-tumor tissues was further validated. Combination of miR-125b, miR-221, and miR-22 was significantly superior compared to the clinical standard of using these miRNAs alone. A clear demarcation was shown by survival analysis between patients with high miR-125b, miR-221, and miR-222 expression and patients with poor prognosis. Similarly, panel of these miRNAs could play a better prognostic role in glioma. In this study, we confirmed the significance of miR-125b, miR-221, and miR-222 in distinguishing glioma tumor from adjacent non-tumor tissues. Higher expressions of miR-125b and miR-222 have also been proved

  3. Development of Brain Structural Connectivity between Ages 12 and 30: A 4-Tesla Diffusion Imaging Study in 439 Adolescents and Adults

    PubMed Central

    Dennis, Emily L.; Jahanshad, Neda; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Hickie, Ian B.; Toga, Arthur W.; Wright, Margaret J.; Thompson, Paul M.

    2013-01-01

    Understanding how the brain matures in healthy individuals is critical for evaluating deviations from normal development in psychiatric and neurodevelopmental disorders. The brain’s anatomical networks are profoundly re-modeled between childhood and adulthood, and diffusion tractography offers unprecedented power to reconstruct these networks and neural pathways in vivo. Here we tracked changes in structural connectivity and network efficiency in 439 right-handed individuals aged 12 to 30 (211 female/126 male adults, mean age=23.6, SD=2.19; 31 female/24 male 12 year olds, mean age=12.3, SD=0.18; and 25 female/22 male 16 year olds, mean age=16.2, SD=0.37). All participants were scanned with high angular resolution diffusion imaging (HARDI) at 4 Tesla. After we performed whole brain tractography, 70 cortical gyral-based regions of interest were extracted from each participant’s co-registered anatomical scans. The degree of fiber connections between all pairs of cortical regions, or nodes, were found to create symmetric fiber density matrices, reflecting the structural brain network. From those 70×70 matrices we computed graph theory metrics characterizing structural connectivity. Several key global and nodal metrics changed across development, showing increased network integration, with some connections pruned and others strengthened. The increases and decreases in fiber density, however, were not distributed proportionally across the brain. The frontal cortex had a disproportionate number of decreases in fiber density while the temporal cortex had a disproportionate number of increases in fiber density. This large-scale analysis of the developing structural connectome offers a foundation to develop statistical criteria for aberrant brain connectivity as the human brain matures. PMID:22982357

  4. Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults.

    PubMed

    Calderón-Garcidueñas, Lilian; Kavanaugh, Michael; Block, Michelle; D'Angiulli, Amedeo; Delgado-Chávez, Ricardo; Torres-Jardón, Ricardo; González-Maciel, Angelica; Reynoso-Robles, Rafael; Osnaya, Norma; Villarreal-Calderon, Rodolfo; Guo, Ruixin; Hua, Zhaowei; Zhu, Hongtu; Perry, George; Diaz, Philippe

    2012-01-01

    Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.

  5. Economics of Malignant Gliomas: A Critical Review

    PubMed Central

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

    2015-01-01

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

  6. [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

  7. Yoga Therapy in Treating Patients With Malignant Brain Tumors

    ClinicalTrials.gov

    2017-01-17

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Recurrent Adult Brain Tumor

  8. 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.

  9. 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.

  10. 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.

  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. 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

  13. 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

  14. Mean diffusivity of globus pallidus associated with verbal creativity measured by divergent thinking and creativity-related temperaments in young healthy adults.

    PubMed

    Takeuchi, Hikaru; Taki, Yasuyuki; Sekiguchi, Atsushi; Hashizume, Hiroshi; Nouchi, Rui; Sassa, Yuko; Kotozaki, Yuka; Miyauchi, Carlos Makoto; Yokoyama, Ryoichi; Iizuka, Kunio; Nakagawa, Seishu; Nagase, Tomomi; Kunitoki, Keiko; Kawashima, Ryuta

    2015-05-01

    Recent investigations revealed mean diffusivity (MD) in gray matter and white matter areas is correlated with individual cognitive differences in healthy subjects and show unique properties and sensitivity that other neuroimaging tools donot have. In this study, we tested the hypothesis that the MD in the dopaminergic system is associated with individual differences in verbal creativity measured by divergent thinking (VCDT) and novelty seeking based on prior studies suggesting associations between these and dopaminergic functions. We examined this issue in a large sample of right-handed healthy young adults. We used analyses of MD and a psychological measure of VCDT, as well as personality measures of the Temperament and Character Inventory (TCI). Our results revealed associations between higher VCDT and lower MD in the bilateral globus pallidus. Furthermore, not only higher novelty seeking, but also lower harm avoidance, higher self-directedness, and higher self-transcendence were robustly associated with lower MD in the right globus pallidus, whereas higher persistence was associated with lower MD in the left globus pallidus. These personality variables were also associated with VCDT. The globus pallidus receives the dopaminergic input from the substantia nigra and plays a key role in motivation which is critically linked to dopamine. These results suggested the MD in the globus pallidus, underlie the association between VCDT and multiple personalities in TCI including novelty seeking.

  15. 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.

  16. 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.

  17. Malignant gliomas: old and new systemic treatment approaches

    PubMed Central

    Mesti, Tanja

    2016-01-01

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

  18. EGFR promoter exhibits dynamic histone modifications and binding of ASH2L and P300 in human germinal matrix and gliomas.

