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Sample records for grade glioma receiving

  1. Quality of life in low-grade glioma patients receiving temozolomide.

    PubMed

    Liu, Raymond; Solheim, Karla; Polley, Mei-Yin; Lamborn, Kathleen R; Page, Margaretta; Fedoroff, Anne; Rabbitt, Jane; Butowski, Nicholas; Prados, Michael; Chang, Susan M

    2009-02-01

    The purpose of this study was to describe the quality of life (QOL) of low-grade glioma (LGG) patients at baseline prior to chemotherapy and through 12 cycles of temozolomide (TMZ) chemotherapy. Patients with histologically confirmed LGG with only prior surgery were given TMZ for 12 cycles. QOL assessments by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) were obtained at baseline prior to chemotherapy and at 2-month intervals while receiving TMZ. Patients with LGG at baseline prior to chemotherapy had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared to a normal population. Compared to patients with left hemisphere tumors, patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared to baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Patients with LGG on TMZ at baseline prior to chemotherapy reported QOL comparable to a normal population with the exception of social and emotional well-being, and those with right hemisphere tumors reported higher physical well-being scores compared to those with left hemisphere tumors. While remaining on therapy, LGG patients were able to maintain their QOL in all realms. LGG patients' QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working. PMID:18713953

  2. Quality of life in low-grade glioma patients receiving temozolomide

    PubMed Central

    Liu, Raymond; Solheim, Karla; Polley, Mei-Yin; Lamborn, Kathleen R.; Page, Margaretta; Fedoroff, Anne; Rabbitt, Jane; Butowski, Nicholas; Prados, Michael; Chang, Susan M.

    2009-01-01

    The purpose of this study was to describe the quality of life (QOL) of low-grade glioma (LGG) patients at baseline prior to chemotherapy and through 12 cycles of temozolomide (TMZ) chemotherapy. Patients with histologically confirmed LGG with only prior surgery were given TMZ for 12 cycles. QOL assessments by the Functional Assessment of Cancer Therapy–Brain (FACT-Br) were obtained at baseline prior to chemotherapy and at 2-month intervals while receiving TMZ. Patients with LGG at baseline prior to chemotherapy had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared to a normal population. Compared to patients with left hemisphere tumors, patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared to baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Patients with LGG on TMZ at baseline prior to chemotherapy reported QOL comparable to a normal population with the exception of social and emotional well-being, and those with right hemisphere tumors reported higher physical well-being scores compared to those with left hemisphere tumors. While remaining on therapy, LGG patients were able to maintain their QOL in all realms. LGG patients’ QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working. PMID:18713953

  3. 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.

  4. Stereotactic radiosurgery of deeply seated low grade gliomas.

    PubMed

    Barcia, J A; Barcia-Salorio, J L; Ferrer, C; Ferrer, E; Algás, R; Hernández, G

    1994-01-01

    The authors report the results of a series of 16 cases of low-grade gliomas in whom radiosurgery was performed. This series started in 1977. All the tumours received a single radiosurgical session (with a mean dose of 21.7 Gy, 5-10 mm. collimator; one patient received two sessions and in another patient two different targets were irradiated in the same session). Prior to radiosurgery, six patients received conventional external fractionated radiotherapy, with two lateral fields of up to 10 x 10 cm. and a mean dose of 55.1 Gy and another six patients with tumours less than 5 cm. in diameter, received stereotactic radiotherapy using four fields of up to 5 x 5 cm. and a mean dose of 53.1 Gy. In both cases, conventional fractionation was used, giving a dose of 1.8 to 2 Gy/day. The tumour disappeared in 8 cases (50%) and shunk or ceased its growth in 5 additional cases (31%). In 3 cases of brainstem gliomas in which the clinical condition was previously very poor there was no evolutional change and the patients eventually died. We conclude that radiosurgery is effective in the treatment of deeply seated low-grade gliomas, where it may become the treatment of choice in the absence of other more definitive choices. PMID:7717138

  5. Diffuse low-grade gliomas and neuroplasticity.

    PubMed

    Duffau, H

    2014-10-01

    The traditional approach in neuro-oncology is to study the tumor in great detail and ultimately give little consideration to the brain itself. Choosing the best treatment strategy for each patient with a diffuse low-grade glioma, in other words optimizing the oncologic and functional balance, implies not only a full knowledge of the natural history of this chronic disease, but also an understanding of the adaptation of the brain in response to growth and spread of the glioma. The aim of this review is to examine the mechanisms underlying this neuroplasticity, allowing functional compensation when the tumor progresses, and opening the way to new treatments with the principle of shifting towards "functional personalized neuro-oncology", improving both median survival and quality of life. PMID:25218490

  6. 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

  7. 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

  8. 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

  9. Intraoperative Contrast Enhanced Ultrasound Evaluates the Grade of Glioma

    PubMed Central

    Cheng, Ling-Gang; He, Wen; Zhang, Hong-Xia; Song, Qian; Ning, Bin; Li, Hui-Zhan; He, Yan; Lin, Song

    2016-01-01

    Objective. The aim of our study was to investigate the value of intraoperative contrast enhanced ultrasound (CEUS) for evaluating the grade of glioma and the correlation between microvessel density (MVD) and vascular endothelial growth factor (VEGF). Methods. We performed intraoperative conventional ultrasound (CUS) and CEUS on 88 patients with gliomas. All of the patients have undergone surgery and obtained the results of pathology. All patients have undergone intraoperative CUS and CEUS to compare the characteristics of different grade gliomas and the results of CUS and CEUS were compared with pathological results. Results. The time to start (TTS) and time to peak (TTP) of low grade glioma (LGG) were similar to those of edema and normal brain surrounding glioma. The enhanced extent of LGG was higher than that of the normal brain and edema. The TTS and TTP of high grade glioma were earlier than those of the edema and normal brain surrounding glioma. The enhancement of HGG was higher than that of LGG. The absolute peak intensity (API) was correlated with MVD and VEGF. Conclusion. Intraoperative CEUS could help in determining boundary of peritumoral brain edema of glioma. Intraoperative CEUS parameters in cerebral gliomas could indirectly reflect the information of MVD and VEGF. PMID:27069921

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

    PubMed Central

    2015-01-01

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

  11. Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas.

    PubMed

    Helfferich, Jelte; Nijmeijer, Ronald; Brouwer, Oebele F; Boon, Maartje; Fock, Annemarie; Hoving, Eelco W; Meijer, Lisethe; den Dunnen, Wilfred F A; de Bont, Eveline S J M

    2016-08-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment. PMID:27263935

  12. Associations of high-grade glioma with glioma risk alleles and histories of allergy and smoking.

    PubMed

    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

    2011-09-01

    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 ratio(allergy-glioma) = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratio(allergy-glioma) = 0.76, 95% confidence interval: 0.59, 0.97; P(interaction) = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratio(allergy-glioma) = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratio(allergy-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

  13. 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

  14. [The role of age and tumor grade in the choice of fractionation regimen in patients with high-grade gliomas].

    PubMed

    Izmaĭlov, T R; Pan'shin, G A; Datsenko, P V

    2012-01-01

    There are currently no conventional guidelines for radiotherapy in gliomas. The treatment program is mainly formed in accordance with tumor morphology and the "golden standard" of irradiation is still the traditional mode of fractionation with a single focal dose of 2 Gy and total focal dose (TFD) of 60 Gy. In this report the treatment results of 396 patients with morphologically verified grade 3-4 malignant brain tumors receiving conventional irradiation regimen and irradiation by medium-sized fractions were analyzed to form institutional guidelines. The standard fractionation mode with a single focal dose of 2 Gy is preferable in patients with grade 3 glioma or elderly patients (over 60 years). TFD increase to 60-62 Gy in grade 4 gliomas and 54-56 Gy in grade 3 gliomas grants a significant improve in overall survival. An increase of a single irradiation fraction to 3 Gy may be used for patients younger than 60 years. In these cases it is advisable to use the TFD of 45 Gy or more (TFD of equivalent regimen with a dose greater than 54 Gy). The mentioned fractionation regimens could be recommended for the use in clinical practice to improve the results of high-grade gliomas treatment. PMID:22888654

  15. Signal transduction molecules in gliomas of all grades

    PubMed Central

    Ermoian, Ralph P.; Kaprealian, Tania; Lamborn, Kathleen R.; Yang, Xiaodong; Jelluma, Nannette; Arvold, Nils D.; Zeidman, Ruth; Berger, Mitchel S.; Stokoe, David

    2010-01-01

    Purpose To interrogate grade II, III, and IV gliomas and characterize the critical effectors within the PI3-kinase pathway upstream and downstream of mTOR. Experimental design Tissues from 87 patients who were treated at UCSF between 1990 and 2004 were analyzed. Twenty-eight grade II, 17 grade III glioma, 26 grade IV gliomas, and 16 non-tumor brain specimens were analyzed. Protein levels were assessed by immunoblots; RNA levels were determined by polymerase chain reaction amplification. To address the multiple comparisons, first an overall analysis was done comparing the four groups using Spearman’s Correlation Coefficient. Only if this analysis was statistically significant were individual pairwise comparisons done. Results Multiple comparison analyses revealed a significant correlation with grade for all variables examined, except phosphorylated-S6. Expression of phosphorylated-4E-BP1, phosphorylated-PKB/Akt, PTEN, TSC1, and TSC2 correlated with grade (P < 0.01 for all). We extended our analyses to ask whether decreases in TSC proteins levels were due to changes in mRNA levels, or due to changes in post-transcriptional alterations. We found significantly lower levels of TSC1 and TSC2 mRNA in GBMs than in grade II gliomas or non-tumor brain (P < 0.01). Conclusions Expression levels of critical signaling molecules upstream and downstream of mTOR differ between non-tumor brain and gliomas of any grade. The single variable whose expression did not differ between non-tumor brain and gliomas was phosphorylated-S6, suggesting that other protein kinases, in addition to mTOR, contribute significantly to S6 phosphorylation. mTOR provides a rational therapeutic target in gliomas of all grades, and clinical benefit may emerge as mTOR inhibitors are combined with additional agents. PMID:18759130

  16. Nimotuzumab in combination with radiotherapy in high grade glioma patients

    PubMed Central

    Solomon, Maria Teresa; Miranda, Nederlay; Jorrín, Eugenia; Chon, Ivonne; Marinello, Jorge Juan; Alert, José; Lorenzo-Luaces, Patricia; Crombet, Tania

    2014-01-01

    Nimotuzumab, a humanized antibody targeting epidermal growth factor receptor, has potent anti-proliferative, anti-angiogenic, and pro-apoptotic effects in vitro and in vivo. It also reduces the number of radio-resistant CD133+ glioma stem cells. The antibody has been extensively evaluated in patients with advanced head and neck, glioma, lung, esophageal, pancreatic, and gastric cancer. In this single institution experience, 35 patients with anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) were treated with irradiation and 200 mg doses of nimotuzumab. The first 6 doses were administered weekly, together with radiotherapy, and then treatment continued every 21 days until 1 year. The median number of doses was 12, and the median cumulative dose was thus 2400 mg of nimotuzumab. The most frequent treatment-related toxicities were increase in liver function tests, fever, nausea, anorexia, asthenia, dizziness, and tremors. These adverse reactions were classified as mild and moderate. The median survival time was 12.4 mo or 27.0 mo for patients with GBM or AA patients, respectively, who received curative-intent radiotherapy in combination with the antibody. The survival time of a matched population treated at the same hospital with irradiation alone was decreased (median 8.0 and 12.2 mo for GBM and AA patients, respectively) compared with that of the patients who received nimotuzumab and curative-intent radiotherapy. We have thus confirmed that nimotuzumab is a very well-tolerated drug, lacking cumulative toxicity after maintenance doses. This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients. PMID:24521695

  17. 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

  18. 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

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

    PubMed

    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

  20. Neurodevelopmental Outcomes of Children with Low-Grade Gliomas

    ERIC Educational Resources Information Center

    Ris, M. Douglas; Beebe, Dean W.

    2008-01-01

    As a group, children with low-grade gliomas (LGGs) enjoy a high rate of long-term survival and do not require the intensity of neurotoxic treatments used with higher risk pediatric brain tumors. Because they are generally considered to have favorable neurobehavioral outcomes, they have not been studied as thoroughly as higher-grade brain tumors by…

  1. 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

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

    PubMed Central

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

    2014-01-01

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

  3. Outcomes of Multidisciplinary Management in Pediatric Low-Grade Gliomas

    SciTech Connect

    Oh, Kevin S.; Hung, Jonathan; Robertson, Patricia L.; Garton, Hugh J.; Muraszko, Karin M.; Sandler, Howard M.; Hamstra, Daniel A.

    2011-11-15

    Purpose: To evaluate the outcomes in pediatric low-grade gliomas managed in a multidisciplinary setting. Methods and Materials: We conducted a single-institution retrospective study of 181 children with Grade I-II gliomas. Log-rank and stepwise Cox proportional hazards models were used to analyze freedom from progression (FFP) and overall survival (OS). Results: Median follow-up was 6.4 years. Thirty-four (19%) of patients had neurofibromatosis Type 1 (NF1) and because of their favorable prognosis were evaluated separately. In the 147 (81%) of patients without NF1, actuarial 7-year FFP and OS were 67 {+-} 4% (standard error) and 94 {+-} 2%, respectively. In this population, tumor location in the optic pathway/hypothalamus was associated with worse FFP (39% vs. 76%, p < 0.0003), but there was no difference in OS. Age {<=}5 years was associated with worse FFP (52% vs. 75%, p < 0.02) but improved OS (97% vs. 92%, p < 0.05). In those with tissue diagnosis, gross total resection (GTR) was associated with improved 7-year FFP (81% vs. 56%, p < 0.02) and OS (100% vs. 90%, p < 0.03). In a multivariate model, only location in the optic pathway/hypothalamus predicted worse FFP (p < 0.01). Fifty patients received radiation therapy (RT). For those with less than GTR, adjuvant RT improved FFP (89% vs. 49%, p < 0.003) but not OS. There was no difference in OS between patient groups given RT as adjuvant vs. salvage therapy. In NF1 patients, 94% of tumors were located in the optic pathway/hypothalamus. With a conservative treatment strategy in this population, actuarial 7-year FFP and OS were 73 {+-} 9% and 100%, respectively. Conclusions: Low-grade gliomas in children {<=}5 years old with tumors in the optic pathway/hypothalamus are more likely to progress, but this does not confer worse OS because of the success of salvage therapy. When GTR is not achieved, adjuvant RT improves FFP but not OS. Routine adjuvant RT can be avoided and instead reserved as salvage.

  4. 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

  5. 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. PMID:26305773

  6. Distinction of brain tissue, low grade and high grade glioma with time-resolved fluorescence spectroscopy.

    PubMed

    Yong, William H; Butte, Pramod V; Pikul, Brian K; Jo, Javier A; Fang, Qiyin; Papaioannou, Thanassis; Black, Keith; Marcu, Laura

    2006-01-01

    Neuropathology frozen section diagnoses are difficult in part because of the small tissue samples and the paucity of adjunctive rapid intraoperative stains. This study aims to explore the use of time-resolved laser-induced fluorescence spectroscopy as a rapid adjunctive tool for the diagnosis of glioma specimens and for distinction of glioma from normal tissues intraoperatively. Ten low grade gliomas, 15 high grade gliomas without necrosis, 6 high grade gliomas with necrosis and/or radiation effect, and 14 histologically uninvolved "normal" brain specimens are spectroscopicaly analyzed and contrasted. Tissue autofluorescence was induced with a pulsed Nitrogen laser (337 nm, 1.2 ns) and the transient intensity decay profiles were recorded in the 370-500 nm spectral range with a fast digitized (0.2 ns time resolution). Spectral intensities and time-dependent parameters derived from the time-resolved spectra of each site were used for tissue characterization. A linear discriminant analysis diagnostic algorithm was used for tissue classification. Both low and high grade gliomas can be distinguished from histologically uninvolved cerebral cortex and white matter with high accuracy (above 90%). In addition, the presence or absence of treatment effect and/or necrosis can be identified in high grade gliomas. Taking advantage of tissue autofluorescence, this technique facilitates a direct and rapid investigation of surgically obtained tissue. PMID:16368511

  7. Combination genetic signature stratifies lower-grade gliomas better than histological grade

    PubMed Central

    Zhang, Zhenyu; Shi, Zhifeng; Chen, Liang; Chung, Nellie Yuk-Fei; Liu, Joseph Shu-Ming; Li, Kay Ka-Wai; Chan, Danny Tat-Ming; Poon, Wai Sang; Wang, Ying; Zhou, Liangfu; Ng, Ho-Keung

    2015-01-01

    We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading. PMID:26369702

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

    ClinicalTrials.gov

    2015-12-14

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

  9. 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

  10. High expression of VEGF and PI3K in glioma stem cells provides new criteria for the grading of gliomas

    PubMed Central

    WANG, LEI; ZHANG, LUYAO; SHEN, WEIGAO; LIU, YANBO; LUO, YINAN

    2016-01-01

    Glioma is a type of tumor derived from glial cells, which is associated with a high level of incidence and mortality. At present, the generation of a fast and efficient method to evaluate the malignancy grade of glioma is required. Cancer stem cells (CSCs) are currently attracting attention in oncological studies; therefore, the present study aimed to investigate novel biomarkers of glioma CSCs, in order to provide new criteria for the grading of glioma. The mRNA expression levels of CD133, (sex determining region Y)-box 2, nestin, vascular endothelial growth factor (VEGF) and phosphoinositide-3-kinase (PI3K) were detected in 15 human samples of high-malignancy glioma and 12 human samples of low-malignancy glioma in vitro. The mRNA expression levels of VEGF and PI3K were higher in the high-malignancy group, as compared with in the low-malignancy group. In conclusion, the mRNA expression levels of VEGF and PI3K in glioma CSCs may be considered a novel criteria for the grading of glioma. PMID:26893649

  11. Diffusion kurtosis imaging can efficiently assess the glioma grade and cellular proliferation

    PubMed Central

    Zhao, Lingyun; Zhang, Jiaxuan; Zhang, Shun; Yao, Yihao; Yang, Shiqi; Shi, Jingjing; Shen, Nanxi; Su, Changliang; Zhang, Ju; Zhu, Wenzhen

    2015-01-01

    Conventional diffusion imaging techniques are not sufficiently accurate for evaluating glioma grade and cellular proliferation, which are critical for guiding glioma treatment. Diffusion kurtosis imaging (DKI), an advanced non-Gaussian diffusion imaging technique, has shown potential in grading glioma; however, its applications in this tumor have not been fully elucidated. In this study, DKI and diffusion weighted imaging (DWI) were performed on 74 consecutive patients with histopathologically confirmed glioma. The kurtosis and conventional diffusion metric values of the tumor were semi-automatically obtained. The relationships of these metrics with the glioma grade and Ki-67 expression were evaluated. The diagnostic efficiency of these metrics in grading was further compared. It was demonstrated that compared with the conventional diffusion metrics, the kurtosis metrics were more promising imaging markers in distinguishing high-grade from low-grade gliomas and distinguishing among grade II, III and IV gliomas; the kurtosis metrics also showed great potential in the prediction of Ki-67 expression. To our best knowledge, we are the first to reveal the ability of DKI to assess the cellular proliferation of gliomas, and to employ the semi-automatic method for the accurate measurement of gliomas. These results could have a significant impact on the diagnosis and subsequent therapy of glioma. PMID:26544514

  12. 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.

  13. Incidental diffuse low-grade gliomas: from early detection to preventive neuro-oncological surgery.

    PubMed

    Lima, Guilherme Lucas de Oliveira; Zanello, Marc; Mandonnet, Emmanuel; Taillandier, Luc; Pallud, Johan; Duffau, Hugues

    2016-07-01

    Although a large amount of data supports early surgical resection for symptomatic diffuse low-grade glioma, the therapeutic strategy is still a matter of debate regarding incidentally discovered diffuse low-grade glioma. Indeed, early and "preventive" surgery has recently been proposed in asymptomatic patients with silent diffuse low-grade glioma with better outcomes. The present review discusses the importance of an early diagnosis and of a preventive surgical treatment to improve the outcomes of incidental diffuse low-grade glioma and suggests the possible relevance of a tailored screening policy. PMID:26610909

  14. 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

  15. Clinical ramifications of "genomic staging" of low-grade gliomas.

    PubMed

    Verma, Vivek; Mehta, Minesh P

    2016-09-01

    "Low-grade gliomas" (LGGs), classification of which is derived from histopathological observations, exhibit significant heterogeneity in clinical behavior. Recently, increasing attention has been paid to genomic analyses of these tumors, to aid in treatment and prognostic decision-making. We discuss herein the recent genomic analysis of gliomas from two major recent publications, and also the results of seminal LGG trials in the context of molecular and genomic stratification, with respect to both prognosis and response to therapy. We also analyze implications of these "molecular classifications". We propose separating out the worst prognostic subsets, whose outcomes resemble those of glioblastoma patients. Lastly, a brief discussion is provided regarding translating this collective knowledge into the clinic and in treatment decisions; also addressed are some of the many questions that still need to be examined in light of these strong and emerging data. PMID:27401152

  16. Sexuality after surgery for diffuse low-grade glioma

    PubMed Central

    Surbeck, Werner; Herbet, Guillaume; Duffau, Hugues

    2015-01-01

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

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

    ClinicalTrials.gov

    2013-10-07

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

  18. 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. |

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

    ERIC Educational Resources Information Center

    Edvardsson, Tanja I.; Ahlstrom, Gerd I.

    2009-01-01

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

  20. Cerebral Glioma Grading Using Bayesian Network with Features Extracted from Multiple Modalities of Magnetic Resonance Imaging

    PubMed Central

    Wang, Huiting; Liu, Renyuan; Zhang, Xin; Li, Ming; Yang, Yongbo; Yan, Jing; Niu, Fengnan; Tian, Chuanshuai; Wang, Kun; Yu, Haiping; Chen, Weibo; Wan, Suiren; Sun, Yu; Zhang, Bing

    2016-01-01

    Many modalities of magnetic resonance imaging (MRI) have been confirmed to be of great diagnostic value in glioma grading. Contrast enhanced T1-weighted imaging allows the recognition of blood-brain barrier breakdown. Perfusion weighted imaging and MR spectroscopic imaging enable the quantitative measurement of perfusion parameters and metabolic alterations respectively. These modalities can potentially improve the grading process in glioma if combined properly. In this study, Bayesian Network, which is a powerful and flexible method for probabilistic analysis under uncertainty, is used to combine features extracted from contrast enhanced T1-weighted imaging, perfusion weighted imaging and MR spectroscopic imaging. The networks were constructed using K2 algorithm along with manual determination and distribution parameters learned using maximum likelihood estimation. The grading performance was evaluated in a leave-one-out analysis, achieving an overall grading accuracy of 92.86% and an area under the curve of 0.9577 in the receiver operating characteristic analysis given all available features observed in the total 56 patients. Results and discussions show that Bayesian Network is promising in combining features from multiple modalities of MRI for improved grading performance. PMID:27077923

  1. Intensity-modulated radiotherapy in high-grade gliomas: Clinical and dosimetric results

    SciTech Connect

    Narayana, Ashwatha . E-mail: narayana@mskcc.org; Yamada, Josh; Berry, Sean; Shah, Priti B.S.; Hunt, Margie; Gutin, Philip H.; Leibel, Steven A.

    2006-03-01

    Purpose: To report preliminary clinical and dosimetric data from intensity-modulated radiotherapy (IMRT) for malignant gliomas. Methods and Materials: Fifty-eight consecutive high-grade gliomas were treated between January 2001 and December 2003 with dynamic multileaf collimator IMRT, planned with the inverse approach. A dose of 59.4-60 Gy at 1.8-2.0 Gy per fraction was delivered. A total of three to five noncoplanar beams were used to cover at least 95% of the target volume with the prescription isodose line. Glioblastoma accounted for 70% of the cases, and anaplastic oligodendroglioma histology (pure or mixed) was seen in 15% of the cases. Surgery consisted of biopsy only in 26% of the patients, and 80% received adjuvant chemotherapy. Results: With a median follow-up of 24 months, 85% of the patients have relapsed. The median progression-free survival time for anaplastic astrocytoma and glioblastoma histology was 5.6 and 2.5 months, respectively. The overall survival time for anaplastic glioma and glioblastoma was 36 and 9 months, respectively. Ninety-six percent of the recurrences were local. No Grade IV/V late neurologic toxicities were noted. A comparative dosimetric analysis revealed that regardless of tumor location, IMRT did not significantly improve target coverage compared with three-dimensional planning. However, IMRT resulted in a decreased maximum dose to the spinal cord, optic nerves, and eye by 16%, 7%, and 15%, respectively, owing to its improved dose conformality. The mean brainstem dose also decreased by 7%. Intensity-modulated radiotherapy delivered with a limited number of beams did not result in an increased dose to the normal brain. Conclusions: It is unlikely that IMRT will improve local control in high-grade gliomas without further dose escalation compared with conventional radiotherapy. However, it might result in decreased late toxicities associated with radiotherapy.

  2. 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

  3. Treatment of children with high grade glioma with nimotuzumab

    PubMed Central

    Cabanas, Ricardo; Saurez, Giselle; Rios, Martha; Alert, Jose; Reyes, Adnolys; Valdes, Jose; Gonzalez, Maria C.; Pedrayes, Jorge L.; Avila, Melba; Herrera, Raiza; Infante, Mariela; Echevarria, Ernesto; Moreno, Myrna; Luaces, Patricia Lorenzo; Ramos, Tania Crombet

    2013-01-01

    Brain tumors are a major cause of cancer-related mortality in children. Overexpression of epidermal growth factor receptor (EGFR) is detected in pediatric brain tumors and receptor density appears to increase with tumor grading. Nimotuzumab is an IgG1 antibody that targets EGFR. Twenty-three children with high-grade glioma (HGG) were enrolled in an expanded access program in which nimotuzumab was administered alone or with radio-chemotherapy. The mean number of doses was 39. Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis. PMID:23575267

  4. 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

  5. The evolving molecular genetics of low-grade glioma

    PubMed Central

    Venneti, Sriram; Huse, Jason T.

    2015-01-01

    Low-grade gliomas (LGG) constitute grade I and grade II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow growing, they may be associated with significant morbidity and mortality due to recurrence and malignant progression, even in the setting of optimal resection. LGG in pediatric and adult age groups are currently classified by morphologic criteria. Recent years have heralded a molecular revolution in understanding brain tumors, including LGG. Next generation sequencing has definitively demonstrated that pediatric and adult LGG fundamentally differ in their underlying molecular characteristics, despite being histologically similar. Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the MAP kinase-signaling pathway. Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors. TERT promoter mutations are also noted in LGG and are mainly associated with oligodendrogliomas. These findings have considerably refined approaches to classifying these tumors. Moreover, many of the molecular alterations identified in LGG directly impact on prognosis, tumor biology, and the development of novel therapies. PMID:25664944

  6. Discrimination between two different grades of human glioma based on blood vessel infrared spectral imaging.

    PubMed

    Wehbe, Katia; Forfar, Isabelle; Eimer, Sandrine; Cinque, Gianfelice

    2015-09-01

    Gliomas are brain tumours classified into four grades with increasing malignancy from I to IV. The development and the progression of malignant glioma largely depend on the tumour vascularization. Due to their tissue heterogeneity, glioma cases can be difficult to classify into a specific grade using the gold standard of histological observation, hence the need to base classification on a quantitative and reliable analytical method for accurately grading the disease. Previous works focused specifically on vascularization study by Fourier transform infrared (FTIR) spectroscopy, proving this method to be a way forward to detect biochemical changes in the tumour tissue not detectable by visual techniques. In this project, we employed FTIR imaging using a focal plane array (FPA) detector and globar source to analyse large areas of glioma tumour tissue sections via molecular fingerprinting in view of helping to define markers of the tumour grade. Unsupervised multivariate analysis (hierarchical cluster analysis and principal component analysis) of blood vessel spectral data, retrieved from the FPA images, revealed the fine structure of the borderline between two areas identified by a pathologist as grades III and IV. Spectroscopic indicators are found capable of discriminating different areas in the tumour tissue and are proposed as biomolecular markers for potential future use of grading gliomas. Graphical Abstract Infrared imaging of glioma blood vessels provides a means to revise the pathologists' line of demarcation separating grade III (GIII) from grade IV (GIV) parts. PMID:26168973

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

    SciTech Connect

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

    1989-09-01

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

  8. Positron emission tomography of high-grade gliomas.

    PubMed

    Frosina, Guido

    2016-05-01

    High-grade gliomas [HGG (WHO grades III-IV)] are almost invariably fatal. Imaging of HGG is important for orientating diagnosis, prognosis and treatment planning and is crucial for development of novel, more effective therapies. Given the potentially unlimited number of usable tracing molecules and the elevated number of available radionuclides, PET allows gathering multiple informations on HGG including data on tissue metabolism and drug pharmacokinetics. PET studies on the diagnosis, prognosis and treatment of HGG carried out by most frequently used tracers and radionuclides ((11)C and (18)F) and published in 2014 have been reviewed. These studies demonstrate that a thorough choice of tracers may confer elevated diagnostic and prognostic power to PET imaging of HGG. They also suggest that a combination of PET and MRI may give the most complete and reliable imaging information on HGG and that research on hybrid PET/MRI may be paying back in terms of improved diagnosis, prognosis and treatment planning of these deadly tumours. PMID:26897013

  9. Neurocognitive effects of proton radiation therapy in adults with low-grade glioma.

    PubMed

    Sherman, Janet Cohen; Colvin, Mary K; Mancuso, Sarah M; Batchelor, Tracy T; Oh, Kevin S; Loeffler, Jay S; Yeap, Beow Y; Shih, Helen A

    2016-01-01

    To understand neurocognitive effects of proton radiation therapy (PRT) in patients with low-grade glioma, we evaluated 20 patients who received this therapy prospectively and over 5 years with a comprehensive neuropsychological battery. 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual, attention, executive, visuospatial and memory functions as well as mood and functional status. We evaluated change in cognitive functioning over time. We analyzed the relationship between cognitive performance and tumor location and also examined whether patients' performance differed from that reported in a study of normative practice effects. Overall, patients exhibited stability in cognitive functioning. Tumor location played a role in performance; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures (p < .05). However, we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors (p < .05). Results of our study, the first to investigate, in depth, neurocognitive effects of PRT in adults with low-grade gliomas, are promising. We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning, although larger sample sizes and a longer period of study are required. Our study also highlights the need to consider normative practice effects when studying neurocognitive functioning in response to treatment over time, and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors. PMID:26498439

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

    PubMed

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

    2016-03-01

    Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG. PMID:26626490

  11. Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas.

    PubMed

    Chen, Ricky; Ravindra, Vijay M; Cohen, Adam L; Jensen, Randy L; Salzman, Karen L; Prescot, Andrew P; Colman, Howard

    2015-03-01

    The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies. PMID:25727224

  12. Serum YKL-40 is a marker of prognosis and disease status in high-grade gliomas.

    PubMed

    Iwamoto, Fabio M; Hottinger, Andreas F; Karimi, Sasan; Riedel, Elyn; Dantis, Jocelynn; Jahdi, Maryam; Panageas, Katherine S; Lassman, Andrew B; Abrey, Lauren E; Fleisher, Martin; DeAngelis, Lisa M; Holland, Eric C; Hormigo, Adília

    2011-11-01

    The objective of this study was to evaluate whether longitudinal levels of serum YKL-40 correlate with disease status or survival in adults with gliomas. Patients with histologically confirmed gliomas were eligible for this longitudinal study. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. YKL-40 levels determined by ELISA were correlated with radiographic disease status and survival. We performed a multivariate survival analysis including well-known prognostic factors such as age, performance status, and extent of surgical resection. Three hundred and forty-three patients with gliomas (41 low-grade, 105 anaplastic, and 197 glioblastoma) were accrued. Two-year survival from registration was 29% for glioblastomas, 62% for anaplastic gliomas, and 83% for low-grade gliomas. A total of 1740 serum samples were collected, and 95.6% of samples had matching MRI scans. Serum YKL-40 level was significantly lower in patients with no radiographic disease compared with patients with radiographic disease in both the anaplastic glioma (P= .0008) and the glioblastoma (P= .0006) cohorts. Serum levels of YKL-40 in patients with low-grade gliomas were not associated with radiographic disease status. Increases in YKL-40 were independently associated with worse survival in anaplastic gliomas (hazard ratio [HR] = 1.4, P= .01) and glioblastomas (HR = 1.4, P< .0001). Longitudinal increases in serum YKL-40 are associated with increased risk of death in patients with glioblastomas and anaplastic gliomas. YKL-40 is also a putative indicator of disease status in these patients. PMID:21831900

  13. Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update

    PubMed Central

    Mishra, Kavita K.; Squire, Sarah; Lamborn, Kathleen; Banerjee, Anuradha; Gupta, Nalin; Wara, William M.; Prados, Michael D.; Berger, Mitchel S.

    2010-01-01

    To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3–16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3–20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival. PMID:20221671

  14. Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update.

    PubMed

    Mishra, Kavita K; Squire, Sarah; Lamborn, Kathleen; Banerjee, Anuradha; Gupta, Nalin; Wara, William M; Prados, Michael D; Berger, Mitchel S; Haas-Kogan, Daphne A

    2010-10-01

    To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3-16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3-20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival. PMID:20221671

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

    PubMed

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

    2016-01-01

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

  16. Cognitive functioning in long-term survivors of high-grade glioma.

    PubMed

    Archibald, Y M; Lunn, D; Ruttan, L A; Macdonald, D R; Del Maestro, R F; Barr, H W; Pexman, J H; Fisher, B J; Gaspar, L E; Cairncross, J G

    1994-02-01

    In a pilot study, two groups of patients with malignant glioma underwent sequential neuropsychological evaluations after successful tumor treatment. Group 1 included nine patients treated from 1981 to 1985; all patients received irradiation and eight underwent chemotherapy. The baseline neuropsychological assessment was performed 1 to 63 months after tumor diagnosis, with follow-up evaluations at irregular intervals over the next 3 to 7 years. Six patients in Group 1 exhibited impairment on most measures at baseline; subsequently, two patients developed profound cognitive impairment. Initially, three patients functioned in the average range on most tasks; thereafter, two deteriorated on one measure each. Group 2 was ascertained prospectively and included 16 patients treated from 1985 to 1987, all of whom received irradiation and chemotherapy. The first evaluation was performed 18 months after diagnosis, then every 6 months for 2 years, and then yearly. Compared to a control group, those in Group 2 had significant cognitive impairment at baseline. Cognitive performance did not change over the next 12 months in 10 patients who remained free of tumor, but within 2 years of baseline testing, deterioration on specific tasks was evident in two of seven disease-free survivors. When last tested, five of six disease-free survivors had deteriorated on one or more measures. Unlike Group 1, severe global cognitive impairment was not seen, perhaps because Group 2 was followed for a shorter time. Verbal and nonverbal composite scores derived from intelligence quotient (IQ) tests showed less impairment at baseline than did other measures and were more likely to remain stable subsequently. Verbal memory and sustained attention were the most impaired at baseline, and verbal learning and flexibility in thinking showed the greatest tendency to decline over time. Cognitive functioning in survivors of high-grade glioma is best measured and monitored by tests that probe a broader

  17. Simultaneous Integrated Boost Intensity-Modulated Radiotherapy in Patients With High-Grade Gliomas

    SciTech Connect

    Cho, Kwan Ho; Kim, Joo-Young; Lee, Seung Hoon

    2010-10-01

    Purpose: We analyzed outcomes of simultaneous integrated boost (SIB) intensity-modulated radiotherapy (IMRT) in patients with high-grade gliomas, compared with a literature review. Methods and Materials: Forty consecutive patients (WHO grade III, 14 patients; grade IV, 26 patients) treated with SIB-IMRT were analyzed. A dose of 2.0 Gy was delivered to the planning target volume with a SIB of 0.4 Gy to the gross tumor volume with a total dose of 60 Gy to the gross tumor volume and 50 Gy to the planning target volume in 25 fractions during 5 weeks. Twenty patients received temozolomide chemotherapy. Results: At a median follow-up of 13.4 months (range, 3.7-55.9 months), median survival was 14.8 months. One- and 2-year survival rates were 78% and 65%, respectively, for patients with grade III tumors and 56% and 31%, respectively, for patients with grade IV tumors. Age ({<=}50 vs. >50), grade (III vs. IV), subtype (astrocytoma vs. oligodendroglioma or mixed), and a Zubrod performance score (0-1 vs. >2) were predictive of survival. Of 25 (63%) patients who had recurrences, 17 patients had local failure, 9 patients had regional failure, and 1 patient had distant metastasis. Toxicities were acceptable. Conclusions: SIB-IMRT with the dose/fractionation used in this study is feasible and safe, with a survival outcome similar to the historical control. The shortening of treatment time by using SIB-IMRT may be of value, although further investigation is warranted to prove its survival advantage.

