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Sample records for high-grade gliomas glio-tep

  1. 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

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

    PubMed

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

    2016-03-01

    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

  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. Surgical Outcomes of High-Grade Spinal Cord Gliomas

    PubMed Central

    Hida, Kazutoshi; Yano, Syunsuke; Aoyama, Takeshi; Koyanagi, Izumi; Houkin, Kiyohiro

    2015-01-01

    Study Design A retrospective study. Purpose The purpose of this study was to obtain useful information for establishing the guidelines for treating high-grade spinal cord gliomas. Overview of Literature The optimal management of high-grade spinal cord gliomas remains controversial. We report the outcomes of the surgical management of 14 high-grade spinal glioma. Methods We analyzed the outcomes of 14 patients with high-grade spinal cord gliomas who were surgically treated between 1989 and 2012. Survival was charted with the Kaplan-Meier plots and comparisons were made with the log-rank test. Results None of the patients with high-grade spinal cord gliomas underwent total resection. Subtotal resection was performed in two patients, partial resection was performed in nine patients, and open biopsy was performed in three patients. All patients underwent postoperative radiotherapy and six patients further underwent radiation cordotomy. The median survival time for patients with high-grade spinal cord gliomas was 15 months, with a 5-year survival rate of 22.2%. The median survival time for patients with World Health Organization grade III tumors was 25.5 months, whereas the median survival time for patients with glioblastoma multiforme was 12.5 months. Both univariate and multivariate Cox proportional hazards models demonstrated a significant effect only in the group that did not include cervical cord lesion as a factor associated with survival (p=0.04 and 0.03). Conclusions The surgical outcome of patients diagnosed with high-grade spinal cord gliomas remains poor. Notably, only the model which excluded cervical cord lesions as a factor significantly predicted survival. PMID:26713128

  5. 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

  6. Studies on high grade cerebral gliomas

    SciTech Connect

    Bleehen, N.M. )

    1990-04-01

    A brief review of attempts in the United Kingdom to improve the results of treatment of high grade (grade 3, 4) supra-tentorial astrocytomas is presented. The radiosensitizer misonidazole failed to improve the results of post-surgical radiotherapy, however, multivariate analysis of data from these patients has provided a prognostic index of use in defining good and poor prognosis patients. An overview study of adjuvant nitrosourea therapy trials has shown a small significant advantage for the chemotherapy. A study of chemosensitization by benznidazole of CCNU treatment of patients in relapse failed to demonstrate any effect. 13 references.

  7. Concurrent thermochemoradiotherapy for brain high-grade glioma

    NASA Astrophysics Data System (ADS)

    Ryabova, A. I.; Novikov, V. A.; Choinzonov, E. L.; Gribova, O. V.; Startseva, Zh. A.; Bober, E. E.; Frolova, I. G.; Baranova, A. V.

    2016-08-01

    Despite the achievements in the current strategies for treatment, the prognosis in malignant glioma patients remains unsatisfactory. Hyperthermia is currently considered to be the most effective and universal modifier of radiotherapy and chemotherapy. Preliminary treatment outcomes for 28 patients with newly diagnosed (23) and recurrent (5) high-grade gliomas were presented. All the patients received multimodality treatment including surgery, thermoche-moradiotherapy followed by 4 cycles of adjuvant chemotherapy. All the patients endured thermochemoradiotherapy well. A complication, limited skin burn (II stage), was diagnosed in two cases and treated conservatively without treatment interruption. A month after thermochemoradiotherapy the results were as follows: complete regression was achieved in 4 cases, partial regression in 4 cases, stable disease in 14 cases and disease progression in 6 cases (one of them is pseudo-progression). After completing the adjuvant chemotherapy 2 more patients demonstrated complete response and 1 patient had disease progression. Introduction of local hyperthermia in multimodal therapy of malignant glioma does not impair the combined modality treatment tolerability of patients with malignant gliomas. A small number of studied patients and short follow-up time do not allow making reliable conclusions about the impact of local hyperthermia on the treatment outcomes; however, there is a tendency towards the increase in disease-free survival in the patients with newly diagnosed malignant gliomas.

  8. Fluorescence and image guided resection in high grade glioma.

    PubMed

    Panciani, Pier Paolo; Fontanella, Marco; Schatlo, Bawarjan; Garbossa, Diego; Agnoletti, Alessandro; Ducati, Alessandro; Lanotte, Michele

    2012-01-01

    The extent of resection in high grade glioma is increasingly been shown to positively effect survival. Nevertheless, heterogeneity and migratory behavior of glioma cells make gross total resection very challenging. Several techniques were used in order to improve the detection of residual tumor. Aim of this study was to analyze advantages and limitations of fluorescence and image guided resection. A multicentric prospective study was designed to evaluate the accuracy of each method. Furthermore, the role of 5-aminolevulinc acid and neuronavigation were reviewed. Twenty-three patients harboring suspected high grade glioma, amenable to complete resection, were enrolled. Fluorescence and image guides were used to perform surgery. Multiple samples were obtained from the resection cavity of each lesion according to 5-ALA staining positivity and boundaries as delineated by neuronavigation. All samples were analyzed by a pathologist blinded to the intra-operative labeling. Decision-making based on fluorescence showed a sensitivity of 91.1% and a specificity of 89.4% (p<0.001). On the other hand, the image-guided resection accuracy was low (sensitivity: 57.8%; specificity: 57.4%; p=0.346). We observed that the sensitivity of 5-ALA can be improved by the combined use of neuronavigation, but this leads to a significant reduction in specificity. Thus, the use of auxiliary techniques should always be subject to critical skills of the surgeon. We advocate a large-scale study to further improve the assessment of multimodal approaches.

  9. 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

  10. Irradiation and Bevacizumab in High-Grade Glioma Retreatment Settings

    SciTech Connect

    Niyazi, Maximilian; Ganswindt, Ute; Schwarz, Silke Birgit; Kreth, Friedrich-Wilhelm; Tonn, Joerg-Christian; Geisler, Julia; Fougere, Christian la; Ertl, Lorenz; Linn, Jennifer; Siefert, Axel; Belka, Claus

    2012-01-01

    Purpose: Reirradiation is a treatment option for recurrent high-grade glioma with proven but limited effectiveness. Therapies directed against vascular endothelial growth factor have been shown to exert certain efficacy in combination with chemotherapy and have been safely tested in combination with radiotherapy in a small cohort of patients. To study the feasibility of reirradiation combined with bevacizumab treatment, the toxicity and treatment outcomes of this approach were analyzed retrospectively. Patients and Methods: After previous treatment with standard radiotherapy (with or without temozolomide) patients with recurrent malignant glioma received bevacizumab (10 mg/kg intravenous) on Day 1 and Day 15 during radiotherapy. Maintenance therapy was selected based on individual considerations, and mainly bevacizumab-containing regimens were chosen. Patients received 36 Gy in 18 fractions. Results: The data of the medical charts of the 30 patients were analyzed retrospectively. All were irradiated in a single institution and received either bevacizumab (n = 20), no additional substance (n = 7), or temozolomide (n = 3). Reirradiation was tolerated well, regardless of the added drug. In 1 patient treated with bevacizumab, a wound dehiscence occurred. Overall survival was significantly better in patients receiving bevacizumab (p = 0.03, log-rank test). In a multivariate proportional hazards Cox model, bevacizumab, Karnovsky performance status, and World Health Organization grade at relapse turned out to be the most important predictors for overall survival. Conclusion: Reirradiation with bevacizumab is a feasible and effective treatment for patients with recurrent high-grade gliomas. A randomized trial is warranted to finally answer the question whether bevacizumab adds substantial benefit to a radiotherapeutic retreatment setting.

  11. Re-irradiation alternatives for recurrent high-grade glioma

    PubMed Central

    Dong, Yuanli; Fu, Chengrui; Guan, Hui; Zhang, Tianyi; Zhang, Zicheng; Zhou, Tao; Li, Baosheng

    2016-01-01

    Despite advances in the fields of surgery, chemotherapy and radiotherapy, the prognosis for high-grade glioma (HGG) remains unsatisfactory. The majority of HGG patients experience disease recurrence. To date, no standard treatments have been established for recurrent HGG. Repeat surgery and chemotherapy demonstrate moderate efficacy. As recurrent lesions are usually located within the previously irradiated field, a second course of irradiation was once considered controversial, as it was considered to exhibit unsatisfactory efficacy and radiation-related toxicities. However, an increasing number of studies have indicated that re-irradiation may present an efficacious treatment for recurrent HGG. Re-irradiation may be delivered via conventionally fractionated stereotactic radiotherapy, hypofractionated stereotactic radiation therapy, stereotactic radiosurgery and brachytherapy techniques. In the present review, the current literature regarding re-irradiation treatment for recurrent HGG is summarized with regard to survival outcome and side effects. PMID:27703519

  12. Molecular characteristics of pediatric high-grade gliomas

    PubMed Central

    Chamdine, Omar; Gajjar, Amar

    2014-01-01

    SUMMARY High-grade gliomas (HGGs) are extremely lethal tumors. Survival has not changed significantly in the past decades. The only known prognostic factors in pediatric HGGs (pHGGs) are extent of resection and histologic grade. Treatment has historically been based on adult trials because of the rarity of pHGGs and the lack of genomic tools to explore their unique molecular characteristics. The recent advances in molecular biological data helped divide these tumors into distinct subgroups. In this review, the authors focus on major molecular targets of alterations in pHGGs: histone H3.3, telomeres, PDGFRA, IDH, BRAFV600E, ACVR1 and NTRK and briefly highlight the difference with the adult counterpart. PMID:25438814

  13. Armodafinil in Reducing Cancer-Related Fatigue in Patients With High Grade Glioma | Division of Cancer Prevention

    Cancer.gov

    This randomized phase III trial studies armodafinil to see how well it works in reducing cancer-related fatigue in patients with high grade glioma. Armodafinil may help relieve fatigue in patients with high grade glioma. |

  14. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas.

    PubMed

    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

    2013-10-15

    The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (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 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 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 nonbrainstem 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

  15. Thromboembolic disease in patients with high-grade glioma.

    PubMed

    Perry, James R

    2012-09-01

    Venous thromboembolism (VTE) is common throughout the course of disease in high-grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced during the postoperative period with adherence to the use of mechanical and medical thromboprophylaxis. Activation of the coagulation cascade occurs throughout the course of disease because of a variety of complex interactions, including tumor hypoxia, upregulation of VEGR expression, and increases in both tumor cell-specific tissue factor (TF) expression and inducible TF expression in numerous intrinsic regulatory pathways. Long-term anticoagulation to prevent VTE is an attractive therapy; however, the therapeutic window is narrow and current data do not support its routine use. Most patients with proven symptomatic VTE can be safely anticoagulated, including those receiving anti-VEGF therapy, such as bevacizumab. Initial therapy should include low molecular weight heparin (LMWH), and protracted anticoagulant treatment, perhaps indefinitely, is indicated for patients with HGG because of the ongoing risk of thrombosis. A variety of coagulation- and tumor-related proteins, such as TF and circulating microparticles, may serve as potential disease-specific biomarkers in relation to disease recurrence, monitoring of therapy, and as potential therapeutic targets. PMID:23095833

  16. Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment

    PubMed Central

    Rizzo, Daniela; Ruggiero, Antonio; Martini, Maurizio; Rizzo, Valentina; Maurizi, Palma; Riccardi, Riccardo

    2015-01-01

    High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas. PMID:26448930

  17. Levetiracetam improves verbal memory in high-grade glioma patients

    PubMed Central

    de Groot, Marjolein; Douw, Linda; Sizoo, Eefje M.; Bosma, Ingeborg; Froklage, Femke E.; Heimans, Jan J.; Postma, Tjeerd J.; Klein, Martin; Reijneveld, Jaap C.

    2013-01-01

    Background Treatment of high-grade glioma (HGG) patients with anti-epileptic drugs (AEDs) has met with various side effects, such as cognitive deterioration. The cognitive effects of both older and newer AEDs in HGG patients are largely unknown. The aim of this study was to determine the effect of older and newer AEDs on cognitive performance in postoperative HGG patients. Methods We selected HGG patients from 3 separate cohorts for use of older, newer, or no AEDs, as they represented distinct treatment eras and provided the opportunity to compare older and newer AEDs. In all 3 cohorts, patients were included within 6 weeks following neurosurgery before the start of postoperative treatment. Cognitive functioning was evaluated by an extensive neuropsychological assessment, executed in 6 cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed). Results One hundred seventeen patients met the inclusion criteria; 44 patients used no AED, 35 were on monotherapy with a newer AED (all levetiracetam), and 38 were on monotherapy with an older AED (valproic acid or phenytoin). Patients on older and newer AEDs performed equally well as patients not on an AED, and patients on levetiracetam performed even better on verbal memory tests than patients not on an AED. Post-hoc analyses revealed that within the group using older AEDs, patients on valproic acid performed better than patients on phenytoin. Conclusions Neither levetiracetam nor valproic acid was associated with additional cognitive deficits in HGG patients. Both AEDs even appeared to have a beneficial effect on verbal memory in these patients. PMID:23233537

  18. 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

  19. Facets and determinants of quality of life in patients with recurrent high grade glioma

    PubMed Central

    Giovagnoli, A; Silvani, A; Colombo, E; Boiardi, A

    2005-01-01

    Objectives: To assess patients with recurrent high grade brain glioma with the aim of evaluating facets of quality of life (QOL) and their association with mood, cognition, and physical performance. Methods: Ninety four glioma patients (four groups with different duration of glioma recurrence) were compared with 24 patients with other chronic neurological diseases and 48 healthy subjects. The Functional Living Index—Cancer (FLIC) provided QOL self evaluations, and standardised scales and neuropsychological tests assessed physical performance, mood, and cognition. Results: In glioma patients, factor analysis of the FLIC items documented five domains: Psychological well being, Role/sociability, Inner experience of disease, Isolation/sharing, and Nausea. Higher FLIC total scores were related to better cognition, physical performances, and mood, and lower grading; poorer Psychological well being and worse Inner experience of disease to depressed mood; minor Role/sociability to worse cognitive and physical performances and higher grading; worse Nausea to longer disease duration. Compared with healthy subjects, all glioma groups were cognitively impaired and more anxious, and two groups with short duration of recurrence were also more depressed. Patients with chronic neurological diseases showed worse mood and cognitive abilities compared with healthy subjects, but performed attention tests better than glioma patients. Glioma and chronic disease patients showed similar FLIC scores and autonomy. Conclusions: These results show that QOL of recurrent high grade glioma patients is multifaceted and determined by multiple factors. Disease severity does not necessarily eliminate the possibility of expressing personal feelings and opinions which could provide criteria for clinical decision making and psychological support. PMID:15774446

  20. Antisense oligonucleotides as innovative therapeutic strategy in the treatment of high-grade gliomas.

    PubMed

    Caruso, Gerardo; Caffo, Mariella; Raudino, Giuseppe; Alafaci, Concetta; Salpietro, Francesco M; Tomasello, Francesco

    2010-01-01

    Despite the intensive recent research in cancer therapy, the prognosis in patients affected by high-grade gliomas is still very unfavorable. The efficacy of classical anti-cancer strategies is seriously limited by lack of specific therapies against malignant cells. The extracellular matrix plays a pivotal role in processes such as differentiation, apoptosis, and migration in both the normal and the pathologic nervous system. Glial tumors seem to be able to create a favorable environment for the invasion of glioma cells in cerebral parenchyma when they combine with the extracellular matrix via cell surface receptors. Glioma cells synthesize matrix proteins, such as tenascin, laminin, fibronectin that facilitate the tumor cell's motility. New treatments have shown to hit the acting molecules in the tumor growth and to increase the efficacy and minimize the toxicity. Antisense oligonucleotides are synthetic stretches of DNA which hybridize with specific mRNA strands. The specificity of hybridization makes antisense method an interesting strategy to selectively modulate the expression of genes involved in tumorigenesis. In this review we will focus on the mechanisms of action of antisense oligonucleotides and report clinical and experimental studies on the treatment of high-grade gliomas. We will also report the patents of preclinical and/or clinical studies that adopt the antisense oligonucleotide therapy list in cerebral gliomas.

  1. Unique genetic and epigenetic mechanisms driving signatures of paediatric diffuse high-grade glioma

    PubMed Central

    Jones, Chris; Baker, Suzanne J

    2016-01-01

    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 tumourigenesis and chromatin regulation as well as developmental signaling pathways. These new genetic findings provide insights into disease pathogenesis, and the challenges and opportunities for improving patient survival in these largely incurable childhood brain tumours. PMID:25230881

  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. Response Assessment and Magnetic Resonance Imaging Issues for Clinical Trials Involving High-Grade Gliomas.

    PubMed

    Boxerman, Jerrold L; Ellingson, Benjamin M

    2015-06-01

    There exist multiple challenges associated with the current response assessment criteria for high-grade gliomas, including the uncertain role of changes in nonenhancing T2 hyperintensity, and the phenomena of pseudoresponse and pseudoprogression in the setting of antiangiogenic and chemoradiation therapies, respectively. Advanced physiological magnetic resonance imaging (MRI), including diffusion and perfusion (dynamic susceptibility contrast MRI and dynamic contrast-enhanced MRI) sensitive techniques for overcoming response assessment challenges, has been proposed, with their own potential advantages and inherent shortcomings. Measurement variability exists for conventional and advanced MRI techniques, necessitating the standardization of image acquisition parameters in order to establish the utility of these imaging methods in multicenter trials for high-grade gliomas. This review chapter highlights the important features of MRI in clinical brain tumor trials, focusing on the current state of response assessment in brain tumors, advanced imaging techniques that may provide additional value for determining response, and imaging issues to be considered for multicenter trials.

  4. 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.

  5. 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.

  6. Patient and caregiver perceptions of communication of prognosis in high grade glioma.

    PubMed

    Lobb, E A; Halkett, G K B; Nowak, A K

    2011-08-01

    This study sought the views of patients and their caregivers on their experience of being diagnosed with high grade glioma. Purposive sampling was used to recruit 19 patients and 21 caregivers from the medical oncology unit of a tertiary hospital. A semi-structured face-to-face interview was conducted. Interviews were audio-taped and transcribed verbatim. Data was analysed based on Grounded Theory and using the constant comparison method. This paper focuses on patient and carer perceptions of the initial communication about the diagnosis of high grade glioma and its prognosis. Themes identified included: (a) shock at hearing the diagnosis; (b) trying to understand and process prognostic information when still in shock; (c) the perception of hope being taken away; (d) individualizing prognostic information; and (e) clinicians' lack of communication skills. This study shows that the first communication of prognosis to patients with high grade glioma and their caregivers requires careful negotiation. It illustrates the inability of individuals to process detailed prognostic information when in a state of initial shock and distress. The importance of balancing honesty with hope in the communication of a poor prognosis is highlighted. We recommend that clinicians seek patient preferences for the amount and type of information they require and that prognostic information be individualized. Detailed discussions of prognosis should only take place with senior medical staff, or advanced trainees who have demonstrated acceptable communication skills.

  7. Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas.

    PubMed

    Rudek, Michelle A; New, Pamela; Mikkelsen, Tom; Phuphanich, Surasak; Alavi, Jane B; Nabors, Louis B; Piantadosi, Steven; Fisher, Joy D; Grossman, Stuart A

    2011-11-01

    COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.

  8. All reovirus subtypes show oncolytic potential in primary cells of human high-grade glioma.

    PubMed

    Alloussi, S H; Alkassar, M; Urbschat, S; Graf, N; Gärtner, B

    2011-09-01

    Reoviridae are non-human pathogenic viruses. The family of reoviridae consists of 4 different subtypes. Many studies have proven that the Dearing subtype 3 has oncolytic potential. This potential is related to the RAS protein expression in tumour cells. The aim of this study, was to investigate whether all reovirus subtypes have oncolytic potential and whether there are differences in their efficacy, in particular for high-grade glioma. To evaluate the oncolytic potential, we performed an in vitro head-to-head study for all reovirus subtypes in 5 primary cell cultures of high-grade gliomas. The oncolytic activity was determined using end-point titration with observation of the cytopathogenic effect. For measurement of RAS activity, we performed an immunofluorescent detection stain on all cell cultures. For quantification of the virus, an RT-PCR measurement for all subtypes was performed. All reovirus subtypes showed oncolytic activity in the observed glioma biopsies. These observations correlated with RAS overexpression in the observed cells. All glioma biopsies overexpressed the RAS protein. The quantitative oncolytic potential differed in relation to the single observed cell culture and in relation to the chosen reovirus subtype. To our knowledge, this is the first study showing oncolytic activity for all reovirus subtypes. We show the relationship and correlation between RAS protein overexpression and vulnerability of cells to reovirus. Efficacy of the different subtypes is interindividually different and cannot be forecast.

  9. Cilengitide in Treating Younger Patients With Recurrent or Progressive High-Grade Glioma That Has Not Responded to Standard Therapy

    ClinicalTrials.gov

    2014-05-05

    Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  10. PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation

    PubMed Central

    van Vuurden, Dannis G.; Hulleman, Esther; Meijer, Olga L.M.; Wedekind, Laurine E.; Kool, Marcel; Witt, Hendrik; Vandertop, Peter W. Peter; Würdinger, Thomas; Noske, David P.; Kaspers, Gertjan J.L.; Cloos, Jacqueline

    2011-01-01

    Poly ADP-ribose polymerase (PARP) is a protein involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy and in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways. In addition, PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy. Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor Olaparib in childhood medulloblastoma, ependymoma and high grade glioma (HGG). Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Pediatric high grade glioma, medulloblastoma and ependymoma gene expression profiling revealed that high PARP1 expression is associated with poor prognosis. Cell growth inhibition assays with Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.4 to 8.4 μM, irrespective of tumor type and PARP1 protein expression. Sensitization to radiation was observed in medulloblastoma, ependymoma and HGG cell lines with subcytotoxic concentrations of Olaparib, which coincided with persistence of double strand breaks. Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome. PMID:22184287

  11. Prognostic Value of MRS Metabolites in Postoperative Irradiated High Grade Gliomas

    PubMed Central

    Tolia, Maria; Verganelakis, Dimitrios; Tsoukalas, Nikolaos; Kyrgias, George; Papathanasiou, Matilda; Mosa, Eftichia; Kokakis, Ioannis; Kouvaris, John R.; Pissakas, George; Pistevou-Gombaki, Kyriaki; Kelekis, Nikolaos; Kouloulias, Vasileios

    2015-01-01

    Purpose. We studied the prognostic significance of Magnetic Resonance Spectroscopy (MRS) in operated high grade gliomas. Materials and Methods. Twelve patients were treated with radiotherapy and Temozolomide. The MRS data were taken four weeks after operation (before radiotherapy) and every six months after the completion of RT. The N-acetyl aspartate, choline, creatine, and myo-inositol parameters were quantified, analyzed, and correlated to recurrence-free survival (RFS). Results. The median RFS was 26.06 months. RFS was significantly worse in elderly patients (P = 0.001) along with the higher choline/creatine ratios at either baseline (P = 0.003) or six months post Radiotherapy (P = 0.042). Median RFS was 23 months in high choline/creatine levels ≥2 at 6 months after radiotherapy and 11 months for those with <2 choline/creatine levels. There was a significant correlation of maximum difference of choline/creatine ratio with RFS (rho = 0.64, P = 0.045). Conclusion. Age and choline/creatine ratio are strong independent prognostic factors in high grade gliomas. PMID:26339606

  12. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma.

    PubMed

    Cloughesy, Timothy F; Landolfi, Joseph; Hogan, Daniel J; Bloomfield, Stephen; Carter, Bob; Chen, Clark C; Elder, J Bradley; Kalkanis, Steven N; Kesari, Santosh; Lai, Albert; Lee, Ian Y; Liau, Linda M; Mikkelsen, Tom; Nghiemphu, Phioanh Leia; Piccioni, David; Walbert, Tobias; Chu, Alice; Das, Asha; Diago, Oscar R; Gammon, Dawn; Gruber, Harry E; Hanna, Michelle; Jolly, Douglas J; Kasahara, Noriyuki; McCarthy, David; Mitchell, Leah; Ostertag, Derek; Robbins, Joan M; Rodriguez-Aguirre, Maria; Vogelbaum, Michael A

    2016-06-01

    Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165). PMID:27252174

  13. The genetic signatures of pediatric high-grade glioma: no longer a one-act play

    PubMed Central

    Diaz, Alexander K.; Baker, Suzanne J.

    2014-01-01

    Advances in understanding pediatric high-grade glioma (pHGG) genetics have revealed key differences between pediatric and adult high-grade gliomas (aHGGs), and have uncovered unique molecular drivers among subgroups within pHGG. The three core aHGG pathways, the receptor tyrosine kinase(RTK)/Ras/Phosphatidylinositide 3-kinase (PI3K), p53, and retinoblastoma (RB) networks, are also disrupted in pHGG, but they exhibit a different spectrum of effectors targeted by mutation. There are also similarities and differences in the genomic landscape of diffuse intrinsic pontine glioma (DIPG) and pediatric non-brainstem high-grade glioma (pNBS-HGG). In 2012, histone H3 mutations were identified in nearly 80% of DIPGs and ∼35% of pNBS-HGG. These were the first reports of histone mutations in human cancer, implicating novel biology in pediatric gliomagenesis. Additionally, DIPG and midline pNBS-HGG vary in the frequency and specific histone H3 amino acid substitution compared to pNBS-HGGs arising in the cerebral hemispheres, demonstrating a molecular difference among pHGG subgroups. The gene expression signatures as well as DNA methylation signatures of these tumors also carry distinctive signatures, reflecting a combination of the driving mutations and the developmental context from which they arise. These data collectively highlight unique selective pressures within the developing brainstem and solidify DIPG as a specific molecular and biological entity among pHGGs. Emerging studies continue to identify novel mutations that distinguish subgroups of pHGG. The molecular heterogeneity among pHGGs will undoubtedly have clinical implications moving forward. The discovery of unique oncogenic drivers is a critical first step in providing patients with appropriate, targeted therapies. Despite these insights, our vantage point has been largely limited to an in-depth analysis of protein coding sequences. Given the clear importance of histone mutations in pHGG, it will be interesting

  14. Review: Molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies

    PubMed Central

    Masui, K.; Cloughesy, T. F.; Mischel, P. S.

    2014-01-01

    The classification of malignant gliomas is moving from a morphology-based guide to a system built on molecular criteria. The development of a genomic landscape for gliomas and a better understanding of its functional consequences have led to the development of internally consistent molecular classifiers. However, development of a biologically insightful classification to guide therapy is still a work in progress. Response to targeted treatments is based not only on the presence of drugable targets, but rather on the molecular circuitry of the cells. Further, tumours are heterogeneous and change and adapt in response to drugs. Therefore, the challenge of developing molecular classifiers that provide meaningful ways to stratify patients for therapy remains a major challenge for the field. In this review, we examine the potential role of MGMT methylation, IDH1/2 mutations, 1p/19q deletions, aberrant epidermal growth factor receptor and PI3K pathways, abnormal p53/Rb pathways, cancer stem-cell markers and microRNAs as prognostic and predictive molecular markers in the setting of adult high-grade gliomas and we outline the clinically relevant subtypes of glioblastoma with genomic, transcriptomic and proteomic integrated analyses. Furthermore, we describe how these advances, especially in epidermal growth factor receptor/PI3K/mTOR signalling pathway, affect our approaches towards targeted therapy, raising new challenges and identifying new leads. PMID:22098029

  15. Insights Gained from Modeling High-Grade Glioma in the Mouse

    PubMed Central

    Rankin, Sherri L.; Zhu, Guo; Baker, Suzanne J.

    2011-01-01

    High grade gliomas (HGG) are devastating primary brain tumors with universally poor prognoses. Advances toward effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumor initiation, progression, and phenotype, the influence of tumor microenviroment, and the analysis of cell types that can give rise to glioma. HGGs are a highly heterogeneous group of tumors, and the complexity of diverse mutations within common signaling pathways as well as the developmental and cell-type context of transformation contribute to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely approximate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing. PMID:22035336

  16. PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas.

    PubMed

    Sooman, Linda; Ekman, Simon; Tsakonas, Georgios; Jaiswal, Archita; Navani, Sanjay; Edqvist, Per-Henrik; Pontén, Fredrik; Bergström, Stefan; Johansson, Mikael; Wu, Xuping; Blomquist, Erik; Bergqvist, Michael; Gullbo, Joachim; Lennartsson, Johan

    2014-05-01

    The prognosis of high-grade glioma patients is poor, and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients, the epigenetic regulation of the expression of PTPN6, and the role of its expression in chemotherapy resistance in glioma-derived cells. PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6-overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite pyrosequencing, and demethylation of PTPN6 was done with decitabine treatment. The PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p = 0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increase resistance (p < 0.05) to the chemotherapeutic drugs bortezomib, cisplatin, and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis, or autophagy. Low PTPN6 promoter methylation correlated to protein expression, and the protein expression was increased upon demethylation in glioma-derived cells. PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients, and in glioma-derived cells, its expression is epigenetically regulated and influences the

  17. High grade glioma mimicking voltage gated potassium channel complex associated antibody limbic encephalitis.

    PubMed

    Athauda, Dilan; Delamont, R S; Pablo-Fernandez, E De

    2014-01-01

    Though raised titres of voltage gated potassium channel (VGKC) complex antibodies have been occasionally associated with extracranial tumours, mainly presenting as Morvan's Syndrome or neuromyotonia, they have not yet been reported to be associated with an intracranial malignancy. This is especially important as misdiagnosis of these conditions and delay of the appropriate treatment can have important prognostic implications. We describe a patient with a high grade glioma presenting with clinical, radiological, and serological features consistent with the diagnosis of VGKC antibody associated limbic encephalitis (LE). This is the first association between a primary brain tumour and high titre of VGKC complex antibodies. Clinicoradiological progression despite effective immunosuppressive treatment should prompt clinicians to look for alternative diagnoses. Further studies to elucidate a possible association between VGKC complex and other surface antigen antibodies with primary brain tumours should be carried out.

  18. High-grade glioma management and response assessment—recent advances and current challenges

    PubMed Central

    Khan, M.N.; Sharma, A.M.; Pitz, M.; Loewen, S.K.; Quon, H.; Poulin, A.; Essig, M.

    2016-01-01

    The management of high-grade gliomas (hggs) is complex and ever-evolving. The standard of care for the treatment of hggs consists of surgery, chemotherapy, and radiotherapy. However, treatment options are influenced by multiple factors such as patient age and performance status, extent of tumour resection, biomarker profile, and tumour histology and grade. Follow-up cranial magnetic resonance imaging (mri) to differentiate treatment response from treatment effect can be challenging and affects clinical decision-making. An assortment of advanced radiologic techniques—including perfusion imaging with dynamic susceptibility contrast mri, dynamic contrast-enhanced mri, diffusion-weighted imaging, proton spectroscopy, mri subtraction imaging, and amino acid radiotracer imaging—can now incorporate novel physiologic data, providing new methods to help characterize tumour progression, pseudoprogression, and pseudoresponse. In the present review, we provide an overview of current treatment options for hgg and summarize recent advances and challenges in imaging technology. PMID:27536188

  19. ADC texture—An imaging biomarker for high-grade glioma?

    SciTech Connect

    Brynolfsson, Patrik; Hauksson, Jón; Karlsson, Mikael; Garpebring, Anders; Nyholm, Tufve; Nilsson, David; Trygg, Johan; Henriksson, Roger; Birgander, Richard; Asklund, Thomas

    2014-10-15

    Purpose: Survival for high-grade gliomas is poor, at least partly explained by intratumoral heterogeneity contributing to treatment resistance. Radiological evaluation of treatment response is in most cases limited to assessment of tumor size months after the initiation of therapy. Diffusion-weighted magnetic resonance imaging (MRI) and its estimate of the apparent diffusion coefficient (ADC) has been widely investigated, as it reflects tumor cellularity and proliferation. The aim of this study was to investigate texture analysis of ADC images in conjunction with multivariate image analysis as a means for identification of pretreatment imaging biomarkers. Methods: Twenty-three consecutive high-grade glioma patients were treated with radiotherapy (2 Gy/60 Gy) with concomitant and adjuvant temozolomide. ADC maps and T1-weighted anatomical images with and without contrast enhancement were collected prior to treatment, and (residual) tumor contrast enhancement was delineated. A gray-level co-occurrence matrix analysis was performed on the ADC maps in a cuboid encapsulating the tumor in coronal, sagittal, and transversal planes, giving a total of 60 textural descriptors for each tumor. In addition, similar examinations and analyses were performed at day 1, week 2, and week 6 into treatment. Principal component analysis (PCA) was applied to reduce dimensionality of the data, and the five largest components (scores) were used in subsequent analyses. MRI assessment three months after completion of radiochemotherapy was used for classifying tumor progression or regression. Results: The score scatter plots revealed that the first, third, and fifth components of the pretreatment examinations exhibited a pattern that strongly correlated to survival. Two groups could be identified: one with a median survival after diagnosis of 1099 days and one with 345 days, p = 0.0001. Conclusions: By combining PCA and texture analysis, ADC texture characteristics were identified, which seems

  20. High-throughput microRNA profiling of pediatric high-grade gliomas

    PubMed Central

    Miele, Evelina; Buttarelli, Francesca Romana; Arcella, Antonella; Begalli, Federica; Garg, Neha; Silvano, Marianna; Po, Agnese; Baldi, Caterina; Carissimo, Giuseppe; Antonelli, Manila; Spinelli, Gian Paolo; Capalbo, Carlo; Donofrio, Vittoria; Morra, Isabella; Nozza, Paolo; Gulino, Alberto; Giangaspero, Felice; Ferretti, Elisabetta

    2014-01-01

    Background High-grade gliomas (HGGs) account for 15% of all pediatric brain tumors and are a leading cause of cancer-related mortality and morbidity. Pediatric HGGs (pHGGs) are histologically indistinguishable from their counterpart in adulthood. However, recent investigations indicate that differences occur at the molecular level, thus suggesting that the molecular path to gliomagenesis in childhood is distinct from that of adults. MicroRNAs (miRNAs) have been identified as key molecules in gene expression regulation, both in development and in cancer. miRNAs have been investigated in adult high-grade gliomas (aHGGs), but scant information is available for pHGGs. Methods We explored the differences in microRNAs between pHGG and aHGG, in both fresh-frozen and paraffin-embedded tissue, by high-throughput miRNA profiling. We also evaluated the biological effects of miR-17-92 cluster silencing on a pHGG cell line. Results Comparison of miRNA expression patterns in formalin versus frozen specimens resulted in high correlation between both types of samples. The analysis of miRNA profiling revealed a specific microRNA pattern in pHGG with an overexpression and a proliferative role of the miR-17-92 cluster. Moreover, we highlighted a possible quenching function of miR-17-92 cluster on its target gene PTEN, together with an activation of tumorigenic signaling such as sonic hedgehog in pHGG. Conclusions Our results suggest that microRNA profiling represents a tool to distinguishing pediatric from adult HGG and that miR-17-92 cluster sustains pHGG. PMID:24305714

  1. Phase I study of terameprocol in patients with recurrent high-grade glioma

    PubMed Central

    Grossman, Stuart A.; Ye, Xiaobu; Peereboom, David; Rosenfeld, Myrna R.; Mikkelsen, Tom; Supko, Jeffrey G.; Desideri, Serena

    2012-01-01

    Terameprocol is a global transcription inhibitor that affects cell division apoptosis, drug resistance, hypoxia responsive genes, and radiation resistance in hypoxia. A multicenter, dose-escalation study was conducted in heavily pretreated patients with recurrent, measurable, high-grade gliomas. Terameprocol was administered intravenously for 5 consecutive days each month and discontinued for toxicity or progression. Patients taking enzyme-inducing antiseizure drugs (EIASDs) were escalated independently. Thirty-five patients with a median Karnofsky performance status of 80, median age of 46 years, and median of 2 prior treatment regimens were accrued. Doses of 750, 1100, 1700, and 2200 mg/day were administered. Terameprocol was reformulated to avoid acidosis related to the excipient and was well tolerated at 1700 mg/day. Hypoxia and interstitial nephritis were noted at 2200 mg/day. Concurrent administration of EIASD did not significantly affect the serum pharmacokinetics of the terameprocol. Although no responses were seen, stable disease was noted in 9 (28%) of 32 evaluable patients, with 5 (13%) continuing treatment for >6 months (≥6, 8, 10, 10, and ≥21 months). The overall median survival was 5.9 months. This phase I study defined the toxicity of terameprocol, determined that EIASDs do not affect its pharmacokinetics, and identified 1700 mg/day as the dose for future studies. Preclinical and human data suggest that this novel transcription inhibitor is worthy of further study. The long-term stability noted in some patients and the lack of associated myelosuppression suggest that terameprocol could be safely combined with radiation and temozolomide in newly diagnosed high-grade gliomas. PMID:22323663

  2. Prognostic Relevance of Histomolecular Classification of Diffuse Adult High-Grade Gliomas with Necrosis.

    PubMed

    Figarella-Branger, Dominique; Mokhtari, Karima; Colin, Carole; Uro-Coste, Emmanuelle; Jouvet, Anne; Dehais, Caroline; Carpentier, Catherine; Villa, Chiara; Maurage, Claude-Alain; Eimer, Sandrine; Polivka, Marc; Vignaud, Jean-Michel; Laquerriere, Annie; Sevestre, Henri; Lechapt-Zalcman, Emmanuelle; Quintin-Roué, Isabelle; Aubriot-Lorton, Marie-Hélène; Diebold, Marie-Danièle; Viennet, Gabriel; Adam, Clovis; Loussouarn, Delphine; Michalak, Sophie; Rigau, Valérie; Heitzmann, Anne; Vandenbos, Fanny; Forest, Fabien; Chiforeanu, Danchristian; Tortel, Marie-Claire; Labrousse, François; Chenard, Marie-Pierre; Nguyen, Anh Tuan; Varlet, Pascale; Kemeny, Jean Louis; Levillain, Pierre-Marie; Cazals-Hatem, Dominique; Richard, Pomone; Delattre, Jean-Yves

    2015-07-01

    Diffuse adult high-grade gliomas (HGGs) with necrosis encompass anaplastic oligodendrogliomas (AOs) with necrosis (grade III), glioblastomas (GBM, grade IV) and glioblastomas with an oligodendroglial component (GBMO, grade IV). Here, we aimed to search for prognostic relevance of histological classification and molecular alterations of these tumors. About 210 patients were included (63 AO, 56 GBM and 91 GBMO). GBMO group was split into "anaplastic oligoastrocytoma (AOA) with necrosis grade IV/GBMO," restricted to tumors showing intermingled astrocytic and oligodendroglial component, and "GBM/GBMO" based on tumors presenting oligodendroglial foci and features of GBM. Genomic arrays, IDH1 R132H expression analyses and IDH direct sequencing were performed. 1p/19q co-deletion characterized AO, whereas no IDH1 R132H expression and intact 1p/19q characterized both GBM and GBM/GBMO. AOA with necrosis/GBMO mainly demonstrated IDH1 R132H expression and intact 1p/19q. Other IDH1 or IDH2 mutations were extremely rare. Both histological and molecular classifications were predictive of progression free survival (PFS) and overall survival (OS) (P < 10(-4) ). Diffuse adult HGGs with necrosis can be split into three histomolecular groups of prognostic relevance: 1p/19q co-deleted AO, IDH1 R132H-GBM and 1p/19q intact IDH1 R132H+ gliomas that might be classified as IDH1 R132H+ GBM. Because of histomolecular heterogeneity, we suggest to remove the name GBMO.

  3. 5-aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach.

    PubMed

    Panciani, Pier Paolo; Fontanella, Marco; Garbossa, Diego; Agnoletti, Alessandro; Ducati, Alessandro; Lanotte, Michele

    2012-02-01

    In high-grade glioma surgery, several techniques are used to achieve the maximum cytoreductive treatment preserving neurological functions. However, the effectiveness of all the methods used alone is reduced by specific limitations of each. We assessed the reliability of a multimodal strategy based on 5-aminolevulinic acid (5-ALA) and neuronavigation. We prospectively studied 18 patients with suspected, non eloquent-area malignant gliomas amenable for complete resection. Conventional illumination was used until the excision appeared complete. The cavity was then systematically inspected in violet-blue light to identify any residual tumour. Multiple biopsies of both fluorescent and non-fluorescent tissue were performed in all cases. Each specimen was labelled according to the sampling location (inside or outside the boundary set by the neuronavigator). The samples were analysed by a neuropathologist blinded to the intraoperative classification. We reviewed the results of both methods, either singly or in combination. Individual analysis showed higher 5-ALA reliability compared to neuronavigation. However, several false-negative fluorescent specimens were detected. With the combined use of fluorescence and neuroimaging, only 1 sample (negative for both 5-ALA and navigation) was tumoral tissue. In our experience, the combined approach showed the best sensitivity and it is recommended in cases of lesions involving non-eloquent areas.

  4. High-grade glioma before and after treatment with radiation and Avastin: Initial observations

    PubMed Central

    Fischer, Ingeborg; Cunliffe, Clare H.; Bollo, Robert J.; Raza, Shahzad; Monoky, David; Chiriboga, Luis; Parker, Erik C.; Golfinos, John G.; Kelly, Patrick J.; Knopp, Edmond A.; Gruber, Michael L.; Zagzag, David; Narayana, Ashwatha

    2008-01-01

    We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor–A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent “normalization” after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following anti-angiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers. PMID:18697955

  5. In Vitro Drug Response and Efflux Transporters Associated with Drug Resistance in Pediatric High Grade Glioma and Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Veringa, Susanna J. E.; Biesmans, Dennis; van Vuurden, Dannis G.; Jansen, Marc H. A.; Wedekind, Laurine E.; Horsman, Ilona; Wesseling, Pieter; Vandertop, William Peter; Noske, David P.; Kaspers, GertJan J. L.; Hulleman, Esther

    2013-01-01

    Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular. PMID:23637844

  6. Prognostic Relevance of Histomolecular Classification of Diffuse Adult High-Grade Gliomas with Necrosis.

    PubMed

    Figarella-Branger, Dominique; Mokhtari, Karima; Colin, Carole; Uro-Coste, Emmanuelle; Jouvet, Anne; Dehais, Caroline; Carpentier, Catherine; Villa, Chiara; Maurage, Claude-Alain; Eimer, Sandrine; Polivka, Marc; Vignaud, Jean-Michel; Laquerriere, Annie; Sevestre, Henri; Lechapt-Zalcman, Emmanuelle; Quintin-Roué, Isabelle; Aubriot-Lorton, Marie-Hélène; Diebold, Marie-Danièle; Viennet, Gabriel; Adam, Clovis; Loussouarn, Delphine; Michalak, Sophie; Rigau, Valérie; Heitzmann, Anne; Vandenbos, Fanny; Forest, Fabien; Chiforeanu, Danchristian; Tortel, Marie-Claire; Labrousse, François; Chenard, Marie-Pierre; Nguyen, Anh Tuan; Varlet, Pascale; Kemeny, Jean Louis; Levillain, Pierre-Marie; Cazals-Hatem, Dominique; Richard, Pomone; Delattre, Jean-Yves

    2015-07-01

    Diffuse adult high-grade gliomas (HGGs) with necrosis encompass anaplastic oligodendrogliomas (AOs) with necrosis (grade III), glioblastomas (GBM, grade IV) and glioblastomas with an oligodendroglial component (GBMO, grade IV). Here, we aimed to search for prognostic relevance of histological classification and molecular alterations of these tumors. About 210 patients were included (63 AO, 56 GBM and 91 GBMO). GBMO group was split into "anaplastic oligoastrocytoma (AOA) with necrosis grade IV/GBMO," restricted to tumors showing intermingled astrocytic and oligodendroglial component, and "GBM/GBMO" based on tumors presenting oligodendroglial foci and features of GBM. Genomic arrays, IDH1 R132H expression analyses and IDH direct sequencing were performed. 1p/19q co-deletion characterized AO, whereas no IDH1 R132H expression and intact 1p/19q characterized both GBM and GBM/GBMO. AOA with necrosis/GBMO mainly demonstrated IDH1 R132H expression and intact 1p/19q. Other IDH1 or IDH2 mutations were extremely rare. Both histological and molecular classifications were predictive of progression free survival (PFS) and overall survival (OS) (P < 10(-4) ). Diffuse adult HGGs with necrosis can be split into three histomolecular groups of prognostic relevance: 1p/19q co-deleted AO, IDH1 R132H-GBM and 1p/19q intact IDH1 R132H+ gliomas that might be classified as IDH1 R132H+ GBM. Because of histomolecular heterogeneity, we suggest to remove the name GBMO. PMID:25407774

  7. Prognostic Significance of Telomere Maintenance Mechanisms in Pediatric High-Grade Gliomas

    PubMed Central

    Dorris, Kathleen; Sobo, Matthew; Onar-Thomas, Arzu; Panditharatna, Eshini; Stevenson, Charles B.; Gardner, Sharon L.; DeWire, Mariko D.; Pierson, Christopher R.; Olshefski, Randal; Rempel, Sandra A.; Goldman, Stewart; Miles, Lili; Fouladi, Maryam; Drissi, Rachid

    2014-01-01

    Background Children with high-grade glioma, including diffuse intrinsic pontine glioma (DIPG), have a poor prognosis despite multimodal therapy. Identifying novel therapeutic targets is critical to improve their outcome. We evaluated prognostic roles of telomere maintenance mechanisms in children with HGG, including DIPG. Methods A multi-institutional retrospective study was conducted involving 50 flash-frozen HGG (35 non-brainstem; 15 DIPG) tumors from 45 children (30 non-brainstem; 15 DIPG). Telomerase activity, expression of hTERT mRNA (encoding telomerase catalytic component) and TERC (telomerase RNA template) and alternative lengthening of telomeres (ALT) mechanism were assayed. Cox Proportional Hazard regression analyses assessed association of clinical and pathological variables, TERC and hTERT levels, telomerase activity, and ALT use with progression-free or overall survival (OS). Results High TERC and hTERT expression was detected in 13/28 non-brainstem HGG samples as compared to non-neoplastic controls. High TERC and hTERT expression was identified in 13/15 and 11/15 DIPG samples, respectively, compared to controls. Evidence of ALT was noted in 3/11 DIPG and 10/19 non-brainstem HGG specimens. ALT and telomerase use were identified in 4/19 non-brainstem HGG and 2/11 DIPG specimens. In multivariable analyses, increased TERC and hTERT levels were associated with worse OS in patients with non-brainstem HGG, after controlling for tumor grade or resection extent. Conclusions Children with HGG and DIPG, have increased hTERT and TERC expression. In children with non-brainstem HGG, increased TERC and hTERT expression levels are associated with a worse OS, making telomerase a promising potential therapeutic target in pediatric HGG. PMID:24477622

  8. The future of high-grade glioma: Where we are and where are we going

    PubMed Central

    Rhun, Emilie Le; Taillibert, Sophie; Chamberlain, Marc C.

    2015-01-01

    High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy. PMID:25722939

  9. Receptor for interleukin 13 is a marker and therapeutic target for human high-grade gliomas.

    PubMed

    Debinski, W; Gibo, D M; Hulet, S W; Connor, J R; Gillespie, G Y

    1999-05-01

    Glioblastoma multiforme (GBM) is an incurable brain tumor. Due to the striking heterogeneity that characterizes GBM, there is no known tumor-specific antigen or receptor that is expressed by a majority of GBM patients. We found that virtually all studied human GBM specimens (23 samples) abundantly expressed a receptor for interleukin (IL)-13 in situ, whereas normal human brain had few, if any, IL-13-binding sites. The GBM-associated IL-13 receptor was both quantitatively and qualitatively different from and, thus, more restrictive than the shared signaling receptor of normal tissue: it was IL-4 independent. The receptor for IL-13 was overexpressed by a majority of cancer cells in situ. Furthermore, cytotoxins targeted to this more restrictive IL-13R produced cures in animals bearing xenografts of human high-grade gliomas. Thus, unexpectedly, the receptor for an immune regulatory cytokine may be a long sought marker and, concomitantly, a unique imaging site and therapeutic target for GBM, the most malignant and the most heterogeneous of brain tumors.

  10. Clinical trial end points for high-grade glioma: the evolving landscape*

    PubMed Central

    Reardon, David A.; Galanis, Evanthia; DeGroot, John F.; Cloughesy, Timothy F.; Wefel, Jeffrey S.; Lamborn, Kathleen R.; Lassman, Andrew B.; Gilbert, Mark R.; Sampson, John H.; Wick, Wolfgang; Chamberlain, Marc C.; Macdonald, David R.; Mehta, Minesh P.; Vogelbaum, Michael A.; Chang, Susan M.; Van den Bent, Martin J.; Wen, Patrick Y.

    2011-01-01

    To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the “gold-standard” end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being. PMID:21310734

  11. Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma

    PubMed Central

    Wu, Wenting; Lamborn, Kathleen R.; Buckner, Jan C.; Novotny, Paul J.; Chang, Susan M.; O'Fallon, Judith R.; Jaeckle, Kurt A.; Prados, Michael D.

    2010-01-01

    The purpose of this study is to determine prognostic factors in patients with high-grade recurrent glioma for 3 outcome variables (overall survival, progression-free survival [PFS], and PFS rate 6 months after study registration [PFS6]). Data from 15 North Central Cancer Treatment Group (NCCTG) trials (n = 469, 1980–2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n = 596, 1998–2002) were included. Eighteen prognostic variables were considered including type of treatment center (community/academic) and initial low-grade histology (yes/no). Recursive partitioning analysis (RPA), Cox proportional hazards, and logistic regression models with bootstrap resampling were used to identify prognostic variables. Longer survival was associated with last known grade (Grade) of III, younger age, ECOG performance score (PS) of 0, shorter time from initial diagnosis (DxTime), and no baseline steroid use. Factors associated with longer PFS were Grade III and shorter DxTime. For patients without temozolomide as part of the treatment regimen, the only factor associated with better PFS6 was Grade III, although DxTime was important in RPA and PS was important in logistic regression. Grade was the most important prognostic factor for all three endpoints regardless of the statistical method used. Other important variables for one or more endpoints included age, PS, and DxTime. Neither type of treatment center nor initial low-grade histology was identified as a major predictor for any endpoint. PMID:20150383

  12. Surgical Ventricular Entry is a Key Risk Factor for Leptomeningeal Metastasis of High Grade Gliomas

    PubMed Central

    Roelz, Roland; Reinacher, Peter; Jabbarli, Ramazan; Kraeutle, Rainer; Hippchen, Beate; Egger, Karl; Weyerbrock, Astrid; Machein, Marcia

    2015-01-01

    Leptomeningeal metastasis (LM) of high grade gliomas (HGG) can lead to devastating disease courses. Understanding of risk factors for LM is important to identify patients at risk. We reviewed patient records and magnetic resonance imaging (MRI) of all patients with a first diagnosis of HGG who underwent surgery in our institution between 2008 and 2012. To assess the influence of potential risk factors for LM and the impact of LM on survival multivariate statistics were performed. 239 patients with a diagnosis of HGG and at least 6 months of MRI and clinical follow-up were included. LM occurred in 27 (11%) patients and was symptomatic in 17 (65%). A strong correlation of surgical entry to the ventricle and LM was found (HR: 8.1). Ventricular entry was documented in 137 patients (57%) and LM ensued in 25 (18%) of these. Only two (2%) of 102 patients without ventricular entry developed LM. Median overall survival of patients after diagnosis of LM (239 days) was significantly shorter compared to patients without LM (626 days). LM is a frequent complication in the course of disease of HGG and is associated with poor survival. Surgical entry to the ventricle is a key risk factor for LM. PMID:26635136

  13. Recurrence patterns in patients with high-grade glioma following temozolomide-based chemoradiotherapy

    PubMed Central

    Zhou, Xiaofeng; Liao, Xiaofang; Zhang, Bicheng; He, Huijuan; Shui, Yongjie; Xu, Wenhong; Jiang, Chaogen; Shen, Li; Wei, Qichun

    2016-01-01

    There is currently no consensus regarding the optimal radiation volume for high-grade glioma (HGG). The brain volume irradiated is associated with the extent of radiation neurotoxicity. When reducing the treatment volume, the risk of geographic tumor miss should be considered. In such cases, the recurrence patterns and, particularly, the rate of marginal tumor recurrence, are important indices for determining the optimal radiation volume. In the present study, a smaller-target delineation protocol with limited margins was adopted. The postoperative enhancing tumor and resection cavity were defined as gross tumor volume (GTV); 1 and 2 cm were added to the GTV to create clinical target volume (CTV1 and CTV2), which received 60 and 54 Gy, respectively. At a median follow-up of 14 months, 54 HGG patients developed tumor recurrence. The median overall and progression-free survival were 14 and 10.5 months, respectively. A total of 34 patients developed central recurrence, 8 presented with in-field recurrence, 2 developed marginal recurrence, 2 had distant recurrence and 11 patients developed cerebrospinal fluid dissemination, 2 of whom developed central recurrence, with 1 patient simultaneously developing marginal recurrence. Local recurrence (central and in-field) was found to be the main recurrence pattern. As the rate of marginal recurrence was low (<5%), it appears that the smaller irradiated volume in the present study was appropriate. However, clinical trials investigating limited irradiation volume are required to validate our findings. PMID:27446566

  14. 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. PMID:27180091

  15. The genetic signatures of pediatric high-grade glioma: no longer a one-act play.

    PubMed

    Diaz, Alexander K; Baker, Suzanne J

    2014-10-01

    Advances in understanding pediatric high-grade glioma (pHGG) genetics have revealed key differences between pHGG and adult HGG and have uncovered unique molecular drivers among subgroups within pHGG. The 3 core adult HGG pathways, the receptor tyrosine kinase-Ras-phosphatidylinositide 3-kinase, p53, and retinoblastoma networks, are also disrupted in pHGG, but they exhibit a different spectrum of effectors targeted by mutation. There are also similarities and differences in the genomic landscape of diffuse intrinsic pontine glioma (DIPG) and pediatric nonbrainstem (pNBS)-HGG. In 2012, histone H3 mutations were identified in nearly 80% of DIPGs and ~35% of pNBS-HGG. These were the first reports of histone mutations in human cancer, implicating novel biology in pediatric gliomagenesis. Additionally, DIPG and midline pNBS-HGG vary in the frequency and specific histone H3 amino acid substitution compared with pNBS-HGGs arising in the cerebral hemispheres, demonstrating a molecular difference among pHGG subgroups. The gene expression signatures as well as DNA methylation signatures of these tumors are also distinctive, reflecting a combination of the driving mutations and the developmental context from which they arise. These data collectively highlight unique selective pressures within the developing brainstem and solidify DIPG as a specific molecular and biological entity among pHGGs. Emerging studies continue to identify novel mutations that distinguish subgroups of pHGG. The molecular heterogeneity among pHGGs will undoubtedly have clinical implications moving forward. The discovery of unique oncogenic drivers is a critical first step in providing patients with appropriate, targeted therapies. Despite these insights, our vantage point has been largely limited to an in-depth analysis of protein coding sequences. Given the clear importance of histone mutations in pHGG, it will be interesting to see how aberrant epigenetic regulation contributes to tumorigenesis in the

  16. High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan.

    PubMed

    Amayiri, Nisreen; Tabori, Uri; Campbell, Brittany; Bakry, Doua; Aronson, Melyssa; Durno, Carol; Rakopoulos, Patricia; Malkin, David; Qaddoumi, Ibrahim; Musharbash, Awni; Swaidan, Maisa; Bouffet, Eric; Hawkins, Cynthia; Al-Hussaini, Maysa

    2016-01-15

    Biallelic mismatch repair deficiency (bMMRD) is a cancer predisposition syndrome affecting primarily individuals from consanguinous families resulting in multiple childhood cancers including high grade gliomas (HGG). This is the first study to assess the prevalence of bMMRD among patients with HGG in countries where consanguinity is high. We collected molecular and clinical information on all children diagnosed with HGG and supratentorial primitive neuroectodermal tumors (sPNET) between 2003 and 2013 at King Hussein Cancer Center, Jordan. Comparison was made to a similar cohort from Toronto. Clinical data regarding presence of café au lait macules(CAL), family history of cancer, consanguinity, pathology and treatment were collected. Tumors were centrally reviewed and tested for MMRD by immunohistochemistry of the corresponding proteins. Forty-two patients fulfilled the inclusion criteria, including 36 with HGG. MMRD was observed in 39% of HGG of whom 79% also lost MMR staining in the corresponding normal cells suggestive of bMMRD. P53 dysfunction was highly enriched in MMR deficient tumors (p = 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p = 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p = 0.005 and 0.05,respectively) but family history of cancer didn't. HGG with all three bMMRD risk factors had evidence of MMRD and all children affected by multiple bMMRD related cancers had identical gene loss by immunohistochemical staining. In Jordan, the frequency of clinical and immunohistochemical alterations suggestive of bMMRD in pediatric HGG is high. Genetic testing will enable appropriate counseling and cancer screening to improve survival of these patients.

  17. Convection-enhanced delivery catheter placements for high-grade gliomas: complications and pitfalls.

    PubMed

    Shahar, Tal; Ram, Zvi; Kanner, Andrew A

    2012-04-01

    Convection-enhanced delivery (CED) of compounds into brain tumors reportedly circumvents the blood brain barrier. CED intends to increase drug delivery to malignant cells, reaching high local therapeutic concentration and decreasing or eliminating systemic side effects. Clinical experience and published data on catheter placement (CP) surgery are scarce. We propose practical and technical guidelines for planning CED based on our experience. We retrospectively analyzed the medical charts and relevant neuroimages of 25 patients following the insertion of 64 CED catheters. The patients were enrolled in at least one of four clinical trials using CED for treating recurrent glioblastoma multiforme in our institution between 2003-2006. Intra- and postoperative complications related to CP surgery and the difficulties and pitfalls of planning were evaluated. There were 29 CP surgeries. Forty-four peritumoral brain tissue catheters were inserted in 16 CP surgeries following tumor resection in 16 patients, and 20 catheters were placed into the tumor in 13 procedures in 10 patients. The lesions were in or near eloquent brain tissue areas in 13 of all CP surgeries. Complications included increased edema (31%), infection (6.9%), bleeding (6.9%) and seizures (13.8%). Significant neurological deterioration occurred in 4 patients (13.8%). Difficulties in adhering to CP surgery guidelines included lesion site (superficial, mesial temporal lobe, proximity to CSF spaces), proximity to eloquent cortical areas, tissue density that interfered with the trajectory, and technical limitations of stereotactic instruments. CED procedures for high-grade gliomas may be associated with surgical morbidity. Adherence to guidelines might be difficult because of lesion site and complicated by brain and tumor tissue characteristics. This should be considered while planning clinical trials that use convection-based technology.

  18. 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.

  19. Cognitive strategies and quality of life of patients with high-grade glioma.

    PubMed

    Lucchiari, C; Botturi, A; Silvani, A; Lamperti, E; Gaviani, P; Innocenti, A; Finocchiaro, C Y; Masiero, M; Pravettoni, G

    2015-12-01

    The purpose of this study was to analyze the psychological well-being, quality of life, and cognitive strategies activated by patients with high-grade glioma. We hypothesized that the self-perceived quality of life is modulated by physical and psychological factors and that in order to understand this modulation more psychometric approaches are necessary. Data were collected from a sample of 73 consecutive patients with a histological diagnosis of primary malignant brain cancer (grade IV glioblastoma and grade III anaplastic astrocytoma) hospitalized in a specialized Italian center. The Functional Assessment of Cancer Therapy (FACT) scale and the Schedule of Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW) scale were used to assess quality of life. The mean FACT-Brain (Br) score was 122.37. Similarly, the median SEIQoL-DW score was 72.9 out of a maximum value of 100. No gender effect was found in relation to overall quality of life. Patients with high depression and/or anxiety scores reported lower quality of life (QoL) scores in all the instruments considered. We did not find any gender effect concerning depression and anxiety levels. However, we found that men and women, though having similar physical and functional well-being, reported different QoL determinants, since men seem to rely more on physical adjustment, while women activate more introspective strategies. Positive actions, family issues, negative thoughts, health, and positive thoughts were found to be the most reported themes. In conclusion, the present study strongly suggests that a positive psychological adjustment is possible also in the event of a severe diagnosis and during aggressive treatments, but QoL determinants might be considered too in order to help health professionals to understand patients' experience and to meet their needs.