    PubMed

    Erfani, Parsa; Tome-Garcia, Jessica; Canoll, Peter; Doetsch, Fiona; Tsankova, Nadejda M

    2015-01-01

    Several signaling pathways important for the proliferation and growth of brain cells are pathologically dysregulated in gliomas, including the epidermal growth factor receptor (EGFR). Expression of EGFR is high in neural progenitors during development and in gliomas but decreases significantly in most adult brain regions. Here we show that EGFR expression is maintained in the astrocyte ribbon of the adult human subventricular zone. The transcriptional regulation of EGFR expression is poorly understood. To investigate the role of epigenetics on EGFR regulation in the contexts of neural development and gliomagenesis, we measured levels of DNA methylation and histone H3 modifications at the EGFR promoter in human brain tissues, glioma specimens, and EGFR-expressing neural cells, acutely isolated from their native niche. While DNA was constitutively hypomethylated in non-neoplastic and glioma samples, regardless of their EGFR-expression status, the activating histone modifications H3K27ac and H3K4me3 were enriched only when EGFR is highly expressed (developing germinal matrix and gliomas). Conversely, repressive H3K27me3 marks predominated in adult white matter where EGFR is repressed. Furthermore, the histone methyltransferase core enzyme ASH2L was bound at EGFR in the germinal matrix and in gliomas where levels of H3K4me3 are high, and the histone acetyltransferase P300 was bound in samples with H3K27ac enrichment. Our studies use human cells and tissues undisturbed by cell-culture artifact, and point to an important, locus-specific role for chromatin remodeling in EGFR expression in human neural development that may be dysregulated during gliomagenesis, unraveling potential novel targets for future drug therapy.

  19. EGFR promoter exhibits dynamic histone modifications and binding of ASH2L and P300 in human germinal matrix and gliomas

    PubMed Central

    Erfani, Parsa; Tome-Garcia, Jessica; Canoll, Peter; Doetsch, Fiona; Tsankova, Nadejda M

    2015-01-01

    Several signaling pathways important for the proliferation and growth of brain cells are pathologically dysregulated in gliomas, including the epidermal growth factor receptor (EGFR). Expression of EGFR is high in neural progenitors during development and in gliomas but decreases significantly in most adult brain regions. Here we show that EGFR expression is maintained in the astrocyte ribbon of the adult human subventricular zone. The transcriptional regulation of EGFR expression is poorly understood. To investigate the role of epigenetics on EGFR regulation in the contexts of neural development and gliomagenesis, we measured levels of DNA methylation and histone H3 modifications at the EGFR promoter in human brain tissues, glioma specimens, and EGFR-expressing neural cells, acutely isolated from their native niche. While DNA was constitutively hypomethylated in non-neoplastic and glioma samples, regardless of their EGFR-expression status, the activating histone modifications H3K27ac and H3K4me3 were enriched only when EGFR is highly expressed (developing germinal matrix and gliomas). Conversely, repressive H3K27me3 marks predominated in adult white matter where EGFR is repressed. Furthermore, the histone methyltransferase core enzyme ASH2L was bound at EGFR in the germinal matrix and in gliomas where levels of H3K4me3 are high, and the histone acetyltransferase P300 was bound in samples with H3K27ac enrichment. Our studies use human cells and tissues undisturbed by cell-culture artifact, and point to an important, locus-specific role for chromatin remodeling in EGFR expression in human neural development that may be dysregulated during gliomagenesis, unraveling potential novel targets for future drug therapy. PMID:25996283

  20. Restoration of Sensitivity in Chemo — Resistant Glioma Cells by Cold Atmospheric Plasma

    PubMed Central

    Köritzer, Julia; Boxhammer, Veronika; Schäfer, Andrea; Shimizu, Tetsuji; Klämpfl, Tobias G.; Li, Yang-Fang; Welz, Christian; Schwenk-Zieger, Sabina; Morfill, Gregor E.; Zimmermann, Julia L.; Schlegel, Jürgen

    2013-01-01

    Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite multimodal treatments including surgery, chemotherapy and radiotherapy the prognosis remains poor and relapse occurs regularly. The alkylating agent temozolomide (TMZ) has been shown to improve the overall survival in patients with malignant gliomas, especially in tumors with methylated promoter of the O6-methylguanine-DNA-methyltransferase (MGMT) gene. However, intrinsic and acquired resistance towards TMZ makes it crucial to find new therapeutic strategies aimed at improving the prognosis of patients suffering from malignant gliomas. Cold atmospheric plasma is a new auspicious candidate in cancer treatment. In the present study we demonstrate the anti-cancer properties of different dosages of cold atmospheric plasma (CAP) both in TMZ-sensitive and TMZ-resistant cells by proliferation assay, immunoblotting, cell cycle analysis, and clonogenicity assay. Importantly, CAP treatment restored the responsiveness of resistant glioma cells towards TMZ therapy. Concomitant treatment with CAP and TMZ led to inhibition of cell growth and cell cycle arrest, thus CAP might be a promising candidate for combination therapy especially for patients suffering from GBMs showing an unfavorable MGMT status and TMZ resistance. PMID:23704990

  1. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria.

    PubMed

    Samid, D; Ram, Z; Hudgins, W R; Shack, S; Liu, L; Walbridge, S; Oldfield, E H; Myers, C E

    1994-02-15

    Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.

  2. Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

    ClinicalTrials.gov

    2016-12-07

    Childhood Cerebral Anaplastic Astrocytoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma

  3. 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.