  18. Plasticity of language pathways in patients with low-grade glioma: A diffusion tensor imaging study☆

    PubMed Central

    Zheng, Gang; Chen, Xiaolei; Xu, Bainan; Zhang, Jiashu; Lv, Xueming; Li, Jinjiang; Li, Fangye; Hu, Shen; Zhang, Ting; Li, Ye

    2013-01-01

    Knowledge of the plasticity of language pathways in patients with low-grade glioma is important for neurosurgeons to achieve maximum resection while preserving neurological function. The current study sought to investigate changes in the ventral language pathways in patients with low-grade glioma located in regions likely to affect the dorsal language pathways. The results revealed no significant difference in fractional anisotropy values in the arcuate fasciculus between groups or between hemispheres. However, fractional anisotropy and lateralization index values in the left inferior longitudinal fasciculus and lateralization index values in the left inferior fronto-occpital fasciculus were higher in patients than in healthy subjects. These results indicate plasticity of language pathways in patients with low-grade glioma. The ventral language pathways may perform more functions in patients than in healthy subjects. As such, it is important to protect the ventral language pathways intraoperatively. PMID:25206710

  19. Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.

    PubMed

    Walsh, Kyle M; Codd, Veryan; Smirnov, Ivan V; Rice, Terri; Decker, Paul A; Hansen, Helen M; Kollmeyer, Thomas; Kosel, Matthew L; Molinaro, Annette M; McCoy, Lucie S; Bracci, Paige M; Cabriga, Belinda S; Pekmezci, Melike; Zheng, Shichun; Wiemels, Joseph L; Pico, Alexander R; Tihan, Tarik; Berger, Mitchell S; Chang, Susan M; Prados, Michael D; Lachance, Daniel H; O'Neill, Brian Patrick; Sicotte, Hugues; Eckel-Passow, Jeanette E; van der Harst, Pim; Wiencke, John K; Samani, Nilesh J; Jenkins, Robert B; Wrensch, Margaret R

    2014-07-01

    Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis. PMID:24908248

  20. Human Cytomegalovirus DNA Quantification and Gene Expression in Gliomas of Different Grades

    PubMed Central

    Medeiros, Raphael Salles Scortegagna; Guerra, Juliana Mariotti; Kimura, Lidia Midori; Shirata, Neuza Kazumi; Nonogaki, Suely; dos Santos, Claudia Januário; Carlan Silva, Maria Cristina

    2016-01-01

    Gliomas are the most common type of primary brain tumors. The most aggressive type, Glioblastoma multiforme (GBM), is one of the deadliest human diseases, with an average survival at diagnosis of about 1 year. Previous evidence suggests a link between human cytomegalovirus (HCMV) and gliomas. HCMV has been shown to be present in these tumors and several viral proteins can have oncogenic properties in glioma cells. Here we have investigated the presence of HCMV DNA, RNA and proteins in fifty-two gliomas of different grades of malignancy. The UL83 viral region, the early beta 2.7 RNA and viral protein were detected in 73%, 36% and 57% by qPCR, ISH and IHC, respectively. Positivity of the viral targets and viral load was independent of tumor type or grade suggesting no correlation between viral presence and tumor progression. Our results demonstrate high prevalence of the virus in gliomas from Brazilian patients, contributing to a better understanding of the association between HCMV infection and gliomas worldwide and supporting further investigations of the virus oncomodulatory properties. PMID:27458810

  1. 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. PMID:27138095

  2. Nrf2 Expressions Correlate with WHO Grades in Gliomas and Meningiomas

    PubMed Central

    Tsai, Wen-Chiuan; Hueng, Dueng-Yuan; Lin, Chii-Ruey; Yang, Thomas C. K.; Gao, Hong-Wei

    2016-01-01

    Background: Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as Nrf2) is associated with cellular progression and chemotherapeutic resistance in some human cancers. We tested the relationship between Nrf2 expression and survival of patients with primary brain tumors (PBTs). Methods: In order to realize Nrf2 protein expression in gliomas, Western blot analysis was performed in normal brain tissue and U87MG, LN229, GBM8401 and U118MG glioma cell lines protein lysates. Then, U87MG, LN229, and GBM8401 mRNA were applied to performed quantitative RT-PCR for detect Nrf2 gene expression in glioma cell lines. At last, immunohistochemical analysis was used to determine the expression of Nrf2 in samples from 178 PBTs and 10 non-neoplastic brain tissues. Results: In these included in vitro studies, both Nrf2 protein and mRNA expression in all human glioma cell lines were higher than normal brain tissue. Similarly, on the viewpoint of immunohistochemistry, Nrf2 expression in gliomas were positively correlated with World Health Organization (WHO) grades. Additionally, compared with the expression of Nrf2 in non-neoplastic brain tissue, expression in meningiomas was of a stronger intensity and was present in a higher percentage of cells. Furthermore, scores were significantly higher in WHO grade II than in WHO grade I meningiomas. Finally, overall survival tended to be shorter in patients whose PBTs had higher expression of Nrf2, although the correlation was not statistically significant. Conclusions: Nrf2 overexpression positively correlated with WHO grade in gliomas and meningiomas. On the other hand, Nrf2 immunohistochemical stain could help pathologists to differentiate atypical meningiomas from benign tumors. Therefore, Nrf2 expression may be a useful biomarker to predict WHO grade and cellular behavior of PBTs. PMID:27187376

  3. ERK1 as a Therapeutic Target for Dendritic Cell Vaccination against High-Grade Gliomas.

    PubMed

    Ku, Min-Chi; Edes, Inan; Bendix, Ivo; Pohlmann, Andreas; Waiczies, Helmar; Prozorovski, Tim; Günther, Martin; Martin, Conrad; Pagès, Gilles; Wolf, Susanne A; Kettenmann, Helmut; Uckert, Wolfgang; Niendorf, Thoralf; Waiczies, Sonia

    2016-08-01

    Glioma regression requires the recruitment of potent antitumor immune cells into the tumor microenvironment. Dendritic cells (DC) play a role in immune responses to these tumors. The fact that DC vaccines do not effectively combat high-grade gliomas, however, suggests that DCs need to be genetically modified specifically to promote their migration to tumor relevant sites. Previously, we identified extracellular signal-regulated kinase (ERK1) as a regulator of DC immunogenicity and brain autoimmunity. In the current study, we made use of modern magnetic resonance methods to study the role of ERK1 in regulating DC migration and tumor progression in a model of high-grade glioma. We found that ERK1-deficient mice are more resistant to the development of gliomas, and tumor growth in these mice is accompanied by a higher infiltration of leukocytes. ERK1-deficient DCs exhibit an increase in migration that is associated with sustained Cdc42 activation and increased expression of actin-associated cytoskeleton-organizing proteins. We also demonstrated that ERK1 deletion potentiates DC vaccination and provides a survival advantage in high-grade gliomas. Considering the therapeutic significance of these results, we propose ERK1-deleted DC vaccines as an additional means of eradicating resilient tumor cells and preventing tumor recurrence. Mol Cancer Ther; 15(8); 1975-87. ©2016 AACR. PMID:27256374

  4. The role of up-front radiation therapy for incompletely resected pediatric WHO grade II low-grade gliomas1

    PubMed Central

    Mishra, Kavita K.; Puri, Dev R.; Missett, Brian T.; Lamborn, Kathleen R.; Prados, Michael D.; Berger, Mitchel S.; Banerjee, Anuradha; Gupta, Nalin; Wara, William M.; Haas-Kogan, Daphne A.

    2006-01-01

    The purpose of this study was to assess the impact of early radiation therapy and extent of surgical resection on progression-free survival (PFS) and overall survival (OS) in children with WHO grade II low-grade gliomas (LGGs). We conducted a historical cohort study of 90 patients, ages 21 or younger, diagnosed with WHO grade II LGGs between 1970 and 1995. Median follow-up for surviving patients was 9.4 years (range, 0.5–22.6 years). Tests for variables correlating with OS and PFS were conducted by using log-rank tests and Cox proportional hazards models. Eleven patients underwent gross total resections (GTRs), 43 had subtotal resections, and 34 underwent biopsy only at diagnosis. Two patients underwent biopsy at time of recurrence. Of the 90 patients, 52 received radiation as part of their initial therapy following diagnosis (early-RT group). The overall five-year PFS and OS rates ± SE were 56% ± 5% and 90% ± 3%, respectively. Ten-year PFS and OS rates were 42% ± 6% and 81% ± 5%, respectively. For patients older than three years and without GTRs, administration of early radiation did not appear to influence PFS or OS (P = 0.98 and P = 0.40, respectively; log-rank test). This was confirmed by multivariate analyses (P = 0.95 and P = 0.33 for PFS and OS, respectively). Of the 11 patients with GTRs, disease progressed in only two, and all were alive with no evidence of disease at last follow-up. Patients who underwent GTRs had significantly longer PFS (P = 0.02), but did not have significantly improved OS. Excellent long-term survival rates were achieved for children with WHO grade II LGGs. We were unable to demonstrate a benefit for administering radiation as part of initial treatment. An outcome benefit was seen with greater extent of resection. PMID:16495375

  5. Prognostic microRNAs in high-grade glioma reveal a link to oligodendrocyte precursor differentiation

    PubMed Central

    Hayes, Josie; Thygesen, Helene; Droop, Alastair; Hughes, Thomas A.; Westhead, David; Lawler, Sean E.; Wurdak, Heiko; Short, Susan C.

    2015-01-01

    MicroRNA expression can be exploited to define tumor prognosis and stratification for precision medicine. It remains unclear whether prognostic microRNA signatures are exclusively tumor grade and/or molecular subtype-specific, or whether common signatures of aggressive clinical behavior can be identified. Here, we defined microRNAs that are associated with good and poor prognosis in grade III and IV gliomas using data from The Cancer Genome Atlas. Pathway analysis of microRNA targets that are differentially expressed in good and poor prognosis glioma identified a link to oligodendrocyte development. Notably, a microRNA expression profile that is characteristic of a specific oligodendrocyte precursor cell type (OP1) correlates with microRNA expression from 597 of these tumors and is consistently associated with poor patient outcome in grade III and IV gliomas. Our study reveals grade-independent and subtype-independent prognostic molecular signatures in high-grade glioma and provides a framework for investigating the mechanisms of brain tumor aggressiveness. PMID:25897422

  6. Genomic profiling of lower-grade gliomas uncovers cohesive disease groups: implications for diagnosis and treatment.

    PubMed

    Zhang, Chang-Ming; Brat, Daniel J

    2016-01-01

    Lower-grade gliomas (including low- and intermediate-grade gliomas, World Health Organization grades II and III) are diffusely infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and have traditionally been classified based on their presumed histogenesis as astrocytomas, oligodendrogliomas, or oligoastrocytomas. Although the histopathologic classification of lower-grade glioma has been the accepted standard for nearly a century, it suffers from high intra- and inter-observer variability and does not adequately predict clinical outcomes. Based on integrated analysis of multiplatform genomic data from The Cancer Genome Atlas, lower-grade gliomas have been found to segregate into three cohesive, clinically relevant molecular classes. Molecular classes were closely aligned with the status of isocitrate dehydrogenase (IDH) mutations, tumor protein 53 mutations and the co-deletion of chromosome arms 1p and 19q, but were not closely aligned with histologic classes. These findings emphasize the potential for improved definition of clinically relevant disease subsets using integrated molecular approaches and highlight the importance of biomarkers for brain tumor classification. PMID:26758195

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

    PubMed

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

    2016-08-15

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

  8. PL-03FEASIBILITY OF GENOMICS-ENABLED THERAPY FOR PEDIATRIC HIGH-GRADE GLIOMAS AND DIFFUSE PONTINE GLIOMAS

    PubMed Central

    Mueller, Sabine; Liang, Winnie; Byron, Sara; Nazemi, Kellie; Leary, Sarah; Kilburn, Lindsay; Prados, Michael; Gupta, Nalin; Craig, David; Carpten, John; Berens, Michael

    2014-01-01

    Children with pediatric high-grade gliomas (pHGG) including diffuse intrinsic pontine gliomas (DIPG) continue to have a dismal prognosis and, as a result, novel therapeutic approaches are needed. We evaluated whether genomic profiling, defined as sequencing of tumor and germline exomes and tumor RNA, can be used to identify distinct, actionable events that may guide treatment of children with pHGG. Tumor from eight archival cases were assessed to confirm high tumor cellularity of samples (>60%) and were evaluated by genomic profiling. Successfully sequenced tumor specimens originated from DIPG (n = 2), astrocytoma grade II (n = 1), astrocytoma grade III (n = 1), glioblastoma (n = 4). We generated average mapped coverages of >145X across all exomes and generated >190M reads for each tumor RNA. Identified alterations were matched to potential therapeutic options using a custom drug-matching pipeline utilizing a pharmacopeia that includes FDA-approved drugs, potential repositioned agents, and investigational compounds. Alterations in genes previously implicated in pediatric glioma were identified, including mutations in histone H3 (H3F3A), PDGFRA, TP53, and ATRX and copy number loss of CDKN2A. Alterations associated with potential sensitivity to FDA-approved oncology agents included frameshift and splice-site mutations in TSC2 and extracellular mutations in PDGFRA (E229K, C235Y mutations; previously reported in pHGG), with predicted sensitivity to mTOR inhibitors and PDGFRA inhibitors, respectively. Inclusion of repositioned therapies and agents in clinical development expanded the actionable roster to include: CDKN2A deletion, BRD4 gain, PRKCI gain, ATM mutation, and overexpression of EZH2, KIF11, MELK, PLK4, and WEE1, several of which are direct targets of investigational agents currently in clinical trials. In conclusion, potentially actionable alterations were uncovered by applying integrative sequencing strategies to pHGG patients. Future efforts will apply this

  9. Downregulation of microRNA-504 is associated with poor prognosis in high-grade glioma

    PubMed Central

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

    2015-01-01

    Several previous reports indicated that microRNA-504 (miR-504) has an oncogenic function through negatively regulating p53. On the other hand, a recent study revealed that miR-504 inhibits cancer cell proliferation through targeting CDK6 in hypopharyngeal squamous cell carcinoma (HSCC), suggesting the tumor suppressive role of this miRNA. However, the role of miR-504 in human malignant glioma remains unclear. Therefore, the aim of this study was to investigate the clinical significance of miR-504 expression in high pathological grade glioma. Quantitative real-time reverse transcriptive-PCR (qRT-PCR) was performed to examine miR-504 expression levels in 63 glioma tissues including 13 anaplastic astrocytomas (AA, WHO grade III) and 50 glioblastomas (GBM, WHO grade IV), as well as 10 non-neoplastic brain tissues. Associations between miR-504 expression and clinicopathological factors and prognosis of glioma patients were statistically analyzed. MiR-504 showed significant decreased expression levels both in AAs and GBMs relative to non-neoplastic brains (P ≤ 0.001, respectively). Additionally, low expression level of miR-504 was significantly associated with advanced WHO grade (P = 0.01). Moreover, Kaplan-Meier survival analysis showed that patients with low expression of miR-504 had significantly poor survival rate (P = 0.002). Cox regression analysis showed that miR-504 expression was independent prognosis-predicting factor for malignant glioma patients (P = 0.038; risk ration = 2.5). Our results suggest that miR-504 may be a prognostic predictor and be involved in tumorigencity as a tumor suppressor of malignant glioma. PMID:25755767

  10. 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 ...

  11. Deep brain stimulation and development of a high-grade glioma: incidental or causal association?

    PubMed

    Mindermann, Thomas; Mendelowitsch, Aminadav

    2016-05-01

    We report the case of a patient in whom 8.8 years following the implantation of a bilateral deep brain stimulation (DBS) into the Vim, a high-grade glioma was diagnosed in close proximity to the two electrode leads. A possible relationship between the permanent DBS and the development of the brain tumour is discussed. PMID:26993141

  12. Outcomes after combined use of intraoperative MRI and 5-aminolevulinic acid in high-grade glioma surgery

    PubMed Central

    Schatlo, Bawarjan; Fandino, Javier; Smoll, Nicolas R.; Wetzel, Oliver; Remonda, Luca; Marbacher, Serge; Perrig, Wolfgang; Landolt, Hans; Fathi, Ali-Reza

    2015-01-01

    Background Previous studies have shown the individual benefits of 5-aminolevulinic acid (5-ALA) and intraoperative (i)MRI in enhancing survival for patients with high-grade glioma. In this retrospective study, we compare rates of progression-free and overall survival between patients who underwent surgical resection with the combination of 5-ALA and iMRI and a control group without iMRI. Methods In 200 consecutive patients with high-grade gliomas, we recorded age, sex, World Health Organization tumor grade, and pre- and postoperative Karnofsky performance status (good ≥80 and poor <80). A 0.15-Tesla magnet was used for iMRI; all patients operated on with iMRI received 5-ALA. Overall and progression-free survival rates were compared using multivariable regression analysis. Results Median overall survival was 13.8 months in the non-iMRI group and 17.9 months in the iMRI group (P = .043). However, on identifying confounding variables (ie, KPS and resection status) in this univariate analysis, we then adjusted for these confounders in multivariate analysis and eliminated this distinction in overall survival (hazard ratio: 1.23, P = .34, 95% CI: 0.81, 1.86). Although 5-ALA enhanced the achievement of gross total resection (odds ratio: 3.19, P = .01, 95% CI: 1.28, 7.93), it offered no effect on overall or progression-free survival when adjusted for resection status. Conclusions Gross total resection is the key surgical variable that influences progression and survival in patients with high-grade glioma and more likely when surgical adjuncts, such as iMRI in combination with 5-ALA, are used to enhance resection. PMID:25858636

  13. 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.

  14. Canine intracranial gliomas: Relationship between magnetic resonance imaging criteria and tumor type and grade

    PubMed Central

    Bentley, R.T.; Ober, C.P.; Anderson, K.L.; Feeney, D.A.; Naughton, J.F.; Ohlfest, J.R.; O’Sullivan, M.G.; Miller, M.A.; Constable, P.D.; Pluhar, G.E.

    2013-01-01

    Limited information is available to assist in the ante-mortem prediction of tumor type and grade for dogs with primary brain tumors. The objective of the current study was to identify magnetic resonance imaging (MRI) criteria related to the histopathological type and grade of gliomas in dogs. A convenience sample utilizing client-owned dogs (n=31) with gliomas was used. Medical records of dogs with intracranial lesions admitted to two veterinary referral hospitals were reviewed and cases with a complete brain MRI and definitive histopathological diagnosis were retrieved for analysis. Each MRI was independently interpreted by five investigators who were provided with standardized grading instructions and remained blinded to the histopathological diagnosis. Mild to no contrast enhancement, an absence of cystic structures (single or multiple), and a tumor location other than the thalamo-capsular region were independently associated with grade II tumors compared to higher grade tumors. In comparison to oligodendrogliomas, astrocytomas were independently associated with the presence of moderate to extensive peri-tumoral edema, a lack of ventricular distortion, and an isointense or hyperintense T1W-signal. When clinical and MRI features indicate that a glioma is most likely, certain MRI criteria can be used to inform the level of suspicion for low tumor grade, particularly poor contrast enhancement. Information obtained from the MRI of such dogs can also assist in predicting an astrocytoma or an oligodendroglioma, but no single imaging characteristic allows for a particular tumor type to be ruled out. PMID:24051197

  15. CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages.

    PubMed

    De, Ishani; Steffen, Megan D; Clark, Paul A; Patros, Clayton J; Sokn, Emily; Bishop, Stephanie M; Litscher, Suzanne; Maklakova, Vilena I; Kuo, John S; Rodriguez, Fausto J; Collier, Lara S

    2016-05-01

    Current therapies for high-grade gliomas extend survival only modestly. The glioma microenvironment, including glioma-associated microglia/macrophages (GAM), is a potential therapeutic target. The microglia/macrophage cytokine CSF1 and its receptor CSF1R are overexpressed in human high-grade gliomas. To determine whether the other known CSF1R ligand IL34 is expressed in gliomas, we examined expression array data of human high-grade gliomas and performed RT-PCR on glioblastoma sphere-forming cell lines (GSC). Expression microarray analyses indicated that CSF1, but not IL34, is frequently overexpressed in human tumors. We found that while GSCs did express CSF1, most GSC lines did not express detectable levels of IL34 mRNA. We therefore studied the impact of modulating CSF1 levels on gliomagenesis in the context of the GFAP-V12Ha-ras-IRESLacZ (Ras*) model. Csf1 deficiency deterred glioma formation in the Ras* model, whereas CSF1 transgenic overexpression decreased the survival of Ras* mice and promoted the formation of high-grade gliomas. Conversely, CSF1 overexpression increased GAM density, but did not impact GAM polarization state. Regardless of CSF1 expression status, most GAMs were negative for the M2 polarization markers ARG1 and CD206; when present, ARG1(+) and CD206(+) cells were found in regions of peripheral immune cell invasion. Therefore, our findings indicate that CSF1 signaling is oncogenic during gliomagenesis through a mechanism distinct from modulating GAM polarization status. Cancer Res; 76(9); 2552-60. ©2016 AACR. PMID:27013192

  16. 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.

  17. Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

    PubMed Central

    2013-01-01

    Background The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation. Trial registration Cuban National Register for clinical trials (No. 1745) (http://registroclinico.sld.cu/ensayos). PMID:23782513

  18. Versican isoform V1 regulates proliferation and migration in high-grade gliomas.

    PubMed

    Onken, Julia; Moeckel, Sylvia; Leukel, Petra; Leidgens, Verena; Baumann, Fusun; Bogdahn, Ulrich; Vollmann-Zwerenz, Arabel; Hau, Peter

    2014-10-01

    Versican is a large chondroitin sulphate proteoglycan produced by several tumor cell types, including high-grade gliomas. Increased expression of distinct versican isoforms in the extracellular matrix plays a role in tumor cell growth, adhesion and migration. We have recently shown that transforming growth factor (TGF-beta)2, an important modulator of glioma invasion, interacts with versican isoforms V0/V1 during malignant progression of glioma in vitro. However, the distinct subtype of versican that modulates these effects could not be specified. Here, we show that transient down-regulation of V1 by siRNA leads to a significant reduction of proliferation and migration in glioblastoma cell lines and glioblastoma progenitor cells, whereas tumor cell attachment stays unaffected. We conclude that V1 plays a predominant role in modulating central pathophysiological mechanisms as proliferation and migration in glioblastoma. Considering that TGF-beta is a master regulator of glioma pathophysiology, and that V0/1 is induced by TGF-beta2, therapeutic regulation of V1 may induce meaningful effects on glioma cell migration not only in vitro, but also in vivo. PMID:25064688

  19. 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

  20. Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences With the Adult Disease

    PubMed Central

    Paugh, Barbara S.; Qu, Chunxu; Jones, Chris; Liu, Zhaoli; Adamowicz-Brice, Martyna; Zhang, Junyuan; Bax, Dorine A.; Coyle, Beth; Barrow, Jennifer; Hargrave, Darren; Lowe, James; Gajjar, Amar; Zhao, Wei; Broniscer, Alberto; Ellison, David W.; Grundy, Richard G.; Baker, Suzanne J.

    2010-01-01

    Purpose To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). Patients and Methods We conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for 53 tumors. Results were compared with publicly available data from adult tumors. Results Significant differences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregulated PDGFRα signaling in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showed minimal copy number changes. Conclusion Integrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFRα may be a useful target for pediatric HGG, including diffuse pontine gliomas. PMID:20479398

  1. Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy

    PubMed Central

    Guillevin, R; Menuel, C; Taillibert, S; Capelle, L; Costalat, R; Abud, L; Habas, C; De Marco, G; Hoang-Xuan, K; Chiras, J; Vallée, J-N

    2011-01-01

    Background: This study was designed to evaluate proton magnetic resonance spectroscopy (1H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ). Methods: This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and 1H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results. Results: A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)n and mean(Cho/NAA)n, were significantly correlated over time (Spearman ρ=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)n and mean(Cho/NAA)n, were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(ΔVn/Vo), according to a linear regression (P<0.001) in the ‘response/no relapse' patient group, and with the evolution of the mean tumour volume (meanVn), according to an exponential regression (P<0.001) in the ‘response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Δ(Cho/Cr)n/(Cho/Cr)o), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)n−(Cho/Cr)n)/(Cho/NAA)n, at n=4 months was

  2. Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties.

    PubMed

    Chen, Yi-Hsien; McGowan, Lucy D'Agostino; Cimino, Patrick J; Dahiya, Sonika; Leonard, Jeffrey R; Lee, Da Yong; Gutmann, David H

    2015-03-24

    The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133(+) multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment. PMID:25772366

  3. 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. PMID:21637921

  4. 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

  5. Advanced MRI may complement histological diagnosis of lower grade gliomas and help in predicting survival.

    PubMed

    Cuccarini, Valeria; Erbetta, A; Farinotti, M; Cuppini, L; Ghielmetti, F; Pollo, B; Di Meco, F; Grisoli, M; Filippini, G; Finocchiaro, G; Bruzzone, M G; Eoli, M

    2016-01-01

    MRI grading of grade II and III gliomas may have an important impact on treatment decisions. Occasionally,both conventional MRI (cMRI) and histology fail to clearly establish the tumour grade. Three cMRI features(no necrosis; no relevant oedema; absent or faint contrast enhancement) previously validated in 196 patients with supratentorial gliomas directed our selection of 68 suspected low-grade gliomas (LGG) that were also investigated by advanced MRI (aMRI), including perfusion weighted imaging (PWI), diffusion weighted imaging(DWI) and spectroscopy. All the gliomas had histopathological diagnoses. Sensitivity and specificity of cMRI preoperative diagnosis were 78.5 and 38.5 %, respectively, and 85.7 and 53.8 % when a MRI was included, respectively. ROC analysis showed that cut-off values of 1.29 for maximum rCBV, 1.69 for minimum rADC, 2.1 for rCho/Cr ratio could differentiate between LGG and HGG with a sensitivity of 61.5, 53.8, and 53.8 % and a specificity of 54.7, 43 and 64.3 %, respectively. A significantly longer OS was observed in patients with a maximum rCBV<1.46 and minimum rADC>1.69 (80 vs 55 months, p = 0.01; 80 vs 51 months, p = 0.002, respectively). This result was also confirmed when cases were stratified according to pathology (LGG vs HGG). The ability of a MRI to differentiate between LGG and HGG and to predict survival improved as the number of a MRI techniques considered increased. In a selected population of suspected LGG,classification by cMRI underestimated the actual fraction of HGG. aMRI slightly increased the diagnostic accuracy compared to histopathology. However, DWI and PWI were prognostic markers independent of histological grade. PMID:26468137

  6. 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.

  7. Normal tissue tolerance for high-grade gliomas: is it an issue?

    PubMed

    Morris, David E; Kimple, Randall J

    2009-07-01

    In this article, we address the currently accepted dose tolerance parameters for the treatment of high-grade gliomas. The issue of normal tissue tolerance is becoming increasingly important because of the long-term survival of a significant subset of young, good performance status patients and the use of hypofractionated regimens for elderly patients with poor performance status. In addition, we address relevant clinical endpoints including clinical, pathologic, and radiographic changes and highlight the difficulty in discriminating between tumor-related and treatment-related effects. Finally, we review relevant clinical trials addressing issues of dose and/or volume parameters. Future trials for patients with high-grade gliomas should consider the inclusion of a prospective evaluation of neurocognitive function and imaging correlates of the brain to assist in the prediction, prevention, and treatment of radiation-induced damage of normal brain tissue. PMID:19464634

  8. Exploiting molecular biology for diagnosis and targeted management of pediatric low-grade gliomas.

    PubMed

    Garcia, Michael A; Solomon, David A; Haas-Kogan, Daphne A

    2016-06-01

    The majority of brain tumors arising in children are low-grade gliomas. Although historically categorized together as pediatric low-grade gliomas (PLGGs), there is significant histologic and genetic diversity within this group. In general, prognosis for PLGGs is excellent, and limitation of sequelae from tumor and treatment is paramount. Advances in high-throughput genetic sequencing and gene expression profiling are fundamentally changing the way PLGGs are classified and managed. Here, we review the histologic subtypes and highlight how recent advances in elucidating the molecular pathogenesis of these tumors have refined diagnosis and prognostication. Additionally, we discuss how characterizing specific genetic alterations has paved the way for the rational use of targeted therapies that are currently in various phase clinical trials. PMID:27072750

  9. The microtubule binding drug EM011 inhibits the growth of paediatric low grade gliomas.

    PubMed

    Ajeawung, Norbert F; Joshi, Harish C; Kamnasaran, Deepak

    2013-07-10

    Low grade gliomas are a heterogeneous group of tumours representing the most common form of neoplasms in the central nervous system among children. Although gross total resection remains the principal treatment, it is often impractical especially for the resection of tumours within eloquent regions of the brain. Instead Radiotherapy is utilised in such cases, but because of its associated toxicities, it is refrained from use among younger children. These limitations coupled with hypersensitivity and toxicities associated with some commonly used chemotherapeutic agents, have ignited the need to search for safer and more effective treatments for paediatric low grade gliomas. In this study, we investigated the EM011 drug on the growth of two pilocytic and one diffuse paediatric astrocytoma cell lines, using an assortment of cancer assays. We discovered that treatments of low grade gliomas with EM011 abrogated cell viability by inducing a decrease in cell proliferation and an arrest in the S and G2M cell cycle phases, followed by a converse increase in apoptosis in a dose and time dependent manner. The cell migratory and invasion indices, as well as anchorage independent growth in soft agarose, were significantly attenuated. These findings were mechanistically associated with a transient release of AIF, a disruption of microtubule architecture, and a decline in the expression of key genes which drive cancer progression including EGFR, mTORC1, JUN and multiple MMPs. In fact, the activity of MMP2 was also perturbed by EM011. These findings, in conjunction with the insignificant adverse side effects established from other studies, make EM011 an appealing chemotherapeutic agent for the treatment of paediatric low grade gliomas. PMID:23402815

  10. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma

    PubMed Central

    Wiencke, John K.; Zheng, Shichun; Jelluma, Nanette; Tihan, Tarik; Vandenberg, Scott; Tamgüney, Tanja; Baumber, Rachel; Parsons, Ramon; Lamborn, Kathleen R.; Berger, Mitchel S.; Wrensch, Margaret R.; Haas-Kogan, Daphne Adele; Stokoe, David

    2007-01-01

    Glioblastoma multiforme (GBM) can present as either de novo or secondary tumors arising from previously diagnosed low-grade gliomas. Although these tumor types are phenotypically indistinguishable, de novo and secondary GBMs are associated with distinct genetic characteristics. PTEN mutations, which result in activation of the phosphoinositide 3-kinase (PI3K) signal transduction pathway, are frequent in de novo but not in secondary GBMs or their antecedent low-grade tumors. Results we present here show that grade II astrocytomas, oligodendrogliomas, and oligoastrocytomas commonly display methylation of the PTEN promoter, a finding that is absent in nontumor brain specimens and rare in de novo GBMs. Methylation of the PTEN promoter correlates with protein kinase B (PKB/Akt) phosphorylation, reflecting functional activation of the PI3K pathway. Our results also demonstrate frequent methylation of the PTEN promoter in grade III astrocytomas and secondary GBMs, consistent with the hypothesis that these tumors arise from lower grade precursors. PTEN methylation is rare in de novo GBMs and is mutually exclusive with PTEN mutations. We conclude that methylation of the PTEN promoter may represent an alternate mechanism by which PI3K signaling is increased in grade II and III gliomas as well as secondary GBMs, a finding that offers new therapeutic approaches in these patients. PMID:17504928

  11. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma.

    PubMed

    Wiencke, John K; Zheng, Shichun; Jelluma, Nanette; Tihan, Tarik; Vandenberg, Scott; Tamgüney, Tanja; Baumber, Rachel; Parsons, Ramon; Lamborn, Kathleen R; Berger, Mitchel S; Wrensch, Margaret R; Haas-Kogan, Daphne Adele; Stokoe, David

    2007-07-01

    Glioblastoma multiforme (GBM) can present as either de novo or secondary tumors arising from previously diagnosed low-grade gliomas. Although these tumor types are phenotypically indistinguishable, de novo and secondary GBMs are associated with distinct genetic characteristics. PTEN mutations, which result in activation of the phosphoinositide 3-kinase (PI3K) signal transduction pathway, are frequent in de novo but not in secondary GBMs or their antecedent low-grade tumors. Results we present here show that grade II astrocytomas, oligodendrogliomas, and oligoastrocytomas commonly display methylation of the PTEN promoter, a finding that is absent in nontumor brain specimens and rare in de novo GBMs. Methylation of the PTEN promoter correlates with protein kinase B (PKB/Akt) phosphorylation, reflecting functional activation of the PI3K pathway. Our results also demonstrate frequent methylation of the PTEN promoter in grade III astrocytomas and secondary GBMs, consistent with the hypothesis that these tumors arise from lower grade precursors. PTEN methylation is rare in de novo GBMs and is mutually exclusive with PTEN mutations. We conclude that methylation of the PTEN promoter may represent an alternate mechanism by which PI3K signaling is increased in grade II and III gliomas as well as secondary GBMs, a finding that offers new therapeutic approaches in these patients. PMID:17504928

  12. Learning and Memory Following Conformal Radiation Therapy for Pediatric Craniopharyngioma and Low-Grade Glioma

    SciTech Connect

    Di Pinto, Marcos; Conklin, Heather M.; Li, Chenghong; Merchant, Thomas E.

    2012-11-01

    Purpose: The primary objective of this study was to examine whether children with low-grade glioma (LGG) or craniopharyngioma had impaired learning and memory after conformal radiation therapy (CRT). A secondary objective was to determine whether children who received chemotherapy before CRT, a treatment often used to delay radiation therapy in younger children with LGG, received any protective benefit with respect to learning. Methods and Materials: Learning and memory in 57 children with LGG and 44 children with craniopharyngioma were assessed with the California Verbal Learning Test-Children's Version and the Visual-Auditory Learning tests. Learning measures were administered before CRT, 6 months later, and then yearly for a total of 5 years. Results: No decline in learning scores after CRT was observed when patients were grouped by diagnosis. For children with LGG, chemotherapy before CRT did not provide a protective effect on learning. Multiple regression analyses, which accounted for age and tumor volume and location, found that children treated with chemotherapy before CRT were at greater risk of decline on learning measures than those treated with CRT alone. Variables predictive of learning and memory decline included hydrocephalus, shunt insertion, younger age at time of treatment, female gender, and pre-CRT chemotherapy. Conclusions: This study did not reveal any impairment or decline in learning after CRT in overall aggregate learning scores. However, several important variables were found to have a significant effect on neurocognitive outcome. Specifically, chemotherapy before CRT was predictive of worse outcome on verbal learning in LGG patients. In addition, hydrocephalus and shunt insertion in craniopharyngioma were found to be predictive of worse neurocognitive outcome, suggesting a more aggressive natural history for those patients.

  13. [The role of functional status and recursive partition analysis (RPA) classes for the choice of fractionation regimen in patients with high-grade gliomas].

    PubMed

    Izmaĭlov, T R; Pan'shin, G A; Datsenko, P V

    2012-01-01

    The treatment results of 396 patients with morphologically verified grade 3-4 malignant brain tumors receiving conventional irradiation regimen and irradiation by medium-sized fractions were analyzed to form institutional guidelines.The standard mode of fractionation with a single dose of 2 Gy and total focal dose (TFD) of 60 Gy is appropriate for patients with initial Karnofsky status of 60-100% and Recursive Partition Analysis (RPA) class I-III. TFD increase to 60-62 Gy in grade 4 gliomas and 54-56 Gy in grade 3 gliomas grants a significant improve in overall survival. An increase of a single irradiation fraction to 3 Gy may be used for patients with initially low functional status (Karnofsky 30-50%) and RPA classes IV-VI. In these cases it is advisable to use the TFD of 45 Gy or more (TFD of equivalent regimen with a dose greater than 54 Gy). The mentioned fractionation regimens could be recommended for the use in clinical practice to improve the results of high-grade gliomas treatment. PMID:22888653

  14. 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.