  20. Seizures during the management of high-grade gliomas: clinical relevance to disease progression.

    PubMed

    Kim, Young-Hoon; Park, Chul-Kee; Kim, Tae Min; Choi, Seung Hong; Kim, Yu Jung; Choi, Byung Se; Han, Jung Ho; Lee, Se-Hoon; Kim, Chae-Yong; Kim, In Ah; Heo, Dae Seog; Kim, Il Han; Kim, Dong Gyu; Jung, Hee-Won

    2013-05-01

    This study was performed to evaluate the incidence of seizures with its implications on disease progression and the diagnostic value of post-ictal magnetic resonance images (MRI) during the management of high-grade gliomas (HGGs). A total of 406 consecutive patients with newly diagnosed HGGs were retrospectively reviewed. The incidence of seizures during the management was investigated. In patients who experienced a seizure, the causality between seizures and disease progression was assessed by pre-ictal, post-ictal (<1 month), and follow-up (<3 months) MRI. After a median follow-up of 17.4 months (range 0.1-88.3), seizures developed in 127 patients (31 %). Of the 127 patients, radiological progression at the post-ictal MRI was found in 83 patients (65 %) and the follow-up MRI confirmed progression in 79 patients (62 %). Four other patients (3 %) were shown to be progression-free. Among those without radiological progression at the post-ictal MRI, the follow-up MRI confirmed progression-free in 31 patients (24 %); however, 13 patients (10 %) revealed eventual progression. In the patients with a seizure, absence of preoperative seizures (p = 0.003), <95 % tumor resection (p = 0.001), and pre-ictal Karnofsky Performance Scale score ≤ 70 (p = 0.025) were significantly associated with disease progression. During the management of HGG, 31 % of patients experienced seizures; of these patients, 72 % harbored progressive disease. The post-ictal MRI is useful for detecting disease progression; however, there are pitfalls. Clinical settings should be considered together for diagnosing disease progression in patients with seizures.

  1. Survival following reirradiation using intensity-modulated radiation therapy with temozolomide in selected patients with recurrent high grade gliomas

    PubMed Central

    Koc, Mehmet; Kanyilmaz, Gul

    2015-01-01

    Background High grade gliomas often recur after initial treatment. Despite so many treatment options, there is no standard treatment for recurrent gliomas. The aim of this study is to offer survival following reirradiation (re-RT) using intensity-modulated radiation therapy (IMRT) with temozolomide in selected patients with recurrent high grade gliomas. Methods We examined the medical records of 21 adult patients with recurrent high grade gliomas who were reirradiated with IMRT at the time of tumor recurrence or progression. Tumor recurrence was shown by gadolinium-enhanced magnetic resonance imaging (MRI) and diagnosis was established by pathology review. Statistical analyses were performed with SPSS version 18.0.1 using Cox regression analyses, log-rank test and Kaplan-Meier method. Results Eighteen patients presented by localized recurrence, three patients with diffuse recurrence. Median radiotherapy (RT) dose was 54 Gy. About 81% patients received temozolomide with re-RT. The time interval between two courses RT was median 39.3 months (range, 9.6-140.8 months). The response was checked by MRI. About 24% patients achieved complete response (CR) and 29% patient partial response (PR). Stable disease (SD) was observed in 47% patients. Median follow-up time from diagnosis was 41.4 months (range, 16.6-145.4 months) and 12.3 months (range, 2-27.6 months) from re-RT. Median time to recurrence was 39.3 months (range, 9.6-140.8 months). Median survival after re-RT was 18 months for anaplastic astrocytoma (AA), 14.1 months for glioblastoma multiforme (GBM) (range, 11-17.2 months) (P=0.1) and 7.1 months for patients with Karnofsky performance status (KPS) <70 before re-RT and 17.4 months for KPS >70 (P=0.02). Conclusions re-RT is one of the treatment options for recurrent high grade gliomas and IMRT can be an effective treatment modality for recurrent high grade brain tumors with only mild side effects. Survival is better in patients with good performance status and in

  2. A novel, integrated PET-guided MRS technique resulting in more accurate initial diagnosis of high-grade glioma.

    PubMed

    Kim, Ellen S; Satter, Martin; Reed, Marilyn; Fadell, Ronald; Kardan, Arash

    2016-06-01

    Glioblastoma multiforme (GBM) is the most common and lethal malignant glioma in adults. Currently, the modality of choice for diagnosing brain tumor is high-resolution magnetic resonance imaging (MRI) with contrast, which provides anatomic detail and localization. Studies have demonstrated, however, that MRI may have limited utility in delineating the full tumor extent precisely. Studies suggest that MR spectroscopy (MRS) can also be used to distinguish high-grade from low-grade gliomas. However, due to operator dependent variables and the heterogeneous nature of gliomas, the potential for error in diagnostic accuracy with MRS is a concern. Positron emission tomography (PET) imaging with (11)C-methionine (MET) and (18)F-fluorodeoxyglucose (FDG) has been shown to add additional information with respect to tumor grade, extent, and prognosis based on the premise of biochemical changes preceding anatomic changes. Combined PET/MRS is a technique that integrates information from PET in guiding the location for the most accurate metabolic characterization of a lesion via MRS. We describe a case of glioblastoma multiforme in which MRS was initially non-diagnostic for malignancy, but when MRS was repeated with PET guidance, demonstrated elevated choline/N-acetylaspartate (Cho/NAA) ratio in the right parietal mass consistent with a high-grade malignancy. Stereotactic biopsy, followed by PET image-guided resection, confirmed the diagnosis of grade IV GBM. To our knowledge, this is the first reported case of an integrated PET/MRS technique for the voxel placement of MRS. Our findings suggest that integrated PET/MRS may potentially improve diagnostic accuracy in high-grade gliomas.

  3. 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

  4. High-definition fiber tractography for the evaluation of perilesional white matter tracts in high-grade glioma surgery

    PubMed Central

    Abhinav, Kumar; Yeh, Fang-Cheng; Mansouri, Alireza; Zadeh, Gelareh; Fernandez-Miranda, Juan C.

    2015-01-01

    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. PMID:26117712

  5. 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

  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. Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

    SciTech Connect

    Patel, Shilpen; DiBiase, Steven; Meisenberg, Barry; Flannery, Todd; Patel, Ashish; Dhople, Anil; Cheston, Sally; Amin, Pradip

    2012-02-01

    Purpose: The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas. Methods and Materials: A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were given tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status {>=}60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m{sup 2} divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m{sup 2} increments until the MTD was reached. When {>=}2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m{sup 2}. A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered. Results: A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m{sup 2}. One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m{sup 2}. Conclusions: The MTD of tamoxifen was 100 mg/m{sup 2} when given concurrently with temozolomide 75 mg/m{sup 2} and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.

  8. Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No?

    PubMed Central

    Koks, Carolien A.E.; De Vleeschouwer, Steven; Graf, Norbert; Van Gool, Stefaan W.

    2015-01-01

    Oncolytic viruses have been seriously considered for glioma therapy over the last 20 years. The oncolytic activity of several oncolytic strains has been demonstrated against human glioma cell lines and in in vivo xenotransplant models. So far, four of these stains have additionally completed the first phase I/II trials in relapsed glioma patients. Though safety and feasibility have been demonstrated, therapeutic efficacy in these initial trials, when described, was only minor. The role of the immune system in oncolytic virotherapy for glioma remained much less studied until recent years. When investigated, the immune system, adept at controlling viral infections, is often hypothesized to be a strong hurdle to successful oncolytic virotherapy. Several preclinical studies have therefore aimed to improve oncolytic virotherapy efficacy by combining it with immune suppression or evasion strategies. More recently however, a new paradigm has developed in the oncolytic virotherapy field stating that oncolytic virus-mediated tumor cell death can be accompanied by elicitation of potent activation of innate and adaptive anti-tumor immunity that greatly improves the efficacy of certain oncolytic strains. Therefore, it seems the three-way interaction between oncolytic virus, tumor and immune system is critical to the outcome of antitumor therapy. In this review we discuss the studies which have investigated how the immune system and oncolytic viruses interact in models of glioma. The novel insights generated here hold important implications for future research and should be incorporated into the design of novel clinical trials. PMID:25663937

  9. ABCG1 maintains high-grade glioma survival in vitro and in vivo

    PubMed Central

    Chen, Yi-Hsien; Cimino, Patrick J.; Luo, Jingqin; Dahiya, Sonika; Gutmann, David H.

    2016-01-01

    The overall survival for adults with malignant glioma (glioblastoma) remains poor despite advances in radiation and chemotherapy. One of the mechanisms by which cancer cells develop relative resistance to treatment is through de-regulation of endoplasmic reticulum (ER) homeostasis. We have recently shown that ABCG1, an ATP-binding cassette transporter, maintains ER homeostasis and suppresses ER stress-induced apoptosis in low-grade glioma. Herein, we demonstrate that ABCG1 expression is increased in human adult glioblastoma, where it correlates with poor survival in individuals with the mesenchymal subtype. Leveraging a mouse model of mesenchymal glioblastoma (NPcis), shRNA-mediated Abcg1 knockdown (KD) increased CHOP ER stress protein expression and resulted in greater NPcis glioma cell death in vitro. Moreover, Abcg1 KD reduced NPcis glioma growth and increased mouse survival in vivo. Collectively, these results demonstrate that ABCG1 is critical for malignant glioma cell survival, and might serve as a future therapeutic target for these deadly brain cancers. PMID:26981778

  10. Favorable Prognosis in Patients With High-Grade Glioma With Radiation Necrosis: The University of Colorado Reoperation Series

    SciTech Connect

    Rusthoven, Kyle E.; Olsen, Christine; Franklin, Wilbur; Kleinschmidt-DeMasters, B.K.; Kavanagh, Brian D.; Gaspar, Laurie E.; Lillehei, Kevin; Waziri, Allen; Damek, Denise M.; Chen, Changhu

    2011-09-01

    Purpose: To analyze the pathology, outcomes, and prognostic factors in patients with high-grade glioma undergoing reoperation after radiotherapy (RT). Methods and Materials: Fifty-one patients with World Health Organization Grade 3-4 glioma underwent reoperation after prior RT. The median dose of prior RT was 60 Gy, and 84% received chemotherapy as part of their initial treatment. Estimation of the percentage of necrosis and recurrent tumor in each reoperation specimen was performed. Pathology was classified as RT necrosis if {>=}80% of the specimen was necrotic and as tumor recurrence if {>=}20% was tumor. Predictors of survival were analyzed using log-rank comparisons and Cox proportional hazards regression. Results: The median interval between the completion of RT and reoperation was 6.7 months (range, 1-59 months). Pathologic analysis showed RT necrosis in 27% and recurrence in 73% of cases. Thirteen patients required a reoperation for uncontrolled symptoms. Among them, 1 patient (8%) had pathology showing RT necrosis, and 12 (92%) had tumor recurrence. Median survival after reoperation was longer for patients with RT necrosis (21.8 months vs. 7.0 months, p = 0.047). In 7 patients with Grade 4 tumors treated with temozolomide-based chemoradiation with RT necrosis, median survival from diagnosis and reoperation were 30.2 months and 21.8 months, respectively. Conclusions: Patients with RT necrosis at reoperation have improved survival compared with patients with tumor recurrence. Future efforts to intensify local therapy and increase local tumor control in patients with high-grade glioma seem warranted.

  11. Segmentation of solid subregion of high grade gliomas in MRI images based on active contour model (ACM)

    NASA Astrophysics Data System (ADS)

    Seow, P.; Win, M. T.; Wong, J. H. D.; Abdullah, N. A.; Ramli, N.

    2016-03-01

    Gliomas are tumours arising from the interstitial tissue of the brain which are heterogeneous, infiltrative and possess ill-defined borders. Tumour subregions (e.g. solid enhancing part, edema and necrosis) are often used for tumour characterisation. Tumour demarcation into substructures facilitates glioma staging and provides essential information. Manual segmentation had several drawbacks that include laborious, time consuming, subjected to intra and inter-rater variability and hindered by diversity in the appearance of tumour tissues. In this work, active contour model (ACM) was used to segment the solid enhancing subregion of the tumour. 2D brain image acquisition data using 3T MRI fast spoiled gradient echo sequence in post gadolinium of four histologically proven high-grade glioma patients were obtained. Preprocessing of the images which includes subtraction and skull stripping were performed and then followed by ACM segmentation. The results of the automatic segmentation method were compared against the manual delineation of the tumour by a trainee radiologist. Both results were further validated by an experienced neuroradiologist and a brief quantitative evaluations (pixel area and difference ratio) were performed. Preliminary results of the clinical data showed the potential of ACM model in the application of fast and large scale tumour segmentation in medical imaging.

  12. Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma

    PubMed Central

    O’Brien, Rebecca; Jadus, Martin R.; Gillespie, G. Yancey; Cloud, Gretchen A.; Hoa, Neil T.; Langford, Catherine P.; Lopez, Richard D.; Harkins, Lualhati E.; Lamb Jr., Lawrence S.

    2015-01-01

    Human γδ T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 mice and measured circulating γδ T cell count, phenotype, Vγ/Vδ repertoire, tumor histopathology, NKG2D ligands expression, and T cell invasion at day 10–12 post-injection and at end stage. Circulating γδ T cells transiently increased and upregulated Annexin V expression at post-tumor day 10–12 followed by a dramatic decline in γδ T cell count at end stage. T cell receptor repertoire showed no changes in Vγ1, Vγ4, Vγ7 or Vδ1 subsets from controls at post-tumor day 10–12 or at end stage except for an end-stage increase in the Vδ4 population. Approximately 12% of γδ T cells produced IFN-γ. IL-17 and IL-4 producing γδ T cells were not detected. Tumor progression was the same in TCRδ-/- C57BL/6 mice as that observed in WT mice, suggesting that γδ T cells exerted neither a regulatory nor a sustainable cytotoxic effect on the tumor. WT mice that received an intracranial injection of γδ T cells 15m following tumor placement showed evidence of local tumor growth inhibition but this was insufficient to confer a survival advantage over untreated controls. Taken together, our findings suggest that an early nonspecific proliferation of γδ T cells followed by their depletion occurs in mice implanted with syngeneic GL261 gliomas. The mechanism by which γδ T cell expansion occurs remains a subject for further investigation of the mechanisms responsible for this immune response in the setting of high-grade glioma. PMID:25955158

  13. The Role of Radiotherapy and Chemotherapy in the Treatment of Primary Adult High Grade Gliomas: Assessment of Patients for These Treatment Approaches and the Common Immediate Side Effects

    PubMed Central

    Philip-Ephraim, E. E.; Eyong, K. I.; Williams, U. E.; Ephraim, R. P.

    2012-01-01

    Gliomas are the commonest primary brain tumours in adults. They are usually classified and graded according to the criteria by the World Health Organisation. High-grade gliomas are the most malignant primary brain tumours. Conventional therapies include surgery, radiotherapy, and chemotherapy. The tumours often demonstrate high levels of resistance to these conventional therapies, and in spite of treatment advances the prognosis remains poor. PMID:23304556

  14. 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

  15. A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

    SciTech Connect

    Wuthrick, Evan J.; Curran, Walter J.; Camphausen, Kevin; Lin, Alexander; Glass, Jon; Evans, James; Andrews, David W.; Axelrod, Rita; Shi, Wenyin; Werner-Wasik, Maria; Haacke, E. Mark; Hillman, Gilda G.; Dicker, Adam P.

    2014-10-01

    Purpose/Objective(s): Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Methods and Materials: Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acute toxicity, and response was assessed via serial magnetic resonance imaging. Results: Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Conclusions: Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival.

  16. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas.

    PubMed

    Lasky, Joseph L; Panosyan, Eduard H; Plant, Ashley; Davidson, Tom; Yong, William H; Prins, Robert M; Liau, Linda M; Moore, Theodore B

    2013-05-01

    Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1 × 10(6) cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required. PMID:23645755

  17. Autologous Tumor Lysate-pulsed Dendritic Cell Immunotherapy for Pediatric Patients with Newly Diagnosed or Recurrent High-grade Gliomas

    PubMed Central

    Lasky, Joseph L.; Panosyan, Eduard H.; Plant, Ashley; Davidson, Tom; Yong, William H.; Prins, Robert M.; Liau, Linda M.; Moore, Theodore B.

    2014-01-01

    Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1×106 cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required. PMID:23645755

  18. Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas: part II.

    PubMed

    Imahori, Y; Ueda, S; Ohmori, Y; Sakae, K; Kusuki, T; Kobayashi, T; Takagaki, M; Ono, K; Ido, T; Fujii, R

    1998-08-01

    Based on pharmacokinetic findings of fluorine-18-labeled L-fluoroboronophenylalanine by positron emission tomography (PET), methods for estimating tumor 10B concentration were devised. In clinical practice of boron neutron capture therapy (BNCT) for high-grade gliomas, a large amount of L-boronophenylalanine (L-10B-BPA)-fructose solution is used. Under these conditions, a slow i.v. infusion of L-10B-BPA-fructose solution should be performed for BNCT; therefore, the changes over time in 10B concentration in the target tissue were estimated by convoluting the actual time course of changes in plasma 10B concentration with a PET-based weight function including the proper rate constants [K1 (ml/g/min), k2 (min(-1)), k3 (min(-1)), and k4 (min(-1))]. With this method, the estimated values of 10B concentration in gliomas were very close to the 10B levels in surgical specimens. This demonstrated the similarity in pharmacokinetics between fluorine-18-labeled L-fluoroboronophenylalanine and L-10B-BPA. This method, using the appropriate rate constant, permits the determination of tumor 10B concentration and is widely suitable for clinical BNCT, because the averaged PET data are enough to use in future patients without individual PET study.

  19. 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

    2016-01-01

    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

  20. 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

  1. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas.

    PubMed

    Lasky, Joseph L; Panosyan, Eduard H; Plant, Ashley; Davidson, Tom; Yong, William H; Prins, Robert M; Liau, Linda M; Moore, Theodore B

    2013-05-01

    Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1 × 10(6) cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required.

  2. 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.

  3. Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib

    SciTech Connect

    Kinsella, Paula; Howley, Rachel; Doolan, Padraig; Clarke, Colin; Madden, Stephen F.; Clynes, Martin; Farrell, Michael; Amberger-Murphy, Verena

    2012-03-10

    High-grade gliomas (HGG), are the most common aggressive brain tumours in adults. Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate. To accurately evaluate response to targeted therapies further in vitro studies are necessary. Growth factor pathway expression using epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), platelet derived growth factor receptor (PDGFR), C-Kit and C-Abl together with phosphatase and tensin homolog (PTEN) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 (P70S6K) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and imatinib. Response to TKIs was assessed using 50% inhibitory concentrations (IC{sub 50}). Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis (HCA) and principal component analysis (PCA). Erlotinib response was not strongly associated with high expression of the growth factor pathway components. PTEN expression did not correlate with response to any of the three TKIs. Increased EGFR expression was associated with gefitinib response; increased PDGFR-{alpha} expression was associated with imatinib response. The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile. -- Highlights: Black-Right-Pointing-Pointer Non-responders had low EGFR expression, high PDGFR-{beta}, and a low proliferation rate. Black-Right-Pointing-Pointer PTEN is not indicative of response to a TKI. Black-Right-Pointing-Pointer Erlotinib response was not associated with expression of the proteins examined. Black-Right-Pointing-Pointer Imatinib-response correlated with expression of PDGFR-{alpha}. Black-Right-Pointing-Pointer Gefitinib response correlated with increased expression of EGFR.

  4. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas.

    PubMed

    Lamborn, Kathleen R; Yung, W K Alfred; Chang, Susan M; Wen, Patrick Y; Cloughesy, Timothy F; DeAngelis, Lisa M; Robins, H Ian; Lieberman, Frank S; Fine, Howard A; Fink, Karen L; Junck, Larry; Abrey, Lauren; Gilbert, Mark R; Mehta, Minesh; Kuhn, John G; Aldape, Kenneth D; Hibberts, Janelle; Peterson, Pamela M; Prados, Michael D

    2008-04-01

    The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.

  5. BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma

    PubMed Central

    Mistry, Matthew; Zhukova, Nataliya; Merico, Daniele; Rakopoulos, Patricia; Krishnatry, Rahul; Shago, Mary; Stavropoulos, James; Alon, Noa; Pole, Jason D.; Ray, Peter N.; Navickiene, Vilma; Mangerel, Joshua; Remke, Marc; Buczkowicz, Pawel; Ramaswamy, Vijay; Guerreiro Stucklin, Ana; Li, Martin; Young, Edwin J.; Zhang, Cindy; Castelo-Branco, Pedro; Bakry, Doua; Laughlin, Suzanne; Shlien, Adam; Chan, Jennifer; Ligon, Keith L.; Rutka, James T.; Dirks, Peter B.; Taylor, Michael D.; Greenberg, Mark; Malkin, David; Huang, Annie; Bouffet, Eric; Hawkins, Cynthia E.; Tabori, Uri

    2015-01-01

    Purpose To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). Patients and Methods We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. Results sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). Conclusion BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG. PMID:25667294

  6. Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children’s Cancer Group high-grade glioma study CCG-945

    PubMed Central

    Pollack, Ian F.; Demers, Alain; Sapp, Mark V.; Lambert, Pascal; Weisfeld-Adams, James D.; Burger, Peter C.; Gilles, Floyd; Davis, Richard L.; Packer, Roger; Boyett, James M.

    2015-01-01

    Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children’s Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG. PMID:25431150

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

    NASA Astrophysics Data System (ADS)

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

    1997-05-01

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

  8. Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer

    PubMed Central

    2012-01-01

    Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, the United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or “BPA”, and sodium borocaptate or “BSH” (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized

  9. Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer.

    PubMed

    Barth, Rolf F; Vicente, M Graca H; Harling, Otto K; Kiger, W S; Riley, Kent J; Binns, Peter J; Wagner, Franz M; Suzuki, Minoru; Aihara, Teruhito; Kato, Itsuro; Kawabata, Shinji

    2012-08-29

    Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials

  10. Fractionated stereotactic radiotherapy plus bevacizumab after response to bevacizumab plus irinotecan as a rescue treatment for high-grade gliomas

    PubMed Central

    Conde-Moreno, Antonio José; García-Gómez, Raquel; Albert-Antequera, María; Almendros-Blanco, Piedad; De Las Peñas-Bataller, Ramón; González-Vidal, Verónica; López-Torrecilla, José Luis; Ferrer-Albiach, Carlos

    2015-01-01

    Aim To evaluate the possibility of implementing a new scheme of rescue treatment after relapse or progression of high-grade glioma (HGG) treated at the first-line with bevacizumab and irinotecan (BVZ+CPT11), evaluating the response and toxicity of associating BVZ and fractionated stereotactic radiotherapy (BVZ+FSRT). Materials and methods We retrospectively analysed data from 59 patients with relapse of HGG. Nine patients with HGG relapse after treatment using the Stupp protocol that were treated with BVZ+CPT11 for progression between July 2007 and August 2012, after which the response was assessed according to the Revised Assessment in Neuro-Oncology (RANO) criteria. BVZ was administered at a dose of 10 mg/kg and FSRT up to a prescribed dose of 30 Gy, 500 cGy per fraction, three days a week. The median follow-up was 38 months. Results The treatment was well-tolerated by all patients. The response after nuclear magnetic resonance imaging (MRI) at 3–6 months was progression in two patients, stable disease in four, and three patients had a partial response. The median overall survival (OS) from diagnosis until death or the last control was 36.8 months. The median progression-free survival (PFS) was 10.8 months. The results from tumour sub-group analysis indicated that the PFS was not statistically significant although it seemed that it was higher in grade-III. The OS was higher in grade-III gliomas. Conclusions The combination of BVZ+FSRT as a second-line HGG relapse rescue treatment is well-tolerated and seems to offer promising results. We believe that multi-centre prospective studies are needed to determine the long-term efficacy and toxicity of this therapeutic approach. PMID:25949228

  11. The Impact of Adjuvant Radiation Therapy for High-Grade Gliomas by Histology in the United States Population

    SciTech Connect

    Rusthoven, Chad G.; Carlson, Julie A.; Waxweiler, Timothy V.; Dally, Miranda J.; Barón, Anna E.; Yeh, Norman; Gaspar, Laurie E.; Liu, Arthur K.; Ney, Douglas E.; Damek, Denise M.; Lillehei, Kevin O.; Kavanagh, Brian D.

    2014-11-15

    Purpose: To compare the survival impact of adjuvant external beam radiation therapy (RT) for malignant gliomas of glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and mixed anaplastic oligoastrocytoma (AOA) histology. Methods and Materials: The Surveillance, Epidemiology, and End Results (SEER) database was queried from 1998 to 2007 for patients aged ≥18 years with high-grade gliomas managed with upfront surgical resection, treated with and without adjuvant RT. Results: The primary analysis totaled 14,461 patients, with 12,115 cases of GBM (83.8%), 1312 AA (9.1%), 718 AO (4.9%), and 316 AOA (2.2%). On univariate analyses, adjuvant RT was associated with significantly improved overall survival (OS) for GBMs (2-year OS, 17% vs 7%, p<.001), AAs (5-year OS, 38% vs 24%, p<.001), and AOAs (5-year OS, 55% vs 44%, p=.026). No significant differences in OS were observed for AOs (5-year OS, with RT 50% vs 56% without RT, p=.277). In multivariate Cox proportional hazards models accounting for extent of resection, age, sex, race, year, marital status, and tumor registry, RT was associated with significantly improved OS for both GBMs (HR, 0.52; 95% CI, 0.50-0.55; P<.001) and AAs (HR, 0.57; 95% CI, 0.48-0.68; P<.001) but only a trend toward improved OS for AOAs (HR, 0.70; 95% CI, 0.45-1.09; P=.110). Due to the observation of nonproportional hazards, Cox regressions were not performed for AOs. A significant interaction was observed between the survival impact of RT and histology overall (interaction P<.001) and in a model limited to the anaplastic (WHO grade 3) histologies. (interaction P=.024), characterizing histology as a significant predictive factor for the impact of RT. Subgroup analyses demonstrated greater hazard reductions with RT among patients older than median age for both GBMs and AAs (all interaction P≤.001). No significant interactions were observed between RT and extent of resection. Identical patterns of significance were

  12. Incidence and management of high grade glioma in Māori and non-Māori patients.

    PubMed

    Alexander, Hamish; Irwin, Chris; Purdie, Gordon; Hunn, Martin

    2010-09-01

    A retrospective analysis of 301 patients was undertaken between 1993 and 2003 to evaluate the relationship of ethnicity with incidence, treatment and survival in patients undergoing surgery for high grade glioma (HGG) in New Zealand. There was no difference in age standardised incidence of HGG in Māori compared to non-Māori patients; 4.2/100,000 person years (95% confidence interval [CI] 2.6-6.9) versus 4.1 (95% CI 3.6-4.6). Māori were more likely to have complete tumour resection (odds ratio 3.59 (95% CI 1.01-12.76)) but waited 1.32 (95% CI 0.98-1.79) times longer for radiotherapy. Median survival was 29 weeks with poorer survival in Māori compared to non-Māori (hazard ratio 1.55 [95% CI 0.95-2.55]). We concluded that the incidence of HGG in Māori is similar to non-Maori. However, Māori with HGG have higher rates of complete resection but wait longer for radiotherapy and may have poorer overall survival than non-Māori.

  13. Phase II Trial of Radiotherapy After Hyperbaric Oxygenation With Multiagent Chemotherapy (Procarbazine, Nimustine, and Vincristine) for High-Grade Gliomas: Long-Term Results

    SciTech Connect

    Ogawa, Kazuhiko; Ishiuchi, Shogo; Inoue, Osamu; Yoshii, Yoshihiko; Saito, Atsushi; Watanabe, Takashi; Iraha, Shiro; Toita, Takafumi; Kakinohana, Yasumasa; Ariga, Takuro; Kasuya, Goro; Murayama, Sadayuki

    2012-02-01

    Purpose: To analyze the long-term results of a Phase II trial of radiotherapy given immediately after hyperbaric oxygenation (HBO) with multiagent chemotherapy in adults with high-grade gliomas. Methods and Materials: Patients with histologically confirmed high-grade gliomas were administered radiotherapy in daily 2 Gy fractions for 5 consecutive days per week up to a total dose of 60 Gy. Each fraction was administered immediately after HBO, with the time interval from completion of decompression to start of irradiation being less than 15 minutes. Chemotherapy consisting of procarbazine, nimustine, and vincristine and was administered during and after radiotherapy. Results: A total of 57 patients (39 patients with glioblastoma and 18 patients with Grade 3 gliomas) were enrolled from 2000 to 2006, and the median follow-up of 12 surviving patients was 62.0 months (range, 43.2-119.1 months). All 57 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. The median overall survival times in all 57 patients, 39 patients with glioblastoma and 18 patients with Grade 3 gliomas, were 20.2 months, 17.2 months, and 113.4 months, respectively. On multivariate analysis, histologic grade alone was a significant prognostic factor for overall survival (p < 0.001). During treatments, no patients had neutropenic fever or intracranial hemorrhage, and no serious nonhematologic or late toxicities were seen in any of the 57 patients. Conclusions: Radiotherapy delivered immediately after HBO with multiagent chemotherapy was safe, with virtually no late toxicities, and seemed to be effective in patients with high-grade gliomas.

  14. A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

    SciTech Connect

    Den, Robert B.; Kamrava, Mitchell; Sheng, Zhi; Werner-Wasik, Maria; Dougherty, Erin; Marinucchi, Michelle; Lawrence, Yaacov R.; Hegarty, Sarah; Hyslop, Terry; Andrews, David W.; Glass, Jon; Friedman, David P.; Green, Michael R.; Camphausen, Kevin; Dicker, Adam P.

    2013-02-01

    Purpose: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. Methods and Materials: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m{sup 2}) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Results: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. Conclusions: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

  15. Differences in the architecture of low-grade and high-grade gliomas evaluated using fiber density index and fractional anisotropy.

    PubMed

    Chen, Yiyong; Shi, Yonghong; Song, Zhijian

    2010-07-01

    Accurate pre-operative assessment of tumor grade is important for the selection of appropriate treatment strategies. The aim of this study was to retrospectively evaluate whether the fiber density index (FDi) and fractional anisotropy (FA) via diffusion tensor MRI (DTI) could assist with pre-operative diagnosis of glioma grade. A total of 31 patients who had histologically confirmed gliomas underwent DTI performed using a 1.5-Tesla magnetic resonance scanner. To reconstruct the white matter adjacent to the tumor, DTI fiber tracking (DTI-FT) using an FA threshold of 0.15 was implemented. Regions of interest (ROIs) were defined (i-iv) as: the tumor center (ROI i); white matter adjacent to the tumor (ROI ii); contralateral centrum semiovale (ROI iii); and the homologous fiber tracts to ROI ii in the contralateral hemisphere (ROI iv). We calculated six parameters from different ROIs and compared high-grade and low-grade gliomas: FA values and ratios; FDi values and ratios with an FA threshold of 0.15; and FDi values and ratios with an FA threshold of 0.25. The results showed that FA ratios and FDi ratios with FA thresholds of 0.25 were significantly different between patients with high-grade and low-grade gliomas. This may be useful for developing surgical strategies and appraising patient prognosis.

  16. Prognostic significance of S-phase fractions in peritumoral invading zone analyzed by laser scanning cytometry in patients with high-grade glioma: A preliminary study

    PubMed Central

    NAKAJIMA, SYOICHI; MORII, KEN; TAKAHASHI, HITOSHI; FUJII, YUKIHIKO; YAMANAKA, RYUYA

    2016-01-01

    The predominant characteristic of malignant glioma is the presence of invading tumor cells in the peritumoral zone. Distinguishing between tumor cells and normal cells in a peritumoral lesion is challenging. Therefore, the aim of the present study was to investigate the cell-cycle phase measurements of fixed paraffin-embedded specimens from the peritumoral invading zone of high-grade gliomas using laser scanning cytometry. A total of 12 high-grade gliomas (2 anaplastic astrocytomas and 10 glioblastomas) were studied. The tumor core and peritumoral invading zone of each tumor specimen were investigated. Tissue sections (50 µm) from the paraffin blocks were deparaffinized, rehydrated and enzymatically disintegrated, and the cells in suspension were stained with propidium iodide and placed on microscope slides. A slight trend for an increased S-phase fraction in the peritumoral invading zone compared with the tumor core was observed (P=0.24). Additionally, there was a trend for a decrease in the overall survival time of patients with increasing peritumoral invading zone S-phase fraction (P=0.12). These data suggest that laser scanning cytometry is a powerful and clinically relevant tool for the objective analysis of the cell cycle in malignant gliomas. PMID:26998130

  17. Clinical and Dosimetric Predictors of Acute Severe Lymphopenia During Radiation Therapy and Concurrent Temozolomide for High-Grade Glioma

    SciTech Connect

    Huang, Jiayi; DeWees, Todd A.; Badiyan, Shahed N.; Speirs, Christina K.; Mullen, Daniel F.; Fergus, Sandra; Tran, David D.; Linette, Gerry; Campian, Jian L.; Chicoine, Michael R.; Kim, Albert H.; Dunn, Gavin; Simpson, Joseph R.; Robinson, Clifford G.

    2015-08-01

    Purpose: Acute severe lymphopenia (ASL) frequently develops during radiation therapy (RT) and concurrent temozolomide (TMZ) for high-grade glioma (HGG) and is associated with decreased survival. The current study was designed to identify potential predictors of ASL, with a focus on actionable RT-specific dosimetric parameters. Methods and Materials: From January 2007 to December 2012, 183 patients with HGG were treated with RT+TMZ and had available data including total lymphocyte count (TLC) and radiation dose-volume histogram parameters. ASL was defined as TLC of <500/μL within the first 3 months from the start of RT. Stepwise logistic regression analysis was used to determine the most important predictors of ASL. Results: Fifty-three patients (29%) developed ASL. Patients with ASL had significantly worse overall survival than those without (median: 12.5 vs 20.2 months, respectively, P<.001). Stepwise logistic regression analysis identified female sex (odds ratio [OR]: 5.30; 95% confidence interval [CI]: 2.46-11.41), older age (OR: 1.05; 95% CI: 1.02-1.09), lower baseline TLC (OR: 0.92; 95% CI: 0.87-0.98), and higher brain volume receiving 25 Gy (V{sub 25Gy}) (OR: 1.03; 95% CI: 1.003-1.05) as the most significant predictors for ASL. Brain V{sub 25Gy} <56% appeared to be the optimal threshold (OR: 2.36; 95% CI: 1.11-5.01), with an ASL rate of 38% versus 20% above and below this threshold, respectively (P=.006). Conclusions: Female sex, older age, lower baseline TLC, and higher brain V{sub 25Gy} are significant predictors of ASL during RT+TMZ therapy for HGG. Maintaining the V{sub 25Gy} of brain below 56% may reduce the risk of ASL.

  18. Coping with a newly diagnosed high-grade glioma: patient-caregiver dyad effects on quality of life.

    PubMed

    Baumstarck, K; Leroy, T; Hamidou, Z; Tabouret, E; Farina, P; Barrié, M; Campello, C; Petrirena, G; Chinot, O; Auquier, P

    2016-08-01

    Patients with high-grade gliomas (HGG) and their caregivers have to confront a very aggressive disease that produces major lifestyle disruptions. There is an interest in studying the ability of patients and their caregivers to cope with the difficulties that affect quality of life (QoL). We examine, in a sample of patient-caregiver dyads in the specific context of newly diagnosed cases of HGG, whether the QoL of patients and caregivers is influenced by the coping processes they and their relatives use from a specific actor-partner interdependence model (APIM). This cross-sectional study involved 42 dyads with patients having recent diagnoses of HGG and assessed in the time-frame between diagnosis and treatment initiation. The self-reported data included QoL (Patient-Generated Index, EORTC QLQ-C30, and CareGiver Oncology QoL), emotional status, and coping strategies (BriefCope). The APIM was used to test the dyadic effects of coping strategies on QoL. Coping strategies, such as social support, avoidance, and problem solving, exhibited evidence of either an actor effect (degree to which the individual's coping strategies are associated with their own QoL) or partner effect (degree to which the individual's coping strategies are associated with the QoL of the other member of the dyad) for patients or caregivers. For positive-thinking coping strategies, actor and partner effect were not observed. This study emphasizes that the QoL for patients and their caregivers was directly related to the coping strategies they used. This finding suggests that targeted interventions should be offered to help patients and their relatives to implement more effective coping strategies. PMID:27300523

  19. Living longer with adult high-grade glioma: setting a research agenda for patients and their caregivers.

    PubMed

    Russell, Bethany; Collins, Anna; Dally, Michael; Dowling, Anthony; Gold, Michelle; Murphy, Michael; Philip, Jennifer

    2014-10-01

    The long-term survival of patients with adult high-grade glioma (HGG) remains poor, but for those who do live longer functional status and neurocognitive ability may be influenced by residual or recurrent tumour, or treatment-related complications. The aim of this review was to examine the current literature regarding the quality of life and experience of patients living longer with adult HGG and their caregivers, with a view to understanding the burden of treatment on patient abilities and deficits over time. Medline, PsychINFO and CINAHL databases were searched for the core concept of HGG in combination with an aspect of quality of long-term survival. Key findings of the 12 included studies were identified and synthesised thematically. There is a paucity of dedicated studies which have investigated the experiences of this cohort. The strength of existing literature is limited by the systematic exclusion of the poorest functioning patients and the under-representation of caregiver perspectives. Discrepancies in how patients view their quality of life were highlighted, despite consistent findings of significant physical and functional impairment. This review confirmed the presence of important differences between patient and caregiver views regarding patient abilities following treatment. Caregiver burden was found to be high, due to multiple dynamic and relentless stressors. The true experience of patients living longer with adult HGG and their caregivers remains unclear, particularly for patients with poorer neurocognitive and functional outcomes. Further research is required to clarify and replicate findings, explore discrepancies between patient and caregiver views, and to specifically investigate how caregiver needs and experiences may evolve over time. PMID:24980038

  20. Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas

    PubMed Central

    Qaddoumi, Ibrahim; Kocak, Mehmet; Pai Panandiker, Atmaram S.; Armstrong, Gregory T.; Wetmore, Cynthia; Crawford, John R.; Lin, Tong; Boyett, James M.; Kun, Larry E.; Boop, Fredrick A.; Merchant, Thomas E.; Ellison, David W.; Gajjar, Amar; Broniscer, Alberto

    2014-01-01

    Background: Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG). Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy (RT) in children with newly diagnosed HGG. Methods: Following maximum surgical resection, patients between 3 and 21 years with non-metastatic HGG received local RT at 59.4 Gy (54 Gy for spinal tumors and those with ≥70% brain involvement). Erlotinib started on day 1 of RT (120 mg/m2 per day) and continued for 2 years unless there was tumor progression or intolerable toxicities. The 2-year progression-free survival (PFS) was estimated for patients with intracranial anaplastic astrocytoma (AA) and glioblastoma (GBM). Results: Median age at diagnosis for 41 patients with intracranial tumors (21 with GBM and 20 with AA) was 10.9 years (range, 3.3–19 years). The 2-year PFS for patients with AA and GBM was 15 ± 7 and 19 ± 8%, respectively. Only five patients remained alive without tumor progression. Twenty-six patients had at least one grade 3 or 4 toxicity irrespective of association with erlotinib; only four required dose modifications. The main toxicities were gastrointestinal (n = 11), dermatologic (n = 5), and metabolic (n = 4). One patient with gliomatosis cerebri who required prolonged corticosteroids died of septic shock associated with pancreatitis. Conclusion: Although therapy with erlotinib was mostly well-tolerated, it did not change the poor outcome of our patients. Our results showed that erlotinib is not a promising medication in the treatment of children with intracranial AA and GBM. PMID:24744992

  1. Patterns of Failure After Concurrent Bevacizumab and Hypofractionated Stereotactic Radiation Therapy for Recurrent High-Grade Glioma

    SciTech Connect

    Shapiro, Lauren Q.; Beal, Kathryn; Goenka, Anuj; Karimi, Sasan; Iwamoto, Fabio M.; Yamada, Yoshiya; Zhang, Zhigang; Lassman, Andrew B.; Abrey, Lauren E.; Gutin, Philip H.

    2013-03-01

    Purpose: Concurrent bevacizumab with hypofractionated stereotactic radiation therapy (HSRT) is safe and effective for the treatment of recurrent high-grade gliomas (HGG). The objective of this study was to characterize the patterns of failure after this treatment regimen. Methods and Materials: Twenty-four patients with recurrent enhancing HGG were previously treated on an institutional review board-approved protocol of concurrent bevacizumab and reirradiation. Patients received 30 Gy in 5 fractions to the recurrent tumor with HSRT. Brain magnetic resonance imaging (MRI) was performed every 2 cycles, and bevacizumab was continued until clinical or radiographic tumor progression according to the criteria of Macdonald et al. MRI at the time of progression was fused to the HSRT treatment plan, and the location of recurrence was classified on the basis of volume within the 95% isodose line. Outcomes based on patient characteristics, tumor grade, recurrence pattern, and best response to treatment were analyzed by the Kaplan-Meier method. Results: Twenty-two patients experienced either clinical or radiographic progression. Recurrent tumor was enhancing in 15 (71.4%) and nonenhancing in 6 (28.6%) patients. Eleven patients (52.4%) had recurrence within the radiation field, 5 patients (23.8%) had marginal recurrence, and 5 patients had recurrence outside the radiation field. Pattern of enhancement and location of failure did not correlate with overall survival or progression-free survival. Radiographic response was the only variable to significantly correlate with progression-free survival. Conclusions: Despite the promising initial response seen with the addition of HSRT to bevacizumab as salvage treatment for recurrent HGG, approximately half of patients ultimately still experience failure within the radiation field. The rate of local failure with the addition of HSRT seems to be lower than that seen with bevacizumab alone in the salvage setting. Our data underscore the

  2. Altered expression of MGMT in high-grade gliomas results from the combined effect of epigenetic and genetic aberrations.

    PubMed

    Ramalho-Carvalho, João; Pires, Malini; Lisboa, Susana; Graça, Inês; Rocha, Patrícia; Barros-Silva, João Diogo; Savva-Bordalo, Joana; Maurício, Joaquina; Resende, Mário; Teixeira, Manuel R; Honavar, Mrinalini; Henrique, Rui; Jerónimo, Carmen

    2013-01-01

    MGMT downregulation in high-grade gliomas (HGG) has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP) or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA). By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation) and genetic (monosomy, locus deletion) changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy.

  3. Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas

    PubMed Central

    Barrow, Jennifer; Adamowicz-Brice, Martyna; Cartmill, Maria; MacArthur, Donald; Lowe, James; Robson, Keith; Brundler, Marie-Anne; Walker, David A.; Coyle, Beth; Grundy, Richard

    2011-01-01

    Overall, pediatric high-grade glioma (pHGG) has a poor prognosis, in part due to the lack of understanding of the underlying biology. High-resolution 244 K oligo array comparative genomic hybridization (CGH) was used to analyze DNA from 38 formalin-fixed paraffin-embedded predominantly pretreatment pHGG samples, including 13 diffuse intrinsic pontine gliomas (DIPGs). The patterns of gains and losses were distinct from those seen in HGG arising in adults. In particular, we found 1q gain in up to 27% of our cohort compared with 9% reported in adults. A total of 13% had a balanced genetic profile with no large-scale copy number alterations. Homozygous loss at 8p12 was seen in 6 of 38 (16%) cases of pHGG. This novel deletion, which includes the ADAM3A gene, was confirmed by quantitative real-time PCR (qPCR). Loss of CDKN2A/CDKN2B in 4 of 38 (10%) samples by oligo array CGH was confirmed by fluorescent in situ hybridization on tissue microarrays and was restricted to supratentorial tumors. Only ∼50% of supratentorial tumors were positive for CDKN2B expression by immunohistochemistry (IHC), while ∼75% of infratentorial tumors were positive for CDKN2B expression (P = 0.03). Amplification of the 4q11–13 region was detected in 8% of cases and included PDGFRA and KIT, and subsequent qPCR analysis was consistent with the amplification of PDGFRA. MYCN amplification was seen in 5% of samples being significantly associated with anaplastic astrocytomas (P= 0.03). Overall, DIPG shared similar spectrum of changes to supratentorial HGG with some notable differences, including high-frequency loss of 17p and 14q and lack of CDKN2A/CDKN2B deletion. Informative genetic data providing insight into the underlying biology and potential therapeutic possibilities can be generated from archival tissue and typically small biopsies from DIPG. Our findings highlight the importance of obtaining pretreatment samples. PMID:21138945

  4. Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: a children's Oncology Group Study ACNS1021.

    PubMed

    Wetmore, Cynthia; Daryani, Vinay M; Billups, Catherine A; Boyett, James M; Leary, Sarah; Tanos, Rachel; Goldsmith, Kelly C; Stewart, Clinton F; Blaney, Susan M; Gajjar, Amar

    2016-07-01

    Sunitinib malate is a small multi-targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high-grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high-grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression-free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high-grade glioma. Most adverse events were of mild-to-moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high-grade glioma or ependymoma but had no single agent objective antitumor activity in these patients. PMID:27109549

  5. Association between small heat shock protein B11 and the prognostic value of MGMT promoter methylation in patients with high-grade glioma.

    PubMed

    Cheng, Wen; Li, Mingyang; Jiang, Yang; Zhang, Chuanbao; Cai, Jinquan; Wang, Kuanyu; Wu, Anhua

    2016-07-01

    OBJECT This study investigated the role and prognostic value of heat shock proteins (HSPs) in glioma. METHODS Data from 3 large databases of glioma samples (Chinese Glioma Genome Atlas, Repository for Molecular Brain Neoplasia Data, and GSE16011), which contained whole-genome messenger RNA microarray expression data and patients' clinical data, were analyzed. Immunohistochemical analysis was performed to validate protein expression in another set of 50 glioma specimens. RESULTS Of 28 HSPs, 11 were overexpressed in high-grade glioma (HGG) compared with low-grade glioma. A univariate Cox analysis revealed that HSPB11 has significant prognostic value for each glioma grade, which was validated by a Kaplan-Meier survival analysis. HSPB11 expression was associated with poor prognosis and was independently correlated with overall survival (OS) in HGG. This study further explored the combined role of HSPB11 and other molecular markers in HGG, such as isocitrate dehydrogenase 1 (IDH1) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. HSPB11 expression was able to refine the prognostic value of IDH1 mutation in patients with HGG. However, when combined with MGMT promoter methylation status, among patients with a methylated MGMT promoter, those with lower levels of HSPB11 expression had longer OS and progression-free survival than patients with higher levels of HSPB11 expression or with an unmethylated MGMT promoter. Moreover, within the MGMT promoter methylation group, patients with low levels of HSPB11 expression were more sensitive to combined radiochemotherapy than those with high levels of HSPB11 expression, which may explain why some patients with HGG with a methylated MGMT promoter show tolerance to radiochemotherapy. CONCLUSIONS HSPB11 was identified as a novel prognostic marker in patients with HGG. Together with MGMT promoter methylation status, HSPB11 expression can predict outcome for patients with HGG and identify those who

  6. Downregulation of miR-137 and miR-6500-3p promotes cell proliferation in pediatric high-grade gliomas

    PubMed Central

    Ng, Kim-Hai; Tsai, Ya-Ni; Tsai, Cheng-Fong; Chao, Meng-En; Liu, Da-Jung; Chu, Shing-Shiung; Chen, Wan; Liu, Yun-Ru; Liu, Ren-Shyan; Lin, Shih-Chieh; Ho, Donald Ming-Tak; Wong, Tai-Tong; Yang, Muh-Hwa; Wang, Hsei-Wei

    2016-01-01

    Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors affecting children, and outcomes have remained dismal, even with access to new multimodal therapies. In this study, we compared the miRNomes and transcriptomes of pediatric low- (pLGGs) and high-grade gliomas (pHGGs) using small RNA sequencing (smRNA-Seq) and gene expression microarray, respectively. Through integrated bioinformatics analyses and experimental validation, we identified miR-137 and miR-6500-3p as significantly downregulated in pHGGs. miR-137 or miR-6500-3p overexpression reduced cell proliferation in two pHGG cell lines, SF188 and UW479. CENPE, KIF14 and NCAPG levels were significantly higher in pHGGs than pLGGs, and were direct targets of miR-137 or miR-6500-3p. Furthermore, knockdown of CENPE, KIF14 or NCAPG combined with temozolomide treatment resulted in a combined suppressive effect on pHGG cell proliferation. In summary, our results identify novel mRNA/miRNA interactions that contribute to pediatric glioma malignancy and represent potential targets for the development of new therapeutic strategies. PMID:26933822

  7. P17.27HIGH GRADE GLIOMAS IN ELDERLY PATIENTS: RESULTS OF SURGERY AND INFLUENCE ON KARNOFSKY'S PERFORMANCE STATUS

    PubMed Central

    Agnoletti, A.; Fornaro, R.; Specchia, F.M. Calamo; Garbossa, D.; Lanotte, M.; Ducati, A.

    2014-01-01

    The management of high grade gliomas (HGG) is complex and multidisciplinar. It has been demonstrated that the extent of resection, achieving gross total volume removal (GTR) has a relevant impact on progression free survival (PFS) and on overall survival (OS). Many strategies have been proven to be effective in achieving GTR such as neuronavigation, fluorescence and intra operative ultra sonography. It is remarkable to say that in multicentric trials, often elderly patients were excluded. Recently the interest in results of surgery in elderly patients has grown, and some studies proved the feasibility and advantages of a surgical resection of HGG in elderly patients. We retrospectively analyzed 73 elderly patients (age at diagnosis at least 70 years old) that were affected by HGG in non eloquent areas, therefore amenable to radical surgical excision, that underwent surgical resection in Our division from January 2008 to December 2012. KPS prior to surgery, post surgery and a month after was assessed. OBJECTIVE: Assess the role of surgery on variation of KPS in elderly patients. Materials and methods: we retrospectively analyzed 73 patients, 42 males (57%), 32 ( 43%) females, age range 70-84, mean age 73.87 years old, that underwent surgical excision of newly diagnosed HGG in Our division from January 2008 to December 2012. KPS assessment was performed prior to surgery, and a month after surgery, before adjuvant therapies administration. RESULTS: From data analysis, mean KPS pre-op was 82.5 (overall); mean KPS post operatory (1 month) was 84.5 (overall). 35/73 (47.9%) patients experienced no change in KPS. 24/73 (32%) improved their KPS score, 14/72 (19%) worsened their KPS score. Of the 14 patients which had a worsening in KPS, one month after surgery (before adjuvant treatment), 8 patients recovered, improving their KPS score, which was similar to pre operatory evaluation. The 35 patients that had stability of KPS after surgery, at 1 month after, did not worse

  8. Dynamics of circulating gamma delta T cell activity in an immunocompetent mouse model of high-grade glioma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 m...

  9. IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas

    PubMed Central

    Moore, Lynette M.; Holmes, Kristen M.; Smith, Sarah M.; Wu, Ying; Tchougounova, Elena; Uhrbom, Lene; Sawaya, Raymond; Bruner, Janet M.; Fuller, Gregory N.; Zhang, Wei

    2009-01-01

    The levels of insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for glioma progression in combination with platelet-derived growth factor-β (PDGFB). Because the INK4a-ARF locus is often deleted in high-grade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous tumor cell IGFBP2. An inverse relationship between p16INK4a and IGFBP2 expression was also observed in human glioma tissue samples and in 90 different cancer cell lines by using Western blotting and reverse-phase protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of anaplastic oligodendroglioma as well as prolonged survival was observed. Thus, p16INK4a is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted gliomas. PMID:19805356

  10. A prospective multicenter study of venous thromboembolism in patients with newly-diagnosed high-grade glioma: hazard rate and risk factors

    PubMed Central

    Ye, Xiaobu; Kickler, Thomas S.; Desideri, Serena; Jani, Jayesh; Fisher, Joy; Grossman, Stuart A.

    2015-01-01

    Venous thromboembolism (VTE) is a common complication in patients with high-grade gliomas. The purpose of this prospective multicenter study was to determine the hazard rate of first symptomatic VTE in newly-diagnosed glioma patients and identify clinical and laboratory risk factors. On enrollment, demographic and clinical information were recorded and a comprehensive coagulation evaluation was performed. Patients were followed until death. The study end point was objectively-documented symptomatic VTE. One hundred seven patients were enrolled with a median age of 57 years (range 29–85) between June 2005 and April 2008. Ninety-one (85 %) had glioblastoma multiforme (GBM). During an average survival of 17.7 months, 26 patients (24 %) (95 % CI 17–34 %) developed VTE (hazard rate 0.15 per person-year) and 94 patients (88 %) died. Median time to VTE was 14.2 weeks post-operation (range 3–126). Patients with an initial tumor biopsy were 3.0 fold more likely to suffer VTE (p = 0.02). Patients with an elevated factor VIII activity (>147 %) were 2.1-fold more likely to develop VTE. ABO blood group, D dimer and thrombin generation were not associated with VTE. No fatal VTE occurred. VTE is a common complication in patients with newly-diagnosed high grade gliomas, particularly in the first six months after diagnosis. Patients with an initial tumor biopsy and elevated factor VIII levels are at increased risk. However, VTE was not judged to be pri-marily responsible for any patient deaths. Therefore, out-patient primary VTE prophylaxis remains investigational until more effective primary prophylaxis strategies and therapies for glioma are identified. PMID:26100546

  11. 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

  12. First Experience of Intraoperative Radiation Therapy in Cerebral High Grade Glioma in Iran: A Report of Three Cases and Literature Review

    PubMed Central

    Seddighi, Afsoun; Esmaeil Akbari, Mohammad; Seddighi, Amir Saied; Rakhsha, Afshin; Vaezi, Marjan; Zohrevand, Amir Hossein

    2015-01-01

    Introduction: Among the high grade cerebral gliomas, Glioblastoma multiform for instance, would be the main pattern of local recurrence causes clinical deterioration and deaths. This has observed 2 - 3 cm upon the initial lesion. During the period of 2 - 4 weeks post-surgery, remaining tumor cells have re-grown until radiochemotherapy has initiated. So it has seemed clear that improved local control could hopefully translate into improved survival. As a matter of fact, mass reduction has insufficiently achieved in almost every case of GBM as that the tumor cell number has not fallen below a “threshold” that tumor control might achieve by the host immune system. Intraoperative Radiation therapy has been one of those add-on therapies, which has performed during or directly after resection and cleared the tumor cavity from microscopically remaining cells. Although IORT has presented a novel and feasible principle, the method faced a number of technical and geometrical errors and limitations, which has decreased its potential in the reports of previous studies. Examples could be mentioned as incomplete target volume coverage that seemed as the greatest influence on survival, due to irradiation with an inadequate electron cone size, due to angle errors, or inadequately low energies. In contrast to the previously used forward-beaming electron cones, spherical irradiation sources were specifically attractive in brain tumor IORT, even in post resection cavities with normal complex shapes. Case Presentation: We have been reporting 3 cases of high grade gliomas, one recurrent GBM, one primary glioma grade III, and the last one recurrent Rhabdoid GBM, which have been fulfilling our entrance criteria of IORT procedure, by using spherical applicators, which has been increasingly discussed in recent studies. Conclusions: It was the first experience of intraoperative radiation therapy for cerebral malignant tumours in Iran. Finally, we had a brief overview on the past and

  13. Cell of origin determines tumor phenotype in an oncogenic Ras/p53 knockout transgenic model of high-grade glioma.

    PubMed

    Ghazi, Sabah O; Stark, Michelle; Zhao, Zhiguo; Mobley, Bret C; Munden, Alex; Hover, Laura; Abel, Ty William

    2012-08-01

    Human high-grade gliomas (HGGs) are known for their histologic diversity. To address the role of cell of origin in glioma phenotype, transgenic mice were generated in which oncogenic Ras and p53 deletion were targeted to neural stem/progenitor cells (NSPCs) and mature astrocytes. The hGFAP-Cre/Kras/p53 mice develop multifocal HGGs that vary histopathologically and with respect to the expression of markers associated with NSPCs. One HGG pattern strongly expressed markers of NSPCs and arose near the subventricular zone. Additional nonoverlapping patterns that recapitulate human HGG variants were present simultaneously in the same brain. These neoplastic foci were more often cortical or leptomeningeal based, and the neoplastic cells lacked expression of NSPC markers. To determine whether cell of origin determines tumor phenotype, astrocytes and NSPCs were harvested from neonatal mutant pups. Onorthotopic transplantation, early-passage astrocytes and NSPCs formed tumors that differed in engraftment rates, latency to clinical signs, histopathology, and protein expression. Astrocyte-derivedtumors were more aggressive, had giant-cell histology, and glial fibrillary acidic protein expression. The NSPC-derived tumors retained NSPC markers and showed evidence of differentiation along astrocytic, oligodendroglial, and neuronal lineages. These results indicate that identical tumorigenic stimuli produce markedly different glioma phenotypes, depending on the differentiation status of the transformed cell.

  14. The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors

    PubMed Central

    Jaber, Mohammed; Wölfer, Johannes; Ewelt, Christian; Holling, Markus; Hasselblatt, Martin; Niederstadt, Thomas; Zoubi, Tarek; Weckesser, Matthias

    2015-01-01

    BACKGROUND: Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade. OBJECTIVE: The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [18F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics. METHODS: Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and 18F-FET PET. Classification and regression tree analysis and receiver-operating-characteristic curves were generated for defining predictors. RESULTS: Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and 18F-FET PET uptake ratio >1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P < .001) and Ki-67/MIB-1 index (P < .001), but not with MGMT promoter methylation status, IDH1 mutation status, or 1p19q co-deletion status. The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted. CONCLUSION: Age, tumor volume, and 18F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased

  15. Retrospective Comparison of Chemoradiotherapy Followed by Adjuvant Chemotherapy, With or Without Prior Gliadel Implantation (Carmustine) After Initial Surgery in Patients With Newly Diagnosed High-Grade Gliomas

    SciTech Connect

    Noeel, Georges; Schott, Roland; Froelich, Sebastien; Gaub, Marie-Pierre; Boyer, Patrick; Fischer-Lokou, David; Dufour, Patrick; Kehrli, Pierre; Maitrot, Daniel

    2012-02-01

    Purpose: Retrospective study of patients treated for high-grade glioma, with or without biodegradable carmustine wafers and according to the Stupp protocol. Methods and Materials: Between May 2007 and June 2008, 65 patients underwent surgery for high-grade glioma, 28 had implantation of Gliadel and 37 patients did not. Patients received radiotherapy with concomitant temozolomide followed by 5 consecutive days of temozolomide every month for 6 months. Results: Overall median follow-up was 17.1 months; the median relapse-free survival (RFS) was 14 months with a RFS of 54% at 12 months, and 38% at 24 months. For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89). According to pathology, Gliadel did not influence RFS of patients with Grade III or glioblastoma. However, for all patients, in multivariate analysis, non-methylated methylguanine methyltransferase (MGMT) was the only unfavorable prognostic factor of RFS (p = 0.017; HR 2.8; CI [1.2-7]). Median overall survival (OS) was 20.8 months; the OS rate at 12 months was 78.5%, and at 24 months 35.4%. For patients treated with and without Gliadel, median and 1-year OS were 20.6 months and 78.6% vs. 20.8 months and 78.4%, respectively. According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma. For all patients, in multivariate analysis, unfavorable prognosticators for OS were non-methylated MGMT (p = 0.001; HR: 6.5; CI [2-20]) and irradiation dose <60 Gy (p = 0.02; HR: 6.3; CI [2-20]). With carmustine wafers, before irradiation, median gross tumor volume plus edema was 84 mL (27-229), whereas it was 68 mL (10-362) without carmustine (p = nonsignificant). Four cases of Grade 3 thrombopenia occurred, all in the carmustine wafer group. Conclusion: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival.