  4. Trends in Malignant Glioma Monoclonal Antibody Therapy

    PubMed Central

    Chekhonin, Ivan; Gurina, Olga

    2015-01-01

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

  5. Overview of current immunotherapeutic strategies for glioma

    PubMed Central

    Calinescu, Anda-Alexandra; Kamran, Neha; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro Ricardo; Castro, Maria Graciela

    2015-01-01

    In the last decade, numerous studies of immunotherapy for malignant glioma (glioblastoma multiforme) have brought new knowledge and new hope for improving the prognosis of this incurable disease. Some clinical trials have reached Phase III, following positive outcomes in Phase I and II, with respect to safety and immunological end points. Results are encouraging especially when considering the promise of sustained efficacy by inducing antitumor immunological memory. Progress in understanding the mechanisms of tumor-induced immune suppression led to the development of drugs targeting immunosuppressive checkpoints, which are used in active clinical trials for glioblastoma multiforme. Insights related to the heterogeneity of the disease bring new challenges for the management of glioma and underscore a likely cause of therapeutic failure. An emerging therapeutic strategy is represented by a combinatorial, personalized approach, including the standard of care: surgery, radiation, chemotherapy with added active immunotherapy and multiagent targeting of immunosuppressive checkpoints. PMID:26598957

  6. Contrasting distribution and seasonal dynamics of carbohydrate reserves in stem wood of adult ring-porous sessile oak and diffuse-porous beech trees.

    PubMed

    Barbaroux, C; Bréda, N

    2002-12-01

    We tested the hypothesis that broad-leaved forest species with contrasting wood anatomy and hydraulic system (ring-porous versus diffuse-porous) also differ in distribution and seasonal dynamics of carbohydrate reserves in stem wood. Total nonstructural carbohydrate (TNC) reserves (starch and sugars) were measured enzymatically in the 10 youngest stem xylem rings of adult oak (Quercus petraea (Matt.) Liebl.) and beech (Fagus sylvatica L.) trees during an annual cycle. Radial distribution of carbohydrates was investigated according to ring age. On all dates, oak trees had twofold higher TNC concentration than beech trees (41 versus 23 mg g(DM)(-1)), with starch accounting for the high TNC concentration in oak. Seasonal dynamics of TNC concentration were significantly (P < 0.05) more pronounced in oak (20-64 mg TNC g(DM)(-1)) than in beech (17-34 mg TNC g(DM)(-1)). A marked decrease in TNC concentration was observed in oak trees during bud burst and early wood growth, whereas seasonal fluctuations in TNC concentrations in beech trees were small. The radial distribution of TNC based on ring age differed between species: TNC was restricted to the sapwood rings in oak, whereas in beech, it was distributed throughout the wood from the outermost sapwood ring to the pith. Although the high TNC concentrations in the outermost rings accounted for most of the observed seasonal pattern, all of the 10 youngest xylem rings analyzed participated in the seasonal dynamics of TNC in beech trees. The innermost sapwood rings of oak trees had low TNC concentrations. Stem growth and accumulation of carbon reserves occurred concomitantly during the first part of the season, when there was no soil water deficit. When soil water content was depleted, stem growth ceased in both species, whereas TNC accumulation was negligibly affected and continued until leaf fall. The contrasting dynamics and distribution of carbohydrate reserves in oak and beech are discussed with reference to differences

  7. 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

  8. 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.

  9. 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.

  10. Autophagy and Akt promote survival in glioma.

    PubMed

    Fan, Qi-Wen; Weiss, William A

    2011-05-01

    Signaling through phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR is frequently activated in cancers including glioblastoma multiforme (GBM), where this kinase network regulates survival. It is thus surprising that inhibitors of these pathways induce minimal cell death in glioma. We showed that the dual PtdIns3K-mTOR inhibitor PI-103 induces autophagy in therapy-resistant, PTEN-mutant glioma, with blockade of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) contributing independently to autophagy. Inhibition of autophagosome maturation synergizes with PI-103 to induce apoptosis through the Bax-dependent intrinsic mitochondrial pathway, indicating that PI-103 induces autophagy as a survival pathway in this setting. Not all inhibitors of PtdIns3K-Akt-mTOR signaling synergize with inhibitors of autophagy. The allosteric mTORC1 inhibitor rapamycin fails to induce apoptosis in conjunction with blockade of autophagy, due to feedback-activation of Akt. Apoptosis in the setting of rapamycin therapy requires concurrent inhibition of both autophagy and of PtdIns3K-Akt. Moreover, the clinical PtdIns3K-mTOR inhibitor NVP-BEZ235 cooperates with the clinical lysosomotropic autophagy inhibitor chloroquine to induce apoptosis in PTEN-mutant glioma xenografts in vivo, offering a therapeutic approach translatable to patients.

  11. 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

  12. 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.

  13. Assessment of multiexponential diffusion features as MRI cancer therapy response metrics.

    PubMed

    Hoff, Benjamin A; Chenevert, Thomas L; Bhojani, Mahaveer S; Kwee, Thomas C; Rehemtulla, Alnawaz; Le Bihan, Denis; Ross, Brian D; Galbán, Craig J

    2010-11-01

    The aim of this study was to empirically test the effect of chemotherapy-induced tissue changes in a glioma model as measured by several diffusion indices calculated from nonmonoexponential formalisms over a wide range of b-values. We also compared these results to the conventional two-point apparent diffusion coefficient calculation using nominal b-values. Diffusion-weighted imaging was performed over an extended range of b-values (120-4000 sec/mm(2) ) on intracerebral rat 9L gliomas before and after a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea. Diffusion indices from three formalisms of diffusion-weighted signal decay [(a) two-point analytical calculation using either low or high b-values, (b) a stretched exponential formalism, and (c) a biexponential fit] were tested for responsiveness to therapy-induced differences between control and treated groups. Diffusion indices sensitive to "fast diffusion" produced the largest response to treatment, which resulted in significant differences between groups. These trends were not observed for "slow diffusion" indices. Although the highest rate of response was observed from the biexponential formalism, this was not found to be significantly different from the conventional monoexponential apparent diffusion coefficient method. In conclusion, parameters from the more complicated nonmonoexponential formalisms did not provide additional sensitivity to treatment response in this glioma model beyond that observed from the two-point conventional monoexponential apparent diffusion coefficient method.

  14. 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

  15. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma.