  15. Decreased FOXD3 Expression Is Associated with Poor Prognosis in Patients with High-Grade Gliomas

    PubMed Central

    Wang, Dongliang; Zhang, Qingjun; Xue, Yake; Jiao, Hongliang; Zhan, Lei; Ma, Qian; Wei, Xinting

    2015-01-01

    Background The transcription factor forkhead box D3 (FOXD3) plays important roles in the development of neural crest and has been shown to suppress the development of various cancers. However, the expression and its potential biological roles of FOXD3 in high-grade gliomas (HGGs) remain unknown. Methods The mRNA and protein expression levels of FOXD3 were examined using real-time quantitative PCR and western blotting in 23 HGG and 13 normal brain samples, respectively. Immunohistochemistry was used to validate the expression FOXD3 protein in 184 HGG cases. The association between FOXD3 expression and the prognosis of HGG patients were analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression models. In addition, we further examined the effects of FOXD3 on the proliferation and serum starvation-induced apoptosis of glioma cells. Results In comparison to normal brain tissues, FOXD3 expression was significantly decreased in HGG tissues at both mRNA and protein levels. Immunohistochemistry further validated the expression of FOXD3 in HGG tissues. Moreover, low FOXD3 expression was significantly associated with poor prognosis in HGG patients. Depletion of FOXD3 expression promoted glioma cell proliferation and inhibited serum starvation-induced apoptosis, whereas overexpression of FOXD3 inhibited glioma cell proliferation and promoted serum starvation-induced apoptosis. Conclusions Our results indicated that FOXD3 might serve as an independent prognostic biomarker and a potential therapeutic target for HGGs, which warrant further investigation. PMID:26011451

  16. Isolated third nerve palsy: A rare presentation of high grade glioma.

    PubMed

    Singh, Deepak Kumar; Singh, Neha; Singh, Ragini

    2016-01-01

    High grade gliomas account for almost one-third of primary central nervous system neoplasm, mainly in adults with a mean age of 41 years. They usually present with symptoms of raised intracranial pressure such as headache, vomiting, and seizures. We report a case of 55-year-old male presenting with right side complete third nerve palsy. Magnetic resonance imaging revealed an intraaxial tumor of the right medial temporal lobe. The tumor was removed grossly, and the histological diagnosis was anaplastic astrocytoma (WHO grade 3). We discuss clinical presentation of this case along with pertinent literature. PMID:27057228

  17. Isolated third nerve palsy: A rare presentation of high grade glioma

    PubMed Central

    Singh, Deepak Kumar; Singh, Neha; Singh, Ragini

    2016-01-01

    High grade gliomas account for almost one-third of primary central nervous system neoplasm, mainly in adults with a mean age of 41 years. They usually present with symptoms of raised intracranial pressure such as headache, vomiting, and seizures. We report a case of 55-year-old male presenting with right side complete third nerve palsy. Magnetic resonance imaging revealed an intraaxial tumor of the right medial temporal lobe. The tumor was removed grossly, and the histological diagnosis was anaplastic astrocytoma (WHO grade 3). We discuss clinical presentation of this case along with pertinent literature. PMID:27057228

  18. Interstitial radiogold implantation for the treatment of recurrent high-grade gliomas

    SciTech Connect

    Larson, G.L.; Wilbanks, J.H.; Dennis, W.S.; Permenter, W.D.; Easley, J.D. )

    1990-07-01

    Thirty-three patients were treated at the Methodist Hospital, Baylor College of Medicine (Houston) between 1983 and 1987, for high-grade gliomas which had recurred after conventional external-beam radiation therapy. The mean dose to the tumor volume from the external-beam therapy was 5800 cGy. Thirteen patients had recurrent astrocytoma Grade 4 (glioblastoma), whereas 20 had recurrent astrocytoma Grade 3 (anaplastic astrocytoma). All patients were treated for their recurrence by the combination of reexcision of as much of the tumor mass as was technically feasible and intraoperative radiogold (198Au) seed implantation of the residual tumor and/or tumor bed. The mean dose to the tumor volume from the implant was 4000 cGy. For the 13 patients treated for recurrent glioblastoma the 1-year, 2-year, and 3-year survival rates were 46%, 15%, and 8%, respectively. For the 20 patients treated for recurrent anaplastic astrocytoma the 1-year, 2-year, and 3-year survival rates were 75%, 50%, and 15%, respectively. Survival was measured from the time of implant. The median survival for patients with glioblastoma was 9 months. The median survival for patients with anaplastic astrocytoma was 17 months. One patient died in the immediate postoperative period from a gastrointestinal bleed. No patient required reoperation for radiation necrosis. The authors believe that this technique is an effective treatment for patients with high-grade gliomas recurring after external-beam radiation therapy, and are now including interstitial irradiation in the initial management of selected patients with high-grade gliomas.

  19. Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma

    PubMed Central

    Wicks, Robert T.; Azadi, Javad; Mangraviti, Antonella; Zhang, Irma; Hwang, Lee; Joshi, Avadhut; Bow, Hansen; Hutt-Cabezas, Marianne; Martin, Kristin L.; Rudek, Michelle A.; Zhao, Ming; Brem, Henry; Tyler, Betty M.

    2015-01-01

    Background 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. Methods Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). Results 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. Conclusion Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect. PMID:25053853

  20. A Comparative Study of Survival Rate in High Grade Glioma Tumors Being Treated by Radiotherapy Alone Versus Chemoradiation With Nitrosourea

    PubMed Central

    Houshyari, Mohammad; Hajalikhani, Farzaneh; Rakhsha, Afshin; Hajian, Parastoo

    2015-01-01

    Background: In adults, malignant glioma (high-grade glioma) is one of the most common brain tumors. In spite of different types of treatment, the outcome is still not likely to be favorable. The aim of this study was to determine the difference between survival rate in adult patients with high grade glioma treated by radiotherapy only and those treated by a combination of radiotherapy and nitrosurea-based chemotherapy. Methods: This study was conducted using the records of 48 patients with grade 3 or 4 of glial brain tumor referred to the radiation-oncology ward of Shohada-e-Tajrish Hospital in Tehran, Iran from 2005 to 2012. The patients had undergone radiotherapy alone or adjuvant chemoradiation with nitrosourea. The median survival of patients after receiving the different types of treatment were evaluated using the Kaplan –Meier method and the log –rank exam. Data were analyzed using univariate analysis for median survival regarding to the patients’ age, gender, extent of surgery, Karnofsky performance status (KPS) with the Kaplan-Meier method, and the log-rank exam. We used the Cox-model for multivariate analysis. Results: Records of 48 patients were studied (34 men and 14 women). The mean survival were 18 months for men and 15.2 months for women (P = 0.05). Around 58% (28 patients) were more than 50 years old, and 42% (20 patients) were less than 50, and mean survival for the two age groups were 13 and 20 months, respectively (P < 0.001). Then, the patients were divided into three groups according to the extent of surgery, i.e., excisional biopsy (11 patients), stereotactic biopsy (22 patients), and resection (15 patients), and the mean survival for the three groups were 14.7, 17.3, and 18.8 months, respectively. There was no significant statistical difference for mean survival between the three groups (P = 0.23). The KPS was greater than 70% in 23 patients and less than 70% in 21 patients, and the mean survival for the former and latter groups were 17

  1. Clinical Outcomes and Late Endocrine, Neurocognitive, and Visual Profiles of Proton Radiation for Pediatric Low-Grade Gliomas

    SciTech Connect

    Greenberger, Benjamin A.; Pulsifer, Margaret B.; Ebb, David H.; MacDonald, Shannon M.; Jones, Robin M.; Butler, William E.; Huang, Mary S.; Marcus, Karen J.; Oberg, Jennifer A.; Tarbell, Nancy J.; Yock, Torunn I.

    2014-08-01

    Purpose/Objective(s): Primary low-grade gliomas are common brain tumors of childhood, many of which require radiation therapy (RT) as definitive treatment. Increased conformality of RT could decrease the incidence and severity of late effects. We report our experience with 32 pediatric patients treated with proton RT. Methods and Materials: Thirty-two pediatric patients with low-grade gliomas of the brain or spinal cord were treated with proton RT from 1995 to 2007. Sixteen patients received at least 1 regimen of chemotherapy before definitive RT. The median radiation dose was 52.2 Gy{sub RBE} (48.6-54 Gy{sub RBE}). Results: The median age at treatment was 11.0 years (range, 2.7-21.5 years), with a median follow-up time of 7.6 years (range, 3.2-18.2 years). The 6-year and 8-year rates of progression-free survival were 89.7% and 82.8%, respectively, with an 8-year overall survival of 100%. For the subset of patients who received serial neurocognitive testing, there were no significant declines in Full-Scale Intelligence Quotient (P=.80), with a median neurocognitive testing interval of 4.5 years (range, 1.2-8.1 years) from baseline to follow-up, but subgroup analysis indicated some significant decline in neurocognitive outcomes for young children (<7 years) and those with significant dose to the left temporal lobe/hippocampus. The incidence of endocrinopathy correlated with a mean dose of ≥40 Gy{sub RBE} to the hypothalamus, pituitary, or optic chiasm. Stabilization or improvement of visual acuity was achieved in 83.3% of patients at risk for radiation-induced injury to the optic pathways. Conclusions: This report of late effects in children with low-grade gliomas after proton RT is encouraging. Proton RT appears to be associated with good clinical outcome, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis.

  2. Symptom resolution in infiltrating WHO grade II-IV glioma patients undergoing surgical resection.

    PubMed

    Burks, Joshua D; Bonney, Phillip A; Glenn, Chad A; Conner, Andrew K; Briggs, Robert G; Ebeling, Peter A; Toho, Lucas C; Sughrue, Michael E

    2016-09-01

    Past studies of morbidity in patients with infiltrating gliomas have focused on the impact of surgery on quality of life. Surprisingly, little attention has been given to the rate at which the presenting symptoms improve after surgery, even though this is often the patient's first concern. This study is an initial effort to provide useful information about symptom resolution and factors predicting persistence of symptoms in glioma patients who undergo surgery. We conducted a retrospective analysis on patients who underwent surgery for World Health Organization (WHO) grade II-IV astrocytoma/oligodendroglioma/oligoastrocytoma at our institution. All patients were seen 2-4months postoperatively, and asked about the persistence of symptoms they experienced preoperatively. Symptoms reported in clinic were assessed against symptoms reported prior to surgery. Our study includes 56 consecutive patients undergoing surgery for gliomas. Of patients who experienced symptoms initially, headache resolved in 18/27 postoperatively, weakness resolved in 8/14 postoperatively, altered mental status resolved in 8/12 postoperatively, vision problems resolved in 7/11 postoperatively, nausea resolved in 5/7 postoperatively, and ataxia resolved in 4/5 postoperatively. Headache was more likely to resolve in patients with frontal or temporal tumors (p=0.02). Preoperative Karnofsky Performance Scale (KPS) of 70 or less was associated with longer postsurgical hospital stay (p<0.01). Younger patients were more likely to experience a resolution of altered mental status (p=0.04). Our analysis provides data regarding the rate at which surgery alleviates patient symptoms and considers variables predicting likelihood of symptom resolution. Some patients will experience symptom resolution following resection of WHO grade II-IV gliomas in the months following surgery. PMID:27394379

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

    PubMed Central

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

    2014-01-01

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

  4. Prolonged survival in adult neurofibromatosis type I patients with recurrent high-grade gliomas treated with bevacizumab.

    PubMed

    Theeler, Brett J; Ellezam, Benjamin; Yust-Katz, Shlomit; Slopis, John M; Loghin, Monica E; de Groot, John F

    2014-08-01

    Astrocytic tumors, especially optic pathway pilocytic astrocytomas, are common in pediatric NF1 patients. High-grade gliomas (HGGs) appear to be rare in adult and pediatric NF1 patients. This is a series of five consecutive, adult NF1 patients with recurrent HGGs treated at The University of Texas MD Anderson Cancer Center. Four patients met consensus clinical criteria for NF1 and one patient had presumed segmental NF1. Three patients had glioblastomas, one gliosarcoma, and one progressive, enhancing optic pathway glioma which was not biopsied. Two tumors had molecular testing performed; both were IDH wild type and activating oncogene mutations (1 BRAFV600E and 1 PIK3CA mutation) were found in these tumors. All five patients received bevacizumab-containing regimens at tumor recurrence. The median number of 4-week cycles of bevacizumab was 20. All five patients experienced prolonged post-recurrence survival following bevacizumab treatment ranging from ten to 72 months. The median overall survival from HGG diagnosis was 72.6 months with three patients alive and progression free at last follow-up. Three out of five patients developed vascular complications leading to bevacizumab discontinuation. In this case series, adult NF1 patients with recurrent HGGs had prolonged, post-recurrence survival after treatment with bevacizumab-containing regimens. Based on these results, further study of antiangiogenic therapy in NF1 patients with HGGs and bevacizumab-response in sporadic HGG patients with NF1-mutated tumors is warranted. PMID:24859329

  5. 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

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

    ClinicalTrials.gov

    2016-07-14

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

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

    PubMed

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

    2010-02-01

    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

  8. 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

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

    PubMed

    Ertosun, Mehmet Günhan; Rubin, Daniel L

    2015-01-01

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

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

    PubMed Central

    Ertosun, Mehmet Günhan; Rubin, Daniel L.

    2015-01-01

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

  11. IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas

    PubMed Central

    Leeper, Heather E.; Caron, Alissa A.; Decker, Paul A.; Jenkins, Robert B.; Lachance, Daniel H.; Giannini, Caterina

    2015-01-01

    Background Epigenetic, genetic, and molecular studies have identified several diagnostic and prognostic markers in diffuse gliomas. Their importance for evaluating WHO grade II gliomas has yet to be specifically delineated. Methods We analyzed markers, including IDH mutation(IDHmut), 1p19q codeletion(1p19qcodel), ATRX expression loss(ATRX loss) and p53 overexpression, and outcomes in 159 patients with WHO grade II oligodendroglioma, oligoastrocytoma, and astrocytoma (2003–2012). Results IDHmut was found in 141(91%) and ATRX loss in 64(87%) of IDHmut-noncodel tumors (p = 0.003). All codeleted tumors (n = 66) were IDHmut. Four subgroups were identified: IDHmut-codel, 66(43%); IDHmut-noncodel-ATRX loss, 60(39%); IDHmut-noncodel-ATRXwt, 9(6%); IDHwt, 14(9%). Median survival among 4 groups was significantly different (p = 0.038), particularly in IDHmut-codel (median survival 15.6 years) compared to the remaining 3 groups (p = 0.025). Survival by histology was not significant. Overall (OS), but not progression-free (PFS), survival was significantly longer with gross total resection vs. biopsy only (p = 0.042). Outcomes for patients with subtotal resection were not significantly different from those with biopsy only. Among these uniformly treated patients, OS far exceeds PFS, particularly in those with 1p/19q codeletion. Conclusions For WHO grade II diffuse glioma, molecular classification using 1p/19qcodel, IDHmut, and ATRX loss more accurately predicts outcome and should be incorporated in the neuropathologic evaluation. PMID:26210286

  12. Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis

    PubMed Central

    Niola, Francesco; Zhao, Xudong; Singh, Devendra; Sullivan, Ryan; Castano, Angelica; Verrico, Antonio; Zoppoli, Pietro; Friedmann-Morvinski, Dinorah; Sulman, Erik; Barrett, Lindy; Zhuang, Yuan; Verma, Inder; Benezra, Robert; Aldape, Ken; Iavarone, Antonio; Lasorella, Anna

    2012-01-01

    High-grade gliomas (HGGs) are incurable brain tumors that are characterized by the presence of glioma-initiating cells (GICs). GICs are essential to tumor aggressiveness and retain the capacity for self-renewal and multilineage differentiation as long as they reside in the perivascular niche. ID proteins are master regulators of stemness and anchorage to the extracellular niche microenvironment, suggesting that they may play a role in maintaining GICs. Here, we modeled the probable therapeutic impact of ID inactivation in HGG by selective ablation of Id in tumor cells and after tumor initiation in a new mouse model of human mesenchymal HGG. Deletion of 3 Id genes induced rapid release of GICs from the perivascular niche, followed by tumor regression. GIC displacement was mediated by derepression of Rap1gap and subsequent inhibition of RAP1, a master regulator of cell adhesion. We identified a signature module of 5 genes in the ID pathway, including RAP1GAP, which segregated 2 subgroups of glioma patients with markedly different clinical outcomes. The model-informed survival analysis together with genetic and functional studies establish that ID activity is required for the maintenance of mesenchymal HGG and suggest that pharmacological inactivation of ID proteins could serve as a therapeutic strategy. PMID:23241957

  13. 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

  14. Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology

    PubMed Central

    Rice, Terri; Zheng, Shichun; Decker, Paul A.; Walsh, Kyle M.; Bracci, Paige; Xiao, Yuanyuan; McCoy, Lucie S.; Smirnov, Ivan; Patoka, Joseph S.; Hansen, Helen M.; Hsuang, George; Wiemels, Joe L.; Tihan, Tarik; Pico, Alexander R.; Prados, Michael D.; Chang, Susan M.; Berger, Mitchel S.; Caron, Alissa; Fink, Stephanie; Kollmeyer, Thomas; Rynearson, Amanda; Voss, Jesse; Kosel, Matthew L.; Fridley, Brooke L.; Lachance, Daniel H.; Eckel-Passow, Jeanette E.; Sicotte, Hugues; O'Neill, Brian Patrick; Giannini, Caterina; Wiencke, John K.; Jenkins, Robert B.; Wrensch, Margaret R.

    2013-01-01

    Introduction Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas. Methods We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele. Results The 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29–1.74; P = 1.3X10−7) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81–1.03; P = 0.14). The associations were independent of the rs55705857 G allele. Conclusion A variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology. PMID:23361564

  15. Volumetric modulated arc therapy for hippocampal-sparing radiotherapy in transformed low-grade glioma: A treatment planning case report.

    PubMed

    Kazda, T; Pospisil, P; Vrzal, M; Sevela, O; Prochazka, T; Jancalek, R; Slampa, P; Laack, N N

    2015-05-01

    Timing of radiotherapy for low-grade gliomas is still controversial due to concerns of possible adverse late effects. Prevention of possible late cognitive sequelae by hippocampal avoidance has shown promise in phase II trials. A patient with progressive low-grade glioma with gradual dedifferentiation into anaplastic astrocytoma is presented along with description of radiotherapy planning process attempting to spare the hippocampus. To our knowledge, this is the first described case using volumetric modulated arc technique to spare hippocampus during transformed low-grade glioma radiotherapy. Using modern intensity-modulated radiotherapy systems it is possible to selectively spare hippocampus together with other standard organs at risk. For selected patients, an attempt to spare hippocampus can be considered as long as other dose characteristics are not significantly compromised compared to standard treatment plan created without any effort to avoid hippocampus. PMID:25835374

  16. Transformation of low grade glioma and correlation with outcome: an NCCTG database analysis.

    PubMed

    Jaeckle, K A; Decker, P A; Ballman, K V; Flynn, P J; Giannini, C; Scheithauer, B W; Jenkins, R B; Buckner, J C

    2011-08-01

    Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3-4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7-10.2); oligoastrocytoma, 4.4 years (95% CI 3.5-5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2-4, 2.1 years) (95% CI 1.7-2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5-1.1 vs. 0.6 years, CI: 0.5-1.0 vs. 1.4 years, 95% CI: 1.1-2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease. PMID:21153680

  17. 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

  18. P13.11USAGE OF CYBER KNIFE HYPOFRACTIONATED RADIOSURGERY IN HIGH GRADE GLIOMAS COMPLEX TREATMENT

    PubMed Central

    Glavatskyi, O.; Buryk, V.M.; Kardash, K.A.; Pylypas, O.P.; Chebotaryova, T.I.

    2014-01-01

    respectively. CONCLUSIONS: Hypofractionated stereotactic radiosurgery is one of possible treatment options for high-grade gliomas which leads to a decrease in tumor volume and improves clinical status of patients even in cases of re-irradiation. Surgical treatment after radiosurgery doesn't worsen median overall survival and progression free survival prognosis.

  19. 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

  20. Resonant Raman spectra of grades of human brain glioma tumors reveal the content of tryptophan by the 1588 cm-1 mode

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-hui; Zhou, Lixin; Zhu, Ke; Liu, Yulong; Zhang, Lin; Boydston-White, Susie; Cheng, Gangge; Pu, Yang; Bidyut, Das; Alfano, Robert R.

    2015-03-01

    RR spectra of brain normal tissue, gliomas in low grade I and II, and malignant glioma tumors in grade III and IV were measured using a confocal micro Raman spectrometer. This report focus on the relative contents of tryptophan (W) in various grades of brain glioma tumors by the intrinsic molecular resonance Raman (RR) spectroscopy method using the 1588cm-1 of tryptophan mode by 532 nm excitation. The RR spectra of key fingerprints of tryptophan, with a main vibrational mode at 1588cm-1 (W8b), were observed. It was found that tryptophan contribution was accumulated in grade I to IV gliomas and the mode of 1588cm-1 in grade III and IV malignant gliomas were enhanced by resonance.

  1. Survival Analysis of Patients with High-Grade Gliomas Based on Data Mining of Imaging Variables

    PubMed Central

    Zacharaki, E.I.; Morita, N.; Bhatt, P.; O’Rourke, D.M.; Melhem, E.R.; Davatzikos, C.

    2015-01-01

    BACKGROUND AND PURPOSE The prediction of prognosis in HGGs is poor in the majority of patients. Our aim was to test whether multivariate prediction models constructed by machine-learning methods provide a more accurate predictor of prognosis in HGGs than histopathologic classification. The prediction of survival was based on DTI and rCBV measurements as an adjunct to conventional imaging. MATERIALS AND METHODS The relationship of survival to 55 variables, including clinical parameters (age, sex), categoric or continuous tumor descriptors (eg, tumor location, extent of resection, multifocality, edema), and imaging characteristics in ROIs, was analyzed in a multivariate fashion by using data-mining techniques. A variable selection method was applied to identify the overall most important variables. The analysis was performed on 74 HGGs (18 anaplastic gliomas WHO grades III/IV and 56 GBMs or gliosarcomas WHO grades IV/IV). RESULTS Five variables were identified as the most significant, including the extent of resection, mass effect, volume of enhancing tumor, maximum B0 intensity, and mean trace intensity in the nonenhancing/edematous region. These variables were used to construct a prediction model based on a J48 classification tree. The average classification accuracy, assessed by cross-validation, was 85.1%. Kaplan-Meier survival curves showed that the constructed prediction model classified malignant gliomas in a manner that better correlates with clinical outcome than standard histopathology. CONCLUSIONS Prediction models based on data-mining algorithms can provide a more accurate predictor of prognosis in malignant gliomas than histopathologic classification alone. PMID:22322603

  2. Acute progression of untreated incidental WHO Grade II glioma to glioblastoma in an asymptomatic patient.

    PubMed

    Cochereau, Jérôme; Herbet, Guillaume; Rigau, Valérie; Duffau, Hugues

    2016-01-01

    WHO Grade II glioma (low-grade glioma [LGG]) is increasingly diagnosed as an incidental finding in patients undergoing MRI for many conditions. Recent data have demonstrated that such incidental LGGs are progressive tumors that undergo clinical transformation and ultimately become malignant. Although asymptomatic LGG seems to represent an earlier step in the natural course of a glioma than the symptomatic LGG, it is nonetheless impossible to predict at the individual level when the tumor will become malignant. The authors report the case of a 43-year-old woman with a right operculo-insular LGG that was incidentally diagnosed because of headaches. No treatment was proposed, and repeated MRI scans were performed for 6 years in another institution. Due to a slow but continuous growth of the lesion, the patient was finally referred to our center to undergo surgery. Interestingly, objective calculation of the velocity of the tumor's diametric expansion demonstrated a sudden acceleration of the growth rate within the 5 months preceding surgery, with the development of contrast enhancement. Remarkably, the patient was still asymptomatic. An awake resection was performed with intraoperative electrical mapping. There was no functional worsening following surgery, as assessed on postoperative neuropsychological examination. Removal of 92% of signal abnormality on FLAIR MRI was achieved, with complete resection of the area of contrast enhancement. Neuropathological examination revealed a glioblastoma, and the patient was subsequently treated with concomitant radiotherapy and chemotherapy. Although a "wait and see" attitude has been advocated by some authors with respect to incidental LGG, our original case demonstrates that acute transformation to glioblastoma may nonetheless occur, even before the onset of any symptoms. Therefore, because the lack of symptoms does not protect from malignant transformation, we propose consideration of earlier resection in a more systematic

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  5. 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

  6. Adult Supratentorial Low-Grade Glioma: Long-Term Experience at a Single Institution

    SciTech Connect

    Bauman, Glenn; Fisher, Barbara; Watling, Christopher; Cairncross, J. Gregory; Macdonald, David

    2009-12-01

    Purpose: To report the long-term follow-up of a cohort of adult patients with supratentorial low-grade glioma treated at a single institution. Methods and Materials: A cohort of 145 adult patients treated at the London Regional Cancer Program between 1979 and 1995 was reviewed. Results: With a median follow-up of 105 months, the median progression-free survival was 61 months (95% confidence interval, 53-77), and the median overall survival was 118 months (95% confidence interval, 93-129). The 10- and 20-year progression-free and overall survival rate was 18% and 0% and 48% and 22%, respectively. Cox regression analysis confirmed the importance of age, histologic type, presence of seizures, Karnofsky performance status, and initial extent of surgery as prognostic variables for overall and cause-specific survival. Function among long-term survivors without tumor progression was good to excellent for most patients. Conclusion: Low-grade glioma is a chronic disease, with most patients dying of their disease. However, long-term survival with good function is possible. Survival is determined primarily by the disease factors with selection and timing of adjuvant treatments having less influence on outcome.

  7. Temozolomide and Radiotherapy versus Radiotherapy Alone in High Grade Gliomas: A Very Long Term Comparative Study and Literature Review

    PubMed Central

    Parisi, Salvatore; Corsa, Pietro; Raguso, Arcangela; Perrone, Antonio; Cossa, Sabrina; Munafò, Tindara; Sanpaolo, Gerardo; Donno, Elisa; Clemente, Maria Antonietta; Piombino, Michele; Parisi, Federico; Valle, Guido

    2015-01-01

    Temozolomide (TMZ) is the first line drug in the care of high grade gliomas. The combined treatment of TMZ plus radiotherapy is more effective in the care of brain gliomas then radiotherapy alone. Aim of this report is a survival comparison, on a long time (>10 years) span, of glioma patients treated with radiotherapy alone and with radiotherapy + TMZ. Materials and Methods. In this report we retrospectively reviewed the outcome of 128 consecutive pts with diagnosis of high grade gliomas referred to our institutions from April 1994 to November 2001. The first 64 pts were treated with RT alone and the other 64 with a combination of RT and adjuvant or concomitant TMZ. Results. Grade 3 (G3) haematological toxicity was recorded in 6 (9%) of 64 pts treated with RT and TMZ. No G4 haematological toxicity was observed. Age, histology, and administration of TMZ were statistically significant prognostic factors associated with 2 years overall survival (OS). PFS was for GBM 9 months, for AA 11. Conclusions. The combination of RT and TMZ improves long term survival in glioma patients. Our results confirm the superiority of the combination on a long time basis. PMID:25815327

  8. 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

  9. Multiparametric Characterization of Grade 2 Glioma Subtypes Using Magnetic Resonance Spectroscopic, Perfusion, and Diffusion Imaging1

    PubMed Central

    Bian, Wei; Khayal, Inas S; Lupo, Janine M; McGue, Colleen; Vandenberg, Scott; Lamborn, Kathleen R; Chang, Susan M; Cha, Soonmee; Nelson, Sarah J

    2009-01-01

    BACKGROUND AND PURPOSE: The purpose of this study was to derive quantitative parameters from magnetic resonance (MR) spectroscopic, perfusion, and diffusion imaging of grade 2 gliomas according to the World Health Organization and to investigate how these multiple imaging modalities can contribute to evaluating their histologic subtypes and spatial characteristics. MATERIALS AND METHODS: MR spectroscopic, perfusion, and diffusion images from 56 patients with newly diagnosed grade 2 glioma (24 oligodendrogliomas, 18 astrocytomas, and 14 oligoastrocytomas) were retrospectively studied. Metabolite intensities, relative cerebral blood volume (rCBV), and apparent diffusion coefficient (ADC) were statistically evaluated. RESULTS: The 75th percentile rCBV and median ADC were significantly different between oligodendrogliomas and astrocytomas (P < .0001) and between oligodendrogliomas and oligoastrocytomas (P < .001). Logistic regression analysis identified both 75th percentile rCBV and median ADC as significant variables in the differentiation of oligodendrogliomas from astrocytomas and oligoastrocytomas. Group differences in metabolite intensities were not significant, but there was a much larger variation in the volumes and maximum values of metabolic abnormalities for patients with oligodendroglioma compared with the other tumor subtypes. CONCLUSIONS: Perfusion and diffusion imaging provide quantitative MR parameters that can help to differentiate grade 2 oligodendrogliomas from grade 2 astrocytomas and oligoastrocytomas. The large variations in the magnitude and spatial extent of the metabolic lesions between patients and the fact that their values are not correlated with the other imaging parameters indicate that MR spectroscopic imaging may provide complementary information that is helpful in targeting therapy, evaluating residual disease, and assessing response to therapy. PMID:19956389

  10. Severe Radiation Necrosis Successfully Treated With Bevacizumab in an Infant with Low-Grade Glioma and Tumor-Associated Intractable Trigeminal Neuralgia.

    PubMed

    Pillay Smiley, Natasha; Alden, Tord; Hartsell, William; Fangusaro, Jason

    2016-09-01

    We present a unique case of radiation necrosis in a child with brain stem low-grade glioma (LGG) presenting with trigeminal neuralgia. Despite extensive therapies, severe pain persisted. She received proton beam radiation with significant improvement. However, she developed radiation necrosis and hydrocephalus. Despite surgical correction of hydrocephalus, the patient remained critically ill. She was treated with dexamethasone and bevacizumab with rapid clinical improvement. Subsequent MRIs revealed almost complete resolution of the necrosis. This case illustrates the successful treatment of trigeminal neuralgia with radiation and a rare case of radiation necrosis in an LGG successfully treated with bevacizumab and dexamethasone. PMID:27187113

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

    PubMed Central

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

    2014-01-01

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

  12. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.

    PubMed

    Wrensch, Margaret; Jenkins, Robert B; Chang, Jeffrey S; Yeh, Ru-Fang; Xiao, Yuanyuan; Decker, Paul A; Ballman, Karla V; Berger, Mitchel; Buckner, Jan C; Chang, Susan; Giannini, Caterina; Halder, Chandralekha; Kollmeyer, Thomas M; Kosel, Matthew L; LaChance, Daniel H; McCoy, Lucie; O'Neill, Brian P; Patoka, Joe; Pico, Alexander R; Prados, Michael; Quesenberry, Charles; Rice, Terri; Rynearson, Amanda L; Smirnov, Ivan; Tihan, Tarik; Wiemels, Joe; Yang, Ping; Wiencke, John K

    2009-08-01

    The causes of glioblastoma and other gliomas remain obscure. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component-adjusted genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA)) and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10(-6) using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 x 10(-8), replication P = 0.0038 and combined P = 1.85 x 10(-10). On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 x 10(-7), replication P = 0.00035 and combined P = 3.40 x 10(-9). For both SNPs, the direction of association was the same in discovery and replication phases. PMID:19578366

  13. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.

    PubMed

    Zhang, Jinghui; Wu, Gang; Miller, Claudia P; Tatevossian, Ruth G; Dalton, James D; Tang, Bo; Orisme, Wilda; Punchihewa, Chandanamali; Parker, Matthew; Qaddoumi, Ibrahim; Boop, Fredrick A; Lu, Charles; Kandoth, Cyriac; Ding, Li; Lee, Ryan; Huether, Robert; Chen, Xiang; Hedlund, Erin; Nagahawatte, Panduka; Rusch, Michael; Boggs, Kristy; Cheng, Jinjun; Becksfort, Jared; Ma, Jing; Song, Guangchun; Li, Yongjin; Wei, Lei; Wang, Jianmin; Shurtleff, Sheila; Easton, John; Zhao, David; Fulton, Robert S; Fulton, Lucinda L; Dooling, David J; Vadodaria, Bhavin; Mulder, Heather L; Tang, Chunlao; Ochoa, Kerri; Mullighan, Charles G; Gajjar, Amar; Kriwacki, Richard; Sheer, Denise; Gilbertson, Richard J; Mardis, Elaine R; Wilson, Richard K; Downing, James R; Baker, Suzanne J; Ellison, David W

    2013-06-01

    The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs. PMID:23583981

  14. CD105 Over-expression Is Associated with Higher WHO Grades for Gliomas.

    PubMed

    Kong, Xiangyi; Wang, Yu; Liu, Shuai; Xing, Bing; Yang, Yi; Li, Yongning; Ren, Zuyuan; Su, Changbao; Ma, Wenbin; Wang, Renzhi

    2016-07-01

    CD105 is an ancillary receptor of transforming growth factor beta (TGF-β), which has been suggested as a suitable biomarker for cancer-related angiogenesis and neovascularization (Nassiri et al. in Anticancer Res 31:2283-2290, 2011). However, the clinical significance of CD105 in WHO grade was rarely reported and the effects of CD105 signal transduction pathway on gliomas remain controversial and unclear. To get a convincing conclusion, performing a meta-analysis is essential. Relevant literature studies were included via careful evaluation, and standard mean difference (SMD) and hazard ratio (HR) with 95 % confidence intervals (95 % CIs) was calculated. We also made funnel plots to test the heterogeneity. In the present meta-analysis, a total of 11 eligible literatures involving 796 patients were incorporated. They were all conducted in China, revealing that CD105 overexpression in glioma tissues was strongly linked to high WHO grading (III+IV) (SMD -1.785, 95 % CI -2.133, -1.437; p = 0.000). No significant associations between CD105 and age (SMD -0.505, 95 % CI -1.054, 0.043; p = 0. 071), CD105 and gender (SMD 0.101, 95 % CI -0.103, 0.305; p = 0.333), and CD105 and tumor size (SMD -0.433, 95 % CI -1.326, 0.459; p = 0. 341) were detected. Besides, CD105 expression was closely associated with glioma patients' 3-year overall survival (OS; n = 2; HR = 4.357, 95 % CI 1.412, 7.303; p = 0.004). On the basis of Begg's and Egger's test or funnel plot, no publication bias was detected. In a nutshell, this meta-analysis demonstrated that CD105 overexpression correlates to higher WHO grade and poor survival and could be indicated as a helpful prognostic and diagnostic marker, or a useful therapy target. PMID:26884265

  15. Management of high-grade gliomas in the pediatric patient: Past, present, and future

    PubMed Central

    Vanan, Magimairajan Issai; Eisenstat, David D.

    2014-01-01

    High-grade gliomas (HGGs) constitute ∼15% of all primary brain tumors in children and adolescents. Routine histopathological diagnosis is based on tissue obtained from biopsy or, preferably, from the resected tumor itself. The majority of pediatric HGGs are clinically and biologically distinct from histologically similar adult malignant gliomas; these differences may explain the disparate responses to therapy and clinical outcomes when comparing children and adults with HGG. The recently proposed integrated genomic classification identifies 6 distinct biological subgroups of glioblastoma (GBM) throughout the age spectrum. Driver mutations in genes affecting histone H3.3 (K27M and G34R/V) coupled with mutations involving specific proteins (TP53, ATRX, DAXX, SETD2, ACVR1, FGFR1, NTRK) induce defects in chromatin remodeling and may play a central role in the genesis of many pediatric HGGs. Current clinical practice in pediatric HGGs includes surgical resection followed by radiation therapy (in children aged > 3 years) with concurrent and adjuvant chemotherapy with temozolomide. However, these multimodality treatment strategies have had a minimal impact on improving survival. Ongoing clinical trials are investigating new molecular targets, chemoradiation sensitization strategies, and immunotherapy. Future clinical trials of pediatric HGG will incorporate the distinction between GBM molecular subgroups and stratify patients using group-specific biomarkers. PMID:26034626

  16. ADVANCED MR IMAGING METHODS FOR PLANNING AND MONITORING RADIATION THERAPY IN PATIENTS WITH HIGH GRADE GLIOMA

    PubMed Central

    Lupo, Janine M.; Nelson, Sarah J.

    2016-01-01

    This review explores how the integration of advanced imaging methods with high quality anatomic images significantly improves the characterization, target definition, assessment of response to therapy, and overall management of patients with high-grade glioma. Metrics derived from diffusion, perfusion, and susceptibility weighted MR imaging in conjunction with MR spectroscopic imaging, allows us to characterize regions of edema, hypoxia, increased cellularity, and necrosis within heterogeneous tumor and surrounding brain tissue. Quantification of such measures may provide a more reliable initial representation of tumor delineation and response to therapy than changes in the contrast enhancing or T2 lesion alone and have a significant impact on targeting resection, planning radiation, and assessing treatment effectiveness. In the long-term, implementation of these imaging methodologies can also aid in the identification of recurrent tumor and its differentiation from treatment-related confounds and facilitate the detection of radiation-induced vascular injury in otherwise normal appearing brain tissue. PMID:25219809

  17. Hypofractionated Stereotactic Radiation Therapy in Recurrent High-Grade Glioma: A New Challenge

    PubMed Central

    Navarria, Pierina; Ascolese, Anna Maria; Tomatis, Stefano; Reggiori, Giacomo; Clerici, Elena; Villa, Elisa; Maggi, Giulia; Bello, Lorenzo; Pessina, Federico; Cozzi, Luca; Scorsetti, Marta

    2016-01-01

    Purpose The aim of this study was to evaluate outcomes of hypofractionated stereotactic radiation therapy (HSRT) in patients re-treated for recurrent high-grade glioma. Materials and Methods From January 2006 to September 2013, 25 patients were treated. Six patients underwent radiation therapy alone, while 19 underwent combined treatment with surgery and/or chemotherapy. Only patients with Karnofsky Performance Status (KPS) > 70 and time from previous radiotherapy greater than 6 months were re-irradiated. The mean recurrent tumor volume was 35 cm3 (range, 2.46 to 116.7 cm3), and most of the patients (84%) were treated with a total dose of 25 Gy in five fractions (range, 20 to 50 Gy in 5-10 fractions). Results The median follow-up was 18 months (range, 4 to 36 months). The progression-free survival (PFS) at 1 and 2 years was 72% and 34% and the overall survival (OS) 76% and 50%, respectively. No severe toxicity was recorded. In univariate and multivariate analysis extent of resection at diagnosis significantly influenced PFS and OS (p < 0.01). Patients with smaller recurren tumor volume treated had better local control and survival. Indeed, the 2-year PFS was 40% (≤ 50 cm3) versus 11% (p=0.1) and the 2-year OS 56% versus 33% (> 50 cm3), respectively (p=0.26). Conclusion In our experience, HSRT could be a safe and feasible therapeutic option for recurrent high grade glioma even in patients with larger tumors. We believe that a multidisciplinary evaluation is mandatory to assure the best treatment for selected patients. Local treatment should also be considered as part of an integrated approach. PMID:25761491

  18. 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

  19. 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

  20. A potential strategy for high-grade gliomas: combination treatment with lithium chloride and BmK CT.

    PubMed

    Fu, Yuejun; Zheng, Shuhua; Huang, Rui; An, Na; Zheng, Yali; Zhang, Zhiyun; Liang, Aihua

    2012-01-01

    Therapies for high-grade gliomas (HHG) that have strong tendency of infiltration and resistance to chemotherapies are currently unavailable. Here, we report that lower-dose combination therapy of Buthus martensii Karsch (BmK) CT, a type of scorpion toxin peptide, and LiCl, clinically used as mood stabilizer, could synergistically inhibit the migration, invasion and proliferation of C6 glioma cells. The decreased invasiveness of C6 glioma cells was accompanied by inhibited activation, catalytic activity and/or expression of matrix metalloproteinase-2. Moreover, TOPfalsh luciferase reporter and immunofluorescence staining showed altered localization pattern of β-catenin at the leading edge of 2D scratch. Our results suggested that the combination treatment of lithium and BmK CT may constitute a novel and potential strategy for HHG therapy. PMID:21932030

  1. Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas.