  16. TH-E-BRF-05: Comparison of Survival-Time Prediction Models After Radiotherapy for High-Grade Glioma Patients Based On Clinical and DVH Features

    SciTech Connect

    Magome, T; Haga, A; Igaki, H; Sekiya, N; Masutani, Y; Sakumi, A; Mukasa, A; Nakagawa, K

    2014-06-15

    Purpose: Although many outcome prediction models based on dose-volume information have been proposed, it is well known that the prognosis may be affected also by multiple clinical factors. The purpose of this study is to predict the survival time after radiotherapy for high-grade glioma patients based on features including clinical and dose-volume histogram (DVH) information. Methods: A total of 35 patients with high-grade glioma (oligodendroglioma: 2, anaplastic astrocytoma: 3, glioblastoma: 30) were selected in this study. All patients were treated with prescribed dose of 30–80 Gy after surgical resection or biopsy from 2006 to 2013 at The University of Tokyo Hospital. All cases were randomly separated into training dataset (30 cases) and test dataset (5 cases). The survival time after radiotherapy was predicted based on a multiple linear regression analysis and artificial neural network (ANN) by using 204 candidate features. The candidate features included the 12 clinical features (tumor location, extent of surgical resection, treatment duration of radiotherapy, etc.), and the 192 DVH features (maximum dose, minimum dose, D95, V60, etc.). The effective features for the prediction were selected according to a step-wise method by using 30 training cases. The prediction accuracy was evaluated by a coefficient of determination (R{sup 2}) between the predicted and actual survival time for the training and test dataset. Results: In the multiple regression analysis, the value of R{sup 2} between the predicted and actual survival time was 0.460 for the training dataset and 0.375 for the test dataset. On the other hand, in the ANN analysis, the value of R{sup 2} was 0.806 for the training dataset and 0.811 for the test dataset. Conclusion: Although a large number of patients would be needed for more accurate and robust prediction, our preliminary Result showed the potential to predict the outcome in the patients with high-grade glioma. This work was partly supported by

  17. Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: Does IMRT increase the integral dose to normal brain?

    SciTech Connect

    Hermanto, Ulrich; Frija, Erik K.; Lii, MingFwu J.; Chang, Eric L.; Mahajan, Anita; Woo, Shiao Y. . E-mail: SYWoo@mdanderson.org

    2007-03-15

    Purpose: To determine whether intensity-modulated radiotherapy (IMRT) treatment increases the total integral dose of nontarget tissue relative to the conventional three-dimensional conformal radiotherapy (3D-CRT) technique for high-grade gliomas. Methods and Materials: Twenty patients treated with 3D-CRT for glioblastoma multiforme were selected for a comparative dosimetric evaluation with IMRT. Original target volumes, organs at risk (OAR), and dose-volume constraints were used for replanning with IMRT. Predicted isodose distributions, cumulative dose-volume histograms of target volumes and OAR, normal tissue integral dose, target coverage, dose conformity, and normal tissue sparing with 3D-CRT and IMRT planning were compared. Statistical analyses were performed to determine differences. Results: In all 20 patients, IMRT maintained equivalent target coverage, improved target conformity (conformity index [CI] 95% 1.52 vs. 1.38, p < 0.001), and enabled dose reductions of normal tissues, including brainstem (D{sub mean} by 19.8% and D{sub max} by 10.7%), optic chiasm (D{sub mean} by 25.3% and D{sub max} by 22.6%), right optic nerve (D{sub mean} by 37.3% and D{sub max} by 28.5%), and left optic nerve (D{sub mean} by 40.6% and D{sub max} by 36.7%), p {<=} 0.01. This was achieved without increasing the total nontarget integral dose by greater than 0.5%. Overall, total integral dose was reduced by 7-10% with IMRT, p < 0.001, without significantly increasing the 0.5-5 Gy low-dose volume. Conclusions: These results indicate that IMRT treatment for high-grade gliomas allows for improved target conformity, better critical tissue sparing, and importantly does so without increasing integral dose and the volume of normal tissue exposed to low doses of radiation.

  18. Predicting Outcome of Patients with High-grade Gliomas After Radiotherapy using Quantitative Analysis of T1-weighted Magnetic Resonance Imaging

    SciTech Connect

    Tsien, Christina . E-mail: ctsien@umich.edu; Gomez-Hassan, Diana; Chenevert, Thomas L.; Lee, Julia; Lawrence, Theodore; Haken, Randall K. ten; Junck, Larry R.; Ross, Brian; Cao Yue

    2007-04-01

    Purpose: The aim of this study was to test the hypothesis that measuring quantitative changes in signal intensity early after radiotherapy (RT) in the contrast-enhancing tumor rim and nonenhancing core may be a noninvasive marker of early treatment response in patients with high-grade gliomas. Methods and Materials: Twenty patients with high-grade gliomas had magnetic resonance imaging (MRI) performed 1 week before RT, during Weeks 1 and 3 of RT, and every 1 to 3 months after RT as part of a clinical prospective study. Regions of interest (ROI) including contrast-enhancing rim, and the nonenhancing core were defined automatically based on a calculated image of post- to precontrast T1-weighted MRI. Pretreatment T1-weighted MRI signal intensity changes were compared with Weeks 1 and 3 RT and 1 and 3 months post-RT MRI. Clinical and MRI parameters were then tested for prediction of overall survival. Results: Regional T1-weighted signal intensity changes in both the contrast-enhancing rim and the nonenhancing core were observed in all patients during Week 1 and Week 3 of RT. Imaging parameters including signal intensity change within the nonenhancing core after Weeks 1 to 2 RT (p = 0.004), Weeks 3 to 4 RT (p = 0.002) and 1 month after completion of RT (p 0.002) were predictive of overall survival. Using multivariate analysis including RTOG recursive partitioning analysis (RPA) and signal intensity change, only the signal intensity change in the nonenhancing core at 1 month after RT (p = 0.01) retained significance. Conclusion: Quantitative measurements of T1-weighted MRI signal intensity changes in the nonenhancing tumor core (using ratios of pre-post values) may provide valuable information regarding early response during treatment and improve our ability to predict posttreatment outcome.

  19. The Efficacy of Ketogenic Diet and Associated Hypoglycemia as an Adjuvant Therapy for High-Grade Gliomas: A Review of the Literature

    PubMed Central

    Carico, Christine; Ortega, Alicia; Patil, Chirag G.

    2015-01-01

    Background: A high-fat, low-carbohydrate diet, often referred to as a ketogenic diet (KD), has been suggested to reduce frequency and severity of chronic pediatric and adult seizures. A hypoglycemic state, perpetuated by administration of a KD, has been hypothesized as a potential aid to the current standard treatments of high-grade gliomas. Methods: To understand the effectiveness of the ketogenic diet as a therapy for malignant gliomas, studies analyzing components of a KD were reviewed. Both preclinical and clinical studies were included. The keywords “ketogenic diet, GBM, malignant glioma, hyperglycemia, hypoglycemia” were utilized to search for both abstracts and full articles in English. Overall, 39 articles were found and included in this review. Results: Studies in animal models showed that a KD is able to control tumor growth and increase overall survival. Other pre-clinical studies have suggested that a KD sustains an environment in which tumors respond better to standard treatments, such as chemoradiation. In human cohorts, the KD was well tolerated. Quality of life was improved, compared to a standard, non-calorie or carbohydrate restricted diet. Hyperglycemia was independently associated with diminished survival. Conclusion: Recent clinical findings have demonstrated that induced hypoglycemia and ketogenic diet are tolerable and can potentially be an adjuvant to standard treatments, such as surgery and chemoradiation. Other findings have advocated for KD as a malignant cell growth inhibitor, and indicate that further studies analyzing larger cohorts of GBM patients treated with a KD are needed to determine the breadth of impact a KD can have on GBM treatment. PMID:26180675

  20. Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma

    PubMed Central

    Vandenberk, Lien; Garg, Abhishek D.; Verschuere, Tina; Koks, Carolien; Belmans, Jochen; Beullens, Monique; Agostinis, Patrizia; De Vleeschouwer, Steven; Van Gool, Stefaan W.

    2016-01-01

    ABSTRACT Dendritic cell (DC)-based immunotherapy has yielded promising results against high-grade glioma (HGG). However, the efficacy of DC vaccines is abated by HGG-induced immunosuppression and lack of attention toward the immunogenicity of the tumor lysate/cells used for pulsing DCs. A literature analysis of DC vaccination clinical trials in HGG patients delineated the following two most predominantly applied methods for tumor lysate preparation: freeze-thaw (FT)-induced necrosis or FT-necrosis followed by X-ray irradiation. However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. Using an orthotopic HGG murine model (GL261-C57BL/6), we observed that prophylactic vaccination with DCs pulsed with irradiated FT-necrotic cells (compared to FT-necrotic cells only) prolonged overall survival by increasing tumor rejection in glioma-challenged mice. This was associated, both in prophylactic and curative vaccination setups, with an increase in brain-infiltrating Th1 cells and cytotoxic T lymphocytes (CTL), paralleled by a reduced accumulation of regulatory T cells, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC). Further analysis showed that irradiation treatment of FT-necrotic cells considerably increased the levels of carbonylated proteins — a surrogate-marker of oxidation-associated molecular patterns (OAMPs). Through further application of antioxidants and hydrogen peroxide, we found a striking correlation between the amount of lysate-associated protein carbonylation/OAMPs and DC vaccine-mediated tumor rejection capacity thereby suggesting for the first time a role for protein carbonylation/OAMPs in at least partially mediating antitumor immunity. Together, these data strongly advocate the use of protein oxidation-inducing modalities like irradiation for increasing the immunogenicity of tumor lysate/cells used for pulsing DC vaccines. PMID:27057467

  1. High-Grade Glioma Relationship to the Neural Stem Cell Compartment: A Retrospective Review of 104 Cases

    SciTech Connect

    Marsh, James C.; Wendt, Julie A.; Herskovic, Arnold M.; Diaz, Aidnag; Gielda, Benjamin T.; Byrne, Richard W.

    2012-02-01

    Purpose: To assess the incidence of involvement of the neural stem cell (NSC) compartment by high-grade astrocytomas in a series of adult patients. Methods and Materials: One hundred four initial diagnostic cranial magnetic resonance imaging series were reviewed. For each series, the gross tumor volume (GTV; enhancing tumor on T{sub 1}), edema (hyperintensity on T{sub 2} FLAIR), and the NSC compartment (hippocampal formation and lateral ventricle plus a 5-mm expansion) were identified. Involvement of NSC by GTV and edema was assessed. For tumors not involving NSC, we measured distances from NSC to GTV and edema. Maximum diameters of GTV were measured for each case. Subset analysis was performed for GTV of {<=}2 cm and {<=}3 cm in maximum diameter to assess the incidence of involvement of NSC by this group of smaller tumors. For 10 representative tumors, minimum distances from GTV center to NSC were calculated. Results: A total of 103/104 (99.0%) tumors, regardless of GTV maximum diameter, demonstrated involvement of NSC. A total of 101/104 (97.1%) tumors had NSC involvement by GTV, and 2/104 (1.9%) patients showed edema only. For GTV not involving NSC, the mean distance from NSC to GTV was 0.8 cm (range, 0.5--1.4 cm). The mean shortest distance from the center of GTV to NSC was 1.5 cm (range, 0.9--2.6 cm). Involvement of NSC by GTV was 90.9% (10/11 tumors) for GTV of {<=}2 cm and 95.7% (22/23 tumors) for GTV of {<=}3 cm. Conclusions: Our results support the hypothesis that the NSC compartment represents the putative site of origin for these tumors. NSC involvement does not appear to represent a volumetric phenomenon.

  2. Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

    PubMed

    Franceschi, E; Cavallo, G; Lonardi, S; Magrini, E; Tosoni, A; Grosso, D; Scopece, L; Blatt, V; Urbini, B; Pession, A; Tallini, G; Crinò, L; Brandes, A A

    2007-04-10

    To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mg day(-1)) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1-36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2-104+) weeks and PFS-6 was 14.3% (95% CI 4.0-32.7%). The median overall survival was 24.6 weeks (range 4-104+). No grade 3-4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

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

    SciTech Connect

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

    2005-06-01

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

  4. Discriminant Analysis of 18F-Fluoro-Thymidine Kinetic Parameters to Predict Survival in Patients with Recurrent High-Grade Glioma

    PubMed Central

    Wardak, Mirwais; Schiepers, Christiaan; Dahlbom, Magnus; Cloughesy, Timothy; Chen, Wei; Satyamurthy, Nagichettiar; Czernin, Johannes; Phelps, Michael E.; Huang, Sung-Cheng

    2011-01-01

    Purpose The primary objective of this study was to investigate if changes in 18F-FLT kinetic parameters, taken at an early stage after start of therapy, could predict overall survival (OS) and progression-free survival (PFS) in patients with recurrent malignant glioma undergoing treatment with bevacizumab and irinotecan. Experimental Design High-grade recurrent brain tumors were investigated in 18 patients (8M, 10F), 26-76 yr. Each had 3 dynamic PET studies: at baseline, and after 2 weeks, and 6 weeks from the start of treatment. 2.0 MBq/kg of 18F-FLT was injected intravenously and dynamic PET images acquired for 1 hr. Factor analysis generated factor images from which blood and tumor uptake curves were derived. A 3-compartment, 2-tissue model was applied to estimate the tumor 18F-FLT kinetic rate constants using a metabolite and partial volume corrected input function. Different combinations of predictor variables were exhaustively searched in a discriminant function to accurately classify patients into their known OS and PFS groups. A leave-one-out cross-validation technique was used to assess the generalizability of the model predictions. Results In this study population, changes in single parameters such as standardized uptake value or influx rate constant did not accurately classify patients into their respective OS groups (<1yr and ≥1yr) [hit-ratios ≤ 78%]. However, changes in a set of 18F-FLT kinetic parameters could perfectly separate these two groups of patients [hit-ratio=100%] and were also able to correctly classify patients into their respective PFS groups (<100 days and ≥100 days) [hit-ratio=88%]. Conclusions Discriminant analysis using changes in 18F-FLT kinetic parameters early during treatment appears to be a powerful method for evaluating the efficacy of therapeutic regimens. PMID:21868765

  5. Phase I Study of Vorinostat in Combination with Temozolomide in Patients with High-Grade Gliomas: North American Brain Tumor Consortium Study 04-03

    PubMed Central

    Lee, Eudocia Q.; Puduvalli, Vinay K.; Reid, Joel M.; Kuhn, John G.; Lamborn, Kathleen R.; Cloughesy, Timothy F.; Chang, Susan M.; Drappatz, Jan; Yung, W. K. Alfred; Gilbert, Mark R.; Robins, H. Ian; Lieberman, Frank S.; Lassman, Andrew B.; McGovern, Renee M.; Xu, Jihong; Desideri, Serena; Ye, Xiabu; Ames, Matthew M.; Espinoza-Delgado, Igor; Prados, Michael D.; Wen, Patrick Y.

    2013-01-01

    Purpose A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). Experimental Design This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day × 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day × 5 days of the first cycle and 200 mg/m2/day × 5 days of the subsequent 28-day cycles. Results In Part 1, the MTD of vorinostat administered on days 1-7 and 15-21 of every 28 day cycle in combination with TMZ was 500 mg daily. Dose-limiting toxicities (DLTs) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In Part 2, the MTD of vorinostat on days 1-7 and 15-21 of every 28 day cycle combined with TMZ was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. Conclusion Vorinostat in combination with temozolomide is well-tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. PMID:22923449

  6. Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma.

    PubMed

    Chornenkyy, Yevgen; Agnihotri, Sameer; Yu, Man; Buczkowicz, Pawel; Rakopoulos, Patricia; Golbourn, Brian; Garzia, Livia; Siddaway, Robert; Leung, Stephie; Rutka, James T; Taylor, Michael D; Dirks, Peter B; Hawkins, Cynthia

    2015-11-01

    Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of niraparib was examined in an orthotopic xenograft model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines, some PARP1 protein expression was required for response to PARP inhibition; however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and Ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 μmol/L) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may be an effective radiosensitizer for pHGA and DIPG. PMID:26351319

  7. A longitudinal, qualitative and quantitative exploration of daily life and need for rehabilitation among patients with high-grade gliomas and their caregivers

    PubMed Central

    Piil, K; Jarden, M; Jakobsen, J; Christensen, K Bang; Juhler, M

    2013-01-01

    Introduction High-grade gliomas (HGGs) are the most malignant type of brain tumours. The 5-year survival is 10% and a significant part of the ongoing research aims to increase survival through surgical and oncological treatments. Accordingly, there is an increasing need for investigating the HGG trajectory in order to recommend specific guidelines for rehabilitative and supportive interventions. Method and analysis This study protocol (phase I) describes a longitudinal, qualitative, explorative and descriptive interview study of the life situation and need for rehabilitation among patients and their caregivers and a quantitative evaluation of health-related quality of life. Qualitative and quantitative data are collected in parallel, analysed separately and then merged. The finding of this study will, together with the existing literature, form the background for phase II, which is a feasibility study with a pre-experimental one-group design testing a rehabilitative and supportive intervention programme. The aim of this paper was to describe the design of an upcoming study. Interviews with 30 patients and 30 caregivers will provide information about how the life situation is experienced during the first year after being diagnosed with HGG. Quantitative measurements of quality of life, well-being and physical activity will provide additional information. More precisely, both qualitative and quantitative data will support the planning of the programme regarding the type of intervention(s), with or without supervision, the appropriate time along the trajectory, frequency, localisation, endpoint measurements and eligible patients and/or caregivers. Ethics and dissemination According to the Research Ethics Committee, approval is not needed for phase I as it is a non-intervention part of the study. Ethical approval of phase II will be sought at the time where the content of the intervention programme has been developed. Dissemination will occur through presentation and

  8. Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review.

    PubMed

    Ashby, Lynn S; Smith, Kris A; Stea, Baldassarre

    2016-08-24

    Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III

  9. Biopsy versus partial versus gross total resection in older patients with high-grade glioma: a systematic review and meta-analysis

    PubMed Central

    Almenawer, Saleh A.; Badhiwala, Jetan H.; Alhazzani, Waleed; Greenspoon, Jeffrey; Farrokhyar, Forough; Yarascavitch, Blake; Algird, Almunder; Kachur, Edward; Cenic, Aleksa; Sharieff, Waseem; Klurfan, Paula; Gunnarsson, Thorsteinn; Ajani, Olufemi; Reddy, Kesava; Singh, Sheila K.; Murty, Naresh K.

    2015-01-01

    Background Optimal extent of surgical resection (EOR) of high-grade gliomas (HGGs) remains uncertain in the elderly given the unclear benefits and potentially higher rates of mortality and morbidity associated with more extensive degrees of resection. Methods We undertook a meta-analysis according to a predefined protocol and systematically searched literature databases for reports about HGG EOR. Elderly patients (≥60 y) undergoing biopsy, subtotal resection (STR), and gross total resection (GTR) were compared for the outcome measures of overall survival (OS), postoperative karnofsky performance status (KPS), progression-free survival (PFS), mortality, and morbidity. Treatment effects as pooled estimates, mean differences (MDs), or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were determined using random effects modeling. Results A total of 12 607 participants from 34 studies met eligibility criteria, including our current cohort of 211 patients. When comparing overall resection (of any extent) with biopsy, in favor of the resection group were OS (MD 3.88 mo, 95% CI: 2.14–5.62, P < .001), postoperative KPS (MD 10.4, 95% CI: 6.58–14.22, P < .001), PFS (MD 2.44 mo, 95% CI: 1.45–3.43, P < .001), mortality (RR = 0.27, 95% CI: 0.12–0.61, P = .002), and morbidity (RR = 0.82, 95% CI: 0.46–1.46, P = .514) . GTR was significantly superior to STR in terms of OS (MD 3.77 mo, 95% CI: 2.26–5.29, P < .001), postoperative KPS (MD 4.91, 95% CI: 0.91–8.92, P = .016), and PFS (MD 2.21 mo, 95% CI: 1.13–3.3, P < .001) with no difference in mortality (RR = 0.53, 95% CI: 0.05–5.71, P = .600) or morbidity (RR = 0.52, 95% CI: 0.18–1.49, P = .223). Conclusions Our findings suggest an upward improvement in survival time, functional recovery, and tumor recurrence rate associated with increasing extents of safe resection. These benefits did not result in higher rates of mortality or morbidity if considered in conjunction with known established

  10. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo

    PubMed Central

    Huse, Jason T.; Brennan, Cameron; Hambardzumyan, Dolores; Wee, Boyoung; Pena, John; Rouhanifard, Sara H.; Sohn-Lee, Cherin; le Sage, Carlos; Agami, Reuven; Tuschl, Thomas; Holland, Eric C.

    2009-01-01

    Activated oncogenic signaling is central to the development of nearly all forms of cancer, including the most common class of primary brain tumor, glioma. Research over the last two decades has revealed the particular importance of the Akt pathway, and its molecular antagonist PTEN (phosphatase and tensin homolog), in the process of gliomagenesis. Recent studies have also demonstrated that microRNAs (miRNAs) may be responsible for the modulation of cancer-implicated genes in tumors. Here we report the identification miR-26a as a direct regulator of PTEN expression. We also show that miR-26a is frequently amplified at the DNA level in human glioma, most often in association with monoallelic PTEN loss. Finally, we demonstrate that miR-26a-mediated PTEN repression in a murine glioma model both enhances de novo tumor formation and precludes loss of heterozygosity and the PTEN locus. Our results document a new epigenetic mechanism for PTEN regulation in glioma and further highlight dysregulation of Akt signaling as crucial to the development of these tumors. PMID:19487573

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

    SciTech Connect

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

    2013-12-01

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

  12. Glioma

    MedlinePlus

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

  13. Long-term response in high-grade optic glioma treated with medically induced hypothyroidism and carboplatin: a case report and review of the literature.

    PubMed

    Ashur-Fabian, Osnat; Blumenthal, Deborah T; Bakon, Mati; Nass, Dvora; Davis, Paul J; Hercbergs, Aleck

    2013-03-01

    Glioblastoma multiforme (GBM) is the most malignant and frequent brain tumor, with an aggressive growth pattern and poor prognosis despite best treatment modalities. Long-term survival of patients with GBM is rare. Optic glioma represents 0.6-1.2% of all brain tumors. Unlike low-grade optic gliomas in children, optic gliomas in adults are highly aggressive and death usually occurs in less than a year. Prolonged progression-free survival and survival rates have been reported in association with induced hypothyroidism in two clinical trials for recurrent GBM. We present the clinical, radiological, and pathological findings in a patient with inoperable GBM of the optic chiasm. Following failure of initial, standard radiation and temozolomide therapy, chemical hypothyroidism was induced using the antithyroid thioamide, propylthiouracil, followed by carboplatin chemotherapy. Initial thyroid stimulating hormone, free T4, and free T3 analysis was carried out and then monthly. This patient responded rapidly to treatment (clinically and with tumor regression within 4 weeks) on two separate occasions with an extended remission period (2.5 years) and prolonged overall survival (4.5 years). We report the successful long-term tumor response to medically induced chemical hypothyroidism in conjunction with carboplatinum chemotherapy of an adult patient with grade IV GBM of the optic chiasm. These clinical observations find mechanistic support from the recent identification of potent mitogenic actions of the thyroid hormone, L-thyroxine, in malignant glioma through binding to a cognate thyroid hormone receptor on the αvβ3 integrin. Approaches to block its activity are now explored in preclinical studies. PMID:23348245

  14. Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas

    PubMed Central

    Oliva, Claudia R.; Markert, Tahireh; Gillespie, G. Yancey; Griguer, Corinne E.

    2015-01-01

    Nuclear-encoded cytochrome c oxidase subunit 4 (COX4) is a key regulatory subunit of mammalian cytochrome c oxidase, and recent studies have demonstrated that COX4 isoform 1 (COX4-1) could have a role in glioma chemoresistance. The Polycomb complex protein BMI1 is a stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including glioma. This study sought to determine if COX4 regulates BMI1 and modulates tumor cell proliferation. Using The Cancer Genome Atlas database and a retrospective data set from patients with glioblastoma multiforme, we found that BMI1 expression levels positively correlated with COX4-1 expression and overall survival. Whereas COX4-1 promoted cell growth by increasing BMI1 expression, COX4-2 inhibited cell growth even in cells overexpressing BMI1. We also demonstrate that COX4-1 attenuates mitochondrial reactive oxygen species (ROS) production, which is required for COX4-1-mediated effects on BMI1 expression and cell proliferation. Notably, mice bearing COX4-1-expressing glioma cell xenografts quickly developed invasive tumors characterized by the presence of multiple lesions positive for Ki-67, BMI1, and COX4-1, whereas mice bearing COX4-2-expressing xenografts rarely developed tumors by this point. COX4-1 also promoted the self-renewal of glioma stem-like cells, consistent with the reported role of BMI1 in stem cell growth. Taken together, these findings identify a novel COX4-1-mitochondrial ROS axis, in which differential expression of COX4 isoforms regulates mitochondrial ROS production and controls BMI1 expression. PMID:25726526

  15. Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma

    PubMed Central

    Wen, Patrick Y.; Omuro, Antonio; Ahluwalia, Manmeet S.; Fathallah-Shaykh, Hassan M.; Mohile, Nimish; Lager, Joanne J.; Laird, A. Douglas; Tang, Jiali; Jiang, Jason; Egile, Coumaran; Cloughesy, Timothy F.

    2015-01-01

    Background This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma. Methods Patients received voxtalisib 30–90 mg once daily (q.d.) or 20–50 mg twice daily (b.i.d.), in combination with 200 mg/m2 TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m2 TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response. Results The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade ≥3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%. Conclusions Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition. PMID:26019185

  16. 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.

  17. Detecting the H3F3A mutant allele found in high-grade pediatric glioma by real-time PCR.

    PubMed

    Zhang, Ray; Han, Jing; Daniels, David; Huang, Haojie; Zhang, Zhiguo

    2016-01-01

    Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain tumor with a median survival of 1 year after diagnosis. It has been reported recently that about 80% of DIPG cases and 70% of midline glioblastomas contain a mutation at one allele of the H3F3A gene (encoding histone H3 variant H3.3), replacing the lysine 27 with methionine (K27M). In order to facilitate diagnosis of DIPG patients, a quick and reliable method to identify the H3F3A K27M mutation is needed. Here, we describe a real-time PCR-based procedure involving a mutant-specific primer, a blocker oligonucleotide, and a reverse primer that can differentiate samples with H3F3A K27M mutation from those that do not. We first tested four different mutant-specific primers for their ability to selectively amplify H3F3A K27M-mutant allele and found that one primer amplified the mutant allele more efficiently than the rest. We then determined the optimal concentration of blocker oligo that significantly improved amplification of the H3F3A K27M-mutant allele. Using this optimized real-time PCR assay, we analyzed eleven samples, two of which containing H3F3A K27M mutation, and found that these two samples were differentially amplified from the nine others. In addition, we were able to discern the H3F3A K27M mutation in a newly obtained pediatric brainstem glioblastoma sample whose H3.3 status was not known previously, and in three other DIPG samples as well as paraffin embedded samples. These results demonstrate that we have developed a new reliable procedure for detecting the H3F3A K27M mutation in pediatric glioblastoma patient samples. PMID:26376656

  18. Targeting CD146 with a 64Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

    PubMed Central

    Yang, Yunan; Hernandez, Reinier; Rao, Jun; Yin, Li; Qu, Yazhuo; Wu, Jinrong; England, Christopher G.; Graves, Stephen A.; Lewis, Christina M.; Wang, Pu; Meyerand, Mary E.; Nickles, Robert J.; Bian, Xiu-wu; Cai, Weibo

    2015-01-01

    Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. 64Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ2 = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors. PMID:26553993

  19. Tumor location, but not H3.3K27M, significantly influences the blood-brain-barrier permeability in a genetic mouse model of pediatric high-grade glioma.

    PubMed

    Subashi, Ergys; Cordero, Francisco J; Halvorson, Kyle G; Qi, Yi; Nouls, John C; Becher, Oren J; Johnson, G Allan

    2016-01-01

    Pediatric high-grade gliomas (pHGGs) occur with strikingly different frequencies in infratentorial and supratentorial regions. Although histologically these malignancies appear similar, they represent distinct diseases. Recent genomic studies have identified histone K27M H3.3/H3.1 mutations in the majority of brainstem pHGGs; these mutations are rarely encountered in pHGGs that arise in the cerebral cortex. Previous research in brainstem pHGGs suggests a restricted permeability of the blood-brain-barrier (BBB). In this work, we use dynamic contrast-enhanced (DCE) MRI to evaluate BBB permeability in a genetic mouse model of pHGG as a function of location (cortex vs. brainstem, n = 8 mice/group) and histone mutation (mutant H3.3K27M vs. wild-type H3.3, n = 8 mice/group). The pHGG models are induced either in the brainstem or the cerebral cortex and are driven by PDGF signaling and p53 loss with either H3.3K27M or wild-type H3.3. T2-weighted MRI was used to determine tumor location/extent followed by 4D DCE-MRI for estimating the rate constant (K (trans) ) for tracer exchange across the barrier. BBB permeability was 67 % higher in cortical pHGGs relative to brainstem pHGGs (t test, p = 0.012) but was not significantly affected by the expression of mutant H3.3K27M versus wild-type H3.3 (t-test, p = 0.78). Although mice became symptomatic at approximately the same time, the mean volume of cortical tumors was 3.6 times higher than the mean volume of brainstem tumors. The difference between the mean volume of gliomas with wild-type and mutant H3.3 was insignificant. Mean K (trans) was significantly correlated to glioma volume. These results present a possible explanation for the poor response of brainstem pHGGs to systemic therapy. Our findings illustrate a potential role played by the microenvironment in shaping tumor growth and BBB permeability. PMID:26511492

  20. Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar

    PubMed Central

    Stieber, V.; Mikkelsen, T.; Judy, K.; Weingart, J.; Barnett, G.; Olson, J.; Desideri, S.; Ye, X.; Grossman, S.

    2016-01-01

    Objectives The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. Methods The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. Results Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1–23.6) for NEW-GBM and 12.8 months (95 % CI 4.2–20.9) for REC-HGG. Conclusion These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

  1. 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 ...

  2. Genetic Analysis of Diffuse High-Grade Astrocytomas in Infancy Defines a Novel Molecular Entity.

    PubMed

    Gielen, Gerrit H; Gessi, Marco; Buttarelli, Francesca R; Baldi, Caterina; Hammes, Jennifer; zur Muehlen, Anja; Doerner, Evelyn; Denkhaus, Dorota; Warmuth-Metz, Monika; Giangaspero, Felice; Lauriola, Libero; von Bueren, André O; Kramm, Christof M; Waha, Andreas; Pietsch, Torsten

    2015-07-01

    Pediatric high-grade gliomas are considered to be different when compared to adult high-grade gliomas in their pathogenesis and biological behavior. Recently, common genetic alterations, including mutations in the H3F3A/ATRX/DAXX pathway, have been described in approximately 30% of the pediatric cases. However, only few cases of infant high-grade gliomas have been analyzed so far. We investigated the molecular features of 35 infants with diffuse high-grade astrocytomas, including 8 anaplastic astrocytomas [World Health Organization (WHO) grade III] and 27 glioblastomas (WHO grade IV) by immunohistochemistry, multiplex ligation probe-dependent amplification (MLPA), pyrosequencing of glioma-associated genes and molecular inversion probe (MIP) assay. MIP and MLPA analyses showed that chromosomal alterations are significantly less frequent in infants compared with high-grade gliomas in older children and adults. We only identified H3F3A K27M in 2 of 34 cases (5.9%), with both tumors located in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss could be observed only in two cases. Conversely, 1q gain (22.7%) and 6q loss (18.2%) were identified in a subgroup of tumors. Loss of SNORD located on chromosome 14q32 was observed in 27.3% of the infant tumors, a focal copy number change not previously described in gliomas. Our findings indicate that infant high-grade gliomas appear to represent a distinct genetic entity suggesting a different pathogenesis and biological behavior. PMID:25231549

  3. Surgical approaches for the gliomas.

    PubMed

    Watts, Colin; Sanai, Nader

    2016-01-01

    Neurosurgical intervention remains the first step in effective glioma management. Mounting evidence suggests that cytoreduction for low- and high-grade gliomas is associated with a survival benefit. Beyond conventional neurosurgical principles, an array of techniques have been refined in recent years to maximize the effect of the neurosurgical oncologist and facilitate the impact of subsequent adjuvant therapy. With intraoperative mapping techniques, aggressive microsurgical resection can be safely pursued even when tumors occupy essential functional pathways. Other adjunct techniques, such as intraoperative magnetic resonance imaging, intraoperative ultrasonography, and fluorescence-guided surgery, can be valuable tools to safely reduce the tumor burden of low- and high-grade gliomas. Taken together, this collection of surgical strategies has pushed glioma extent of resection towards the level of cellular resolution.

  4. High-Grading Lunar Samples

    NASA Technical Reports Server (NTRS)

    Allen, Carlton; Sellar, Glenn; Nunez, Jorge; Mosie, Andrea; Schwarz, Carol; Parker, Terry; Winterhalter, Daniel; Farmer, Jack

    2009-01-01

    Astronauts on long-duration lunar missions will need the capability to high-grade their samples to select the highest value samples for transport to Earth and to leave others on the Moon. We are supporting studies to define the necessary and sufficient measurements and techniques for high-grading samples at a lunar outpost. A glovebox, dedicated to testing instruments and techniques for high-grading samples, is in operation at the JSC Lunar Experiment Laboratory. A reference suite of lunar rocks and soils, spanning the full compositional range found in the Apollo collection, is available for testing in this laboratory. Thin sections of these samples are available for direct comparison. The Lunar Sample Compendium, on-line at http://www-curator.jsc.nasa.gov/lunar/compendium.cfm, summarizes previous analyses of these samples. The laboratory, sample suite, and Compendium are available to the lunar research and exploration community. In the first test of possible instruments for lunar sample high-grading, we imaged 18 lunar rocks and four soils from the reference suite using the Multispectral Microscopic Imager (MMI) developed by Arizona State University and JPL (see Farmer et. al. abstract). The MMI is a fixed-focus digital imaging system with a resolution of 62.5 microns/pixel, a field size of 40 x 32 mm, and a depth-of-field of approximately 5 mm. Samples are illuminated sequentially by 21 light emitting diodes in discrete wavelengths spanning the visible to shortwave infrared. Measurements of reflectance standards and background allow calibration to absolute reflectance. ENVI-based software is used to produce spectra for specific minerals as well as multi-spectral images of rock textures.

  5. Cell surface GRP78 as a biomarker and target for suppressing glioma cells

    PubMed Central

    Kang, Bo Ram; Yang, Seung-Hoon; Chung, Bo-Ryehn; Kim, Woong; Kim, YoungSoo

    2016-01-01

    High-grade glioma is a highly malignant and metastatic brain cancer, resistant to many existing anticancer treatments. In such glioma cancer cells, the glucose-regulated protein 78 kDa (GRP78) is particularly highly up-regulated. Former studies have thus targeted mutation-free GRP78 not only to detect glioma cancer cells specifically but also to enhance cytotoxic effect. We focus on cell surface-expressed GRP78 as a target for suppressing high-grade glioma cell lines. Glioblastoma multiforme (GBM) cell line, highly malignant glioma cells, was first injected into 5-week-old athymic mice to confirm and compare GRP78 expression in vivo in xenografted and normal brain tissue. Immunofluorescence and immunoblotting were utilized to detect surface-localized GRP78 in diverse high-grade glioma cell lines. By treating glioma cell lines with the polyclonal N-20 antibody against surface-localized GRP78, we subsequently studied the significance of surface GRP78 to the survival and growth of the glioma cell lines. We found that inhibiting the function of surface GRP78 suppressed cancer cell survival and growth proving that the surface-expressed GRP78 is a vital receptor involved in the proliferation of high-grade glioma. Our findings provide opportunities to target surface GRP78 as a biomarker for high-grade glioma and to develop effective cell-specific anticancer therapy. PMID:27713511

  6. 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

  7. 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.

  8. 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. PMID:26297251

  9. Genomic characterization of recurrent high-grade astroblastoma.

    PubMed

    Bale, Tejus A; Abedalthagafi, Malak; Bi, Wenya Linda; Kang, Yun Jee; Merrill, Parker; Dunn, Ian F; Dubuc, Adrian; Charbonneau, Sarah K; Brown, Loreal; Ligon, Azra H; Ramkissoon, Shakti H; Ligon, Keith L

    2016-01-01

    Astroblastomas are rare primary brain tumors, diagnosed based on histologic features. Not currently assigned a WHO grade, they typically display indolent behavior, with occasional variants taking a more aggressive course. We characterized the immunohistochemical characteristics, copy number (high-resolution array comparative genomic hybridization, OncoCopy) and mutational profile (targeted next-generation exome sequencing, OncoPanel) of a cohort of seven biopsies from four patients to identify recurrent genomic events that may help distinguish astroblastomas from other more common high-grade gliomas. We found that tumor histology was variable across patients and between primary and recurrent tumor samples. No common molecular features were identified among the four tumors. Mutations commonly observed in astrocytic tumors (IDH1/2, TP53, ATRX, and PTEN) or ependymoma were not identified. However one case with rapid clinical progression displayed mutations more commonly associated with GBM (NF1(N1054H/K63)*, PIK3CA(R38H) and ERG(A403T)). Conversely, another case, originally classified as glioblastoma with nine-year survival before recurrence, lacked a GBM mutational profile. Other mutations frequently seen in lower grade gliomas (BCOR, BCORL1, ERBB3, MYB, ATM) were also present in several tumors. Copy number changes were variable across tumors. Our findings indicate that astroblastomas have variable growth patterns and morphologic features, posing significant challenges to accurate classification in the absence of diagnostically specific copy number alterations and molecular features. Their histopathologic overlap with glioblastoma will likely confound the observation of long-term GBM "survivors". Further genomic profiling is needed to determine whether these tumors represent a distinct entity and to guide management strategies. PMID:27425854

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

    PubMed

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

    2013-11-01

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

  11. The Value of Glioma Extent of Resection in the Modern Neurosurgical Era

    PubMed Central

    Hardesty, Douglas A.; Sanai, Nader

    2012-01-01

    Objective: There remains no general consensus in the neurosurgical oncology literature regarding the role of extent of glioma resection in improving patient outcome. Although the value of resection in establishing a diagnosis and alleviating mass effect is clear, there is less certainty in ascertaining the influence of extent of resection (EOR). Here, we review the recent literature to synthesize a comprehensive review of the value of extent of resection for gliomas in the modern neurosurgical era. Methods: We reviewed every major peer-reviewed clinical publication since 1990 on the role of EOR in glioma outcome. Results: Thirty-two high-grade glioma articles and 11 low-grade glioma articles were examined in terms of quality of evidence, expected EOR, and survival benefit. Conclusion: Despite limitations in the quality of data, mounting evidence suggests that more extensive surgical resection is associated with longer life expectancy for both low- and high-grade newly diagnosed gliomas. PMID:23087667

  12. Functionally Active Gap Junctions between Connexin 43-Positive Mesenchymal Stem Cells and Glioma Cells.

    PubMed

    Gabashvili, A N; Baklaushev, V P; Grinenko, N F; Levinskii, A B; Mel'nikov, P A; Cherepanov, S A; Chekhonin, V P

    2015-05-01

    The formation of functional gap junctions between mesenchymal stem cells and cells of low-grade rat glioma C6 cells was studied in in vitro experiments. Immunocytochemical analysis with antibodies to connexin 43 extracellular loop 2 showed that mesenchymal stem cells as well as C6 glioma cells express the main astroglial gap junction protein connexin 43. Analysis of migration activity showed that mesenchymal stem cells actively migrate towards C6 glioma cells. During co-culturing, mesenchymal stem cells and glioma C6 form functionally active gap junctions mediating the transport of cytoplasmic dye from glioma cells to mesenchymal stem cells in the opposite direction. Fluorometry showed that the intensity of transport of low-molecular substances through heterologous gap junctions between mesenchymal stem cells and glioma cells is similar to that through homologous gap junctions between glioma cells. This phenomenon can be used for the development of new methods of cell therapy of high-grade gliomas.

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

    PubMed

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

    2015-01-01

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

  14. Recent surgical management of gliomas.

    PubMed

    Sanai, Nader; Berger, Mitchel S

    2012-01-01

    Refinement of neurosurgical technique has enabled safer operations with more aggressive outcomes. One cornerstone of modern-day practice is the utilization of intraoperative stimulation mapping. In addition to identifying critical motor pathways, this technique can be adapted to reliable identify language pathways, as well. Given the individual variability of cortical language localization, such awake language mapping is essential to minimize language deficits following tumor resection. Our experience suggests that cortical language mapping is a safe and efficient adjunct to optimize tumor resection while preserving essential language sites, even in the setting of negative mapping data. However, the value of maximizing glioma resections remains surprisingly unclear, as there is no general consensus in the literature regarding the efficacy of extent of glioma resection in improving patient outcome. While the importance of resection in obtaining tissue diagnosis and to alleviate symptoms is clear, a lack of Class I evidence prevents similar certainty in assessing the influence of extent of resection. Beyond an analysis of modern intraoperative mapping techniques, we examine every major clinical publication since 1990 on the role of extent of resection in glioma outcome. The mounting evidence suggests that, despite persistent limitations in the quality of available studies, a more extensive surgical resection is associated with longer life expectancy for both low-grade and high-grade gliomas.

  15. Immunoglobulin genes implicated in glioma risk.

    PubMed

    Pandey, Janardan P; Kaur, Navtej; Costa, Sandra; Amorim, Julia; Nabico, Rui; Linhares, Paulo; Vaz, Rui; Viana-Pereira, Marta; Reis, Rui M

    2014-01-01

    Both genetic and environmental factors are thought to be causal in gliomagenesis. Several genes have been implicated in glioma development, but the putative role of a major immunity-related gene complex member, immunoglobulin heavy chain γ (IGHG) has not been evaluated. Prior observations that IGHG-encoded γ marker (GM) allotypes exhibit differential sensitivity to an immunoevasion strategy of cytomegalovirus, a pathogen implicated as a promoter of gliomagenesis, has lead us to hypothesize that these determinants are risk factors for glioma. To test this hypothesis, we genotyped the IGHG locus comprising the GM alleles, specifically GM alleles 3 and 17, of 120 glioma patients and 133 controls via TaqMan® genotyping assay. To assess the associations between GM genotypes and the risk of glioma, we applied an unconditional multivariate logistic regression analysis adjusted for potential confounding variables. In comparison to subjects who were homozygous for the GM 17 allele, the GM 3 homozygotes were over twice as likely, and the GM 3/17 heterozygotes were over three times as likely, to develop glioma. Similar results were achieved when analyzed by combining the data corresponding to alleles GM 3 and GM 3/17 in a dominant model. The GM 3/17 genotype and the combination of GM 3 and GM 3/17 were found to be further associated with over 3 times increased risk for high-grade astrocytoma (grades III-IV). Allele frequency analyses also showed an increased risk for gliomas and high-grade astrocytoma in association with GM 3. Our findings support the premise that the GM 3 allele may present risk for the development of glioma, possibly by modulating immunity to cytomegalovirus.

  16. Nonlinear ghost waves accelerate the progression of high-grade brain tumors

    NASA Astrophysics Data System (ADS)

    Pardo, Rosa; Martínez-González, Alicia; Pérez-García, Víctor M.

    2016-10-01

    We study a reduced continuous model describing the evolution of high grade gliomas in response to hypoxic events through the interplay of different cellular phenotypes. We show that hypoxic events, even when sporadic and/or limited in space, may have a crucial role on the acceleration of high grade gliomas growth. Our modeling approach is based on two cellular phenotypes. One of them is more migratory and a second one is more proliferative. Transitions between both phenotypes are driven by the local oxygen values, assumed in this simple model to be uniform. Surprisingly, even very localized in time hypoxia events leading to transient migratory populations have the potential to accelerate the tumor's invasion speed up to speeds close to those of the migratory phenotype. The high invasion speed persists for times much longer than the lifetime of the hypoxic event. Moreover, the phenomenon is observed both when the migratory cells form a persistent wave of cells located on the invasion front and when they form a evanescent "ghost" wave disappearing after a short time by decay to the more proliferative phenotype. Our findings are obtained through numerical simulations of the model equations both in 1D and higher dimensional scenarios. We also provide a deeper mathematical analysis of some aspects of the problem such as the conditions for the existence of persistent waves of cells with a more migratory phenotype.

  17. Expression and Prognostic Significance of p53 in Glioma Patients: A Meta-analysis.

    PubMed

    Jin, Yueling; Xiao, Weizhong; Song, Tingting; Feng, Guangjia; Dai, Zhensheng

    2016-07-01

    Glioma is a brain tumor deriving from the neoplastic glial cells or neuroglia. Due to its resistance to anticancer drugs and different disease progress of individuals, patients with high-grade glioma are difficult to completely cure, leading to a poor prognosis and low overall survival. Therefore, there is an urgent need to look for prognostic and diagnostic indicators that can predict glioma grades. P53 is one of the widely studied biomarkers in human glioma. The purpose of this study was to comprehensively evaluate the significance of p53 expression in glioma grades and overall survival. We searched commonly used electronic databases to retrieve related articles of p53 expression in glioma. Overall, a total of 21 studies including 1322 glioma patients were finally screened out. We observed that the frequency of p53 immuno-positivity was higher in high-grade patients than that in low-grade category (63.8 vs. 41.6 %), and our statistic analysis indicated that p53 expression was associated with pathological grade of glioma (OR 2.93, 95 % CI 1.87-4.60, P < 0.00001). This significant correction was also found in 1-, 3- and 5-year overall survival. However, no positive relationship was found between age, sex, tumor size and p53 expression in patients with glioma. In conclusion, our results suggested that p53 immunohistochemical expression might have an effective usefulness in predicting the prognosis in patients with glioma.

  18. Expression and Prognostic Significance of p53 in Glioma Patients: A Meta-analysis.

    PubMed

    Jin, Yueling; Xiao, Weizhong; Song, Tingting; Feng, Guangjia; Dai, Zhensheng

    2016-07-01

    Glioma is a brain tumor deriving from the neoplastic glial cells or neuroglia. Due to its resistance to anticancer drugs and different disease progress of individuals, patients with high-grade glioma are difficult to completely cure, leading to a poor prognosis and low overall survival. Therefore, there is an urgent need to look for prognostic and diagnostic indicators that can predict glioma grades. P53 is one of the widely studied biomarkers in human glioma. The purpose of this study was to comprehensively evaluate the significance of p53 expression in glioma grades and overall survival. We searched commonly used electronic databases to retrieve related articles of p53 expression in glioma. Overall, a total of 21 studies including 1322 glioma patients were finally screened out. We observed that the frequency of p53 immuno-positivity was higher in high-grade patients than that in low-grade category (63.8 vs. 41.6 %), and our statistic analysis indicated that p53 expression was associated with pathological grade of glioma (OR 2.93, 95 % CI 1.87-4.60, P < 0.00001). This significant correction was also found in 1-, 3- and 5-year overall survival. However, no positive relationship was found between age, sex, tumor size and p53 expression in patients with glioma. In conclusion, our results suggested that p53 immunohistochemical expression might have an effective usefulness in predicting the prognosis in patients with glioma. PMID:27038932

  19. Clinical characteristics of high grade foveal hypoplasia.

    PubMed

    Park, Kyung-Ah; Oh, Sei Yeul

    2013-02-01

    To report clinical characteristics of high grade foveal hypoplasia. Patients with foveal hypoplasia of grade 3 or 4 on spectral domain optical coherence tomography according to a previously published scheme were enrolled. All patients underwent a full ophthalmologic assessment including visual acuity testing, slit lamp biomicroscopy, fundus examination, and evaluation of ocular alignment. The underlying causes of foveal hypoplasia were identified as albinism in five patients and aniridia in six patients. The mean logMAR visual acuity was 0.57 ± 0.24 (range 0.22-1.00) in the right eyes and 0.58 ± 0.21 (range 0.30-1.00) in the left eyes. On fundus examination in patients with albinism, two patients showed marked transparency, one patient showed moderate transparency, and two patients showed minimal transparency. Among six patients with aniridia, five patients showed normal macular pigmentation without macular reflex and one patient showed decreased macular pigmentation with no macular reflex. Patients with high grade macular hypoplasia tended to have poor visual acuities; however, the range of visual acuity was quite variable. Other factors associated with underlying disease could be the reason of this variability. Therefore, careful consideration should be given when assessing visual prognosis in foveal hypoplasia using optical coherence tomography. PMID:23124196

  20. High-Grade Prostatic Intraepithelial Neoplasia

    PubMed Central

    Bostwick, David G; Liu, Lina; Brawer, Michael K; Qian, Junqi

    2004-01-01

    High-grade prostatic intraepithelial neoplasia is considered the most likely precursor of prostatic carcinoma. The only method of detection is biopsy; prostatic intraepithelial neoplasia (PIN) does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultra-sonography. The incidence of PIN in prostate biopsies averages 9% (range, 4%–16%), representing 115,000 new cases of PIN diagnosed each year in United States. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeated biopsy for concurrent or subsequent invasive carcinoma. Carcinoma will develop in most patients with PIN within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention. PMID:16985598

  1. Ion channel gene expression predicts survival in glioma patients.

    PubMed

    Wang, Rong; Gurguis, Christopher I; Gu, Wanjun; Ko, Eun A; Lim, Inja; Bang, Hyoweon; Zhou, Tong; Ko, Jae-Hong

    2015-08-03

    Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients.

  2. 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

  3. Management of Elderly Patients With Gliomas

    PubMed Central

    Gállego Pérez-Larraya, Jaime

    2014-01-01

    The current progressive aging of the population is resulting in a continuous increase in the incidence of gliomas in elderly people, especially the most frequent subtype, glioblastoma (GBM). This sociohealth shift, known as the “silver tsunami,” has prompted the neuro-oncology community to investigate the role of specific antitumor treatments, such as surgery, radiotherapy, chemotherapy, and other targeted therapies, for these traditionally undertreated patients. Advanced age, a widely recognized poor prognostic factor in both low-grade glioma (LGG) and high-grade glioma patients, should no longer be the sole reason for excluding such older patients from receiving etiologic treatments. Far from it, results from recent prospective trials conducted on elderly patients with GBM demonstrate that active management of these patients can have a positive impact on survival without impairing either cognition or quality of life. Although prospective studies specifically addressing the management of grade 2 and 3 gliomas are lacking and thus needed, the aforementioned tendency toward acknowledging a therapeutic benefit for GBM patients might also apply to the treatment of patients with LGG and anaplastic gliomas. In order to optimize such etiologic treatment in conjunction with symptomatic management, neuro-oncology multidisciplinary boards must individually consider important features such as resectability of the tumor, functional and cognitive status, associated comorbidities, and social support. PMID:25342314

  4. 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

  5. Alu methylation serves as a biomarker for non-invasive diagnosis of glioma

    PubMed Central

    Zuo, Hao; Zhao, Longxiang; Huang, Chuanjun; Liu, Xiaojiang; Hou, Shiqiang; Qi, Jing; Shi, Wei

    2016-01-01

    Current techniques for diagnosing glioma are invasive and do not accurately predict prognosis. We developed a novel, non-invasive liquid chip assay to diagnose glioma and predict prognosis. Using this method, we determined the methylation state of the Alu element in cell-free DNA extracted from the serum of 109 glioma patients. Controls included 56 patients with benign intracranial tumors and 50 healthy subjects. Matched tumor tissues were processed for 36 patients. The cfDNA from glioma patients showed lower levels of Alu methylation than the controls (P<0.01). Alu methylation was also lower in high-grade than low-grade gliomas (P<0.01), indicating that Alu methylation correlates negatively with disease severity. Moreover, Alu methylation correlated positively with survival (P<0.01). These findings suggest high-throughput liquid chip could serve as a non-invasive diagnostic assay for glioma. PMID:27028997

  6. Expression and clinical significance of P53, O6-methylguanine-dna methyltransferase and epidermal growth factor receptor in glioma.

    PubMed

    Fu, X R; Sun, Z C; Chang, Y

    2015-01-01

    Glioma is a serious life-threatening disease, the pathogenesis of which remains to be investigated. The objective of the present investigation was to explore the expression and clinical significance of tumor suppressor gene (P53), O6-methylguanine-DNA methyltransferase (MGMT) and epidermal growth factor receptor (EGFR) in glioma. Immunohistochemical staining was applied to study the clinical characteristics of 40 samples from glioma patients, detect the expression of and analyse the relationship between P53, MGMT and EGFR and glioma. The results demonstrated that the positive expression rate of P53 was 47.5% in 40 cases of glioma samples, of which the expression of P53 in the high grade glioma was higher than that of the low grade samples (P < 0.05); the positive expression rate of MGMT was 37.5%, but there was no significant significance of MGMT expression between the high grade glioma and the low grade glioma (P < 0.05); the positive expression rate of EGFR was 55%, of which the expression of EGFR of the high grade glioma was higher than that of the low grade glioma (P < 0.05). There was no significant difference in the expressions of P53, MGMT and EGFR in the glioma patients of different ages, gender and with different tumor sizes. The expressions of P53 and MGMT were negatively correlated (P < 0.05). The expressions of P53 and EGFR were positively correlated (P < 0.05). In conclusion, P53, EGFR and MGMT could play a role in the occurrence, development and deterioration of glioma. PMID:26753647

  7. 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

  8. Facing contrast-enhancing gliomas: perfusion MRI in grade III and grade IV gliomas according to tumor area.

    PubMed

    Di Stefano, Anna Luisa; Bergsland, Niels; Berzero, Giulia; Farina, Lisa; Rognone, Elisa; Gastaldi, Matteo; Aquino, Domenico; Frati, Alessandro; Tomasello, Francesco; Ceroni, Mauro; Marchioni, Enrico; Bastianello, Stefano

    2014-01-01

    Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV), calculated with Dynamic Susceptibility Contrast (DSC) Perfusion-Weighted Imaging (PWI), allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI) approach in three tumor areas-the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map-in patients affected by contrast-enhancing glioma (grades III and IV). Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast-enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp.), the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, P = 0.036). In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading.

  9. Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells.

    PubMed

    Vila-Carriles, Wanda H; Kovacs, Gergely Gy; Jovov, Biljana; Zhou, Zhen-Hong; Pahwa, Amit K; Colby, Garrett; Esimai, Ogenna; Gillespie, G Yancey; Mapstone, Timothy B; Markert, James M; Fuller, Catherine M; Bubien, James K; Benos, Dale J

    2006-07-14

    Gliomas are primary brain tumors with a complex biology characterized by antigenic and genomic heterogeneity and a propensity for invasion into normal brain tissue. High grade glioma cells possess a voltage-independent, amiloride-inhibitable, inward Na+ current. This current does not exist in normal astrocytes or low grade tumor cells. Inhibition of this conductance decreases glioma growth and cell migration making it a potential therapeutic target. Our previous results have shown that the acid-sensing ion channels (ASICs), members of the epithelial Na+ channel (ENaC)/degenerin (DEG) family of ion channels are part of this current pathway. We hypothesized that one member of the ENaC/DEG family, ASIC2, is retained intracellularly and that it is the lack of functional expression of ASIC2 at the cell surface that results in hyperactivity of this conductance in high grade gliomas. In this study we show that the chemical chaperone, glycerol, and the transcriptional regulator, sodium 4-phenylbutyrate, inhibit the constitutively activated inward current and reduce cell growth and migration in glioblastoma multiforme. The results suggest that these compounds induce the movement of ASIC2 to the plasma membrane, and once there, the basally active inward current characteristic of glioma cells is abolished by inherent negative regulatory mechanisms. This in turn compromises the ability of the glioma cell to migrate and proliferate. These results support the hypothesis that the conductance pathway in high grade glioma cells is comprised of ENaC/DEG subunits and that abolishing this channel activity promotes a reversion of a high grade glioma cell to a phenotype resembling that of normal astrocytes. PMID:16704974

  10. L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor.

    PubMed

    Mohanan, Vishnu; Temburni, Murali K; Kappes, John C; Galileo, Deni S

    2013-04-01

    The L1CAM cell adhesion/recognition molecule (L1, CD171) and fibroblast growth factor receptor (FGFR) both are expressed by human high-grade glioma cells, but their potential actions in controlling cell behavior have not been linked. L1 actions in cancer cells have been attributed mainly to integrin receptors, and we demonstrated previously that L1-stimulated glioma cell migration correlates with integrin expression, increased focal adhesion kinase activation and focal complex turnover. Our analyses of datasets revealed FGFR is overexpressed in glioma regardless of grade, while ADAM10 metalloprotease expression increases with glioma grade. Here, we used dominant-negative and short hairpin RNA approaches to inhibit the activation of FGFR1 and expression of L1, respectively. An L1 peptide that inhibits L1-FGFR interaction and PD173074, a chemical inhibitor of FGFR1 activity, also were used to elucidate the involvement of L1-FGFR interactions on glioma cell behavior. Time-lapse cell motility studies and flow cytometry cell cycle analyses showed that L1 operates to increase glioma cell motility and proliferation through FGFR activation. Shutdown of both L1 expression and FGFR activity in glioma cells resulted in a complete termination of cell migration in vitro. These studies show for the first time that soluble L1 ectodomain (L1LE) acts on glioma cells through FGFRs, and that FGFRs are used by glioma cells for increasing motility as well as proliferation in response to activation by L1LE ligand. Thus, effective treatment of high-grade glioma may require simultaneous targeting of L1, FGFRs, and integrin receptors, which would reduce glioma cell motility as well as proliferation.

  11. Molecular analysis of diffuse intrinsic brainstem gliomas in adults.

    PubMed

    Reyes-Botero, German; Giry, Marine; Mokhtari, Karima; Labussière, Marianne; Idbaih, Ahmed; Delattre, Jean-Yves; Laigle-Donadey, Florence; Sanson, Marc

    2014-01-01

    Diffuse intrinsic brainstem gliomas (DIBG) account for 1-2 % of adult gliomas. Their biological characteristics are scarcely understood and whether DIBG are biologically different from supratentorial gliomas remains to be established. We analyzed 17 DIBG samples for IDH1 R132H, alpha internexin, p53, and Ki67 expression, and, in a subset with sufficient DNA amount, for IDH1 and histone H3 mutational status, genomic profiling and MGMT promoter methylation status. A series of 738 adult supratentorial gliomas was used for comparison. Median age at diagnosis was 41 years (range 18.9-65.3 years). Median overall survival was 48.7 months (57 months for low-grade vs. 16 months for high-grade gliomas, p < 0.01). IDH1 sequencing revealed two mutations (IDH1 (R132G) , IDH1 (R132C) ) out of 7 DIBG whereas the R132H IDH1 enzyme was detected in 1/17 DIBG, suggesting that IDH1 mutations are mostly non R132H in DIBG (2/2), in contrast to supratentorial gliomas (31/313; p = 0.01). Mutations in histone genes H3F3A (encoding H3.3) and HIST1H3B (encoding H3.1) were found in 3/8 (37.5 %) of the DIBG (two H3F3A (K27M) and one HIST1H3B (K27M) ) versus 6/205 (2.9 %) of the supratentorial high-grade gliomas (four H3F3A (G34R) and two H3F3A (K27M) ) (p = 0.002). The CGH array showed a higher frequency of chromosome arm 1q gain, 9q gain and 11q loss in DIBG compared to the supratentorial high-grade gliomas, which had a less frequent chromosome 7 gain, and a less frequent chromosome 10 loss. No EGFR amplification was found. These data suggest that adult DIBG differ from adult supratentorial gliomas. In particular, histone genes (H3F3A (K27M) , HIST1H3B (K27M) ) mutations are frequent in adult DIBG whereas IDH1 (R132H) mutations are rare. PMID:24242757

  12. Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma.