    PubMed

    Huse, Jason T; Holland, Eric C

    2010-05-01

    Malignant brain tumours continue to be the cause of a disproportionate level of morbidity and mortality across a wide range of individuals. The most common variants in the adult and paediatric populations - malignant glioma and medulloblastoma, respectively - have been the subject of increasingly intensive research over the past two decades that has led to considerable advances in the understanding of their basic biology and pathogenesis. This Review summarizes these developments in the context of the evolving notion of molecular pathology and discusses the implications that this work has on the design of new treatment regimens.

  16. 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

  17. Association Between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma.

    PubMed

    Zigmont, Victoria; Garrett, Amy; Peng, Jin; Seweryn, Michal; Rempala, Grzegorz A; Harris, Randall; Holloman, Christopher; Gundersen, Thomas E; Ahlbom, Anders; Feychting, Maria; Johannesen, Tom Borge; Grimsrud, Tom Kristian; Schwartzbaum, Judith

    2015-01-01

    There are no previous studies of the association between prediagnostic serum vitamin D concentration and glioma. Vitamin D has immunosuppressive properties; as does glioma. It was, therefore, our hypothesis that elevated vitamin D concentration would increase glioma risk. We conducted a nested case-control study using specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 592), between 1974 and 2007, were matched to donors without glioma (n = 1112) on date and age at blood collection and sex. We measured 25-hydroxyvitamin D [25(OH)D], an indicator of vitamin D availability, using liquid chromatography coupled with mass spectrometry. Seasonally adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for each control quintile of 25(OH)D using conditional logistic regression. Among men diagnosed with high grade glioma >56, we found a negative trend (P = .04). Men diagnosed ≤ 56 showed a borderline positive trend (P = .08). High levels (>66 nmol/L) of 25(OH)D in men >56 were inversely related to high grade glioma from ≥2 yr before diagnosis (OR = 0.59; 95% CI = 0.38, 0.91) to ≥15 yr before diagnosis (OR = 0.61; 95% CI = 0.38,0.96). Our findings are consistent long before glioma diagnosis and are therefore unlikely to reflect preclinical disease.

  18. 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

  19. Association between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma

    PubMed Central

    Zigmont, Victoria; Garrett, Amy; Peng, Jin; Seweryn, Michal; Rempala, Grzegorz A.; Harris, Randall; Holloman, Christopher; Gundersen, Thomas E.; Ahlbom, Anders; Feychting, Maria; Johannesen, Tom Borge; Grimsrud, Tom Kristian; Schwartzbaum, Judith

    2016-01-01

    There are no previous studies of the association between prediagnostic serum vitamin D concentration and glioma. Vitamin D has immunosuppressive properties; as does glioma. It was, therefore, our hypothesis that elevated vitamin D concentration would increase glioma risk. We conducted a nested case–control study using specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 592), between 1974 and 2007, were matched to donors without glioma (n = 1112) on date and age at blood collection and sex. We measured 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D availability, using liquid chromatography coupled with mass spectrometry. Seasonally adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated for each control quintile of 25(OH)D using conditional logistic regression. Among men diagnosed with high grade glioma >56, we found a negative trend (P=.04). Men diagnosed ≤ 56 showed a borderline positive trend (P=.08). High levels (>66 nmol/L) of 25(OH)D in men > 56 were inversely related to high grade glioma from ≥ 2 years before diagnosis (OR=0.59; 95%CI=0.38,0.91) to ≥ 15 years before diagnosis (OR=0.61; 95%CI=0.38,0.96). Our findings are consistent long before glioma diagnosis and are therefore unlikely to reflect preclinical disease. PMID:26317248

  20. 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

  1. 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.

  2. Enhanced radiation-induced cytotoxic effect by 2-ME in glioma cells is mediated by induction of cell cycle arrest and DNA damage via activation of ATM pathways.

    PubMed

    Zou, Huichao; Zhao, Shiguang; Zhang, Jianhua; Lv, Gongwei; Zhang, Xu; Yu, Hongwei; Wang, Huibo; Wang, Ligang

    2007-12-14

    Glioblastoma multiform is the most common malignant primary brain tumor in adults, but there remains no effective therapeutic approach. 2-methoxyestradiol (2-ME), which is a naturally occurring metabolite of 17beta-estradiol, was shown to enhance radiotherapeutic effect in certain tumors; however, whether 2-ME can also enhance the sensitivity of glioma cells to radiotherapy remains unknown. The present study, therefore, was to address this issue using two human glioma cell lines (T98G and U251MG). These cells were irradiated with and without 2-ME and then clonogenic assay, apoptosis assay, DNA damage, and cell cycle change were examined. Results showed that 2-ME significantly enhances radiation-induced cell death in both glioma cells, shown by decreasing cell viability and increasing apoptotic cell death. No such radiosensitizing effect was observed if cells pre-treated with Estrodiol, suggesting the specifically radiosensitizing effect of 2-ME rather than a general effect of estrodials. The enhanced radio-cytotoxic effect in glioma cells by 2-ME was found to be associated with its enhancement of G(2)/M arrest and DNA damage, and phosphorylated ATM protein kinases as well as cell cycle checkpoint protein Chk2. Furthermore, inhibition of ATM by ATM inhibitor abolished 2-ME-activated Chk2 and enhanced radio-cytotoxic effects. These results suggest that 2-ME enhancement of the sensitivity of glioma cell lines to radiotherapy is mediated by induction of G2/M cell cycle arrest and increased DNA damage via activation of ATM kinases.