    PubMed

    Shi, Wenyin; Palmer, Joshua D; Werner-Wasik, Maria; Andrews, David W; Evans, James J; Glass, Jon; Kim, Lyndon; Bar-Ad, Voichita; Judy, Kevin; Farrell, Christopher; Simone, Nicole; Liu, Haisong; Dicker, Adam P; Lawrence, Yaacov R

    2016-05-01

    Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30-35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma. PMID:26821711

  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. PMID:27122050

  3. 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. PMID:18356283

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

    PubMed Central

    Lamborn, Kathleen R.; Alfred Yung, W. K.; 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.

    2008-01-01

    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. PMID:18356283

  5. Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models.

    PubMed

    Di, Kaijun; Keir, Stephen T; Alexandru-Abrams, Daniela; Gong, Xing; Nguyen, Howard; Friedman, Henry S; Bota, Daniela A

    2014-12-01

    Retaspimycin hydrochloride (IPI-504), an Hsp90 (heat shock protein 90) inhibitor, has shown activity in multiple preclinical cancer models, such as lung, breast and ovarian cancers. However, its biological effects in gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the expression pattern of Hsp90α/β mRNA in stable glioma cell lines, multiple glioma-derived primary cultures and human neural stem/progenitor cells. The effects of IPI-504 on cell proliferation, apoptosis, motility and expression of Hsp90 client proteins were evaluated in glioma cell lines. In vivo activity of IPI-504 was investigated in subcutaneous glioma xenografts. Our results showed Hsp90α and Hsp90β expression levels to be patient-specific, higher in high-grade glioma-derived primary cells than in low-grade glioma-derived primary cells, and strongly correlated with CD133 expression and differentiation status of cells. Hsp90 inhibition by IPI-504 induced apoptosis, blocked migration and invasion, and significantly decreased epidermal growth factor receptor levels, mitogen-activated protein kinase and/or Akt activities, and secretion of vascular endothelial growth factor in glioma cell lines. In vivo study showed that IPI-504 could mildly attenuate tumor growth in immunocompromised mice. These findings suggest that targeting Hsp90 by IPI-504 has the potential to become an active therapeutic strategy in gliomas in a selective group of patients, but further research into combination therapies is still needed. PMID:25115740

  6. High frequency of the X-chromosome inactivation in young female patients with high-grade glioma

    PubMed Central

    2013-01-01

    Background Gliomas are common tumors and high-grade ones account for 62% of primary malignant brain tumors. Though current evidence have suggested that inherited risks play a role in glioma susceptibility, it was conveyed that glioma was such a complex disease, and the direct genetic contribution to glioma risk factors and its relation to other factors should be discussed more deeply. X-chromosome inactivation (XCI) is the mechanism by which gene dosage equivalence is achieved between female mammals with two X chromosomes and male mammals with a single X chromosome. As skewed XCI has been linked to development of some solid tumors, including ovarian, breast, and pulmonary and esophageal carcinomas, it is challenging to elucidate the relation of skewed XCI to high-grade gliomas development. Objective The present study aimed to determine the general concordance between XCI pattern in blood cells and brain tissues, and SXCI frequencies in female patients with high-grade glioma compared to healthy controls. Methods 1,103 Chinese females without a detectable tumor and 173 female high-grade glioma patients, were detected in the study. Normal brain tissues surrounding the lesions in gliomas were obtained from 49 patients among the 173 ones, with the microdissection using a laser microdissection microscope Genomic DNA was extracted from the peripheral blood cells and the normal brain tissues from the subjects. Exon 1 of androgen receptor (AR) gene was amplified, and its products of different alleles were resolved on denaturing polyacrylamide gels and visualized after silver staining. The corrected ratios (CR) of the products before and after HpaII digestion were calculated. Results Occurrence of SXCI was detected in both the patients and controls at similar frequencies. However, the phenomenon, as defined as CR ≥ 3, was more frequent in the patients aging ≤40 (23.6%) compared to the corresponding reference group (5.1%, P <0.0001). When CR ≥ 10 was adopted

  7. TERT promoter mutated WHO grades II and III gliomas are located preferentially in the frontal lobe and avoid the midline

    PubMed Central

    Sun, Ze-Lin; Chan, Aden Ka-Yin; Chen, Ling-Chao; Tang, Chao; Zhang, Zhen-Yu; Ding, Xiao-Jie; Wang, Yang; Sun, Chong-Ran; Ng, Ho-Keung; Yao, Yu; Zhou, Liang-Fu

    2015-01-01

    The promoter region of telomerase reverse transcriptase (TERTp) and isocitrate dehydrogenase (IDH) have been regarded as biomarkers with distinct clinical and phenotypic features. Investigated the possible correlations between tumor location and genetic alterations would enhance our understanding of gliomagenesis and heterogeneity of glioma. We examined mutations of TERTp and IDH by direct sequencing and fluorescence in-situ hybridization in a cohort of 225 grades II and III diffuse gliomas. Correlation analysis between molecular markers and tumor locations was performed by Chi-square tests/Fisher’s exact test and multivariate logistic regression analysis. We found gliomas in frontal lobe showed higher frequency of TERTp mutation (P=0.0337) and simultaneously mutations of IDH and TERTp (IDH mut-TERTpmut) (P=0.0281) than frequency of biomarkers mutation of tumors in no-Frontal lobes, while lower frequency of TERTp mutation (P<0.0001) and simultaneously wild type of IDH and TERTp (IDH wt-TERTpwt) (P<0.0001) in midline than no-midline lobes. Logistic regression analysis indicated that locations of tumors associated with TERTp mutation (OR=0.540, 95% CI 0.324-0.900, P=0.018) and status of combinations of IDH and TERTp (IDH mut-TERTp mut vs. IDH wt-TERTp wt OR=0.162, 95% CI 0.075-0.350, P<0.001). In conclusion, grades II and III gliomas harboring TERTp mutation were located preferentially in the frontal lobe and rarely in midline. Association of IDH-TERTp status and tumor location suggests their potential values in molecular classification of grades II and III gliomas. PMID:26617880

  8. 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

  9. A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation.

    PubMed

    Ho, Cheng-Ying; Mobley, Bret C; Gordish-Dressman, Heather; VandenBussche, Christopher J; Mason, Gary E; Bornhorst, Miriam; Esbenshade, Adam J; Tehrani, Mahtab; Orr, Brent A; LaFrance, Delecia R; Devaney, Joseph M; Meltzer, Beatrix W; Hofherr, Sean E; Burger, Peter C; Packer, Roger J; Rodriguez, Fausto J

    2015-10-01

    Among brain tumors, the BRAF (V600E) mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF (V600) mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (grade astrocytomas (LGAs) was 22 ± 12 %, shorter than BRAF (V600)-WT PAs (52 ± 13 %) but higher than PMAs (10 ± 6 %). Of note, long-term PFS was observed in several adolescent patients with BRAF (V600)-mutant tumors. In children aged 0-12 years, 5-year PFS rate and median PFS in BRAF (V600)-mutant LGAs are 9 ± 9 % and 19 months (95 % CI 3-37 months), respectively. The PFS is comparable to that in BRAF (V600)-WT PMAs (5-year PFS rate: 10 ± 9 %; median PFS: 15 months, 95 % CI 3-32 months; p = 0.96) and significantly shorter than BRAF (V600)-WT PAs (5-year PFS rate: 46 ± 13 %; median PFS: 51 months, 95 % CI 20-∞ months; p < 0.05). In summary, diencephalic BRAF (V600)-mutant pediatric LGAs are associated with unique clinicopathologic features and have a more aggressive clinical course, especially in children

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

    PubMed

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

    2016-04-01

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

  11. 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

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

    PubMed Central

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

    2015-01-01

    Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II–III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and wild-type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR)=1.21, 95% confidence interval (CI)=0.91–1.61] compared to IDH-wild type tumors (HR=1.74, 95% CI=0.95–3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p<0.0001, HR=4.41, 95% CI=2.55–7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p=0.5157, HR=1.10, 95% CI=0.80–1.51), and could demonstrate a statistical interaction (p<0.0001) between IDH mutation and mitotic index (i.e. suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II–III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II–III gliomas as independent entities. PMID:25701198

  13. 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.

  14. 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

  15. Retrospective protein expression and epigenetic inactivation studies of CDH1 in patients affected by low-grade glioma.

    PubMed

    D'Urso, Pietro Ivo; D'Urso, Oscar Fernando; Storelli, Carlo; Catapano, Giuseppe; Gianfreda, Cosimo Damiano; Montinaro, Antonio; Muscella, Antonella; Marsigliante, Santo

    2011-08-01

    Aberrant methylation of CpG islands in the promoter regions of tumour cells results in loss of gene function. In addition to genetic lesions, changes in the methylation profile of the promoters may be considered a factor for tumour-specific aberrant expression of the genes.We investigated the methylation status of E-cadherin gene (CDH1) promoter in low-grade glioma and correlated it with clinical outcome. Eighty-four cases of low-grade glioma (43 diffuse astrocytomas, 27 oligodendrogliomas and 14 oligoastrocytomas) with assessable paraffin-embedded tumour blocks and normal brain tissue, derived from non-cancerous tissue adjacent to tumour and commercially normal brain tissue, were collected, from which we determined CDH1 promoter methylation status and E-cadherin protein expression by methylation-specific polymerase chain reaction (MSP) and immunohistochemistry, respectively. CDH1 promoter was found hypermethylated in 54 out of 84 low grade gliomas (64%) compared with 84 normal brain tissue. CDH1 hypermethylation was found in 65% astrocytomas, 66% oligodendrogliomas and 57% oligoastrocytomas. A significant correlation between hypermethylation status, patient survival and progression-free survival was found (P = 0.04). Survival and progression-free survival were lower in patients with hypermethylated CDH1 promoter. We found that 15 astrocytomas, 9 oligodendrogliomas and 6 oligoastrocytomas were immunoreactive for E-cadherin. The incidence of loss of immunoreactivity for E-cadherin decreased significantly with age, overall survival and progression-free survival (P = 0.001, Kaplan-Meier test). We have demonstrated that CDH1 promoter hypermethylation significantly associated with down-regulated E-cadherin expression and overall survival of patients. This may have a bearing on the prognosis of low-grade glioma. PMID:21127944

  16. 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. PMID:25761757

  17. IDH1 and IDH2 mutations in different histologic subtypes and WHO grading gliomas in a sample from Northern Brazil.

    PubMed

    Pessôa, I A; Sagica, F E S; Anselmo, N P; Brito, J R N; de Oliveira, E H C

    2015-01-01

    Glioma is a term used to describe tumors derived from glial cells. These tumors are divided into subgroups based on the histological morphology and similarity of their differentiated glia cells. Traditionally, they are classified according to the World Health Organization and include astrocytomas, oligodendrogliomas, ependymomas, and oligoastrocytomas. Like most cancers, gliomas develop as a result of genetic changes that accumulate with tumor progression. Alterations in isocitrate dehydrogenase 1 (IDH1) and IDH2 were found to be relevant in the classification and prognostic of gliomas. Because of the importance of mutations in these genes, particularly in IDH1, in different proposals of the genesis and progression of gliomas, we analyzed the occurrence of mutations in these genes in samples obtained from patients from Belém (PA, Brazil) using polymerase chain reaction-single-strand conformation polymorphism followed by sequencing. We compared the results obtained from tumors of different malignancy grades, evaluating the significance of the associations between different variables. R132H was the only mutation found in 17.6% (6/34) of cases, including in astrocytomas, anaplastic astrocytomas, oligodendroglioma, and anaplastic oligoastrocytoma. No mutations were found in the IDH2 gene. We found no significant relationship between the identified mutations in IDH1 and the variables. Our data could not confirm that mutations in IDH1/IDH2 are indicative of malignancy and prognosis. However, the results support that the mutation in IDH1 gene was an early event in the development of gliomas, as it was found in tumors of different malignancy grades. PMID:26125858

  18. Phase I Study of Temozolomide and Irinotecan for Recurrent Malignant Gliomas in Patients Receiving Enzyme-Inducing Antiepileptic Drugs: A North American BrainTumor Consortium Study

    PubMed Central

    Loghin, Monica E.; Prados, Michael D.; Wen, Patrick; Junck, Larry; Lieberman, Frank; Fine, Howard; Fink, Karen L.; Metha, Minesh; Kuhn, John; Lamborn, Kathleen; Chang, Susan M.; Cloughesy, Timothy; DeAngelis, Lisa M.; Robins, Ian H.; Aldape, Kenneth D.; AlfredYung, W.K.

    2016-01-01

    Purpose To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38. Design Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m2) daily for 5 days from days1to 5 every 28 days, and an i.v. infusion of irinotecan on days1and15 of each cycle. The starting dose of irinotecan was 350 mg/m2, which was escalated to 550 mg/m2 in 50-mg/m2 increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1. Results Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m2. Conclusions The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m2, administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan. PMID:18056194

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

    ClinicalTrials.gov

    2016-04-21

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

  20. Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma

    PubMed Central

    Liu, Cang; Gu, Zheng; Chen, Shizhang; Guo, Ying; Fan, Zhong; Wang, Xiao; Chen, Jianfei; Zhao, Yanyan; Zhou, Jianfeng; Wang, Jisheng; Ma, Ding; Li, Ning

    2016-01-01

    Background This randomized, open-label, multicenter, phase II clinical trial was conducted to assess the anti-tumor efficacy and safety of replication-deficient adenovirus mutant thymidine kinase (ADV-TK) in combination with ganciclovir administration in patients with recurrent high-grade glioma (HGG). Patients and Methods 53 patients with recurrent HGG were randomly allocated to receive intra-arterial cerebral infusion of ADV-TK or conventional treatments. The primary end point was 6-month progression-free survival (PFS-6). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and clinical benefit. This trial is registered with Clinicaltrials.gov, NCT00870181. Results In ADV-TK group, PFS-6 was 54.5%, the median PFS was 29.6 weeks, the median OS was 45.4 weeks, and better survivals were achieved when compared with control group. The one-year PFS and OS were 22.7% and 44.6% in ADV-TK group respectively, and clinical benefit was 68.2%. There are 2 patients alive for more than 4 years without progression in ADV-TK group. In the subgroup of glioblastoma received ADV-TK, PFS-6 was 71.4%, median PFS was 34.9 weeks, median OS was 45.7 weeks respectively, much better than those in control group. The one-year PFS and OS were 35.7% and 50.0% in ADV-TK group respectively. ADV-TK/ganciclovir gene therapy was well tolerated, and no treatment-related severe adverse events were noted. Conclusion Our study demonstrated a notable improvement of PFS-6, PFS and OS in ADV-TK treated group, and the efficacy and safety appear to be comparable to other reported treatments used for recurrent HGG. ADV-TK gene therapy is therefore a valuable therapeutic option for recurrent HGG. PMID:26716896

  1. Detection of KIAA1549-BRAF Fusion Transcripts in Formalin-Fixed Paraffin-Embedded Pediatric Low-Grade Gliomas

    PubMed Central

    Tian, Yongji; Rich, Benjamin E.; Vena, Natalie; Craig, Justin M.; MacConaill, Laura E.; Rajaram, Veena; Goldman, Stewart; Taha, Hala; Mahmoud, Madeha; Ozek, Memet; Sav, Aydin; Longtine, Janina A.; Lindeman, Neal I.; Garraway, Levi A.; Ligon, Azra H.; Stiles, Charles D.; Santagata, Sandro; Chan, Jennifer A.; Kieran, Mark W.; Ligon, Keith L.

    2011-01-01

    Alterations of BRAF are the most common known genetic aberrations in pediatric gliomas. They frequently are found in pilocytic astrocytomas, where genomic duplications involving BRAF and the poorly characterized gene KIAA1549 create fusion proteins with constitutive B-Raf kinase activity. BRAF V600E point mutations are less common and generally occur in nonpilocytic tumors. The development of BRAF inhibitors as drugs has created an urgent need for robust clinical assays to identify activating lesions in BRAF. KIAA1549-BRAF fusion transcripts have been detected in frozen tissue, however, methods for FFPE tissue have not been reported. We developed a panel of FFPE-compatible quantitative RT-PCR assays for the most common KIAA1549-BRAF fusion transcripts. Application of these assays to a collection of 51 low-grade pediatric gliomas showed 97% sensitivity and 91% specificity compared with fluorescence in situ hybridization or array comparative genomic hybridization. In parallel, we assayed samples for the presence of the BRAF V600E mutation by PCR pyrosequencing. The data further support previous observations that these two alterations of the BRAF, KIAA1549 fusions and V600E point mutations, are associated primarily with pilocytic astrocytomas and nonpilocytic gliomas, respectively. These results show that fusion transcripts and mutations can be detected reliably in standard FFPE specimens and may be useful for incorporation into future studies of pediatric gliomas in basic science or clinical trials. PMID:21884820

  2. Diffusion-weighted imaging-based probabilistic segmentation of high- and low-proliferative areas in high-grade gliomas

    PubMed Central

    Fritzsche, Klaus H.; Thieke, Christian; Klein, Jan; Parzer, Peter; Weber, Marc-André; Stieltjes, Bram

    2012-01-01

    Abstract The apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) correlates inversely with tumor proliferation rates. High-grade gliomas are typically heterogeneous and the delineation of areas of high and low proliferation is impeded by partial volume effects and blurred borders. Commonly used manual delineation is further impeded by potential overlap with cerebrospinal fluid and necrosis. Here we present an algorithm to reproducibly delineate and probabilistically quantify the ADC in areas of high and low proliferation in heterogeneous gliomas, resulting in a reproducible quantification in regions of tissue inhomogeneity. We used an expectation maximization (EM) clustering algorithm, applied on a Gaussian mixture model, consisting of pure superpositions of Gaussian distributions. Soundness and reproducibility of this approach were evaluated in 10 patients with glioma. High- and low-proliferating areas found using the clustering correspond well with conservative regions of interest drawn using all available imaging data. Systematic placement of model initialization seeds shows good reproducibility of the method. Moreover, we illustrate an automatic initialization approach that completely removes user-induced variability. In conclusion, we present a rapid, reproducible and automatic method to separate and quantify heterogeneous regions in gliomas. PMID:22487677

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

    PubMed

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

    1987-05-01

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

  4. 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

  5. Clinical Management of Seizures in Patients With Low-Grade Glioma

    PubMed Central

    Piotrowski, Anna F.; Blakeley, Jaishri

    2015-01-01

    Seizures, transient disruptions of normal brain electrical activity, are common for patients with low-grade glioma (LGG) and significantly affect quality of life. Up to 75% of patients with a LGG will have seizures in the course of their disease (compared with 1%–2% of the general population). Depending on the type of abnormal electrical activity, the functional implications of seizure can impact any domain, including mental status, sensation or strength. In most cases, either the seizure or the medications used to treat the seizure may contribute to cognitive and psychosocial difficulties of various degrees of severity. Hence, effective management of seizures is a major priority for patients with LGG. Evidence-based guidelines suggest that levetiracetam is the best first-line agent for treatment of seizures in this population due to both its efficacy and tolerability. An important consideration in the field of neuro-oncology is that levetiracetam has very few drug interactions. Unfortunately, approximately one-third of patients with LGG have refractory epilepsy where additional agents such as valproic acid, or lacosamide, lamotrigine and nonpharmacologic therapies such as diet-based interventions, epilepsy surgery, and devices are considered. PMID:26050593

  6. The Changing Landscape of Pediatric Low-Grade Gliomas: Clinical Challenges and Emerging Therapies.

    PubMed

    Guerreiro Stucklin, Ana S; Tabori, Uri; Grotzer, Michael A

    2016-04-01

    Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. Though histologically benign and associated with excellent outcome, patients with unresectable lesions-mostly young children with midline tumors-experience multiple progressions and are at increased risk for long-term neurological sequelae. PLGGs in children with underlying genetic predisposition syndromes-especially neurofibromatosis type 1 and tuberous sclerosis-have a distinct natural history and biology with important treatment implications. Given the complexity of medical issues, optimal management requires a large network of health care providers; treatment decisions must address both tumor control and potential side effects of the therapy. Current treatment strategies often fail to induce sustained tumor regression and many children require several lines of therapy, highlighting the need for novel therapies. Here, we review the current management of PLGG and discuss how new molecular targets-in particular alterations of the Ras/MAPK pathway-are rapidly changing our approach to PLGG. PMID:26764564

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

    PubMed

    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

    2011-03-01

    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

  8. 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

  9. Alisertib and Fractionated Stereotactic Radiosurgery in Treating Patients With Recurrent High Grade Gliomas

    ClinicalTrials.gov

    2016-04-11

    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

  10. The effect of pregnancy on survival in a low-grade glioma cohort.

    PubMed

    Rønning, Pål A; Helseth, Eirik; Meling, Torstein R; Johannesen, Tom B

    2016-08-01

    OBJECTIVE The impact of pregnancy on survival in female patients with low-grade glioma (LGG) is unknown and controversial. The authors designed a retrospective cohort study on prospectively collected registry data to assess the influence of pregnancy and child delivery on the survival of female patients with LGG. METHODS In Norway, the reporting of all births and cancer diagnoses to the Medical Birth Registry of Norway (MBRN) and the Cancer Registry of Norway (CRN), respectively, is compulsory by law. Furthermore, every individual has a unique 11-digit identification number. The CRN was searched to identify all female patients with a histologically confirmed diagnosis of World Health Organization (WHO) Grade II astrocytoma, oligoastrocytoma, oligodendroglioma, or pilocytic astrocytoma who were 16-40 years of age at the time of diagnosis during the period from January 1, 1970, to December 31, 2008. Obstetrical information was obtained from the MBRN for each patient. The effect of pregnancy on survival was evaluated using a Cox model with parity as a time-dependent variable. RESULTS The authors identified 65 patients who gave birth to 95 children after an LGG diagnosis. They also identified 281 patients who did not give birth after an LGG diagnosis. The median survival was 14.3 years (95% CI 11.7-20.6 years) for the entire study population. The effect of pregnancy was insignificant in the multivariate model (HR 0.71, 95% CI 0.35-1.42). CONCLUSIONS Pregnancy does not seem to have an impact on the survival of female patients with LGG. PMID:26722849

  11. Two-peaked 5-ALA-induced PpIX fluorescence emission spectrum distinguishes glioblastomas from low grade gliomas and infiltrative component of glioblastomas

    PubMed Central

    Montcel, Bruno; Mahieu-Williame, Laurent; Armoiry, Xavier; Meyronet, David; Guyotat, Jacques

    2013-01-01

    5-ALA-induced protoporphyrin IX (PpIX) fluorescence enables to guiding in intra-operative surgical glioma resection. However at present, it has yet to be shown that this method is able to identify infiltrative component of glioma. In extracted tumor tissues we measured a two-peaked emission in low grade gliomas and in the infiltrative component of glioblastomas due to multiple photochemical states of PpIX. The second emission peak appearing at 620 nm (shifted by 14 nm from the main peak at 634 nm) limits the sensibility of current methods to measured PpIX concentration. We propose new measured parameters, by taking into consideration the two-peaked emission, to overcome these limitations in sensitivity. These parameters clearly distinguish the solid component of glioblastomas from low grade gliomas and infiltrative component of glioblastomas. PMID:23577290

  12. 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.

  13. Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas

    PubMed Central

    Ye, Xiaobu; Gladstone, Douglas E.; Ambady, Prakash; Nirschl, Thomas R.; Borrello, Ivan; Golightly, Marc; King, Karen E.; Holdhoff, Matthias; Karp, Judith; Drake, Charles G.; Grossman, Stuart A.

    2015-01-01

    Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and assessed safety, feasibility, and trends in lymphocyte counts. Patients with newly diagnosed HGG and total lymphocyte counts (TLC) ≥ 1000 cells/mm3 underwent apheresis. Cryopreserved autologous lymphocytes were reinfused once radiation was completed. Safety, feasibility, and trends in TLC, T cell subsets and cytokines were studied. Serial TLC were also compared with an unreinfused matched control group. Ten patients were harvested (median values: age 56 years, dexamethasone 3 mg/day, TLC/CD4 1980/772 cells/mm3). After 6 weeks of RT/TMZ, TLC fell 69 % (p < 0.0001) with similar reductions in CD4, CD8 and NK cells but not Tregs. Eight patients received lymphocyte reinfusions (median = 7.0 × 107 lymphocytes/kg) without adverse events. A post-reinfusion TLC rise of ≥300 cells/mm3 was noted in 3/8 patients at 4 weeks and 7/8 at 14 weeks which was similar to 23 matched controls. The reduced CD4/CD8 ratio was not restored by lymphocyte reinfusion. Severe lymphopenia was not accompanied by elevated serum interleukin-7 (IL-7) levels. This study confirms that severe TRL is common in HGG and is not associated with high plasma IL-7 levels. Although lymphocyte harvesting/rein-fusion is feasible and safe, serial lymphocyte counts are similar to unreinfused matched controls. Studies administering higher lymphocyte doses and/or IL-7 should be considered to restore severe treatment-related lymphopenia in HGG. PMID:26070554

  14. Apparent diffusion coefficient and fractional anisotropy of newly diagnosed grade II gliomas.

    PubMed

    Khayal, Inas S; McKnight, Tracy R; McGue, Colleen; Vandenberg, Scott; Lamborn, Kathleen R; Chang, Susan M; Cha, Soonmee; Nelson, Sarah J

    2009-05-01

    Distinguishing between low-grade oligodendrogliomas (ODs) and astrocytomas (AC) is of interest for defining prognosis and stratifying patients to specific treatment regimens. The purpose of this study was to determine if the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) from diffusion imaging can help to differentiate between newly diagnosed grade II OD and AC subtypes and to evaluate the ADC and FA values for the mixed population of oligoastrocytomas (OA). Fifty-three patients with newly diagnosed grade II gliomas were studied using a 1.5T whole body scanner (23 ODs, 16 ACs, and 14 OAs). The imaging protocol included post-gadolinium T1-weighted images, T2-weighted images, and either three and/or six directional diffusion imaging sequence with b = 1000 s/mm(2). Diffusion-weighted images were analyzed using in-house software to calculate maps of ADC and for six directional acquisitions, FA. The intensity values were normalized by values from normal appearing white matter (NAWM) to generate maps of normalized apparent diffusion coefficient (nADC) and normalized fractional anisotropy (nFA). The hyperintense region in the T2 weighted image was defined as the T2All region. A Mann-Whitney rank-sum test was performed on the 25th, median, and 75th nADC and nFA among the three subtypes. Logistic regression was performed to determine how well the nADC and nFA predict subtype. Lesions diagnosed as being OD had significantly lower nADC and significantly higher nFA, compared to AC. The nADC and nFA values individually classified the data with an accuracy of 87%. Combining the two did not enhance the classification. The patients with OA had nADC and nFA values between those of OD and AC. This suggests that ADC and FA may be helpful in directing tissue sampling to the most appropriate regions for taking biopsies in order to make a definitive diagnosis. PMID:19125391

  15. Biomarkers predictive of venous thromboembolism in patients with newly diagnosed high-grade gliomas

    PubMed Central

    Thaler, Johannes; Ay, Cihan; Kaider, Alexandra; Reitter, Eva-Maria; Haselböck, Johanna; Mannhalter, Christine; Zielinski, Christoph; Marosi, Christine; Pabinger, Ingrid

    2014-01-01

    Background High-grade gliomas (HGGs) are among the most prothrombotic of malignancies. Methods We performed a prospective study to investigate 11 potential biomarkers for prediction of venous thromboembolism (VTE) in newly diagnosed HGG patients who had undergone a neurosurgical intervention. In addition, we tested 2 VTE risk assessment models (RAMs). The strongest predictors of VTE, which were identified by statistical forward selection, were used for the first RAM. The parameters used for the second RAM were both predictive of VTE and available in routine clinical practice. Results One hundred forty-one HGG patients were included in this study, and 24 (17%) of them developed VTE during follow-up. An association with the risk of future VTE was found for the following parameters: leukocyte count, platelet count, sP-selectin, prothrombin-fragment 1 + 2, FVIII activity, and D-dimer. The first RAM included low platelet count (<25th percentile of the study population) and elevated sP-selectin (≥75th percentile). The cumulative VTE probability after 12 months was 9.7% for score 0 (n = 76), 18.9% for score 1 (n = 59), and 83.3% for score 2 (n = 6). The second RAM included low platelet count (<25th percentile), elevated leukocyte count, and elevated D-dimer (≥75th percentile). The probability of VTE was 3.3% for score 0 (n = 63), 23.0% for score 1 (n = 53), and 37.7% for score 2 (n = 22) or score 3 (n = 3). Conclusions We identified biomarkers suitable for assessing the VTE risk in newly diagnosed HGG patients. The application of 2 RAMs allowed identification of patients at high risk of developing VTE. We could also define patients at low risk of VTE, who would most probably not benefit from extended primary thromboprophylaxis. PMID:24987133

  16. Longitudinal Investigation of Adaptive Functioning following Conformal Irradiation for Pediatric Craniopharyngioma and Low-Grade Glioma

    PubMed Central

    Netson, Kelli L.; Conklin, Heather M.; Wu, Shengjie; Xiong, Xiaoping; Merchant, Thomas E.

    2013-01-01

    Purpose Children treated for brain tumors with conformal radiation therapy experience preserved cognitive outcomes. Early evidence suggests that adaptive functions or independent living skills may be spared. This longitudinal investigation prospectively examined intellectual and adaptive functioning during the first 5 years following irradiation for childhood craniopharyngioma and low-grade glioma (LGG). The effect of visual impairment on adaptive outcomes was investigated. Methods and Materials Children with craniopharyngioma (n=62) and LGG (n=77) were treated using conformal or intensity-modulated radiation therapy. The median age was 8.05 years (3.21 years –17.64 years) and 8.09 years (2.20 years–19.27 years), respectively. Serial cognitive evaluations including measures of intelligence quotient (IQ) and the Vineland Adaptive Behavior Scales (VABS) were conducted at pre-irradiation baseline, 6 months after treatment, and annually through 5 years. A total of 588 evaluations were completed during the follow-up period. Results Baseline assessment revealed no deficits in IQ and VABS indices for children with craniopharyngioma, with significant (p < .05) longitudinal decline in VABS Communication and Socialization indices. Clinical factors associated with more rapid decline included females and pre-irradiation chemotherapy (interferon). The only change in VABS Daily Living Skills correlated with IQ change (r = .34; p = .01) in children with craniopharyngioma. Children with LGG performed below population norms (p < .05) at baseline on VABS Communication, Daily Living Indices, and the Adaptive Behavior Composite, with significant (p < .05) longitudinal decline limited to VABS Communication. Older age at irradiation was a protective factor against longitudinal decline. Severe visual impairment did not independently correlate with poorer adaptive outcomes for either tumor group. Conclusions There was relative sparing of post-irradiation functional outcomes over time

  17. Longitudinal Investigation of Adaptive Functioning Following Conformal Irradiation for Pediatric Craniopharyngioma and Low-Grade Glioma

    SciTech Connect

    Netson, Kelli L.; Conklin, Heather M.; Wu, Shengjie; Xiong, Xiaoping; Merchant, Thomas E.

    2013-04-01

    Purpose: Children treated for brain tumors with conformal radiation therapy experience preserved cognitive outcomes. Early evidence suggests that adaptive functions or independent-living skills may be spared. This longitudinal investigation prospectively examined intellectual and adaptive functioning during the first 5 years following irradiation for childhood craniopharyngioma and low-grade glioma (LGG). The effect of visual impairment on adaptive outcomes was investigated. Methods and Materials: Children with craniopharyngioma (n=62) and LGG (n=77) were treated using conformal or intensity modulated radiation therapy. The median age was 8.05 years (3.21-17.64 years) and 8.09 years (2.20-19.27 years), respectively. Serial cognitive evaluations including measures of intelligence quotient (IQ) and the Vineland Adaptive Behavior Scales (VABS) were conducted at preirradiation baseline, 6 months after treatment, and annually through 5 years. Five hundred eighty-eight evaluations were completed during the follow-up period. Results: Baseline assessment revealed no deficits in IQ and VABS indices for children with craniopharyngioma, with significant (P<.05) longitudinal decline in VABS Communication and Socialization indices. Clinical factors associated with more rapid decline included females and preirradiation chemotherapy (interferon). The only change in VABS Daily Living Skills correlated with IQ change (r=0.34; P=.01) in children with craniopharyngioma. Children with LGG performed below population norms (P<.05) at baseline on VABS Communication, Daily Living Indices, and the Adaptive Behavior Composite, with significant (P<.05) longitudinal decline limited to VABS Communication. Older age at irradiation was a protective factor against longitudinal decline. Severe visual impairment did not independently correlate with poorer adaptive outcomes for either tumor group. Conclusions: There was relative sparing of postirradiation functional outcomes over time in this sample

  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. A disconnection account of subjective empathy impairments in diffuse low-grade glioma patients.

    PubMed

    Herbet, Guillaume; Lafargue, Gilles; Moritz-Gasser, Sylvie; Menjot de Champfleur, Nicolas; Costi, Emanuele; Bonnetblanc, François; Duffau, Hugues

    2015-04-01

    Human empathic experience is a multifaceted psychological construct which arises from functional integration of multiple neural networks. Despite accumulating knowledge about the cortical circuitry of empathy, almost nothing is known about the connectivity that may be concerned in conveying empathy-related neural information. To bridge this gap in knowledge, we studied dispositional empathy in a large-sized cohort of 107 patients who had undergone surgery for a diffuse low-grade glioma. The self-report questionnaire used enabled us to obtain a global measure of subjective empathy but also, importantly, to assess the two main components of empathy (cognitive and emotional). Data were processed by combining voxelwise and tractwise lesion-symptom analyses. Several major findings emerged from our analyses. First of all, topological voxelwise analyses were inconclusive. Conversely, tractwise multiple regression analyses, including all major associative white matter pathways as potential predictors, yielded to significant models explaining substantial part of the behavioural variance. Among the main results, we found that disconnection of the left cingulum bundle was a strong predictor of a low cognitive empathy (p<0.0005 Bonferroni-corrected). Similarly, we found that disconnection of the right uncinate fasciculus and the right inferior fronto-occipital fasciculus predicted, respectively, a low (p<0.05 Bonferroni-corrected) and a high (p<0.05 Bonferroni-corrected) subjective empathy. Finally, although we failed to relate emotional empathy to disruption of a specific tract, correlation analyses indicated a positive association between this component of empathy and the volumes of residual lesion infiltration in the right hemisphere (p<0.01). Taken as a whole, these findings provide key fundamental insights into the anatomical connectivity of empathy. They may help to better understand the pathophysiology of empathy impairments in pathological conditions characterized by

  20. 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. PMID:26293621

  1. 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

  2. Molecular fingerprinting reflects different histotypes and brain region in low grade gliomas

    PubMed Central

    2013-01-01

    Background Paediatric low-grade gliomas (LGGs) encompass a heterogeneous set of tumours of different histologies, site of lesion, age and gender distribution, growth potential, morphological features, tendency to progression and clinical course. Among LGGs, Pilocytic astrocytomas (PAs) are the most common central nervous system (CNS) tumours in children. They are typically well-circumscribed, classified as grade I by the World Health Organization (WHO), but recurrence or progressive disease occurs in about 10-20% of cases. Despite radiological and neuropathological features deemed as classic are acknowledged, PA may present a bewildering variety of microscopic features. Indeed, tumours containing both neoplastic ganglion and astrocytic cells occur at a lower frequency. Methods Gene expression profiling on 40 primary LGGs including PAs and mixed glial-neuronal tumours comprising gangliogliomas (GG) and desmoplastic infantile gangliogliomas (DIG) using Affymetrix array platform was performed. A biologically validated machine learning workflow for the identification of microarray-based gene signatures was devised. The method is based on a sparsity inducing regularization algorithm l1l2 that selects relevant variables and takes into account their correlation. The most significant genetic signatures emerging from gene-chip analysis were confirmed and validated by qPCR. Results We identified an expression signature composed by a biologically validated list of 15 genes, able to distinguish infratentorial from supratentorial LGGs. In addition, a specific molecular fingerprinting distinguishes the supratentorial PAs from those originating in the posterior fossa. Lastly, within supratentorial tumours, we also identified a gene expression pattern composed by neurogenesis, cell motility and cell growth genes which dichotomize mixed glial-neuronal tumours versus PAs. Our results reinforce previous observations about aberrant activation of the mitogen-activated protein kinase

  3. 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 ...