    PubMed

    van Lith, Sanne A M; Navis, Anna C; Lenting, Krissie; Verrijp, Kiek; Schepens, Jan T G; Hendriks, Wiljan J A J; Schubert, Nil A; Venselaar, Hanka; Wevers, Ron A; van Rooij, Arno; Wesseling, Pieter; Molenaar, Remco J; van Noorden, Cornelis J F; Pusch, Stefan; Tops, Bastiaan; Leenders, William P J

    2016-01-01

    The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased α-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1(R314C), which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1(R314C) lacks isocitrate-to-α-KG conversion activity due to reduced affinity for NADP(+), and differs from the IDH1(R132) mutants in that it does not produce D-2-HG. Because IDH1(R314C) is defective in producing α-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite. PMID:27460417

  13. Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma

    PubMed Central

    van Lith, Sanne A. M.; Navis, Anna C.; Lenting, Krissie; Verrijp, Kiek; Schepens, Jan T. G.; Hendriks, Wiljan J. A. J.; Schubert, Nil A.; Venselaar, Hanka; Wevers, Ron A.; van Rooij, Arno; Wesseling, Pieter; Molenaar, Remco J.; van Noorden, Cornelis J. F.; Pusch, Stefan; Tops, Bastiaan; Leenders, William P. J.

    2016-01-01

    The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP+ to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased α-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1R314C, which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1R314C lacks isocitrate-to-α-KG conversion activity due to reduced affinity for NADP+, and differs from the IDH1R132 mutants in that it does not produce D-2-HG. Because IDH1R314C is defective in producing α-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite. PMID:27460417

  14. Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas.

    PubMed

    Bender, Aaron M; Collier, Lara S; Rodriguez, Fausto J; Tieu, Christina; Larson, Jon D; Halder, Chandralekha; Mahlum, Eric; Kollmeyer, Thomas M; Akagi, Keiko; Sarkar, Gobinda; Largaespada, David A; Jenkins, Robert B

    2010-05-01

    The Sleeping Beauty (SB) transposon system has been used as an insertional mutagenesis tool to identify novel cancer genes. To identify glioma-associated genes, we evaluated tumor formation in the brain tissue from 117 transgenic mice that had undergone constitutive SB-mediated transposition. Upon analysis, 21 samples (18%) contained neoplastic tissue with features of high-grade astrocytomas. These tumors expressed glial markers and were histologically similar to human glioma. Genomic DNA from SB-induced astrocytoma tissue was extracted and transposon insertion sites were identified. Insertions in the growth factor gene Csf1 were found in 13 of the 21 tumors (62%), clustered in introns 5 and 8. Using reverse transcription-PCR, we documented increased Csf1 RNAs in tumor versus adjacent normal tissue, with the identification of transposon-terminated Csf1 mRNAs in astrocytomas with SB insertions in intron 8. Analysis of human glioblastomas revealed increased levels of Csf1 RNA and protein. Together, these results indicate that SB-insertional mutagenesis can identify high-grade astrocytoma-associated genes and they imply an important role for CSF1 in the development of these tumors. PMID:20388773

  15. 1. Mill exterior, high grade chute partially restored on the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Mill exterior, high grade chute partially restored on the outside of mill building center of picture. Looking northeast from below bridge. - Kennecott Copper Corporation, Concentration Mill, On Copper River & Northwestern Railroad, Kennicott, Valdez-Cordova Census Area, AK

  16. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 25 2011-07-01 2011-07-01 false High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  17. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  18. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 25 2014-07-01 2014-07-01 false High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  19. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 26 2013-07-01 2013-07-01 false High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  20. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 26 2012-07-01 2011-07-01 true High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  1. Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas

    PubMed Central

    Halani, Sameer H; Adamson, D Cory

    2016-01-01

    Surgical resection is typically the first line of treatment for gliomas. However, the neurosurgeon faces a major challenge in achieving maximal resection in high-grade gliomas as these infiltrative tumors make it difficult to discern tumor margins from normal brain with conventional white-light microscopy alone. To aid in resection of these infiltrative tumors, fluorescence-guided surgery has gained much popularity in intraoperative visualization of malignant gliomas, with 5-aminolevulinic acid (5-ALA) leading the way. First introduced in an article in Neurosurgery, 5-ALA has since become a safe, effective, and inexpensive method to visualize and improve resection of gliomas. This has undoubtedly led to improvements in the clinical course of patients as demonstrated by the increased overall and progression-free survival in patients with such devastating disease. This literature review aims to discuss the major studies and trials demonstrating the clinical utility of 5-ALA and its ability to aid in complete resection of malignant gliomas.

  2. Expression of voltage-activated chloride currents in acute slices of human gliomas.

    PubMed

    Ullrich, N; Bordey, A; Gillespie, G Y; Sontheimer, H

    1998-04-01

    Using whole-cell patch-clamp recordings, we identified a novel voltage-activated chloride current that was selectively expressed in glioma cells from 23 patient biopsies. Chloride currents were identified in 64% of glioma cells studied in acute slices of nine patient biopsies. These derived from gliomas of various pathological grades. In addition, 98% of cells acutely isolated or in short-term culture from 23 patients diagnosed with gliomas showed chloride current expression. These currents, which we termed glioma chloride currents activated at potentials >45 mV, showed pronounced outward rectification, and were sensitive to bath application of the presumed Cl- channel specific peptide chlorotoxin (approximately 600 nM) derived from Leiurus scorpion venom. Interestingly, low grade tumours (e.g., pilocytic astrocytomas), containing more differentiated, astrocyte-like cells showed expression of glioma chloride currents in concert with voltage-activated sodium and potassium currents also seen in normal astrocytes. By contrast, high grade tumours (e.g., glioblastoma multiforme) expressed almost exclusively chloride currents, suggesting a gradual loss of Na+ currents and gain of Cl- currents with increasing pathological tumour grade. To expand on the observation that these chloride currents are glioma-specific, we introduced experimental tumours in scid mice by intracranial injection of D54MG glioma cells and subsequently recorded from tumour cells and adjacent normal glial cells in acute slices. We consistently observed expression of chlorotoxin-sensitive chloride channels in implanted glioma cells, but without evidence for expression of chloride channels in surrounding "normal" host glial cells, suggesting that these chloride channels are probably a glioma-specific feature. Finding of this novel glioma specific Cl- channel in gliomas in situ and it's selective binding of chlorotoxin may provide a way to identify or target glioma cells in the future.

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

    PubMed

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

    2016-03-15

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

  4. Expression and prognostic significance of CTBP2 in human gliomas

    PubMed Central

    Wang, Yong; Che, Shusheng; Cai, Gang; He, Yuchao; Chen, Jialei; Xu, Wei

    2016-01-01

    Deregulated expression of C-terminal-binding protein 2 (CTBP2) has been observed previously in a number of tumors, such as hepatocellular carcinoma and prostatic cancer, in the colorectal cancer SW480 cell line and in the human embryonic kidney 293 cell line. In the present study, western blot analysis and immunohistochemistry were performed to investigate whether gliomas exhibit deregulated CTBP2 expression. Kaplan-Meier survival analyses were performed to evaluate the associations between CTBP2 expression, clinicopathological data and patient survival in glioma patients. The results revealed that CTBP2 expression was significantly upregulated in high grade glioma tissues compared with that in low grade glioma and normal brain tissues. Furthermore, increased CTBP2 expression in gliomas was significantly associated with a higher World Health Organization (WHO) tumor grade (P<0.005) and poorer disease-specific survival (P<0.005). In conclusion, these results suggest that CTBP2 may act as an intrinsic regulator of progression in glioma cells and thus may serve as an important prognostic factor for the disease.

  5. History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC).

    PubMed

    Amirian, E Susan; Scheurer, Michael E; Zhou, Renke; Wrensch, Margaret R; Armstrong, Georgina N; Lachance, Daniel; Olson, Sara H; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Jenkins, Robert B; Bernstein, Jonine L; Merrell, Ryan T; Davis, Faith G; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Melin, Beatrice S; Bondy, Melissa L

    2016-06-01

    Varicella zoster virus (VZV) is a neurotropic α-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted.

  6. History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC).

    PubMed

    Amirian, E Susan; Scheurer, Michael E; Zhou, Renke; Wrensch, Margaret R; Armstrong, Georgina N; Lachance, Daniel; Olson, Sara H; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Jenkins, Robert B; Bernstein, Jonine L; Merrell, Ryan T; Davis, Faith G; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Melin, Beatrice S; Bondy, Melissa L

    2016-06-01

    Varicella zoster virus (VZV) is a neurotropic α-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted. PMID:26972449

  7. KIF23 is an independent prognostic biomarker in glioma, transcriptionally regulated by TCF-4.

    PubMed

    Sun, Lihua; Zhang, Chuanbao; Yang, Zhengxiang; Wu, Yiping; Wang, Hongjun; Bao, Zhaoshi; Jiang, Tao

    2016-04-26

    Kinesin family member 23 (KIF23), a nuclear protein and a key regulator of cellular cytokinesis, has been found to be overexpressed as an oncogene in glioma. However, the prognostic and clinicopathological features of glioma with KIF23 expression was not clear yet. Here, we analyzed KIF23 expression pattern by using whole genome mRNA expression microarray data from Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn), and found that KIF23 overexpression was significantly associated with high grade glioma as well as the higher mortality in survival analysis (log-rank test, p<0.01). The results of the three other validation datasets showed similar findings. Furthermore, KIF23 also served as an independent prognostic biomarker in glioma patients. Finally, functional assay showed that reduction of KIF23 suppressed glioma cell proliferation both in vivo and vitro. Additionally, we found that KIF23 was regulated by TCF-4 at transcriptionally level. Therefore, this evidence indicates KIF23 over-expression is associated with glioma malignancy and conferred a worse survival time in glioma, which suggests KIF23 is a new novel prognostic biomarker with potential therapeutic implications in glioma. PMID:27013586

  8. KIF23 is an independent prognostic biomarker in glioma, transcriptionally regulated by TCF-4

    PubMed Central

    Yang, Zhengxiang; Wu, Yiping; Wang, Hongjun; Bao, Zhaoshi; Jiang, Tao

    2016-01-01

    Kinesin family member 23 (KIF23), a nuclear protein and a key regulator of cellular cytokinesis, has been found to be overexpressed as an oncogene in glioma. However, the prognostic and clinicopathological features of glioma with KIF23 expression was not clear yet. Here, we analyzed KIF23 expression pattern by using whole genome mRNA expression microarray data from Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn), and found that KIF23 overexpression was significantly associated with high grade glioma as well as the higher mortality in survival analysis (log-rank test, p<0.01). The results of the three other validation datasets showed similar findings. Furthermore, KIF23 also served as an independent prognostic biomarker in glioma patients. Finally, functional assay showed that reduction of KIF23 suppressed glioma cell proliferation both in vivo and vitro. Additionally, we found that KIF23 was regulated by TCF-4 at transcriptionally level. Therefore, this evidence indicates KIF23 over-expression is associated with glioma malignancy and conferred a worse survival time in glioma, which suggests KIF23 is a new novel prognostic biomarker with potential therapeutic implications in glioma. PMID:27013586

  9. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

    PubMed

    Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

    2015-12-01

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization. PMID:26645582

  10. Novel therapeutic delivery approaches in development for pediatric gliomas.

    PubMed

    Warren, Katherine E

    2013-09-01

    Pediatric gliomas are a heterogeneous group of diseases, ranging from relatively benign pilocytic astrocytomas with >90% 5-year survival, to glioblastomas and diffuse intrinsic pontine gliomas with <20% 5-year survival. Chemotherapy plays an important role in the management of these tumors, particularly in low-grade gliomas, but many high-grade tumors are resistant to chemotherapy. A major obstacle and contributor to this resistance is the blood–brain barrier, which protects the CNS by limiting entry of potential toxins, including chemotherapeutic agents. Several novel delivery approaches that circumvent the blood–brain barrier have been developed, including some currently in clinical trials. This review describes several of these novel approaches to improve delivery of chemotherapeutic agents to their site of action at the tumor, in attempts to improve their efficacy and the prognosis of children with this disease.

  11. Targeting autophagy to sensitive glioma to temozolomide treatment.

    PubMed

    Yan, Yuanliang; Xu, Zhijie; Dai, Shuang; Qian, Long; Sun, Lunquan; Gong, Zhicheng

    2016-02-02

    Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.

  12. Intraoperative radiation therapy in malignant glioma: early clinical results.

    PubMed

    Ortiz de Urbina, D; Santos, M; Garcia-Berrocal, I; Bustos, J C; Samblas, J; Gutierrez-Diaz, J A; Delgado, J M; Donckaster, G; Calvo, F A

    1995-08-01

    Intraoperative radiation therapy (IORT) with high energy electron beams is a treatment modality that has been included in multimodal programs in oncology to improve local tumor control. From August 1991 to December 1993, 17 patients with primary (8) or recurrent (9) high grade malignant gliomas, anaplastic astrocytoma (4), anaplastic oligodendroglioma (6) and glioblastoma multiforme (7), underwent surgical resection and a single dose of 10-20 Gy intraoperative radiation therapy was delivered in tumor bed. Fourteen patients received either pre-operative (8) or post-operative (6) external beam radiation therapy. Primary gliomas: 18-months actuarial survival rate has been 56% (range: 1-21+ months) and the median survival time has not yet been achieved. Four patients developed tumor progression (median time to tumor progression: 9 months). Recurrent gliomas: 18-months actuarial survival rate and median survival time has been 47% and 13 months (range: 6-32+ months) respectively. The median time to tumor progression was 11 months. No IORT related mortality has been observed. IORT is an attractive, tolerable and feasible treatment modality as antitumoral intensification procedure in high grade malignant gliomas.

  13. Institutional experience of paediatric high-grade central nervous system tumours: an analysis of 74 patients and review of the literature

    PubMed Central

    Oguz, Aynur; Karadeniz, Ceyda; Okur, Arzu; Sarac, Avni; Baykaner, Kemali; Bora, Huseyin; Poyraz, Aylar

    2012-01-01

    Aim of the study Although the survival for children with certain central nervous system (CNS) tumour types has improved through current surgical and adjuvant treatment modalities, the prognosis of many high-grade tumours remains poor despite aggressive treatment. The aim of this study is to analyse patients with high-grade brain tumours in our institution to determine the histopathology, clinical characteristics, treatment modalities, and survival. Material and methods A total of 74 patients with a diagnosis of high-grade brain tumour were analysed. There were a total of 31 patients with embryonal tumours, 27 patients with high-grade glial tumours, 12 patients with brain stem gliomas and 4 patients with other high-grade brain tumours. Results There were 48 (65%) boys and 26 (35%) girls (ratio: 1.85) with a median age of 99.7 months (range = 2-204 months). The median follow-up period was 19 months (range = 1-204 months). Tumour recurrence was observed in 38 patients (51.4%). The overall survival rate and event-free survival rate of our patients were 27% and 19.5%, respectively. Conclusions Pediatric high-grade CNS tumours have a very aggressive behaviour and a significant number of children eventually succumb to disease despite multimodal treatment. There is a need of more effective therapeutic approaches for these tumours with poor prognosis. The future improvement in childhood high-grade brain tumour management depends on a better understanding of the molecular genetics and biology of brain tumours. PMID:23788851

  14. Photodynamic therapy of Cervical Intraepithelial Neoplasia (CIN) high grade

    NASA Astrophysics Data System (ADS)

    Carbinatto, Fernanda M.; Inada, Natalia M.; Lombardi, Welington; da Silva, Eduardo V.; Belotto, Renata; Kurachi, Cristina; Bagnato, Vanderlei S.

    2016-02-01

    Cervical intraepithelial neoplasia (CIN) is the precursor of invasive cervical cancer and associated with human papillomavirus (HPV) infection. Photodynamic therapy (PDT) is a technique that has been used for the treatment of tumors. PDT is based on the accumulation of a photosensitizer in target cells that will generate cytotoxic reactive oxygen species upon illumination, inducing the death of abnormal tissue and PDT with less damaging to normal tissues than surgery, radiation, or chemotherapy and seems to be a promising alternative procedure for CIN treatment. The CIN high grades (II and III) presents potential indications for PDT due the success of PDT for CIN low grade treatment. The patients with CIN high grade that were treated with new clinic protocol shows lesion regression to CIN low grade 60 days after the treatment. The new clinical protocol using for treatment of CIN high grade shows great potential to become a public health technique.

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

    SciTech Connect

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

    2007-06-01

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

  16. Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells.

    PubMed

    Roy, Ananya; Coum, Antoine; Marinescu, Voichita D; Põlajeva, Jelena; Smits, Anja; Nelander, Sven; Uhrbom, Lene; Westermark, Bengt; Forsberg-Nilsson, Karin; Pontén, Fredrik; Tchougounova, Elena

    2015-09-15

    Glioblastoma (GBM) is a high-grade glioma with a complex microenvironment, including various inflammatory cells and mast cells (MCs) as one of them. Previously we had identified glioma grade-dependent MC recruitment. In the present study we investigated the role of plasminogen activator inhibitor 1 (PAI-1) in MC recruitment.PAI-1, a primary regulator in the fibrinolytic cascade is capable of forming a complex with fibrinolytic system proteins together with low-density lipoprotein receptor-related protein 1 (LRP1). We found that neutralizing PAI-1 attenuated infiltration of MCs. To address the potential implication of LRP1 in this process, we used a LRP1 antagonist, receptor-associated protein (RAP), and demonstrated the attenuation of MC migration. Moreover, a positive correlation between the number of MCs and the level of PAI-1 in a large cohort of human glioma samples was observed. Our study demonstrated the expression of LRP1 in human MC line LAD2 and in MCs in human high-grade glioma. The activation of potential PAI-1/LRP1 axis with purified PAI-1 promoted increased phosphorylation of STAT3 and subsequently exocytosis in MCs.These findings indicate the influence of the PAI-1/LRP1 axis on the recruitment of MCs in glioma. The connection between high-grade glioma and MC infiltration could contribute to patient tailored therapy and improve patient stratification in future therapeutic trials.

  17. Glioma grading using apparent diffusion coefficient map: application of histogram analysis based on automatic segmentation.

    PubMed

    Lee, Jeongwon; Choi, Seung Hong; Kim, Ji-Hoon; Sohn, Chul-Ho; Lee, Sooyeul; Jeong, Jaeseung

    2014-09-01

    The accurate diagnosis of glioma subtypes is critical for appropriate treatment, but conventional histopathologic diagnosis often exhibits significant intra-observer variability and sampling error. The aim of this study was to investigate whether histogram analysis using an automatically segmented region of interest (ROI), excluding cystic or necrotic portions, could improve the differentiation between low-grade and high-grade gliomas. Thirty-two patients (nine low-grade and 23 high-grade gliomas) were included in this retrospective investigation. The outer boundaries of the entire tumors were manually drawn in each section of the contrast-enhanced T1 -weighted MR images. We excluded cystic or necrotic portions from the entire tumor volume. The histogram analyses were performed within the ROI on normalized apparent diffusion coefficient (ADC) maps. To evaluate the contribution of the proposed method to glioma grading, we compared the area under the receiver operating characteristic (ROC) curves. We found that an ROI excluding cystic or necrotic portions was more useful for glioma grading than was an entire tumor ROI. In the case of the fifth percentile values of the normalized ADC histogram, the area under the ROC curve for the tumor ROIs excluding cystic or necrotic portions was significantly higher than that for the entire tumor ROIs (p < 0.005). The automatic segmentation of a cystic or necrotic area probably improves the ability to differentiate between high- and low-grade gliomas on an ADC map. PMID:25042540

  18. Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study.

    PubMed

    Buck, Jason R; McKinley, Eliot T; Fu, Allie; Abel, Ty W; Thompson, Reid C; Chambless, Lola; Watchmaker, Jennifer M; Harty, James P; Cooper, Michael K; Manning, H Charles

    2015-01-01

    Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.

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

    PubMed Central

    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.

    2014-01-01

    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. PMID:23903690

  20. The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas.

    PubMed

    Dasgupta, Tina; Haas-Kogan, Daphne A

    2013-01-01

    Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent, or refractory pediatric brain tumors, radiation therapy (XRT) is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in pediatric gliomas is being exploited with the use of specific targeted inhibitors. These agents are additionally being combined with XRT to increase the efficacy and duration of local control. In this review, we discuss novel agents targeting three different pathways in gliomas, and their potential combination with XRT. BRAF is a serine/threonine kinase in the RAS/RAF/MAPK kinase pathway, which is integral to cellular division, survival, and metabolism. Two-thirds of pilocytic astrocytomas, a low-grade pediatric glioma, contain a translocation within the BRAF gene called KIAA1549:BRAF that causes an overactivation of the MEK/MAPK signaling cascade. In vitro and in vivo data support the use of MEK or mammalian target of rapamycin (mTOR) inhibitors in low-grade gliomas expressing this translocation. Additionally, 15-20% of high-grade pediatric gliomas express BRAF V600E, an activating mutation of the BRAF gene. Pre-clinical in vivo and in vitro data in BRAF V600E gliomas demonstrate dramatic cooperation between XRT and small molecule inhibitors of BRAF V600E. Another major signaling cascade that plays a role in pediatric glioma pathogenesis is the PI3-kinase (PI3K)/mTOR pathway, known to be upregulated in the majority of high- and low-grade pediatric gliomas. Dual PI3K/mTOR inhibitors are in clinical trials for adult high-grade gliomas and are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis that render them refractory to treatment. An analog of thalidomide, CC-5103 increases the secretion of critical cytokines of the tumor

  1. Corpus callosum involvement and postoperative outcomes of patients with gliomas.

    PubMed

    Chen, Ko-Ting; Wu, Tai-Wei Erich; Chuang, Chi-Cheng; Hsu, Yung-Hsin; Hsu, Peng-Wei; Huang, Yin-Cheng; Lin, Tzu-Kang; Chang, Chen-Nen; Lee, Shih-Tseng; Wu, Chieh-Tsai; Tseng, Chen-Kan; Wang, Chun-Chieh; Pai, Ping-Ching; Wei, Kuo-Chen; Chen, Pin-Yuan

    2015-09-01

    Corpus callosum involvement is associated with poorer survival in high grade glioma (HGG), but the prognostic value in low grade glioma (LGG) is unclear. To determine the prognostic impact of corpus callosum involvement on progression free survival (PFS) and overall survival (OS) in HGG and LGG, the records of 233 glioma patients treated from 2008 to 2011 were retrospectively reviewed. Preoperative magnetic resonance (MR) images were used to identify corpus callosum involvement. Age, sex, preoperative Karnofsky performance scale, postoperative Eastern Cooperative Oncology Group (ECOG) score and extent of resection (EOR) were evaluated with respect to PFS and OS. The incidence of corpus callosum involvement was similar among HGG (14 %) and LGG (14.5 %). Univariate analysis revealed that PFS and OS were significantly shorter in both WHO grade II and grade IV glioma with corpus callosum involvement (both, p < 0.05). Multivariate analysis showed that grade II glioma with corpus callosum involvement have shorter PFS (p = 0.03), while EOR, instead of corpus callosum involvement (p = 0.16), was an independent factor associated with PFS in grade IV glioma (p < 0.05). Corpus callosum involvement was no longer significantly associated with OS after adjusting age, gender, EOR, preoperative and postoperative performance status (p = 0.16, 0.17 and 0.56 in grade II, III and IV gliomas, respectively). Corpus callosum involvement happened in both LGG and HGG, and is associated with lower EOR and higher postoperative ECOG score both in LGG and HGG. Corpus callosum involvement tends to be an independent prognostic factor for PFS in LGG, but not for OS in LGG or in HGG.

  2. Differential proteomics analysis of low- and high-grade of astrocytoma using iTRAQ quantification

    PubMed Central

    Ren, Tong; Lin, Shide; Wang, Zhongfeng; Shang, Aijia

    2016-01-01

    Astrocytoma is one of the most common types of brain tumor, which is histologically and clinically classified into four grades (I–IV): I (pilocytic astrocytoma), II (diffuse astrocytoma), III (anaplastic astrocytoma), and IV (glioblastoma multiforme). A higher grade astrocytoma represents a worse prognosis and is more aggressive. In this study, we compared the differential proteome profile of astrocytoma from grades I to IV. The protein samples from clinical specimens of grades I, II, III, and IV astrocytoma were analyzed by two-dimensional liquid chromatography–tandem mass spectrometry and isobaric tags for relative and absolute quantitation and quantification. A total of 2,190 proteins were identified. Compared to grade I astrocytoma, 173 (12.4%), 304 (14%), and 462 (21.2%) proteins were aberrantly expressed in grades II, III, and IV, respectively. By bioinformatics analysis, the cell proliferation, invasion, and angiogenesis-related pathways increase from low- to high-grade of astrocytoma. Five differentially expressed proteins were validated by Western blot. Within them, matrix metalloproteinase-9 and metalloproteinase inhibitor 1 were upregulated in glioblastoma multiforme group; whereas fibulin-2 and -5 were downregulated in grade II/III/IV astrocytoma, and the negative expression was significantly associated with advanced clinical stage. Functional analysis showed that both fibulin-2 and -5 may exert an antitumor effect by inhibiting cell proliferation, in vitro migration/invasion in glioma cells. New molecular biomarkers are likely to be used for accurate classification of astrocytoma and likely to be the target for drug development. PMID:27713642

  3. Pediatric high-grade astrocytomas: a distinct neuro-oncological paradigm.

    PubMed

    Gerges, Noha; Fontebasso, Adam M; Albrecht, Steffen; Faury, Damien; Jabado, Nada

    2013-01-01

    Brain tumors are the leading cause of cancer-related death in children. High-grade astrocytomas (HGAs), in particular, are lethal in children across all ages. Integrative genome-wide analyses of the tumor's genome, transcriptome and epigenome, using next-generation sequencing technologies and genome-wide DNA methylation arrays, have provided valuable breakthroughs in our understanding of the pathogenesis of HGAs across all ages. Recent profiling studies have provided insight into the epigenetic nature of gliomas in young adults and HGAs in children, particularly with the identification of recurrent gain-of-function driver mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) and the epigenetic influence of their oncometabolite 2-hydroxyglutarate, as well as mutations in the histone 3 variant 3 gene (H3F3A) and loss-of-function mutations in the histone 3 lysine 36 trimethyltransferase gene (SETD2). Mutations in H3F3A result in amino acid substitutions at residues thought to directly (K27M) or indirectly (G34R/V) affect histone post-translational modifications, suggesting they have the capacity to affect the epigenome in a profound manner. Here, we review recent genomic studies, and discuss evidence supporting the molecular characterization of pediatric HGAs to complement traditional approaches, such as histology of resected tumors. We also describe newly identified molecular mechanisms and discuss putative therapeutic approaches for HGAs specific to pediatrics, highlighting the necessity for the evolution of HGA disease management approaches. PMID:23906214

  4. Genetic epidemiology of glioma.

    PubMed

    Malmer, B; Iselius, L; Holmberg, E; Collins, A; Henriksson, R; Grönberg, H

    2001-02-01

    The present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second- and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model chi(2)(3) = 6.13, P< 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases. PMID:11161412

  5. Genetic epidemiology of glioma.

    PubMed

    Malmer, B; Iselius, L; Holmberg, E; Collins, A; Henriksson, R; Grönberg, H

    2001-02-01

    The present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second- and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model chi(2)(3) = 6.13, P< 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases.

  6. Comparison of Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging and Arterial Spin Labeling MR Imaging in Gliomas

    PubMed Central

    Zhang, Zhiqiang; Zhou, Zhenyu; Zhang, Zhongping; Zhang, Yong; Zhang, Zongjun

    2015-01-01

    Gliomas grading is important for treatment plan; we aimed to investigate the application of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in gliomas grading, by comparing with the three-dimensional pseudocontinuous arterial spin labeling (3D pCASL). 24 patients (13 high grade gliomas and 11 low grade gliomas) underwent IVIM DWI and 3D pCASL imaging before operation; maps of fast diffusion coefficient (D∗), slow diffusion coefficient (D), fractional perfusion-related volume (f), and apparent diffusion coefficient (ADC) as well as cerebral blood flow (CBF) were calculated and then coregistered to generate the corresponding parameter values. We found CBF and D∗ were higher in the high grade gliomas, whereas ADC, D, and f were lower (all P < 0.05). In differentiating the high from low grade gliomas, the maximum areas under the curves (AUC) of D∗, CBF, and ADC were 0.857, 0.85, and 0.902, respectively. CBF was negatively correlated with f in tumor (r = −0.619, P = 0.001). ADC was positively correlated with D in both tumor and white matter (r = 0.887, P = 0.000 and r = 0.824, P = 0.000, resp.). There was no correlation between CBF and D∗ in both tumor and white matter (P > 0.05). IVIM DWI showed more efficiency than 3D pCASL but less validity than conventional DWI in differentiating the high from low grade gliomas. PMID:25945328

  7. High Grade Leiomyosarcoma Mimicking a Recurrent Angiomyxoma in the Perineum

    PubMed Central

    Sood, Neha; Swaika, Abhisek; Hanooshi, Bashar; Waldorf, James; Peterson, Jennifer; Wu, Kevin; Attia, Steven; Dinh, Tri A.

    2015-01-01

    Perineal leiomyosarcoma is an extremely rare and aggressive cancer with a high metastatic potential and no defined standard treatment. There are only a few (six) reported cases in the literature. We report the case of a 67-year-old woman with a perineal leiomyosarcoma arising at the same site of a previously resected superficial angiomyxoma. Initially, she was treated for a presumptive recurrence of angiomyxoma. As she did not respond to medical therapy, she underwent repeat surgical excision. Pathology revealed a high grade leiomyosarcoma, histologically strikingly distinct from the initial diagnosis. She received adjuvant local radiation therapy, and remains without evidence of recurrent disease 36 months after completion of all therapy. This is the first reported case of a high grade perineal leiomyosarcoma originating at the same site as a resected benign superficial angiomyxoma. Our case emphasizes the necessity of a prompt histological diagnosis in cases of presumed recurrent perineal angiomyxoma. PMID:26266017

  8. High Grade Leiomyosarcoma Mimicking a Recurrent Angiomyxoma in the Perineum.

    PubMed

    Sood, Neha; Swaika, Abhisek; Hanooshi, Bashar; Waldorf, James; Peterson, Jennifer; Wu, Kevin; Attia, Steven; Dinh, Tri A

    2015-05-01

    Perineal leiomyosarcoma is an extremely rare and aggressive cancer with a high metastatic potential and no defined standard treatment. There are only a few (six) reported cases in the literature. We report the case of a 67-year-old woman with a perineal leiomyosarcoma arising at the same site of a previously resected superficial angiomyxoma. Initially, she was treated for a presumptive recurrence of angiomyxoma. As she did not respond to medical therapy, she underwent repeat surgical excision. Pathology revealed a high grade leiomyosarcoma, histologically strikingly distinct from the initial diagnosis. She received adjuvant local radiation therapy, and remains without evidence of recurrent disease 36 months after completion of all therapy. This is the first reported case of a high grade perineal leiomyosarcoma originating at the same site as a resected benign superficial angiomyxoma. Our case emphasizes the necessity of a prompt histological diagnosis in cases of presumed recurrent perineal angiomyxoma.

  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. PMID:26948349

  10. Selective nonoperative management of high grade splenic trauma.

    PubMed

    Branco, Bernardino C; Tang, Andrew L; Rhee, Peter; Fraga, Gustavo Pereira; Nascimento, Bartolomeu; Rizoli, Sandro; O'Keeffe, Terence

    2013-01-01

    The "Evidence-based Telemedicine - Trauma & Acute Care Surgery" (EBT-TACS) Journal Club performed a critical review of the literature and selected three up-to-date articles on the management of splenic trauma. Our focus was on high-grade splenic injuries, defined as AAST injury grade III-V. The first paper was an update of the 2003 Eastern Association for the Surgery of Trauma (EAST) practice management guidelines for nonoperative management of injury to the spleen. The second paper was an American Association for the Surgery of Trauma (AAST) 2012 plenary paper evaluating the predictive role of contrast blush on CT scan in AAST grade IV and V splenic injuries. Our last article was from Europe and investigates the effects of angioembolization of splenic artery on splenic function after high-grade splenic trauma (AAST grade III-V). The EBT-TACS Journal Club elaborated conclusions and recommendations for the management of high-grade splenic trauma. PMID:23912375

  11. Rare synchronous association of vestibular schwannoma and indolent insular oligodendroglioma in a patient without neurofibromatosis: controversial issue of timing for surgical treatment of asymptomatic low-grade gliomas.

    PubMed

    Iacoangeli, Maurizio; Di Rienzo, Alessandro; Colasanti, Roberto; Alvaro, Lorenzo; Nocchi, Niccolò; Polonara, Gabriele; Di Somma, Lucia Giovanna Maria; Zizzi, Antonio; Scarpelli, Marina; Scerrati, Massimo

    2012-01-01

    The co-occurrence of a vestibular schwannoma and a low-grade glioma is rare, and even rarer is the association with an oligodendroglioma. Although various authors have addressed the problem of treating patients with incidentally discovered indolent low-grade gliomas, an established protocol does not exist to date. The common approach is to reserve surgery until there is radiological evidence of tumor growth or high-grade transformation. However, because incidental low-grade glioma may represent the first stage of unavoidable pathological progression towards high-grade glioma, early and radical surgical resection should be advocated in order to increase the chance of a "cure" and prolonged survival. This case report supports this view, and suggests reflection on a possible change from a conservative philosophy to preventative surgical treatment.

  12. Brainstem Glioma in Adults

    PubMed Central

    Hu, Jethro; Western, Stephen; Kesari, Santosh

    2016-01-01

    Brainstem gliomas are not nearly as common in adults as they are in children. They are likely the final common consequence not of a single disease process but of several. They can be difficult to diagnose, and are challenging to treat. Clinical studies of this diagnosis are few and generally small. Because of these factors, our understanding of the biology of adult brainstem glioma is incomplete. However, the knowledge base is growing and progress is being made. In this article, we review the current state of knowledge for brainstem glioma in adults and identify key areas for which additional information is required. PMID:27556016

  13. Pathophysiology of glioma cyst formation.

    PubMed

    Adn, Mahmoudreza; Saikali, Stephan; Guegan, Yvon; Hamlat, Abderrahmane

    2006-01-01

    Fluid filled cystic cavities are accompaniments of some cerebral gliomas. These tumoural cysts together with peritumoural vasogenic brain oedema add to the morbid effects of the gliomas in terms of mass effect and increased intracranial pressure. Although different mechanisms have been suggested as to the pathogenesis of glioma-associated cysts, it is still unclear why these cysts appear in only a limited number of cerebral gliomas while brain oedema, a probable precursor of glioma cysts, is a usual accompaniment of most gliomas. Here, the authors present a two-hit hypothesis of brain glioma cyst formation. We suggest that after the formation of vasogenic tumoural brain oedema, microvascular phenomena may lead to the formation of microcysts, which might later become confluent and grow to form macroscopic cysts. Progress in the understanding of pathogenesis of cerebral glioma cysts might set targets for treatment of brain edema and glioma cysts.

  14. 18F FDOPA PET/CT or PET/MRI in Measuring Tumors in Patients With Newly Diagnosed or Recurrent Gliomas

    ClinicalTrials.gov

    2016-06-22

    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

  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. PMID:26510398

  16. (68)Ga-PRGD2 PET/CT in the evaluation of Glioma: a prospective study.

    PubMed

    Li, Deling; Zhao, Xiaobin; Zhang, Liwei; Li, Fang; Ji, Nan; Gao, Zhixian; Wang, Jisheng; Kang, Peng; Liu, Zhaofei; Shi, Jiyun; Chen, Xiaoyuan; Zhu, Zhaohui

    2014-11-01

    Integrin αvβ3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate (68)gallium-BNOTA-PRGD2 ((68)Ga-PRGD2) as a new reagent for noninvasive integrin αvβ3 imaging in glioma patients. With informed consent, 12 patients with suspicious brain glioma, as diagnosed by enhanced magnetic resonance imaging (MRI) scanning, were enrolled to undergo (68)Ga-PRGD2 PET/CT and (18)F-FDG PET/CT scans before surgery. The preoperative images were compared and correlated with the pathologically determined WHO grade. Next, the expression of integrin αvβ3, CD34, and Ki-67 were determined by immunohistochemical staining of the resected brain tumor tissue. Our findings demonstrated that (68)Ga-PRGD2 specifically accumulated in the brain tumors that were rich of integrin αvβ3 and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus. Therefore, (68)Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than (18)F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of (68)Ga-PRGD2, rather than those of (18)F-FDG, were significantly correlated with the glioma grading. The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas (68)Ga-PRGD2 seemed to be more superior to (18)F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, (68)Ga-PRGD2 PET/CT showed different accumulation patterns for HGG of WHO grades III and IV. This is the first noninvasive integrin imaging study, to the best of our knowledge, conducted in preoperative patients with different grades of glioma, and it preliminarily indicated the effectiveness of this novel method for evaluating glioma grading and demarcation.

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

    PubMed

    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

  18. 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

  19. Intraoperative stimulation techniques for functional pathway preservation and glioma resection.

    PubMed

    Sanai, Nader; Berger, Mitchel S

    2010-02-01

    Although a primary tenet of neurosurgical oncology is that survival can improve with greater tumor resection, this principle must be tempered by the potential for functional loss following a radical removal. Preoperative planning with functional and physiological imaging paradigms, combined with intraoperative strategies such as cortical and subcortical stimulation mapping, can effectively reduce the risks associated with operating in eloquent territory. In addition to identifying critical motor pathways, these techniques can be adapted to identify language function reliably. The authors review the technical nuances of intraoperative mapping for low- and high-grade gliomas, demonstrating their efficacy in optimizing resection even in patients with negative mapping data. Collectively, these surgical strategies represent the cornerstone for operating on gliomas in and around functional pathways.

  20. Trends in fluorescence image-guided surgery for gliomas.

    PubMed

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

    2014-07-01

    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 because of 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.

  1. The Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism

    PubMed Central

    Chinnaiyan, Prakash; Kensicki, Elizabeth; Bloom, Gregory; Prabhu, Antony; Sarcar, Bhaswati; Kahali, Soumen; Eschrich, Steven; Qu, Xiaotao; Forsyth, Peter; Gillies, Robert

    2015-01-01

    Although considerable progress has been made toward understanding glioblastoma biology through large-scale genetic and protein expression analyses, little is known about the underlying metabolic alterations promoting their aggressive phenotype. We conducted global metabolomic profiling on patient-derived glioma specimens and identified specific metabolic programs differentiating low- and high-grade tumors, with the metabolic signature of glioblastoma reflecting accelerated anabolic metabolism. When coupled with transcriptional profiles, we identified the metabolic phenotype of the mesenchymal subtype to consist of accumulation of the glycolytic intermediate phosphoenolpyruvate and decreased pyruvate kinase activity. Unbiased hierarchical clustering of metabolomic profiles identified three subclasses, which we term energetic, anabolic, and phospholipid catabolism with prognostic relevance. These studies represent the first global metabolomic profiling of glioma, offering a previously undescribed window into their metabolic heterogeneity, and provide the requisite framework for strategies designed to target metabolism in this rapidly fatal malignancy. PMID:23026133

  2. Immunotherapeutic Approaches for Glioma

    PubMed Central

    Okada, Hideho; Kohanbash, Gary; Zhu, Xinmei; Kastenhuber, Edward R.; Hoji, Aki; Ueda, Ryo; Fujita, Mitsugu

    2009-01-01

    The development of effective immunotherapy strategies for glioma requires adequate understanding of the unique immunological microenvironment in the central nervous system (CNS) and CNS tumors. Although the CNS is often considered to be an immunologically privileged site and poses unique challenges for the delivery of effector cells and molecules, recent advances in technology and discoveries in CNS immunology suggest novel mechanisms that may significantly improve the efficacy of immunotherapy against gliomas. In this review, we first summarize recent advances in the CNS and CNS tumor immunology. We address factors that may promote immune escape of gliomas. We also review advances in passive and active immunotherapy strategies for glioma, with an emphasis on lessons learned from recent early-phase clinical trials. We also discuss novel immunotherapy strategies that have been recently tested in non-CNS tumors and show great potential for application to gliomas. Finally, we discuss how each of these promising strategies can be combined to achieve clinical benefit for patients with gliomas. PMID:19348609

  3. Cell migration in paediatric glioma; characterisation and potential therapeutic targeting

    PubMed Central

    Cockle, J V; Picton, S; Levesley, J; Ilett, E; Carcaboso, A M; Short, S; Steel, L P; Melcher, A; Lawler, S E; Brüning-Richardson, A

    2015-01-01

    Background: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. Methods: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays. Results: All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging. Conclusions: Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours. PMID:25628092

  4. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.

    PubMed

    Bhat, Krishna P L; Salazar, Katrina L; Balasubramaniyan, Veerakumar; Wani, Khalida; Heathcock, Lindsey; Hollingsworth, Faith; James, Johanna D; Gumin, Joy; Diefes, Kristin L; Kim, Se Hoon; Turski, Alice; Azodi, Yasaman; Yang, Yuhui; Doucette, Tiffany; Colman, Howard; Sulman, Erik P; Lang, Frederick F; Rao, Ganesh; Copray, Sjef; Vaillant, Brian D; Aldape, Kenneth D

    2011-12-15

    Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.

  5. Diffuse intrinsic pontine glioma: poised for progress.

    PubMed

    Warren, Katherine E

    2012-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Numerous clinical trials of new agents and novel therapeutic approaches have been performed over the course of several decades in efforts to improve the outcome of children with DIPG, yet without success. The diagnosis of DIPG is based on radiographic findings in the setting of a typical clinical presentation, and tissue is not routinely obtained as the standard of care. The paradigm for treating children with these tumors has been based on that for supratentorial high-grade gliomas in adults as the biology of these lesions were presumed to be similar. However, recent pivotal studies demonstrate that DIPGs appear to be their own entity. Simply identifying this fact releases a number of constraints and opens opportunities for biologic investigation of these lesions, setting the stage to move forward in identifying DIPG-specific treatments. This review will summarize the current state of knowledge of DIPG, discuss obstacles to therapy, and summarize results of recent biologic studies.

  6. Irradiation of Pediatric High-Grade Spinal Cord Tumors

    SciTech Connect

    Tendulkar, Rahul D.; Pai Panandiker, Atmaram S.; Wu Shengjie; Kun, Larry E.; Broniscer, Alberto; Sanford, Robert A.; Merchant, Thomas E.

    2010-12-01

    Purpose: To report the outcome using radiation therapy (RT) for pediatric patients with high-grade spinal cord tumors. Methods and Materials: A retrospective chart review was conducted that included 17 children with high-grade spinal cord tumors treated with RT at St. Jude Children's Research Hospital between 1981 and 2007. Three patients had gross total resection, 11 had subtotal resection, and 3 underwent biopsy. The tumor diagnosis was glioblastoma multiforme (n = 7), anaplastic astrocytoma (n = 8), or anaplastic oligodendroglioma (n = 2). Seven patients received craniospinal irradiation (34.2-48.6 Gy). The median dose to the primary site was 52.2 Gy (range, 38-66 Gy). Results: The median progression-free and overall survivals were 10.8 and 13.8 months, respectively. Local tumor progression at 12 months (79% vs. 30%, p = 0.02) and median survival (13.1 vs. 27.2 months, p = 0.09) were worse for patients with glioblastoma multiforme compared with anaplastic astrocytoma or oligodendroglioma. The median overall survival was shorter for patients when failure included neuraxis dissemination (n = 8) compared with local failure alone (n = 5), 9.6 vs. 13.8 months, p = 0.08. Three long-term survivors with World Health Organization Grade III tumors were alive with follow-up, ranging from 88-239 months. Conclusions: High-grade spinal cord primary tumors in children have a poor prognosis. The propensity for neuraxis metastases as a component of progression after RT suggests the need for more aggressive therapy.

  7. High grade prostatic intraepithelial neoplasia with squamous differentiation

    PubMed Central

    Melissari, M; Beltran, A Lopez; Mazzucchelli, R; Froio, E; Bostwick, D G; Montironi, R

    2006-01-01

    An unusual variant of prostatic intraepithelial neoplasia with prominent and extensive squamous differentiation is described. The lesion was identified in the transition zone of a 79 year old man with a three year history of increasing urinary obstructive symptoms and a clinical diagnosis of benign prostatic hyperplasia who underwent simple prostatectomy. Two years after surgery, prostatic biopsies showed atrophy and mild chronic inflammation, with no evidence of malignancy. This unusual intraepithelial lesion seems not to have been described before and may represent a new variant of high grade prostatic intraepithelial neoplasia (HGPIN) with squamous differentiation. PMID:16567473

  8. Histopathological case report of high grade salivary duct carcinoma.

    PubMed

    Borovec, Jiri; Cegan, Martin; Mala, Katerina; Harmash, Natalia; Chramosta, Petr; Kobierzycki, Christopher; Bobek, Vladimir

    2015-01-01

    The case of a 39-year-old man with slowly growing mass in the superior part of left parotid region is described. Patient presented neurological symptoms including hypomobility of lower left eyelid and inability of complete closure of left side eyelids resulting in conjunctivitis and hyperlacrimation. Routine physical examination supported by image and laboratory tests was performed. Pathomorphological results of hematoxylin and eosin staining as well immunohistochemical examination in view of clinical presentation pointed to diagnosis of high grade salivary duct carcinoma. Rare incidence, histological view similar to breast cancer and body localization are sufficient reasons for further analyses and descriptions of this type of lesions. PMID:26691893

  9. Successful Management of Intraoperative Acute Bilateral Pulmonary Embolism in a High Grade Astrocytoma Patient.

    PubMed

    Khraise, Wail N; Allouh, Mohammed Z; Hiasat, Mohammad Y; Said, Raed S

    2016-01-01

    BACKGROUND Intraoperative pulmonary embolism (PE) is a rare life-threatening complication in patients undergoing surgical intervention. Generally, cancer patients have a higher risk for developing this complication. Unfortunately, there is no standard procedure for its management. CASE REPORT We report the case of a 39-year-old woman with high-grade glioma in the right frontal lobe who was admitted to the surgical theater for craniotomy and excision of the tumor. During the general anesthesia procedure and just before inserting the central venous line, her end-tidal CO2 and O2 saturation dropped sharply. The anesthesiologist quickly responded with an aggressive resuscitation procedure that included aspiration through the central venous line, 100% O2, and IV administration of ephedrine 6 mg, colloid 500 mL, normal saline 500 mL, and heparin 5000 IU. The patient was extubated and remained in the supine position until she regained consciousness and her vital signs returned to normal. Subsequent radiological examination revealed a massive bilateral PE. A retrievable inferior vena cava (IVC) filter was inserted, and enoxaparin anticoagulant therapy was prescribed to stabilize the patient's condition. After 3 weeks, she underwent an uneventful craniotomy procedure and was discharged a week later under the enoxaparin therapy. CONCLUSIONS The successful management of intraoperative PE requires a quick, accurate diagnosis accompanied with an aggressive, fast response. Anesthesiologists are usually the ones who are held accountable for the diagnosis and early management of this complication. They must be aware of the possibility of such a complication and be ready to react properly and decisively in the operation theater. PMID:27578311

  10. Successful Management of Intraoperative Acute Bilateral Pulmonary Embolism in a High Grade Astrocytoma Patient

    PubMed Central

    Khraise, Wail N.; Allouh, Mohammed Z.; Hiasat, Mohammad Y.; Said, Raed S.

    2016-01-01

    Patient: Female, 39 Final Diagnosis: Acute bilateral pulmonary embolism Symptoms: Headache • amnesia • seizure • urinary incontinence Medication: — Clinical Procedure: — Specialty: Anesthesiology Objective: Management of emergency care Background: Intraoperative pulmonary embolism (PE) is a rare life-threatening complication in patients undergoing surgical intervention. Generally, cancer patients have a higher risk for developing this complication. Unfortunately, there is no standard procedure for its management. Case Report: We report the case of a 39-year-old woman with high-grade glioma in the right frontal lobe who was admitted to the surgical theater for craniotomy and excision of the tumor. During the general anesthesia procedure and just before inserting the central venous line, her end-tidal CO2 and O2 saturation dropped sharply. The anesthesiologist quickly responded with an aggressive resuscitation procedure that included aspiration through the central venous line, 100% O2, and IV administration of ephedrine 6 mg, colloid 500 mL, normal saline 500 mL, and heparin 5000 IU. The patient was extubated and remained in the supine position until she regained consciousness and her vital signs returned to normal. Subsequent radiological examination revealed a massive bilateral PE. A retrievable inferior vena cava (IVC) filter was inserted, and enoxaparin anticoagulant therapy was prescribed to stabilize the patient’s condition. After 3 weeks, she underwent an uneventful craniotomy procedure and was discharged a week later under the enoxaparin therapy. Conclusions: The successful management of intraoperative PE requires a quick, accurate diagnosis accompanied with an aggressive, fast response. Anesthesiologists are usually the ones who are held accountable for the diagnosis and early management of this complication. They must be aware of the possibility of such a complication and be ready to react properly and decisively in the operation theater. PMID

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

    PubMed Central

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

    2014-01-01

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

  12. 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. PMID:26948350

  13. H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas.

    PubMed

    Gielen, Gerrit H; Gessi, Marco; Hammes, Jennifer; Kramm, Christof M; Waha, Andreas; Pietsch, Torsten

    2013-03-01

    Brain tumors are one of the most common childhood malignancies. Diffuse high-grade gliomas represent approximately 10% of pediatric brain tumors. Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors. We performed a pyrosequencing-based analysis for the identification of H3F3A codon 27 and codon 34 mutations in 338 pediatric brain tumors. The K27M mutation occurred in 35 of 129 glioblastomas (27.1%) and in 5 of 28 (17.9%) anaplastic astrocytomas. None of the other tumor entities showed H3F3A K27M mutation. Because H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas, analysis of codon 27 mutational status could be useful in the differential diagnosis of these neoplasms. PMID:23429371

  14. 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. PMID:26824661

  15. 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.

  16. Comprehensive protein tyrosine phosphatase mRNA profiling identifies new regulators in the progression of glioma.

    PubMed

    Bourgonje, Annika M; Verrijp, Kiek; Schepens, Jan T G; Navis, Anna C; Piepers, Jolanda A F; Palmen, Chantal B C; van den Eijnden, Monique; Hooft van Huijsduijnen, Rob; Wesseling, Pieter; Leenders, William P J; Hendriks, Wiljan J A J

    2016-01-01

    The infiltrative behavior of diffuse gliomas severely reduces therapeutic potential of surgical resection and radiotherapy, and urges for the identification of new drug-targets affecting glioma growth and migration. To address the potential role of protein tyrosine phosphatases (PTPs), we performed mRNA expression profiling for 91 of the 109 known human PTP genes on a series of clinical diffuse glioma samples of different grades and compared our findings with in silico knowledge from REMBRANDT and TCGA databases. Overall PTP family expression levels appeared independent of characteristic genetic aberrations associated with lower grade or high grade gliomas. Notably, seven PTP genes (DUSP26, MTMR4, PTEN, PTPRM, PTPRN2, PTPRT and PTPRZ1) were differentially expressed between grade II-III gliomas and (grade IV) glioblastomas. For DUSP26, PTEN, PTPRM and PTPRT, lower expression levels correlated with poor prognosis, and overexpression of DUSP26 or PTPRT in E98 glioblastoma cells reduced tumorigenicity. Our study represents the first in-depth analysis of PTP family expression in diffuse glioma subtypes and warrants further investigations into PTP-dependent signaling events as new entry points for improved therapy. PMID:27586084

  17. Neoadjuvant chemotherapy for high-grade advanced gastric cancer.

    PubMed

    Yonemura, Y; Sawa, T; Kinoshita, K; Matsuki, N; Fushida, S; Tanaka, S; Ohoyama, S; Takashima, T; Kimura, H; Kamata, T

    1993-01-01

    Fifty-five patients with high-grade advanced gastric cancer in whom the presence of stage IV was confirmed by preoperative diagnostic imaging were treated with PMUE therapy by a combined use of cisplatin (CDDP) 75 mg/m2, mitomycin C (MMC) 10 mg/body, etoposide 150 mg/body, and UFT (a combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil in a molar ratio of 1:4) 400 mg/day. CDDP and MMC was administered intravenously on the first day, followed by etoposide 50 mg/day on the 3rd, 4th, and 5th days. All the patients had measurable lesions that were evaluated by computed tomography scanning before and after the treatments. These patients were allocated randomly to two groups. Of these cases, 29 belonged to the neoadjuvant chemotherapy (NAC) group to whom PMUE therapy was given preoperatively; the remaining 26 patients underwent operation first and received PMUE thereafter (control group). Background factors did not differ significantly between the two groups. The response rate was higher in the NAC group than in the control group (62% in the former versus 35% in the latter). The resectability rates were 79% and 88% in the NAC and control groups, respectively. However, the rate of potentially curable cases was higher in the NAC group than in the control group (38% in the former versus 15% in the latter). Among the nonresection cases, the prognosis was highly unfavorable in both groups. In the resection cases, however, the survival rate was significantly better in the NAC group than in the control group. These results may indicate that in patients with high-grade, advanced gastric cancer initial chemotherapy (neoadjuvant chemotherapy) and then surgery should be considered. PMID:8511923

  18. Chromosomal Aberrations in Canine Gliomas Define Candidate Genes and Common Pathways in Dogs and Humans.

    PubMed

    Dickinson, Peter J; York, Dan; Higgins, Robert J; LeCouteur, Richard A; Joshi, Nikhil; Bannasch, Danika

    2016-07-01

    Spontaneous gliomas in dogs occur at a frequency similar to that in humans and may provide a translational model for therapeutic development and comparative biological investigations. Copy number alterations in 38 canine gliomas, including diffuse astrocytomas, glioblastomas, oligodendrogliomas, and mixed oligoastrocytomas, were defined using an Illumina 170K single nucleotide polymorphism array. Highly recurrent alterations were seen in up to 85% of some tumor types, most notably involving chromosomes 13, 22, and 38, and gliomas clustered into 2 major groups consisting of high-grade IV astrocytomas, or oligodendrogliomas and other tumors. Tumor types were characterized by specific broad and focal chromosomal events including focal loss of the INK4A/B locus in glioblastoma and loss of the RB1 gene and amplification of the PDGFRA gene in oligodendrogliomas. Genes associated with the 3 critical pathways in human high-grade gliomas (TP53, RB1, and RTK/RAS/PI3K) were frequently associated with canine aberrations. Analysis of oligodendrogliomas revealed regions of chromosomal losses syntenic to human 1p involving tumor suppressor genes, such as CDKN2C, as well as genes associated with apoptosis, autophagy, and response to chemotherapy and radiation. Analysis of high frequency chromosomal aberrations with respect to human orthologues may provide insight into both novel and common pathways in gliomagenesis and response to therapy.

  19. Chromosomal Aberrations in Canine Gliomas Define Candidate Genes and Common Pathways in Dogs and Humans.

    PubMed

    Dickinson, Peter J; York, Dan; Higgins, Robert J; LeCouteur, Richard A; Joshi, Nikhil; Bannasch, Danika

    2016-07-01

    Spontaneous gliomas in dogs occur at a frequency similar to that in humans and may provide a translational model for therapeutic development and comparative biological investigations. Copy number alterations in 38 canine gliomas, including diffuse astrocytomas, glioblastomas, oligodendrogliomas, and mixed oligoastrocytomas, were defined using an Illumina 170K single nucleotide polymorphism array. Highly recurrent alterations were seen in up to 85% of some tumor types, most notably involving chromosomes 13, 22, and 38, and gliomas clustered into 2 major groups consisting of high-grade IV astrocytomas, or oligodendrogliomas and other tumors. Tumor types were characterized by specific broad and focal chromosomal events including focal loss of the INK4A/B locus in glioblastoma and loss of the RB1 gene and amplification of the PDGFRA gene in oligodendrogliomas. Genes associated with the 3 critical pathways in human high-grade gliomas (TP53, RB1, and RTK/RAS/PI3K) were frequently associated with canine aberrations. Analysis of oligodendrogliomas revealed regions of chromosomal losses syntenic to human 1p involving tumor suppressor genes, such as CDKN2C, as well as genes associated with apoptosis, autophagy, and response to chemotherapy and radiation. Analysis of high frequency chromosomal aberrations with respect to human orthologues may provide insight into both novel and common pathways in gliomagenesis and response to therapy. PMID:27251041

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

    ClinicalTrials.gov

    2016-07-08

    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

  1. Fractal analysis: fractal dimension and lacunarity from MR images for differentiating the grades of glioma.

    PubMed

    Smitha, K A; Gupta, A K; Jayasree, R S

    2015-09-01

    Glioma, the heterogeneous tumors originating from glial cells, generally exhibit varied grades and are difficult to differentiate using conventional MR imaging techniques. When this differentiation is crucial in the disease prognosis and treatment, even the advanced MR imaging techniques fail to provide a higher discriminative power for the differentiation of malignant tumor from benign ones. A powerful image processing technique applied to the imaging techniques is expected to provide a better differentiation. The present study focuses on the fractal analysis of fluid attenuation inversion recovery MR images, for the differentiation of glioma. For this, we have considered the most important parameters of fractal analysis, fractal dimension and lacunarity. While fractal analysis assesses the malignancy and complexity of a fractal object, lacunarity gives an indication on the empty space and the degree of inhomogeneity in the fractal objects. Box counting method with the preprocessing steps namely binarization, dilation and outlining was used to obtain the fractal dimension and lacunarity in glioma. Statistical analysis such as one-way analysis of variance and receiver operating characteristic (ROC) curve analysis helped to compare the mean and to find discriminative sensitivity of the results. It was found that the lacunarity of low and high grade gliomas vary significantly. ROC curve analysis between low and high grade glioma for fractal dimension and lacunarity yielded 70.3% sensitivity and 66.7% specificity and 70.3% sensitivity and 88.9% specificity, respectively. The study observes that fractal dimension and lacunarity increases with an increase in the grade of glioma and lacunarity is helpful in identifying most malignant grades.

  2. Visualization of heterogeneity and regional grading of gliomas by multiple features using magnetic resonance-based clustered images

    PubMed Central

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

    2016-01-01

    Preoperative glioma grading is important for therapeutic strategies and influences prognosis. Intratumoral heterogeneity can cause an underestimation of grading because of the sampling error in biopsies. We developed a voxel-based unsupervised clustering method with multiple magnetic resonance imaging (MRI)-derived features using a self-organizing map followed by K-means. This method produced novel magnetic resonance-based clustered images (MRcIs) that enabled the visualization of glioma grades in 36 patients. The 12-class MRcIs revealed the highest classification performance for the prediction of glioma grading (area under the receiver operating characteristic curve = 0.928; 95% confidential interval = 0.920–0.936). Furthermore, we also created 12-class MRcIs in four new patients using the previous data from the 36 patients as training data and obtained tissue sections of the classes 11 and 12, which were significantly higher in high-grade gliomas (HGGs), and those of classes 4, 5 and 9, which were not significantly different between HGGs and low-grade gliomas (LGGs), according to a MRcI-based navigational system. The tissues of classes 11 and 12 showed features of malignant glioma, whereas those of classes 4, 5 and 9 showed LGGs without anaplastic features. These results suggest that the proposed voxel-based clustering method provides new insights into preoperative regional glioma grading. PMID:27456199

  3. Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis

    PubMed Central

    Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

    2015-01-01

    Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1+ tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the “classical-like” (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients’ outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1+ cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1- cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1+ cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

  4. Expression and prognostic value of the WEE1 kinase in gliomas.

    PubMed

    Music, Darija; Dahlrot, Rikke Hedegaard; Hermansen, Simon Kjær; Hjelmborg, Jacob; de Stricker, Karin; Hansen, Steinbjørn; Kristensen, Bjarne Winther

    2016-04-01

    High-grade gliomas have an aggressive clinical course and new clinical biomarkers and therapeutic targets are highly needed. WEE1 is a regulator of the G2 checkpoint in glioblastoma (GBM) cells. Inhibition of this kinase has, in experimental glioma studies, been suggested to enhance sensitivity to irradiation and temozolomide. However, expression level and prognostic potential of WEE1 protein in gliomas remain uninvestigated. In this study, glioma samples from 235 patients across all four WHO grades were analyzed by immunohistochemistry. Using image analysis, we calculated the area fraction of WEE1 positive nuclei. We found that WEE1 protein was localized in tumor cell nuclei and expressed in all glioma types and grades. Although WEE1 protein levels are higher in GBMs (mean 24.5%) relative to grade III (mean 14,0%, p < 0.05) and grade II (mean 6.8%, p < 0.001) gliomas, high WEE1 protein was associated with better survival in GBMs (p = 0.002). This was confirmed in multivariate analysis (HR 0.60, p = 0.003) even when adjusted for MGMT status (HR 0.60, p = 0.005). In conclusion, we report a nuclear expression of WEE1 protein in all glioma grades and types. The WEE1 positive nuclear area was correlated with malignancy grade but it was inversely associated with prognosis in GBM. Although WEE1 is a frequently occurring protein and has been proposed as a novel target in GBM, the role of WEE1 in glioma patient survival appears to be connected to the MGMT status and is more complex than previously anticipated.