  3. 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

  4. Glioma coexisting with angiographically occult cerebrovascular malformation: A case report

    PubMed Central

    Chen, Junhui; Chen, Lei; Zhang, Chunlei; He, Jianqing; Li, Peipei; Zhou, Jingxu; Zhu, Jun; Wang, Yuhai

    2016-01-01

    Angiographically occult cerebrovascular malformation (AOVM) is a type of complex cerebrovascular malformation that is not visible on digital subtraction angiography (DSA). Vascular malformation coexisting with glioma is clinically rare, and glioma coexisting with AOVM is even more rare. To the best of our knowledge, the present study is the first to report glioma coexisting with AOVM in the literature. The present study reports a rare case of glioma coexisting with AOVM in a 30-year-old male patient. Computed tomography (CT) scan revealed calcification, hemorrhage and edema in the right frontal lobe. CT angiography revealed a vascular malformation in the right frontal lobe, which was not observed on DSA. Finally, glioma coexisting with AOVM was confirmed by 2.0T magnetic resonance imaging and postoperative pathological examination. The present patient had a positive outcome and no neurological dysfunctions during the 6-month follow-up subsequent to surgery. PMID:27698825

  5. 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

  6. Magnetic resonance analysis of malignant transformation in recurrent glioma

    PubMed Central

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

    2016-01-01

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

  7. Fokas method for a multi-domain linear reaction-diffusion equation with discontinuous diffusivity

    NASA Astrophysics Data System (ADS)

    Asvestas, M.; Sifalakis, A. G.; Papadopoulou, E. P.; Saridakis, Y. G.

    2014-03-01

    Motivated by proliferation-diffusion mathematical models for studying highly diffusive brain tumors, that also take into account the heterogeneity of the brain tissue, in the present work we consider a multi-domain linear reaction-diffusion equation with a discontinuous diffusion coefficient. For the solution of the problem at hand we implement Fokas transform method by directly following, and extending in this way, our recent work for a white-gray-white matter brain model pertaining to high grade gliomas. Fokas's novel approach for the solution of linear PDE problems, yields novel integral representations of the solution in the complex plane that, for appropriately chosen integration contours, decay exponentially fast and converge uniformly at the boundaries. Combining these method-inherent advantages with simple numerical quadrature rules, we produce an efficient method, with fast decaying error properties, for the solution of the discontinuous reaction-diffusion problem.

  8. 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.

  9. 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.

  10. Automated Grading of Gliomas using Deep Learning in Digital Pathology Images: A modular approach with ensemble of convolutional neural networks

    PubMed Central

    Ertosun, Mehmet Günhan; Rubin, Daniel L.

    2015-01-01

    Brain glioma is the most common primary malignant brain tumors in adults with different pathologic subtypes: Lower Grade Glioma (LGG) Grade II, Lower Grade Glioma (LGG) Grade III, and Glioblastoma Multiforme (GBM) Grade IV. The survival and treatment options are highly dependent of this glioma grade. We propose a deep learning-based, modular classification pipeline for automated grading of gliomas using digital pathology images. Whole tissue digitized images of pathology slides obtained from The Cancer Genome Atlas (TCGA) were used to train our deep learning modules. Our modular pipeline provides diagnostic quality statistics, such as precision, sensitivity and specificity, of the individual deep learning modules, and (1) facilitates training given the limited data in this domain, (2) enables exploration of different deep learning structures for each module, (3) leads to developing less complex modules that are simpler to analyze, and (4) provides flexibility, permitting use of single modules within the framework or use of other modeling or machine learning applications, such as probabilistic graphical models or support vector machines. Our modular approach helps us meet the requirements of minimum accuracy levels that are demanded by the context of different decision points within a multi-class classification scheme. Convolutional Neural Networks are trained for each module for each sub-task with more than 90% classification accuracies on validation data set, and achieved classification accuracy of 96% for the task of GBM vs LGG classification, 71% for further identifying the grade of LGG into Grade II or Grade III on independent data set coming from new patients from the multi-institutional repository. PMID:26958289

  11. ET-05INTRANASAL DELIVERY OF NEURAL STEM CELLS LOADED WITH ONCOLYTIC ADENOVIRUS EXTENDS SURVIVAL OF MICE WITH INTRACRANIAL GLIOMA

    PubMed Central

    Balyasnikova, Irina; Dey, Mahua; Tobias, Alex; Kanojia, Deepak; Lee, Gina; Han, Yu; Zhang, Lingjiao; Ahmed, Atique; Aboody, Karen; Lesniak, Maciej

    2014-01-01

    Glioblastoma multiforme (GBM), the most common adult primary brain tumor, is in need of better and effective therapeutic options. In this study, we hypothesized that neural stem cells (NSCs) loaded with CRAd-S-pK7 oncolytic adenovirus (OV) can be successfully delivered via nasal application (IN) and will impart therapeutic efficacy in a murine model of human glioma. Recently, we demonstrated that radiation therapy increases the expression of CXCL12 in glioma xenografts, thus contributing to the enhanced migration of stem cells to the tumor site. We now show that hypoxic preconditioning of NSCs for 24h (1% oxygen) results in the two-fold increase of the CXCR4 expression on the surface of NSCs and doubles the rate of their migration towards glioma cells (p < 0.001) compared to untreated group. Hypoxic preconditioning of NSCs did not alter the OV replication as measured by E1A copy number. For in vivo studies, a patient derived GBM43 glioma cells were intracranially inoculated in nude mice. One week later, mice were treated with fractioned dose of irradiation at 2Gy for 5 days. NSCs (5x105) cultured under normoxic and hypoxic conditions were loaded with OV at 50 viral particles per cell, and IN inoculated 24h following the completion of the radiation. Kaplan-Meier survival analysis demonstrated that irradiation resulted in 44% improvement (p < 0.001) in median survival versus non-treated group. Survival of irradiated mice was not affected by either NSC's or OV-loaded NSCs, but was extended (p < 0.05) another 25% in the group of animals treated with OV-loaded NSCs cultured under hypoxic conditions. Thus, our data further validate the IN delivery as a novel route for the stem cell-based anti-glioma therapy, and suggest that modification of NSCs by enhancing their ability to migrate might significantly increase their therapeutic potential for IN delivery to target GBM.