  4. 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.

  5. A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma.

    PubMed

    Au, Karolyn; Singh, Sanjay K; Burrell, Kelly; Sabha, Nesrin; Hawkins, Cynthia; Huang, Annie; Zadeh, Gelareh

    2015-05-01

    Solid tumors arising from malignant transformation of glial cells are one of the leading causes of central nervous system tumor-related death in children. Recurrence in spite of rigorous surgical and chemoradiation therapies remains a major hurdle in management of these tumors. Here, we investigate the efficacy of the second-generation receptor tyrosine kinase inhibitor nilotinib as a therapeutic option for the management of pediatric gliomas. We have utilized two independent pediatric high-grade glioma cell lines with either high platelet-derived growth factor receptor alpha (PDGFRα) or high PDGFRβ expression in in vitro assays to investigate the specific downstream effects of nilotinib treatment. Using in vitro cell-based assays we show that nilotinib inhibits PDGF-BB-dependent activation of PDGFRα. We further show that nilotinib is able to decrease cell proliferation and anchorage-independent growth via suppression of AKT and ERK1/2 signaling pathways. Our results suggest that nilotinib may be effective for management of a PDGFRα-dependent group of pediatric gliomas. PMID:25732621

  6. Early change in glucose metabolic rate measured using FDG-PET in patients with high-grade glioma predicts response to temozolomide but not temozolomide plus radiotherapy

    SciTech Connect

    Charnley, Natalie . E-mail: natalie.charnley@mmic.man.ac.uk; West, Catharine M.; Barnett, Carolyn M.; Brock, Catherine; Bydder, Graeme M.; Glaser, Mark; Newlands, Ed S.; Swindell, Ric; Matthews, Julian; Price, Pat

    2006-10-01

    Purpose: To compare the ability of positron emission tomography (PET) to predict response to temozolomide vs. temozolomide plus radiotherapy. Methods and Materials: Nineteen patients with high-grade glioma (HGG) were studied. Patients with recurrent glioma received temozolomide 75 mg/m{sup 2} daily for 7 weeks (n = 8). Newly diagnosed patients received temozolomide 75 mg/m{sup 2} daily plus radiotherapy 60 Gy/30 fractions over 6 weeks, followed by six cycles of adjuvant temozolomide 200 mg/m{sup 2}/day (Days 1-5 q28) starting 1 month after radiotherapy (n = 11). [{sup 18}F]Fluorodeoxyglucose ([{sup 18}F]FDG) PET scan and magnetic resonance imaging (MRI) were performed at baseline, and 7 and 19 weeks after initiation of temozolomide administration. Changes in glucose metabolic rate (MRGlu) and MRI response were correlated with patient survival. Results: In the temozolomide-alone group, patients who survived >26 vs. {<=}26 weeks showed a greater reduction in MRGlu measured at 7 weeks with median changes of -34% and -4%, respectively (p = 0.02). PET responders, defined as a reduction in MRGlu {>=}25%, survived longer than nonresponders with mean survival times of 75 weeks (95% CI, 34-115 vs. 20 weeks (95% CI, 14-26) (p = 0.0067). In the small group of patients studied, there was no relationship between MRI response and survival (p = 0.52). For patients receiving temozolomide plus radiotherapy, there was no difference in survival between PET responders and nonresponders (p = 0.32). Conclusions: Early changes in MRGlu predict response to temozolomide, but not temozolomide plus radiotherapy.

  7. Differential expression of miR200a-3p and miR21 in grade II–III and grade IV gliomas

    PubMed Central

    Berthois, Yolande; Delfino, Christine; Metellus, Philippe; Fina, Frederic; Nanni-Metellus, Isabelle; Al Aswy, Hayat; Pirisi, Victor; Ouafik, L’Houcine; Boudouresque, Françoise

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumor and is among the deadliest of human cancers. Dysregulation of microRNAs (miRNAs) expression is an important step in tumor progression as miRNAs can act as tumor suppressors or oncogenes and may affect cell sensitivity to chemotherapy. Whereas the oncogenic miR21 has been shown to be overexpressed in gliomas, the expression and function of the tumor-supressor miR200a in GBMs remains unknown. In this study, we show that miR21 is upregulated in grade IV (GBMs) vs. grade II–III (LGs) gliomas, confirming that miR21 expression level is correlated with tumor grade, and that it may be considered as a marker of tumor progression. Conversely, miR200a is demonstrated for the first time to be downregulated in GBMs compared with LGs, and overexpression of miR200a in GBM cells is shown to promote TMZ-sensitivity. Interestingly, miR200a but not miR21 expression level is significantly higher in TMZ-responsive vs. -unresponsive tumoral glial cells in primary culture. Furthermore, miR200a appears negatively correlated with the expression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), and the inhibition of MGMT activity results in an increase of miR200a expression in GBM cells. Taken together, these data strongly suggest that miR200a is likely to act as a crucial antitumoral factor regarding glioma progression. Interplay between miR200a and MGMT should be considered as potential mechanism involved in therapeutic response. PMID:24755707

  8. BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 Proteins Are Related to Human Glioma Tumor Grade: Immunohistochemistry and Public Microarray Data Meta-Analysis

    PubMed Central

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

    2013-01-01

    Gliomas are common and lethal tumors of the central nervous system (CNS). Genetic alterations, inflammatory and angiogenic processes have been identified throughout tumor progression; however, treatment still remains palliative for most cases. Biological research on parameters influencing cell survival, invasion and tumor heterogeneity identified several cytokines interfering in CNS inflammation, oxidative stress and malignant transformation, including TNF-superfamily (TNFSF) members. In this report we performed a meta-analysis of public gene-array data on the expression of a group of TNFSF ligands (BAFF, APRIL, TWEAK) and their receptors (BAFF-R, TACI, BCMA, Fn14) in gliomas. In addition, we investigated by immunohistochemistry (IHC) the tumor cells' expression of these ligands and receptors in a series of 56 gliomas of different grade. We show that in IHC, BAFF and APRIL as well as their cognate receptors (BCMA, TACI) and Fn14 expression correlate with tumor grade. This result was not evidenced in micro-arrays meta-analysis. Finally, we detected for the first time Fn14, BAFF, BCMA and TACI in glioma-related vascular endothelium. Our data, combined with our previous report in glioma cell lines, suggest a role for these receptors and ligands in glioma biology and advance these molecules as potential markers for the classification of these tumors to the proliferative, angiogenic or stem-like molecular subtype. PMID:24376672

  9. GE-01MOLECULAR AND PATHOLOGIC SUBSETS OF LOW GRADE GLIOMAS AND GLIONEURONAL TUMORS IDENTIFIED BY microRNA PROFILING

    PubMed Central

    Ames, Heather; Vizcaino, M. Adelita; Rodriguez, Fausto

    2014-01-01

    Low-grade (WHO I-II) gliomas represent the most frequent primary tumors of the central nervous system in children. They often have a good prognosis following total resection, however they can create many neurological complications due to mass effect, and may be difficult to resect depending on anatomic location. MicroRNAs have been identified as molecular regulators of protein expression that can repress multiple mRNAs concurrently through base pairing. Specific microRNAs are often suppressed during early cell differentiation to promote the expression of mitogenic proteins that are associated with the maintenance of specific stem cell types, a mechanism for growth and survival that is frequently exploited in cancer cells. Identification of these microRNA signatures present in low grade glioma and glioneuronal tumor sub-types could therefore lead to a wealth of candidate biomarkers. We used NanoString technology to analyze the expression levels of 800 microRNAs in nine low-grade glial and glioneuronal tumor subtypes (n = 45) using formalin-fixed paraffin-embedded tissue. We then generated hierarchical clusters following evaluation via significant analysis of microarrays (SAMs). Hierarchical clustering separated tumors from non-neoplastic brain. When looking at individual tumors, subependymal giant cell astrocytomas (SEGA) clustered sharply together, consistent with a unique microRNA expression signature in this tuberous sclerosis associated tumor subtype, compared to other low grade glial and glioneuronal tumors. Candidate microRNAs were validated using qRT-PCR. In SEGAs, microRNAs miR-219-5p, miR-129-2-3p, miR-338-3p, miR-487b, miR-885-5p, and miR-323-3p were significantly down-regulated by more than 15 fold as compared to normal brain and were also significantly down-regulated as compared to other low grade gliomas. In summary, altered microRNA expression is a feature of low grade glial and glioneuronal tumors. MicroRNA profiling may therefore be useful in

  10. 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

  11. 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

  12. Detection of Human Herpesvirus-6 Variants in Pediatric Brain Tumors: Association of Viral Antigen in Low Grade Gliomas

    PubMed Central

    Crawford, John R.; Santi, Maria R.; Thorarinsdottir, Halldora K.; Cornelison, Robert; Rushing, Elisabeth J.; Zhang, Huizhen; Yao, Karen; Jacobson, Steven; MacDonald, Tobey J.

    2009-01-01

    Background Human Herpesvirus-6 (HHV-6) has been associated with a diverse spectrum of central nervous system (CNS) diseases and reported glial tropism. Objective To determine if HHV-6 is present in a series of pediatric brain tumors. Study Design Pediatric gliomas from 88 untreated patients represented in a tissue microarray (TMA) were screened for HHV-6 by nested polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemistry (IHC) and compared to non glial tumors (N=22) and control brain (N=32). Results were correlated with tumor grade and overall survival. Results HHV-6 U57 was detected by nested PCR in 68/120 (57%) tumors and 7/32 (22%) age-matched non-tumor brain (P=0.001). HHV-6 U31 was positive in 73/120 (61%) tumors and 11/32 (34%) controls (P=0.019). Seventy-two percent (43/60) of tumors were HHV-6 Variant A. HHV-6 U57 was confirmed by ISH in 83/150 (54%) tumors and 10/32 (31%) controls (P=0.021), revealing a non-lymphocytic origin of HHV-6. HHV-6A/B gp116/64/54 late antigen was detected by IHC in 50/124 (40%) tumors and 6/32 (18%) controls (P=0.013). Interestingly, 58% of low grade gliomas (N=67) were IHC positive compared to 19% of high grade gliomas (N=21, P=0.002) and 25% of non gliomas (N=36; P=0.001). HHV-6A/B gp116/64/54 antigen co-localized with glial fibrillary acidic protein, confirming the astrocytic origin of antigen. Overall, there was no primary association between HHV-6A/B gp116/64/54 antigen detection and survival (P=0.861). Conclusions We provide the first reported series of HHV-6 detection in pediatric brain tumors. The predominance of HHV-6 in glial tumors warrants further investigation into potential neurooncologic disease mechanisms. PMID:19505845

  13. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients.

    PubMed

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  14. Indications for Treatment: Is Observation or Chemotherapy Alone a Reasonable Approach in the Management of Low-Grade Gliomas?

    PubMed

    Schaff, Lauren R; Lassman, Andrew B

    2015-07-01

    The treatment of newly diagnosed low-grade gliomas remains controversial. Recently published results from the long-term follow-up of Radiation Therapy Oncology Group (RTOG) trial 9802 demonstrated medically meaningful and statistically significant survival prolongation by adding chemotherapy with procarbazine, lomustine (CCNU), and vincristine after radiotherapy (RT) vs RT alone for "high"-risk patients (median 13.3 vs 7.8 years, hazard ratio = 0.59, P = 0.03). However, in the 17 years since that trial was launched, there have been advances in the understanding of low-grade gliomas biology and patient heterogeneity, an increased recognition of late neurocognitive injury from early RT, and the emergence of temozolomide as an alternative chemotherapy to procarbazine, lomustine (CCNU), and vincristine. These and other changes in the treatment landscape make the applicability of results from RTOG 9802 to all patients less clear. Moreover, in some patients, especially those at the lowest risk for early disease progression, deferred RT in favor of active surveillance or chemotherapy alone may remain a reasonable treatment approach. PMID:26050591

  15. Cognitive function after radiotherapy for supratentorial low-grade glioma: A North Central Cancer Treatment Group prospective study

    SciTech Connect

    Laack, Nadia N.; Brown, Paul D. . E-mail: brown.paul@mayo.edu; Ivnik, Robert J.; Furth, Alfred F. M.S.; Ballman, Karla V.; Hammack, Julie E.; Arusell, Robert M.; Shaw, Edward G.; Buckner, Jan C.

    2005-11-15

    Purpose: To evaluate the effects of cranial radiotherapy (RT) on cognitive function in patients with supratentorial low-grade glioma. Methods and Materials: Twenty adult patients with supratentorial low-grade glioma were treated with 50.4 Gy (10 patients) or 64.8 Gy (10 patients) localized RT. The patients then were evaluated with an extensive battery of psychometric tests at baseline (before RT) and at approximately 18-month intervals for as long as 5 years after completing RT. To allow patients to serve as their own controls, cognitive performance was evaluated as change in scores over time. All patients underwent at least two evaluations. Results: Baseline test scores were below average compared with age-specific norms. At the second evaluation, the groups' mean test scores were higher than their initial performances on all psychometric measures, although the improvement was not statistically significant. No changes in cognitive performance were seen during the evaluation period when test scores were analyzed by age, treatment, tumor location, tumor type, or extent of resection. Conclusions: Cognitive function was stable after RT in these patients evaluated prospectively during 3 years of follow-up. Slight improvements in some cognitive areas are consistent with practice effects attributable to increased familiarity with test procedures and content.

  16. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients

    PubMed Central

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  17. 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

  18. Preoperative Quantitative MR Tractography Compared with Visual Tract Evaluation in Patients with Neuropathologically Confirmed Gliomas Grades II and III: A Prospective Cohort Study

    PubMed Central

    Delgado, Anna F.; Nilsson, Markus; Latini, Francesco; Mårtensson, Johanna; Zetterling, Maria; Berntsson, Shala G.; Alafuzoff, Irina; Lätt, Jimmy; Larsson, Elna-Marie

    2016-01-01

    Background and Purpose. Low-grade gliomas show infiltrative growth in white matter tracts. Diffusion tensor tractography can noninvasively assess white matter tracts. The aim was to preoperatively assess tumor growth in white matter tracts using quantitative MR tractography (3T). The hypothesis was that suspected infiltrated tracts would have altered diffusional properties in infiltrated tract segments compared to noninfiltrated tracts. Materials and Methods. Forty-eight patients with suspected low-grade glioma were included after written informed consent and underwent preoperative diffusion tensor imaging in this prospective review-board approved study. Major white matter tracts in both hemispheres were tracked, segmented, and visually assessed for tumor involvement in thirty-four patients with gliomas grade II or III (astrocytomas or oligodendrogliomas) on postoperative neuropathological evaluation. Relative fractional anisotropy (rFA) and mean diffusivity (rMD) in tract segments were calculated and compared with visual evaluation and neuropathological diagnosis. Results. Tract segment infiltration on visual evaluation was associated with a lower rFA and high rMD in a majority of evaluated tract segments (89% and 78%, resp.). Grade II and grade III gliomas had similar infiltrating behavior. Conclusion. Quantitative MR tractography corresponds to visual evaluation of suspected tract infiltration. It may be useful for an objective preoperative evaluation of tract segment involvement. PMID:27190647

  19. Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas

    PubMed Central

    Sarmiento, J Manuel; Venteicher, Andrew S; Patil, Chirag G

    2015-01-01

    Background In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. Objectives To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection. Search methods We searched up to September 2014 the following electronic databases: the Cochrane Register of Controlled Trials (CENTRAL, Issue 8, 2014), MEDLINE (1948 to Aug week 3, 2014), and EMBASE (1980 to Aug week 3, 2014) to identify trials for inclusion in this Cochrane review. Selection criteria We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity-modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS). Data collection and analysis Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random-effects model with inverse variance weighting. Main results We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy is associated with an increase in time to

  20. The Clinical Implications of Human Telomerase Reverse Transcriptase Expression in Grade and Prognosis of Gliomas: a Systematic Review and Meta-analysis.

    PubMed

    Li, Jing; Li, Huiying; Liu, Jihong; Feng, Bin; Feng, Man; Lv, Baoyu; Cheng, Shaomei; Yang, Xiangshan

    2016-07-01

    Human telomerase reverse transcriptase (hTERT), a ribonucleoprotein, is reported as an important complex, which is required for stability of DNA molecular structure at the rear of the chromosome. Until now, hTERT has been linked to cell immortalization and tumorigenesis. A couple of articles have been published about the telomerase function in the gliomas; however, these results are conflicting in some degree. Thus, it is crucial to perform a meta-analysis to identify their real actions. We included eligible articles, and estimated odds ratios (ORs) with 95 % confidence intervals (95 % CIs). In our meta-analysis, all 15 eligible articles included 932 patients. Results from 10 studies on WHO grade showed that high hTERT gene or protein expression in glioma tissues was obviously related to high WHO grade (III + IV) (OR 2.45, 95 % CI 1.92-3.13; p = 0.000). What is more, hTERT expression was not associated with old age (OR 0.91, 95 % CI 0.72-1.16; p = 0.448) as well as gender (OR 1.06, 95 % CI 0.82-1.37; p = 0.664). Importantly, hTERT expression was significantly associated with 5-year overall survival (OS; n = 3; hazard ratio (HR) 2.25, 95 % CI 1.36-3.70; p = 0.002) of glioma patients. No heterogeneity was found in all studies. In conclusion, this meta-analysis suggests that hTERT is significantly associated with high glioma grade and poor 5-year overall survival, and pathological test of hTERT mRNA and protein in glioma tissues should be suggested as criteria of glioma grade in the clinical practice. PMID:25895660

  1. 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.

  2. 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.

  3. 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

  4. A systematic pipeline for the objective comparison of whole-brain spectroscopic MRI with histology in biopsy specimens from grade III glioma

    PubMed Central

    Cordova, J. Scott; Gurbani, Saumya S.; Olson, Jeffrey J.; Liang, Zhongxing; Cooper, Lee A. D.; Shu, Hui-Kuo G.; Schreibmann, Eduard; Neill, Stewart G.; Hadjipanayis, Constantinos G.; Holder, Chad A.; Shim, Hyunsuk

    2016-01-01

    The diagnosis, prognosis, and management of patients with gliomas are largely dictated by the pathological analysis of tissue biopsied from a selected region within the lesion. However, due to the heterogeneous and infiltrative nature of gliomas, identifying the optimal region for biopsy with conventional magnetic resonance imaging (MRI) can be quite difficult. This is especially true for low grade gliomas, which often are non-enhancing tumors. To improve the management of patients with these tumors, the field of neuro-oncology requires an imaging modality that can specifically identify a tumor’s most anaplastic/aggressive region(s) for biopsy targeting. The addition of metabolic mapping using spectroscopic MRI (sMRI) to supplement conventional MRI could improve biopsy targeting and, ultimately, diagnostic accuracy. Here, we describe a pipeline for the integration of state-of-the-art, high-resolution whole-brain 3D sMRI maps into a stereotactic neuronavigation system for guiding biopsies in gliomas with nonenhancing components. We also outline a machine-learning method for automated histology analysis that generates normalized, quantitative metrics describing tumor infiltration in immunohistochemically-stained tissue specimens. As a proof of concept, we describe the combination of these two techniques in a small cohort of grade III glioma patients. In this work, we aim to set forth a systematic pipeline to stimulate histopathology-image validation of advanced MRI techniques, such as sMRI. PMID:27489883

  5. 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

  6. 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

  7. Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity.

    PubMed

    Ricklefs, Franz; Mineo, Marco; Rooj, Arun K; Nakano, Ichiro; Charest, Al; Weissleder, Ralph; Breakefield, Xandra O; Chiocca, E Antonio; Godlewski, Jakub; Bronisz, Agnieszka

    2016-05-15

    A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high-grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications; however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EVs isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargos transferred between proneural and mesenchymal GSC increased protumorigenic behaviors in vitro and in vivo Clinically, analyses of HGG patient data from the The Cancer Genome Atlas database revealed that proneural tumors with mesenchymal EV signatures or mesenchymal tumors with proneural EV signatures were both associated with worse outcomes, suggesting influences by the proportion of tumor cells of varying subtypes in tumors. Collectively, our findings illuminate the heterogeneity among tumor EVs and the complexity of HGG heterogeneity, which these EVs help to maintain. Cancer Res; 76(10); 2876-81. ©2016 AACR. PMID:27013191

  8. Delay effects in the response of low-grade gliomas to radiotherapy: a mathematical model and its therapeutical implications.

    PubMed

    Pérez-García, Víctor M; Bogdanska, Magdalena; Martínez-González, Alicia; Belmonte-Beitia, Juan; Schucht, Philippe; Pérez-Romasanta, Luis A

    2015-09-01

    Low-grade gliomas (LGGs) are a group of primary brain tumours usually encountered in young patient populations. These tumours represent a difficult challenge because many patients survive a decade or more and may be at a higher risk for treatment-related complications. Specifically, radiation therapy is known to have a relevant effect on survival but in many cases it can be deferred to avoid side effects while maintaining its beneficial effect. However, a subset of LGGs manifests more aggressive clinical behaviour and requires earlier intervention. Moreover, the effectiveness of radiotherapy depends on the tumour characteristics. Recently Pallud et al. (2012. Neuro-Oncology, 14: , 1-10) studied patients with LGGs treated with radiation therapy as a first-line therapy and obtained the counterintuitive result that tumours with a fast response to the therapy had a worse prognosis than those responding late. In this paper, we construct a mathematical model describing the basic facts of glioma progression and response to radiotherapy. The model provides also an explanation to the observations of Pallud et al. Using the model, we propose radiation fractionation schemes that might be therapeutically useful by helping to evaluate tumour malignancy while at the same time reducing the toxicity associated to the treatment. PMID:24860116

  9. Current Understanding of BRAF Alterations in Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade Gliomas

    PubMed Central

    Penman, Catherine Louise; Faulkner, Claire; Lowis, Stephen P.; Kurian, Kathreena M.

    2015-01-01

    The mitogen-activated protein kinase (MAPK) pathway is known to play a key role in the initiation and maintenance of many tumors as well as normal development. This often occurs through mutation of the genes encoding RAS and RAF proteins which are involved in signal transduction in this pathway. BRAF is one of three RAF kinases which act as downstream effectors of growth factor signaling leading to cell cycle progression, proliferation, and survival. Initially reported as a point mutation (V600E) in the majority of metastatic melanomas, other alterations in the BRAF gene have now been reported in a variety of human cancers including papillary thyroid cancer, colon carcinomas, hairy cell leukemia, and more recently in gliomas. The identification of oncogenic mutations in the BRAF gene have led to a revolution in the treatment of metastatic melanoma using targeted molecular therapies that affect the MAPK pathway either directly through BRAF inhibition or downstream through inhibition of MEK. This review describes the molecular biology of BRAF in the context of pediatric low-grade gliomas, the role of BRAF as a diagnostic marker, the prognostic implications of BRAF, and evidence for therapeutic targeting of BRAF. PMID:25785246

  10. 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

  11. 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

  12. 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

    Eisenstat, David D; 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; Finlay, Jonathan L

    2015-02-01

    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

  13. 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

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

    PubMed

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

    2015-05-01

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

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

    PubMed Central

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

    2015-01-01

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

  16. 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

  17. OP30DIAGNOSTIC DELAY AND SURVIVAL IN HIGH GRADE GLIOMAS - EVIDENCE OF THE “WAITING TIME PARADOX”

    PubMed Central

    Aggarwal, Ajay; Herz, Naomi; Arkush, Leo; Short, Susan; Rees, Jeremy

    2014-01-01

    INTRODUCTION: We present a retrospective single centre study to determine whether delays in diagnosis in high grade glioma (HGG) impact on overall survival (OS). METHOD: Consecutive patients diagnosed with HGG at The National Hospital for Neurology and Neurosurgery, a single neuroscience centre in 2011 were reviewed. Route of referral and time from initial presentation to diagnosis were analysed and correlated with OS. RESULTS: 118 patients were studied, 92 had with glioblastoma (GBM). Diagnosis of GBM in patients presenting to emergency services was quicker than through outpatients (8 days vs 26 days, p < 0.0001), but these patients had significantly worse OS (181 days vs 386 days p = 0.0075 ). CONCLUSION: Earlier diagnosis is paradoxically associated with a worse OS in GBM. An “aggressive” phenotype with rapid symptomatic deterioration and hence emergency presentation is a poor prognostic factor not influenced by more rapid treatment or earlier diagnosis.

  18. Long-Term Results of Brachytherapy With Temporary Iodine-125 Seeds in Children With Low-Grade Gliomas

    SciTech Connect

    Korinthenberg, Rudolf; Neuburger, Daniela; Trippel, Michael; Ostertag, Christoph; Nikkhah, Guido

    2011-03-15

    Purpose: To retrospectively review the results of temporary I-125 brachytherapy in 94 children and adolescents with low-grade glioma. Methods and Materials: Treatment was performed in progressive tumors roughly spherical in shape with a diameter of up to 5 cm, including 79 astrocytomas, 5 oligodendrogliomas, 4 oligoastrocytomas, 1 ependymoma, and 5 other tumors. Location was suprasellar/chiasmal in 44, thalamic/basal ganglia in 18, hemispheric in 15, midbrain/pineal region in 13, and lower brainstem in 3. Initially, 8% of patients were free of symptoms, 47% were symptomatic but not disabled, and 30% were slightly, 6% moderately, and 3% severely disabled. Results: 5- and 10-year survival was 97% and 92%. The response to I-125 brachytherapy over the long term was estimated after a median observation period of 38.4 (range, 6.4-171.0) months. At that time, 4 patients were in complete, 27 in partial, and 18 in objective remission; 15 showed stable and 30 progressive tumors. Treatment results did not correlate with age, sex, histology, tumor size, location, or demarcation of the tumor. Secondary treatment became necessary in 36 patients, including 19 who underwent repeated I-125 brachytherapy. At final follow-up, the number of symptom-free patients had risen to 21%. Thirty-eight percent showed symptoms without functional impairment, 19% were slightly and 11% moderately disabled, and only 4% were severely disabled. Conclusions: Response rates similar to those of conventional radiotherapy or chemotherapy can be anticipated with I-125 brachytherapy in tumors of the appropriate size and shape. We believe it to be a useful contribution to the treatment of low-grade gliomas in children.

  19. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

    PubMed

    Wen, Patrick Y; Macdonald, David R; Reardon, David A; Cloughesy, Timothy F; Sorensen, A Gregory; Galanis, Evanthia; Degroot, John; Wick, Wolfgang; Gilbert, Mark R; Lassman, Andrew B; Tsien, Christina; Mikkelsen, Tom; Wong, Eric T; Chamberlain, Marc C; Stupp, Roger; Lamborn, Kathleen R; Vogelbaum, Michael A; van den Bent, Martin J; Chang, Susan M

    2010-04-10

    Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas. PMID:20231676

  20. Spatial Characteristics of Newly Diagnosed Grade 3 Glioma Assessed by Magnetic Resonance Metabolic and Diffusion Tensor Imaging1

    PubMed Central

    Ozturk-Isik, Esin; Pirzkall, Andrea; Lamborn, Kathleen R; Cha, Soonmee; Chang, Susan M; Nelson, Sarah J

    2012-01-01

    The spatial heterogeneity in magnetic resonance (MR) metabolic and diffusion parameters and their relationship were studied for patients with treatment-naive grade 3 gliomas. MR data were evaluated from 51 patients with newly diagnosed grade 3 gliomas. Anatomic, diffusion, and metabolic imaging data were considered. Variations in metabolite levels, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were evaluated in regions of gadolinium enhancement and T2 hyperintensity as well as regions with abnormal metabolic signatures. Contrast enhancement was present in only 21 of the 51 patients. When present, the enhancing component of the lesion had higher choline-to-N-acetylaspartate index (CNI), higher choline, lower N-acetylaspartate, similar creatine, similar ADC and FA, and higher lactate/lipid than the nonenhancing lesion. Regions with CNI ≥ 4 had higher choline, lower N-acetylaspartate, higher lactate/lipid, higher ADC, and lower FA than normal-appearing white matter and regions with intermediate CNI values. For lesions that exhibited gadolinium enhancement, the metabolite levels and diffusion parameters in the region of enhancement were consistent with it corresponding to the most abnormal portion of the tumor. For nonenhancing lesions, areas with CNI ≥ 4 were the most abnormal in metabolic and diffusion parameters. This suggests that the region with the highest CNI might provide a good target for biopsies for nonenhancing lesions to obtain a representative histologic diagnosis of its degree of malignancy. Metabolic and diffusion parameter levels may be of interest not only for directing tissue sampling but also for defining the targets for focal therapy and assessing response to therapy. PMID:22348171

  1. Spatial characteristics of newly diagnosed grade 3 glioma assessed by magnetic resonance metabolic and diffusion tensor imaging.

    PubMed

    Ozturk-Isik, Esin; Pirzkall, Andrea; Lamborn, Kathleen R; Cha, Soonmee; Chang, Susan M; Nelson, Sarah J

    2012-02-01

    The spatial heterogeneity in magnetic resonance (MR) metabolic and diffusion parameters and their relationship were studied for patients with treatment-naive grade 3 gliomas. MR data were evaluated from 51 patients with newly diagnosed grade 3 gliomas. Anatomic, diffusion, and metabolic imaging data were considered. Variations in metabolite levels, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were evaluated in regions of gadolinium enhancement and T2 hyperintensity as well as regions with abnormal metabolic signatures. Contrast enhancement was present in only 21 of the 51 patients. When present, the enhancing component of the lesion had higher choline-to-N-acetylaspartate index (CNI), higher choline, lower N-acetylaspartate, similar creatine, similar ADC and FA, and higher lactate/lipid than the nonenhancing lesion. Regions with CNI ≥ 4 had higher choline, lower N-acetylaspartate, higher lactate/lipid, higher ADC, and lower FA than normal-appearing white matter and regions with intermediate CNI values. For lesions that exhibited gadolinium enhancement, the metabolite levels and diffusion parameters in the region of enhancement were consistent with it corresponding to the most abnormal portion of the tumor. For nonenhancing lesions, areas with CNI ≥ 4 were the most abnormal in metabolic and diffusion parameters. This suggests that the region with the highest CNI might provide a good target for biopsies for nonenhancing lesions to obtain a representative histologic diagnosis of its degree of malignancy. Metabolic and diffusion parameter levels may be of interest not only for directing tissue sampling but also for defining the targets for focal therapy and assessing response to therapy. PMID:22348171

  2. 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

  3. 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.

  4. 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

  5. Where are we now? And where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) Low-grade Glioma Research Workshop

    PubMed Central

    Huse, Jason T.; Wallace, Max; Aldape, Kenneth D.; Berger, Mitchel S.; Bettegowda, Chetan; Brat, Daniel J.; Cahill, Daniel P.; Cloughesy, Timothy; Haas-Kogan, Daphne A.; Marra, Marco; Miller, C. Ryan; Nelson, Sarah J.; Salama, Sofie R.; Soffietti, Riccardo; Wen, Patrick Y.; Yip, Stephen; Yen, Katharine; Costello, Joseph F.; Chang, Susan

    2014-01-01

    Diffuse gliomas consist of both low- and high-grade varieties, each with distinct morphological and biological features. The often extended periods of relative indolence exhibited by low-grade gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV). Nevertheless, until recently, the molecular foundations underlying this stark biological contrast between glioma variants remained largely unknown. The discoveries of distinctive and highly recurrent genomic and epigenomic abnormalities in LGG have both informed a more accurate classification scheme and pointed to viable avenues for therapeutic development. As such, the field of neuro-oncology now seems poised to capitalize on these gains to achieve significant benefit for LGG patients. This report will briefly recount the proceedings of a workshop held in January 2013 and hosted by Accelerate Brain Cancer Cure (ABC2) on the subject of LGG. While much of the meeting covered recent insights into LGG biology, its focus remained on how best to advance the clinical management, whether by improved preclinical modeling, more effective targeted therapeutics and clinical trial design, or innovative imaging technology. PMID:24305708

  6. Detection and grading of human gliomas by FTIR spectroscopy and a genetic classification algorithm

    NASA Astrophysics Data System (ADS)

    Steiner, Gerald; Shaw, R. A.; Choo-Smith, Lin-P'ing; Steller, Wolfram; Shapoval, Laryssa; Schackert, Gabriele; Sobottka, Stephan; Salzer, Reiner; Mantsch, Henry H.

    2002-03-01

    A new approach is presented to distinguish cancerous from normal brain tissue via linear discriminant analysis of Fourier transform infrared (FTIR) spectra. FTIR microspectroscopy was used to map various thin-section tumor samples with different malignancy grades (grades II-VI) and non-tumor samples obtained from various patients by surgical removal. Spectral analysis revealed features characteristic of tumors with increasing malignancy. A genetic region selection algorithm combined with linear discriminant analysis was used to derive classifiers distinguishing among spectra of control tissue, astrocytoma grade II, astrocytoma grade III and glioblastoma grade IV. Employing the World Health Organization histopathological diagnostic scheme as the gold standard, the spectra were classified with a success rate of approximately 85 percent. These results demonstrate the potential of the combination of FTIR spectroscopy and pattern recognition routines in providing a more objective method for brain tumour grading and diagnosis.

  7. Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study

    PubMed Central

    Teixidor, Pilar; Vidal, Xavier; Montané, Eva

    2016-01-01

    Background During the last decade, the use of 5-aminolevulinic acid (5-ALA) has been steadily increasing in neurosurgery. The study's main objectives were to prospectively evaluate the effectiveness and safety of 5-ALA when used in clinical practice setting on high-grade gliomas’ patients. Methods National, multicenter and prospective observational study. Inclusion criteria: authorized conditions of use of 5-ALA. Exclusion criteria: contraindication to 5-ALA, inoperable or partial resected tumors, pregnancy and children. Epidemiological, clinical, laboratory, radiological, and safety data were collected. Effectiveness was assessed using complete resection of the tumor, and progression-free and overall survival probabilities. Results Between May 2010 and September 2014, 85 patients treated with 5-ALA were included, and 77 were suitable for the effectiveness analysis. Complete resection was achieved in 41 patients (54%). Surgeons considered suboptimal the fluorescence of 5-ALA in 40% of the patients assessed. The median duration of follow-up was 12.3 months. The progression-free survival probability at 6 months was 58%. The median duration overall survival was 14.2 months. Progression tumor risk factors were grade of glioma, age and resection degree; and death risk factors were grade of glioma and gender. No severe adverse effects were reported. At one month after surgery, new or increased neurological morbidity was 6.5%. Hepatic enzymes were frequently increased within the first month after surgery; however, they subsequently normalized, and this was found to have no clinical significance. Conclusion In clinical practice, the 5-ALA showed a good safety profile, but the benefits related to 5-ALA have not been yet clearly shown. The improved differentiation expected by fluorescence between normal and tumor cerebral tissue was suboptimal in a relevant number of patients; in addition, the expected higher degree of resection was lower than in clinical trials as well as

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

    PubMed

    Duffau, H

    2015-12-01

    The traditional dilemma making surgery for diffuse low-grade gliomas (DLGGs) challenging is underlain by the need to optimize tumor resection in order to significantly increase survival versus the risk of permanent neurological morbidity. Development of neuroimaging led neurosurgeons to achieve tumorectomy according to the oncological limits provided by preoperative or intraoperative structural and metabolic imaging. However, this principle is not coherent, neither with the infiltrative nature of DLGGs nor with the limited resolution of current neuroimaging. Indeed, despite technical advances, MRI still underestimates the actual spatial extent of gliomas, since tumoral cells are present several millimeters to centimeters beyond the area of signal abnormalities. Furthermore, cortical and subcortical structures may be still crucial for brain functions despite their invasion by this diffuse tumoral disease. Finally, the lack of reliability of functional MRI has also been demonstrated. Therefore, to talk about "maximal safe resection" based upon neuroimaging is a non-sense, because oncological MRI does not show the tumor and functional MRI does not show critical neural pathways. This review proposes an original concept in neuro-oncological surgery, i.e. to resect DLGG to the boundaries of brain functions, thanks to intraoperative electrical mapping performed in awake patients. This paradigmatic shift from image-guided resection to functional mapping-guided resection, based upon an accurate study of brain connectomics and neuroplasticity in each patient throughout tumor removal has permitted to solve the classical dilemma, by increasing both survival and quality of life in DLGG patients. With this in mind, brain surgeons should also be neuroscientists. PMID:25907410

  9. Health-related quality of life in patients with high-grade gliomas: a quantitative longitudinal study.

    PubMed

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

    2015-09-01

    The diagnosis of a high-grade glioma usual is followed by functional impairment(s), cognitive decline and an impaired psycho-social well-being. This might well have a significant and negative impact on the health related quality of life. The purpose of this study was to explore physical activity levels, prevalence and severity of anxiety and depressive symptoms and health-related quality of life among patients with a highgrade glioma. This paper is based on a longitudinal mixed methods study. Patients (n = 30) completed questionnaires at 5 time points from time of diagnosis until the final follow-up after 1 year. Scores of Karnofsky Performance Status (KPS), physical activity, anxiety and depression and health-related quality of life (FACT-Br) are obtained. Patients' physical activity level and KPS decrease during the disease- and treatment trajectory. The majority of patients did not report any depressive symptoms, eight individuals (26.7 %) being depressed at various time points. Among a sub-group of participants who completed all study requirements for the entire study period the level of anxiety decreased significantly during the study. The FACT-Br sub-scale of emotional well-being increased significant, indicating a better HRQOL attend of followup. The diagnosis of a HGG leads to an ongoing functional decline measured as a decline of the KPS and a reduced physical activity during leisure time. Supportive care combined with rehabilitative and palliative approaches might well be valuable along the trajectory especially during the post-surgery period when anxiety is at its highest peak. PMID:26026860

  10. Molecular biology of malignant gliomas.

    PubMed

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

    2006-09-01

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

  11. Tl-201 brain SPECT imaging in preoperative supratentorial glioma: Is it useful in the grading of nonehancing CT or MRI lesions?