  5. Potential Diagnostic and Prognostic Value of Plasma Circulating MicroRNA-182 in Human Glioma

    PubMed Central

    Xiao, Yilei; Zhang, Lina; Song, Zikun; Guo, Chuanjun; Zhu, Jianxin; Li, Zhongmin; Zhu, Shugan

    2016-01-01

    Background Previous studies showed the aberrant expression of microRNA-182 (miR-182) in glioma tissue. However, the exact role of circulating miR-182 in glioma remains unclear. Here, we confirmed the expression of plasma circulating miR-182 in glioma patients, and further explored its potential diagnostic and prognostic value. Material/Methods Real-time quantitative PCR (RT-PCR) was used to measure circulating cell-free miR-182 from 112 glioma patients and 54 healthy controls. Results Our findings showed that the level of circulating miR-182 in glioma patients was higher than that in healthy controls (P<0.001), which was significantly associated with KPS score (P=0.025) and WHO grade (P<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.778. The optimal cut-off value was 1.56, and the sensitivity and specificity were 58.5% and 85.2%, respectively. Interestingly, a high predictive value of circulating miR-182 was observed in high-grade glioma (AUC=0.815). However, the AUC was lower in low-grade glioma (AUC=0.621). Kaplan-Meier analysis demonstrated that the cumulative 5-year overall survival rate in the high miR-182 group was significantly lower than that in the low miR-182 group in both overall survival (OS) (P=0.003) and disease-free survival (DFS) (P=0.006). Moreover, multivariate Cox analysis revealed that circulating miR-182 was an independent prognostic indicator for OS (P=0.034) and DFS (P=0.013). Conclusions These results suggest that circulating miR-182 may be a potential noninvasive biomarker for the diagnosis and prognosis of human glioma. PMID:26978735

  6. Expression and prognostic value of the WEE1 kinase in gliomas.

    PubMed

    Music, Darija; Dahlrot, Rikke Hedegaard; Hermansen, Simon Kjær; Hjelmborg, Jacob; de Stricker, Karin; Hansen, Steinbjørn; Kristensen, Bjarne Winther

    2016-04-01

    High-grade gliomas have an aggressive clinical course and new clinical biomarkers and therapeutic targets are highly needed. WEE1 is a regulator of the G2 checkpoint in glioblastoma (GBM) cells. Inhibition of this kinase has, in experimental glioma studies, been suggested to enhance sensitivity to irradiation and temozolomide. However, expression level and prognostic potential of WEE1 protein in gliomas remain uninvestigated. In this study, glioma samples from 235 patients across all four WHO grades were analyzed by immunohistochemistry. Using image analysis, we calculated the area fraction of WEE1 positive nuclei. We found that WEE1 protein was localized in tumor cell nuclei and expressed in all glioma types and grades. Although WEE1 protein levels are higher in GBMs (mean 24.5%) relative to grade III (mean 14,0%, p < 0.05) and grade II (mean 6.8%, p < 0.001) gliomas, high WEE1 protein was associated with better survival in GBMs (p = 0.002). This was confirmed in multivariate analysis (HR 0.60, p = 0.003) even when adjusted for MGMT status (HR 0.60, p = 0.005). In conclusion, we report a nuclear expression of WEE1 protein in all glioma grades and types. The WEE1 positive nuclear area was correlated with malignancy grade but it was inversely associated with prognosis in GBM. Although WEE1 is a frequently occurring protein and has been proposed as a novel target in GBM, the role of WEE1 in glioma patient survival appears to be connected to the MGMT status and is more complex than previously anticipated. PMID:26738845

  7. Barrett's esophagus: management of high-grade dysplasia and cancer.

    PubMed

    Ruol, Alberto; Zaninotto, Giovanni; Costantini, Mario; Battaglia, Giorgio; Cagol, Matteo; Alfieri, Rita; Epifani, Magdalena; Ancona, Ermanno

    2004-03-01

    Esophagectomy remains the treatment of choice for the appropriate patient with Barrett's adenocarcinoma invading beyond the mucosa, without evidence of distant metastasis or invasion of adjacent organs. On the other hand, therapeutic management of patients with Barrett's high-grade dysplasia (HGD) or mucosal adenocarcinoma should be individualized, taking into account the patient's preferences, willingness to return for frequent endoscopic biopsies, and medical fitness to undergo esophagectomy. Surgery has to be considered the best treatment for HGD or superficial carcinoma, unless contraindicated by severe comorbidities, because it has proven to be the only treatment that is successful in curing the condition and preventing recurrent HGD or the development of invasive cancer. Nonsurgical treatment by photodynamic therapy or endoscopic mucosal resection may be a less invasive and organ-sparing option for elderly, poor-risk patients but it is still to be considered an investigational therapy that should only be conducted under a clinical trial protocol. Finally, intensive endoscopic biopsy surveillance of patients with HGD is another investigational option that may allow prompt treatment of cancer if it develops. However, few data document the safety of this observational approach. PMID:15013713

  8. Second Surgery in Insular Low-Grade Gliomas

    PubMed Central

    Ius, Tamara; Pauletto, Giada; Cesselli, Daniela; Isola, Miriam; Turella, Luca; Budai, Riccardo; DeMaglio, Giovanna; Eleopra, Roberto; Fadiga, Luciano; Lettieri, Christian; Pizzolitto, Stefano; Beltrami, Carlo Alberto; Skrap, Miran

    2015-01-01

    Background. Given the technical difficulties, a limited number of works have been published on insular gliomas surgery and risk factors for tumor recurrence (TR) are poorly documented. Objective. The aim of the study was to determine TR in adult patients with initial diagnosis of insular Low-Grade Gliomas (LGGs) that subsequently underwent second surgery. Methods. A consecutive series of 53 patients with insular LGGs was retrospectively reviewed; 23 patients had two operations for TR. Results. At the time of second surgery, almost half of the patients had experienced progression into high-grade gliomas (HGGs). Univariate analysis showed that TR is influenced by the following: extent of resection (EOR) (P < 0.002), ΔVT2T1 value (P < 0.001), histological diagnosis of oligodendroglioma (P = 0.017), and mutation of IDH1 (P = 0.022). The multivariate analysis showed that EOR at first surgery was the independent predictor for TR (P < 0.001). Conclusions. In patients with insular LGG the EOR at first surgery represents the major predictive factor for TR. At time of TR, more than 50% of cases had progressed in HGG, raising the question of the oncological management after the first surgery. PMID:26539503

  9. Identification and Evaluation of Serum MicroRNA-29 Family for Glioma Screening.

    PubMed

    Wu, Junhua; Li, Liwen; Jiang, Chunping

    2015-12-01

    Glioma is one of the most common primary central nervous system tumors with high mortality and poor 5-year survival rate. Current diagnostic methods for glioma were either invasive or expensive. MicroRNAs (miRNAs) are small non-coding RNAs which play an important part in the regulation of gene expression. Considering the fact that miRNAs are stable in serum, plasma, urine, and other body fluids, they show great promises to be convenient and non-invasive biomarkers for cancers. This study aimed at evaluating the availability of serum microRNA-29 (miR-29) family in screening of glioma. A meta-analysis was also performed to assess the predictive value of miR-29 family in multi-cancer screening. Serum samples were collected from 83 glioma patients at different stages and 69 healthy controls. RNA was extracted and the relative expression of serum miR-29 was acquired by qRT-PCR and calculated by Cycle threshold (Ct) with microRNA-24 as an internal control. In the meta-analysis, studies concerning the predictive value of miR-29 family in cancer were retrieved. The predictive value of serum miR-29 family for glioma was moderate (AUC = 0.74). But the predictive value of serum miR-29 family in high-graded glioma detection was sufficient (AUC = 0.81). Also, serum miR-29 family might not be applicable in early-stage glioma detection (AUC = 0.66). A high predictive value of miR-29 family in multi-cancer detection was observed from meta-analysis (AUC = 0.83). This study manifested that serum miR-29 family could be applied as a biomarker for high-graded glioma screening, but the sensitivity and specificity for low-graded glioma detection might not be sufficient. A meta-analysis concerning the predictive value of miR-29 family in multi-cancer detection concluded that miR-29 family might be a sufficient universal biomarker for cancer.

  10. Collapse in High-Grade Stenosis during Pulsatile Flow Experiments

    NASA Astrophysics Data System (ADS)

    Kobayashi, Shunichi; Tang, Dalin; Ku, David N.

    It has been hypothesized that blood flow through high grade stenotic arteries may produce conditions in which elastic flow choking may occur. The development of atherosclerotic plaque fracture may be exacerbated by the compressive stresses during collapse. This study explored the effects of pulsatile flow on stenotic flow collapse. Pulsatile flow was produced using a gear pump controlled by a digitized physiologic waveform. Upstream and downstream mean pressures and pulsatile flow rates were measured and digitized. An improved model of arterial stenosis was created using an elastomer with an incremental modulus of elasticity matched to a bovine carotid artery in the relevant range of collapse. Additionally, the model retained a very thick wall in the stenotic region similar to arterial disease. Flow choking was observed for pulsatile pressure drops close to those previously reported for steady flow. The phase difference between flow rate and pressure between upstream and downstream of the stenosis occurred by the compliance of tube and stenosis resistance. For 80% nominal stenosis by diameter and 100+/-30mmHg upstream pressure, collapse occurred for average pulsatile pressure drops of 93mmHg. Pulsatile flow experiments in this model revealed the range of conditions for the flow choking and the paradoxical collapse of the stenosis during systole with expansion during diastole. The stenosis severity was dynamic through the pulse cycle and was significantly greater under flow than the nominal severity. The results indicate that flow choking and stenotic compression may be significant in thick-walled arterial stenoses subjected to pulsatile flow.

  11. Suprasellar chordoid glioma.

    PubMed

    Ricoy, J R; Lobato, R D; Báez, B; Cabello, A; Martínez, M A; Rodríguez, G

    2000-06-01

    Brat et al. (J Neuropathol Exp Neurol 57:288-290, 1998) reported eight cases of a new clinico-pathological entity, which occurs mainly in the third ventricle of middle-aged females, which they described as chordoid glioma of the third ventricle. We report a new case of a 41-year-old woman with a suprasellar chordoid glioma with histological, immunohistochemical and ultrastructural studies. We discuss the differential diagnosis between chordoma, chordoid meningioma, germinoma and pituitary adenoma. Histologically, the tumour showed cords and lobules of isomorphic epithelioid cells in a vacuolated matrix with prominent multifocal lymphoplasmacytic infiltrates in which some histiocytes and isolated Touton-type giant cells were seen; cells were immunoreactive for glial fibrillary acidic protein but negative for epithelial membrane antigen. Ultrastructural examination revealed abundant intermediate filament but no desmosomes, microvilli nor cilia were seen.

  12. 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

  13. Epidermal growth factor (EGF) as a potential targeting agent for delivery of boron to malignant gliomas

    SciTech Connect

    Capala, J.; Barth, R.F.; Adams, D.M.; Bailey, M.Q.; Soloway, A.H.; Carlsson, J.

    1994-12-31

    The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of {sup 10}B to tumor cells with an amplified number of EGFR. Human glioma cells can expresses as many as 10{sup 5} {minus}10{sup 6} EGF receptors per cell, and if these could be saturated with boronated EGF, then > 10{sup 8} boron atoms would be delivered per cell. Since EGF has a comparatively low molecular weight ({approximately} 6 kD), this has allowed us to construct relatively small bioconjugates containing {approximately} 900 boron atoms per EGF molecule{sup 3}, which also had high affinity for EGFR on tumor cells. In the present study, the feasibility of using EGF receptors as a potential target for therapy of gliomas was investigated by in vivo scintigraphic studies using {sup 131}I{minus} or {sup 99m}{Tc}-labeled EGF in a rat brain tumor model. Our results indicate that intratumorally delivered boron- EGF conjugates might be useful for targeting EGFR on glioma cells if the boron containing moiety of the conjugates persisted intracellularly. Further studies are required, however, to determine if this approach can be used for BNCT of the rat glioma.

  14. Construction and analysis of dynamic transcription factor regulatory networks in the progression of glioma.

    PubMed

    Li, Yongsheng; Shao, Tingting; Jiang, Chunjie; Bai, Jing; Wang, Zishan; Zhang, Jinwen; Zhang, Lili; Zhao, Zheng; Xu, Juan; Li, Xia

    2015-11-03

    The combinatorial cross-regulation of transcription factors (TFs) plays an important role in cellular identity and function; however, the dynamic regulation of TFs during glioma progression remains largely unknown. Here, we used the genome-wide expression of TFs to construct an extensive human TF network comprising interactions among 513 TFs and to analyse the dynamics of the TF-TF network during glioma progression. We found that the TF regulatory networks share a common architecture and that the topological structures are conserved. Strikingly, despite the conservation of the network architecture, TF regulatory networks are highly grade specific, and TF circuitry motifs are dynamically rewired during glioma progression. In addition, the most frequently observed structure in the grade-specific TF networks was the feedforward loop (FFL). We described applications that show how investigating the behaviour of FFLs in glioblastoma can reveal FFLs (such as RARG-NR1I2-CDX2) that are associated with prognosis. We constructed comprehensive TF-TF networks and systematically analysed the circuitry, dynamics, and topological principles of the networks during glioma progression, which will further enhance our understanding of the functions of TFs in glioma.

  15. Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas.

    PubMed

    Halani, Sameer H; Adamson, D Cory

    2016-01-01

    Surgical resection is typically the first line of treatment for gliomas. However, the neurosurgeon faces a major challenge in achieving maximal resection in high-grade gliomas as these infiltrative tumors make it difficult to discern tumor margins from normal brain with conventional white-light microscopy alone. To aid in resection of these infiltrative tumors, fluorescence-guided surgery has gained much popularity in intraoperative visualization of malignant gliomas, with 5-aminolevulinic acid (5-ALA) leading the way. First introduced in an article in Neurosurgery, 5-ALA has since become a safe, effective, and inexpensive method to visualize and improve resection of gliomas. This has undoubtedly led to improvements in the clinical course of patients as demonstrated by the increased overall and progression-free survival in patients with such devastating disease. This literature review aims to discuss the major studies and trials demonstrating the clinical utility of 5-ALA and its ability to aid in complete resection of malignant gliomas. PMID:27672334

  16. Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas

    PubMed Central

    Halani, Sameer H; Adamson, D Cory

    2016-01-01

    Surgical resection is typically the first line of treatment for gliomas. However, the neurosurgeon faces a major challenge in achieving maximal resection in high-grade gliomas as these infiltrative tumors make it difficult to discern tumor margins from normal brain with conventional white-light microscopy alone. To aid in resection of these infiltrative tumors, fluorescence-guided surgery has gained much popularity in intraoperative visualization of malignant gliomas, with 5-aminolevulinic acid (5-ALA) leading the way. First introduced in an article in Neurosurgery, 5-ALA has since become a safe, effective, and inexpensive method to visualize and improve resection of gliomas. This has undoubtedly led to improvements in the clinical course of patients as demonstrated by the increased overall and progression-free survival in patients with such devastating disease. This literature review aims to discuss the major studies and trials demonstrating the clinical utility of 5-ALA and its ability to aid in complete resection of malignant gliomas. PMID:27672334

  17. Transcriptome and small RNA deep sequencing reveals deregulation of miRNA biogenesis in human glioma.

    PubMed

    Moore, Lynette M; Kivinen, Virpi; Liu, Yuexin; Annala, Matti; Cogdell, David; Liu, Xiuping; Liu, Chang-Gong; Sawaya, Raymond; Yli-Harja, Olli; Shmulevich, Ilya; Fuller, Gregory N; Zhang, Wei; Nykter, Matti

    2013-02-01

    Altered expression of oncogenic and tumour-suppressing microRNAs (miRNAs) is widely associated with tumourigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumours. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and examined expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression.

  18. Transcriptome and Small RNA Deep Sequencing Reveals Deregulation of miRNA Biogenesis in Human Glioma

    PubMed Central

    Moore, Lynette M.; Kivinen, Virpi; Liu, Yuexin; Annala, Matti; Cogdell, David; Liu, Xiuping; Liu, Chang-Gong; Sawaya, Raymond; Yli-Harja, Olli; Shmulevich, Ilya; Fuller, Gregory N.; Zhang, Wei; Nykter, Matti

    2013-01-01

    Altered expression of oncogenic and tumor-suppressing microRNAs (miRNAs) is widely associated with tumorigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumors. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and interrogated expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression. PMID:23007860

  19. Inhibition of pentraxin 3 in glioma cells impairs proliferation and invasion in vitro and in vivo.

    PubMed

    Tung, Jai-Nien; Ko, Chung-Po; Yang, Shun-Fa; Cheng, Chun-Wen; Chen, Pei-Ni; Chang, Chia-Yu; Lin, Chia-Liang; Yang, Te-Fang; Hsieh, Yi-Hsien; Chen, Kun-Chung

    2016-09-01

    Pentraxin 3 (PTX3) is an inflammatory molecule that is involved in immune responses, inflammation, and cancer. Recent evidence suggests that PTX3 plays a critical role in tumor progression; however, its impact on the biological function of gliomas remains unknown. In the present study, immunohistochemical staining showed that patients with high-grade gliomas exhibited increased expression levels of PTX3 compared to those with low-grade gliomas (P < 0.001). Furthermore, knockdown of PTX3 in GBM8401 cells inhibits proliferation, increases p21 protein levels, and decreases cyclin D1 protein levels, resulting in cell cycle arrest at the G0/G1 phase. In addition, knockdown of PTX3 significantly decreases GBM8401 cell migration and invasion through the downregulation of matrix metalloproteinase-1 and -2 (MMP-1 and MMP-2) expression. In a GBM8401 xenograft animal model, PTX3 knockdown decreases tumor growth in vivo. In conclusion, PTX3 plays an important role in glioma cell proliferation and invasion, and may thus serve as a novel potential therapeutic target in the treatment of gliomas.

  20. Imaging hypoxia in gliomas

    PubMed Central

    Mendichovszky, I; Jackson, A

    2011-01-01

    Hypoxia plays a central role in tumour development, angiogenesis, growth and resistance to treatment. Owing to constant developments in medical imaging technology, significant advances have been made towards in vitro and in vivo imaging of hypoxia in a variety of tumours, including gliomas of the central nervous system. The aim of this article is to review the literature on imaging approaches currently available for measuring hypoxia in human gliomas and provide an insight into recent advances and future directions in this field. After a brief overview of hypoxia and its importance in gliomas, several methods of measuring hypoxia will be presented. These range from invasive monitoring by Eppendorf polarographic O2 microelectrodes, positron electron tomography (PET) tracers based on 2-nitroimidazole compounds [18F-labelled fluoro-misonidazole (18F-MISO) or 1-(2-[(18)F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole (FRP-170)], 64Cu-ATSM Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) or 99mTc- and 68Ga-labelled metronidazole (MN) agents to advanced MRI methods, such as blood oxygenation level dependent (BOLD) MRI, oxygen-enhanced MRI, diffusion-weighted MRI (DWI-MRI), dynamic contrast-enhanced MRI (DCE-MRI) and 1H-magnetic resonance spectroscopy. PMID:22433825

  1. Methylation of the miR-126 gene associated with glioma progression.

    PubMed

    Cui, Hongwei; Mu, Yongping; Yu, Lei; Xi, Ya-guang; Matthiesen, Rune; Su, Xiulan; Sun, Wenjie

    2016-04-01

    Gliomas are the most common and the most malignant brain tumors, accouting for 45-55% of all intracranial tumors. The incidence of glioma worldwide is about 6-12 per 100,000. Recently, several studies showed that the activation of the oncogenes and the inactivation and/or loss of the tumor suppressor genes, especially for miRNA-21, let-7 and so on, are the most primary molecule event in gliomas. MicroRNAs (miRNAs) are a class of endogenously expressed small noncoding RNAs which are usually 21-23 nucleotides long. miRNAs regulate gene expression and play important roles in a variety of physiological and pathological processes, such as cell proliferation, differentiation and apoptosis. To date, Growing evidence has shown that mi RNAs are frequently dysregulated in human cancers and can act as both tumor suppressors and oncogenes. Along with the discovery of micro RNA, more and more research focusing on its relationship with glioma was carried out to investigate the biological features of glioma and to provide experimental evidence for glioma mechanism. In the present study, we aimed to verify the miRNA-126 down-regulation which showed in the results of glioma tissue miRNAs chip and discuss the miRNA-126 methylation in patients with glioma. A total of 50 samples from patients with glioma and 20 control samples from patients with cerebral trauma were included in this study. The expression levels of the miR-126 gene were detected using quantitative polymerase chain reaction (PCR), and the methylation status of miR-126 was examined using methylation-specific PCR-denaturing high-performance liquid chromatography (MSP-DHPLC). The expression level of miRNA-126 was found to be significantly higher in the control group (0.6134 ± 0.1214) than in the glioma group (0.2771 ± 0.1529; P < 0.05). The expression was also significantly elevated in low-grade gliomas (0.3117 ± 0.1474) compared with high-grade gliomas (0.1582 ± 0.1345; P < 0.05). In addition, increased methylation of

  2. MicroRNA-326 functions as a tumor suppressor in glioma by targeting the Nin one binding protein (NOB1).

    PubMed

    Zhou, Jingxu; Xu, Tao; Yan, Yong; Qin, Rong; Wang, Hongxiang; Zhang, Xiaoping; Huang, Yan; Wang, Yuhai; Lu, Yicheng; Fu, Da; Chen, Juxiang

    2013-01-01

    Malignant glioma is the most common type of primary brain tumor in adults, characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. Alterations in the activity of the 26S proteasome have been associated with malignant glioma cells, although the specific defects have not been identified. Recently, microRNA-326 (miR-326) was shown to play an important role in glioblastoma and breast cancer, but the underlying molecular mechanisms remain unclear. In the present study, the human Nin one binding protein (NOB1) was identified as a direct target of miR-326 and a potential oncogene in human glioma. Similar to NOB1 silencing by shRNA, overexpression of miR-326 in human glioma cell lines (A172 and U373) caused cell cycle arrest at the G1 phase, delayed cell proliferation and enhanced apoptosis. MiR-326 inhibited colony formation in soft agar and decreased growth of a xenograft tumor model, suggesting that miR-326 and NOB1 are required for tumorigenesis in vitro and in vivo. Furthermore, these processes were shown to involve the MAPK pathway. NOB1 overexpression in human glioma samples was detected by Affymetrix array analysis, and NOB1 mRNA and protein levels were shown to be increased in high-grade glioma compared to low-grade glioma and normal brain tissue. Furthermore, high levels of NOB1 were associated with unfavorable prognosis of glioma patients. Taken together, these results indicate that miR-326 and NOB1 may play an important role in the development of glioma.

  3. The positive correlation between DJ-1 and β-catenin expression shows prognostic value for patients with glioma.

    PubMed

    Wang, Chao; Fang, Mao; Zhang, Meng; Li, Weiping; Guan, Hong; Sun, Yanhua; Xie, Siming; Zhong, Xueyun

    2013-12-01

    The relationship between DJ-1 and β-catenin, and its impact on the prognosis for glioma patients has not been fully understood. This study determined the effect of DJ-1 on β-catenin and the prognostic significance of this interaction in glioma patients. We collected tumor specimens from 88 glioma patients and determined the expression of DJ-1, β-catenin and PTEN by using immunohistochemical staining. The involvement of DJ-1 and β-catenin in glioma cell lines was evaluated by immunohistochemistry and Western blotting. High DJ-1 expression (37.5%) and high β-catenin expression (34.1%) in glioma specimens were significantly associated with high grade and poor prognosis in glioma patients. However, only high levels of DJ-1 (P = 0.014) was a strong independent prognostic factor, correlated with a reduced overall survival time. In vitro DJ-1 expression was positively correlated with the expression levels of β-catenin and p-Akt, and negatively correlated with PTEN expression in U87, U251 MG, SWO-38 and SHG44 human glioma cell lines. After the knockdown of DJ-1, Akt, p-Akt or β-catenin expression levels were not affected in the PTEN-null cell lines (U87 and U251 MG). However, in the SWO-38 cell line, which has wild-type PTEN protein, the level of PTEN increased while Akt/p-Akt and β-catenin levels were reduced. Furthermore, β-catenin staining weakened in SWO-38 cells after DJ-1 levels decreased according to immunocytochemical analysis. In conclusion, DJ-1 and β-catenin may contribute to the development and recurrence of glioma and are valuable prognostic factors for glioma patients. DJ-1 may regulate β-catenin expression via PTEN and p-Akt.

  4. 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.

  5. HOXA13 is a potential GBM diagnostic marker and promotes glioma invasion by activating the Wnt and TGF-β pathways

    PubMed Central

    Duan, Ran; Han, Lei; Wang, Qixue; Wei, Jianwei; Chen, Luyue; Zhang, Jianning; Kang, Chunsheng; Wang, Lei

    2015-01-01

    Homeobox (HOX) genes, including HOXA13, are involved in human cancer. We found that HOXA13 expression was associated with glioma grade and prognosis. Bioinformatics analysis revealed that most of the HOXA13-associated genes were enriched in cancer-related signaling pathways and mainly involved in the regulation of transcription. We transfected four glioma cell lines with Lenti-si HOXA13. HOXA13 increased cell proliferation and invasion and inhibited apoptosis. HOXA13 decreased β-catenin, phospho-SMAD2, and phospho-SMAD3 in the nucleus and increased phospho-β-catenin in the cytoplasm. Furthermore, downregulation of HOXA13 in orthotopic tumors decreased tumor growth. We suggest that HOXA13 promotes glioma progression in part via Wnt- and TGF-β-induced EMT and is a potential diagnostic biomarker for glioblastoma and an independent prognostic factor in high-grade glioma. PMID:26356815

  6. Contributors to contrast between glioma and brain tissue in chemical exchange saturation transfer sensitive imaging at 3 Tesla.

    PubMed

    Scheidegger, Rachel; Wong, Eric T; Alsop, David C

    2014-10-01

    Off-resonance saturation transfer images have shown intriguing differences in intensity in glioma compared to normal brain tissues. Interpretation of these differences is complicated, however, by the presence of multiple sources of exchanging magnetization including amide, amine, and hydroxyl protons, asymmetric magnetization transfer contrast (MTC) from macromolecules, and various protons with resonances in the aliphatic spectral region. We report a study targeted at separating these components and identifying their relative contributions to contrast in glioma. Off-resonance z-spectra at several saturation powers and durations were obtained from 6 healthy controls and 8 patients with high grade glioma. Results indicate that broad macromolecular MTC in normal brain tissue is responsible for the majority of contrast with glioma. Amide exchange could be detected with lower saturation power than has previously been reported in glioma, but it was a weak signal source with no detectable contrast from normal brain tissue. At higher saturation powers, amine proton exchange was a major contributor to the observed signal but showed no significant difference from normal brain. Robust acquisition strategies that effectively isolate the contributions of broad macromolecular MTC asymmetry from amine exchange were demonstrated that may provide improved contrast between glioma and normal tissue. PMID:24857712

  7. Suppressor of fused (Sufu) represses Gli1 transcription and nuclear accumulation, inhibits glioma cell proliferation, invasion and vasculogenic mimicry, improving glioma chemo-sensitivity and prognosis

    PubMed Central

    Chen, Lingchao; Wang, Guangzhi; Cui, Yuqiong; Liu, Yang; Dou, Zhijin; Wang, Hongjun; Zhang, Ping; Chang, Liang; Yi, Liye; Cai, Jinquan; Jiang, Chuanlu

    2014-01-01

    Glioblastoma are highly aggressive brain tumors with poor prognosis. While various dysregulation of signaling pathways in gliomas have been described, the identification of biomarkers and therapy targets remains an important task for novel diagnostic and therapeutic approaches. Here we described that the Suppressor of fused (also known as Sufu) is significantly down-regulated in high-grade gliomas, correlating with a poor prognosis. We demonstrated that ectopic expression of Sufu inhibited cell proliferation, invasion and vasculogenic mimicry. In addition, overexpression of Sufu reduced Gli reporter gene transcription activity and prevented Gli1 nuclear accumulation, whereas knockdown of Sufu reversed these effects. Furthermore, overexpressed Sufu sensitized glioblastoma to Temozolomide and Cyclopamine. Thus, Sufu is potential tumor suppressor and therapeutic target in glioblastoma. PMID:25373737

  8. Gliomas: Application of Cumulative Histogram Analysis of Normalized Cerebral Blood Volume on 3 T MRI to Tumor Grading

    PubMed Central

    Kim, Hyungjin; Choi, Seung Hong; Kim, Ji-Hoon; Ryoo, Inseon; Kim, Soo Chin; Yeom, Jeong A.; Shin, Hwaseon; Jung, Seung Chai; Lee, A. Leum; Yun, Tae Jin; Park, Chul-Kee; Sohn, Chul-Ho; Park, Sung-Hye

    2013-01-01

    Background Glioma grading assumes significant importance in that low- and high-grade gliomas display different prognoses and are treated with dissimilar therapeutic strategies. The objective of our study was to retrospectively assess the usefulness of a cumulative normalized cerebral blood volume (nCBV) histogram for glioma grading based on 3 T MRI. Methods From February 2010 to April 2012, 63 patients with astrocytic tumors underwent 3 T MRI with dynamic susceptibility contrast perfusion-weighted imaging. Regions of interest containing the entire tumor volume were drawn on every section of the co-registered relative CBV (rCBV) maps and T2-weighted images. The percentile values from the cumulative nCBV histograms and the other histogram parameters were correlated with tumor grades. Cochran’s Q test and the McNemar test were used to compare the diagnostic accuracies of the histogram parameters after the receiver operating characteristic curve analysis. Using the parameter offering the highest diagnostic accuracy, a validation process was performed with an independent test set of nine patients. Results The 99th percentile of the cumulative nCBV histogram (nCBV C99), mean and peak height differed significantly between low- and high-grade gliomas (P = <0.001, 0.014 and <0.001, respectively) and between grade III and IV gliomas (P = <0.001, 0.001 and <0.001, respectively). The diagnostic accuracy of nCBV C99 was significantly higher than that of the mean nCBV (P = 0.016) in distinguishing high- from low-grade gliomas and was comparable to that of the peak height (P = 1.000). Validation using the two cutoff values of nCBV C99 achieved a diagnostic accuracy of 66.7% (6/9) for the separation of all three glioma grades. Conclusion Cumulative histogram analysis of nCBV using 3 T MRI can be a useful method for preoperative glioma grading. The nCBV C99 value is helpful in distinguishing high- from low-grade gliomas and grade IV from III gliomas. PMID:23704910

  9. Low c-Met expression levels are prognostic for and predict the benefits of temozolomide chemotherapy in malignant gliomas

    PubMed Central

    Li, Ming-Yang; Yang, Pei; Liu, Yan-Wei; Zhang, Chuan-Bao; Wang, Kuan-Yu; Wang, Yin-Yan; Yao, Kun; Zhang, Wei; Qiu, Xiao-Guang; Li, Wen-Bin; Peng, Xiao-Xia; Wang, Yong-Zhi; Jiang, Tao

    2016-01-01

    Aberrant c-Met has been implicated in the development of many cancers. The objective of this study was to identify an unfavorable prognostic marker that might guide decisions regarding clinical treatment strategies for high-grade gliomas. C-Met expression was measured using immunohistochemistry in 783 gliomas, and we further analyzed c-Met mRNA levels using the Agilent Whole Genome mRNA Microarray in 286 frozen samples. In vitro, we performed cell migration and invasion assays. Cell sensitivity to temozolomide (TMZ) chemotherapy was determined using MTT assays. Both mRNA and protein levels of c-Met were significantly associated with tumor grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas (all P < 0.0001). These findings were nearly consistent at the mRNA level across 3 independent cohorts. Multivariable analysis indicated that c-Met was an independent prognostic marker after adjusting for age, preoperative Karnofsky Performance Status (KPS) score, the extent of resection, radiotherapy, TMZ chemotherapy, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Further analysis in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy in H4 and U87 glioma cells. Our results suggest that c-Met may serve as a potential predictive maker for clinical decision making. PMID:26879272

  10. Identification of miRNA-Mediated Core Gene Module for Glioma Patient Prediction by Integrating High-Throughput miRNA, mRNA Expression and Pathway Structure

    PubMed Central

    Han, Junwei; Shang, Desi; Zhang, Yunpeng; Zhang, Wei; Yao, Qianlan; Han, Lei; Xu, Yanjun; Yan, Wei; Bao, Zhaoshi; You, Gan; Jiang, Tao; Kang, Chunsheng; Li, Xia

    2014-01-01

    The prognosis of glioma patients is usually poor, especially in patients with glioblastoma (World Health Organization (WHO) grade IV). The regulatory functions of microRNA (miRNA) on genes have important implications in glioma cell survival. However, there are not many studies that have investigated glioma survival by integrating miRNAs and genes while also considering pathway structure. In this study, we performed sample-matched miRNA and mRNA expression profilings to systematically analyze glioma patient survival. During this analytical process, we developed pathway-based random walk to identify a glioma core miRNA-gene module, simultaneously considering pathway structure information and multi-level involvement of miRNAs and genes. The core miRNA-gene module we identified was comprised of four apparent sub-modules; all four sub-modules displayed a significant correlation with patient survival in the testing set (P-values≤0.001). Notably, one sub-module that consisted of 6 miRNAs and 26 genes also correlated with survival time in the high-grade subgroup (WHO grade III and IV), P-value = 0.0062. Furthermore, the 26-gene expression signature from this sub-module had robust predictive power in four independent, publicly available glioma datasets. Our findings suggested that the expression signatures, which were identified by integration of miRNA and gene level, were closely associated with overall survival among the glioma patients with various grades. PMID:24809850

  11. Complications of glioma surgery.

    PubMed

    Jackson, Christina; Westphal, Manfred; Quiñones-Hinojosa, Alfredo

    2016-01-01

    Even with current advances in adjunctive therapies, including radiation, chemotherapy, and various clinical trials of gene therapy and immunotherapy, surgical resection remains one of the most effective treatment for intra-axial gliomas. Survival in these patients has been shown to be related to the extent of resection. In some cases, it can provide cures of long-term remission; in others, it can provide disease control when combined with the above adjunctive treatments. However, surgical resection carries its own risks and complications. These complications can be broadly divided into neurologic, regional, and systemic, including direct cortical and vascular injury, surgical wound complications, and postsurgical medical complications. Certain patient characteristics, including Karnofsky performance status score (KPS) and pathology of the tumor, have been shown to have an impact on the risk of postsurgical complications. Advancement in preoperative and intraoperative adjunct technology such as cortical mapping and navigation has improved the surgeon's ability to safely and maximally resect the tumors. It is therefore important to understand the perioperative complications after craniotomy and tumor resection and factors affecting morbidity and mortality in order for surgeons to optimally select and counsel patients who will benefit the most from surgical resection. This chapter will focus on the complications associated with craniotomy for intrinsic glioma and ways of avoiding these events.

  12. Chromosome abnormalities in glioma

    SciTech Connect

    Li, Y.S.; Ramsay, D.A.; Fan, Y.S.

    1994-09-01

    Cytogenetic studies were performed in 25 patients with gliomas. An interesting finding was a seemingly identical abnormality, an extra band on the tip of the short arm of chromosome 1, add(1)(p36), in two cases. The abnormality was present in all cells from a patient with a glioblastoma and in 27% of the tumor cells from a patient with a recurrent irradiated anaplastic astrocytoma; in the latter case, 7 unrelated abnormal clones were identified except 4 of those clones shared a common change, -Y. Three similar cases have been described previously. In a patient with pleomorphic astrocytoma, the band 1q42 in both homologues of chromosome 1 was involved in two different rearrangements. A review of the literature revealed that deletion of the long arm of chromosome 1 including 1q42 often occurs in glioma. This may indicate a possible tumor suppressor gene in this region. Cytogenetic follow-up studies were carried out in two patients and emergence of unrelated clones were noted in both. A total of 124 clonal breakpoints were identified in the 25 patients. The breakpoints which occurred three times or more were: 1p36, 1p22, 1q21, 1q25, 3q21, 7q32, 8q22, 9q22, 16q22, and 22q13.

  13. Molecular voting for glioma classification reflecting heterogeneity in the continuum of cancer progression.

    PubMed

    Fuller, Gregory N; Mircean, Cristian; Tabus, Ioan; Taylor, Ellen; Sawaya, Raymond; Bruner, Janet M; Shmulevich, Ilya; Zhang, Wei

    2005-09-01

    Gliomas, the most common brain tumors, are generally categorized into two lineages (astrocytic and oligodendrocytic) and further classified as low-grade (astrocytoma and oligodendroglioma), mid-grade (anaplastic astrocytoma and anaplastic oligodendroglioma), and high-grade (glioblastoma multiforme) based on morphological features. A strict classification scheme has limitations because a specific glioma can be at any stage of the continuum of cancer progression and may contain mixed features. Thus, a more comprehensive classification based on molecular signatures may reflect the biological nature of specific tumors more accurately. In this study, we used microarray technology to profile the gene expression of 49 human brain tumors and applied the k-nearest neighbor algorithm for classification. We first trained the classification gene set with 19 of the most typical glioma cases and selected a set of genes that provide the lowest cross-validation classification error with k=5. We then applied this gene set to the 30 remaining cases, including several that do not belong to gliomas such as atypical meningioma. The results showed that not only does the algorithm correctly classify most of the gliomas, but the detailed voting results also provide more subtle information regarding the molecular similarities to neighboring classes. For atypical meningioma, the voting was equally split among the four classes, indicating a difficulty in placement of meningioma into the four classes of gliomas. Thus, the actual voting results, which are typically used only to decide the winning class label in k-nearest neighbor algorithms, provide a useful method for gaining deeper insight into the stage of a tumor in the continuum of cancer development.

  14. Heparan sulfate in the regulation of neural differentiation and glioma development.

    PubMed

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

    2014-11-01

    Heparan sulfate proteoglycans (HSPGs) are the main components of the extracellular matrix, where they interact with a large number of physiologically important macromolecules. The sulfation pattern of heparan sulfate (HS) chains determines the interaction potential of the proteoglycans. Enzymes of the biosynthetic and degradation pathways for HS chains are thus important regulators in processes ranging from embryonic development to tissue homeostasis, but also for tumor development. Formation of the nervous system is also critically dependent on intact HSPGs, and several studies have outlined the role of HS in neural induction from embryonic stem cells. High-grade glioma is the most common malignant primary brain tumor among adults, and the outcome is poor. Neural stem cells and glioma stem cells have several common traits, such as sustained proliferation and a highly efficient migratory capacity in the brain. There are also similarities between the neurogenic niche where adult neural stem cells reside, and the tumorigenic niche. These include interactions with the extracellular matrix, and many of the matrix components are deregulated in glioma, e.g. HSPGs and enzymes implementing the biosynthesis and modification of HS. In this article, we will present how HS-regulated pathways are involved in neural differentiation, and discuss their impact on brain development. We will also review and critically discuss the important role of structural modifications of HS in glioma growth and invasion. We propose that targeting invasive mechanisms of glioma cells through modulation of HS structure and HS-mediated pathways may be an attractive alternative to other therapeutic attempts, which so far have only marginally increased survival for glioma patients. PMID:25284049

  15. Specific Visualization of Glioma Cells in Living Low-Grade Tumor Tissue

    PubMed Central

    Kantelhardt, Sven R.; Caarls, Wouter; de Vries, Anthony H. B.; Hagen, Guy M.; Jovin, Thomas M.; Schulz-Schaeffer, Walter; Rohde, Veit; Giese, Alf; Arndt-Jovin, Donna J.

    2010-01-01

    Background The current therapy of malignant gliomas is based on surgical resection, radio-chemotherapy and chemotherapy. Recent retrospective case-series have highlighted the significance of the extent of resection as a prognostic factor predicting the course of the disease. Complete resection in low-grade gliomas that show no MRI-enhanced images are especially difficult. The aim in this study was to develop a robust, specific, new fluorescent probe for glioma cells that is easy to apply to live tumor biopsies and could identify tumor cells from normal brain cells at all levels of magnification. Methodology/Principal Findings In this investigation we employed brightly fluorescent, photostable quantum dots (QDs) to specifically target epidermal growth factor receptor (EGFR) that is upregulated in many gliomas. Living glioma and normal cells or tissue biopsies were incubated with QDs coupled to EGF and/or monoclonal antibodies against EGFR for 30 minutes, washed and imaged. The data include results from cell-culture, animal model and ex vivo human tumor biopsies of both low-grade and high-grade gliomas and show high probe specificity. Tumor cells could be visualized from the macroscopic to single cell level with contrast ratios as high as 1000: 1 compared to normal brain tissue. Conclusions/Significance The ability of the targeted probes to clearly distinguish tumor cells in low-grade tumor biopsies, where no enhanced MRI image was obtained, demonstrates the great potential of the method. We propose that future application of specifically targeted fluorescent particles during surgery could allow intraoperative guidance for the removal of residual tumor cells from the resection cavity and thus increase patient survival. PMID:20614029

  16. View looking northwest toward HIghGrade Ore Bin and Concentrate Bin ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View looking northwest toward HIgh-Grade Ore Bin and Concentrate Bin - Kennecott Copper Corporation, Concentration Mill, On Copper River & Northwestern Railroad, Kennicott, Valdez-Cordova Census Area, AK

  17. Human leukocyte antigen-G overexpression predicts poor clinical outcomes in low-grade gliomas.

    PubMed

    Fan, Xing; Wang, Yinyan; Zhang, Chuanbao; Liu, Xing; Qian, Zenghui; Jiang, Tao

    2016-05-15

    Overexpression of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex class-I molecule associated with immunosuppression, has been reported in various human malignancies. In the present study, we examined the role of HLA-G in gliomas. Clinical characteristics, mRNA expression microarrays and follow-up data pertaining to 293 patients with histologically confirmed gliomas were analyzed. The expression levels of HLA-G were compared between different grades of gliomas and correlated with progression-free survival (PFS) and overall survival (OS) to evaluate its prognostic value. We found that HLA-G was overexpressed in gliomas as compared to that in normal brain tissue samples (-1.288±0.265). The highest expression levels were in glioblastomas (GBMs), anaplastic gliomas (AGs) and low-grade gliomas (LGGs), in that order (0.328±0.778, 0.176±0.881, -0.388±0.686, respectively). Significant inter-group differences were observed between low-grade and high-grade glioma tissues (p<0.001 and p<0.001, t-test, AGs and GBMs, respectively). More astrocytoma patients exhibited increased HLA-G expression as compared to other LGG patients (p=0.004, Chi-square test). Significant differences were observed with respect to PFS and OS (p=0.009 and 0.032, log-rank test, for PFS and OS, respectively) between the high- and low-expression subgroups in patients with LGGs. On Cox regression analysis, overexpression of HLA-G appeared to be an independent predictor of clinical outcomes (p=0.007 and 0.026, for PFS and OS, respectively). Our results suggest that HLA-G expression may serve as a potential biomarker for predicting aggressive tumor grades of gliomas and for histological subtype of LGGs. Elevated HLA-G expression could serve as an independent predictor of poor clinical outcomes in patients with low-grade gliomas.

  18. High-grade sarcomatous overgrowth in solitary fibrous tumors: a clinicopathologic study of 10 cases.

    PubMed

    Collini, Paola; Negri, Tiziana; Barisella, Marta; Palassini, Elena; Tarantino, Eva; Pastorino, Ugo; Gronchi, Alessandro; Stacchiotti, Silvia; Pilotti, Silvana

    2012-08-01

    We describe 10 solitary fibrous tumors (SFT) with high-grade malignant overgrowth, all of which showed the presence of a synchronous or previous classic SFT/malignant SFT (MSFT) component. Seven were "dedifferentiated," with an abrupt transition from a classic SFT/MSFT to a high-grade component consisting of a nondistinctive high-grade sarcoma in 4 cases and divergent differentiation in 3. The nondistinctive high-grade component consisted of epithelioid and/or spindle cells often associated with overt pleomorphism or small round cell sarcomas. The divergent differentiation featured a rhabdomyosarcoma in 2 cases and an osteosarcoma in 1. Three cases (tentatively called "evolved") showed a gradual transition from classic SFT/MSFT to a nondistinctive high-grade sarcoma or presented features of high-grade sarcoma at the time of metastasis (assessed by fine-needle aspiration cytology) without any component suggesting a diagnosis of classic SFT/MSFT. The high-grade component showed loss of CD34 expression in half of the dedifferentiated SFTs and all of the dedifferentiated SFTs with divergent differentiation, whereas Ki-67 was markedly increased in all of the evaluable cases and paralleled the tumor grade. In 4 cases, the expression and phosphorylation status of key factors that control transcription and protein synthesis were also investigated. Both S6 and 4E-BP1 showed low activation in the low-grade MSFT and a high level of activation in the high-grade component. Seven of the 10 patients died of their disease during follow-up, with a median overall survival of 73 months (range, 5 to 288 mo). The median time to distant metastasis was 156 months after the initial diagnosis, and median overall survival from the first signs of metastasis was 8 months.

  19. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression.

    PubMed

    Turner, Kristen M; Sun, Youting; Ji, Ping; Granberg, Kirsi J; Bernard, Brady; Hu, Limei; Cogdell, David E; Zhou, Xinhui; Yli-Harja, Olli; Nykter, Matti; Shmulevich, Ilya; Yung, W K Alfred; Fuller, Gregory N; Zhang, Wei

    2015-03-17

    Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.

  20. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

    PubMed Central

    Turner, Kristen M.; Sun, Youting; Ji, Ping; Granberg, Kirsi J.; Bernard, Brady; Hu, Limei; Cogdell, David E.; Zhou, Xinhui; Yli-Harja, Olli; Nykter, Matti; Shmulevich, Ilya; Yung, W. K. Alfred; Fuller, Gregory N.; Zhang, Wei

    2015-01-01

    Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. PMID:25737557

  1. Operative techniques for gliomas and the value of extent of resection.

    PubMed

    Sanai, Nader; Berger, Mitchel S

    2009-07-01

    Refinement of neurosurgical technique has enabled safer operations with more aggressive outcomes. One cornerstone of modern-day practice is the utilization of intraoperative stimulation mapping. In addition to identifying critical motor pathways, this technique can be adapted to reliably identify language pathways. Given the individual variability of cortical language localization, such awake language mapping is essential to minimize language deficits following tumor resection. Our experience suggests that cortical language mapping is a safe and efficient adjunct to optimize tumor resection while preserving essential language sites, even in the setting of negative mapping data. However, the value of maximizing glioma resections remains surprisingly unclear, as there is no general consensus in the literature regarding the efficacy of extent of glioma resection in improving patient outcome. While the importance of resection in obtaining tissue diagnosis and alleviating symptoms is clear, a lack of Class I evidence prevents similar certainty in assessing the influence of extent of resection. Beyond an analysis of modern intraoperative mapping techniques, we examine every major clinical publication since 1990 on the role of extent of resection in glioma outcome. The mounting evidence suggests that, despite persistent limitations in the quality of available studies, a more extensive surgical resection is associated with longer life expectancy for both low-grade and high-grade gliomas.

  2. Inhibition of the Sodium-Potassium-Chloride Cotransporter Isoform-1 Reduces Glioma Invasion

    PubMed Central

    Haas, Brian R.; Sontheimer, Harald

    2010-01-01

    Malignant gliomas metastasize throughout the brain by infiltrative cell migration into peritumoral areas. Invading cells undergo profound changes in cell shape and volume as they navigate extracellular spaces along blood vessels and white matter tracts. Volume changes are aided by the concerted release of osmotically active ions, most notably K+ and Cl−. Their efflux through ion channels along with obligated water causes rapid cell shrinkage. Suitable ionic gradients must be established and maintained through the activity of ion transport systems. Here, we show that the Sodium-Potassium-Chloride Cotransporter Isoform-1 (NKCC1) provides the major pathway for Cl− accumulation in glioma cells. NKCC1 localizes to the leading edge of invading processes and pharmacological inhibition using the loop diuretic bumetanide inhibits in vitro Transwell migration by 25–50%. shRNA-knockdowns of NKCC1 yielded a similar inhibition and a loss of bumetanide-sensitive cell volume regulation. A loss of NKCC1 function did not affect cell motility in two dimensional assays lacking spatial constraints but manifested only when cells had to undergo volume changes during migration. Intracranial implantation of human gliomas into SCID mice showed a marked reduction in cell invasion when NKCC1 function was disrupted genetically or by twice daily injection of the FDA approved NKCC1 inhibitor Bumex. This data supports consideration of Bumex as adjuvant therapy for patients with high grade gliomas. PMID:20570904

  3. Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.

    PubMed

    Venkatesh, Humsa S; Johung, Tessa B; Caretti, Viola; Noll, Alyssa; Tang, Yujie; Nagaraja, Surya; Gibson, Erin M; Mount, Christopher W; Polepalli, Jai; Mitra, Siddhartha S; Woo, Pamelyn J; Malenka, Robert C; Vogel, Hannes; Bredel, Markus; Mallick, Parag; Monje, Michelle

    2015-05-01

    Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

  4. Expressions of Endocan in Patients with Meningiomas and Gliomas

    PubMed Central

    Turk, Okan; Turkmen Inanir, Nursel

    2016-01-01

    Objective. Endocan has been shown to be a marker for several cancers and may show degree of malignancy. The aim of this study is to assess tissue levels of endocan in common brain tumors, namely, meningiomas, low-grade gliomas (LGGs), and high-grade gliomas (HGGs). Patients and Methods. Endocan was assayed by commercially available enzyme linked immunosorbent assay (ELISA) kits in a total of 50 brain tumors (20 meningiomas, 19 LGGs, and 20 HGGs) and 15 controls. The results were compared to control brain tissues. Results. Each tumor group showed significant higher levels of endocan compared to controls (p < 0.05). In addition, endocan levels showed steady increase from the least (meningiomas) to the most (HGGs) malignant tumors and positive correlation was noted between the degree of malignancy and endocan level (p = 0.0001). Conclusion. Endocan, a vital molecule for angiogenesis, is expressed in common brain tumors and results suggest that endocan could be a marker for malignancy. PMID:27528791

  5. High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis.

    PubMed

    Yi, Huan; Ye, Jun; Yang, Xiao-Mei; Zhang, Li-Wen; Zhang, Zhi-Gang; Chen, Ya-Ping

    2015-01-01

    Ovarian cancer, the most lethal gynecological cancer, related closely to tumor stage. High-grade ovarian cancer always results in a late diagnose and high recurrence, which reduce survival within five years. Until recently, curable therapy is still under research and anti-angiogenesis proves a promising way. Tumor-derived exosomes are essential in tumor migration and metastases such as angiogenesis is enhanced by exosomes. In our study, we have made comparison between high-grade and unlikely high-grade serous ovarian cancer cells on exosomal function of endothelial cells proliferation, migration and tube formation. Exosomes derived from high-grade ovarian cancer have a profound impact on angiogenesis with comparison to unlikely high-grade ovarian cancer. Proteomic profiles revealed some potential proteins involved in exosomal function of angiogenesis such as ATF2, MTA1, ROCK1/2 and so on. Therefore, exosomes plays an influential role in angiogenesis in ovarian serous cancer and also function more effectively in high-grade ovarian cancer cells.

  6. Surgery for gliomas.

    PubMed

    Tate, Matthew C

    2015-01-01

    Surgical resection, with the goal of maximal tumor removal, is now standard of care for the overwhelming majority of newly diagnosed gliomas. In order to achieve this goal while minimizing the risk of postoperative neurologic deficits, intraoperative brain mapping remains the gold standard. Recent advances in technical aspects of preoperative and intraoperative brain mapping, as well as our understanding of the functional anatomy of the human brain with respect to language, movement, sensation, and cognition, particularly at the subcortical level, have improved our ability to safely perform aggressive resective surgeries in eloquent areas. In this chapter, the functional anatomy of the human brain relevant to intrinsic tumor resection is reviewed. In addition, general principles governing surgical management of patients are highlighted, with a particular emphasis on awake brain mapping.

  7. Neural Stem Cell-Mediated Enzyme-Prodrug Therapy for Glioma: Preclinical Studies

    PubMed Central

    Aboody, Karen S.; Najbauer, Joseph; Metz, Marianne Z.; D’Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J.; Synold, Timothy W.; Couture, Larry A.; Blanchard, Suzette; Moats, Rex A.; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V.; Frank, Richard T.; Barish, Michael E.; Brown, Christine E.; Kim, Seung U.; Badie, Behnam; Portnow, Jana

    2013-01-01

    High-grade gliomas are extremely difficult to treat because they are invasive and therefore are not curable by surgical resection; the toxicity of currently chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles that can target enzyme/prodrug therapy selectively to tumors. We have used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the tumor-localized prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, indicating that these cells are genetically and functionally stable. In vivo biodistribution studies demonstrated that these NSCs retained tumor tropism, even in mice pre-treated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor bearing, and in orthotopic glioma-bearing, immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was approximately one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, non-toxic and effective in mice. These data have led to approval of a first-inhuman study of an allogeneic NSC-mediated enzyme/prodrug targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244

  8. 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.

  9. 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. PMID:27573687

  10. Pathology, Molecular Genetics, and Epigenetics of Diffuse Intrinsic Pontine Glioma.

    PubMed

    Buczkowicz, Pawel; Hawkins, Cynthia

    2015-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy. Histological similarity of DIPG to supratentorial high-grade astrocytomas of adults has led to assumptions that these entities possess similar underlying molecular properties and therefore similar therapeutic responses to standard therapies. The failure of all clinical trials in the last 30 years to improve DIPG patient outcome has suggested otherwise. Recent studies employing next-generation sequencing and microarray technologies have provided a breadth of evidence highlighting the unique molecular genetics and epigenetics of this cancer, distinguishing it from both adult and pediatric cerebral high-grade astrocytomas. This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity's unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels. The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues. PMID:26175967

  11. Pathology, Molecular Genetics, and Epigenetics of Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Buczkowicz, Pawel; Hawkins, Cynthia

    2015-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy. Histological similarity of DIPG to supratentorial high-grade astrocytomas of adults has led to assumptions that these entities possess similar underlying molecular properties and therefore similar therapeutic responses to standard therapies. The failure of all clinical trials in the last 30 years to improve DIPG patient outcome has suggested otherwise. Recent studies employing next-generation sequencing and microarray technologies have provided a breadth of evidence highlighting the unique molecular genetics and epigenetics of this cancer, distinguishing it from both adult and pediatric cerebral high-grade astrocytomas. This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity’s unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels. The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues. PMID:26175967

  12. General Information about Childhood Brain Stem Glioma

    MedlinePlus

    ... Brain Stem Glioma Treatment (PDQ®)–Patient Version General Information About Childhood Brain Stem Glioma Go to Health ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  13. Overdiagnosis of high-grade dysplasia in Barrett's esophagus: a multicenter, international study.

    PubMed

    Sangle, Nikhil A; Taylor, Shari L; Emond, Mary J; Depot, Michelle; Overholt, Bergein F; Bronner, Mary P

    2015-06-01

    Numerous histological mimics of high-grade dysplasia in Barrett's esophagus predispose to overdiagnosis and potential serious mismanagement, including unnecessary esophagectomy. This study investigates the prevalence and sources of this problem. Biopsies from 485 patients diagnosed with Barrett's high-grade dysplasia were screened for a multi-institutional, international Barrett's endoscopic ablation trial. Screening included review of the original diagnostic slides and an additional protocol endoscopy with an extensive biopsy sampling. Observer variability by the study pathologists was assessed through two blinded diagnostic rounds on 437 biopsies from 26 random study endoscopies. Study diagnostic reassessments revealed significantly lower rates of high-grade dysplasia. Only 248 patients (51%) were confirmed to have high-grade dysplasia. The remaining patients had inflamed gastric cardia without Barrett's (n=18; 7%), Barrett's without dysplasia (n=35; 15%), indefinite change (n=61; 26%), low-grade dysplasia (n=79; 33%), adenocarcinoma (n=43; 18%), and other (n=1; <1%), yielding an alarming total of 194 or 40% of patients who were overdiagnosed with Barrett's high-grade dysplasia. Study pathologists achieved a high-level agreement (90% three-way inter-observer agreement per biopsy, Kappa value 0.77) for high-grade dysplasia. Confounding factors promoting overdiagnosis included Barrett's inflammatory atypia (n=182), atypia limited to the basal metaplastic glands (n=147), imprecise criteria for low grade neoplasia (n=102), tangential sectioning artifact (n=59), and reactive gastric cardiac mucosa (n=38). A total of 194 patients (40%) were overdiagnosed with Barrett's high-grade dysplasia, as affirmed by the extensive screening process and high-level study pathologist agreement. The multiple diagnostic pitfalls uncovered should help raise pathologists' awareness of this problem and improve diagnostic accuracy.

  14. Comprehensive analysis of the functional microRNA–mRNA regulatory network identifies miRNA signatures associated with glioma malignant progression

    PubMed Central

    Li, Yongsheng; Xu, Juan; Chen, Hong; Bai, Jing; Li, Shengli; Zhao, Zheng; Shao, Tingting; Jiang, Tao; Ren, Huan; Kang, Chunsheng; Li, Xia

    2013-01-01

    Glioma is the most common and fatal primary brain tumour with poor prognosis; however, the functional roles of miRNAs in glioma malignant progression are insufficiently understood. Here, we used an integrated approach to identify miRNA functional targets during glioma malignant progression by combining the paired expression profiles of miRNAs and mRNAs across 160 Chinese glioma patients, and further constructed the functional miRNA–mRNA regulatory network. As a result, most tumour-suppressive miRNAs in glioma progression were newly discovered, whose functions were widely involved in gliomagenesis. Moreover, three miRNA signatures, with different combinations of hub miRNAs (regulations≥30) were constructed, which could independently predict the survival of patients with all gliomas, high-grade glioma and glioblastoma. Our network-based method increased the ability to identify the prognostic biomarkers, when compared with the traditional method and random conditions. Hsa-miR-524-5p and hsa-miR-628-5p, shared by these three signatures, acted as protective factors and their expression decreased gradually during glioma progression. Functional analysis of these miRNA signatures highlighted their critical roles in cell cycle and cell proliferation in glioblastoma malignant progression, especially hsa-miR-524-5p and hsa-miR-628-5p exhibited dominant regulatory activities. Therefore, network-based biomarkers are expected to be more effective and provide deep insights into the molecular mechanism of glioma malignant progression. PMID:24194606

  15. EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway.

    PubMed

    Bonavia, R; Inda, M M; Vandenberg, S; Cheng, S-Y; Nagane, M; Hadwiger, P; Tan, P; Sah, D W Y; Cavenee, W K; Furnari, F B

    2012-09-01

    Sustaining a high growth rate requires tumors to exploit resources in their microenvironment. One example of this is the extensive angiogenesis that is a typical feature of high-grade gliomas. Here, we show that expression of the constitutively active mutant epidermal growth factor receptor, ΔEGFR (EGFRvIII, EGFR*, de2-7EGFR) is associated with significantly higher expression levels of the pro-angiogenic factor interleukin (IL)-8 in human glioma specimens and glioma stem cells. Furthermore, the ectopic expression of ΔEGFR in different glioma cell lines caused up to 60-fold increases in the secretion of IL-8. Xenografts of these cells exhibit increased neovascularization, which is not elicited by cells overexpressing wild-type (wt)EGFR or ΔEGFR with an additional kinase domain mutation. Analysis of the regulation of IL-8 by site-directed mutagenesis of its promoter showed that ΔEGFR regulates its expression through the transcription factors nuclear factor (NF)-κB, activator protein 1 (AP-1) and CCAAT/enhancer binding protein (C/EBP). Glioma cells overexpressing ΔEGFR showed constitutive activation and DNA binding of NF-κB, overexpression of c-Jun and activation of its upstream kinase c-Jun N-terminal kinase (JNK) and overexpression of C/EBPβ. Selective pharmacological or genetic targeting of the NF-κB or AP-1 pathways efficiently blocked promoter activity and secretion of IL-8. Moreover, RNA interference-mediated knock-down of either IL-8 or the NF-κB subunit p65, in ΔEGFR-expressing cells attenuated their ability to form tumors and to induce angiogenesis when injected subcutaneously into nude mice. On the contrary, the overexpression of IL-8 in glioma cells lacking ΔEGFR potently enhanced their tumorigenicity and produced highly vascularized tumors, suggesting the importance of this cytokine and its transcription regulators in promoting glioma angiogenesis and tumor growth.