  12. Dexamethasone inhibits proliferation and stimulates ecto-5'-nucleotidase/CD73 activity in C6 rat glioma cell line.

    PubMed

    Bavaresco, Luci; Bernardi, Andressa; Braganhol, Elizandra; Wink, Márcia R; Battastini, Ana Maria Oliveira

    2007-08-01

    Malignant gliomas are the most common and devastating primary tumors of the adult central nervous system. Dexamethasone, a synthetic glucocorticoid, is commonly co-administered to control edema in the management of brain tumors during chemotherapy and radiotherapy. In the present study, the effect of dexamethasone on proliferation and ectonucleotidase activities in rat C6 glioma cell line was investigated. Dexamethasone concentrations ranging from 0.001 to 10 microM induced a time- and concentration-dependent inhibition of C6 rat glioma cell proliferation after 24, 48 and 72-h treatment. The tetrazolium reduction assay (MTT) indicated a reduction of in cell viability (44 +/- 7.6%) after 48-h treatment with 1 microM dexamethasone. Pretreatment with 10 microM of RU38486, an antagonist of glucocorticoid receptors, abolished the effect of 1 microM dexamethasone by 78 +/- 9.8% after 48 h of treatment, indicating that this action is mediated via the glucocorticoid receptor. Members of the E-NTPDase family and ecto-5'-nucleotidase/CD73 can modulate extracellular ATP degradation and adenosine formation, both of which have been described as proliferation factors. Treatment of C6 glioma cells for 48 h with 1 microM dexamethasone increased in 38 +/- 8.09% the AMP hydrolysis and in 3.7-fold the ecto-5'-nucleotidase/CD73 expression, suggesting an increase in adenosine formation and, therefore, a possible modulatory role in the elicitation of cell death responses. In addition, pretreatment with 5 microM GF 109203X, a protein kinase C (PKC) inhibitor, abolished the effect of dexamethasone on cell proliferation and on ecto-5'-NT activity, suggesting that dexamethasone could exert this action via PKC. The alterations in the catabolism of extracellular purines induced by dexamethasone treatment in glioma C6 cells could be related to its pharmacological effects.

  13. Automated Grading of Gliomas using Deep Learning in Digital Pathology Images: A modular approach with ensemble of convolutional neural networks.

    PubMed

    Ertosun, Mehmet Günhan; Rubin, Daniel L

    2015-01-01

    Brain glioma is the most common primary malignant brain tumors in adults with different pathologic subtypes: Lower Grade Glioma (LGG) Grade II, Lower Grade Glioma (LGG) Grade III, and Glioblastoma Multiforme (GBM) Grade IV. The survival and treatment options are highly dependent of this glioma grade. We propose a deep learning-based, modular classification pipeline for automated grading of gliomas using digital pathology images. Whole tissue digitized images of pathology slides obtained from The Cancer Genome Atlas (TCGA) were used to train our deep learning modules. Our modular pipeline provides diagnostic quality statistics, such as precision, sensitivity and specificity, of the individual deep learning modules, and (1) facilitates training given the limited data in this domain, (2) enables exploration of different deep learning structures for each module, (3) leads to developing less complex modules that are simpler to analyze, and (4) provides flexibility, permitting use of single modules within the framework or use of other modeling or machine learning applications, such as probabilistic graphical models or support vector machines. Our modular approach helps us meet the requirements of minimum accuracy levels that are demanded by the context of different decision points within a multi-class classification scheme. Convolutional Neural Networks are trained for each module for each sub-task with more than 90% classification accuracies on validation data set, and achieved classification accuracy of 96% for the task of GBM vs LGG classification, 71% for further identifying the grade of LGG into Grade II or Grade III on independent data set coming from new patients from the multi-institutional repository.

  14. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma.

    PubMed

    Reuss, David E; Sahm, Felix; Schrimpf, Daniel; Wiestler, Benedikt; Capper, David; Koelsche, Christian; Schweizer, Leonille; Korshunov, Andrey; Jones, David T W; Hovestadt, Volker; Mittelbronn, Michel; Schittenhelm, Jens; Herold-Mende, Christel; Unterberg, Andreas; Platten, Michael; Weller, Michael; Wick, Wolfgang; Pfister, Stefan M; von Deimling, Andreas

    2015-01-01

    Diffuse gliomas are represented in the 2007 WHO classification as astrocytomas, oligoastrocytomas and oligodendrogliomas of grades II and III and glioblastomas WHO grade IV. Molecular data on these tumors have a major impact on prognosis and therapy of the patients. Consequently, the inclusion of molecular parameters in the WHO definition of brain tumors is being planned and has been forwarded as the "ISN-Haarlem" consensus. We, here, analyze markers of special interest including ATRX, IDH and 1p/19q codeletion in a series of 405 adult patients. Among the WHO 2007 classified tumors were 152 astrocytomas, 61 oligodendrogliomas, 63 oligoastrocytomas and 129 glioblastomas. Following the concepts of the "ISN-Haarlem", we rediagnosed the series to obtain "integrated" diagnoses with 155 tumors being astrocytomas, 100 oligodendrogliomas and 150 glioblastomas. In a subset of 100 diffuse gliomas from the NOA-04 trial with long-term follow-up data available, the "integrated" diagnosis had a significantly greater prognostic power for overall and progression-free survival compared to WHO 2007. Based on the "integrated" diagnoses, loss of ATRX expression was close to being mutually exclusive to 1p/19q codeletion, with only 2 of 167 ATRX-negative tumors exhibiting 1p/19q codeletion. All but 4 of 141 patients with loss of ATRX expression and diffuse glioma carried either IDH1 or IDH2 mutations. Interestingly, the majority of glioblastoma patients with loss of ATRX expression but no IDH mutations exhibited an H3F3A mutation. Further, all patients with 1p/19 codeletion carried a mutation in IDH1 or IDH2. We present an algorithm based on stepwise analysis with initial immunohistochemistry for ATRX and IDH1-R132H followed by 1p/19q analysis followed by IDH sequencing which reduces the number of molecular analyses and which has a far better association with patient outcome than WHO 2007.