    SciTech Connect

    Ryu, J.S.; Moon, D.H.; Lee, H.K.

    1995-05-01

    Contrast enhanced MRI is valuable in predicting the histologic grade of gliomas. However, some high grade tumors may not demonstrate any significant enhancement. The purpose of this study was to assess the contribution of Tl-201 brain SPECT in the grading of preoperative glioma and the correlation with contrast enhancement in MRI or CT. The subjects consisted of 30 patients(pts) with suspected gliomas on contrast enhanced MR(n=27) or CT(n=3). Tl-201 brain SPECT was performed after injection of 74MBq of Tl-201 using triple head SPECT system. To quantify Tl-201 uptake, Tl indices (Tl average pixel counts of tumor ROl/normal contralateral hemisphere) were obtained. Histologic diagnoses were glioblastoma multiforme(GM) in 13, asrtrocytoma grade III (GIII) in 7, astrocytoma grade II(GII) in 6 and reactive gliosis(RG) in 4. All 13 pts with GM showed positive Tl-201 uptake(mean Tl; 9.0 {plus_minus}4.7), when Tl over 2.5 was considered as positive. Four of the 7 pts with GIII were positive(Tl: 4.6 {approximately}8.5) and the other 3 pts were negative. Tl-201 uptake(Tl; 0.8{approximately}1.5). All with GII showed negative Tl-201 uptake except one with 4.7 of Tl. Three of the 4 pts with RG also showed negative Tl-201 uptake and one showed positive uptake(Tl; 4.9). Overall sensitivity and specificity of Tl-201 SPECT in differentiating high grade glioma were 85% and 80%. In the correlation with contrast enhancement in MRI or CT, all nonenhancing lesions were negative Tl-201 uptake including 2 lesions with GIII. Nineteen out of the 23 pts with enhancing lesions had positive Tl-201 uptake. Three pts with RG and one with GIII who had enhancing lesions in MRI showed negative Tl-201 uptake. In conclusion, Tl-201 brain SPECT imaging is a useful method in differentiating the high grade gliomas in contrast enhancing lesions in MRI or CT. It has no additional value in differential diagnosis of nonenhancing lesions.

  12. 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

  13. Analysis of IDH mutation, 1p/19q deletion, and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas

    PubMed Central

    Sabha, Nesrin; Knobbe, Christiane B.; Maganti, Majula; Al Omar, Soha; Bernstein, Mark; Cairns, Rob; Çako, Besmira; von Deimling, Andreas; Capper, David; Mak, Tak W.; Kiehl, Tim-Rasmus; Carvalho, Philippe; Garrett, Evelyn; Perry, Arie; Zadeh, Gelareh; Guha, Abhijit; Croul, Sidney

    2014-01-01

    Background Grades II and III gliomas have unpredictable rates of progression, making management decisions difficult. Currently, several clinical and radiological characteristics are utilized to predict progression and survival but collectively are suboptimal. Methods In this study, we analyzed a set of 108 nonenhancing hemispheric grade II–III gliomas. Demographic variables, including patient age, tumor diameter, extent of resection, and performance status, were combined with molecular data (IDH mutation status [mIDH], 1p/19q codeletion, PTEN deletion, and EGFR amplification). A complete dataset for all variables was compiled for 70 of the 108 patients. Both univariable and multivariable analyses were performed to determine whether the molecular data singly or in combination offer advantages over tumor type and grade for prediction of overall survival (OS) and/or progression-free rate (PFR). Results Patient age, clinical variables (tumor diameter, extent of resection, performance status), and pathology (tumor type and grade) were not predictive of OS or PFR. IDH mutation status alone was predictive of longer OS and PFR for the entire group of tumors; 1p/19q deletion alone was predictive of OS but not PFR. In the multivariable analysis, none of the clinical or demographic factors were predictive of OS or PFR. IDH mutation status, 1p/19q codeletion, and PTEN deletion were predictive of OS (P = .003, P = .005, P = .02, respectively). Both mIDH (P < .001) and the interaction term of 1p/19q and PTEN (P < .001) were found to be predictive of PFR. Conclusions We conclude that the combination of mIDH, 1p/19q codeletion, and PTEN deletion may be particularly effective in discriminating good prognosis from poor prognosis hemispheric gliomas. We propose that such a scheme merits testing on larger prospective cohorts. Should our findings be confirmed, routine clinical analysis of hemispheric gliomas for mIDH, 1p/19q codeletion, and PTEN deletion would be justified. PMID

  14. P64QUANTITATIVE MGMT METHYLATION ANALYSIS BY PYROSEQUENCING REVEALS A STRONG CORRELATION BETWEEN 1P/19Q CO-DELETION AND HIGH LEVEL METHYLATION IN HIGH GRADE GLIOMAS

    PubMed Central

    Laxton, R.; Doey, L.; Aizpurua, M.; Bodi, I.; King, A.; Chandler, C.; Bhangoo, R.; Beaney, R.; Brazil, L.; Ashkan, K.; Al-Sarraj, S.

    2014-01-01

    INTRODUCTION: Pyrosequencing is a method that allows MGMT methylation to be measured in a quantitative manner. MGMT methylation, along with 1p/19q co-deletion and IDH1 mutation, is an important biomarker in high grade gliomas. MGMT methylation indicates an improved response to temozolomide chemotherapy; patients with 1p/19q co-deleted anaplastic oligodendrogliomas benefit from the addition of chemotherapy to radiotherapy. Aim: To compare the average MGMT promoter methylation level of high grade gliomas and correlate it with other clinical parameters and markers including IDH1&2 mutation and 1p/19q co-deletion. METHOD: For 171 high grade gliomas MGMT methylation analysis was performed by pyrosequencing, mutations to IDH1 and IDH2 genes were also detected by pyrosequencing, or immunohistochemistry (n = 166). Screening for 1p/19q deletion was by fluorescence in situ hybridisation (n = 46). Statistical analysis was performed using R-Stats v2.15.2. RESULTS: The results show that higher methylation was correlated with lower grade and mutation to either IDH1 or IDH2 (27.0% vs. 16.6% p = 0.008; and 27.5 vs. 16.1 p = 0.002 respectively). Interestingly 1p/19q co-deletion versus non co-deletion was associated with a particularly high level of methylation (42.2% vs. 17.7% p = 0.001). No significant differences were seen for age or gender. CONCLUSION: The results offer a potential explanation for the improved prognosis seen in glioma patients with 1p/19q co-deletion and when combined with IDH mutation status may provide an extra control to confirm true 1p/19q co-deletion.

  15. Ki-67 proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas.

    PubMed

    Duregon, Eleonora; Bertero, Luca; Pittaro, Alessandra; Soffietti, Riccardo; Rudà, Roberta; Trevisan, Morena; Papotti, Mauro; Ventura, Laura; Senetta, Rebecca; Cassoni, Paola

    2016-04-19

    Despite several molecular signatures for "lower grade diffuse gliomas" (LGG) have been identified, WHO grade still remains a cornerstone of treatment guidelines. Mitotic count bears a crucial role in its definition, although limited by the poor reproducibility of standard Hematoxylin & Eosin (H&E) evaluation. Phospho-histone-H3 (PHH3) and Ki-67 have been proposed as alternative assays of cellular proliferation. Therefore in the present series of 141 LGG, the molecular characterization (namely IDH status, 1p/19q co-deletion and MGMT promoter methylation) was integrated with the tumor "proliferative trait" (conventional H&E or PHH3-guided mitotic count and Ki-67 index) in term of prognosis definition. Exclusively high PHH3 and Ki-67 values were predictor of poor prognosis (log rank test, P = 0.0281 for PHH3 and P = 0.032 for Ki-67), unlike standard mitotic count. Based on Cox proportional hazard regression analyses, among all clinical (age), pathological (PHH3 and Ki-67) and molecular variables (IDH, 1p/19q codeletion and MGMT methylation) with a prognostic relevance at univariate survival analysis, only IDH expression (P = 0.001) and Ki-67 proliferation index (P = 0.027) proved to be independent prognostic factors. In addition, stratifying by IDH expression status, high Ki-67 retained its prognostic relevance uniquely in the IDH negative patient (P = 0.029) doubling their risk of death (hazard ratio = 2.27). Overall, PHH3 immunostaining is the sole reliable method with a prognostic value to highlight mitotic figures in LGG. Ki-67 proliferation index exceeds PHH3 mitotic count as a predictor of patient's prognosis, and should be integrated with molecular markers in a comprehensive grading system for LGG. PMID:27049832

  16. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors.

    PubMed

    Bleeker, Fonnet E; Lamba, Simona; Leenstra, Sieger; Troost, Dirk; Hulsebos, Theo; Vandertop, W Peter; Frattini, Milo; Molinari, Francesca; Knowles, Margaret; Cerrato, Aniello; Rodolfo, Monica; Scarpa, Aldo; Felicioni, Lara; Buttitta, Fiamma; Malatesta, Sara; Marchetti, Antonio; Bardelli, Alberto

    2009-01-01

    Systematic sequence profiling of the Glioblastoma Multiforme (GBM) genome has recently led to the identification of somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Interestingly, only the evolutionarily conserved residue R132 located in the substrate binding site of IDH1 was found mutated in GBM. At present, the occurrence and the relevance of p.R132 (IDH1(R132)) variants in tumors other than GBMs is largely unknown. We searched for mutations at position R132 of the IDH1 gene in a panel of 672 tumor samples. These included high-grade glioma, gastrointestinal stromal tumors (GIST), melanoma, bladder, breast, colorectal, lung, ovarian, pancreas, prostate, and thyroid carcinoma specimens. In addition, we assessed a panel of 84 cell lines from different tumor lineages. Somatic mutations affecting the IDH1(R132) residue were detected in 20% (23 of 113) high-grade glioma samples. In addition to the previously reported p.R132H and p.R132S alleles, we identified three novel somatic mutations (p.R132C, p.R132G, and p.R132L) affecting residue IDH1(R132) in GBM. Strikingly, no IDH1 mutations were detected in the other tumor types. These data indicate that cancer mutations affecting IDH1(R132) are tissue-specific, and suggest that it plays a unique role in the development of high-grade gliomas. PMID:19117336

  17. Comparing high-resolution microscopy techniques for potential intraoperative use in guiding low-grade glioma resections

    PubMed Central

    Meza, Daphne; Wang, Danni; Wang, Yu “Winston”; Borwege, Sabine; Sanai, Nader; Liu, Jonathan T.C.

    2015-01-01

    Background and Objectives Fluorescence image-guided surgery (FIGS), with contrast provided by 5-ALA-induced-PpIX, has been shown to enable a higher extent of resection of high-grade gliomas. However, conventional FIGS with low-power microscopy lacks the sensitivity to aid in low-grade glioma (LGG) resection because PpIX signal is weak and sparse in such tissues. Intraoperative high-resolution microscopy of PpIX fluorescence has been proposed as a method to guide LGG resection, where sub-cellular resolution allows for the visualization of sparse and punctate mitochondrial PpIX production in tumor cells. Here, we assess the performance of three potentially portable high-resolution microscopy techniques that may be used for the intraoperative imaging of human LGG tissue samples with PpIX contrast: high-resolution fiber-optic microscopy (HRFM), high-resolution wide-field microscopy (WFM), and dual-axis confocal (DAC) microscopy. Materials and Methods Thick unsectioned human LGG tissue samples (n = 7) with ALA-induced-PpIX contrast were imaged using three imaging techniques (HRFM, WFM, DAC). The average signal-to-background ratio (SBR) was then calculated for each imaging modality (5 images per tissue, per modality). Results HRFM provides the ease of use and portability of a flexible fiber bundle, and is simple and inexpensive to build. However, in most cases (6/7), HRFM is not capable of detecting PpIX signal from LGGs due to high autofluorescence, generated by the fiber bundle under laser illumination at 405 nm, which overwhelms the PpIX signal and impedes its visualization. WFM is a camera-based method possessing high lateral resolution but poor axial resolution, resulting in sub-optimal image contrast. Conclusions Consistent successful detection of PpIX signal throughout our human LGG tissue samples (n = 7), with an acceptable image contrast (SBR > 2), was only achieved using DAC microscopy, which offers superior image resolution and contrast that is comparable to

  18. 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

  19. Adult Brainstem Gliomas

    PubMed Central

    Reyes-Botero, German; Mokhtari, Karima; Martin-Duverneuil, Nadine; Delattre, Jean-Yves

    2012-01-01

    Brainstem gliomas are uncommon in adults and account for only 1%–2% of intracranial gliomas. They represent a heterogeneous group of tumors that differ from those found in their pediatric counterparts. In adults, a low-grade phenotype predominates, which is a feature that likely explains their better prognosis compared to that in children. Because biopsies are rarely performed, classifications based on the radiological aspect of magnetic resonance imaging results have been proposed to establish treatment strategies and to determine outcomes: (a) diffuse intrinsic low-grade, (b) enhancing malignant glioma, (c) focal tectal gliomas, and (d) exophytic gliomas. Despite significant advances in neuroradiology techniques, a purely radiological classification remains imperfect in the absence of a histological diagnosis. Whereas a biopsy may often be reasonably avoided in the diffuse nonenhancing forms, obtaining histological proof seems necessary in many contrast-enhanced brainstem lesions because of the wide variety of differential diagnoses in adults. Conventional radiotherapy is the standard treatment for diffuse intrinsic low-grade brainstem gliomas in adults (the median survival is 5 years). In malignant brainstem gliomas, radiotherapy is the standard treatment. However, the possible benefit of combined radiotherapy and chemotherapy (temozolomide or other agents) has not been thoroughly evaluated in adults. The role of anti-angiogenic therapies in brainstem gliomas remains to be defined. A better understanding of the biology of these tumors is of primary importance for identifying homogeneous subgroups and for improving therapy options and outcomes. PMID:22382458

  20. Prognostic value of increase in transcript levels of Tp73 DeltaEx2-3 isoforms in low-grade glioma patients.

    PubMed

    Wager, M; Guilhot, J; Blanc, J-L; Ferrand, S; Milin, S; Bataille, B; Lapierre, F; Denis, S; Chantereau, T; Larsen, C-J; Karayan-Tapon, L

    2006-10-23

    Glial tumours are a devastating, poorly understood condition carrying a gloomy prognosis for which clinicians sorely lack reliable predictive parameters facilitating a sound treatment strategy. Tp73, a p53 family member, expresses two main classes of isoforms--transactivatory activity (TA)p73 and DeltaTAp73--exhibiting tumour suppressor gene and oncogene properties, respectively. The authors examined their expression status in high- and low-grade adult gliomas. Isoform-specific real-time reverse transcription-polymerase chain reaction was used for the analysis of Tp73 isoform transcript expression in a series of 51 adult patients harbouring glial tumours, in order to compare tumour grades with each other, and with non-tumoural samples obtained from epileptic patients as well. Our data demonstrate increase of TAp73 and DeltaTAp73 transcript levels at onset and early stage of the disease. We also show that DeltaEx2-3 isoform expression in low-grade tumours anticipates clinical and imaging progression to higher grades, and correlates to the patients' survival. Expression levels of P1 promoter generated Tp73 isoforms--and particularly DeltaEx2-3--indeed allow for prediction of the clinical progression of low-grade gliomas in adults. Our data are the first such molecular biology report regarding low-grade tumours and as such should be of help for sound decision-making. PMID:17047653

  1. Protocol for the Care-IS Trial: a randomised controlled trial of a supportive educational intervention for carers of patients with high-grade glioma (HGG)

    PubMed Central

    Halkett, Georgia K B; Lobb, Elizabeth A; Miller, Lisa; Phillips, Jane L; Shaw, Thérése; Moorin, Rachael; Long, Anne; King, Anne; Clarke, Jenny; Fewster, Stephanie; Hudson, Peter; Agar, Meera; Nowak, Anna K

    2015-01-01

    Introduction High-grade glioma (HGG) is a rapidly progressive and debilitating disease. Primary carers experience significant levels of distress which impacts on their experience of caregiving, the quality of care received and the community in terms of the increased reliance on healthcare due to the potential development of complicated grief. This paper describes the protocol for testing the efficacy and feasibility of an intervention for primary carers of patients with HGG in order to improve preparedness to care and reduce carer distress. Methods Randomised controlled trial. The target population is carers of patients with HGG who are undergoing combined chemoradiotherapy. The intervention consists of 4 components: (1) initial telephone assessment of unmet needs of the carer, (2) tailoring of a personalised resource folder, (3) home visit, (4) ongoing monthly telephone contact and support for 12 months. The control arm will receive usual care. Primary hypothesis This intervention will improve preparedness for caring and reduce carer psychological distress. Secondary hypothesis This intervention will reduce carer unmet needs. The longer term aim of the intervention is to reduce patient healthcare resource utilisation and, by doing so, reduce costs. Assessments will be obtained at baseline, 8 weeks post intervention, then 4, 6 and 12 months. Participants will also complete a healthcare utilisation checklist and proxy performance status which will be assessed at baseline and monthly. 240 carers will be recruited. The sample size is 180. Multilevel mixed effects regression models will be applied to test the effect of the intervention. Ethics Ethics approval has been gained from Curtin University and the participating sites. Dissemination Results will be reported in international peer-reviewed journals. Trial registration number Australian and New Zealand Clinical Trials Registration (ACTRN)12612001147875. PMID:26503395

  2. Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma.

    PubMed

    Renner, G; Janouskova, H; Noulet, F; Koenig, V; Guerin, E; Bär, S; Nuesch, J; Rechenmacher, F; Neubauer, S; Kessler, H; Blandin, A-F; Choulier, L; Etienne-Selloum, N; Lehmann, M; Lelong-Rebel, I; Martin, S; Dontenwill, M

    2016-04-01

    Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5β1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5β1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5β1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5β1 integrin may benefit from associated therapies

  3. 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.

  4. Improving seroreactivity-based detection of glioma.

    PubMed

    Ludwig, Nicole; Keller, Andreas; Heisel, Sabrina; Leidinger, Petra; Klein, Veronika; Rheinheimer, Stefanie; Andres, Claudia U; Stephan, Bernhard; Steudel, Wolf-Ingo; Graf, Norbert M; Burgeth, Bernhard; Weickert, Joachim; Lenhof, Hans-Peter; Meese, Eckart

    2009-12-01

    Seroreactivity profiling emerges as valuable technique for minimal invasive cancer detection. Recently, we provided first evidence for the applicability of serum profiling of glioma using a limited number of immunogenic antigens. Here, we screened 57 glioma and 60 healthy sera for autoantibodies against 1827 Escherichia coli expressed clones, including 509 in-frame peptide sequences. By a linear support vector machine approach, we calculated mean specificity, sensitivity, and accuracy of 100 repetitive classifications. We were able to differentiate glioma sera from sera of the healthy controls with a specificity of 90.28%, a sensitivity of 87.31% and an accuracy of 88.84%. We were also able to differentiate World Health Organization grade IV glioma sera from healthy sera with a specificity of 98.45%, a sensitivity of 80.93%, and an accuracy of 92.88%. To rank the antigens according to their information content, we computed the area under the receiver operator characteristic curve value for each clone. Altogether, we found 46 immunogenic clones including 16 in-frame clones that were informative for the classification of glioma sera versus healthy sera. For the separation of glioblastoma versus healthy sera, we found 91 informative clones including 26 in-frame clones. The best-suited in-frame clone for the classification glioma sera versus healthy sera corresponded to the vimentin gene (VIM) that was previously associated with glioma. In the future, autoantibody signatures in glioma not only may prove useful for diagnosis but also offer the prospect for a personalized immune-based therapy. PMID:20019846

  5. Krüppel-Like Factor 8 (KLF8) Is Expressed in Gliomas of Different WHO Grades and Is Essential for Tumor Cell Proliferation

    PubMed Central

    Schnell, Oliver; Romagna, Alexander; Jaehnert, Irene; Albrecht, Valerie; Eigenbrod, Sabina; Juerchott, Kathrin; Kretzschmar, Hans; Tonn, Jörg-Christian; Schichor, Christian

    2012-01-01

    Krüppel-like factor 8 (KLF8) has only recently been identified to be involved in tumor cell proliferation and invasion of several different tumor entities like renal cell carcinoma, hepatocellular carcinoma and breast cancer. In the present study, we show for the first time the expression of KLF8 in gliomas of different WHO grades and its functional impact on glioma cell proliferation. In order to get information about KLF8-mRNA regulation qPCR was performed and did not reveal any significant difference in samples (n = 10 each) of non-neoplastic brain (NNB), low-grade gliomas (LGG, WHO°II) and glioblastomas (GBM, WHO°IV). Immunohistochemistry of tissue samples (n = 7 LGG, 11 AA and 12 GBM) did not show any significant difference in the fraction of KLF8-immunopositive cells of all analyzed cells in LGG (87%), AA (80%) or GBM (89%). Tissue samples from cerebral breast cancer metastasis, meningiomas but also non-neoplastic brain demonstrated comparable relative cell counts as well. Moreover, there was no correlation between KLF8 expression and the expression pattern of the assumed proliferation marker Ki67, which showed high variability between different tumor grade (9% (LGG), 6% (AA) and 15% (GBM) of Ki67-immunopositive cells). Densitometric analysis of Western blotting revealed that the relative amount of KLF8-protein did also not differ between the highly aggressive and proliferative GBM (1.05) compared to LGG (0.93; p<0.05, studens t-test). As demonstrated for some other non-glial cancer entities, KLF8-knockdown by shRNA in U87-MG cells confirmed its functional relevance, leading to an almost complete loss of tumor cell proliferation. Selective blocking of KLF8 might represent a novel anti-proliferative treatment strategy for malignant gliomas. Yet, its simultaneous expression in non-proliferating tissues could hamper this approach. PMID:22276196

  6. Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells

    PubMed Central

    Kim, Tae Hyong; Song, Jieun; Kim, Sung-Hak; Parikh, Arav Krishnavadan; Mo, Xiaokui; Palanichamy, Kamalakannan; Kaur, Balveen; Yu, Jianhua; Yoon, Sung Ok; Nakano, Ichiro; Kwon, Chang-Hyuk

    2014-01-01

    Backgrounds Piperlongumine, a natural plant product, kills multiple cancer types with little effect on normal cells. Piperlongumine raises intracellular levels of reactive oxygen species (ROS), a phenomenon that may underlie the cancer-cell killing. Although these findings suggest that piperlongumine could be useful for treating cancers, the mechanism by which the drug selectively kills cancer cells remains unknown. Methods We treated multiple high-grade glioma (HGG) sphere cultures with piperlongumine and assessed its effects on ROS and cell-growth levels as well as changes in downstream signaling. We also examined the levels of putative piperlongumine targets and their roles in HGG cell growth. Results Piperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells. Piperlongumine reportedly increases ROS levels after interactions with several redox regulators. We found that HGG cells expressed higher levels of the putative piperlongumine targets than did normal neural stem cells (NSCs). Furthermore, piperlongumine treatment in HGG cells, but not in normal NSCs, increased oxidative inactivation of peroxiredoxin 4 (PRDX4), an ROS-reducing enzyme that is overexpressed in HGGs and facilitates proper protein folding in the endoplasmic reticulum (ER). Moreover, piperlongumine exacerbated intracellular ER stress, an effect that was mimicked by suppressing PRDX4 expression. Conclusions Our results reveal that the mechanism by which piperlongumine preferentially kills HGG cells involves PRDX4 inactivation, thereby inducing ER stress. Therefore, piperlongumine treatment could be considered as a novel therapeutic option for HGG treatment. PMID:24879047

  7. Indications for Treatment: Is Observation or Chemotherapy Alone a Reasonable Approach in the Management of Low Grade Gliomas?

    PubMed Central

    Schaff, Lauren R.; Lassman, Andrew B.

    2015-01-01

    The treatment of newly diagnosed low grade gliomas (LGG) remains controversial. Recently published results from the long-term follow up of Radiation Therapy Oncology Group (RTOG) trial 9802 demonstrated medically meaningful and statistically significant survival prolongation by adding chemotherapy with procarbazine, lomustine, and vincristine (PCV) after radiotherapy vs. radiotherapy alone for “high” risk patients (median 13.3 vs. 7.8 years, HR 0.59, p=0.03). However, in the 17 years since that trial was launched there have been advances in the understanding of LGG biology and patient heterogeneity, an increased recognition of late neuro-cognitive injury from early radiotherapy and the emergence of temozolomide as an alternative chemotherapy to PCV. These and other changes in the treatment landscape make the applicability of results from RTOG 9802 to all patients less clear. Moreover, in some patients, especially those at the lowest risk for early disease progression, deferred radiotherapy in favor of active surveillance or chemotherapy alone may remain reasonable treatment approaches. PMID:26050591

  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. Evidence for potentials and limitations of brain plasticity using an atlas of functional resectability of WHO grade II gliomas: towards a "minimal common brain".

    PubMed

    Ius, Tamara; Angelini, Elsa; Thiebaut de Schotten, Michel; Mandonnet, Emmanuel; Duffau, Hugues

    2011-06-01

    Despite recent advances in non-invasive brain mapping imaging, the resectability of a given area in a patient harboring a WHO grade II glioma cannot be predicted preoperatively with high reliability, due to mechanisms of functional reorganization. Therefore, intraoperative mapping by direct electrical stimulation remains the gold standard for detection and preservation of eloquent areas during glioma surgery, because it enables to perform on-line anatomo-functional correlations. To study potentials and limitations of brain plasticity, we gathered 58 postoperative MRI of patients operated on for a WHO grade II glioma under direct electrical cortico-subcortical stimulation. Postoperative images were registered on the MNI template to construct an atlas of functional resectability for which each voxel represents the probability to observe residual non-resectable tumor, that is, non-compensable area. The resulting atlas offers a rigorous framework to identify areas with high plastic potential (i.e. with probabilities of residual tumor close to 0), with low compensatory capabilities (i.e. probabilities of residual tumor close to 1) and with intermediate level of resectability (probability around 0.5). The resulting atlas highlights the utmost importance of preserving a core of connectivity through the main associative pathways, namely, it supports the existence of a "minimal common brain" among patients. PMID:21414413

  10. 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

  11. Radiotherapy of high-grade gliomas: current standards and new concepts, innovations in imaging and radiotherapy, and new therapeutic approaches.

    PubMed

    Dhermain, Frederic

    2014-01-01

    The current standards in radiotherapy of high-grade gliomas (HGG) are based on anatomic imaging techniques, usually computed tomography (CT) scanning and magnetic resonance imaging (MRI). The guidelines vary depending on whether the HGG is a histological grade 3 anaplastic glioma (AG) or a grade 4 glioblastoma multiforme (GBM). For AG, T2-weighted MRI sequences plus the region of contrast enhancement in T1 are considered for the delineation of the gross tumor volume (GTV), and an isotropic expansion of 15 to 20 mm is recommended for the clinical target volume (CTV). For GBM, the Radiation Therapy Oncology Group favors a two-step technique, with an initial phase (CTV1) including any T2 hyperintensity area (edema) plus a 20 mm margin treated with up to 46 Gy in 23 fractions, followed by a reduction in CTV2 to the contrast enhancement region in T1 with an additional 25 mm margin. The European Organisation of Research and Treatment of Cancer recommends a single-phase technique with a unique GTV, which comprises the T1 contrast enhancement region plus a margin of 20 to 30 mm. A total dose of 60 Gy in 30 fractions is usually delivered for GBM, and a dose of 59.4 Gy in 33 fractions is typically given for AG. As more than 85% of HGGs recur in field, dose-escalation studies have shown that 70 to 75 Gy can be delivered in 6 weeks with relevant toxicities developing in <10% of the patients. However, the only randomized dose-escalation trial, in which the boost dose was guided by conventional MRI, did not show any survival advantage of this treatment over the reference arm. HGGs are amongst the most infiltrative and heterogeneous tumors, and it was hypothesized that the most highly aggressive areas were missed; thus, better visualization of these high-risk regions for radiation boost could decrease the recurrence rate. Innovations in imaging and linear accelerators (LINAC) could help deliver the right doses of radiation to the right subvolumes according to the dose

  12. Neurological Impairment Linked with Cortico-Subcortical Infiltration of Diffuse Low-Grade Gliomas at Initial Diagnosis Supports Early Brain Plasticity

    PubMed Central

    Smits, Anja; Zetterling, Maria; Lundin, Margareta; Melin, Beatrice; Fahlström, Markus; Grabowska, Anna; Larsson, Elna-Marie; Berntsson, Shala Ghaderi

    2015-01-01

    Diffuse low-grade gliomas (DLGG) are slow-growing brain tumors that in spite of an indolent behavior at onset show a continuous expansion over time and inevitably transform into malignant gliomas. Extensive tumor resections may be performed with preservation of neurological function due to neuroplasticity that is induced by the slow tumor growth. However, DLGG prefer to migrate along subcortical pathways, and white matter plasticity is considerably more limited than gray matter plasticity. Whether signs of functional decompensating white matter that may be found as early as at disease presentation has not been systematically studied. Here, we examined 52 patients who presented with a DLGG at the time of radiological diagnosis. We found a significant correlation between neurological impairment and eloquent cortico-subcortical tumor localization, but not between neurological function and tumor volume. These results suggest that even small tumors invading white matter pathways may lack compensatory mechanisms for functional reorganization already at disease presentation. PMID:26113841

  13. Decreased survival of glioma patients with astrocytoma grade IV (glioblastoma multiforme) associated with long-term use of mobile and cordless phones.

    PubMed

    Carlberg, Michael; Hardell, Lennart

    2014-01-01

    On 31 May 2011 the WHO International Agency for Research on Cancer (IARC) categorised radiofrequency electromagnetic fields (RF-EMFs) from mobile phones, and from other devices that emit similar non-ionising electromagnetic fields, as a Group 2B, i.e., a "possible", human carcinogen. A causal association would be strengthened if it could be shown that the use of wireless phones has an impact on the survival of glioma patients. We analysed survival of 1678 glioma patients in our 1997-2003 and 2007-2009 case-control studies. Use of wireless phones in the >20 years latency group (time since first use) yielded an increased hazard ratio (HR) = 1.7, 95% confidence interval (CI) = 1.2-2.3 for glioma. For astrocytoma grade IV (glioblastoma multiforme; n = 926) mobile phone use yielded HR = 2.0, 95% CI = 1.4-2.9 and cordless phone use HR = 3.4, 95% CI = 1.04-11 in the same latency category. The hazard ratio for astrocytoma grade IV increased statistically significant per year of latency for wireless phones, HR = 1.020, 95% CI = 1.007-1.033, but not per 100 h cumulative use, HR = 1.002, 95% CI = 0.999-1.005. HR was not statistically significant increased for other types of glioma. Due to the relationship with survival the classification of IARC is strengthened and RF-EMF should be regarded as human carcinogen requiring urgent revision of current exposure guidelines. PMID:25325361

  14. 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

  15. 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

  16. Measuring health-related quality of life in high-grade glioma patients at the end of life using a proxy-reported retrospective questionnaire.

    PubMed

    Sizoo, Eefje M; Dirven, Linda; Reijneveld, Jaap C; Postma, Tjeerd J; Heimans, Jan J; Deliens, Luc; Pasman, H Roeline W; Taphoorn, Martin J B

    2014-01-01

    To develop, validate, and report on the use of a retrospective proxy-reported questionnaire measuring health-related quality of life (HRQoL) in the end-of-life (EOL) phase of high-grade glioma (HGG) patients. Items relevant for the defined construct were selected using existing questionnaires, topics identified as important in literature, and expert opinion (experienced neuro-oncologists and EOL experts). Psychometric properties, content validity and internal consistency, were determined and the questionnaire was subsequently adapted. Proxy-reported HRQoL data of HGG patients in the EOL, including changes over time, were analyzed. Twenty-nine items were selected covering seven domains; physical comfort, physical and cognitive functioning, psychological, social and spiritual well-being, and overall quality of life. Relatives of 83 deceased HGG patients completed the questionnaire. Content validity was assessed to be adequate. Internal consistency in the domains varied from reasonable to good. Two items were excluded due to poor psychometric properties. Symptom burden increased (p < 0.01), except for nausea (p = 0.058), as death approached. Cognitive, physical and psychological functioning deteriorated over time (all p < 0.01). Acceptance of disease seemed to increase slightly towards death, but this was not significant (p = 0.058). Participating in social activities and family life was rated as poor (≤ 50), whereas received support from their social environment and dying with dignity were rated as good (>50). Overall quality of life was rated as poor, mean (SD) of 29 (26). Measuring HRQoL at the EOL of HGG patients with a retrospective, proxy-reported questionnaire was feasible, yielding a validated instrument. HRQoL was reported as poor and deteriorated as death approached. PMID:24162875

  17. 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

  18. 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

  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. 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

  1. Right inferior frontal gyrus activation is associated with memory improvement in patients with left frontal low-grade glioma resection.

    PubMed

    Miotto, Eliane C; Balardin, Joana B; Vieira, Gilson; Sato, Joao R; Martin, Maria da Graça M; Scaff, Milberto; Teixeira, Manoel J; Junior, Edson Amaro

    2014-01-01

    Patients with low-grade glioma (LGG) have been studied as a model of functional brain reorganization due to their slow-growing nature. However, there is no information regarding which brain areas are involved during verbal memory encoding after extensive left frontal LGG resection. In addition, it remains unknown whether these patients can improve their memory performance after instructions to apply efficient strategies. The neural correlates of verbal memory encoding were investigated in patients who had undergone extensive left frontal lobe (LFL) LGG resections and healthy controls using fMRI both before and after directed instructions were given for semantic organizational strategies. Participants were scanned during the encoding of word lists under three different conditions before and after a brief period of practice. The conditions included semantically unrelated (UR), related-non-structured (RNS), and related-structured words (RS), allowing for different levels of semantic organization. All participants improved on memory recall and semantic strategy application after the instructions for the RNS condition. Healthy subjects showed increased activation in the left inferior frontal gyrus (IFG) and middle frontal gyrus (MFG) during encoding for the RNS condition after the instructions. Patients with LFL excisions demonstrated increased activation in the right IFG for the RNS condition after instructions were given for the semantic strategies. Despite extensive damage in relevant areas that support verbal memory encoding and semantic strategy applications, patients that had undergone resections for LFL tumor could recruit the right-sided contralateral homologous areas after instructions were given and semantic strategies were practiced. These results provide insights into changes in brain activation areas typically implicated in verbal memory encoding and semantic processing. PMID:25157573

  2. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis.

    PubMed

    Metellus, Philippe; Coulibaly, Bema; Colin, Carole; de Paula, Andre Maues; Vasiljevic, Alexandre; Taieb, David; Barlier, Anne; Boisselier, Blandine; Mokhtari, Karima; Wang, Xiao Wei; Loundou, Anderson; Chapon, Frederique; Pineau, Sandrine; Ouafik, L'Houcine; Chinot, Olivier; Figarella-Branger, Dominique

    2010-12-01

    The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P = 0.031) and p53 expression (P = 0.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, P = 0.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio = 40.9; 95% CI, 2.89-578.49, P = 0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P = 0.020) and that these tumors involved significantly more frequently the insula (P = 0.004), were larger in size (>6 cm, P = 0.047), displayed an infiltrative pattern on MRI (P = 0.007) and were all p53 negative with no 1p19q deletion (P < 10⁻⁶). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new tool to guide patient-tailored therapy. PMID:21080178

  3. ADC histograms predict response to anti-angiogenic therapy in patients with recurrent high-grade glioma

    PubMed Central

    2011-01-01

    Introduction The purpose of this study is to evaluate apparent diffusion coefficient (ADC) maps to distinguish anti-vascular and anti-tumor effects in the course of anti-angiogenic treatment of recurrent high-grade gliomas (rHGG) as compared to standard magnetic resonance imaging (MRI). Methods This retrospective study analyzed ADC maps from diffusion-weighted MRI in 14 rHGG patients during bevacizumab/irinotecan (B/I) therapy. Applying image segmentation, volumes of contrast-enhanced lesions in T1 sequences and of hyperintense T2 lesions (hT2) were calculated. hT2 were defined as regions of interest (ROI) and registered to corresponding ADC maps (hT2-ADC). Histograms were calculated from hT2-ADC ROIs. Thereafter, histogram asymmetry termed “skewness” was calculated and compared to progression-free survival (PFS) as defined by the Response Assessment Neuro-Oncology (RANO) Working Group criteria. Results At 8–12 weeks follow-up, seven (50%) patients showed a partial response, three (21.4%) patients were stable, and four (28.6%) patients progressed according to RANO criteria. hT2-ADC histograms demonstrated statistically significant changes in skewness in relation to PFS at 6 months. Patients with increasing skewness (n=11) following B/I therapy had significantly shorter PFS than did patients with decreasing or stable skewness values (n=3, median percentage change in skewness 54% versus −3%, p=0.04). Conclusion In rHGG patients, the change in ADC histogram skewness may be predictive for treatment response early in the course of anti-angiogenic therapy and more sensitive than treatment assessment based solely on RANO criteria. PMID:21125399

  4. Learning Geospatial Analysis Skills with Consumer-Grade GPS Receivers and Low Cost Spatial Analysis Software

    ERIC Educational Resources Information Center

    Linehan, Peter E.