  16. EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway

    PubMed Central

    Bonavia, R; Inda, MM; Vandenberg, S; Cheng, S-Y; Nagane, M; Hadwiger, P; Tan, P; Sah, DWY; Cavenee, WK; Furnari, FB

    2012-01-01

    Sustaining a high growth rate requires tumors to exploit resources in their microenvironment. One example of this is the extensive angiogenesis that is a typical feature of high-grade gliomas. Here, we show that expression of the constitutively active mutant epidermal growth factor receptor, ΔEGFR (EGFRvIII, EGFR*, de2-7EGFR) is associated with significantly higher expression levels of the pro-angiogenic factor interleukin (IL)-8 in human glioma specimens and glioma stem cells. Furthermore, the ectopic expression of ΔEGFR in different glioma cell lines caused up to 60-fold increases in the secretion of IL-8. Xenografts of these cells exhibit increased neovascularization, which is not elicited by cells overexpressing wildtype (wt)EGFR or ΔEGFR with an additional kinase domain mutation. Analysis of the regulation of IL-8 by site-directed mutagenesis of its promoter showed that ΔEGFR regulates its expression through the transcription factors nuclear factor (NF)-κB, activator protein 1 (AP-1) and CCAAT/enhancer binding protein (C/EBP). Glioma cells overexpressing ΔEGFR showed constitutive activation and DNA binding of NF-κB, overexpression of c-Jun and activation of its upstream kinase c-Jun N-terminal kinase (JNK) and overexpression of C/EBPβ. Selective pharmacological or genetic targeting of the NF-κB or AP-1 pathways efficiently blocked promoter activity and secretion of IL-8. Moreover, RNA interference-mediated knock-down of either IL-8 or the NF-κB subunit p65, in ΔEGFR-expressing cells attenuated their ability to form tumors and to induce angiogenesis when injected subcutaneously into nude mice. On the contrary, the overexpression of IL-8 in glioma cells lacking ΔEGFR potently enhanced their tumorigenicity and produced highly vascularized tumors, suggesting the importance of this cytokine and its transcription regulators in promoting glioma angiogenesis and tumor growth. PMID:22139077

  17. 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. PMID:26948361

  18. Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma.

    PubMed

    Fonseca, Paula J; Uriol, Esther; Galván, José A; Alvarez, Carlos; Pérez, Quionia; Villanueva, Noemi; Berros, José P; Izquierdo, Marta; Viéitez, José M

    2013-01-01

    Treatment options for patients with high-grade pancreatic neuroendocrine tumors (pNET) are limited, especially for those with progressive disease and for those who experience treatment failure. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has been approved for the treatment of patients with low- or intermediate-grade advanced pNET. In the randomized phase III RADIANT-3 study in patients with low- or intermediate-grade advanced pNET, everolimus significantly increased progression-free survival (PFS) and decreased the relative risk for disease progression by 65% over placebo. This case report describes a heavily pretreated patient with high-grade pNET and liver and peritoneal metastases who achieved prolonged PFS, clinically relevant partial radiologic tumor response, and resolution of constitutional symptoms with improvement in Karnofsky performance status while receiving a combination of everolimus and octreotide long-acting repeatable (LAR). Radiologic and clinical responses were maintained for 19 months, with minimal toxicity over the course of treatment. This case supports the findings that the combination of everolimus plus octreotide LAR may be considered for use in patients with high-grade pNET and progressive disease. Although behavior and aggressiveness are different between low- or intermediate-grade and high-grade pNET, some high-grade pNET may express mTOR; hence, everolimus should be considered in a clinical trial.

  19. Prolonged Clinical Benefit of Everolimus Therapy in the Management of High-Grade Pancreatic Neuroendocrine Carcinoma

    PubMed Central

    Fonseca, Paula J.; Uriol, Esther; Galván, José A.; Álvarez, Carlos; Pérez, Quionia; Villanueva, Noemi; Berros, José P.; Izquierdo, Marta; Viéitez, José M.

    2013-01-01

    Treatment options for patients with high-grade pancreatic neuroendocrine tumors (pNET) are limited, especially for those with progressive disease and for those who experience treatment failure. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has been approved for the treatment of patients with low- or intermediate-grade advanced pNET. In the randomized phase III RADIANT-3 study in patients with low- or intermediate-grade advanced pNET, everolimus significantly increased progression-free survival (PFS) and decreased the relative risk for disease progression by 65% over placebo. This case report describes a heavily pretreated patient with high-grade pNET and liver and peritoneal metastases who achieved prolonged PFS, clinically relevant partial radiologic tumor response, and resolution of constitutional symptoms with improvement in Karnofsky performance status while receiving a combination of everolimus and octreotide long-acting repeatable (LAR). Radiologic and clinical responses were maintained for 19 months, with minimal toxicity over the course of treatment. This case supports the findings that the combination of everolimus plus octreotide LAR may be considered for use in patients with high-grade pNET and progressive disease. Although behavior and aggressiveness are different between low- or intermediate-grade and high-grade pNET, some high-grade pNET may express mTOR; hence, everolimus should be considered in a clinical trial. PMID:24019785

  20. Immunotherapy for malignant glioma.

    PubMed

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

    2015-01-01

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

  1. Research and development of intelligent controller for high-grade sanitary ware

    NASA Astrophysics Data System (ADS)

    Bao, Kongjun; Shen, Qingping

    2013-03-01

    With the social and economic development and people's living standards improve, more and more emphasis on modern society, people improve the quality of family life, the use of intelligent controller applications in high-grade sanitary ware physiotherapy students. Analysis of high-grade sanitary ware physiotherapy common functions pointed out in the production and use of the possible risks, proposed implementation of the system hardware and matching, given the system software implementation process. High-grade sanitary ware physiotherapy intelligent controller not only to achieve elegant and beautiful, simple, physical therapy, water power, deodorant, multi-function, intelligent control, to meet the consumers, the high-end sanitary ware market, strong demand, Accelerate the enterprise product Upgrade and improve the competitiveness of enterprises.

  2. ALDH1A3: A Marker of Mesenchymal Phenotype in Gliomas Associated with Cell Invasion

    PubMed Central

    Hu, Huimin; Huang, Hua; Bao, Zhaoshi; Yang, Pei; Wang, Yinyan; You, Gan; Yan, Wei; Jiang, Tao; Wang, Jiangfei; Zhang, Wei

    2015-01-01

    Aldehyde dehydrogenases (ALDH) is a family of enzymes including 19 members. For now, ALDH activity had been wildly used as a marker of cancer stem cells (CSCs). But biological functions of relevant isoforms and their clinical applications are still controversial. Here, we investigate the clinical significance and potential function of ALDH1A3 in gliomas. By whole-genome transcriptome microarray and mRNA sequencing analysis, we compared the expression of ALDH1A3 in high- and low- grade gliomas as well as different molecular subtypes. Microarray analysis was performed to identify the correlated genes of ALDH1A3. We further used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis to explore the biological function of ALDH1A3. Finally, by mRNA knockdown we revealed the relationship between ALDH1A3 and the ability of tumor invasion. ALDH1A3 overexpression was significantly associated with high grade as well as the higher mortality of gliomas in survival analysis. ALDH1A3 was characteristically highly expressed in Mesenchymal (Mes) subtype gliomas. Moreover, we found that ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro. In conclusion, ALDH1A3 can serve as a novel marker of Mes phenotype in gliomas with potential clinical prognostic value. The expression of ALDH1A3 is associated with tumor cell invasion. PMID:26575197

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

    NASA Astrophysics Data System (ADS)

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

    2015-03-01

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

  4. High-grade adenocarcinoma, (ductal type) arising in unilateral Warthin tumor of the parotid gland.

    PubMed

    Deodhar, Kedar K; Shah, Milap; Chaturvedi, Pankaj

    2011-01-01

    Warthin tumor is a well-recognized benign salivary gland neoplasm consisting of an epithelial as well as a lymphoid component. Malignant transformation in Warthin tumor is rare and its reported incidence is up to 1%. The more common types of carcinomas described in Warthin tumor are the squamous and mucoepidermoid types, with high-grade adenocarcinoma being extremely rare. A high-grade adenocarcinoma (ductal type) arising in the Warthin tumor in a 72-year-old man is presented for its rarity and diagnostic difficulties.

  5. Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma.

    PubMed

    Mieczkowski, Jakub; Kocyk, Marta; Nauman, Pawel; Gabrusiewicz, Konrad; Sielska, Małgorzata; Przanowski, Piotr; Maleszewska, Marta; Rajan, Wenson D; Pszczolkowska, Dominika; Tykocki, Tomasz; Grajkowska, Wieslawa; Kotulska, Katarzyna; Roszkowski, Marcin; Kostkiewicz, Boguslaw; Kaminska, Bozena

    2015-10-20

    Glioblastoma (GBM) is an aggressive malignancy associated with profound host immunosuppression. Microglia and macrophages infiltrating GBM acquire the pro-tumorigenic, M2 phenotype and support tumor invasion, proliferation, survival, angiogenesis and block immune responses both locally and systematically. Mechanisms responsible for immunological deficits in GBM patients are poorly understood. We analyzed immune/inflammatory gene expression in five datasets of low and high grade gliomas, and performed Gene Ontology and signaling pathway analyses to identify defective transcriptional responses. The expression of many immune/inflammatory response and TLR signaling pathway genes was reduced in high grade gliomas compared to low grade gliomas. In particular, we found the reduced expression of the IKBKB, a gene coding for IKKβ, which phosphorylates IκB proteins and represents a convergence point for most signal transduction pathways leading to NFκB activation. The reduced IKBKB expression and IKKβ levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKKβ expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NFκB activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NFκB signaling in microglia/macrophages infiltrating glioblastoma correlates with defective expression of immune/inflammatory genes and M2 polarization that may result in the global impairment of anti-tumor immune responses in glioblastoma.

  6. Perfusion MRI Derived Indices of Microvascular Shunting and Flow Control Correlate with Tumor Grade and Outcome in Patients with Cerebral Glioma

    PubMed Central

    Tietze, Anna; Mouridsen, Kim; Lassen-Ramshad, Yasmin; Østergaard, Leif

    2015-01-01

    Objectives Deficient microvascular blood flow control is thought to cause tumor hypoxia and increase resistance to therapy. In glioma patients, we tested whether perfusion-weighted MRI (PWI) based indices of microvascular flow control provide more information on tumor grade and patient outcome than does the established PWI angiogenesis marker, cerebral blood volume (CBV). Material and Methods Seventy-two glioma patients (sixty high-grade, twelve low-grade gliomas) were included. Capillary transit time heterogeneity (CTH) and the coefficient of variation (COV), its ratio to blood mean transit time, provide indices of microvascular flow control and the extent to which oxygen can be extracted by tumor tissue. The ability of these parameters and CBV to differentiate tumor grade were assessed by receiver operating characteristic curves and logistic regression. Their ability to predict time to progression and overall survival was examined by the Cox proportional-hazards regression model, and by survival curves using log-rank tests. Results The best prediction of grade (AUC = 0.876; p < 0.05) was achieved by combining knowledge of CBV and CTH in the enhancing tumor and peri-focal edema, and patients with glioblastoma multiforme were identified best by CTH (AUC = 0.763; p<0.001). CTH outperformed CBV and COV in predicting time to progression and survival in all gliomas and in a subgroup consisting of only high-grade gliomas. Conclusion Our study confirms the importance of microvascular flow control in tumor growth by demonstrating that determining CTH improves tumor grading and outcome prediction in glioma patients compared to CBV alone. PMID:25875182

  7. Postirradiation cerebellar glioma. Case report

    SciTech Connect

    Raffel, C.; Edwards, M.S.; Davis, R.L.; Ablin, A.R.

    1985-02-01

    A 13-year-old girl developed an anaplastic astrocytoma of the cerebellum 7 years after irradiation of the central nervous system and prophylactic chemotherapy for acute lymphocytic leukemia. The fact that the astrocytoma was anaplastic and infiltrative was unusual for astroglial tumors at this site. It is proposed that this is a radiation-induced glioma.

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

    PubMed

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

    2015-10-01

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

  9. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

    PubMed Central

    Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

    2015-01-01

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

  10. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    PubMed

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  11. Products of cells cultured from gliomas. VI. Immunofluorescent, morphometric, and ultrastructural characterization of two different cell types growing from explants of human gliomas.

    PubMed Central

    McKeever, P. E.; Smith, B. H.; Taren, J. A.; Wahl, R. L.; Kornblith, P. L.; Chronwall, B. M.

    1987-01-01

    Explants derived from human gliomas have been characterized with respect to their cellular outgrowth pattern after 1-22 weeks in culture. A mat of cells which were fibronectin (FN)-positive and glial fibrillary acidic protein (GFAP)-negative (hereafter designated FN+ cells) with a polygonal, flat morphology covered the growth substrate in a swirling pattern for a mean diameter of 9.2 mm around FN+ explants. FN+ cells showed ruffled plasmalemma, dilated rough endoplasmic reticulin (RDR), and extracellular filamentous strands. Rare desmosomes were compatible with at most minor leptomeningeal components or differentiation. FN+ cells predominated in six of seven cultures at passage 2, and their features were the same from various high-grade gliomas and gliosarcoma. Around other explants, elongated or stellate cells which were GFAP+ and FN- grew in a netlike pattern with little cell-to-cell contact. These GFAP+ cells surrounded explants at a mean diameter of 2 mm, substantially less than FN+ cells (P less than 0.005), and they grew more slowly than FN+ cells around explants. GFAP+ cells had an area/perimeter ratio which was less than that of FN+ cells. GFAP+ cells contained abundant intracellular filaments, rare desmosomes, and narrow RER cisternae. In mixed explants, GFAP+ cells often grew on top of FN+ cells. Individual cells which stained for both GFAP and FN were evident only from one glioma (8% doubly positive). Cells negative for both proteins resembled FN+ cells morphologically. Frozen sections of original glioma tissue showed FN+ vessel walls and GFAP+ parenchyma. Results are evidence for very early overgrowth of a preexistent FN+ cell type distinct from the GFAP+ parenchymal cell. The features of this distinct cell type are mesenchymal and resemble the proliferating vascular elements of gliomas in situ. The tendency for GFAP+ cells to grow on top of these FN+ cells suggests a feeder layer interaction. More knowledge of the origins and interactions of these two

  12. Ischemic stroke in patients with gliomas at The University of Texas-M.D. Anderson Cancer Center.

    PubMed

    Kamiya-Matsuoka, Carlos; Cachia, David; Yust-Katz, Shlomit; Rodriguez, Yvo A; Garciarena, Pedro; Rodarte, Elsa M; Tremont-Lukats, Ivo W

    2015-10-01

    Patients with gliomas are at risk of cerebrovascular accidents (CVA) with potential consequences on survival, function, and local tumor control. Our objective was to provide information about CVA in patients with gliomas and to estimate survival in this group. We reviewed all adult glioma patients with ischemic CVA at the University of Texas-M.D. Anderson Cancer Center from 2003 through 2014. We extracted demographic, clinical, imaging, treatment and outcome data. We used descriptive summary data and estimated or compared survival rates where appropriate. 60 of 6500 patients (0.1%) with high-grade (HGG, n = 47) or low-grade glioma (LGG, n = 13) had ischemic CVA Thirty-two (53%) patients had postoperative strokes, and 20 (33%) had CVA after 2 weeks of surgery. Forty-one patients (68%) had gross total resection. For HGG and CVA, the poststroke median overall survival was 17 months versus 61 months in LGG and CVA (P = 0.03; hazard ratio (HR): 2.8; 95% CI 1.07-4.60). Survival stratified by modified Rankin Scale grade was significant (X(2) = 9.8, P = 0.007). Five patients received bevacizumab before stroke onset; none responded to antiangiogenic therapy. There was no stroke-related death. At our institution for 10 years, ischemic CVA in glioma patients was a rare complication, clearly associated in half of cases to surgery, and with a variable negative impact on performance status and neurologic function. In this group, patients with more neurological deficits lived less. The survival difference between and within subgroups was most likely due to tumor grade. More research is necessary to improve prevention of postoperative stroke in glioma patients.

  13. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas

    PubMed Central

    Bao, Zhao-Shi; Yang, Ming-Yu; Zhang, Chuan-Bao; Yu, Kai; Ye, Wan-Lu; Hu, Bo-Qiang; Yan, Wei; Zhang, Wei; Akers, Johnny; Ramakrishnan, Valya; Li, Jie; Carter, Bob; Liu, Yan-Wei; Hu, Hui-Min; Wang, Zheng; Li, Ming-Yang; Yao, Kun; Qiu, Xiao-Guang; Kang, Chun-Sheng; You, Yong-Ping; Fan, Xiao-Long; Song, Wei Sonya; Li, Rui-Qiang

    2014-01-01

    Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs. PMID:25135958

  14. Multicentric glioma with unusual clinical presentation.

    PubMed

    Zamponi, N; Rychlicki, F; Ducati, A; Regnicolo, L; Salvolini, U; Ricciuti, R A

    2001-01-01

    Multiple glioma is a well-recognized but uncommon entity. They are grouped in two categories: multifocal and multicentric gliomas. Multifocal gliomas grow through dissemination along an established route, spreading through commissural pathways, CSF channels, or the blood or by local extension through satellite formation; at the opposite end of the spectrum, multicentric gliomas are widely separated lesions whose simultaneous presence cannot be attributed to any of the above pathways. Reports in the literature refer to single cases or small series of multicentric gliomas, almost always in adult patients, their occurrence in children being even less frequent. We report the case of a 12-year-old boy with multicentric glioma, atypical acute clinical onset and fast growth of three other tumors in 8 months, and then discuss the problems of diagnosis and therapy.

  15. Body mass index, serum total cholesterol, and risk of gastric high-grade dysplasia

    PubMed Central

    Huang, Ya-Kai; Kang, Wei-Ming; Ma, Zhi-Qiang; Liu, Yu-Qin; Zhou, Li; Yu, Jian-Chun

    2016-01-01

    Abstract Obesity is related to an increased risk of gastric cardia cancer. However, the influences of excess body weight and serum total cholesterol on the risk of gastric high-grade dysplasia have not been fully characterized. A case–control study was conducted to explore the relationships between body mass index (BMI), serum total cholesterol level, and the risk of gastric high-grade dysplasia in Chinese adults. A total of 893 consecutive patients with gastric high-grade dysplasia (537 men and 356 women) and 902 controls (543 men and 359 women) were enrolled from January 2000 to October 2015. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated, and a multivariate analysis was conducted. After adjusting for age, alcohol consumption, smoking status, family history of gastric cancer or esophageal cancer, and serum total cholesterol level, a BMI ranging from 27.5 to 29.9 was significantly related to an increased risk of gastric high-grade dysplasia in both men (adjusted OR = 1.87, 95% CI = 1.24–2.81) and women (adjusted OR = 2.72, 95% CI = 1.44–5.16). The 2 highest BMI categories (27.5–29.9 and ≥30.0) were identified as risk factors for gastric cardia high-grade dysplasia in both men (BMI = 27.5–29.9: adjusted OR = 1.78, 95% CI = 1.02–3.10; BMI ≥ 30.0: adjusted OR = 2.54, 95% CI = 1.27–5.08) and women (BMI = 27.5–29.9: adjusted OR = 2.88, 95% CI = 1.27–6.55; BMI ≥ 30.0: adjusted OR = 2.77, 95% CI = 1.36–5.64), whereas only a BMI ranging from 27.5 to 29.9 was a risk factor for gastric noncardia high-grade dysplasia in both men (adjusted OR = 1.98, 95% CI = 1.25–3.14) and women (adjusted OR = 2.88, 95% CI = 1.43–5.81). In addition, higher serum total cholesterol was associated with an increased risk of gastric noncardia high-grade dysplasia (adjusted OR = 1.83, 95% CI = 1.25–2.69) in women. Increased BMI was associated with an increased risk

  16. MR-04DICER REGULATES GLIOMA STEM CELL STATE

    PubMed Central

    Singh, Sanjay; Burrell, Kelly; Alamhabspour, Amir; Agnihotri, Sameer; Vartanian, Alenoush; Jalali, Shahrzad; Gumin, Joy; Sulman, Erik; Lang, Frederick; Zadeh, Gelareh

    2014-01-01

    The role of cancer stem cells in tumor formation and tumor heterogeneity is currently one of the most researched topics in cancer biology, and microRNAs likely have functional relevance in regulation of critical genes and parameters implicated in glioma stem cell (GSC) behavior and differentiation. To address this, we investigated global role of microRNA in GSCs, focusing on DICER, which regulates double-stranded RNA processing for microRNA biogenesis. Analysis of data from the Cancer Genome Atlas (TCGA) database suggests that high Dicer expression level is correlated with better prognosis of GBM patients. Gene signatures correlated with DICER expression levels suggest DICER/miRNA mediated mechanisms potentially regulate a multitude of cellular pathways in GBMs. Immunohistochemistry analysis of GBM tissue microarray reveals that of 54 tumor samples, 26 (48%) of GBM patients have low or undetectable levels of DICER1 protein, indicating frequent inactivation in high grade glioma. To characterize this functionally, we utilized various in vitro approaches, including exposure to hypoxia, to characterize the GSC properties after knockdown of DICER (GSCs did not have significant variation in endogenous DICER levels). Using three different GSC lines, we found in all cases with Dicer knockdown resulted in increased proliferation of three independent GSC lines with concomitant decrease in levels of stem cell markers (Sox2, Bmi1 etc.), a phenotype observed even upon exposure to hypoxia, a state that is known to preserve and promote the stem-like cell phenotype. Results from self-renewal assays as well as expression profiling show that GSCs with depleted levels of Dicer lose stem cell characteristics and acquire a progenitor-cell like state. Our results highlight the role of DICER as potential regulators of GSC stem-like versus progenitor-like state.

  17. Rare earth element patterns in Archean high-grade metasediments and their tectonic significance

    NASA Technical Reports Server (NTRS)

    Taylor, Stuart Ross; Rudnick, Roberta L.; Mclennan, Scott M.; Eriksson, Kenneth A.

    1986-01-01

    REE data on metasedimentary rocks from two different types of high-grade Archean terrains are presented and analyzed. The value of REEs as indicators of crustal evolution is explained; the three geologic settings (in North America, Southern Africa, and Australia) from which the samples were obtained are described; and the data are presented in extensive tables and graphs and discussed in terms of metamorphic effects, the role of accessory phases, provenance, and tectonic implications (recycling, the previous extent of high-grade terrains, and a model of Archean crustal growth). The diversity of REE patterns in shallow-shelf metasediments is attributed to local provenance, while the Eu-depleted post-Archean patterns are associated with K-rich plutons from small, stable early Archean terrains.

  18. Malignant transformation of a high-grade osteoblastoma of the petrous apex with subcutaneous metastasis.

    PubMed

    Kraft, Casey T; Morrison, Robert J; Arts, H Alexander

    2016-06-01

    We describe the clinical presentation, management, and pathologic findings in a case of osteosarcoma of the petrous apex with an atypical metastasis to the lower abdominal wall. We retrospectively reviewed the record of a 49-year-old man who was diagnosed with a right petrous apex lesion, which biopsy identified as a high-grade osteoblastoma. After two attempts at en bloc resection were not curative, radiation and chemotherapy were recommended. The patient subsequently developed a cutaneous lower abdominal mass that was diagnosed as an osteosarcoma. Meanwhile, the petrous apex tumor continued to grow despite treatment until the patient died from the burden of disease. Temporal bone osteoblastomas and osteosarcomas are both extremely rare, and they can be difficult to differentiate histologically. Our case illustrates this difficulty and demonstrates the possibility of a high-grade osteoblastoma's malignant conversion to an osteosarcoma. PMID:27304442

  19. Pediatric Low-Grade Gliomas

    PubMed Central

    Sievert, Angela J.; Fisher, Michael J.

    2010-01-01

    Pediatric low-grade gliomas encompass a heterogeneous set of tumors of different histologies. Cerebellar pilocytic astrocytomas occur most frequently followed by supratentorial diffuse fibrillary astrocytomas. Recent research has implicated activation of the RAS/RAF/MEK pathway in tumorigenesis of these tumors. Surgery is the mainstay of therapy. Overall survival rates for patients whose tumors are completely resected are 90% or greater, 10 years from diagnosis. Conversely, most optic pathway/hypothalamic, deep midline, and brain stem gliomas have minimal potential for resection; these tumors can be difficult to treat and deserve special attention. Combination chemotherapy is currently recommended as front-line adjuvant treatment for progressive or recurrent tumors. Second-line radiotherapy can also improve overall survival but is associated with more frequent and significant neurocognitive, endocrine, and other long-term toxicities. PMID:19841428

  20. Toppling high-grade pulmonary neuroendocrine tumors with a DLL3-targeted trojan horse.

    PubMed

    Dylla, Scott J

    2016-03-01

    Delta-like protein 3 (DLL3) is a novel and tractable tumor-initiating cell-associated target for the antibody-drug conjugate SC16LD6.5 in high-grade pulmonary neuroendocrine tumors. Elevated expression of DLL3, an inhibitor of Notch pathway activation, marks the second recent observation that impairment of Notch receptor signaling may play a critical role in neuroendocrine tumorigenesis. PMID:27308627

  1. Specific localization of thallium 201 in human high-grade astrocytoma by microautoradiography.

    PubMed

    Mountz, J M; Raymond, P A; McKeever, P E; Modell, J G; Hood, T W; Barthel, L K; Stafford-Schuck, K A

    1989-07-15

    The ability to accurately distinguish remaining or recurrent high-grade astrocytoma from necrosis or edema following treatment is essential to optimal patient management. Thallium 201 planar gamma-camera imaging has been shown to be helpful in detecting recurrent high-grade astrocytoma; however, due to tissue heterogeneity adjacent to and within tumor, the cellular specificity and quantification of 201Tl uptake are largely unknown. In order to determine which tissues are responsible for the radioisotope uptake, microautoradiographic techniques were used to examine multiple tissue sections from five patients with high-grade astrocytoma. Each patient received 5 mCi of 201Tl i.v. 1 h prior to tumor removal. Additionally, all patients received computerized tomographic and 201Tl planar gamma-camera scans prior to surgery. Following surgery, the excised tissue specimens were tentatively classified by gross pathological examination and then immediately processed for dry mount autoradiography; grain density was determined over regions containing tumor, adjacent and uninvolved brain tissue, necrotic tissue, and background. Highly significant differences were found in grain densities (201Tl uptake) between tumor and uninvolved brain tissue, as well as between uninvolved brain tissue and necrotic tissue; there was no significant difference between background grain density and that in necrotic tissue. Mean grain densities (grains/cm2 +/- 1 SD) across patients were: tumor, 102 +/- 23; adjacent, uninvolved brain tissue, 29 +/- 11; necrotic tissue, 6.2 +/- 1.1; and background, 7.0 +/- 4.1. We conclude that the ability of 201Tl to selectively image high-grade astrocytoma is due to its preferential uptake into tumor cells.

  2. Total enbloc spondylectomy for metastatic high grade spinal tumors: Early results

    PubMed Central

    Patil, Sanganagouda S; Nene, Abhay M

    2016-01-01

    Background: High grade metastatic spinal tumors are most common and are invasive. These patients can succumb to disease progression if not treated timely. Although considered as invasive and morbid, total enbloc spondylectomy (TES) in selected cases has better survival rates. The authors describe the results of TES for high grade metastatic spinal tumors. Materials and Methods: Five patients (four females and one male) underwent TES for solitary metastatic vertebral lesion between November 2012 and January 2014. These patients presented to us with spinal instability, unrelenting severe spinal pain and/or with severe progressive radiculopathy. Average age was 46.2 years (range 39–62 years). After complete investigations, computed tomography scan, magnetic resonance imaging scan and positron emission tomography (PET) scan, it was confirmed that these patients had high grade solitary vertebral metastatic tumor. Results: Average duration of followup was 18 months (range 16–20 months). The average preoperative visual analog scale score of 9.4 (range 9–10) improved to 2 (range 1–4) at last followup. Average blood loss was 1440 mL (range 1000–2000 mL). Average duration of surgery was 198 min (range 180–240 min). Significant pain relief was noticed in each patient in the immediate postoperative period and during followups. These patients attained complete functional activities of daily living with in a month. The imaging showed implants in situ, no recurrence of tumor, and no activity on PET scan at the final followup. Conclusion: The present series shows favorable short term results of TES for solitary, metastatic, high grade vertebral body tumors by a team approach. PMID:27512215

  3. High-grade metamafic blocks in Franciscan mélanges--olistostromal and/or tectonic?

    NASA Astrophysics Data System (ADS)

    Ernst, W. G.

    2013-12-01

    At ~175 Ma, onset of transpressive plate underflow generated an Andean-type arc along the Californian margin. The east-descending oceanic crust was metamorphosed to eclogite, garnet-blueschist, and amphibolite facies high-pressure (HP) assemblages in an inboard subduction zone at ~165-150 Ma. Except for the fragmentary Red Ant blueschists that crop out in the northern Sierran Foothills, most such metamafic rocks apparently were stored in a low-T environment well into mid- and Late Cretaceous time. Many of the high-grade metamafic rocks returned surfaceward transported as HP tectonic blocks in buoyant Franciscan serpentinite or in subducting, circulating, low-density mud-matrix mélange. However, the rare occurrence of high-grade clasts in relatively feebly recrystallized Franciscan metaconglomerates reflects a sedimentary (including olistostromal) deposition for some HP metamafic blocks. Actinolitic rinds partially encircle many high-grade blocks of either tectonic or olistostromal putative origin. These rinds are only very slightly younger than the subduction-zone metamorphism, suggesting that an early stage of metasomatic exchange took place between HP metabasalt and serpentinized harzburgite along the dynamic oceanic crust-mantle hanging-wall junction, probably while the metamafic rocks were sequestered at moderately shallow mantle depths. For HP metabasaltic rocks to have been added to the Cretaceous Franciscan clastic section as olistoliths, they must first have been carried surfaceward as tectonic blocks immersed in a low-density lithology--probably serpentinite diapirs--then eroded and transported into the trench. Whatever their origin, due to widespread post-depositional convergent-margin shearing, the original natures of many such HP metamafic blocks have been obliterated. In any case, these dense, high-grade rocks of latest Jurassic recrystallization age must have been supplied to the Cretaceous Franciscan accretionary prism by a stage of entrainment in a

  4. Predictors of Progression to High-Grade Dysplasia or Adenocarcinoma in Barrett's Esophagus.

    PubMed

    Whitson, Matthew J; Falk, Gary W

    2015-06-01

    The prevalence of esophageal adenocarcinoma is increasing dramatically. Barrett's esophagus remains the most well-established risk factor for the development of esophageal adenocarcinoma. There are multiple clinical, endoscopic, and pathologic factors that increase the risk of neoplastic progression to high-grade dysplasia or esophageal adenocarcinoma in Barrett's esophagus. This article reviews both risk and protective factors for neoplastic progression in patients with Barrett's esophagus.

  5. Reproducibility of histological cell type in high-grade endometrial carcinoma.

    PubMed

    Han, Guangming; Sidhu, Davinder; Duggan, Máire A; Arseneau, Jocelyne; Cesari, Matthew; Clement, Philip B; Ewanowich, Carol A; Kalloger, Steve E; Köbel, Martin

    2013-12-01

    Subclassification of endometrial carcinoma according to histological type shows variable interobserver agreement. The aim of this study was to assess specifically the interobserver agreement of histological type in high-grade endometrial carcinomas, recorded by gynecological pathologists from five academic centers across Canada. In a secondary aim, the agreement of consensus diagnosis with immunohistochemical marker combinations was assessed including six routine (TP53, CDKN2A (p16), ER, PGR, Ki67, and VIM) and six experimental immunohistochemical markers (PTEN, ARID1A, CTNNB1, IGF2BP3, HNF1B, and TFF3). The paired interobserver agreement ranged from κ 0.50 to 0.63 (median 0.58) and the intraobserver agreement from κ 0.49 to 0.67 (median 0.61). Consensus about histological type based on morphological assessment was reached in 72% of high-grade endometrial carcinomas. A seven-marker immunohistochemical panel differentiated FIGO grade 3 endometrioid from serous carcinoma with a 100% concordance rate compared with the consensus diagnosis. More practically, a three-marker panel including TP53, ER, and CDKN2A (p16) can aid in the differential diagnosis of FIGO grade 3 endometrioid from endometrial serous carcinoma. Our study demonstrates that the inter- and intraobserver reproducibility of histological type based on morphology alone are mostly moderate. Ancillary techniques such as immunohistochemical marker panels are likely needed to improve diagnostic reproducibility of histological types within high-grade endometrial carcinomas.

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

    ClinicalTrials.gov

    2016-03-16

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

  7. B7-H3, a potential therapeutic target, is expressed in diffuse intrinsic pontine glioma.

    PubMed

    Zhou, Zhiping; Luther, Neal; Ibrahim, George M; Hawkins, Cynthia; Vibhakar, Rajeev; Handler, Michael H; Souweidane, Mark M

    2013-02-01

    Diffuse intrinsic pontine glioma (DIPG) is a brain cancer with a median survival of only 1 year. Lack of molecular characterization of this tumor impedes the development of novel therapies. Membrane protein B7-H3, aka CD276, involved in interactions with host defenses in certain cancers, has been shown to be over-expressed in the majority of malignant neuroectodermal tumors including adult high-grade glioma. Targeting B7-H3 with a monoclonal antibody has demonstrated safety and efficacy in the salvage treatment of stage IV childhood neuroblastoma, another neuroectodermal tumor. It thus stands to reason that B7-H3 might serve as a therapeutic target in DIPG. B7-H3 immunoreactivity was determined in DIPG and non-diffuse brainstem glioma specimens with immunohistochemistry. In addition, B7-H3 mRNA expression was evaluated with microarrays in another set of specimens. All of the nine (100 %) DIPG specimens were shown to be B7-H3 immunoreactive. In the non-diffuse brainstem glioma group, none of the eight WHO grade I specimens showed B7-H3 immunoreactivity and nine of the 24 WHO grade II specimens (37.5 %) showed B7-H3 immunoreactivity. The association between histological grade and B7-H3 immunoreactivity was statistically highly significant. B7-H3 mRNA expression was also significantly higher in DIPG samples than in normal brain and juvenile pilocytic astrocytoma (WHO grade I) specimens. In summary, B7-H3 is over-expressed in DIPG. Given the need for novel treatment in this disease, antibody-based immunotherapy against B7-H3 in DIPG warrants further investigation.

  8. A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells12

    PubMed Central

    Misuraca, Katherine L.; Hu, Guo; Barton, Kelly L.; Chung, Alexander; Becher, Oren J.

    2016-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3 +/Nestin +/Sox2 + population lining the fourth ventricle and a Pax3 +/NeuN + parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53fl/fl mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67 +, Nestin +, Olig2 +, and largely GFAP − and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease. PMID:26806352

  9. The Potential of Tetrandrine against Gliomas.

    PubMed

    Chen, Yun; Tseng, Sheng-Hong

    2010-09-01

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

  10. 5α-reductase Inhibitors and Risk of High-grade or Lethal Prostate Cancer

    PubMed Central

    Preston, Mark A.; Wilson, Kathryn; Markt, Sarah C.; Ge, Rongbin; Morash, Christopher; Stampfer, Meir J.; Loda, Massimo F.; Giovannucci, Edward; Mucci, Lorelei A.; Olumi, Aria F.

    2014-01-01

    Importance 5α-reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear. Objective To determine the association between 5ARI use and development of high-grade or lethal prostate cancer. Design, Setting, and Participants Prospective observational study of 38,058 men followed for prostate cancer diagnosis and outcomes between 1996–2010 in the Health Professionals Follow-up Study. Exposure Use of 5ARIs between 1996–2010. Main Outcome Measures Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing. Results During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high-grade (Gleason 8–10), 1238 were Gleason grade 7, and 1600 were low-grade (Gleason 2–6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (HR 0.77; 95% CI, 0.65–0.91). 5ARI users had a reduced risk of Gleason 7 (HR 0.67; 95% CI, 0.49–0.91) and low-grade (Gleason 2–6) prostate cancer (HR 0.74; 95% CI, 0.57–0.95). 5ARI use was not associated with risk of high-grade (Gleason 8–10, HR 0.97; 95% CI, 0.64–1.46) or lethal disease (HR 0.99; 95% CI, 0.58–1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use 0.95; 95% CI, 0.92–0.99), localized (HR 0.95; 95% CI, 0.90–1.00), and low-grade disease (HR 0.92; 95% CI, 0.85–0.99). There was no association for lethal, high-grade, or grade 7 disease. Conclusions and

  11. hHSS1: a novel secreted factor and suppressor of glioma growth located at chromosome 19q13.33.

    PubMed

    Junes-Gill, Katiana S; Gallaher, Timothy K; Gluzman-Poltorak, Zoya; Miller, Joseph D; Wheeler, Christopher J; Fan, Xuemo; Basile, Lena A

    2011-04-01

    The completion of the Human Genome Project resulted in discovery of many unknown novel genes. This feat paved the way for the future development of novel therapeutics for the treatment of human disease based on novel biological functions and pathways. Towards this aim, we undertook a bioinformatics analysis of in-house microarray data derived from purified hematopoietic stem cell populations. This effort led to the discovery of HSS1 (Hematopoietic Signal peptide-containing Secreted 1) and its splice variant HSM1 (Hematopoietic Signal peptide-containing Membrane domain-containing 1). HSS1 gene is evolutionarily conserved across species, phyla and even kingdoms, including mammals, invertebrates and plants. Structural analysis showed no homology between HSS1 and known proteins or known protein domains, indicating that it was a truly novel protein. Interestingly, the human HSS1 (hHSS1) gene is located at chromosome 19q13.33, a genomic region implicated in various cancers, including malignant glioma. Stable expression of hHSS1 in glioma-derived A172 and U87 cell lines greatly reduced their proliferation rates compared to mock-transfected cells. hHSS1 expression significantly affected the malignant phenotype of U87 cells both in vitro and in vivo. Further, preliminary immunohistochemical analysis revealed an increase in hHSS1/HSM1 immunoreactivity in two out of four high-grade astrocytomas (glioblastoma multiforme, WHO IV) as compared to low expression in all four low-grade diffuse astrocytomas (WHO grade II). High-expression of hHSS1 in high-grade gliomas was further supported by microarray data, which indicated that mesenchymal subclass gliomas exclusively up-regulated hHSS1. Our data reveal that HSS1 is a truly novel protein defining a new class of secreted factors, and that it may have an important role in cancer, particularly glioma.

  12. Integrating diffusion kurtosis imaging, dynamic susceptibility-weighted contrast-enhanced MRI, and short echo time chemical shift imaging for grading gliomas

    PubMed Central

    Van Cauter, Sofie; De Keyzer, Frederik; Sima, Diana M.; Croitor Sava, Anca; D'Arco, Felice; Veraart, Jelle; Peeters, Ronald R.; Leemans, Alexander; Van Gool, Stefaan; Wilms, Guido; Demaerel, Philippe; Van Huffel, Sabine; Sunaert, Stefan; Himmelreich, Uwe

    2014-01-01

    Background We assessed the diagnostic accuracy of diffusion kurtosis imaging (DKI), dynamic susceptibility-weighted contrast-enhanced (DSC) MRI, and short echo time chemical shift imaging (CSI) for grading gliomas. Methods In this prospective study, 35 patients with cerebral gliomas underwent DKI, DSC, and CSI on a 3 T MR scanner. Diffusion parameters were mean diffusivity (MD), fractional anisotropy, and mean kurtosis (MK). Perfusion parameters were mean relative regional cerebral blood volume (rrCBV), mean relative regional cerebral blood flow (rrCBF), mean transit time, and relative decrease ratio (rDR). The diffusion and perfusion parameters along with 12 CSI metabolite ratios were compared among 22 high-grade gliomas and 14 low-grade gliomas (Mann–Whitney U-test, P < .05). Classification accuracy was determined with a linear discriminant analysis for each MR modality independently. Furthermore, the performance of a multimodal analysis is reported, using a decision-tree rule combining the statistically significant DKI, DSC-MRI, and CSI parameters with the lowest P-value. The proposed classifiers were validated on a set of subsequently acquired data from 19 clinical patients. Results Statistically significant differences among tumor grades were shown for MK, MD, mean rrCBV, mean rrCBF, rDR, lipids over total choline, lipids over creatine, sum of myo-inositol, and sum of creatine. DSC-MRI proved to be the modality with the best performance when comparing modalities individually, while the multimodal decision tree proved to be most accurate in predicting tumor grade, with a performance of 86%. Conclusions Combining information from DKI, DSC-MRI, and CSI increases diagnostic accuracy to differentiate low- from high-grade gliomas, possibly providing diagnosis for the individual patient. PMID:24470551

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

    SciTech Connect

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

    2012-04-01

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

  14. Unique biology of gliomas: challenges and opportunities

    PubMed Central

    Watkins, Stacey; Sontheimer, Harald

    2013-01-01

    Gliomas are terrifying primary brain tumors for which patient outlook remains bleak. Recent research provides novel insights into the unique biology of gliomas. For example, these tumors exhibit an unexpected pluripotency that enables them to grow their own vasculature. They have an unusual ability to navigate tortuous extracellular pathways as they invade, and they use neurotransmitters to inflict damage and create room for growth. Here, we review studies that illustrate the importance of considering interactions of gliomas with their native brain environment. Such studies suggest that gliomas constitute a neurodegenerative disease caused by the malignant growth of brain support cells. The chosen examples illustrate how targeted research into the biology of gliomas is yielding new and much needed therapeutic approaches to this challenging nervous system disease. PMID:22683220

  15. Glioma Surgery: Technological Advances to Achieve a Maximal Safe Resection.

    PubMed

    Altieri, Roberto; Zenga, Francesco; Fontanella, Marco Maria; Cofano, Fabio; Agnoletti, Alessandro; Spena, Giannantonio; Crobeddu, Emanuela; Fornaro, Riccardo; Ducati, Alessandro; Garbossa, Diego

    2015-11-01

    Glioblastoma multiforme (GBM) is the most frequent primary central nervous system (CNS) tumor. Despite the best treatment and advances in therapy, prognosis remains poor. One of the mainstays of therapy in GBM is surgical excision. Several studies have confirmed that the extent of resection (EOR) positively influences overall survival (OS) in patients with high-grade gliomas (HGGs). A literature search was performed using PubMed to assess the useful neurosurgical tools to achieve the best neurosurgical performance. In order to achieve the major extent of resection, preserving neurological function, many tools are now available, especially neuronavigation, intraoperative fluorescence, intraoperative ultrasound, and neuromonitoring. In addition to the maximal excision of tumor, the neurosurgeon can use photodynamic therapy (PTD) and local drug delivery (LDD) to improve the local control and bridge conventional radio and chemotherapy. EOR improves OS in patients with HGGs. There are technological possibilities for achieving a complete resection preserving neurological function, and it is not acceptable to perform only biopsy of these lesions.

  16. The eastern limit of Acadian high grade metamorphism in northern New England: Implications for the location of the Acadian Suture''

    SciTech Connect

    West, D.P. Jr. . Dept. of Geological Sciences)

    1993-03-01

    Identifying the eastern limit of Acadian high grade metamorphism in New England is complicated by the presence of pre-Devonian high grade relics, locally intense Late Paleozoic thermal overprints, and post-metamorphic faults. New [sup 40]Ar/[sup 39]Ar mineral ages from along the eastern margin of high grade metamorphism in Maine and New Hampshire help delineate the eastern limit of Devonian amphibolite facies metamorphism thereby placing constraints on the location of the Acadian suture. In New Hampshire, Acadian high grade metamorphism extends southeast at least as far as the Campbell Hill fault and perhaps as far as the Flint Hill fault. New [sup 40]Ar/[sup 39]Ar hornblende ages and previously published U-Pb monazite ages from the Massabesic Gneiss Complex are Permian indicating high grade Alleghanian metamorphism. New [sup 40]Ar/[sup 39]Ar hornblende ages from the Rye Formation, although complicated by excess argon, are considerably older, indicating an earlier Pre-Silurian amphibolite facies metamorphism affected these rocks. North of Portland, [sup 40]Ar/[sup 39]Ar hornblende ages east of the Norumbega Fault Zone from high grade rocks of the Casco Bay Group have ages that range from Middle Devonian to Early Carboniferous, consistent with diachronous cooling following Acadian metamorphism. Further northeast, in upper amphibolite facies rocks of the Passagassawakeag Gneiss, new [sup 40]Ar/[sup 39]Ar hornblende ages range from 385--395 Ma suggesting that these rocks were also affected by high grade Acadian metamorphism.

  17. Radio-chemotherapy improves survival in IDH-mutant, 1p/19q non-codeleted secondary high-grade astrocytoma patients.

    PubMed

    Juratli, Tareq A; Lautenschläger, Tim; Geiger, Kathrin D; Pinzer, Thomas; Krause, Mechthild; Schackert, Gabriele; Krex, Dietmar

    2015-09-01

    Isocitrate dehydrogenase (IDH) mutations are beginning to drive decisions on therapy for glioma patients. Here we sought to determine the impact of adjuvant treatment in patients with IDH-mutant, 1p/19q non-codeleted secondary high-grade astrocytoma (sHGA) WHO grades III/IV. Clinical data of 109 sHGA patients grades III/IV, in addition to IDH mutation-, 1p/19q-codeletion- and MGMT-promoter methylation status-were retrospectively analyzed. Survival analysis in relation to adjuvant treatment modalities and molecular profiling were performed. Out of 109 patients, 88 patients (80.7 %) harbored IDH mutations, 30 patients had a 1p/19q-codeletion (27.5 %) and 69 patients (63.3 %) exhibited a methylated MGMT-promoter status. At a median follow-up of 9.8 years, 62 patients (57 %) died. The postsurgical treatment included: radio-chemotherapy (RT-CT; 54.5 %), RT alone (19.3 %), and CT alone (22.7 %). The median overall survival (OS) in the entire group was 3.4 years (1.9-6.7 years). Patients who received RT-CT had a significantly longer OS compared with those who underwent RT alone (6.5 vs. 1.2 years, HR 0.35, CI 0.32-0.51, p = 0.011). In the IDH-mutant 1p/19q non-codeleted sHGA subgroup the RT-CT cohort had a significantly longer OS in comparison to the RT cohort (6.4 vs. 1.2 years, HR 2.7, CI 1.1-6.5, p = 0.022). In the stepwise multivariable Cox model for OS of all 88 IDH-mutant sHGA patients, survival was strongly associated with only one factor, namely, adjuvant RT-CT at diagnosis of a sHGA. This retrospective long-term study demonstrates that RT and CT (mostly PCV) significantly improves progression-free and overall survival in IDH-mutant secondary high-grade astrocytoma patients, regardless of 1p/19q-codeletion status. PMID:26033545

  18. Wild-Type Reovirus in Combination With Sargramostim in Treating Younger Patients With High-Grade Recurrent or Refractory Brain Tumors

    ClinicalTrials.gov

    2016-08-03

    Childhood Astrocytoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Diffuse Intrinsic Pontine Glioma; Glioma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Glioblastoma; Recurrent Childhood Medulloblastoma; Recurrent Primitive Neuroectodermal Tumor; Refractory Brain Neoplasm

  19. The Tumor Suppressor Prostate Apoptosis Response-4 (Par-4) is Regulated by Mutant IDH1 and Kills Glioma Stem Cells

    PubMed Central

    Liu, Yinxing; Gilbert, Misty R.; Kyprianou, Natasha; Rangnekar, Vivek M.; Horbinski, Craig

    2014-01-01

    Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P < 0.0001), which was validated by The Cancer Genome Atlas dataset (P = 2.0 E-13). The metabolic product of mutant IDH1, D-2-hydroxyglutarate (2-HG), can suppress Par-4 transcription in vitro via inhibition of promoter activity as well as enhanced mRNA degradation, but interestingly not by direct DNA promoter hypermethylation. The Selective for Apoptosis induction in Cancer cells (SAC) domain within Par-4 is highly active against glioma cells, including orthotopic xenografts of patient-derived primary GSCs (P < 0.0001). Among high-grade gliomas that are IDH1 wild-type, those that express more Par-4 have significantly longer median survival (18.4 versus 8.0 months, P = 0.002), a finding confirmed in two external GBM cohorts. Together, these data suggest that Par-4 is a significant component of the mutant IDH1 phenotype, that the activity of 2-HG is complex and can extend beyond direct DNA hypermethylation, and that Par-4 is a promising therapeutic strategy against GSCs. Furthermore, not every effect of mutant IDH1 necessarily contributes to the overall favorable prognosis seen in such tumors; inhibition of Par-4 may be one such effect. PMID:25135281

  20. Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.

    PubMed

    Misuraca, Katherine L; Barton, Kelly L; Chung, Alexander; Diaz, Alexander K; Conway, Simon J; Corcoran, David L; Baker, Suzanne J; Becher, Oren J

    2014-01-01

    High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis. PMID:25330836

  1. Preferential expression of functional IL-17R in glioma stem cells: potential role in self-renewal

    PubMed Central

    Parajuli, Prahlad; Anand, Rohit; Mandalaparty, Chandramouli; Suryadevara, Raviteja; Sriranga, Preethi U.; Michelhaugh, Sharon K.; Cazacu, Simona; Finniss, Susan; Thakur, Archana; Lum, Lawrence G.; Schalk, Dana; Brodie, Chaya; Mittal, Sandeep

    2016-01-01

    Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17−IL-17R interaction in gliomas. Immunohistochemistry and flow cytometry analysis of 12 tumor samples obtained from patients with high grade gliomas revealed that a considerable population (2–19%) of cells in all malignant gliomas expressed IL-17RA, with remarkable co-expression of the glioma stem cell (GSC) markers CD133, Nestin, and Sox2. IL-17 enhanced the self-renewal of GSCs as determined by proliferation and Matrigel® colony assays. IL-17 also induced cytokine/chemokine (IL-6, IL-8, interferon-γ-inducible protein [IP-10], and monocyte chemoattractant protein-1 [MCP-1]) secretion in GSCs, which were differentially blocked by antibodies against IL-17R and IL-6R. Western blot analysis showed that IL-17 modulated the activity of signal transducer and activator of transcription 3 (STAT3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), glycogen synthase kinase-3β (GSK-3β) and β-catenin in GSCs. While IL-17R-mediated secretion of IL-6 and IL-8 were significantly blocked by inhibitors of NF-κB and STAT3; NF-κB inhibitor was more potent than STAT3 inhibitor in blocking IL-17-induced MCP-1 secretion. Overall, our results suggest that IL-17–IL-17R interaction in GSCs induces an autocrine/paracrine cytokine feedback loop, which may provide an important signaling component for maintenance/self-renewal of GSCs via constitutive activation of both NF-κB and STAT3. The results also strongly implicate IL-17R as an important functional biomarker for therapeutic targeting of GSCs. PMID:26755664

  2. Role of Combined Circumareolar Skin Excision and Liposuction in Management of High grade Gynaecomastia

    PubMed Central

    Sarkar, Arindam; Bain, Jayanta; Bhattacharya, Debtanu; Sawarappa, Raghavendra; Munian, Kinkar; Dutta, Gouranga; Naiyer, Ghulam Jeelani; Ahmad, Shamshad

    2014-01-01

    Introduction: High-grade gynaecomastia (Simon IIb and III) has tissue excess (skin excess, enlarged areola, and displaced nipple), which is best managed surgically; however, results of conventional breast reduction surgeries and liposuction is not very good. Aim of our study was to describe a combined technique to manage these problems to produce a good result. Material and Method: This was a 2-year study among 12 patients of high grade gynaecomastia. Clinical and laboratory findings were normal. Pre-operatively in standing position, diameter of breast and areola, position of nipple, and amount of skin excess were marked. Under general anaesthesia, tumescent infiltration, circumareolar de-epithelisation of skin excess, and liposuction was completed. Redundant portion of the breast was sharply dissected and pulled out. Areola was fixed over pectoralis fascia at mid humerus level, just medial to the mid-clavicular line. Outer borders of the de-epithelised area were apposed by the purse-string effect of a subdermal suture, and further apposed by few half buried horizontal mattress sutures. Drains for 24 hour and compressive dressings for 6 weeks were used. Result: Mean age of presentation was 25.8 year; emotional discomfort was the chief complaint. Among 12 patients, 10 patients had bilateral gynaecomastia and 8 patients had enlarged and displaced nipple-areola complex. Average hospital stay was 2.41 days and recoveries were usually uneventful. Conclusion: The problem of tissue excess and tissue displacement in high grade gynaecomastia can be well managed by this combined circumareolar skin reduction and liposuction technique to achieve a scar-less flat male chest. PMID:25136214

  3. 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma

    PubMed Central

    Lee, Cheng-Han; Ou, Wen-Bin; Mariño-Enriquez, Adrian; Zhu, Meijun; Mayeda, Mark; Wang, Yuexiang; Guo, Xiangqian; Brunner, Alayne L.; Amant, Frédéric; French, Christopher A.; West, Robert B.; McAlpine, Jessica N.; Gilks, C. Blake; Yaffe, Michael B.; Prentice, Leah M.; McPherson, Andrew; Jones, Steven J. M.; Marra, Marco A.; Shah, Sohrab P.; van de Rijn, Matt; Huntsman, David G.; Dal Cin, Paola; Debiec-Rychter, Maria; Nucci, Marisa R.; Fletcher, Jonathan A.

    2012-01-01

    14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE–FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE–FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE–FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE–FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE–FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions. PMID:22223660

  4. An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia

    PubMed Central

    Li, Yi-Ju; Guggenheim, Jeremy A.; Bulusu, Anuradha; Metlapally, Ravikanth; Abbott, Diana; Malecaze, Francois; Calvas, Patrick; Rosenberg, Thomas; Paget, Sandrine; Creer, Rosalind C.; Kirov, George; Owen, Michael J.; Zhao, Bei; White, Tristan; Mackey, David A.; Young, Terri L.

    2013-01-01

    Purpose Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite markers and a limited number of pedigrees. In this study, whole-genome linkage scans were performed for high-grade myopia, using single nucleotide polymorphisms (SNPs) in 254 families from five independent sites. Methods Genomic DNA samples from 1411 subjects were genotyped (Linkage Panel IVb; Illumina, San Diego, CA). Linkage analyses were performed on 1201 samples from 10 Asian, 12 African-American, and 221 Caucasian families, screening for 5744 SNPs after quality-control exclusions. Two disease states defined by sphere (SPH) and spherical equivalence (SE; sphere+cylinder/2) were analyzed. Parametric and nonparametric two-point and multipoint linkage analyses were performed using the FASTLINK, HOMOG, and MERLIN programs. Multiple stratified datasets were examined, including overall, center-specific, and race-specific. Linkage regions were declared suggestive if they had a peak LOD score ≥ 1.5. Results The MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated. The novel region q34.11 on chromosome 9 (max NPL= 2.07 at rs913275) was identified. Chromosome 12, region q21.2-24.12 (36.59 cM, MYP3 locus) showed significant linkage (peak HLOD = 3.48) at rs337663 in the overall dataset by SPH and was detected by the Duke, Asian, and Caucasian subsets as well. Potential shared interval was race dependent—a 9.4-cM region (rs163016–rs1520724) driven by the Asian subset and a 1343-cM region (rs163016–rs1520724) driven by the Caucasian subset. Conclusions The present study is the largest linkage scan to date for familial high-grade myopia. The outcomes will facilitate the identification of genes implicated in myopic refractive error development and ocular growth. PMID:19324860

  5. Proliferative activity (ki-67 expression) and outcome in high grade osteosarcoma: a study of 27 cases.

    PubMed

    Jong, R; Davis, A M; Mendes, M G; Wunder, J S; Bell, R S; Kandel, R

    2000-01-01

    Purpose. Although pre-operative chemotherapy has improved the prognosis for individuals with osteosarcoma, approximately 40% of patients will die of their disease.The aim of this study was to quantitate proliferative activity in high grade osteosarcomas and to determine whether proliferation is a prognostic factor.Patients. The study consisted of 27 patients with high grade non-metastatic osteosarcoma at various sites for whom pre-operative biopsies and resection specimens were available for review. All patients were treated similarly and had at least 24 months' follow-up from the date of diagnosis.Methods. Proliferative activity (Ki-67 expression) was examined in the diagnostic biopsies immunohistochemically using the MIB-1 antibody. Proliferation was quantitated in two ways; (1) the number of immunopositive cells was counted manually using an ocular grid; or (2) the percentage of immunopositive nuclear area was assessed using morphometric image analysis. Proliferative index was evaluated in relation to patient outcome.Results. Proliferative activity was seen in all biopsies.The median proliferative index as determined by counting cells was 24% (mean of 27%, range of 7-61%) and by image analysis was 2% (mean 3%, range 0.32-8.4).The correlation between MIB-1 proliferation indices determined either by image analysis methodology or manual cell counting was high (Spearman's rho=0.79). Proliferative index did not appear to predict either disease-free or overall survival.Discussion. Tumor proliferation does not appear to be prognostic for high grade osteosarcomas.Whether assessment of this feature in conjunction with other tumor characteristics might be prognostic requires further study. PMID:18521434

  6. Circulating gamma delta T cells are activated and depleted during progression of high-grade gliomas: Implications for gamma delta T cell therapy of GBM

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glioblastoma multiforme (GBM) remains frustratingly impervious to any existing therapy. We have previously shown that GBM is sensitive to recognition and lysis by ex vivo activated gamma delta T cells, a minor subset of lymphocytes that innately recognize autologous stress-associated target antigens...

  7. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas.

    PubMed

    Bender, Sebastian; Tang, Yujie; Lindroth, Anders M; Hovestadt, Volker; Jones, David T W; Kool, Marcel; Zapatka, Marc; Northcott, Paul A; Sturm, Dominik; Wang, Wei; Radlwimmer, Bernhard; Højfeldt, Jonas W; Truffaux, Nathalène; Castel, David; Schubert, Simone; Ryzhova, Marina; Seker-Cin, Huriye; Gronych, Jan; Johann, Pascal David; Stark, Sebastian; Meyer, Jochen; Milde, Till; Schuhmann, Martin; Ebinger, Martin; Monoranu, Camelia-Maria; Ponnuswami, Anitha; Chen, Spenser; Jones, Chris; Witt, Olaf; Collins, V Peter; von Deimling, Andreas; Jabado, Nada; Puget, Stephanie; Grill, Jacques; Helin, Kristian; Korshunov, Andrey; Lichter, Peter; Monje, Michelle; Plass, Christoph; Cho, Yoon-Jae; Pfister, Stefan M

    2013-11-11

    Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ∼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs. PMID:24183680

  8. Incidence of gliomas by anatomic location.

    PubMed

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

    2007-07-01

    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 x 1 x 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.