  15. 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

  16. 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.

  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. 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.

  19. Gene therapy for high-grade glioma

    PubMed Central

    Natsume, Atsushi

    2008-01-01

    The treatment of high-grade gliomas remains difficult despite recent advances in surgery, radiotherapy and chemotherapy. True advances may emerge from the increasing understanding in molecular biology and discovery of novel mechanisms for the delivery of tumoricidal agents. In an attempt to overcome this formidable neoplasm, molecular approaches using gene therapy have been investigated clinically since 1992. The clinical trials have mainly been classified into three approaches: suicide gene therapy, immune gene therapy and oncolytic viral therapy. In this article, we review these approaches, which have been studied in previous and ongoing clinical trials. PMID:19262115

  20. 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

  1. Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study.

    PubMed

    Schumacher, T; Hofer, S; Eichhorn, K; Wasner, M; Zimmerer, S; Freitag, P; Probst, A; Gratzl, O; Reubi, J-C; Maecke, R; Mueller-Brand, J; Merlo, A

    2002-04-01

    We have previously presented preliminary observations on targeting somatostatin receptor-positive malignant gliomas of all grades by local injection of the radiolabelled peptidic vector 90Y-DOTATOC. We now report on our more thorough clinical experience with this novel compound, focussing on low-grade and anaplastic gliomas. Small peptidic vectors have the potential to target invisible infiltrative disease within normal surrounding brain tissue, thereby opening a window of opportunity for early intervention. Five progressive gliomas of WHO grades II and III and five extensively debulked low-grade gliomas were treated with varying fractions of 90Y-DOTATOC. The vectors were locally injected into the resection cavity or into solid tumour. The activity per single injection ranged from 555 to 1,875 MBq, and the cumulative activity from 555 to 7,030 MBq, according to tumour volumes and eloquence of the affected brain area, yielding dose estimates from 76+/-15 to 312+/-62 Gy. Response was assessed by the clinical status, by steroid dependence and, every 4-6 months, by magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography. In the five progressive gliomas, lasting responses were obtained for at least 13-45 months without the need for steroids. Radiopeptide brachytherapy had been the only modality applied to counter tumour progression. Interestingly, we observed the slow transformation of a solid, primarily inoperable anaplastic astrocytoma into a resectable multi-cystic lesion 2 years after radiopeptide brachytherapy. Based on these observations, we also assessed the feasibility of local radiotherapy following extensive debulking, which was well tolerated. Targeted beta-particle irradiation based on diffusible small peptidic vectors appears to be a promising modality for the treatment of malignant gliomas.

  2. Xeroderma pigmentosum complementation group f polymorphisms influence risk of glioma.

    PubMed

    Cheng, Hong-Bin; Xie, Chen; Zhang, Ru-You; Hu, Shao-Shan; Wang, Zhi; Yue, Wu

    2013-01-01

    We conducted an exploratory investigation of whether variation in six common SNPs of xeroderma pigmentosum complementation group F (XPF) is associated with risk of glioma in a Chinese population. Six single nucleotide polymorphisms (SNPs) were genotyped in 207 glioma cases and 236 cancer-free controls by a 384-well plate format on the Sequenom MassARRAY platform (Sequenom, San Diego, USA). The rs1800067 G and rs2276466 G allele frequencies were significantly higher in the glioma group than controls. Individuals with the rs1800067 GG genotype were at greater risk of glioma when compared with the A/A genotype in the codominant model, with an OR (95% CI) of 2.63 (1.04-7.25). The rs2276466 polymorphism was significantly associated with moderate increased risk of glioma in codominant and dominant models, with ORs (95% CI) of 1.90 (1.05-3.44) and 1.55 (1.07-2.47), respectively. The combination genotype of rs1800067 G and rs2276466 G alleles was associated with a reduced risk of glioma (OR=0.44, 95% CI=0.19-0.98). These findings indicate that genetic variants of the XPF gene have critical functions in the development of glioma.

  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. 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

  5. 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

  6. 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.

  7. Use of cardiac glycosides and risk of glioma.

    PubMed

    Seliger, Corinna; Meier, Christoph R; Jick, Susan S; Uhl, Martin; Bogdahn, Ulrich; Hau, Peter; Leitzmann, M F

    2016-04-01

    Cardiac glycosides induce apoptotic effects on glioma cells, but whether cardiac glycosides protect against risk for glioma is unknown. We therefore explored the relation between glycoside use and glioma risk using a large and validated database. We performed a case-control analysis using the Clinical Practice Research Datalink involving 2005 glioma cases diagnosed between 1995 and 2012 that were individually matched to 20,050 controls on age, gender, general practice, and number of years of active history in the database. Conditional logistic regression analysis was used to evaluate the association between cardiac glycosides and the risk of glioma adjusting for body mass index and smoking. We also examined use of common heart failure and arrhythmia medications to differentiate between a specific glycoside effect and a generic effect of treatment for congestive heart failure or arrhythmia. Cardiac glycoside use was inversely related to glioma incidence. After adjustment for congestive heart failure, arrhythmia, diabetes, and common medications used to treat those conditions, the OR of glioma was 0.47 (95% CI 0.27-0.81, Bonferroni-corrected p value = 0.024) for use versus non-use of cardiac glycosides, based on 17 exposed cases. In contrast, no associations were noted for other medications used to treat congestive heart failure or arrhythmias. The OR of glioma in people with congestive heart failure was 0.65 (95% CI 0.40-1.04), and for arrhythmia it was 1.01 (95% CI 0.78-1.31). These data indicate that cardiac glycoside use is independently associated with reduced glioma risk.