    2006-01-01

    Spatial analysis technologies are increasingly important tools for all aspects of forest resource management. Field work previously accomplished with map, compass, and engineers' scale is now being augmented, or superseded, by the use of GPS and GIS. Professional-grade GPS receivers and commercial GIS software are preferred for their accuracy and…

  5. 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

  6. 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

    2016-01-01

    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

  7. Can metronomic maintenance with weekly vinblastine prevent early relapse/progression after bevacizumab-irinotecan in children with low-grade glioma?

    PubMed

    Heng, Marie Amélie; Padovani, Laetitia; Dory-Lautrec, Philippe; Gentet, Jean Claude; Verschuur, Arnaud; Pasquier, Eddy; Figarella-Branger, Dominique; Scavarda, Didier; André, Nicolas

    2016-07-01

    The association of bevacizumab and irinotecan has been shown to display a quick efficacy in low-grade glioma (LGG), but most patients relapse within months after cessation of therapy. From October 2012 to March 2014, four patients have been treated with irinotecan-bevacizumab followed by a metronomic maintenance with weekly vinblastine to try to prevent relapses. After a median follow-up of 23 months after the end of the bevacizumab-irinotecan induction, no patient relapsed. These observations suggest that maintenance chemotherapy with weekly vinblastine after an induction by irinotecan-bevacizumab can improve progression-free survival in children with LGG. PMID:27037940

  8. Prognostic factors and survival study in high-grade glioma in the elderly.

    PubMed

    Álvarez de Eulate-Beramendi, Sayoa; Álvarez-Vega, Marco Antonio; Balbin, Milagros; Sanchez-Pitiot, Ana; Vallina-Alvarez, Aitana; Martino-González, Juan

    2016-06-01

    Background Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in adults. Due to the ageing of the population, diagnosis in the elderly is becoming more common. The aim of this study was to analyse different combinations of treatments and to identify preoperative factors, including O6-methylguanine-DNA methyltransferase status, that may be associated with decreased survival among patients older than 70 years. Methods and materials We retrospectively included all patients over 70 years of age, who underwent surgery at the Department of Neurosurgery (HUCA and HUMV) and were diagnosed of GBM by pathological criteria from January 2007 to September 2014. Results Eighty-one patients were analysed, whose mean age was 75 (SD 4) and 48 were male. Karnofsky performance status (KPS) was over 70 in 61 patients and 38.3% presented with motor deficit. Sixty-three patients underwent resection, and 18 had only a diagnostic biopsy. The complication rate was 17.28% and mortality rate was 7.4%. Survival was increased in patients who received radiotherapy (n = 41) or additional chemotherapy (n = 26) (p < 0.001). KPS < 70 was an independent factor associated with low-rate survival. Patients with optimal treatment had a median survival of 8 months compared to patients with suboptimal treatment who had a median survival of 4 months (p < 0.001). Conclusions This study suggests that KPS is the most important preoperative prognostic factor. Maximal safe resection followed by radical radiotherapy and temozolomide might be the optimal treatment of choice since glioblastoma-diagnosed patients over 70 years of age showed a statistically significant survival benefit. PMID:26828095

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

    SciTech Connect

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

    2011-09-01

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

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

    PubMed

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

    2016-05-01

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

  11. Demographic and School Characteristics of Students Receiving Special Education in the Elementary Grades. Issue Brief. NCES 2007-005

    ERIC Educational Resources Information Center

    Herring, William L.; McGrath, Daniel J.; Buckley, Jacquelyn A.

    2007-01-01

    This Issue Brief provides a detailed description of the proportion of elementary school students receiving special education in kindergarten, first grade, third grade, and fifth grade; the primary disabilities of these students; and the variation in these measures across a range of demographic and school characteristics. Data for this analysis are…

  12. Treatment With Bevacizumab Plus Carboplatin for Recurrent Malignant Glioma

    PubMed Central

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

    2016-01-01

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

  13. 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

  14. Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery

    NASA Astrophysics Data System (ADS)

    Valdés, Pablo A.; Kim, Anthony; Leblond, Frederic; Conde, Olga M.; Harris, Brent T.; Paulsen, Keith D.; Wilson, Brian C.; Roberts, David W.

    2011-11-01

    Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin concentration, oxygen saturation, and optical scattering parameters. We developed a diagnostic algorithm for intra-operative tissue delineation that accounts for the combined tumor-specific predictive capabilities of these quantitative biomarkers. Tumor tissue delineation achieved accuracies of up to 94% (specificity = 94%, sensitivity = 94%) across a range of glioma histologies beyond current state-of-the-art optical approaches, including state-of-the-art fluorescence image guidance. This multiple biomarker strategy opens the door to optical methods for surgical guidance that use quantification of well-established neoplastic processes. Future work would seek to validate the predictive power of this proof-of-concept study in a separate larger cohort of patients.

  15. Calcification on CT is a simple and valuable preoperative indicator of 1p/19q loss of heterozygosity in supratentorial brain tumors that are suspected grade II and III gliomas.

    PubMed

    Saito, Taiichi; Muragaki, Yoshihiro; Maruyama, Takashi; Komori, Takashi; Tamura, Manabu; Nitta, Masayuki; Tsuzuki, Shunsuke; Kawamata, Takakazu

    2016-07-01

    Gliomas with 1p/19q loss of heterozygosity (LOH) are known to be associated with longer patient survival and higher sensitivity to treatment than tumors without 1p/19q LOH. This study was designed to clarify whether the preoperative finding of calcification on CT was correlated with 1p/19q LOH in patients with suspected WHO grade II and III gliomas. This study included 250 adult patients who underwent resection for primary supratentorial tumors at Tokyo Women's Medical University Hospital. The tumors were suspected, based on MRI findings, to be WHO grade II or III gliomas. The presence of calcification on the patients' CT images was qualitatively evaluated before treatment. After surgery, the resected tumors were examined to determine their 1p/19q status and mutations of IDH1 and p53. The presence of calcification was significantly correlated with 1p/19q LOH (P < 0.0001), with a positive predictive value of 91 %. The tumors of all the 78 patients with calcification were diagnosed as oligodendroglial tumors. Seventy of these patients showed classic oligodendroglial features, while 8 patients showed non-classic features. Calcification on CT is a simple and valuable preoperative indicator of 1p/19q LOH in supratentorial brain tumors that are suspected to be WHO grade II and III gliomas. PMID:26849373

  16. Diffusion and Perfusion MRI to Differentiate Treatment-Related Changes Including Pseudoprogression from Recurrent Tumors in High-Grade Gliomas with Histopathologic Evidence

    PubMed Central

    Prager, A.J.; Martinez, N.; Beal, K.; Omuro, A.; Zhang, Z.; Young, R.J.

    2016-01-01

    BACKGROUND AND PURPOSE Treatment-related changes and recurrent tumors often have overlapping features on conventional MR imaging. The purpose of this study was to assess the utility of DWI and DSC perfusion imaging alone and in combination to differentiate treatment-related effects and recurrent high-grade gliomas. MATERIALS AND METHODS We retrospectively identified 68 consecutive patients with high-grade gliomas treated by surgical resection followed by radiation therapy and temozolomide, who then developed increasing enhancing mass lesions indeterminate for treatment-related changes versus recurrent tumor. All lesions were diagnosed by histopathology at repeat surgical resection. ROI analysis was performed of the enhancing lesion on the ADC and DSC maps. Measurements made by a 2D ROI of the enhancing lesion on a single slice were recorded as ADCLesion and rCBVLesion, and measurements made by the most abnormal small fixed diameter ROI as ADCROI and rCBVROI. Statistical analysis was performed with Wilcoxon rank sum tests with P = .05. RESULTS Ten of the 68 patients (14.7%) had treatment-related changes, while 58 patients (85.3%) had recurrent tumor only (n = 19) or recurrent tumor mixed with treatment effect (n = 39). DWI analysis showed higher ADCLesion in treatment-related changes than in recurrent tumor (P = .003). DSC analysis revealed lower relative cerebral blood volume (rCBV)Lesion and rCBVROI in treatment-related changes (P=.003 andP=.011, respectively). Subanalysis of patients with suspected pseudoprogression also revealed higher ADCLesion (P = .001) and lower rCBVLesion (P = .028) and rCBVROI (P = .032) in treatment-related changes. Applying a combined ADCLesion and rCBVLesion model did not outperform either the ADC or rCBV metric alone. CONCLUSIONS Treatment-related changes showed higher diffusion and lower perfusion than recurrent tumor. Similar correlations were found for patients with suspected pseudoprogression. PMID:25593202

  17. Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival.

    PubMed

    McBride, Sean M; Perez, Daniel A; Polley, Mei-Yin; Vandenberg, Scott R; Smith, Justin S; Zheng, Shichun; Lamborn, Kathleen R; Wiencke, John K; Chang, Susan M; Prados, Michael D; Berger, Mitchel S; Stokoe, David; Haas-Kogan, Daphne A

    2010-03-01

    Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway. Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 5'-promoter region of PTEN using methylation-specific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma. PMID:19705067

  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. Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma

    PubMed Central

    Tabouret, Emeline; Boudouresque, Françoise; Barrie, Maryline; Matta, Mona; Boucard, Celine; Loundou, Anderson; Carpentier, Antoine; Sanson, Marc; Metellus, Philippe; Figarella-Branger, Dominique; Ouafik, L'Houcine; Chinot, Olivier

    2014-01-01

    Background A predictive marker of bevacizumab activity is an unmet medical need. We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high-grade glioma treated with bevacizumab. Methods Analyzed in plasma were a set of 11 prebiomakers of interest (vascular endothelial growth factor receptor [VEGF]; VEGF receptor 2; basic fibroblast growth factor; stromal cell derived factor 1; placenta growth factor; urokinase-type plasminogen activator; plasminogen activator inhibitor 1; matrix metalloproteinases 2, 7, and 9; and adrenomedulline), using ELISA, at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients (Cohort 1). Correlations were validated in a separate retrospective cohort (Cohort 2; n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort 3; n = 34). Dosages were correlated to objective response, progression-free survival (PFS), and overall survival (OS). Results In Cohort 1, high MMP2 baseline level was associated with a probability of objective response of 83.3% versus 15.4% for low MMP2 level (P = .001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46–10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58–13.53; P = .005), as decrease of VEGF (P = .038 for PFS and P = .013 for OS) and MMP9 (P = .016 for PFS and P = .025 for OS). In Cohort 2, MMP2, but not MMP9, confirmed its predictive significance. In Cohort 3, no association was found between MMP2, MMP9, and outcome. Conclusion In patients with recurrent high-grade glioma treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed. PMID:24327581

  20. 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

  1. 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review.

    PubMed

    Guyotat, Jacques; Pallud, Johan; Armoiry, Xavier; Pavlov, Vladislav; Metellus, Philippe

    2016-01-01

    The current first-line treatment of malignant gliomas consists in surgical resection (if possible) as large as possible. The existing tools don't permit to identify the limits of tumor infiltration, which goes beyond the zone of contrast enhancement on MRI. The fluorescence-guided malignant gliomas surgery was started 15 years ago and had become a standard of care in many countries. The technique is based on fluorescent molecule revelation using the filters, positioned within the surgical microscope. The fluorophore, protoporphyrin IX (PpIX), is converted in tumoral cells from 5-aminolevulinic acid (5-ALA), given orally before surgery. Many studies have shown that the ratio of gross total resections was higher if the fluorescence technique was used. The fluorescence signal intensity is correlated to the cell density and the PpIX concentration. The current method has a very high specificity but still lower sensibility, particularly regarding the zones with poor tumoral infiltration. This book reviews the principles of the technique and the results (extent of resection and survival). PMID:26508406

  2. 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

  3. Receivers

    NASA Astrophysics Data System (ADS)

    Donnelly, H.

    1983-07-01

    Before discussing Deep Space Network receivers, a brief description of the functions of receivers and how they interface with other elements of the Network is presented. Different types of receivers are used in the Network for various purposes. The principal receiver type is used for telemetry and tracking. This receiver provides the capability, with other elements of the Network, to track the space probe utilizing Doppler and range measurements, and to receive telemetry, including both scientific data from the onboard experiments and engineering data pertaining to the health of the probe. Another type of receiver is used for radio science applications. This receiver measures phase perturbations on the carrier signal to obtain information on the composition of solar and planetary atmospheres and interplanetary space. A third type of receiver utilizes very long baseline interferometry (VLBI) techniques for both radio science and spacecraft navigation data. Only the telemetry receiver is described in detail in this document. The integration of the Receiver-Exciter subsystem with other portions of the Deep Space Network is described.

  4. Receivers

    NASA Technical Reports Server (NTRS)

    Donnelly, H.

    1983-01-01

    Before discussing Deep Space Network receivers, a brief description of the functions of receivers and how they interface with other elements of the Network is presented. Different types of receivers are used in the Network for various purposes. The principal receiver type is used for telemetry and tracking. This receiver provides the capability, with other elements of the Network, to track the space probe utilizing Doppler and range measurements, and to receive telemetry, including both scientific data from the onboard experiments and engineering data pertaining to the health of the probe. Another type of receiver is used for radio science applications. This receiver measures phase perturbations on the carrier signal to obtain information on the composition of solar and planetary atmospheres and interplanetary space. A third type of receiver utilizes very long baseline interferometry (VLBI) techniques for both radio science and spacecraft navigation data. Only the telemetry receiver is described in detail in this document. The integration of the Receiver-Exciter subsystem with other portions of the Deep Space Network is described.

  5. The role of 5-aminolevulinic acid in enhancing surgery for high-grade glioma, its current boundaries, and future perspectives: A systematic review.

    PubMed

    Mansouri, Alireza; Mansouri, Sheila; Hachem, Laureen D; Klironomos, George; Vogelbaum, Michael A; Bernstein, Mark; Zadeh, Gelareh

    2016-08-15

    5-Aminolevulinic acid (5-ALA) has been approved as an intraoperative adjunct in glioma surgery in Europe, but not North America. A systematic review was conducted to assess the evidence regarding 5-ALA as a surgical adjunct. The MEDLINE, EMBASE, and CENTRAL databases were searched, using terms relevant to "5-ALA" and "high-grade gliomas." Included studies were based on adults aged ≥18 years who underwent surgical resection/biopsy. No language or date limitations were used. Forty-three studies (1830 patients) were identified. Thirty-six were coordinated by European countries, 2 were in the United States, and none were in Canada. One was randomized, 28 were prospective, and 14 were retrospective. Twenty-six studies assessed the utility of 5-ALA as a diagnostic tool, 24 assessed its influence on the extent of resection (EOR), 9 assessed survival, and 22 reported adverse events. 5-ALA had high sensitivity and positive predictive value, whereas its specificity increased with additional adjuncts. The EOR increased with 5-ALA, but only progression-free survival was significantly influenced. Reporting of adverse events was not systematic. The use of 5-ALA improved tumor visualization and thus enabled a greater EOR and perhaps increased survival. However, additional adjuncts may be necessary for maximizing the specificity of resection and patient safety. Additional parameters, such as patient quality of life and health economic analyses, would be informative. Thus, additional systematic collection of prospective evidence may be necessary for the global incorporation of this potentially valuable surgical adjunct into routine practice. Cancer 2016;122:2469-78. © 2016 American Cancer Society. PMID:27183272

  6. Prospective longitudinal evaluation of emotional and behavioral functioning in pediatric patients with low-grade glioma treated with conformal radiation therapy.

    PubMed

    Willard, Victoria W; Conklin, Heather M; Wu, Shengjie; Merchant, Thomas E

    2015-03-01

    Patients with low-grade glioma (LGG) who are successfully treated with irradiation are at increased risk for cognitive and psychosocial late effects. Conformal radiation therapy (CRT) allows sparing of cognitive deficits, but how it affects emotional and behavioral functioning remains unclear. We performed a prospective longitudinal study of the emotional and behavioral functioning of pediatric patients with LGG in the first 5 years post-CRT. Ninety-five pediatric patients with LGG treated on an institutional Phase II trial (August 1997-June 2009) underwent neuropsychological assessments pre-CRT and 6, 12, 24, 36, 48, and 60 months post-CRT. Parent-reported scores on the Child Behavior Checklist (CBCL) were analyzed. Three competence scales (School Competence, Social Competence, and Activities), two summary scales (Internalizing Problems and Externalizing Problems), and two subscales of theoretical interest (Attention Problems and Social Problems) from the CBCL were used. Among 80 eligible patients [44 female, 68 white], 51 had pilocytic astrocytoma and 13 had optic pathway glioma. Mean age at diagnosis was 6.8 years (SD = 4.3 years) and at CRT initiation was 8.9 years (SD = 3.4 years). Before CRT, deficits were demonstrated on the competence scales (mean scores below normative mean) and the Attention Problems and Social Problems subscales (mean scores above normative means). This trend continued at 5 years post-CRT. Longitudinal trajectories of emotional and behavioral functioning were stable over 5 years. Emotional and behavioral deficits remain relatively stable over the 5 years post-CRT in patients with LGG, suggesting that CRT may not exacerbate pre-existing psychosocial difficulties in this population. PMID:25573605

  7. 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

  8. Prognostic value of blood flow measurements using arterial spin labeling in gliomas.

    PubMed

    Furtner, Julia; Bender, Benjamin; Braun, Christian; Schittenhelm, Jens; Skardelly, Marco; Ernemann, Ulrike; Bisdas, Sotirios

    2014-01-01

    The period of event-free survival (EFS) within the same histopathological glioma grades may have high variability, mainly without a known cause. The purpose of this study was to reveal the prognostic value of quantified tumor blood flow (TBF) values obtained by arterial spin labeling (ASL) for EFS in patients with histopathologically proven astrocytomas independent of WHO (World Health Organization) grade. Twenty-four patients with untreated gliomas underwent tumor perfusion quantification by means of pulsed ASL in 3T. The clinical history of the patients was retrospectively extracted from the local database. Six patients had to be excluded due to insufficent follow-up data for further evaluation or histopathologically verified oligodendroglioma tumor components. Receiver operating characteristic (ROC) curves were used to define an optimal cut-off value of maximum TBF (mTBF) values for subgrouping in low-perfused and high-perfused gliomas. Kaplan-Meier curves and Cox proportional hazard regression model were used to determine the prognostic value of mTBF for EFS. An optimal mTBF cut-off value of 182 ml/100 g/min (sensitivity  = 83%, specificity  = 100%) was determined. Patients with low-perfused gliomas had significantly longer EFS compared to patients with high-perfused gliomas (p = 0.0012) independent of the WHO glioma grade. Quantified mTBF values obtained by ASL offer a new and totally non-invasive marker to prognosticate the EFS, independently on histopathological tumor grading, in patients with gliomas. PMID:24911025

  9. Prognostic Value of Blood Flow Measurements Using Arterial Spin Labeling in Gliomas

    PubMed Central

    Furtner, Julia; Bender, Benjamin; Braun, Christian; Schittenhelm, Jens; Skardelly, Marco; Ernemann, Ulrike; Bisdas, Sotirios

    2014-01-01

    The period of event-free survival (EFS) within the same histopathological glioma grades may have high variability, mainly without a known cause. The purpose of this study was to reveal the prognostic value of quantified tumor blood flow (TBF) values obtained by arterial spin labeling (ASL) for EFS in patients with histopathologically proven astrocytomas independent of WHO (World Health Organization) grade. Twenty-four patients with untreated gliomas underwent tumor perfusion quantification by means of pulsed ASL in 3T. The clinical history of the patients was retrospectively extracted from the local database. Six patients had to be excluded due to insufficent follow-up data for further evaluation or histopathologically verified oligodendroglioma tumor components. Receiver operating characteristic (ROC) curves were used to define an optimal cut-off value of maximum TBF (mTBF) values for subgrouping in low-perfused and high-perfused gliomas. Kaplan-Meier curves and Cox proportional hazard regression model were used to determine the prognostic value of mTBF for EFS. An optimal mTBF cut-off value of 182 ml/100 g/min (sensitivity  = 83%, specificity  = 100%) was determined. Patients with low-perfused gliomas had significantly longer EFS compared to patients with high-perfused gliomas (p = 0.0012) independent of the WHO glioma grade. Quantified mTBF values obtained by ASL offer a new and totally non-invasive marker to prognosticate the EFS, independently on histopathological tumor grading, in patients with gliomas. PMID:24911025

  10. Risk factors for seizures and antiepileptic drug-associated adverse effects in high-grade glioma patients: A multicentre, retrospective study in Hong Kong

    PubMed Central

    Woo, Peter Yat-Ming; Chan, Danny Tat-Ming; Chan, Kwong-Yau; Wong, Wai-Kei; Po, Yin-Chung; Kwok, John Ching-Kong; Poon, Wai-Sang

    2015-01-01

    Aim The aim of this present study was to determine the frequency, as well as risk factors, for seizures and antiepileptic drug (AED)-associated adverse effects among high-grade glioma (HGG) patients. Patients and Methods A multicentre, retrospective study of adult Chinese Hong Kong patients from three neurosurgical centres diagnosed with supratentorial HGG between 1 January 2001 and 31 December 2010 was performed. Results A total of 198 patients, with a mean age of 55 years (range: 18–88) and a mean follow up of 15 months, was recruited. Most suffered from glioblastoma multiforme (GBM) (63 per cent) followed by anaplastic astrocytoma (25 per cent). Median overall survival for patients with GBM was 8 months, and 11 months for those with grade III gliomas. Prophylactic AED was prescribed in 165 patients (83 per cent), and 64 per cent of patients were continued until end of life or last follow up. A total of 112 patients (57 per cent) experienced seizures at a mean duration of 8 months postoperatively (range: 1 day–75 months). Independent predictors for seizures were a diagnosis of GBM [adjusted odds ratio (OR): 2.33, 95 per cent confidence interval (CI): 1.21–4.52] and adjuvant radiotherapy (adjusted OR: 2.97, 95 per cent CI: 1.49–6.62). One-fifth of patients (21 per cent) experienced AED adverse effects, with idiosyncratic cutaneous reactions and hepatotoxicity most frequently observed. An independent predictor for adverse effects was exposure to aromatic AED, such as phenytoin, carbamazepine and phenobarbital (adjusted OR: 3.32, 95 per cent CI: 1.32–8.40). Conclusions Antiepileptic drug prescription for primary seizure prophylaxis is both pervasive and prolonged for HGG patients. Seizures occur frequently, but most were delayed and none were life threatening. Judicious prescription of AED is required, especially when a significant proportion of patients experience adverse effects. Patients with a diagnosis of GBM and exposure to radiotherapy

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

    PubMed

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

    2016-01-01

    Diffuse low grade gliomas (DLGG) are continuously progressive primary brain neoplasms that lead to neurological deficits and death. Treatment strategies are controversial. Randomized trials establishing the prognostic value of surgery do not exist. Here, we report the results of a nine-year near-randomized patient distribution between resection and biopsy. Until 2012, the Department of Neurosurgery and the Department of Stereotactic Neurosurgery at the University Medical Center Freiburg were organized as separate administrative units both coordinating DLGG patient treatment independently. All consecutive adult patients with a new diagnosis of DLGG by either stereotactic biopsy or resection were included. Pre- and post-operative tumor volumetry was performed. 126 patients, 87 men (69%), 39 women (31%), median age 41 years, were included. 77 (61%) were initially managed by biopsy, 49 (39%) by resection. A significant survival benefit was found for patients with an initial management by resection (5-year OS 82% vs. 54%). The survival benefit of patients with initial resection was reserved to patients with a residual tumor volume of less than 15 cm(3). Maximum safe resection is the first therapy of choice in DLGG patients if a near-complete tumor removal can be achieved. Accurate prediction of the extent-of-resection is required for selection of surgical candidates. PMID:27574036

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

    PubMed Central

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

    2016-01-01

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

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

    ClinicalTrials.gov

    2016-04-18

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

  14. 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

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

    PubMed

    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

    2015-11-24

    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. (64)Cu-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 (χ(2) = 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

  16. Phase 2 Study of Temozolomide-Based Chemoradiation Therapy for High-Risk Low-Grade Gliomas: Preliminary Results of Radiation Therapy Oncology Group 0424

    SciTech Connect

    Fisher, Barbara J.; Hu, Chen; Macdonald, David R.; Lesser, Glenn J.; Coons, Stephen W.; Brachman, David G.; Ryu, Samuel; Werner-Wasik, Maria; Bahary, Jean-Paul; Liu, Junfeng; Chakravarti, Arnab; Mehta, Minesh

    2015-03-01

    Purpose: Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power. Methods and Materials: Patients with LGGs with 3 or more risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of >1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ. Results: From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%-80.8%), which was significantly improved compared to that of prespecified historical control values (P<.001). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis. Conclusions: The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P<.001) and the study-hypothesized rate of 65%.

  17. Practical molecular pathologic diagnosis of infiltrating gliomas.

    PubMed

    Pekmezci, Melike; Perry, Arie

    2015-03-01

    Recent advances in molecular diagnostics have led to better understanding of glioma tumorigenesis and biology. Numerous glioma biomarkers with diagnostic, prognostic, and predictive value have been identified. Although some of these markers are already part of the routine clinical management of glioma patients, data regarding others are limited and difficult to apply routinely. In addition, multiple methods for molecular subclassification have been proposed either together with or as an alternative to the current morphologic classification and grading scheme. This article reviews the literature regarding glioma biomarkers and offers a few practical suggestions. PMID:25783821

  18. O8.07HISTOLOGY, LOCALISATION, TREATMENT AND OUTCOME OF 339 CONSECUTIVE CHILDREN AND ADOLESCENTS WITH LOW GRADE GLIOMAS TREATED AT THE MEDICAL UNIVERSITY OF VIENNA BETWEEN 1993 AND 2012

    PubMed Central

    Slavc, I.; Chocholous, M.; Woehrer, A.; Heumesser, R.; Azizi, A.; Haberler, C.; Peyrl, A.; Dorfer, C.; Dieckmann, K.; Czech, T.

    2014-01-01

    Low grade gliomas (LGG) comprise a spectrum of different tumor entities corresponding to WHO grade I and II, including pilocytic astrocytoma, diffuse glioma and glioneuronal tumors. LGG in children differ in histologic distribution, molecular profile, localisation in the CNS and outcome from LGGs in adults. We report on a series of patients treated at a single center over 20 years. PATIENTS: Between 1993 and 2012, 339 consecutive patients with a median age of 8 years (range 4 months - 18 years, p25 = 3.7 years, p75 = 13.4 years) were treated at the Medical University of Vienna. 19.5% of the patients were <3 years of age at diagnosis. Gender distribution was equal. Tumors were associated with syndromes in 84 of the patients (NF1: n = 64, TSC: n = 17, and other: n = 3). Localisation was supratentorial midline in 112, cerebral hemispheres in 105, posterior fossa in 86, ventricular system in 27 and spinal in 9 patients. 66 patients with a median age of 4.4 years had optic pathway gliomas. RESULTS: Gross total resection was performed in 109, subtotal resection in 49, partial resection in 57, and biopsy in 22 patients. 83 patients had no surgery (patients with NF1, TSC, tectal glioma or tumors confined to the optic nerves and chiasm), and in the remaining the degree of resection was not evaluable. 37 patients had 2 tumor surgeries, 14 three, 5 four and one had 5 tumor surgeries during their course of disease. Histology was pilocytic astrocytoma in 122, pilomyxoid astrocytoma in 10, diffuse astrocytoma in 42, ganglioglioma in 30, subependymal giant cell astrocytoma in 17, oligoastrocytoma in 11, and other rarer histologies in the remaining patients. Twelve patients (3.5%) died and 84 patients (24.8%) had at least one event. After a median follow-up of 107 months (14-300) the 1-year overall survival (OS) was 100%, the 10-year OS 96.1 ± 1.2%, and the 20-year OS 95.3 ± 1.4%. Event-free survival (EFS) after 1 year was 92.9 ± 1.4%, after 10 years 73.8 ± 2.6% and after 20

  19. Biomarker-driven diagnosis of diffuse gliomas.

    PubMed

    Appin, Christina L; Brat, Daniel J

    2015-11-01

    The diffuse gliomas are primary central nervous system tumors that arise most frequently in the cerebral hemispheres of adults. They are currently classified as astrocytomas, oligodendrogliomas or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), grade IV, is the highest grade and most common form. The diagnosis of diffuse gliomas has historically been based primarily on histopathologic features, yet these tumors have a wide range of biological behaviors that are only partially explained by morphology. Biomarkers have now become an established component of the neuropathologic diagnosis of gliomas, since molecular alterations aid in classification, prognostication and prediction of therapeutic response. Isocitrate dehydrogenase (IDH) mutations are frequent in grades II and III infiltrating gliomas of adults, as well as secondary GBMs, and are a major discriminate of biologic class. IDH mutant infiltrating astrocytomas (grades II and III), as well as secondary GBMs, are characterized by TP53 and ATRX mutations. Oligodendrogliomas are also IDH mutant, but instead are characterized by 1p/19q co-deletion and mutations of CIC, FUBP1, Notch1 and the TERT promoter. Primary GBMs typically lack IDH mutations and demonstrate EGFR, PTEN, TP53, PDGFRA, NF1 and CDKN2A/B alterations and TERT promoter mutations. Pediatric gliomas differ in their spectrum of disease from those in adults; high grade gliomas occurring in children frequently have mutations in H3F3A, ATRX and DAXX, but not IDH. Circumscribed, low grade gliomas, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma and ganglioglioma, need to be distinguished from diffuse gliomas in the pediatric population. These gliomas often harbor mutations or activating gene rearrangements in BRAF. PMID:26004297

  20. Pediatric gliomas as neurodevelopmental disorders.

    PubMed

    Baker, Suzanne J; Ellison, David W; Gutmann, David H

    2016-06-01

    Brain tumors represent the most common solid tumor of childhood, with gliomas comprising the largest fraction of these cancers. Several features distinguish them from their adult counterparts, including their natural history, causative genetic mutations, and brain locations. These unique properties suggest that the cellular and molecular etiologies that underlie their development and maintenance might be different from those that govern adult gliomagenesis and growth. In this review, we discuss the genetic basis for pediatric low-grade and high-grade glioma in the context of developmental neurobiology, and highlight the differences between histologically-similar tumors arising in children and adults. GLIA 2016;64:879-895. PMID:26638183

  1. Optic glioma

    MedlinePlus

    ... et al. Optic Glioma in Children: A Retrospective Analysis of 101 Cases. American Journal of Clinical Oncology. 2013; 36(3):287-292. Karcioglu ZA, Haik BG. Eye, orbit, and adnexal structures. In: Abeloff MD, Armitage JO, ...

  2. Ki-67 proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas

    PubMed Central

    Duregon, Eleonora; Bertero, Luca; Pittaro, Alessandra; Soffietti, Riccardo; Rudà, Roberta; Trevisan, Morena; Papotti, Mauro; Ventura, Laura; Senetta, Rebecca; Cassoni, Paola

    2016-01-01

    Despite several molecular signatures for “lower grade diffuse gliomas” (LGG) have been identified, WHO grade still remains a cornerstone of treatment guidelines. Mitotic count bears a crucial role in its definition, although limited by the poor reproducibility of standard Hematoxylin & Eosin (H&E) evaluation. Phospho-histone-H3 (PHH3) and Ki-67 have been proposed as alternative assays of cellular proliferation. Therefore in the present series of 141 LGG, the molecular characterization (namely IDH status, 1p/19q co-deletion and MGMT promoter methylation) was integrated with the tumor “proliferative trait” (conventional H&E or PHH3-guided mitotic count and Ki-67 index) in term of prognosis definition. Exclusively high PHH3 and Ki-67 values were predictor of poor prognosis (log rank test, P = 0.0281 for PHH3 and P = 0.032 for Ki-67), unlike standard mitotic count. Based on Cox proportional hazard regression analyses, among all clinical (age), pathological (PHH3 and Ki-67) and molecular variables (IDH, 1p/19q codeletion and MGMT methylation) with a prognostic relevance at univariate survival analysis, only IDH expression (P = 0.001) and Ki-67 proliferation index (P = 0.027) proved to be independent prognostic factors. In addition, stratifying by IDH expression status, high Ki-67 retained its prognostic relevance uniquely in the IDH negative patient (P = 0.029) doubling their risk of death (hazard ratio = 2.27). Overall, PHH3 immunostaining is the sole reliable method with a prognostic value to highlight mitotic figures in LGG. Ki-67 proliferation index exceeds PHH3 mitotic count as a predictor of patient's prognosis, and should be integrated with molecular markers in a comprehensive grading system for LGG. PMID:27049832

  3. 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

  4. Imaging signatures of meningioma and low-grade glioma: a diffusion tensor, magnetization transfer and quantitative longitudinal relaxation time MRI study.

    PubMed

    Piper, Rory J; Mikhael, Shadia; Wardlaw, Joanna M; Laidlaw, David H; Whittle, Ian R; Bastin, Mark E

    2016-05-01

    Differentiation of cerebral tumor pathology currently relies on interpretation of conventional structural MRI and in some cases histology. However, more advanced MRI methods may provide further insight into the organization of cerebral tumors and have the potential to aid diagnosis. The objective of this study was to use multimodal quantitative MRI to measure the imaging signatures of meningioma and low-grade glioma (LGG). Nine adults with meningioma and 11 with LGG were identified, and underwent standard structural, quantitative longitudinal relaxation time (T1) mapping, magnetization transfer and diffusion tensor MRI. Maps of mean (〈D〉), axial (λAX) and radial (λRAD) diffusivity, fractional anisotropy (FA), magnetization transfer ratio (MTR) and T1 were generated on a voxel-by-voxel basis. Using structural and echo-planar T2-weighted MRI, manual region-of-interest segmentation of brain tumor, edema, ipsilateral and contralateral normal-appearing white matter (NAWM) was performed. Differences in imaging signatures between the different tissue types, both absolute mean values and ratios relative to contralateral NAWM, were assessed using t-tests with statistical significance set at p<0.05. For both absolute mean values and ratios relative to contralateral NAWM, there were significant differences in 〈D〉, λAX, λRAD, FA, MTR and T1 between meningioma and LGG tumor tissue, respectively. Only T1 and FA differed significantly between edematous tissue associated with the two tumor types. These results suggest that multimodal MRI biomarkers are significantly different, particularly in tumor tissue, between meningioma and LGG. By using quantitative multimodal MRI it may be possible to identify tumor pathology non-invasively. PMID:26708035

  5. Comparison of long-term survival between temozolomide-based chemoradiotherapy and radiotherapy alone for patients with low-grade gliomas after surgical resection

    PubMed Central

    Gai, Xiu-juan; Wei, Yu-mei; Tao, Heng-min; An, Dian-zheng; Sun, Jia-teng; Li, Bao-sheng

    2016-01-01

    Purpose This study was designed to compare the survival outcomes of temozolomide-based chemoradiotherapy (TMZ + RT) vs radiotherapy alone (RT-alone) for low-grade gliomas (LGGs) after surgical resection. Patients and methods In this retrospective analysis, we reviewed postoperative records of 69 patients with LGGs treated with TMZ + RT (n=31) and RT-alone (n=38) at the Shandong Cancer Hospital Affiliated to Shandong University between June 2011 and December 2013. Patients in the TMZ + RT group were administered 50–100 mg oral TMZ every day until the radiotherapy regimen was completed. Results The median follow-up since surgery was 33 months and showed no significant intergroup differences (P=0.06). There were statistically significant intergroup differences in the progression-free survival rate (P=0.037), with 83.9% for TMZ-RT group and 60.5% for RT-alone group. The overall 2-year overall survival (OS) rate was 89.86%. Age distribution (≥45 years and <45 years) and resection margin (complete resection or not) were significantly associated with OS (P=0.03 and P=0.004, respectively). Conclusion Although no differences were found in the 2-year OS between the TMZ + RT and RT-alone groups, there was a trend toward increased 2-year progression-free survival in the TMZ + RT group. With better tolerability, concurrent TMZ chemoradiotherapy may be beneficial for postoperative patients with LGGs. Age distribution and surgical margin are likely potential indicators of disease prognosis. The possible differences in long-term survival between the two groups and the links between prognostic factors and long-term survival may be worthy of further investigation. PMID:27574452

  6. Advanced MR Imaging of Gliomas: An Update

    PubMed Central

    Chiang, Shih-Wei; Chung, Hsiao-Wen; Tsai, Fong Y.; Chen, Cheng-Yu

    2013-01-01

    Recent advances in the treatment of cerebral gliomas have increased the demands on noninvasive neuroimaging for the diagnosis, therapeutic planning, tumor monitoring, and patient outcome prediction. In the meantime, improved magnetic resonance (MR) imaging techniques have shown much potentials in evaluating the key pathological features of the gliomas, including cellularity, invasiveness, mitotic activity, angiogenesis, and necrosis, hence, further shedding light on glioma grading before treatment. In this paper, an update of advanced MR imaging techniques is reviewed, and their potential roles as biomarkers of tumor grading are discussed. PMID:23862163

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

    SciTech Connect

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

    2006-11-15

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

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

    PubMed Central

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

    2011-01-01

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

  9. Epilepsy in patients with gliomas: incidence and control of seizures.

    PubMed

    Iuchi, Toshihiko; Hasegawa, Yuzo; Kawasaki, Koichiro; Sakaida, Tsukasa

    2015-01-01

    Brain tumor-related epilepsy (BTRE) is a unique condition that is distinct from primary epilepsy. The aim of this retrospective study was to clarify the epidemiology and results of treatment of BTRE in a single institution. From a database of 121 consecutive patients with supratentorial gliomas treated at Chiba Cancer Center from 2006-2012, the incidence and control of seizures before and after surgery were retrospectively evaluated. Epilepsy occurred in 33.9% of patients before surgery. All patients received prophylactic anti-epileptic drugs (AED) during surgery; however, seizures occurred in 9.1% of patients within the first postoperative week. During follow-up, seizures occurred in 48.3% of patients. The overall incidence of seizures was 73.7% in patients with World Health Organization Grade II gliomas, 66.7% in those with Grade III and 56.8% in those with Grade IV gliomas. Levetiracetam was very well tolerated. However, carbamazepine and phenytoin were poorly tolerated because of adverse effects. AED were discontinued in 56 patients. Fifteen of these patients (26.8%) had further seizures, half occurring within 3 months and 80% within 6 months of AED withdrawal. No clinical factors that indicated it was safe to discontinue AED were identified. The unpredictable epileptogenesis associated with gliomas and their excision requires prolonged administration of AED. To maintain quality of life and to safely and effectively control the tumor, it is necessary to select AED that do not adversely affect cognitive function or interact with other drugs, including anti-cancer agents. PMID:25192590

  10. 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.