  9. Glioma Stem Cell-Targeted Dendritic Cells as a Tumor Vaccine Against Malignant Glioma

    PubMed Central

    Ji, Baowei; Liu, Baohui; Wu, Liquan; Tian, Daofeng; Guo, Zhentao; Yi, Wei

    2013-01-01

    Purpose Cancer stem cells have recently been thought to be closely related to tumor development and reoccurrence. It may be a promising way to cure malignant glioma by using glioma stem cell-targeted dendritic cells as a tumor vaccine. In this study, we explored whether pulsing dendritic cells with antigens of glioma stem cells was a potent way to induce specific cytotoxic T lymphocytes and anti-tumor immunity. Materials and Methods Cancer stem cells were cultured from glioma cell line U251. Lysate of glioma stem cells was obtained by the repeated freezing and thawing method. Dendritic cells (DCs) were induced and cultured from the murine bone marrow cells, the biological characteristics were detected by electron microscope and flow cytometry. The DC vaccine was obtained by mixing DCs with lysate of glioma stem cells. The DC vaccine was charactirizated through the mixed lymphocyte responses and cell killing experiment in vitro. Level of interferon-γ (IFN-γ) in the supernatant was checked by ELISA. Results After stimulation of lysate of glioma stem cell, expression of surface molecules of DC was up-regulated, including CD80, CD86, CD11C and MHC-II. DCs pulsed with lysate of glioma stem cells were more effective than the control group in stimulating original glioma cells-specific cytotoxic T lymphocytes responses, killing glioma cells and boosting the secretion of IFN-γ in vitro. Conclusion The results demonstrated DCs loaded with antigens derived from glioma stem cells can effectively stimulate naive T cells to form specific cytotoxic T cells, kill glioma cells cultured in vitro. PMID:23225804

  10. [Neuropathology and molecular pathology of gliomas].

    PubMed

    Janzer, Robert-Charles

    2009-07-15

    Gliomas are the most frequent primary brain tumours. The WHO classification is essentially based on histological and immunohistochemical criteria. More recently multiple cytogenetic and molecular alterations associated with initiation and progression have been shown and the genetic profiles of tumour entities have been incorporated in the WHO classifiacation. Molecular testing of the MGMT promotor methylation in glioblastoma, predictive for the response to combined radio-/chimiothérapie, and the LOH 1p/19q in oligodendroglial tumours, as prognostic factor supplements the histopathological diagnosis. In the near futur array-based profiling techniques will contribute to a refinement of glioma classification and identify targets for more individualized glioma therapies.

  11. A chemotherapy response classifier based on support vector machines for high-grade serous ovarian carcinoma

    PubMed Central

    Zhou, Bo; Guo, En-Song; Yang, Zong-Yuan; Liao, Jing; Ding, Dong; Xu, Qin; Lu, Hao; Meng, Li; Wang, Shi-Xuan; Zhou, Jian-Feng; Xing, Hui; Weng, Dan-Hui; Ma, Ding; Chen, Gang

    2016-01-01

    Long-term outcome of high-grade serous epithelial ovarian carcinoma (HGSOC) remains poor as a result of recurrence and the emergence of drug resistance. Almost all the patients were given the same platinum-based chemotherapy after debulking surgery even though some of them are naturally resistant to the first-line chemotherapy. No method could verify this part of patients right after the surgery currently. In this study, we used 156 paraffin-embedded high-grade HGSOC specimens for immunohistochemical analysis with 37 immunology markers, and association between the expression levels of these markers and the chemoresponse were evaluated. A support vector machine (SVM)-based HGSOC prognostic classifier was then established, and was validated by a 95-patient independent cohort. The classifier was strongly predictive of chemotherapy resistance, and divided patients into low- and high-risk groups with significant differences progression-free survival (PFS) and overall survival (OS). This classifier may provide a potential way to predict the chemotherapy resistance of HGSOC right after the surgery, and then allow clinicians to make optimal clinical decision for those potentially chemoresistant patients. The potential clinical application of this classifier will benefit those patients with primary drug resistance. PMID:26675546

  12. Structural patterns in high grade terrain in parts of Tamil Nadu and Karnataka

    NASA Technical Reports Server (NTRS)

    Sugavanam, E. B.; Vidyadharan, K. T.

    1988-01-01

    Detailed geological mapping in parts of Tamil Nadu and Karnataka has brought out vast areas occupied by highly deformed charnockite and high grade gneisses. These areas, similar to high grade shield terrains in other parts of the world have the impress of extensive tectonic reworking multideformation and polymetamorphism and are closely associated with layered ultramafics, shelf type sediments and different igneous events. In North Arcot and Charmapuri districts of Tamil Nadu and Kollegal taluk in Mysore district in Karnataka, charnockite is intensely cofolded with a supracrustal succession of layered ultramafics, pyroxene granulite, pink granolites, magnetite quartzite and khondalites. These areas have undergone five phases of deformation, five generations of basic dyke activities, four phases of migmatisation and two periods of metallogeny. Geochronological data ranges from 2900 m.y. to 750 m.y. In working out the tectanostratigraphy of the above areas the basic dykes of different generations have served as major time markers. In addition, the persistent strike continuity of linear bands of pyroxene granulite, pink granolite and magnetite quartzite has been of great utility in using them as structural markers for bringing out the complex structural history in these areas.

  13. ADVANCES IN IMAGING TECHNOLOGIES IN THE EVALUATION OF HIGH-GRADE BLADDER CANCER

    PubMed Central

    Zlatev, Dimitar V.; Altobelli, Emanuela; Liao, Joseph C.

    2015-01-01

    Bladder cancer is a heterogeneous disease that ranges from low-grade variant with an indolent course, to high-grade subtype with a recurrent, progressive, and potentially lethal outcome. Accurate assessment for individualized treatment depends critically on the diagnostic accuracy of white light cystoscopy. Despite its central role, white light cystoscopy has several well-documented shortcomings including difficult flat lesion detection, imprecise tumor delineation that limits complete resection, differentiation between inflammation and malignancy, and grade and stage determination. As the limitations of white light cystoscopy contribute to the risk of cancer persistence, recurrence, and progression, there is a need for improved visualization of flat, multifocal, high-grade, and muscle-invasive lesions. Optical imaging technologies have emerged as an adjunct to white light cystoscopy with the goal to guide more effective treatment by improving cancer detection and patient stratification on the basis of grade and stage. Photodynamic diagnosis and narrow band imaging are macroscopic imaging modalities similar to white light cystoscopy, but provide additional contrast enhancement of bladder tumors and have been shown to improve detection rates. Confocal laser endomicroscopy and optical coherence tomography are microscopic imaging technologies that enable real-time high resolution, subsurface tissue characterization with spatial resolutions similar to histology. Molecular imaging offers the potential for the combination of optical imaging technologies with cancer-specific molecular agents to improve the specificity of disease detection. PMID:25882557

  14. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.

    PubMed

    Quail, Daniela F; Bowman, Robert L; Akkari, Leila; Quick, Marsha L; Schuhmacher, Alberto J; Huse, Jason T; Holland, Eric C; Sutton, James C; Joyce, Johanna A

    2016-05-20

    Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors. PMID:27199435

  15. Telomerase activity is a biomarker for high grade malignant peripheral nerve sheath tumors in neurofibromatosis type 1 individuals.

    PubMed

    Mantripragada, Kiran K; Caley, Matthew; Stephens, Phil; Jones, Christopher J; Kluwe, Lan; Guha, Abhijit; Mautner, Victor; Upadhyaya, Meena

    2008-03-01

    Telomerase activity (TA) and the expression of its enzymatic subunits, which have been demonstrated in many tumors, remain poorly investigated in tumors associated with neurofibromatosis type 1 (NF1). In this study, we analysed the association of TA and the expression of telomerase RNA (TR) and telomerase reverse transcriptase (TERT) in 23 malignant peripheral nerve sheath tumors (MPNST) (17 high grade and 6 low grade tumors), 11 plexiform neurofibromas (PNF) and 6 dermal neurofibromas (DNF). TA was studied using telomerase repeat amplification protocol (TRAP) assay and expression of TR and TERT was investigated using reverse transcription PCR (RT-PCR) and real-time PCR. TA was detected in 14 out of 17 (82%) high grade MPNST, whereas all 6 low grade MPNST and 17 benign tumors were telomerase negative. The TERT transcripts were detected in all high grade MPNST, 50% of the low grade MPNST, and 4 benign tumors. However, the expression level of the TERT strikingly correlated with TA and high grade MPNST. Thus, while TERT expression was similar in both low grade MPNST and PNF (P = 0.115), it was significantly higher in high grade MPNST when compared to either low grade MPNST (P = 0.042), PNF (P = 0.001) or DNF tumors (P = 0.010). These findings indicate that TA and expression level of TERT are potential markers for high grade malignancy in NF1 patients.

  16. Effect of disease burden on health-related quality of life in patients with malignant gliomas.

    PubMed Central

    Osoba, D.; Brada, M.; Prados, M. D.; Yung, W. K.

    2000-01-01

    The burden imposed by disease recurrence in patients with high-grade gliomas is not well documented. We studied the frequency of self-report symptoms and the effects on health-related quality of life in patients who had recurrent glioblastoma multiforme or anaplastic astrocytoma and who had a Karnofsky performance score > or = 70. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items (QLQ-C30) and the Brain Cancer Module (BCM20) before initiation of treatment for first recurrence of disease. Six symptoms (fatigue, uncertainty about the future, motor difficulties, drowsiness, communication difficulties, and headache) were reported with a frequency > 50% by both groups of patients. An additional two symptoms (visual problems and pain) were also reported with frequencies of > 50% by patients with recurrent glioblastoma multiforme. Most of the symptoms were likely due to recurrence, but previous radiation therapy and on-going corticosteroid treatment may have also been casual factors for fatigue, whereas uncertainty about the future and pain were probably nonspecific for brain cancer. Problems with motor functioning, vision, leg strength, and pain were reported more frequently by patients with recurrent glioblastoma multiforme than by those with recurrent anaplastic astrocytoma. Scores on health-related quality-of-life functioning scales were similar in the two groups. Finally, the scores for patients who had recurrent high-grade gliomas and a Karnofsky performance score > or = 70 were compared with the reported health-related quality of life scores of patients with other cancers. Their scores were similar to those of patients with metastatic cancers and worse than those of patients with localized cancers. PMID:11265231

  17. Combined efficacy of cediranib and quinacrine in glioma is enhanced by hypoxia and causally linked to autophagic vacuole accumulation.

    PubMed

    Lobo, Merryl R; Wang, Xiaoyan; Gillespie, G Yancey; Woltjer, Randall L; Pike, Martin M

    2014-01-01

    We have previously reported that the in vivo anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib is substantially enhanced via combination with the late-stage autophagy inhibitor quinacrine. The current study investigates the role of hypoxia and autophagy in combined cediranib/quinacrine efficacy. EF5 immunostaining revealed a prevalence of hypoxia in mouse intracranial 4C8 glioma, consistent with high-grade glioma. MTS cell viability assays using 4C8 glioma cells revealed that hypoxia potentiated the efficacy of combined cediranib/quinacrine: cell viability reductions induced by 1 µM cediranib +2.5 µM quinacrine were 78±7% (hypoxia) vs. 31±3% (normoxia), p<0.05. Apoptosis was markedly increased for cediranib/quinacrine/hypoxia versus all other groups. Autophagic vacuole biomarker LC3-II increased robustly in response to cediranib, quinacrine, or hypoxia. Combined cediranib/quinacrine increased LC3-II further, with the largest increases occurring with combined cediranib/quinacrine/hypoxia. Early stage autophagy inhibitor 3-MA prevented LC3-II accumulation with combined cediranib/quinacrine/hypoxia and substantially attenuated the associated reduction in cell viability. Combined efficacy of cediranib with bafilomycin A1, another late-stage autophagy inhibitor, was additive but lacked substantial potentiation by hypoxia. Substantially lower LC3-II accumulation was observed with bafilomycin A1 in comparison to quinacrine. Cediranib and quinacrine each strongly inhibited Akt phosphoryation, while bafilomycin A1 had no effect. Our results provide compelling evidence that autophagic vacuole accumulation plays a causal role in the anti-glioma cytotoxic efficacy of combined cediranib/quinacrine. Such accumulation is likely related to stimulation of autophagosome induction by hypoxia, which is prevalent in the glioma tumor microenvironment, as well as Akt signaling inhibition from both cediranib and quinacrine. Quinacrine's unique

  18. Phase II trial of temozolomide and reirradiation using conformal 3D-radiotherapy in recurrent brain gliomas

    PubMed Central

    2014-01-01

    Purpose This phase II trial was designed to assess the response rate, survival benefits and toxicity profile of temozolomide, and brain reirradiation using conformal radiotherapy (RT) for treatment of recurrent high grade glioma. Design Open-label phase II trial. Patients Twenty-nine patients had been enrolled in the study between February 2006 and June 2009. Patients had to show unequivocal evidence of tumour recurrence on gadolinium-enhanced magnetic resonance imaging (MRI) after failing conventional RT with or without temozolomide and surgery for initial disease. Histology included recurrent anaplastic astrocytoma, glioblastoma multiforme. Interventions Patients were treated by temozolomide at a dose of 200 mg/m2/day for chemonaïve patients, and at a dose of 150 mg/m2/day to previously treated patients, for 4-5 cycles. Then, patients underwent reirradiation by conformal RT at a dose of 30-40 Gy by conventional fractionation. Main outcome measures The primary end point of the study was response. The secondary end points included survival benefit. Results All the 29 patients were treated with temozolomide and reirradiation. Two patients achieved complete remission (CR), 4 achieved partial remission (PR), with an overall objective response rate of 20.6%, and further 10 patients had stable disease (SD), with a SD rate of 34.4%. The mean progression free survival (PFS) was 10.1 months, and the mean overall survival (OS) was 11.4 months. Additionally, treatment significantly improved quality of life (QOL). Treatment was tolerated well with mild grade 1, 2 nausea/vomiting in 40% of cycles, and mild grade 1, 2 haematological toxicities (neutropenia/thrombocytoprnia) in 8.6% of cycles. Conclusions Temozolomide and conformal RT had an anti-tumor activity in recurrent high grade glioma, and represented a good treatment hope for patients with recurrent brain glioma. PMID:25333019

  19. Differential expression of myc, max and RB1 genes in human gliomas and glioma cell lines.

    PubMed Central

    Hirvonen, H. E.; Salonen, R.; Sandberg, M. M.; Vuorio, E.; Västrik, I.; Kotilainen, E.; Kalimo, H.

    1994-01-01

    Deregulated expression of myc proto-oncogenes is implicated in several human neoplasias. We analysed the expression of c-myc, N-myc, L-myc, max and RB1 mRNAs in a panel of human gliomas and glioma cell lines and compared the findings with normal neural cells. The max and RB1 genes were included in the study because their protein products can interact with the Myc proteins, being thus putative modulators of Myc activity. Several gliomas contained c/L-myc mRNAs at levels higher than those in fetal brain, L-myc predominantly in grade II/III and c-myc in grade III gliomas. High-level N-myc expression was detected. In one small-cell glioblastoma and lower levels in five other gliomas. In contrast, glioma cell lines totally lacked N/L-myc expression. The in situ hybridisations revealed mutually exclusive topographic distribution of myc and glial fibrillary acidic protein (GFAP) mRNAs, and a lack of correlation between myc expression and proliferative activity, max and RB1 mRNAs were detected in most tumours and cell lines. The glioma cells displayed interesting alternative splicing patterns of max mRNAs encoding Max proteins which either suppress (Max) or augment (delta Max) the transforming activity of Myc. We conclude that (1) glioma cells in vivo may coexpress several myc genes, thus resembling fetal neural cells; but (2) cultured glioma cells expression only c-myc; (3) myc, max and RB1 are regulated independently in glioma cells; and (4) alternative processing of max mRNA in some glioma cells results in delta Max encoding mRNAs not seen in normal fetal brain. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8286200

  20. 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

  1. Improving vaccine efficacy against malignant glioma.

    PubMed

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

    2016-08-01

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

  2. Treatment Options for Childhood Brain Stem Glioma

    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 ...

  3. Stages of Childhood Brain Stem Glioma

    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 ...

  4. Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies.

    PubMed

    Phillips, Lynette M; Zhou, Xinhui; Cogdell, David E; Chua, Corrine Yingxuan; Huisinga, Anouk; R Hess, Kenneth; Fuller, Gregory N; Zhang, Wei

    2016-07-01

    Insulin-like growth factor binding protein 2 (IGFBP2) overexpression is common in high-grade glioma and is both a strong biomarker of aggressive behaviour and a well-documented prognostic factor. IGFBP2 is a member of the secreted IGFBP family that functions by interacting with circulating IGFs to modulate IGF-mediated signalling. This traditional view of IGFBP2 activities has been challenged by the recognition of the diverse functions and cellular locations of members of the IGFBP family. IGFBP2 has been previously established as a driver of glioma progression to a higher grade. In this study, we sought to determine whether IGFBP2-overexpressing tumours are dependent on continued oncogene expression and whether IGFBP2 is a viable therapeutic target in glioma. We took advantage of the well-characterized RCAS/Ntv-a mouse model to create a doxycycline-inducible IGFBP2 model of glioma and demonstrated that the temporal expression of IGFBP2 has dramatic impacts on tumour progression and survival. Further, we demonstrated that IGFBP2-driven tumours are dependent on the continued expression of IGFBP2, as withdrawal of this oncogenic signal led to a significant decrease in tumour progression and prolonged survival. Inhibition of IGFBP2 also impaired tumour cell spread. To assess a therapeutically relevant inhibition strategy, we evaluated a neutralizing antibody against IGFBP2 and demonstrated that it impaired downstream IGFBP2-mediated oncogenic signalling pathways. The studies presented here indicate that IGFBP2 not only is a driver of glioma progression and a prognostic factor but is also required for tumour maintenance and thus represents a viable therapeutic target in the treatment of glioma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  5. ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas

    PubMed Central

    Allo, Ghassan; Bernardini, Marcus Q; Wu, Ren-Chin; Shih, Ie-Ming; Kalloger, Steve; Pollett, Aaron; Gilks, C Blake; Clarke, Blaise A

    2015-01-01

    BAF250a (ARID1A) loss is a frequent event in high-grade endometrial cancers. It has been proposed that ARID1A is a driver gene, with ARID1A mutations occurring secondary to deregulated mismatch repair mechanism in gastric cancers, representing an alternative oncogenic pathway to p53 alteration. The prognostic significance of ARID1A loss is controversial. In this study, we investigated the frequency of BAF250a immunohistochemical loss in a cohort of high-grade endometrial cancers (n = 190) and correlated it with mismatch repair (hMLH1, hMSH2, hMSH6, and hPMS2) and p53 protein expression. The 190 cases consisted of 82 high-grade endometrioid, 88 serous, 10 clear cell, and 10 mixed (carcinosarcomas and mixed histology). There was BAF250a loss in 55/190 (29%) cancers, most commonly in high-grade endometrioid carcinomas (46 vs 9% in serous carcinomas, P<0.0001). Loss of any mismatch repair proteins was observed in 63/190 (33%) cancers, most commonly in high-grade endometrioid carcinomas (57 vs 10% in serous carcinomas, P<0.0001). Aberrant p53 expression was found in 86/190 (45%) cancers, more commonly in serous carcinomas (77 vs 18% in high-grade endometrioid carcinomas, P<0.0001). BAF250a loss was associated with mismatch repair loss (P<0.0001) and normal p53 expression (P<0.0001). These associations were maintained in the subset analysis within the high-grade endometrioid (P = 0.026 and P = 0.0083, respectively) and serous carcinoma cases (P = 0.0031 and P<0.0001, respectively). Survival analysis revealed a superior progression-free survival (P = 0.017) for patients with BAF250a loss within the entire cohort but not within the high-grade endometrioid and serous subtypes. Additionally, data from The Cancer Genome Atlas were extracted to correlate mutations in ARID1A, TP53, and MMR genes; we found that ARID1A mutations were negatively associated with TP53 mutations but were unrelated to mismatch repair gene mutations. In conclusion, BAF250a loss is more common in high-grade

  6. Prevalence of Human Papillomavirus Genotypes Among Women With High-Grade Cervical Lesions in Beijing, China.

    PubMed

    Xiao, Meizhu; Xu, Qiuxiang; Li, Hongyan; Gao, Huiqiao; Bie, Yachun; Zhang, Zhenyu

    2016-01-01

    The aim of the study is to investigate the prevalence of high-risk human papillomavirus (hr-HPV) genotypes among Han women with high-grade cervical lesions in Beijing, China.Cervical cell specimens from patients with histopathologically confirmed cervical lesions at 7 hospitals in Beijing were examined with a validated HPV kit for 13 hr-HPV genotypes during the study period. The patients were divided into a low-grade cervical lesions group (cervical intraepithelial neoplasia grade 1, CIN1) and a high-grade cervical lesions group (CIN2+, including cervical intraepithelial neoplasia grade 2, CIN2; cervical intraepithelial neoplasia grade 3, CIN3; squamous cervical cancer, SCC; and adenocarcinoma of the cervix, ACC) based on the histopathology results.A total of 2817 eligible patients were enrolled, including 610 cases identified as CIN1 and 2207 as CIN2+. The hr-HPV positive rates in the CIN1 and CIN2+ groups were 78.2% (477/610) and 93.3% (2060/2207), respectively. The most frequently detected genotypes were HPV16, 58, 52 and18 in the CIN1 group and HPV16, 58, 33, and 52 in the CIN2+ group, in descending order of prevalence. In addition, the prevalence of HPV18 among the patients with ACC was 28.6% (14/49), significantly >7.2% (54/752) prevalence among the SCC patients (P < 0.001). Additionally, significantly more women in the CIN2+ group had multiple infections compared with those in the CIN1 group (38.1% and 24.9%, respectively; P < 0.001). However, as the cervical lesion grade increased, the prevalence of multiple hr-HPV infections gradually deceased to 44.2% in the CIN2 patients, 36.7% in the CIN3 patients, and 35.3% in the cervical cancer (CC) patients, which included SCC and ACC patients. In cases of multiple hr-HPV infections in the CIN2+ group, double infections accounted for ∼76.6%, and HPV16+58, HPV16+52, and HPV16+18 were the most common combinations, in descending order. The most frequent combination for triple infections was HPV16+58+31, with

  7. Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma.

    PubMed

    Milea, Anca; George, Sophia H L; Matevski, Donco; Jiang, Haiyan; Madunic, Mary; Berman, Hal K; Gauthier, Mona L; Gallie, Brenda; Shaw, Patricia A

    2014-07-01

    Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n=42), mutation (n=75), methylation (n=31), and SNP array analyses (n=75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1+ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P=0.016) compared with the p16 heterogeneous/RB1+ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1- subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1- subgroup showed a significant increase in overall survival (>60 months; P=0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1- subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1+ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1+ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical

  8. Prevalence of Human Papillomavirus Genotypes Among Women With High-Grade Cervical Lesions in Beijing, China

    PubMed Central

    Xiao, Meizhu; Xu, Qiuxiang; Li, Hongyan; Gao, Huiqiao; Bie, Yachun; Zhang, Zhenyu

    2016-01-01

    Abstract The aim of the study is to investigate the prevalence of high-risk human papillomavirus (hr-HPV) genotypes among Han women with high-grade cervical lesions in Beijing, China. Cervical cell specimens from patients with histopathologically confirmed cervical lesions at 7 hospitals in Beijing were examined with a validated HPV kit for 13 hr-HPV genotypes during the study period. The patients were divided into a low-grade cervical lesions group (cervical intraepithelial neoplasia grade 1, CIN1) and a high-grade cervical lesions group (CIN2+, including cervical intraepithelial neoplasia grade 2, CIN2; cervical intraepithelial neoplasia grade 3, CIN3; squamous cervical cancer, SCC; and adenocarcinoma of the cervix, ACC) based on the histopathology results. A total of 2817 eligible patients were enrolled, including 610 cases identified as CIN1 and 2207 as CIN2+. The hr-HPV positive rates in the CIN1 and CIN2+ groups were 78.2% (477/610) and 93.3% (2060/2207), respectively. The most frequently detected genotypes were HPV16, 58, 52 and18 in the CIN1 group and HPV16, 58, 33, and 52 in the CIN2+ group, in descending order of prevalence. In addition, the prevalence of HPV18 among the patients with ACC was 28.6% (14/49), significantly >7.2% (54/752) prevalence among the SCC patients (P < 0.001). Additionally, significantly more women in the CIN2+ group had multiple infections compared with those in the CIN1 group (38.1% and 24.9%, respectively; P < 0.001). However, as the cervical lesion grade increased, the prevalence of multiple hr-HPV infections gradually deceased to 44.2% in the CIN2 patients, 36.7% in the CIN3 patients, and 35.3% in the cervical cancer (CC) patients, which included SCC and ACC patients. In cases of multiple hr-HPV infections in the CIN2+ group, double infections accounted for ∼76.6%, and HPV16+58, HPV16+52, and HPV16+18 were the most common combinations, in descending order. The most frequent combination for triple infections was HPV16

  9. High-grade endometrial carcinoma: serous and grade 3 endometrioid carcinomas have different immunophenotypes and outcomes.

    PubMed

    Alkushi, Abdulmohsen; Köbel, Martin; Kalloger, Steve E; Gilks, C Blake

    2010-07-01

    High-grade endometrial carcinomas are a heterogeneous group of tumors and include grade 3 endometrioid (EC-3), serous (SC), and clear cell carcinomas (CCC). There are conflicting data about the prognosis of these subtypes of high-grade endometrial carcinoma; this may be a result of lack of reproducibility in classifying tumor cell type. The purpose of this study was to examine differences in immunophenotype and outcome in a series of high-grade endometrial carcinomas, focusing on the comparison of EC-3 versus SC. We selected 180 endometrial carcinomas of SC, EC, or CCC type. No mixed carcinomas were included in the study. We chose the following immunohistochemical markers, estrogen receptor (ER), insulin-like growth factor 2 mRNA-binding protein 3 (IMP3), p16, p53, progesterone receptor (PR), and phosphatase and tensin homolog (PTEN) as being significantly differentially expressed in endometrial carcinoma subtypes. The tumors were stratified into 4 groups on the basis of their cell type and grade: EC grade 1 or 2, EC-3, SC, and CCC. Univariate survival analysis revealed significant differences in outcome between the 4 groups (P<0.0001), with significantly longer disease-specific survival for grade 1 or 2 EC versus EC-3 (P=0.0001), and EC-3 versus SC (P=0.0003). p16, PTEN, and IMP3 expression was observed more frequently in SC compared with EC-3 (P<0.0001, P=0.021, and P=0.031, respectively). These 3 markers showed the highest sensitivity and specificity in distinguishing between EC-3 and SC, with receiver operating characteristics area under the curve of 0.85, 0.69, and 0.71, respectively. ER and p53 approached but did not reach significance for differential expression in EC-3 versus SC (P=0.055 and P=0.068, respectively). A combination of p16 and PTEN predicts EC-3 versus SC with a sensitivity of 90.0% and specificity of 96.8%. p16 and PTEN can aid in distinguishing between EC-3 and SC of the endometrium, and are superior to ER, PR, and p53 for this purpose. EC-3

  10. Prevalence of Human Papillomavirus Genotypes Among Women With High-Grade Cervical Lesions in Beijing, China.

    PubMed

    Xiao, Meizhu; Xu, Qiuxiang; Li, Hongyan; Gao, Huiqiao; Bie, Yachun; Zhang, Zhenyu

    2016-01-01

    The aim of the study is to investigate the prevalence of high-risk human papillomavirus (hr-HPV) genotypes among Han women with high-grade cervical lesions in Beijing, China.Cervical cell specimens from patients with histopathologically confirmed cervical lesions at 7 hospitals in Beijing were examined with a validated HPV kit for 13 hr-HPV genotypes during the study period. The patients were divided into a low-grade cervical lesions group (cervical intraepithelial neoplasia grade 1, CIN1) and a high-grade cervical lesions group (CIN2+, including cervical intraepithelial neoplasia grade 2, CIN2; cervical intraepithelial neoplasia grade 3, CIN3; squamous cervical cancer, SCC; and adenocarcinoma of the cervix, ACC) based on the histopathology results.A total of 2817 eligible patients were enrolled, including 610 cases identified as CIN1 and 2207 as CIN2+. The hr-HPV positive rates in the CIN1 and CIN2+ groups were 78.2% (477/610) and 93.3% (2060/2207), respectively. The most frequently detected genotypes were HPV16, 58, 52 and18 in the CIN1 group and HPV16, 58, 33, and 52 in the CIN2+ group, in descending order of prevalence. In addition, the prevalence of HPV18 among the patients with ACC was 28.6% (14/49), significantly >7.2% (54/752) prevalence among the SCC patients (P < 0.001). Additionally, significantly more women in the CIN2+ group had multiple infections compared with those in the CIN1 group (38.1% and 24.9%, respectively; P < 0.001). However, as the cervical lesion grade increased, the prevalence of multiple hr-HPV infections gradually deceased to 44.2% in the CIN2 patients, 36.7% in the CIN3 patients, and 35.3% in the cervical cancer (CC) patients, which included SCC and ACC patients. In cases of multiple hr-HPV infections in the CIN2+ group, double infections accounted for ∼76.6%, and HPV16+58, HPV16+52, and HPV16+18 were the most common combinations, in descending order. The most frequent combination for triple infections was HPV16+58+31, with

  11. MicroRNA 203 Modulates Glioma Cell Migration via Robo1/ERK/MMP-9 Signaling.

    PubMed

    Dontula, Ranadheer; Dinasarapu, Ashok; Chetty, Chandramu; Pannuru, Padmavathi; Herbert, Engelhard; Ozer, Howard; Lakka, Sajani S

    2013-07-01

    Glioblastoma (GBM) is the most common and malignant primary adult brain cancer. Allelic deletion on chromosome 14q plays an important role in the pathogenesis of GBM, and this site was thought to harbor multiple tumor suppressor genes associated with GBM, a region that also encodes microRNA-203 (miR-203). In this study, we sought to identify the role of miR-203 as a tumor suppressor in the pathogenesis of GBM. We analyzed the miR-203 expression data of GBM patients in 10 normal and 495 tumor tissue samples derived from The Cancer Genome Atlas data set. Quantitative real-time PCR and in situ hybridization in 10 high-grade GBM and 10 low-grade anaplastic astrocytoma tumor samples showed decreased levels of miR-203 expression in anaplastic astrocytoma and GBM tissues and cell lines. Exogenous expression of miR-203 using a plasmid expressing miR-203 precursor (pmiR-203) suppressed glioma cell proliferation, migration, and invasion. We determined that one relevant target of miR-203 was Robo1, given that miR-203 expression decreased mRNA and protein levels as determined by RT-PCR and Western blot analysis. Moreover, cotransfection experiments using a luciferase-based transcription reporter assay have shown direct regulation of Robo1 by miR-203. We also show that Robo1 mediates miR-203 mediated antimigratory functions as up-regulation of Robo1 abrogates miR-203 mediated antimigratory effects. We also show that miR-203 expression suppressed ERK phosphorylation and MMP-9 expression in glioma cells. Furthermore, we demonstrate that miR-203 inhibits migration of the glioma cells by disrupting the Robo1/ERK/MMP-9 signaling axis. Taken together, these studies demonstrate that up-regulation of Robo1 in response to the decrease in miR-203 in glioma cells is responsible for glioma tumor cell migration and invasion.

  12. L1 stimulation of human glioma cell motility correlates with FAK activation.

    PubMed

    Yang, Muhua; Li, Yupei; Chilukuri, Kalyani; Brady, Owen A; Boulos, Magdy I; Kappes, John C; Galileo, Deni S

    2011-10-01

    The neural adhesion/recognition protein L1 (L1CAM; CD171) has been shown or implicated to function in stimulation of cell motility in several cancer types, including high-grade gliomas. Our previous work demonstrated the expression and function of L1 protein in stimulation of cell motility in rat glioma cells. However, the mechanism of this stimulation is still unclear. This study further investigated the function of L1 and L1 proteolysis in human glioblastoma multiforme (GBM) cell migration and invasion, as well as the mechanism of this stimulation. L1 mRNA was found to be present in human T98G GBM cell line but not in U-118 MG grade III human glioma cell line. L1 protein expression, proteolysis, and release were found in T98G cells and human surgical GBM cells by Western blotting. Exosome-like vesicles released by T98G cells were purified and contained full-length L1. In a scratch assay, T98G cells that migrated into the denuded scratch area exhibited upregulation of ADAM10 protease expression coincident with loss of surface L1. GBM surgical specimen cells exhibited a similar loss of cell surface L1 when xenografted into the chick embryo brain. When lentivirally introduced shRNA was used to attenuate L1 expression, such T98G/shL1 cells exhibited significantly decreased cell motility by time lapse microscopy in our quantitative Super Scratch assay. These cells also showed a decrease in FAK activity and exhibited increased focal complexes. L1 binding integrins which activate FAK were found in T98G and U-118 MG cells. Addition of L1 ectodomain-containing media (1) rescued the decreased cell motility of T98G/shL1 cells and (2) increased cell motility of U-118 MG cells but (3) did not further increase T98G cell motility. Injection of L1-attenuated T98G/shL1 cells into embryonic chick brains resulted in the absence of detectable invasion compared to control cells which invaded brain tissue. These studies support a mechanism where glioma cells at the edge of a cell mass

  13. 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

  14. 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

  15. Rapid Intraoperative Molecular Characterization of Glioma

    PubMed Central

    Shankar, Ganesh M.; Francis, Joshua M.; Rinne, Mikael L.; Ramkissoon, Shakti H.; Huang, Franklin W.; Venteicher, Andrew S.; Akama-Garren, Elliot H.; Kang, Yun Jee; Lelic, Nina; Kim, James C.; Brown, Loreal E.; Charbonneau, Sarah K.; Golby, Alexandra J.; Pedamallu, Chandra Sekhar; Hoang, Mai P.; Sullivan, Ryan J.; Cherniack, Andrew D.; Garraway, Levi A.; Stemmer-Rachamimov, Anat; Reardon, David A.; Wen, Patrick Y.; Brastianos, Priscilla K.; Curry, William T.; Barker, Fred G.; Hahn, William C.; Nahed, Brian V.; Ligon, Keith L.; Louis, David N.; Cahill, Daniel P.; Meyerson, Matthew

    2016-01-01

    IMPORTANCE Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%–99%) and 100% specificity (95% CI, 95%–100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations. PMID:26181761

  16. Nuclear microprobe determination of platinum quantitative distribution in rat brain tumors after cisplatin or carboplatin injection for PAT treatment of glioma

    NASA Astrophysics Data System (ADS)

    Ortega, R.; Biston, M.-C.; Devès, G.; Bohic, S.; Carmona, A.

    2005-04-01

    Conventional radiotherapy of high-grade glioma is unsuccessful since less than 50% of patients survive at 6 months, therefore glioma treatment is still challenging. A new radiotherapy procedure has been recently proposed, the photoactivation therapy (PAT), associating synchrotron radiation with a chemotherapy agent, such as cisplatin. PAT aims at using the monochromaticity and the very high brilliance of the synchrotron radiation for selective excitation of a high-Z compound introduced in tumor cell DNA to maximize the photoelectric effect probability, thus increasing local toxicity. Synchrotron irradiation of cisplatin at the platinum absorption K-edge resulted in a dramatic increase in life span relative to median survival time in the F98 glioma model in Fisher rat. In the purpose to optimize the platinum concentration into the tumor, the platinum content of irradiated target needs to be quantified. These results will enable to correlate injected dose to cellular platinum content in the tumor at the time of irradiation, and to study the spatial diffusion and distribution of the platinum into the tumor and the surrounding healthy tissues from the point of injection. Male Fisher 344 rats were inoculated with 103 F98 glioma cells. Thirteen days after stereotactic inoculation, intracerebral injection at the tumor site of 40 μg of carboplatin and 3 or 5 μg of cisplatin was performed. Platinum quantitative distribution in tumors and adjacent brain tissues was determined using μ-PIXE and μ-RBS analysis.

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

    PubMed Central

    Landi, Daniel; Hegde, Meenakshi; Ahmed, Nabil

    2014-01-01

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

  18. Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology.

    PubMed

    Schroeder, Kristin M; Hoeman, Christine M; Becher, Oren J

    2014-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that originates in the pons and is seen exclusively in children. Despite numerous efforts to improve treatment, DIPG remains incurable with 90% of children dying within 2 y of diagnosis, making it one of the leading causes of death in children with brain tumors. With the advent of new genomic tools, the genetic landscape of DIPG is slowly being unraveled. The most common genetic alterations include a K27M mutation in H3.3 or H3.1, which are found in up to 78% of DIPGs, whereas p53 mutations are found in up to 77%. Other recently discovered alterations include amplification of components of the receptor tyrosine kinase/Ras/phosphatidylinositol 3-kinase signaling pathway, particularly platelet-derived growth factor receptor A. Recapitulating such alterations, genetically engineered DIPG preclinical models have been developed, and DIPG xenograft models have also been established. Both models have strengths and weaknesses but can help with the prioritization of novel agents for clinical trials for children with DIPG. As we move forward, it is important that we continue to study the complex and unique biology of DIPG and develop improved preclinical models to increase our understanding of DIPG pathogenesis, allowing translation into successful therapies in the not too distant future. PMID:24192697

  19. PET and SPECT studies in children with hemispheric low-grade gliomas.

    PubMed

    Juhász, Csaba; Bosnyák, Edit

    2016-10-01

    Molecular imaging is playing an increasing role in the pretreatment evaluation of low-grade gliomas. While glucose positron emission tomography (PET) can be helpful to differentiate low-grade from high-grade tumors, PET imaging with amino acid radiotracers has several advantages, such as better differentiation between tumors and non-tumorous lesions, optimized biopsy targeting, and improved detection of tumor recurrence. This review provides a brief overview of single-photon emission computed tomography (SPECT) studies followed by a more detailed review of the clinical applications of glucose and amino acid PET imaging in low-grade hemispheric gliomas. We discuss key differences in the performance of the most commonly utilized PET radiotracers and highlight the advantage of PET/MRI fusion to obtain optimal information about tumor extent, heterogeneity, and metabolism. Recent data also suggest that simultaneous acquisition of PET/MR images and the combination of advanced MRI techniques with quantitative PET can further improve the pretreatment and post-treatment evaluation of pediatric brain tumors. PMID:27659825

  20. A 31-year-old woman with a transformed low-grade glioma.

    PubMed

    Warnke, Peter C

    2010-03-10

    Low-grade gliomas in adults have an incidence of 0.8 to 1.2 per 100,000, and their causes are unknown. Despite their histological classification as low-grade, they cannot be cured by any current treatment mode, and no class I evidence exists to guide initial treatment of these tumors. Median survival ranges between 7.5 years and 10 years, with a 5-year survival probability between 55% and 86%. The prognosis depends on age, World Health Organization (WHO) tumor grade, Karnofsky performance score, cytological type (oligodendroglioma vs astrocytoma), and, potentially, the extent of resection. Oligodendrogliomas with loss of heterozygosity on chromosomes 1p and 19q have a distinctly more favorable prognosis and therapeutic response rate. Low-grade tumors progress to high-grade gliomas with aggressive biological behavior at increasing frequency with advancing age. Ms P is a young woman with a previously treated oligodendroglioma, WHO grade II, with loss of heterozygosity on chromosomes 1p and 19q, which at a third resection had transformed into an oligodendroglioma of WHO grade III. She wants to know her current and future therapeutic options.

  1. High grade anorectal stricture complicating Crohn's disease: endoscopic treatment using insulated-tip knife

    PubMed Central

    Chon, Hyung Ku; Shin, Ik Sang; Kim, Sang Wook

    2016-01-01

    Endoscopic treatments have emerged as an alternative to surgery, in the treatment of benign colorectal stricture. Unlike endoscopic balloon dilatation, there is limited data on endoscopic electrocautery incision therapy for benign colorectal stricture, especially with regards to safety and long-term patency. We present a case of a 29-year-old female with Crohn's disease who had difficulty in defecation and passing thin stools. A pelvic magnetic resonance imaging scan, gastrograffin enema, and sigmoidoscopy showed a high-grade anorectal stricture. An endoscopic insulated-tip knife incision was successfully performed to resolve the problem. From our experience, we suggest that endoscopic insulated-tip knife treatment may be a feasible and effective modality for patients with short-segment, very rigid, fibrotic anorectal stricture. PMID:27433152

  2. High grade anorectal stricture complicating Crohn's disease: endoscopic treatment using insulated-tip knife.

    PubMed

    Chon, Hyung Ku; Shin, Ik Sang; Kim, Sang Wook; Lee, Soo Teik

    2016-07-01

    Endoscopic treatments have emerged as an alternative to surgery, in the treatment of benign colorectal stricture. Unlike endoscopic balloon dilatation, there is limited data on endoscopic electrocautery incision therapy for benign colorectal stricture, especially with regards to safety and long-term patency. We present a case of a 29-year-old female with Crohn's disease who had difficulty in defecation and passing thin stools. A pelvic magnetic resonance imaging scan, gastrograffin enema, and sigmoidoscopy showed a high-grade anorectal stricture. An endoscopic insulated-tip knife incision was successfully performed to resolve the problem. From our experience, we suggest that endoscopic insulated-tip knife treatment may be a feasible and effective modality for patients with short-segment, very rigid, fibrotic anorectal stricture.

  3. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer.

    PubMed

    Zhang, Hui; Liu, Tao; Zhang, Zhen; Payne, Samuel H; Zhang, Bai; McDermott, Jason E; Zhou, Jian-Ying; Petyuk, Vladislav A; Chen, Li; Ray, Debjit; Sun, Shisheng; Yang, Feng; Chen, Lijun; Wang, Jing; Shah, Punit; Cha, Seong Won; Aiyetan, Paul; Woo, Sunghee; Tian, Yuan; Gritsenko, Marina A; Clauss, Therese R; Choi, Caitlin; Monroe, Matthew E; Thomas, Stefani; Nie, Song; Wu, Chaochao; Moore, Ronald J; Yu, Kun-Hsing; Tabb, David L; Fenyö, David; Bafna, Vineet; Wang, Yue; Rodriguez, Henry; Boja, Emily S; Hiltke, Tara; Rivers, Robert C; Sokoll, Lori; Zhu, Heng; Shih, Ie-Ming; Cope, Leslie; Pandey, Akhilesh; Zhang, Bing; Snyder, Michael P; Levine, Douglas A; Smith, Richard D; Chan, Daniel W; Rodland, Karin D

    2016-07-28

    To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT. PMID:27372738

  4. Concurrent use of endourological and radiologic methods in the management of high-grade renal trauma

    PubMed Central

    Akbari, Ardalan; Heran, Manraj K.S.; Afshar, Kourosh

    2016-01-01

    This case report explores the efficacy of simultaneous use of endourological and radiological methods to assess and manage high-grade renal trauma. A male rugby player was diagnosed with Grade 4 blunt renal trauma. A segment of the patient’s kidney was isolated from the main renal pelvis with intact perfusion. This resulted in urinary extravasation. Ureteral stenting and angioembolization were used to treat the patient’s severe symptoms. Angioembolization ablated functional tissue that was causing a persistent urinary leak. Following the treatment, the patient was discharged with no significant bleeding or leakage from the kidney. This report illustrates an uncommon use of this combined approach. Followup 18 months post-trauma revealed normal blood pressure and approximately 30% loss of volume of the affected kidney. PMID:27695587

  5. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer.

    PubMed

    Zhang, Hui; Liu, Tao; Zhang, Zhen; Payne, Samuel H; Zhang, Bai; McDermott, Jason E; Zhou, Jian-Ying; Petyuk, Vladislav A; Chen, Li; Ray, Debjit; Sun, Shisheng; Yang, Feng; Chen, Lijun; Wang, Jing; Shah, Punit; Cha, Seong Won; Aiyetan, Paul; Woo, Sunghee; Tian, Yuan; Gritsenko, Marina A; Clauss, Therese R; Choi, Caitlin; Monroe, Matthew E; Thomas, Stefani; Nie, Song; Wu, Chaochao; Moore, Ronald J; Yu, Kun-Hsing; Tabb, David L; Fenyö, David; Bafna, Vineet; Wang, Yue; Rodriguez, Henry; Boja, Emily S; Hiltke, Tara; Rivers, Robert C; Sokoll, Lori; Zhu, Heng; Shih, Ie-Ming; Cope, Leslie; Pandey, Akhilesh; Zhang, Bing; Snyder, Michael P; Levine, Douglas A; Smith, Richard D; Chan, Daniel W; Rodland, Karin D

    2016-07-28

    To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT.

  6. High grade anorectal stricture complicating Crohn's disease: endoscopic treatment using insulated-tip knife.

    PubMed

    Chon, Hyung Ku; Shin, Ik Sang; Kim, Sang Wook; Lee, Soo Teik

    2016-07-01

    Endoscopic treatments have emerged as an alternative to surgery, in the treatment of benign colorectal stricture. Unlike endoscopic balloon dilatation, there is limited data on endoscopic electrocautery incision therapy for benign colorectal stricture, especially with regards to safety and long-term patency. We present a case of a 29-year-old female with Crohn's disease who had difficulty in defecation and passing thin stools. A pelvic magnetic resonance imaging scan, gastrograffin enema, and sigmoidoscopy showed a high-grade anorectal stricture. An endoscopic insulated-tip knife incision was successfully performed to resolve the problem. From our experience, we suggest that endoscopic insulated-tip knife treatment may be a feasible and effective modality for patients with short-segment, very rigid, fibrotic anorectal stricture. PMID:27433152

  7. Induction of high grade astrocytoma (HGA) by protons: Molecular mechanisms and RBE considerations

    NASA Astrophysics Data System (ADS)

    Dalrymple, G. V.; Leichner, P. K.; Harrison, K. A.; Cox, A. B.; Hardy, K. A.; Salmon, Y. L.; Mitchell, J. C.

    1994-10-01

    Protons of a specific energy, 55 MeV, have been found to induce primary high grade astrocytomas (HGA) in the Rhesus monkey (Macaca mulatta). Brain tumors of this type were not induced by protons of other energies (32-2,300 MeV). Induction of HGA has been identified in human patients who have had radiation therapy to the head. We believe that the induction of HGA in the monkey is a consequence of dose distribution, not some unique ``toxic'' property of protons. Comparison of the human experience with the monkey data indicates the RBE for induction of brain tumors to be about one. It is unlikely that protons cause an unusual change in oncogenic expression, as compared to conventional electromagnetic radiation.

  8. Origin of deep crystal reflections: seismic profiling across high-grade metamorphic terranes in Canada

    USGS Publications Warehouse

    Green, A.; Milkereit, B.; Percival, J.; Davidson, A.; Parrish, R.; Cook, F.; Geis, W.; Cannon, W.; Hutchinson, D.; West, G.; Clowes, R.

    1990-01-01

    In an attempt to better understand the origin of deep crustal reflections LITHOPROBE has sponsored or co-sponsored Seismic reflection surveys across tracts of high-grade metamorphic rock in the Archean Superior craton, the Proterozoic Grenville orogen and the Phanerozoic Cordilleran orogen. Common to these three diverse terranes are near-surface zones of prominent Seismic reflectivity that are typically associated with velocity discontinuities at highly strained contacts between gneissic rocks of varying lithology. At some locations the reflective layering resulted from transposition and rearrangement of previously layered rocks (stratified assemblages, sills, etc.), whereas in other regions it was generated by extreme attenuation, stretching and ductile flow of weakly layered or irregularly organized rocks. It seems likely that compositionally layered gneissic rock is a common source of reflections in the deep crust, with reflections originating at lithological boundaries and zones of mylonite. ?? 1990.

  9. Concurrent use of endourological and radiologic methods in the management of high-grade renal trauma

    PubMed Central

    Akbari, Ardalan; Heran, Manraj K.S.; Afshar, Kourosh

    2016-01-01

    This case report explores the efficacy of simultaneous use of endourological and radiological methods to assess and manage high-grade renal trauma. A male rugby player was diagnosed with Grade 4 blunt renal trauma. A segment of the patient’s kidney was isolated from the main renal pelvis with intact perfusion. This resulted in urinary extravasation. Ureteral stenting and angioembolization were used to treat the patient’s severe symptoms. Angioembolization ablated functional tissue that was causing a persistent urinary leak. Following the treatment, the patient was discharged with no significant bleeding or leakage from the kidney. This report illustrates an uncommon use of this combined approach. Followup 18 months post-trauma revealed normal blood pressure and approximately 30% loss of volume of the affected kidney.

  10. Congenital high-grade sarcoma presenting as skin nodules and respiratory distress in a neonate.

    PubMed

    Powers, J W; Teitell, M; Milisavljevic, V

    2008-02-01

    We report, to our knowledge, the first case of a congenital, widespread, aggressive high-grade sarcoma, presented as multiple skin nodules and respiratory distress in a neonate that had a t(9;22)(q22;q11-12) cytogenetic abnormality suggestive of a more indolent extraskeletal myxoid chondrosarcoma (EMC). EMC is generally thought of as a slow-growing tumor that presents between the fourth and sixth decades of life. Our patient was a 45,XY, t(13;14) newborn who presented at birth with subcutaneous nodules involving the face, scalp, back and extremities, as well as multiple intrathoracic, intraabdominal and intracranial masses. Diagnosis was made using electron microscopy and immunohistochemical and cytogenetic studies. Despite attempts to control rapid growth of lesions using high-dose steroids and cis-retinoic acid, patient's clinical status continued to deteriorate and life support was withdrawn at the 26 day of life.

  11. 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

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

    PubMed

    Li, Xue-Tao; Tang, Wei; Jiang, Ying; Wang, Xiao-Min; Wang, Yan-Hong; Cheng, Lan; Meng, Xian-Sheng

    2016-04-26

    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

  13. Preparation of High-Grade Powders from Tomato Paste Using a Vacuum Foam Drying Method.

    PubMed

    Sramek, Martin; Schweiggert, Ralf Martin; van Kampen, Andreas; Carle, Reinhold; Kohlus, Reinhard

    2015-08-01

    We present a rapid and gentle drying method for the production of high-grade tomato powders from double concentrated tomato paste, comparing results with powders obtained by foam mat air drying and freeze dried powders. The principle of this method consists of drying tomato paste in foamed state at low temperatures in vacuum. The formulations were dried at temperatures of 50, 60, and 70 °C and vacuum of 200 mbar. Foam stability was affected by low serum viscosity and the presence of solid particles in tomato paste. Consequently, serum viscosity was increased by maltodextrin addition, yielding optimum stability at tomato paste:maltodextrin ratio of 2.4:1 (w/w) in dry matter. Material foamability was improved by addition of 0.5% (w/w, fresh weight) egg white. Because of solid particles in tomato paste, foam air filling had to be limited to critical air volume fraction of Φ = 0.7. The paste was first pre-foamed to Φ = 0.2 and subsequently expanded in vacuo. After drying to a moisture content of 5.6% to 7.5% wet base (w.b.), the materials obtained were in glassy state. Qualities of the resulting powders were compared with those produced by freeze and air drying. Total color changes were the least after vacuum drying, whereas air drying resulted in noticeable color changes. Vacuum foam drying at 50 °C led to insignificant carotenoid losses, being equivalent to the time-consuming freeze drying method. In contrast, air drying caused lycopene and β-carotene losses of 18% to 33% and 14% to 19% respectively. Thus, vacuum foam drying enables production of high-grade tomato powders being qualitatively similar to powders obtained by freeze drying.

  14. CIP2A protein expression in high-grade, high-stage bladder cancer

    PubMed Central

    Huang, Lisa P; Savoly, Diana; Sidi, Abraham A; Adelson, Martin E; Mordechai, Eli; Trama, Jason P

    2012-01-01

    Bladder cancer is one of the most common cancers in the United States. Numerous markers have been evaluated for suitability of bladder cancer detection and surveillance. However, few of them are acceptable as a routine tool. Therefore, there exists a continuing need for an assay that detects the presence of bladder cancer in humans. It would be advantageous to develop an assay with a protein that is associated with the development of bladder cancer. We have identified the cancerous inhibitor of PP2A (CIP2A) protein as a novel bladder cancer biomarker. In this study, Western blot analysis was used to assess the expression level of CIP2A protein in bladder cancer cell lines and bladder cancer patient tissues (n = 43). Our studies indicated CIP2A protein was abundantly expressed in bladder cancer cell lines but not in nontumor epithelial cell lines. Furthermore, CIP2A was specifically expressed in transitional cell carcinoma (TCC) of the bladder tumor tissues but not in adjacent nontumor bladder tissue. Our data showed that CIP2A protein detection in high-grade TCC tissues had a sensitivity of 65%, which is 3.4-fold higher than that seen in low-grade TCC tissues (19%). The level of CIP2A protein expression increased with the stage of disease (12%, 27%, 67%, and 100% for pTa, pT1, pT2, and pT3 tumor, respectively). In conclusion, our studies suggest that CIP2A protein is specifically expressed in human bladder tumors. CIP2A is preferentially expressed in high-grade and high-stage TCC tumors, which are high-risk and invasive tumors. Our studies reported here support the role of CIP2A in bladder cancer progression and its usefulness for the surveillance of recurrence or progression of human bladder cancer. PMID:23342256

  15. Zircon ion microprobe dating of high-grade rocks in Sri Lanka

    SciTech Connect

    Kroener, A.; Williams, I.S.; Compston, W.; Baur, N.; Vitanage, P.W.; Perera, L.R.K.

    1987-11-01

    The high-grade gneisses of Sri Lanka display spectacular in-situ granulitization phenomena similar to those observed in southern India and of current interest for evolutionary models of the lower continental crust. The absolute ages of these rocks are poorly constrained and so, using the SHRIMP ion microprobe, the authors have analyzed small spots on zircons from upper amphibolite to granulite grade quartzitic and pelitic metasediments. Detrital grains from a metaquartzite of the Highland Group preserve premetamorphic U-Pb ages of between 3.17 and 2.4 Ga and indicate derivation of the sediment from an unidentified Archean source terrain. The Pb-loss patterns of these zircons and the other samples suggest severe disturbance at ca 1100 Ma ago, which the authors attribute to high-grade regional metamorphism. Two pelitic gneisses contain detrital zircons with ages up to 2.04 Ga and also record an approx. = 1100 Ma event that is also apparent from metamorphic rims around old cores and new zircon growth. A granite intrusive into the Highland Group granulites records an emplacement age of 1000-1100 Ma as well as metamorphic disturbance some 550 Ma ago but also contains older, crustally derived xenocrysts. Zircons from a metaquartzite xenolith within the granitoid Vijayan Complex are not older than approx. 1100 Ma; therefore the Vijayan is neither Archean in age nor acted as basement to the Highland Group, as previously proposed. The authors suggest that the Vijayan Complex formed significantly later than the Highland Group and that the two units were brought into contact through post-1.1 Ga thrusting. Although the granulitization phenomena in India and Sri Lanka are similar, the granulite event in Sri Lanka is not Archean in age but took place in the late Proterozoic.

  16. Preparation of High-Grade Powders from Tomato Paste Using a Vacuum Foam Drying Method.

    PubMed

    Sramek, Martin; Schweiggert, Ralf Martin; van Kampen, Andreas; Carle, Reinhold; Kohlus, Reinhard

    2015-08-01

    We present a rapid and gentle drying method for the production of high-grade tomato powders from double concentrated tomato paste, comparing results with powders obtained by foam mat air drying and freeze dried powders. The principle of this method consists of drying tomato paste in foamed state at low temperatures in vacuum. The formulations were dried at temperatures of 50, 60, and 70 °C and vacuum of 200 mbar. Foam stability was affected by low serum viscosity and the presence of solid particles in tomato paste. Consequently, serum viscosity was increased by maltodextrin addition, yielding optimum stability at tomato paste:maltodextrin ratio of 2.4:1 (w/w) in dry matter. Material foamability was improved by addition of 0.5% (w/w, fresh weight) egg white. Because of solid particles in tomato paste, foam air filling had to be limited to critical air volume fraction of Φ = 0.7. The paste was first pre-foamed to Φ = 0.2 and subsequently expanded in vacuo. After drying to a moisture content of 5.6% to 7.5% wet base (w.b.), the materials obtained were in glassy state. Qualities of the resulting powders were compared with those produced by freeze and air drying. Total color changes were the least after vacuum drying, whereas air drying resulted in noticeable color changes. Vacuum foam drying at 50 °C led to insignificant carotenoid losses, being equivalent to the time-consuming freeze drying method. In contrast, air drying caused lycopene and β-carotene losses of 18% to 33% and 14% to 19% respectively. Thus, vacuum foam drying enables production of high-grade tomato powders being qualitatively similar to powders obtained by freeze drying. PMID:26189747

  17. Mechanisms for folding of high-grade rocks in extensional tectonic settings

    NASA Astrophysics Data System (ADS)

    Harris, Lyal B.; Koyi, Hemin A.; Fossen, Haakon

    2002-11-01

    This review of structures developed in extensional high-grade terrains, combined with results of centrifuge analogue modelling, illustrates the range of fold styles and mechanisms for folding of amphibolite to granulite facies rocks during rifting or the collapse of a thrust-thickened orogen. Several extensional fold mechanisms (such as folding within detachment shear zones) are similar to those in contractional settings. The metamorphic P- T- t path, and not fold style or mode of formation, is therefore required to determine the tectonic setting in which some folds developed. Other mechanisms such as rollover above and folding between listric normal shear zones, and folding due to isostatic adjustments during crustal thinning, are unique to extensional tectonic settings. Several mechanisms for folding during crustal extension produce structures that could easily be misinterpreted as implying regional contraction and hence lead to errors in their tectonic interpretation. It is shown that isoclinal recumbent folds refolded by open, upright folds may develop during regional extension in the deep crust. Folds with a thrust sense of asymmetry can develop due to high shear strains within an extensional detachment, or from enhanced back-rotation of layers between normal shear zones. During back-rotation folding, layers rotated into the shortening field undergo further buckle folding, and all may rotate towards orthogonality to the maximum shortening direction. This mechanism explains the presence of many transposed folds, folds with axial planar pegmatites and folds with opposite vergence in extensional terrains. Examples of folds in high-grade rocks interpreted as forming during regional extension included in this paper are from the Grenville Province of Canada, Norwegian Caledonides, Albany Mobile Belt and Leeuwin Complex of Western Australia, Ruby Mountains in the Basin and Range Province of Nevada, the Atâ Sund area of Greenland, the Napier Complex of Enderby Land

  18. Wingspan Stent for High-Grade Symptomatic Vertebrobasilar Artery Atherosclerotic Stenosis

    SciTech Connect

    Li Jian Zhao Zhenwei Gao Guodong Deng Jianping; Yu Jia; Gao Li; Yuan Yang; Qv Youzhi

    2012-04-15

    Purpose: This study was designed to present the treatment outcomes with Wingspan stent angioplasty of high-grade intracranial vertebrobasilar artery (VBA) stenosis in symptomatic patients. Methods: Between 2007 and 2010, the records of 30 patients with 31 intracranial high-grade VBA stenoses (all{>=}70%) who underwent elective stenting due to the failure of medical therapy were retrospectively reviewed. Clinical evaluation was performed based on the modified Rankin scale and the National Institutes of Health Stroke Scale. Results: In all cases, the stent deployment was technically successful. The mean stenosis decreased significantly from 82.28 {+-} 8.02% (range, 72-99%) to 11.18 {+-} 7.28% (range, 0-25%) after stent-assisted angioplasty (P < 0.05). Periprocedure complications occurred in 3 (10%) of 30 patients; there were 2 cases of perforator strokes and 1 case of transient flow insufficiency with stent overlap. Clinical follow-up (mean, 17.81 {+-} 11.49 months; range, 5-40 months) was available for 27 patients, and angiographic follow-up (mean, 9.95 {+-} 5.74 months, range, 5-20 months) was available for 19 patients. Only one case demonstrated recurrent symptoms with restenosis ({>=}50%). There were no recurrent ischemic events and no cases of restenosis in the other patients. Conclusions: According to our data, the Wingspan stent for symptomatic intracranial VBA stenoses is a safe and efficacious treatment alternative in cases with recurrent symptoms despite medical therapy. However, the improvement of outcome requires the reduction in the rate of procedure-related complications and long-term outcomes still have to be demonstrated.