  8. 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

  9. Localisation of malignant glioma by a radiolabelled human monoclonal antibody.

    PubMed Central

    Phillips, J; Alderson, T; Sikora, K; Watson, J

    1983-01-01

    Human monoclonal antibodies were produced by fusing intratumoral lymphocytes from patients with malignant gliomas with a human myeloma line. One antibody was selected for further study after screening for binding activity to glioma cell lines. The patient from whom it was derived developed recurrent glioma. 1 mg of antibody was purified, radiolabelled with 131I, and administered intravenously. The distribution of antibody was determined in the blood, CSF and tumour cyst fluid and compared with that of a control human monoclonal immunoglobulin. Antibody localisation in the tumour was observed and confirmed by external scintiscanning. Images PMID:6101173

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. Photodynamic therapy of recurrent cerebral glioma

    NASA Astrophysics Data System (ADS)

    Zhu, Shu-Gan; Wu, Si-En; Chen, Zong-Qian; Sun, Wei

    1993-03-01

    Photodynamic therapy (PDT) was performed on 11 cases of recurrent cerebral glioma, including 3 cases of recurrent glioblastoma, 7 of recurrent anaplastic astrocytoma, and 1 recurrent ependymoma. Hematoporphyrin derivative (HPD) was administered intravenously at a dose of 4 - 7 mg/kg 5 - 24 hours before the operation. All patients underwent a craniotomy with a nearly radical excision of the tumor following which the tumor bed was irradiated with 630 nm laser light emitting either an argon pumped dye laser or frequency double YAG pumped dye laser for 30 to 80 minutes with a total dose of 50 J/cm2 (n equals 1), 100 J/cm2 (n equals 2), 200 J/cm2 (n equals 7), and 300 J/cm2 (n equals 1). The temperature was kept below 37 degree(s)C by irrigation. Two patients underwent postoperative radiotherapy. There was no evidence of increased cerebral edema, and no other toxicity by the therapy. All patients were discharged from the hospital within 15 days after surgery. We conclude that PDT using 4 - 7 mg/kg of HPD and 630 nm light with a dose of up to 300 J/cm2 can be used as an adjuvant therapy with no additional complications. Adjuvant PDT in the treatment of recurrent glioma is better than simple surgery.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. Glioma Stemlike Cells Enhance the Killing of Glioma Differentiated Cells by Cytotoxic Lymphocytes

    PubMed Central

    Bassoy, Esen Yonca; Chiusolo, Valentina; Jacquemin, Guillaume; Riccadonna, Cristina; Walker, Paul R.; Martinvalet, Denis

    2016-01-01

    Glioblastoma multiforme, the most aggressive primary brain tumor, is maintained by a subpopulation of glioma cells with self-renewal properties that are able to recapitulate the entire tumor even after surgical resection or chemo-radiotherapy. This typifies the vast heterogeneity of this tumor with the two extremes represented on one end by the glioma stemlike cells (GSC) and on the other by the glioma differentiated cells (GDC). Interestingly, GSC are more sensitive to immune effector cells than the GDC counterpart. However, how GSC impact on the killing on the GDC and vice versa is not clear. Using a newly developed cytotoxicity assay allowing to simultaneously monitor cytotoxic lymphocytes-mediated killing of GSC and GDC, we found that although GSC were always better killed and that their presence enhanced the killing of GDC. In contrast, an excess of GDC had a mild protective effect on the killing of GSC, depending on the CTL type. Overall, our results suggest that during combination therapy, immunotherapy would be the most effective after prior treatment with conventional therapies. PMID:27073883

  2. Clinically feasible NODDI characterization of glioma using multiband EPI at 7 T

    PubMed Central

    Wen, Qiuting; Kelley, Douglas A.C.; Banerjee, Suchandrima; Lupo, Janine M.; Chang, Susan M.; Xu, Duan; Hess, Christopher P.; Nelson, Sarah J.

    2015-01-01

    Recent technological progress in the multiband echo planer imaging (MB EPI) technique enables accelerated MR diffusion weighted imaging (DWI) and allows whole brain, multi-b-value diffusion imaging to be acquired within a clinically feasible time. However, its applications at 7 T have been limited due to B1 field inhomogeneity and increased susceptibility artifact. It is an ongoing debate whether DWI at 7 T can be performed properly in patients, and a systematic SNR comparison for multiband spin-echo EPI between 3 T and 7 T has not been methodically studied. The goal of this study was to use MB EPI at 7 T in order to obtain 90-directional multi-shell DWI within a clinically feasible acquisition time for patients with glioma. This study included an SNR comparison between 3 T and 7 T, and the application of B1 mapping and distortion correction procedures for reducing the impact of variations in B0 and B1. The optimized multiband sequence was applied in 20 patients with glioma to generate both DTI and NODDI maps for comparison of values in tumor and normal appearing white matter (NAWM). Our SNR analysis showed that MB EPI at 7 T was comparable to that at 3 T, and the data quality acquired in patients was clinically acceptable. NODDI maps provided unique contrast within the T2 lesion that was not seen in anatomical images or DTI maps. Such contrast may reflect the complexity of tissue compositions associated with disease progression and treatment effects. The ability to consistently obtain high quality diffusion data at 7 T will contribute towards the implementation of a comprehensive brain MRI examination at ultra-high field. PMID:26509116

  3. 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

  4. 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.

  5. 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

  6. Primary Role for Kinin B1 and B2 Receptors in Glioma Proliferation.