  19. Metal recovery from high-grade WEEE: a life cycle assessment.

    PubMed

    Bigum, Marianne; Brogaard, Line; Christensen, Thomas H

    2012-03-15

    Based on available data in the literature the recovery of aluminium, copper, gold, iron, nickel, palladium and silver from high-grade WEEE was modeled by LCA. The pre-treatment of WEEE included manual sorting, shredding, magnetic sorting, Eddy-current sorting, air classification and optical sorting. The modeled metallurgical treatment facility included a Kaldo plant, a converter aisle, an anode refinery and a precious metal refinery. The metallurgic treatment showed significant environmental savings when credited the environmental load from avoided production of the same amount of metals by mining and refining of ore. The resource recovery per tonne of high-grade WEEE ranged from 2g of palladium to 386kg of iron. Quantified in terms of person-equivalents the recovery of palladium, gold, silver, nickel and copper constituted the major environmental benefit of the recovery of metals from WEEE. These benefits are most likely underestimated in the model, since we did not find adequate data to include all the burdens from mining and refining of ore; burdens that are avoided when metals are recovered from WEEE. The processes connected to the pre-treatment of WEEE were found to have little environmental effect compared to the metallurgical treatment. However only 12-26% of silver, gold and palladium are recovered during pre-treatment, which suggest that the reduction of the apparent losses of precious metals as palladium, gold and silver during pre-treatment of WEEE is of environmental importance. Our results support in a quantitative manner that metal recovery from WEEE should be quantified with respect to the individual metals recovered and not as a bulk metal recovery rate.

  20. Simultaneous Bilateral Carotid Stenting for Symptomatic Bilateral High-Grade Carotid Stenosis: A Retrospective Clinical Investigation.

    PubMed

    Ye, Ziming; Liu, Ying; Deng, Xiao; Chen, Xiangren; Lin, Cuiting; Tang, Yanyan; Su, Ying; Fang, Lanji; Wu, Yuan; Qin, Chao

    2016-01-01

    BACKGROUND This retrospective clinical investigation aimed to evaluate the short-term effectiveness and safety of SBCAS for symptomatic bilateral high-grade CS. MATERIAL AND METHODS From 2009 to 2014, 145 patients were recruited. Among them, 70 underwent SBCAS, and other 75 patients underwent SAMM and served as controls. The immediate postprocedural complications and postprocedural neurological evaluation, as well as restenosis at 6-month and 1-year follow-ups in the SBCAS group are reported. Additionally, baseline risk factors for ischemic stroke, adverse effects of drugs, and outcomes at 30-day, 6-month, and 1-year follow-ups were compared between the 2 groups. RESULTS Our data did not reveal significant differences between the 2 groups in baseline risk factors for ischemic stroke. In the SBCAS group, both HPS (5.7%) and HD (40%) occurred, but they were not very severe, and no patients had postprocedural neurological deficit. Moreover, restenosis only occurred in 3 patients at 3 stent placement sites (4.3%) at 1-year follow-up. Adverse effects of drugs did not occur in SBCAS group, but adverse effects of Bayer aspirin and Lipitor occurred in 4 patients (5.4%) and 18 patients (24.3%), respectively, at 6-month follow-up in the control group. Furthermore, there were significant differences in outcomes between the 2 groups at 30-day, 6-month, and 1-year follow-ups, in that NIHSS, CS ratio, and incidence of endpoint events, as well as 1-year cumulative probability of endpoint events, were all lower in the SBCAS group than in the control group (p<0.05). CONCLUSIONS Compared to SAMM, we found that SBCAS was more effective and safer for symptomatic bilateral high-grade CS. PMID:27542158

  1. DAPK1, MGMT and RARB promoter methylation as biomarkers for high-grade cervical lesions.

    PubMed

    Sun, Yin; Li, Shu; Shen, Keng; Ye, Shuang; Cao, Dongyan; Yang, Jiaxin

    2015-01-01

    Gene promoter methylation may be used a potential biomarker for detecting solid tumor including cervical cancer. Here, we used methylation sensitive-high resolution melting (MS-HRM) analysis to detecting promoter methylation ratios of DAPK1, MGMT and RARB gene in patients with different cervical disease grade. The detection of gene promoter methylation was conducted in two hundred fifty patients' samples including normal cytology (n=48), cervical intraepithelial neoplasia grade 1 (CIN1, n=54), cervical intraepithelial neoplasia grade 2 (CIN2, n=47), cervical intraepithelial neoplasia grade 3 (CIN3, n=56) and cervical squamous cell carcinomas (SCS, n=45). We found there were a significant positive correlation between the promoter methylation status of DAPK1 and cervical disease grade (P=0.022). In addition, the methylated promoters of DAPK1 combined with MGMT, MGMT combined with RARB, DAPK1 combined with RARB were positive correlated with cervical disease grade (P < 0.05). All three genes promoters methylated were positive correlated with cervical disease grade (P < 0.001). Receiver operating characteristic (ROC) curves was conducted to evaluate whether the three genes methylation could be used to be a potential marker for diagnosing high grade cervical disease (HSIL and SCC). The cutoff values for the methylation rates of all these genes were 0-5%. Regrettably, only the methylation of MGMT combined with DAPK1 gave 43.4% sensitivity and 68.6% specificity. The current results indicated that MS-HRM-based testing for DNA methylations of MGMT plus DAPK1 genes holds some promise for high grade cervical disease screening. PMID:26823825

  2. Simultaneous Bilateral Carotid Stenting for Symptomatic Bilateral High-Grade Carotid Stenosis: A Retrospective Clinical Investigation

    PubMed Central

    Ye, Ziming; Liu, Ying; Deng, Xiao; Chen, Xiangren; Lin, Cuiting; Tang, Yanyan; Su, Ying; Fang, Lanji; Wu, Yuan; Qin, Chao

    2016-01-01

    Background This retrospective clinical investigation aimed to evaluate the short-term effectiveness and safety of SBCAS for symptomatic bilateral high-grade CS. Material/Methods From 2009 to 2014, 145 patients were recruited. Among them, 70 underwent SBCAS, and other 75 patients underwent SAMM and served as controls. The immediate postprocedural complications and postprocedural neurological evaluation, as well as restenosis at 6-month and 1-year follow-ups in the SBCAS group are reported. Additionally, baseline risk factors for ischemic stroke, adverse effects of drugs, and outcomes at 30-day, 6-month, and 1-year follow-ups were compared between the 2 groups. Results Our data did not reveal significant differences between the 2 groups in baseline risk factors for ischemic stroke. In the SBCAS group, both HPS (5.7%) and HD (40%) occurred, but they were not very severe, and no patients had postprocedural neurological deficit. Moreover, restenosis only occurred in 3 patients at 3 stent placement sites (4.3%) at 1-year follow-up. Adverse effects of drugs did not occur in SBCAS group, but adverse effects of Bayer aspirin and Lipitor occurred in 4 patients (5.4%) and 18 patients (24.3%), respectively, at 6-month follow-up in the control group. Furthermore, there were significant differences in outcomes between the 2 groups at 30-day, 6-month, and 1-year follow-ups, in that NIHSS, CS ratio, and incidence of endpoint events, as well as 1-year cumulative probability of endpoint events, were all lower in the SBCAS group than in the control group (p<0.05). Conclusions Compared to SAMM, we found that SBCAS was more effective and safer for symptomatic bilateral high-grade CS. PMID:27542158

  3. Metal recovery from high-grade WEEE: a life cycle assessment.

    PubMed

    Bigum, Marianne; Brogaard, Line; Christensen, Thomas H

    2012-03-15

    Based on available data in the literature the recovery of aluminium, copper, gold, iron, nickel, palladium and silver from high-grade WEEE was modeled by LCA. The pre-treatment of WEEE included manual sorting, shredding, magnetic sorting, Eddy-current sorting, air classification and optical sorting. The modeled metallurgical treatment facility included a Kaldo plant, a converter aisle, an anode refinery and a precious metal refinery. The metallurgic treatment showed significant environmental savings when credited the environmental load from avoided production of the same amount of metals by mining and refining of ore. The resource recovery per tonne of high-grade WEEE ranged from 2g of palladium to 386kg of iron. Quantified in terms of person-equivalents the recovery of palladium, gold, silver, nickel and copper constituted the major environmental benefit of the recovery of metals from WEEE. These benefits are most likely underestimated in the model, since we did not find adequate data to include all the burdens from mining and refining of ore; burdens that are avoided when metals are recovered from WEEE. The processes connected to the pre-treatment of WEEE were found to have little environmental effect compared to the metallurgical treatment. However only 12-26% of silver, gold and palladium are recovered during pre-treatment, which suggest that the reduction of the apparent losses of precious metals as palladium, gold and silver during pre-treatment of WEEE is of environmental importance. Our results support in a quantitative manner that metal recovery from WEEE should be quantified with respect to the individual metals recovered and not as a bulk metal recovery rate. PMID:22115841

  4. Vaccine Therapies in Malignant Glioma

    PubMed Central

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

    2015-01-01

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

  5. Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma.

    PubMed

    Dasgupta, Tina; Olow, Aleksandra K; Yang, Xiaodong; Hashizume, Rintaro; Nicolaides, Theodore P; Tom, Maxwell; Aoki, Yasuyuki; Berger, Mitchel S; Weiss, William A; Stalpers, Lukas J A; Prados, Michael; James, C David; Mueller, Sabine; Haas-Kogan, Daphne A

    2016-02-01

    Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10-20% of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.

  6. DiME: A Scalable Disease Module Identification Algorithm with Application to Glioma Progression

    PubMed Central

    Liu, Yunpeng; Tennant, Daniel A.; Zhu, Zexuan; Heath, John K.; Yao, Xin; He, Shan

    2014-01-01

    Disease module is a group of molecular components that interact intensively in the disease specific biological network. Since the connectivity and activity of disease modules may shed light on the molecular mechanisms of pathogenesis and disease progression, their identification becomes one of the most important challenges in network medicine, an emerging paradigm to study complex human disease. This paper proposes a novel algorithm, DiME (Disease Module Extraction), to identify putative disease modules from biological networks. We have developed novel heuristics to optimise Community Extraction, a module criterion originally proposed for social network analysis, to extract topological core modules from biological networks as putative disease modules. In addition, we have incorporated a statistical significance measure, B-score, to evaluate the quality of extracted modules. As an application to complex diseases, we have employed DiME to investigate the molecular mechanisms that underpin the progression of glioma, the most common type of brain tumour. We have built low (grade II) - and high (GBM) - grade glioma co-expression networks from three independent datasets and then applied DiME to extract potential disease modules from both networks for comparison. Examination of the interconnectivity of the identified modules have revealed changes in topology and module activity (expression) between low- and high- grade tumours, which are characteristic of the major shifts in the constitution and physiology of tumour cells during glioma progression. Our results suggest that transcription factors E2F4, AR and ETS1 are potential key regulators in tumour progression. Our DiME compiled software, R/C++ source code, sample data and a tutorial are available at http://www.cs.bham.ac.uk/~szh/DiME. PMID:24523864

  7. Microglial action in glioma: a boon turns bane.

    PubMed

    Ghosh, Anirban; Chaudhuri, Swapna

    2010-06-15

    Microglia has the potential to shape the neuroimmune defense with vast array of functional attributes. The cells prime infiltrated lymphocytes to retain their effector functions, play crucial role in controlling microenvironmental milieu and significantly participate in glioma. Reports demonstrate microglial accumulation in glioma and predict their assistance in glioma growth and spreading. Clarification of the 'double-edged' appearance of microglia is necessary to unfold its role in glioma biology. In this article the interpretation of microglial activities has been attempted to reveal their actual function in glioma. Contrary to the trendy acceptance of its glioma promoting infamy, accumulated evidences make an effort to view the state of affairs in favor of the cell. Critical scrutiny indicates that microglial immune assaults are intended to demolish the neoplastic cells in brain. But the weaponry of microglia has been tactically utilized by glioma in their favor as the survival strategy. Hence the defender appears as enemy in advanced glioma. PMID:20338195

  8. Effect of High-Grade Pre-operative Knee Laxity on Outcomes of Anterior Cruciate Ligament Reconstruction

    PubMed Central

    Magnussen, Robert A.; Reinke, Emily; Huston, Laura J.; Group, MOON knee; Hewett, Timothy E.; Spindler, Kurt P.

    2015-01-01

    Objectives: Knee laxity in the setting of suspected anterior cruciate ligament (ACL) injury is frequently assessed through physical examination using the Lachman, pivot-shift, and anterior drawer tests. The degree of laxity noted on these examinations may influence treatment decisions and prognosis. We hypothesized that increased pre-operative knee laxity (Grade 3+ pivot-shift, Lachman > 10mm, or anterior drawer greater than 10mm) are associated with increased risk of revision ACL reconstruction and poorer patient-reported outcomes at two years post-operative. Methods: From an ongoing prospective cohort study, 1394 patients that underwent primary isolated ACL reconstruction within 3 months of injury with autograft tissue without medial collateral, lateral collateral, or posterior cruciate injury requiring treatment or prior contralateral ACL injury were identified. Demographic data, physical examination findings under anesthesia at the time of ACL reconstruction, information regarding meniscus status and treatment, and pre-operative and 2 year post-operative International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score Knee Related Quality of Life subscale (KOOS-QOL), and Marx activity scores were collected. Patients reported by the operating surgeons as having a Lachman or anterior drawer examination at least 10mm greater than the contralateral side were classified as having a high grade Lachman or anterior drawer respectively. Patients reported by the operating surgeon as having a 3+ pivot-shift were classified as having a high-grade pivot-shift. Patients demonstrating high-grade laxity on any of these examinations were classified as having high-grade pre-operative knee laxity. Multiple logistic regression modeling was used to evaluate whether having high-grade pre-operative laxity was associated with increased odds of undergoing revision ACL reconstruction within 2 years of the index procedure, controlling for patient age, sex

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

    PubMed

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

    2016-01-01

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

  10. Phenotypic Transition as a Survival Strategy of Glioma

    PubMed Central

    ICHIKAWA, Tomotsugu; OTANI, Yoshihiro; KUROZUMI, Kazuhiko; DATE, Isao

    2016-01-01

    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. PMID:27169497

  11. 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.

  12. The Sum of Tumour-to-Brain Ratios Improves the Accuracy of Diagnosing Gliomas Using 18F-FET PET

    PubMed Central

    Zyromska, Agnieszka; Wisniewski, Tomasz; Harat, Aleksandra; Lopatto, Rita; Furtak, Jacek

    2015-01-01

    Gliomas are common brain tumours, but obtaining tissue for definitive diagnosis can be difficult. There is, therefore, interest in the use of non-invasive methods to diagnose and grade the disease. Although positron emission tomography (PET) with 18F-fluorethyltyrosine (18F-FET) can be used to differentiate between low-grade (LGG) and high-grade (HGG) gliomas, the optimal parameters to measure and their cut-points have yet to be established. We therefore assessed the value of single and dual time-point acquisition of 18F-FET PET parameters to differentiate between primary LGGs (n = 22) and HGGs (n = 24). PET examination was considered positive for glioma if the metabolic activity was 1.6-times higher than that of background (contralateral) brain, and maximum tissue-brain ratios (TBRmax) were calculated 10 and 60 min after isotope administration with their sums and differences calculated from individual time-point values. Using a threshold-based method, the overall sensitivity of PET was 97%. Several analysed parameters were significantly different between LGGs and HGGs. However, in a receiver operating characteristics analysis, TBR sum had the best diagnostic accuracy of 87% and sensitivity, specificity, and positive and negative predictive values of 100%, 72.7%, 80%, and 100%, respectively. 18F-FET PET is valuable for the non-invasive determination of glioma grade, especially when dual time-point metrics are used. TBR sum shows the greatest accuracy, sensitivity, and negative predictive value for tumour grade differentiation and is a simple method to implement. However, the cut-off may differ between institutions and calibration strategies would be useful. PMID:26468649

  13. The Sum of Tumour-to-Brain Ratios Improves the Accuracy of Diagnosing Gliomas Using 18F-FET PET.

    PubMed

    Malkowski, Bogdan; Harat, Maciej; Zyromska, Agnieszka; Wisniewski, Tomasz; Harat, Aleksandra; Lopatto, Rita; Furtak, Jacek

    2015-01-01

    Gliomas are common brain tumours, but obtaining tissue for definitive diagnosis can be difficult. There is, therefore, interest in the use of non-invasive methods to diagnose and grade the disease. Although positron emission tomography (PET) with 18F-fluorethyltyrosine (18F-FET) can be used to differentiate between low-grade (LGG) and high-grade (HGG) gliomas, the optimal parameters to measure and their cut-points have yet to be established. We therefore assessed the value of single and dual time-point acquisition of 18F-FET PET parameters to differentiate between primary LGGs (n = 22) and HGGs (n = 24). PET examination was considered positive for glioma if the metabolic activity was 1.6-times higher than that of background (contralateral) brain, and maximum tissue-brain ratios (TBRmax) were calculated 10 and 60 min after isotope administration with their sums and differences calculated from individual time-point values. Using a threshold-based method, the overall sensitivity of PET was 97%. Several analysed parameters were significantly different between LGGs and HGGs. However, in a receiver operating characteristics analysis, TBR sum had the best diagnostic accuracy of 87% and sensitivity, specificity, and positive and negative predictive values of 100%, 72.7%, 80%, and 100%, respectively. 18F-FET PET is valuable for the non-invasive determination of glioma grade, especially when dual time-point metrics are used. TBR sum shows the greatest accuracy, sensitivity, and negative predictive value for tumour grade differentiation and is a simple method to implement. However, the cut-off may differ between institutions and calibration strategies would be useful. PMID:26468649

  14. 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

  15. OVARIAN LOW-GRADE AND HIGH-GRADE SEROUS CARCINOMA: Pathogenesis, Clinicopathologic and Molecular Biologic Features, and Diagnostic Problems

    PubMed Central

    Vang, Russell; Shih, Ie-Ming; Kurman, Robert J.

    2009-01-01

    Ovarian serous carcinomas have been graded using various systems. Recently, a 2-tier system in which tumors are subdivided into low-grade and high-grade has been proposed. This approach is simplistic, reproducible, and based on biologic evidence indicating that both tumors develop via different pathways. Low-grade serous carcinomas exhibit low-grade nuclei with infrequent mitotic figures. They evolve from adenofibromas or borderline tumors, have frequent mutations of the KRAS, BRAF, or ERBB2 genes, and lack TP53 mutations (Type I pathway). The progression to invasive carcinoma is a slow step-wise process. Low-grade tumors are indolent and have better outcome than high-grade tumors. In contrast, high-grade serous carcinomas have high-grade nuclei and numerous mitotic figures. Identification of a precursor lesion in the ovary has been elusive and therefore the origin of ovarian carcinoma has been described as de novo. More recently, studies have suggested that a proportion appear to originate from intraepithelial carcinoma in the fallopian tube. The development of these tumors is rapid (Type II pathway). The vast majority are characterized by TP53 mutations and lack mutations of KRAS, BRAF, or ERBB2. Although both types of serous carcinomas evolve along different pathways, rare high-grade serous carcinomas seem to arise through the Type I pathway. Immunohistochemical stains for p53, p16, and Ki-67 for distinction of low- from high-grade tumors are of limited value but can be helpful in selected instances. This review provides an update on the pathogenesis and clinicopathologic features of these two types of serous carcinomas and addresses some of the diagnostic problems that are encountered in routine practice. PMID:19700937

  16. Primary high-grade B-cell lymphoma of the choroid plexus.

    PubMed

    Cecchi, Paolo C; Billio, Atto; Colombetti, Vito; Rizzo, Paolo; Ricci, Umberto M; Schwarz, Andreas

    2008-01-01

    Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma arising from and confined to the neuraxis. It represents about 3-4% of all primitive brain neoplasms and is mainly located in deep supratentorial regions. A ventricular involvement is quite frequent, but in the vast majority of cases it is secondary to an extension from a subependymal location. Amongst the primary ventricular forms occasionally reported, a choroid plexus origin is extremely rare; to date, only three cases have been described in the English literature. We report the case of a 71-year-old left-handed woman admitted to our department after a progressive 2-week history of confusion, motor speech disturbances and left hemiparesis. A brain MRI scan displayed an intraventricular lesion located in the right atrium, about 2.5cm in its major axis, homogeneously enhancing after gadolinium administration, surrounded by edema in the homolateral deep hemispheric region; the main diagnostic hypothesis was meningioma. She underwent a parieto-occipital craniotomy and a navigation-assisted posterior parietal transcortical approach, achieving complete removal of the intraventricular lesion originating from the choroid plexus. The histological diagnosis was of high-grade diffuse large B-cell lymphoma. Both an MRI scan of the entire craniospinal axis and a thoracic and abdominal CT scan showed no other neoplastic lesions; a bone marrow biopsy was normal; a final diagnosis of primary central nervous system lymphoma was made. CSF cytological analysis did not show any signs of lymphoma dissemination. Adjuvant chemotherapy with methotrexate was administered, and at the last follow-up (26 months) our patient is clinically and radiologically disease-free. Primary choroid plexus lymphoma is a very rare tumor that should be included in the differential diagnosis of intraventricular neoplasms. It usually occurs in the lateral ventricles (with a predilection for the atrium) of adult people (>50

  17. Glioma-Associated Oncogene Homolog1 (Gli1)-Aquaporin1 pathway promotes glioma cell metastasis

    PubMed Central

    Liao, Zheng-qiang; Ye, Ming; Yu, Pei-gen; Xiao, Chun; Lin, Feng-yun

    2016-01-01

    Glioma-Associated Oncogene Homolog1 (Gli1) is known to be activated in malignant glioma; however, its downstream pathway has not been fully explained. The aim of this study was to explore the role of Gli1-Aquaporin1 (AQP1) signal pathway in glioma cell survival. Our data suggests that both Gli1 and AQP1 are upregulated in glioma tissues, as in comparison to in normal tissues. These up-regulation phenomena were also observed in glioma U251 and U87 cells. It was demonstrated that Gli1 positively regulated the AQP1 expression. By luciferase reporter gene and ChIP assay, we observed that this modulation process was realized by combination of Gli1 with AQP1 promotor. In addition, knock down of Gli1 by siRNA interference reduced the viability of glioma cells as well as suppressed cell metastasis. Also, the inhibitory effects of cell survival by silenced Gli1 were abrogated by AQP1 overexpression. In summary, glioma cell survival is a regulatory process and can be mediated by Gli1-AQP1 pathway. [BMB Reports 2016; 49(7): 394-399] PMID:27157540

  18. Geophysical evidences for a thick crust south of Palghat-Tiruchi gap in the High Grade Terrains of South India

    NASA Technical Reports Server (NTRS)

    Mishra, D. C.

    1988-01-01

    The regional gravity and magnetic features of the South Indian Shield were discussed. The prominent regional gravity low of 20 to 30 mgls over the charnockite terrain of South India, coupled with the correlation of a steep gravity gradient with a prominent shear zone to the north, can be interpreted in terms of increased crustal thickness in the South Indian high-grade terrain. There is some support for this from deep seismic sounding. The magnetic signature of the high-grade terrain is also distinctive, and Mishra argued that the Palghat-Tiruchi line might represent a Precambrian boundary such as a suture between two distinct crustal blocks.

  19. [Chemotherapy of chiasmal gliomas in children].

    PubMed

    Helcl, F

    1995-04-01

    Chiasmal gliomas are rare tumors occurring predominantly in childhood. Their optimal treatment is still controversial. In the past only neurosurgeons (performing partial or subtotal removal of the tumor, biopsy or shunting procedure in hydrocephalus) and radiotherapeutists participated in their treatment. In the middle of the eighties there was only a single article dealing with chemotherapy of these tumors (Rosenstock, 1985). Since that time there was an increased number of articles about harmful effects of radiotherapy on the developing child's brain. Neurosurgeons are aware that they will not solve this problem alone. During the past 7 years we have observed gradual retreat from radiotherapy and an inclination to combined chemotherapy of the chiasmal gliomas in children. The author has been engaged in the research of this clinical entity for more than 10 years and he offers to readers a summary of the contemporary knowledge about chemotherapy of chiasmal gliomas in children. Despite the fact that there is lacking experience with long-term survivors after chemotherapy, which is extremely important especially in this disease, the preliminary short-term results of combined chemotherapy of chiasmal gliomas in children are promising. Rapid development of chemistry and pharmacology in the last few years is promising for the discovery of further, more effective anti-tumor drugs. Their new combinations could improve present non-satisfactory results of treatment of chiasmal gliomas in children. (Ref. 25.)

  20. Genetic characterization of adult infratentorial gliomas.

    PubMed

    Miwa, Tomoru; Hirose, Yuichi; Sasaki, Hikaru; Ikeda, Eiji; Yoshida, Kazunari; Kawase, Takeshi

    2009-02-01

    Adult infratentorial gliomas are rare and have not been well studied. We therefore conducted genetic analysis of those tumors to see if there was any characteristic that could be relevant in clinical management and understanding of tumorigenesis. Nineteen adult infratentorial gliomas were analyzed for chromosomal aberration by comparative genomic hybridization, and for expression of p53 and epidermal growth factor receptor (EGFR) by immunohistochemistry. The most frequent chromosomal aberration was the gain of 7p, and five of the seven cerebellar or fourth ventricle malignant gliomas had that aberration. However, the gain of 7q, the characteristic abnormality of supratentorial astrocytomas commonly associated with the gaining of 7p, was observed only in 1 of 11 adult infratentorial astrocytic tumors. Combined losses of 1p and 19q, the genetic hallmark of oligodendroglioma, were not observed. Results of immunohistochemistry of p53 and EGFR were comparable to those reported in supratentorial gliomas. Our findings might suggest the presence of distinct tumorigenic pathway in adult infratentorial gliomas.

  1. High-grade astroblastoma in a child: Report of one case and review of literature

    PubMed Central

    de la Garma, Victor Hugo Escobar; Arcipreste, Arturo Ayala; Vázquez, Felipe Padilla; Aguilar, Ricardo Ramírez; Castruita, Uriel Oliva; Guerra, Rafael Mendizábal

    2014-01-01

    Background: Astroblastoma is a rare glial neoplastic lesion that affects children and adolescents; its histogenesis remains uncertain. It is considered to account for 0.5% of all glial neoplasms, and two different subtypes have been defined based upon histologic characteristics. Case Description: We present the case of a 9-year-old girl who presented with headache, motor symptoms, and seizures few days before she was admitted to our institution. Computed tomography (CT) and magnetic resonance imaging (MRI) scans showed an intra-axial heterogeneous frontoparietal lesion with a striking “bubbly” appearance in MRI T2-weighted sequences and features of intracranial hypertension. Gross total resection of the tumor was achieved and the histopathologic diagnosis revealed high-grade astroblastoma. We reviewed the current published cases of astroblastoma to highlight the demographic, clinical, radiologic, and pathologic data. Conclusion: Astroblastomas are a distinct clinicopathologic entity, with well-described radiologic, pathologic, and cytogenetic features. Its recurrence is high and efforts must be made to elucidate the role and usefulness of radiotherapy and chemotherapy in these tumors. PMID:25101206

  2. [Histological evaluation of cryosurgery in high grade intraepithelial neoplasia (CIN-III)] of the uterine cervix].

    PubMed

    Rojas, I; Rodríguez, T; Pierotic, M; Le Cerf, P

    1993-01-01

    Sixty patients, having high grade cervical intraepithelial neoplasia (CIN III) are analyzed. They are all treated primarily with cryosurgery followed, approximately 12 weeks thereafter, by cervical conization, in order to histologically evaluate the response to treatment. The mean follow up of the whole series was 36 months. Ninetieth five percentage of the patients were included in the series, having an abnormal PAP smear, suggesting presence of a CIN. Colposcopically directed biopsy prior to cryosurgery showed grade CIN III, with no glandular involvement in 61.7% of the cases. In 38.3% the endocervical glands were involved, cryotherapy was done in 60 patients, with single freezing in 26 (43.3%) and double freezing in 34 (53.7%) patients. On analyzing the cone specimen, 71.7% of the cases showed no residual disease. The group that received double freezing did better than the single one (79 versus 61%). As well, the group with out gland involvement did better than the group showing such condition (83.8 versus 52.2%). Cryosurgery is a good therapeutic modality in cases with CIN III, following street selection criteria and having a good and reliable follow up.

  3. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma

    PubMed Central

    Verhaak, Roel G.W.; Tamayo, Pablo; Yang, Ji-Yeon; Hubbard, Diana; Zhang, Hailei; Creighton, Chad J.; Fereday, Sian; Lawrence, Michael; Carter, Scott L.; Mermel, Craig H.; Kostic, Aleksandar D.; Etemadmoghadam, Dariush; Saksena, Gordon; Cibulskis, Kristian; Duraisamy, Sekhar; Levanon, Keren; Sougnez, Carrie; Tsherniak, Aviad; Gomez, Sebastian; Onofrio, Robert; Gabriel, Stacey; Chin, Lynda; Zhang, Nianxiang; Spellman, Paul T.; Zhang, Yiqun; Akbani, Rehan; Hoadley, Katherine A.; Kahn, Ari; Köbel, Martin; Huntsman, David; Soslow, Robert A.; Defazio, Anna; Birrer, Michael J.; Gray, Joe W.; Weinstein, John N.; Bowtell, David D.; Drapkin, Ronny; Mesirov, Jill P.; Getz, Gad; Levine, Douglas A.; Meyerson, Matthew

    2012-01-01

    Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named “Classification of Ovarian Cancer” (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens. PMID:23257362

  4. High-grade undifferentiated pleomorphic sarcoma of the pelvis: A case report and review of literature

    PubMed Central

    Agafonoff, Slava; Vaidya, Shrikant K.; DeFade, Brian

    2016-01-01

    High-grade spindle cell sarcomas are rare undifferentiated pleomorphic cancers that present a treatment challenge to urological practices, especially when they present in the pelvis. We report a 46-year-old male patient who presented to our urology clinic with urinary retention after having a Foley catheter placed at an outlying facility. A voiding trial was attempted, but the patient failed this trial. This failure resulted in cystoscopy with bilateral retrograde pyelograms, which revealed a compressed bladder due to extrinsic compression. This finding had been evaluated with a computed tomography (CT) scan with and without intravenous contrast that showed a 14 cm pelvic mass with bladder displacement and compression. A fine needle aspiration was done at this outlying facility, prior to referral to our office, and it confirmed spindle cell pathology. The mass was surgically excised with the histology revealing a pelvic spindle cell sarcoma with positive surgical margins. Further, metastatic work-up with CT/positron emission tomography revealed bone and lung metastasis. The patient is currently undergoing chemotherapy and radiation. In this case study, we will review staging, management, differential diagnosis, chemotherapy, and radiation. PMID:27453666

  5. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

    PubMed Central

    Fontebasso, Adam M.; Papillon-Cavanagh, Simon; Schwartzentruber, Jeremy; Nikbakht, Hamid; Gerges, Noha; Fiset, Pierre-Olivier; Bechet, Denise; Faury, Damien; De Jay, Nicolas; Ramkissoon, Lori; Corcoran, Aoife; Jones, David T W; Sturm, Dominik; Johann, Pascal; Tomita, Tadanori; Goldman, Stewart; Nagib, Mahmoud; Bendel, Anne; Goumnerova, Liliana; Bowers, Daniel C.; Leonard, Jeffrey R.; Rubin, Joshua B.; Alden, Tord; Browd, Samuel; Geyer, J. Russell; Leary, Sarah; Jallo, George; Cohen, Kenneth; Gupta, Nalin; Prados, Michael D.; Carret, Anne-Sophie; Ellezam, Benjamin; Crevier, Louis; Klekner, Almos; Bognar, Laszlo; Hauser, Peter; Garami, Miklos; Myseros, John; Dong, Zhifeng; Siegel, Peter M.; Malkin, Hayley; Ligon, Azra; Albrecht, Steffen; Pfister, Stefan M.; Ligon, Keith L.; Majewski, Jacek; Jabado, Nada; Kieran, Mark W

    2014-01-01

    Midline pediatric high-grade astrocytomas (pHGAs) are incurable with few treatment targets identified. Most tumors harbor K27M mutations on histone 3 variants. In 40 treatment-naïve midline pHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with H3.1 K27M, while FGFR1 mutations/fusions occur in thalamic tumors associated with H3.3 K27M. Hyper-activation of the bone morphogenetic protein (BMP)/ACVR1 developmental pathway in pHGAs harbouring ACVR1 mutations led to increased phospho-SMAD1/5/8 expression and up-regulation of BMP downstream early response genes in tumour cells. Global DNA methylation profiles were significantly associated with the K27M mutation regardless of the mutant H3 variant and irrespective of tumor location, supporting its role in driving the epigenetic phenotype. This significantly expands the potential treatment targets and further justifies pre-treatment biopsy in pHGA as a means to orient therapeutic efforts in this disease. PMID:24705250

  6. Development of high-grade lymphoma in Helicobacter pylori-infected C57BL/6 mice.

    PubMed

    Wang, X; Willén, R; Andersson, C; Wadström, T

    2000-01-01

    Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. Mice with H. pylori infection develop severe gastritis and atrophic changes in their stomachs after 6 months. We followed H. pylori-infected animals for 13 months to find out whether dysplasia, carcinoma or lymphoma developed. Six-week-old C57BL/6 mice were infected with the CagA-positive and VacA-positive H. pylori mouse-passaged strain 119/95, fed a low antioxidant diet, and kept in microisolated cages. Histopathological changes were examined after 13 months' infection. All H. pylori-inoculated mice (n = 5) developed a gastric squamous papilloma with nagging of the lamina muscularis after 13 months. Three out of five animals developed high-grade B-cell lymphoma derived from a MALT lymphoma at the squamous-corpus border with manifestations also in the liver, spleen and kidney. There was a suspicion of local gastric lymphoma in the two remaining mice but with no significant changes in the liver, spleen or kidney. The normal control mice showed no pathological changes in any of these organs. It is concluded that this mouse model with infection by the CagA-positive, vac-toxin-producing H. pylori strain 119/95 is suitable for use in the study of lymphoma development and also development of squamous cell papilloma with proliferative features.

  7. YAP Induces High-Grade Serous Carcinoma in Fallopian Tube Secretory Epithelial Cells

    PubMed Central

    Hua, Guohua; Lv, Xiangmin; He, Chunbo; Remmenga, Steven W.; Rodabough, Kerry J.; Dong, Jixin; Yang, Liguo; Lele, Subodh M.; Yang, Peixin; Zhou, Jin; Karst, Alison; Drapkin, Ronny I.; Davis, John S.; Wang, Cheng

    2015-01-01

    Accumulating evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from Fallopian tube secretory epithelial cells (FTSECs). However, the molecular mechanisms underlying the initiation and progression of HGSC derived from FTSECs remains unclear. In the present study, we found that the Hippo/YAP signaling pathway plays a critical role in the initiation and progression of Fallopian tube and ovarian HGSC. Importantly, YAP was overexpressed in inflammatory and cancerous Fallopian tube tissues. Further, overexpression of wild-type YAP, or constitutively active YAP in immortalized FTSECs, induced cell proliferation, migration, colony formation, and tumorigenesis. Moreover, the Hippo/YAP and the fibroblast growth factor (FGF) signaling pathways formed an autocrine/paracrine positive feedback loop to drive the progression of the FTSECs-derived HGSC. Evidence in this study strongly suggests that combined therapy with inhibitors of YAP (such as verteporfin) and FGFRs (such as BGJ398) can provide a novel therapeutic strategy to treat Fallopian tube and ovarian HGSC. PMID:26364602

  8. Recycling of an electric arc furnace flue dust to obtain high grade ZnO.

    PubMed

    Ruiz, Oscar; Clemente, Carmen; Alonso, Manuel; Alguacil, Francisco Jose

    2007-03-01

    The production of steel in electric arc furnace (EAF) generates a by-product called EAF dusts. These steelmaking flue dusts are classified in most industrialized countries as hazardous residues because the heavy metals contained in them, tend to leach under slightly acidic rainfall conditions. However, and at the same time they contain zinc species which can be used as a source to obtain valuable by-products. The present investigation shows results on the processing of an EAF flue dust using ammonium carbonate solutions. Once zinc is dissolved: ZnO + 4NH3 + H2O --> Zn(NH3)4(2+) + 2OH- with other impurities (i.e. cadmium and copper), these are eliminated from the zinc solution via cementation with metallic zinc. The purified zinc solution was evaporated (distilled) until precipitation of a zinc carbonate species, which then was calcined to yield a zinc oxide of a high grade. For the unattacked dust residue from the leaching operation, mainly composed of zinc ferrite, several options can be considered: back-recycling to the furnace, further treatment by sodium hydroxide processing or a more safely dumping due to its relatively inertness.

  9. Detection of high-grade atypia nuclei in breast cancer imaging

    NASA Astrophysics Data System (ADS)

    Noël, Henri; Roux, Ludovic; Lu, Shijian; Boudier, Thomas

    2015-03-01

    Along with mitotic count, nuclear pleomorphism or nuclear atypia is an important criterion for the grading of breast cancer in histopathology. Though some works have been done in mitosis detection (ICPR 2012,1 MICCAI 2013,2 and ICPR 2014), not much work has been dedicated to automated nuclear atypia grading, especially the most difficult task of detection of grade 3 nuclei. We propose the use of Convolutional Neural Networks for the automated detection of cell nuclei, using images from the three grades of breast cancer for training. The images were obtained from ICPR contests. Additional manual annotation was performed to classify pixels into five classes: stroma, nuclei, lymphocytes, mitosis and fat. At total of 3,000 thumbnail images of 101 × 101 pixels were used for training. By dividing this training set in an 80/20 ratio we could obtain good training results (around 90%). We tested our CNN on images of the three grades which were not in the training set. High grades nuclei were correctly classified. We then thresholded the classification map and performed basic analysis to keep only rounded objects. Our results show that mostly all atypical nuclei were correctly detected.

  10. 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

  11. 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

  12. [Surgical treatment of chiasmal gliomas in children].

    PubMed

    Helcl, F

    1997-03-01

    Chiasmal gliomas are rare brain tumors occurring especially in children. Their proper treatment is still controversial and consists of surgery, radiotherapy and chemotherapy. Surgical removal of these tumors can usually be only partial or subtotal and radiotherapy frequently follows. There are supporters of surgical approach, as well as its enemies. The author has been engaged in problems of optimal treatment of this entity for more than 10 years. He is offering a review of knowledge from the literature concerning surgical treatment of this disease in children. The great majority of articles in the literature are dealing with retrospective analysis of relatively small series of patients usually treated in single neurosurgical department and the surgical treatment is enclosed like a part of combined therapy. Articles dealing only with surgical treatment of chiasmal gliomas are few and reviews determining the contemporary role of surgery of this entity are also lacking. This was the main impulse for writing this compilation. The short history of surgical therapy is reviewed. Some new trends of this therapy are also mentioned (microsurgery, Cavitron Ultrasonic Surgical Aspirator and peroperative use of visual evoked potentials). Up to date criteria for surgical treatment of chiasmal gliomas in children are given-exploration of chiasmal region and performing a biopsy in all cases, radical surgery only in extrinsic gliomas of the chiasmal region and conservative surgical approach to intrinsic chiasmal gliomas. It is emphasized that the significance of obstructive hydrocephalus in this entity has not been fully estimated till now, as well as the role of shunting procedures. Surgical treatment remains, nevertheless, an important armamentarium in the management of chiasmal gliomas in children. (Ref. 20.)

  13. Persistent infection with human papillomavirus 16 or 18 is strongly linked with high-grade cervical disease

    PubMed Central

    Radley, David; Saah, Alfred; Stanley, Margaret

    2016-01-01

    Abstract We investigated the relationship between high-grade cervical disease (cervical intraepithelial neoplasia [CIN] 2, CIN3 or adenocarcinoma in situ) and persistent infection with HPV16 and/or HPV18 (HPV16/18) among 3970 women who received placebo in 3 clinical trials of a quadrivalent HPV vaccine. Statistical analysis (odds ratios, sensitivity, specificity, negative and positive predictive values, negative and positive likelihood ratios) showed that patients with a persistent infection with HPV16/18 had a much greater risk of HPV16/18-related high-grade cervical disease. Furthermore, subjects without a persistent infection with HPV16/18 were unlikely to have HPV16/18-related high-grade cervical disease. These results suggest that persistent infection with HPV16/18 meets the criteria for a surrogate endpoint for HPV16/18-related high-grade cervical disease and may be used as such in future clinical studies with prophylactic HPV vaccines and in natural history studies. PMID:26383553

  14. Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas.

    PubMed

    Bechet, Denise; Gielen, Gerrit G H; Korshunov, Andrey; Pfister, Stefan M; Rousso, Caterina; Faury, Damien; Fiset, Pierre-Olivier; Benlimane, Naciba; Lewis, Peter W; Lu, Chao; David Allis, C; Kieran, Mark W; Ligon, Keith L; Pietsch, Torsten; Ellezam, Benjamin; Albrecht, Steffen; Jabado, Nada

    2014-11-01

    Studies in pediatric high-grade astrocytomas (HGA) by our group and others have uncovered recurrent somatic mutations affecting highly conserved residues in histone 3 (H3) variants. One of these mutations leads to analogous p.Lys27Met (K27M) mutations in both H3.3 and H3.1 variants, is associated with rapid fatal outcome, and occurs specifically in HGA of the midline in children and young adults. This includes diffuse intrinsic pontine gliomas (80 %) and thalamic or spinal HGA (>90 %), which are surgically challenging locations with often limited tumor material available and critical need for specific histopathological markers. Here, we analyzed formalin-fixed paraffin-embedded tissues from 143 pediatric HGA and 297 other primary brain tumors or normal brain. Immunohistochemical staining for H3K27M was compared to tumor genotype, and also compared to H3 tri-methylated lysine 27 (H3K27me3) staining, previously shown to be drastically decreased in samples carrying this mutation. There was a 100 % concordance between genotype and immunohistochemical analysis of H3K27M in tumor samples. Mutant H3K27M was expressed in the majority of tumor cells, indicating limited intra-tumor heterogeneity for this specific mutation within the limits of our dataset. Both H3.1 and H3.3K27M mutants were recognized by this antibody while non-neoplastic elements, such as endothelial and vascular smooth muscle cells or lymphocytes, did not stain. H3K27me3 immunoreactivity was largely mutually exclusive with H3K27M positivity. These results demonstrate that mutant H3K27M can be specifically identified with high specificity and sensitivity using an H3K27M antibody and immunohistochemistry. Use of this antibody in the clinical setting will prove very useful for diagnosis, especially in the context of small biopsies in challenging midline tumors and will help orient care in the context of the extremely poor prognosis associated with this mutation. PMID:25200321

  15. Radical resection for the treatment of glioma.

    PubMed

    Laws, E R

    1995-01-01

    The surgical management of gliomas of the brain continues to be an area for investigation and of some controversy. Many of the questions can be answered by careful clinical investigation, using modern techniques of epidemiology and carefully controlled prospective studies. Until these studies are available, a strong case can be made for the treatment of many gliomas of the brain with radical surgical resection. In some cases this strategy can provide cures or long-term remissions, and in others it can provide disease control when combined with adjunctive measures, such as radiation therapy.

  16. Using bioluminescence imaging in glioma research.

    PubMed

    Luwor, Rodney B; Stylli, Stanley S; Kaye, Andrew H

    2015-05-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumour and has the worst prognosis. Over the last decade, the use of bioluminescence imaging technology has rapidly become widespread to further understand the mechanisms that drive GBM development and progression. Pre-clinical evaluation and optimisation of therapeutic efficacy in GBM research has also utilised this simple non-invasive technology. Here we summarise recent advances made in glioma biology and therapeutic intervention using bioluminescence imaging. This review also describes the current knowledge regarding the use of luciferase-based reporters in examining the role of specific cancer signalling cascades that promote glioma progression.

  17. [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.

  18. Selenoprotein and antioxidant genes and the risk of high-grade prostate cancer and prostate cancer recurrence

    PubMed Central

    Gerstenberger, John P.; Bauer, Scott R.; Blarigan, Erin L. Van; Sosa, Eduardo; Song, Xiaoling; Witte, John S.; Carroll, Peter R.; Chan, June M.

    2014-01-01

    Background Observational studies suggest an inverse association between selenium and risk of prostate cancer. However, randomized controlled trials of selenium supplementation have reported conflicting results. Thus, we examined plasma selenium and selenium-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with non-metastatic disease. Methods We measured plasma selenium and genotyped 73 single nucleotide polymorphisms in TXNRD1, TXNRD2, GPX1, GPX3, GPX4, SEP15, SEPP1, SELENBP1, OGG1, and CAT among 568 men with non-metastatic prostate cancer who underwent radical prostatectomy. We examined associations between plasma selenium, genotypes, and risk of high-grade prostate cancer (Gleason grade ≥8 or 7 with primary score ≥4; n=111) using logistic regression, and risk of prostate cancer recurrence (61 events; 3.8 y median follow-up) using Cox proportional hazards regression. Results Plasma selenium was not associated with risk of high-grade prostate cancer or prostate cancer recurrence. Less common alleles of rs11913319 in TXNRD2 and rs125701 in OGG1 were associated with an increased risk of high-grade prostate cancer. We observed associations between the risk of prostate cancer recurrence and multiple SNPs in TXNRD1, TXNRD2, GPX3, and SEP15. These associations were no longer statistically significant after adjustment for multiple comparisons. Conclusions Among men with non-metastatic prostate cancer, there is suggestive evidence that genetic variation in selenoproteins and related antioxidant enzymes may be associated with risk of high-grade disease at diagnosis and prostate cancer recurrence. PMID:25284284

  19. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma.

    PubMed

    Kurman, R J

    2013-12-01

    A new paradigm for the pathogenesis of ovarian cancer has recently been proposed which helps to explain persistent problems in describing the development and diverse morphology of these neoplasms. The paradigm incorporates recent advances in our understanding of the molecular pathogenesis of epithelial 'ovarian' cancer with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies led to the development of a dualistic model that divides all the various histologic types of epithelial ovarian carcinomas into two broad categories designated 'type I' and 'type II'. The prototypic type I tumor is low-grade serous carcinoma and the prototypic type II tumor is high-grade serous carcinomas (HGSCs). As the serous tumors comprise ∼70% of all epithelial ovarian tumors and account for the majority of deaths, the serous tumors will be the subject of this review. There are marked differences between the low-grade and high-grade serous tumors. Briefly, the former are indolent, present in stage I (tumor confined to the ovary) and develop from well-established precursors, so-called 'atypical proliferative (borderline) tumors,' which are characterized by specific mutations, including KRAS, BRAF and ERBB2; they are relatively genetically stable. In contrast, HGSCs are aggressive, present in the advanced stage, and develop from intraepithelial carcinomas in the fallopian tube. They harbor TP53 mutations in over 95% of cases, but rarely harbor the mutations detected in the low-grade serous tumors. At the time of diagnosis they demonstrate marked chromosomal aberrations but over the course of the disease these changes remain relatively stable. Along with the recent advances in understanding the molecular pathogenesis of these tumors, studies have demonstrated that the long sought for precursor of ovarian HGSC appears to develop from an occult intraepithelial carcinoma in the fimbrial region of the fallopian tube designated 'serous tubal

  20. 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.

  1. 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.

  2. ALA PDT for high grade dysplasia in Barrett's oesophagus: review of a decade's experience

    NASA Astrophysics Data System (ADS)

    Bown, Stephen G.; Mackenzie, Gary D.; Dunn, Jason M.; Thorpe, Sally M.; Lovat, Laurence B.

    2009-06-01

    We have been investigating PDT with 5 aminolaevulinic acid (ALA) for the treatment of high grade dysplasia (HGD) in Barrett's oesophagus (BO) for over a decade. This drug has inherent advantages over porfimer sodium (Photofrin), the current approved photosensitiser in the UK and USA, which causes strictures in 18-50% and light sensitivity for up to three months. ALA has a lower rate of oesophageal strictures due to its preferential activity in the mucosa, sparing the underlying muscle, and patients are only light sensitive for 1-2 days. Within a randomised controlled trial, we demonstrated that an ALA dose of 60mg/kg activated by 1000J/cm red laser light is the most effective. Using these values we achieved complete reversal of HGD at 1 year in 89% of 27 patients. A randomised controlled trial of ALA vs porfimer sodium PDT for HGD is currently under way with end points of efficacy and safety. 50 of 66 patients have been recruited. Preliminary data suggest ALA PDT is safer with a trend to higher efficacy. Late relapse can occur in 20% of patients. New prognostic markers, in particular aneuploidy, are helping us to identify and target patients at risk of late relapse. Furthermore optical biopsy techniques such as elastic scattering spectroscopy (ESS) may allow detection of nuclear abnormalities in vivo and enable us to target areas of interest whilst reducing sampling error. PDT faces new challenges for the treatment of HGD in BO, with the recent introduction of balloon based radiofrequency ablation. This technique appears simpler and as effective as PDT, but follow up is currently short and long term safety data is lacking. In our experience ALA PDT is currently the most effective minimally invasive treatment for HGD in BO. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.

  3. Abnormal Pap Smear and Diagnosis of High-Grade Vaginal Intraepithelial Neoplasia

    PubMed Central

    Sopracordevole, Francesco; Mancioli, Francesca; Clemente, Nicolò; De Piero, Giovanni; Buttignol, Monica; Giorda, Giorgio; Ciavattini, Andrea

    2015-01-01

    Abstract The aim of this study was to analyze the correlation between the first diagnosis of high-grade Vaginal Intraepithelial Neoplasia (HG-VaIN: VaIN 2–VaIN 3) and the cytological abnormalities on the referral pap smear. All the women with histological diagnosis of HG-VaIN consecutively referred to the Gynecological Oncology Unit of the Aviano National Cancer Institute (Aviano, Italy) from January 1991 to April 2014 and with a pap smear performed in the 3 months before the diagnosis were considered, and an observational cohort study was performed. A total of 87 women with diagnosis of HG-VaIN were identified. Major cytological abnormalities (HSIL and ASC-H) on the referral pap smear were significantly more frequent than lesser abnormalities (ASC-US and LSIL) in postmenopausal women (64.9% vs 36.7%, P = 0.02) and in women with a previous diagnosis of HPV-related cervical preinvasive or invasive lesions (70.5% vs 39.5%, P = 0.01). Diagnosis of VaIN 3 was preceded by major cytological abnormalities in most of the cases (72.7% vs 27.3%, P < 0.001). The diagnosis of HG-VaIN can be preceded by different abnormalities on referral pap smear. Major abnormalities are usually reported in postmenopausal women and in women with previous cervical HPV-related disease. However, ASC-US or LSIL do not exclude HG-VaIN, especially VaIN2. An accurate examination of the whole vaginal walls (or vaginal vault) must be performed in all the women who underwent colposcopy for an abnormal pap smear, and a biopsy of all suspicious areas is mandatory. PMID:26496321

  4. Abnormal Pap Smear and Diagnosis of High-Grade Vaginal Intraepithelial Neoplasia: A Retrospective Cohort Study.

    PubMed

    Sopracordevole, Francesco; Mancioli, Francesca; Clemente, Nicolò; De Piero, Giovanni; Buttignol, Monica; Giorda, Giorgio; Ciavattini, Andrea

    2015-10-01

    The aim of this study was to analyze the correlation between the first diagnosis of high-grade Vaginal Intraepithelial Neoplasia (HG-VaIN: VaIN 2-VaIN 3) and the cytological abnormalities on the referral pap smear.All the women with histological diagnosis of HG-VaIN consecutively referred to the Gynecological Oncology Unit of the Aviano National Cancer Institute (Aviano, Italy) from January 1991 to April 2014 and with a pap smear performed in the 3 months before the diagnosis were considered, and an observational cohort study was performed.A total of 87 women with diagnosis of HG-VaIN were identified. Major cytological abnormalities (HSIL and ASC-H) on the referral pap smear were significantly more frequent than lesser abnormalities (ASC-US and LSIL) in postmenopausal women (64.9% vs 36.7%, P = 0.02) and in women with a previous diagnosis of HPV-related cervical preinvasive or invasive lesions (70.5% vs 39.5%, P = 0.01). Diagnosis of VaIN 3 was preceded by major cytological abnormalities in most of the cases (72.7% vs 27.3%, P < 0.001).The diagnosis of HG-VaIN can be preceded by different abnormalities on referral pap smear. Major abnormalities are usually reported in postmenopausal women and in women with previous cervical HPV-related disease. However, ASC-US or LSIL do not exclude HG-VaIN, especially VaIN2. An accurate examination of the whole vaginal walls (or vaginal vault) must be performed in all the women who underwent colposcopy for an abnormal pap smear, and a biopsy of all suspicious areas is mandatory. PMID:26496321

  5. Glucocorticoid Receptor Activation Inhibits Chemotherapy-induced Cell Death in High-grade Serous Ovarian Carcinoma

    PubMed Central

    Stringer-Reasor, Erica M.; Baker, Gabrielle M.; Skor, Maxwell N.; Kocherginsky, Masha; Lengyel, Ernst; Fleming, Gini F.; Conzen, Suzanne D.

    2015-01-01

    Objectives To test the hypothesis that glucocorticoid receptor (GR) activation increases resistance to chemotherapy in high-grade serous ovarian cancer (HGS-OvCa) and that treatment with a GR antagonist will improve sensitivity to chemotherapy. Methods GR expression was assessed in OvCa cell lines by qRT-PCR and Western blot analysis and in xenografts and primary human tumors using immunohistochemistry (IHC). We also examined the effect of GR activation versus inhibition on chemotherapy-induced cytotoxicity in OvCa cell lines and in a xenograft model. Results With the exception of IGROV-1 cells, all OvCa cell lines tested had detectable GR expression by Western blot and qRT-PCR analysis. Twenty-five out of the 27 human primary HGS-OvCas examined expressed GR by IHC. No cell line expressed detectable progesterone receptor (PR) or androgen receptor (AR) by Western blot analysis. In vitro assays showed that in GR-positive HeyA8 and SKOV3 cells, dexamethasone (100 nM) treatment upregulated the pro-survival genes SGK1 and MKP1/DUSP1 and inhibited carboplatin/gemcitabine-induced cell death. Concurrent treatment with two GR antagonists, either mifepristone (100 nM) or CORT125134 (100 nM), partially reversed these effects. There was no anti-apoptotic effect of dexamethasone on chemotherapy-induced cell death in IGROV-1 cells, which did not have detectable GR protein. Mifepristone treatment alone was not cytotoxic in any cell line. HeyA8 OvCa xenograft studies demonstrated that adding mifepristone to carboplatin/gemcitabine increased tumor shrinkage by 48% compared to carboplatin/gemcitabine treatment alone (P=0.0004). Conclusions These results suggest that GR antagonism sensitizes GR+ OvCa to chemotherapy-induced cell death through inhibition of GR-mediated cell survival pathways. PMID:26115975

  6. Identification of appropriate cone length to avoid positive cone margin in high grade cervical intraepithelial neoplasia

    PubMed Central

    Tsuda, Naotake; Nishio, Shin; Ushijima, Kimio

    2016-01-01

    Objective To identify key factors for predicting positive cone margin and appropriate cone length. Methods We retrospectively reviewed the margin status of patients who received conization with high grade cervical intraepithelial neoplasia, along with other factors such as patient age, parity, preoperative cytology, size of disease, type of transformation zone, and cone length from patient records. Cut-off value of cone length was analyzed in women younger than 40 years old because we design conization with minimum length especially for women who wish for future pregnancy. Cut-off value of cone length was defined as length corresponds to estimated probability of positive cone margin equal to 0.1 by logistic regression analysis with variables selected by stepwise methods. Results Among 300 patients, 75 patients had positive cone margin. Multivariable analysis revealed that squamous cell carcinoma at preoperative cytology (p=0.001), 2 or more quadrant disease (p=0.011), and shorter cone length (p<0.001) were risk factors for positive cone margin. Stepwise methods identified cone length and size of lesion as important variables. With this condition, cut-off value of cone length was estimated as 15 mm in single quadrant disease and 20 mm in 2 or more quadrant disease, respectively. Conclusion We identified the independent risk factors of positive cone margin and identified the cut-off value of cone length to avoid positive cone margin in women younger than 40 years old. Conization should be performed not only according to colposcopic findings including type of transformation zone but size of disease and cone length. PMID:27401478

  7. A comparison of geochemical core scanning methods on high-grade metamorphic COSC-1 cores

    NASA Astrophysics Data System (ADS)

    Harms, Ulrich; Hierold, Johannes; Meima, Jeannette; Rammlmair, Dieter; Kollaske, Tina

    2016-04-01

    Micro-XRF core scanning of marine and lacustrine sediment cores provides geochemical data for many elements and has become a standard tool in paleoclimate and environmental studies. In contrast, such investigations are unusual on crystalline cores due to limitations such as crystal lattice reflections. We tested micro-XRF scanning on gneisses and mylonites of the COSC-1 ICDP project in the Swedish Caledonides. The data obtained was compared with new high-resolution half-split core surface mapping using an ED-XRF instrument (50 μm res.) and Laser Induced Breakdown Spectroscopy (LIBS) core scanner (200 μm res.). In addition, an assessment was made with whole-core box oversight XRF scanning (Minalyze AB) with 10 cm resolution. High-grade metamorphic rocks including metasedimentary leucocratic gneisses and intercalated mica-rich mylonites of the lower Seve Nappe drilled during COSC-1 have been investigated to compare scanning methods. All data sets show a clear compositional step between gneiss and mylonite indicating a metasedimentary mixed layer origin (sandy to clayey) of the source rocks with extremely limited metasomatic exchange. Micro-XRF profiles are in full accord with high-resolution mapping data but cannot reproduce the detailed structural information provided by mapping data. LIBS data include light elements such as Li that are not measurable with XRF methods and confirm a sharp non-metasomatic transition between gneisses and mylonite. The whole-core box XRF scans are extremely useful to scan the 2500 m of cored material in a short time compared with other methods, and the data is very helpful, for example, for geochemical reconstructing of lithologies.

  8. A Molecular Portrait of High-Grade Ductal Carcinoma In Situ

    PubMed Central

    Abba, Martin C.; Gong, Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; Lacunza, Ezequiel; Butti, Matias; Takata, Yoko; Gaddis, Sally; Shen, Jianjun; Estecio, Marcos R.; Sahin, Aysegul A.; Aldaz, C. Marcelo

    2016-01-01

    Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. PMID:26249178

  9. Transcriptional Consequence and Impaired Gametogenesis with High-Grade Aneuploidy in Arabidopsis thaliana

    PubMed Central

    Chen, I-Ju; Liu, Yu-Chen; Chung, Mei-Chu; Lo, Wan-Sheng

    2014-01-01

    Aneuploidy features a numerical chromosome variant that the number of chromosomes in the nucleus of a cell is not an exact multiple of the haploid number, which may have an impact on morphology and gene expression. Here we report a tertiary trisomy uncovered by characterizing a T-DNA insertion mutant (aur2-1/+) in the Arabidopsis (Arabidopsis thaliana) AURORA2 locus. Whole-genome analysis with DNA tiling arrays revealed a chromosomal translocation linked to the aur2-1 allele, which collectively accounted for a tertiary trisomy 2. Morphologic, cytogenetic and genetic analyses of aur2-1 progeny showed impaired male and female gametogenesis to various degrees and a tight association of the aur2-1 allele with the tertiary trisomy that was preferentially inherited. Transcriptome analysis showed overlapping and distinct gene expression profiles between primary and tertiary trisomy 2 plants, particularly genes involved in response to stress and various types of external and internal stimuli. Additionally, transcriptome and gene ontology analyses revealed an overrepresentation of nuclear-encoded organelle-related genes functionally involved in plastids, mitochondria and peroxisomes that were differentially expressed in at least three if not all Arabidopsis trisomics. These observations support a