  11. IDH1 Mutation in Gliomas in Mosul City - Iraq

    PubMed Central

    Saeed, Mohammed Sami

    2015-01-01

    BACKGROUND: IDH1 (isocitrate dehydrogenase 1) mutation might be encounter in the low grade glioma and directs the progression of the tumor to a higher grade. OBJECTIVE: To assess the frequency of IDH1 mutations in gliomas and to correlate the IDH1 positivity with the type and grade of tumors, the age and sex of the patients. MATERIAL AND METHODS: A retro– and prospective case series study. One hundred and nine cases of intracranial gliomas were collected between 2008 and 2014 from Mosul Private Laboratories and Al-Jamboree Teaching Hospitals in Mosul. IDH1 mutations were assessed immunohistochemically using anti-IDH1 R132H mouse monoclonal antibody. RESULTS: IDH1 mutation was perceived in 34.86% of gliomas. In adult gliomas, the secondary glioblastoma and the low-grade astrocytoma had the greatest values of IDH1 positivity (88.88% and 62.5% respectively), followed by oligoastrocytoma/oligodendroglioma (50.0%), and anaplastic astrocytoma (47.36%). The primary glioblastomsa showed 17.64% IDH1 positivity. Males and females expressed the IDH1 equally. While, there was no role of IDH1 in pediatric gliomas. CONCLUSION: IDH1 mutation is commonly present in adult gliomas particularly in low-grade gliomas, and secondary glioblastoma, with equal sex distribution, but it has no role in pediatric gliomas.

  12. ELTD1, A Potential New Biomarker for Gliomas

    PubMed Central

    Towner, Rheal A.; Jensen, Randy L.; Colman, Howard; Vaillant, Brian; Smith, Nataliya; Casteel, Rebba; Saunders, Debra; Gillespie, David L.; Silasi-Mansat, Robert; Lupu, Florea; Giles, Cory B.; Wren, Jonathan D.

    2012-01-01

    Background Glioblastoma multiforme (GBM), high-grade glioma, is characterized by being diffuse, invasive, and highly angiogenic, and has a very poor prognosis. Identification of new biomarkers could help in the further diagnosis of GBM. Objective To identify ELTD1 ([epidermal growth factor (EGF), latrophilin and seven transmembrane domain-containing 1] on chromosome 1) as a putative glioma-associated marker via a bioinformatic method. Methods We used advanced data mining and a novel bioinformatics method to predict ELTD1 as a potential novel biomarker that is associated with gliomas. Validation was done with immunohistochemistry (IHC), which was used to detect levels of ELTD1 in human high-grade gliomas, and rat F98 glioma tumors. In vivo levels of ELTD1 in rat F98 gliomas were assessed using molecular MRI (mMRI). Results ELTD1 was found to be significantly higher (P=.03) in high-grade gliomas (50 patients) compared to low-grade gliomas (21 patients), and compared well to traditional IHC markers including VEGF, GLUT-1,CAIX, and HIF-1α. ELTD1 gene expression indicates an association with grade, survival across grade, and an increase in the mesenchymal subtype. Significantly high (P<0.001) in vivo levels of ELTD1 were additionally found in F98 tumors, compared to normal brain tissue. Conclusion This study strongly suggests that associative analysis was able to accurately identify ELTD1 as a putative glioma-associated biomarker. The detection of ELTD1 was also validated in both rodent and human gliomas, and may serve as an additional biomarker for gliomas in pre-clinical and clinical diagnosis of gliomas. PMID:23096411

  13. Presence of neural progenitors in spontaneous canine gliomas: A histopathological and immunohistochemical study of 20 cases.

    PubMed

    Fernández, Francisco; Deviers, Alexandra; Dally, Claire; Mogicato, Giovanni; Delverdier, Maxence; Cauzinille, Laurent; Gnirs, Kirsten; Añor, Sònia; de la Fuente, Cristian; Fondevila, Dolors; Pumarola, Martí

    2016-03-01

    Gliomas are the most common primary brain tumours in humans and are associated with a poor prognosis. An accurate animal model of human glioma tumorigenesis is needed to test new treatment strategies. Dogs represent a promising model because they develop spontaneous diffusely-infiltrating gliomas. This study investigated whether spontaneous canine gliomas contain cancer stem cells previously identified in all grades of human gliomas. Twenty spontaneous cases of canine gliomas were graded according to the human WHO classification. The expression of different markers of lineage differentiation was evaluated with immunohistochemistry as follows: nestin and CD133 for neural stem cells, doublecortin for neuronal progenitor cells, Olig2 for glial progenitor cells, glial fibrillary acidic protein, vimentin and S-100 for mature glial cells, and NeuN and βIII-tubulin for mature neurons. Gliomas were characterised as follows: five grade II (oligodendrogliomas); nine grade III (seven anaplastic oligodendrogliomas, one anaplastic astrocytoma, one anaplastic oligoastrocytoma); six grade IV (glioblastomas). Immunohistochemical evaluation revealed that (1) nestin and CD133 were expressed in all grades of gliomas with a higher proportion of positive cells in high-grade gliomas; (2) the expression of S-100 protein and Olig2 did not differ substantially between astrocytic and oligodendroglial tumours, and (3) all gliomas were negative for mature neuron markers. The results demonstrated the presence of undifferentiated neural progenitors in all grades of spontaneous canine gliomas, confirming the relevance of this animal model for further studies on cancer stem cells. PMID:26831167

  14. 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

  15. An Intra-Individual Comparison of MRI, [18F]-FET and [18F]-FLT PET in Patients with High-Grade Gliomas

    PubMed Central

    Putzer, Daniel; Seiz, Marcel; Recheis, Wolfgang; Jacobs, Andreas H.; Stockhammer, Günther; Hutterer, Markus

    2014-01-01

    Objectives Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [18F]-FET and the nucleoside PET tracer [18F]-FLT in high-grade gliomas (HGG). Methods MRI, [18F]-FET and [18F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for [18F]-FET and [18F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearman's rank correlation coefficient and the Mann-Whitney U test. Results [18F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [18F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [18F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [18F]-FET PET detected 22 of 23 (96%) HGG. [18F]-FET uptake beyond areas of cT1 was found in 61% of cases and [18F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [18F]-FET compared to [18F]-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001). Conclusion In HGG [18F]-FET but not [18F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [18F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [18F]-FLT tracer uptake. PMID:24759867

  16. ARPP-19 promotes proliferation and metastasis of human glioma.

    PubMed

    Jiang, Tao; Zhao, Bing; Li, Xiaocan; Wan, Jinghai

    2016-09-01

    Glioma is the most common and aggressive type of human primary brain tumor with a poor outcome. The molecular mechanisms underlying glioma development and progression are still poorly understood. Recent studies have reported a novel role of ARPP-19 in the regulation of cell mitosis and cancer progression. However, no study has been carried out to determine the role of ARPP-19 in human glioma cells and assess the expression and clinical significance of ARPP-19 in human glioma. In this study, we systematically examined the role of ARPP-19 in glioma A172 cells and examined the expression of ARPP-19 and CD147 in 81 cases of human glioma tissue specimens and correlated them to clinicopathological parameters and patient survival. We found that ARPP-19 promoted both proliferation and metastasis of human glioma cells and the expression of ARPP-19 and CD147 in high-grade glioma was significantly higher than that in the low-grade glioma. Patients whose tumors were positive for expression of ARPP-19 or CD147 showed lower relapse-free survival and overall survival than patients whose tumors were negative for ARPP-19 or CD147, respectively. Pearson correlation analysis indicated that there was a statistically significant correlation between ARPP-19 and CD147. Expressions of ARPP-19 and CD147 may serve as biomarkers for high-grade glioma and poor patient survival. PMID:27380244

  17. Palliative and supportive care for glioma patients.

    PubMed

    Walbert, Tobias; Chasteen, Kristen

    2015-01-01

    The diagnosis of a brain tumor is a life-changing event for patients and families. High-grade gliomas are incurable and long-term survival remains limited. While low-grade glioma patients have better outcomes, their quality of life is often affected by a variety of symptoms as well. Helping glioma patients improve quality of life at all stages of illness is an important goal for the interdisciplinary care team. There is evidence from advanced lung cancer patients that early involvement of a palliative care team can improve patient's quality of life, symptom burden, and even survival and a similar approach benefits glioma patients as well. Patients with high-grade and low-grade glioma often suffer from significant symptom burden. We discuss how validated global symptom assessments and symptom-specific screening tools are useful to identify distressing symptoms. Seizures, fatigue, depression, and anxiety are some of the more common symptoms throughout the disease course and should be managed actively. Patients with glioma also have high symptom burden at the end of life and the majority lose decision-making capacity. Advance care planning conversations early in the disease course are essential to elicit the patient's wishes for end of life care and effective communication with surrogate decision makers during all stages of the disease helps ensure that those wishes are respected. PMID:25468232

  18. 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

  19. 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

  20. The Potential of Tetrandrine against Gliomas.

    PubMed

    Chen, Yun; Tseng, Sheng-Hong

    2010-09-01

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

  1. FINAL RESULTS OF A PROSPECTIVE MULTI-INSTITUTIONAL PHASE II STUDY OF EVEROLIMUS (RAD001), AN MTOR INHIBITOR, IN PEDIATRIC PATIENTS WITH RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA. A POETIC CONSORTIUM TRIAL

    PubMed Central

    Kieran, Mark W.; Yao, X.; Macy, M.; Leary, S.; Cohen, K.; MacDonald, T.; Allen, J.; Boklan, J.; Smith, A.; Nazemi, K.; Gore, L.; Trippett, T.; DiRenzo, J.; Narendran, A.; Perentesis, J.; Prabhu, S.; Pinches, N.; Robison, N.; Manley, P.; Chi, S.

    2014-01-01

    BACKGROUND: Purpose: The ras/raf signaling pathway is crucial in the development of pediatric low-grade gliomas (LGGs). Aberrant ras/raf signaling is involved in tumorigenesis through promotion of cell proliferation, survival, and differentiation in sporadic LGG. Everolimus (RAD001) is a potent and selective inhibitor of mTOR, a downstream element of the ras/raf pathway. The activity, safety and pharmacokinetics of everolimus in pediatric patients with radiographic recurrent/progressive LGG are presented. METHODS: Pediatric patients with radiographic progressive or recurrent LGGs without neurofibromatosis type I were treated with oral everolimus 5mg/m2/dose once daily. Therapy was provided for 28 days (one cycle) and could be repeated for a total of 12 cycles. Response, as determined by standard 2-D MRI criteria, was assessed for all patients. Pharmacokinetics, pharmacogenetics, pharmacodynamic parameters including inhibition of p70s6 kinase activity, 4E-BP1 phosphorylation inhibition and suppression of cMyc expression, as well as the toxicity profile of everolimus were evaluated. RESULTS: Twenty-three patients with a median age of 9 years (range, 3–17 years) were enrolled, all of whom had received prior chemotherapy (average # regimens = 2.7) including progression after a carboplatin-containing regimen. Median number of cycles of therapy was 10 (range, 1-12). Responses were determined by blinded central review and included 4 patients with PR (>50% decrease) and 13 with stable disease. Six patients had progressive disease by one year. Overall therapy was well tolerated; two patients discontinued therapy due to mouth sores (n = 1) and withdrawal of consent (n = 1). Everolimus PK parameters were similar to those previously reported in both adult and pediatric patients and drug trough levels were maintained above 5ng/ml. Pharmacodynamic analysis demonstrated inhibition of downstream targets of mTOR including phospho-S6 kinase, 4E-BP1 phosphorylation and c

  2. 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 0.08mm. 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 infiltrative

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

    ClinicalTrials.gov

    2014-07-09

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

  4. Outcomes of WHO Grade I Meningiomas Receiving Definitive or Postoperative Radiotherapy

    SciTech Connect

    Tanzler, Emily; Morris, Christopher G.; Kirwan, Jessica M.; Amdur, Robert J.; Mendenhall, William M.

    2011-02-01

    Purpose: We analyzed long-term local control and complications in patients with either pathologically confirmed or clinical World Health Organization Grade I meningiomas treated with definitive or postoperative radiotherapy (RT) at the University of Florida. Methods: Between 1984 and 2006, 146 patients were treated with definitive (n = 88) or postoperative RT after subtotal resection (n = 57) or gross total resection (n = 1). Patients were treated with conventional (n = 41), stereotactic (n = 103), or intensity-modulated RT (n = 2) to a median dose of 52.7 Gy and followed for a median of 7.3 years (range, 0.6-22.0 years) Results: The local control rates at 5 and 10 years were as follows: definitive RT, 99% and 99%; postoperative RT, 96% and 93%; and overall, 97% and 96%, respectively. The 5- and 10-year cause-specific survival rates were as follows: definitive RT 94% and 94%, postoperative RT, 100% and 96%; and overall, 96% and 95%, respectively. The 5- and 10-year overall survival rates were as follows: definitive RT, 81% and 75%; postoperative RT, 96% and 85%; and overall, 87% and 79%, respectively. Severe RT complications occurred in 6.8% of patients; severe surgery-related complications occurred in 10 (17%) of 58 patients treated surgically. Conclusions: The likelihood of cure after definitive RT or following subtotal resection is excellent. However, a small population of patients experience severe complications, even at the moderate dose used for this disease.

  5. 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

  6. ASSOCIATION OF MATRIX METALLOPROTEINASE 2 (MMP2) BASELINE PLASMA LEVEL WITH RESPONSE AND SURVIVAL AND CHANGE OVERTIME IN PATIENTS TREATED WITH BEVACIZUMAB FOR RECURRENT HIGH GRADE GLIOMA

    PubMed Central

    Chinot, Olivier-L; Boudouresque, Françoise; Barrie, Maryline; Matta, Mona; Boucard, Celine; Loundou, Anderson; Figarella-Branger, Dominique; Ouafik, L'Houcine; Tabouret, Emeline

    2014-01-01

    BACKGROUND: Predictive marker of bevacizumab activity is an unmet medical need. We evaluated predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high grade glioma (HGG) treated with bevacizumab. METHODS: A set of eleven prebiomakers of interest (VEGF, VEGF-R2, bFGF, SDF1, PlGF, uPA, PAI1, MMP2, MMP7, MMP9, and adrenomedulline) were analyzed in plasma, using ELISA, at baseline and 2 weeks apart from bevacizumab initiation in a prospective cohort of 26 patients (Cohort1). Correlations were validated in a separate retrospective cohort (Cohort2;n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort3;n = 34). Dosages were correlated to objective response (OR), Progression-free survival (PFS), and overall survival (OS). In cohort 1, multiple time points were performed up to progression. Additionally MMP2 and MMP9 plasma levels were analyzed in patients with newly diagnosed GB, after surgery. Finally, MMP2 and 9 RNA were assessed in tumor tissue of a separated group of paired newly diagnosed and recurrent GB (n = 29). RESULTS: In cohort1, high MMP2 baseline level was associated to a probability of OR of 83.3% versus 15.4% in case of low MMP2 level (p = 0.001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard-ratio(HR), 3.92; 95% confidence-interval(CI):1.46-10.52; p = 0.007) and OS (HR, 4.62; 95%CI 1.58-13.53; p = 0.005), as decrease of VEGF (p = 0.038 for PFS and p = 0.013 for OS) and MMP9 (p = 0.016 for PFS and p= 0.025 for OS). In cohort2, MMP2, but not MMP9, confirmed its predictive significance. In cohort3, no association was found between MMP2, MMP9 and outcome. In cohort 1, significant changes in MMP2 and MMP9 plasma levels were observed during treatment. MMP2 increased after Bev initiation (p = 0.002), and decreased at progression (p = 0.002) while MMP9 initially decreased (p = 0.007) then increased at progression (p = 0

  7. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas.

    PubMed

    Lau, Darryl; Hervey-Jumper, Shawn L; Chang, Susan; Molinaro, Annette M; McDermott, Michael W; Phillips, Joanna J; Berger, Mitchel S

    2016-05-01

    OBJECT There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity. METHODS A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated. RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating

  8. 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

  9. 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. PMID:26033611

  10. Analysis of hsa-miR-30a-5p expression in human gliomas.

    PubMed

    Wang, Kun; Jia, Zhifan; Zou, Jian; Zhang, Anling; Wang, Guangxiu; Hao, Jianwei; Wang, Yirong; Yang, Shuxu; Pu, Peiyu

    2013-07-01

    Our previous study demonstrated that miR-30a-5p was upregulated in six malignant glioma cell lines by microRNA(miRNA) array. For further verification of this finding, the expression of miR-30a-5p in 7 more malignant glioma cell lines, 43 freshly resected glioma samples and 75 archival paraffin embedded glioma specimens with different grade of malignancy were examined by qRT-PCR and in situ hybridization(ISH). Here, we present the first evidence that miR-30a-5p is overexpressed in glioma cell lines and glioma samples as compared to the normal brain tissues (NBTs), and its expression level is positively correlated with tumor grade of malignancy. It is concluded that miR-30a-5p may have the potential as a diagnostic or prognostic marker of gliomas and as the target of miRNA-based glioma therapy in further studies. PMID:23606081

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

    PubMed

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

    2013-01-01

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

  12. Immunohistochemical evaluation of tissue factor, fibrin/fibrinogen and D-dimers in canine gliomas.

    PubMed

    de la Fuente, Cristian; Pumarola, Martí; Blasco, Ester; Fernández, Francisco; Viu, Judit; Añor, Sònia

    2014-06-01

    In human gliomas, tissue factor (TF) is overexpressed, associated with the grade of malignancy and influences tumour biology. Intra-tumoural fibrin/fibrinogen deposition and activation of the fibrinolytic system also play a role in tumour cell proliferation and angiogenesis. The first aim of the present study was to investigate TF expression and the presence of fibrin/fibrinogen and D-dimers in canine glioma biopsies, graded according to the World Health Organization (WHO) classification of tumours of the central nervous system. The second aim was to investigate the occurrence of intravascular thrombosis (IVT) in canine gliomas, as a potential histological marker of glioma type or grade of malignancy. An immunohistochemical study using antibodies against TF, fibrin/fibrinogen and D-dimers was performed with 24 glioma samples, including 15 oligodendrogliomas, 6 astrocytomas and 3 mixed gliomas. Immunohistochemical data were statistically analysed to determine whether there was any relationship between glioma type and grade of malignancy. All gliomas were moderate to strongly positive for TF and the staining score was significantly higher (P = 0.04) in high-grade (III or IV) than in low-grade (II) gliomas. Intra-tumoural fibrin/fibrinogen deposition was detected in all tumour biopsies assessed, and D-dimers were detected in 17/24 gliomas. IVT was a frequent finding, but was not linked to a specific glioma type or malignancy grade. TF expression, fibrin/fibrinogen deposition, extravascular fibrinolytic system activation and IVT occur in canine gliomas. Canine glioma might be a suitable model for studying coagulation and fibrinolysis as potential therapeutic targets for human gliomas. PMID:24745770

  13. Glycosilated nucleolin as marker for human gliomas.

    PubMed

    Galzio, R; Rosati, F; Benedetti, E; Cristiano, L; Aldi, S; Mei, S; D'Angelo, B; Gentile, R; Laurenti, G; Cifone, M G; Giordano, A; Cimini, A

    2012-02-01

    Nucleolin is a multifunctional DNA and RNA binding protein involved in regulation of gene transcription, chromatin remodeling, RNA metabolism, and ribosomal RNA synthesis. Nucleolin seems to be over-expressed in highly proliferative cells and is involved in many aspect of gene expression: DNA recombination and replication, RNA transcription by RNA polymerase I and II, rRNA processing, mRNA stabilization, cytokinesis, and apoptosis. Although nucleolin is localized predominantly in the nucleolus, it has also been shown to be localized in a phosphorylated/glycolsilated form on the cell surface of different cells. Numerous articles dealing with surface nucleolin targeting for tumor therapy have been recently published. However, at present, no extensive informations are so far available for the presence of nucleolin in human gliomas. In the present work we investigated on the presence and localization of nucleolin in glioma on glioma specimens at different grade of malignancy and on primary glioma cell cultures derived by surgical resection, trying to correlate the presence of glycosilated membrane nucleolin with the malignancy grade. To this purpose an antibody produced by us against gp273 protein, demonstrated to recognized the glycosilated surface nucleolin, has been used. The results obtained demonstrate that surface nucleolin increase with the malignancy grade thus suggesting that it may constitute a histopathological marker for glioma grading and a possible tool for targeted therapy. PMID:21938743

  14. P17.05MAGIC MIRROR ON THE WALL, WHICH IS THE SHARPEST ONE OF ALL? EXTERNAL VALIDATION AND COMPARISON OF THREE DIFFERENT SCORES PREDICTING SURVIVAL AFTER REIRRADIATION OF PROGRESSIVE HIGH-GRADE GLIOMAS

    PubMed Central

    Müller, K.; Henke, G.; Compter, I.; Hundsberger, T.; Kortmann, R.D.; Baumert, B.G.

    2014-01-01

    BACKGROUND: Accurate predictive scores for the survival after salvage-treatment which are based on simple clinical parameters would be beneficial for the management of progressive high-grade gliomas (HGG). However, such scores should not enter clinical practice unless being validated with an independent dataset. Universal validity of a prognostic score is reflected by its capability to discriminate between different prognostic groups and good calibration. PATIENTS AND METHODS: Focusing on reirradiation, we assessed three different prognostic scores suggested by Combs et al., 2013 (Score A), De Vleeschouwer et al., 2012 (Score B) and Carson et al., 2007 (Score C). The scores were based on the following clinical parameters: Score A: age, time between initial radiotherapy and reirradiation and WHO grading; Score B: age, karnofsky performance score, WHO grading and minimal mental score; Score C: KPS, age, tumor location, use of steroids and WHO grading. Validation was performed with an independent dataset containing 175 HGG patients from 4 different institutions in Germany, Switzerland and the Netherlands, who all underwent a second course of radiotherapy at disease progression. Discrimination was checked by visual comparison of the respective Kaplan-Meier plots and by calculating the hazard ratios of the better prognostic groups in relation to the worst prognostic group defined by each score. Calibration was assessed generating calibration curves and prediction error curves. RESULTS: Median survival in the validation cohort was 9.2 ± 0.2 months from the start of reirradiation. Each score discriminated well between at least 3 different prognostic groups (good - intermediate -poor). However, scores A and B overestimated survival in the intermediate group, whereas score C tended to underestimate survival in the case of poor prognosis. Score A was most accurate in predicting an individual patient's short-term prognosis (< 10 months). For long-term prognosis (>10 months

  15. Frequent Nek1 overexpression in human gliomas.

    PubMed

    Zhu, Jun; Cai, Yu; Liu, Pin; Zhao, Weiguo

    2016-08-01

    Never in mitosis A (NIMA)-related kinase 1 (Nek1) regulates cell cycle progression to mitosis. Its expression and potential functions in human gliomas have not been studied. Here, our immunohistochemistry (IHC) assay and Western blot assay results showed that Nek1 expression was significantly upregulated in fresh and paraffin-embedded human glioma tissues. Its level in normal brain tissues was low. Nek1 overexpression in human gliomas was correlated with the proliferation marker (Ki-67), tumor grade, Karnofsky performance scale (KPS) and more importantly, patients' poor survival. Further studies showed that Nek1 expression level was also increased in multiple human glioma cell lines (U251-MG, U87-MG, U118, H4 and U373). Significantly, siRNA-mediated knockdown of Nek1 inhibited glioma cell (U87-MG/U251-MG) growth. Nek1 siRNA also sensitized U87-MG/U251-MG cells to temozolomide (TMZ), causing a profound apoptosis induction and growth inhibition. The current study indicates Nek1 might be a novel and valuable oncotarget of glioma, it is important for glioma cell growth and TMZ-resistance. PMID:27251576

  16. 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

  17. Overexpression of TREM2 enhances glioma cell proliferation and invasion: a therapeutic target in human glioma

    PubMed Central

    Wang, Xiao-Qiang; Tao, Bang-Bao; Li, Bin; Wang, Xu-Hui; Zhang, Wen-Chuan; Wan, Liang; Hua, Xu-Ming; Li, Shi-Ting

    2016-01-01

    Gliomas are the most common and aggressive type of primary adult brain tumors. Although TREM2 mutation is reported to be related to Nasu-Hakola disease and Alzheimer's disease, little is known about the association between TREM2 and gliomas. Here, we reported that TREM2 was significantly overexpressed in glioma tissues compared with non-tumorous brain tissues. Furthermore, TREM2 expression was closely related to pathological grade and overall survival of patients with gliomas. Down-regulation of TREM2 in two glioma cell lines, U87 and U373, resulted in a significant reduction in cell proliferation, migration and invasion and a dramatic increase in S phase arrest and apoptosis. In vivo tumorigenesis experiment also revealed that depletion of TREM2 expression inhibited U87 cell proliferation. Moreover, based on gene set enrichment analysis (GSEA) with The Cancer Genome Atlas (TCGA) dataset, we found that TREM2 was positive related to Kyoto Encyclopedia of Genes and Genomes (KEGG) apoptosis, Cromer metastasis and KEGG chemokine pathways, which was further validated by western blot in TREM2 knockdown glioma cells and indicated a possible mechanism underlying its effects on glioma. In summary, our study suggests that TREM2 may work as an oncogene and a new effective therapeutic target for glioma treatment. PMID:26506595

  18. Radiation-induced intracranial malignant gliomas

    SciTech Connect

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

    1989-07-01

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

  19. 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

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

    SciTech Connect

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

    2009-09-01

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

  2. P04.18PROGNOSIS IMPACT OF THE REGIONAL DISTRIBUTION OF MGMT GENE METHYLATION ACCORDING TO THE CPGISLAND METHYLATOR PHENOTYPE AND AGE IN HIGH-GRADE GLIOMAS

    PubMed Central

    Mur, P.; de Lope, A. Rodriguez; Hernandez-Iglesias, T.; Diaz, F.; Ribalta, T.; Fiaño, C.; Garcia, J.F.; Rey, J.A.; Mollejo, M.; Meléndez, B.

    2014-01-01

    Clinical and molecular prognostic factors in gliomas include age, IDH mutation, the glioma CpG island methylator phenotype (G-CIMP) and promoter methylation of the O6-methylguanine DNA-methyltransferase (MGMT) gene, among others. Clinical trials supported the predictive value of MGMT promoter methylation for benefit from alkylating chemotherapy in elderly GBM patients. In this study, methylation data were obtained from 46 oligodendroglial samples with the Illumina 450K platform, and were analyzed with external data to reach a total 247 glioma samples. MGMT gene methylation analysis with this platform revealed two significant survival-associated CpG regions, one within the promoter (cg12981137) and the other within the gene body (cg07933035), both significantly associated with better overall survival (OS) and strongly correlated with the G-CIMP+ status. However, although around 50% of G-CIMP- tumors were MGMT methylated on these CpG sites, their prognostic relevance were not observed in these patients. Only the gene body methylation was prognostic, but in the context of age, showing significant differences of OS in elderly patients. The absence of the MGMT promoter prognostic value in G-CIMP- tumors was validated in an independent series of 59 chemoradiated GBM patients by MSP and qMSP assays. Our study suggests that the prognostic value of MGMT methylation should be reviewed in the context of specific G-CIMP profiles and age groups. Further analysis on the impact of MGMT methylation on gene and protein expression is necessary for better clinical treatment settings. The routine use of MGMT methylation for the individual treatment of patients should be still viewed with caution.

  3. Diffusion tensor imaging suggests extrapontine extension of pediatric diffuse intrinsic pontine gliomas

    PubMed Central

    Wagner, Matthias W.; Bell, W. Robert; Kern, Jason; Bosemani, Thangamadhan; Mhlanga, Joyce; Carson, Kathryn A.; Cohen, Kenneth J.; Raabe, Eric H.; Rodriguez, Fausto; Huisman, Thierry A.G.M.; Poretti, Andrea

    2016-01-01

    Purpose To apply DTI to detect early extrapontine extension of pediatric diffuse intrinsic pontine glioma along the corticospinal tracts. Methods In children with diffuse intrinsic pontine glioma, low-grade brainstem glioma, and age-matched controls, DTI metrics were measured in the posterior limb of the internal capsule and posterior centrum semiovale. Histological examination was available in one patient. Results 6 diffuse intrinsic pontine glioma, 8 low-grade brainstem glioma, and two groups of 25 controls were included. In diffuse intrinsic pontine glioma compared to controls, fractional anisotropy was lower in the bilateral posterior limb of the internal capsule, axial diffusivity was lower in the bilateral posterior centrum semiovale and posterior limb of the internal capsule, while radial diffusivity was higher in the bilateral posterior limb of the internal capsule. No significant differences were found between low-grade brainstem glioma and controls. In diffuse intrinsic pontine glioma compared to low-grade brainstem glioma, axial diffusivity was lower in the bilateral posterior limb of the internal capsule. Histological examination in one child showed tumor cells in the posterior limb of the internal capsule. Conclusion Reduction in fractional anisotropy and axial diffusivity and increase in radial diffusivity in diffuse intrinsic pontine glioma may reflect tumor extension along the corticospinal tracts as shown by histology. DTI may detect early extrapontine tumor extension in diffuse intrinsic pontine glioma before it becomes apparent on conventional MRI sequences. PMID:26971411

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

    PubMed Central

    WANG, ZHENG; JIANG, WEI; WANG, YAHONG; GUO, YANG; CONG, ZHENG; DU, FANGFANG; SONG, BIN

    2015-01-01

    O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a conventional technique to predict the prognosis or individualized treatment of glioma in tumor tissue following surgery or biopsy. However, the technique cannot be applied in those glioma patients with concomitant neurological dysfunctions or advanced age. The present study aimed to find a new minimally invasive and efficient alternative method for the detection of MGMT promoter methylation. The expression of MGMT promoter methylation was assessed in peripheral blood and cerebrospinal fluid (CSF), and compared to the corresponding tumor tissue from glioma patients. The 89 patients in the study [32 World Health Organization (WHO) grade II, 19 WHO grade III and 38 WHO grade IV) were pathologically-diagnosed glioma and received radiation therapy following sample collection. The resected glioma tumor tissue (89), corresponding serum (89) and CSF (78) samples were collected for the detection of MGMT promoter methylation using methylation-specific polymerase chain reaction. The sensitivity and specificity of detecting MGMT promoter methylation in CSF and serum were compared. Among the tumor tissue samples, 51/89 (57.3%) showed MGMT promoter methylation. The specificity of the detection in the CSF and serum samples reached 100%. The sensitivity of MGMT promoter methylation detection in CSF and serum were 26/40 (65.0%) and 19/51 (37.3%), respectively (P<0.05). In the WHO II, III and IV subgroups, the sensitivities of MGMT promoter methylation detection using CSF were 8/12 (66.7%), 11/18 (61.1%) and 7/10 (70.0%), respectively, which were significantly higher than the sensitivities using serum (7/21, 33.3%; 7/19, 36.8%; and 5/11, 45.5%, respectively P<0.05). Among patients with residual postoperative tumors, the sensitivities of detecting MGMT promoter methylation using CSF and serum were 18/25 (72.0%) and 10/24 (41.7%), respectively, both of which were significantly higher than the corresponding values

  5. IDH1 and IDH2 Mutations in Gliomas

    PubMed Central

    Cohen, Adam; Holmen, Sheri; Colman, Howard

    2014-01-01

    Mutations in isocitrate dehydrogenase (IDH) 1 and 2, originally discovered in 2009, occur in the vast majority of low grade gliomas and secondary high grade gliomas. These mutations, which occur early in gliomagenesis, change the function of the enzymes, causing them to produce 2-hydroxyglutarate, a possible oncometabolite, and to not produce NADPH. IDH mutations are oncogenic, although whether the mechanism is through alterations in hydroxylases, redox potential, cellular metabolism, or gene expression is not clear. The mutations also drive increased methylation in gliomas. Gliomas with mutated IDH1 and IDH2 have improved prognosis compared to gliomas with wild-type IDH. Mutated IDH can now be detected by immunohistochemistry and magnetic resonance spectroscopy. No drugs currently target mutated IDH, although this remains an area of active research. PMID:23532369

  6. 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

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

    PubMed

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

    2010-02-01

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

  8. Identification of low miR-105 expression as a novel poor prognostic predictor for human glioma

    PubMed Central

    Guan, Yanlei; Chen, Ling; Bao, Yijun; Li, Zhipeng; Cui, Run; Li, Guangyu; Wang, Yunjie

    2015-01-01

    Glioma is the most common and aggressive brain tumor with poor clinical outcome. Identification and development of new biomarkers could be beneficial for diagnosis and prognosis of glioma patients. Recent studies have showed evidences that dysregulation of microRNAs (miRNAs) is involved in glioma tumorigenesis. Therefore, we attempted to identify specific miRNAs as prognostic and predictive markers for glioma. We statistically compared expression profile of 365 miRNAs between WHO grade IV and grade III gliomas, by qRT-PCR. MiR-105 was identified as a remarkably decreased miRNA in grade IV gliomas compared with grade III gliomas (P=0.012, fold change =0.04). We subsequently examined its expression levels in an independent series of gliomas, and statistically analyzed the associations between miR-105 expression and clinicopathological characteristics and survivals of these glioma patients. MiR-105 showed remarkably decreased expression in gliomas as compared to non-neoplastic brains. And grade IV gliomas had significantly lower miR-105 expression compared with grade III and II gliomas (both P<0.001). Additionally, low miR-105 expression was statistically associated with advanced tumor grade, advanced patient’s age and low pre-operative Karnofsky performance score (all P<0.001). Furthermore, patients with low miR-105 expression had significantly poorer survival by Kaplan-Meier method (P<0.001). Multivariate analysis indicated miR-105 as an independent prognostic indicator for glioma patients (P=0.018, risk ratio =4.2). Our results suggested that low expression of miR-105 may correlate with unfavorable clinical outcome and be involved in tumorigenesis and aggressive progression of glioma. And miR-105 may be a novel biomarker in prognostic prediction for glioma. PMID:26379879

  9. 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

  10. Adult brainstem gliomas: Correlation of clinical and molecular features

    PubMed Central

    Theeler, Brett J.; Ellezam, Benjamin; Melguizo-Gavilanes, Isaac; de Groot, John F.; Mahajan, Anita; Aldape, Kenneth D.; Bruner, Janet M.; Puduvalli, Vinay K.

    2016-01-01

    Background Brainstem gliomas are rare in adults and overall have superior survival outcomes compared to pediatric brainstem gliomas. Patients and methods We conducted a retrospective data and tissue analysis of all adult patients (≥18 years old) with World Health Organization (WHO) Grade II, III, and IV brainstem gliomas in the University of Texas MD Anderson Cancer Center institutional database from 1990 to 2012. Results We identified 143 cases in adults ages 18 and over. There were 28 glioblastomas, 43 anaplastic astrocytomas, 15 diffuse astrocytomas, and 11 gliomas not otherwise specified, and in 46 cases the diagnosis was made radiographically. 128 (89.5%) cases were classified radiographically as diffuse and of the focal tumors, 9 of the 15 were WHO Grade III or IV tumors. Increasing tumor grade and contrast enhancement were associated with significantly reduced overall survival. The median overall survival for the entire cohort was 32.1 months similar to previously published studies. Two of 25 grade II and III tumors, and 1 of 17 glioblastomas had IDH1 mutations on immunohistochemical testing. Nine cases had sufficient tissue for mutation profiling, 1 case had a BRAF V600E mutation and 2 had 2 PIK3CA mutations. Conclusions Survival outcomes for adult WHO Grade II to IV brainstem gliomas were similar to supratentorial IDH1 wild-type tumors of similar grade and histology. Potentially actionable mutations can be identified from small biopsy samples in a subset of adult brainstem gliomas. PMID:25934342

  11. 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

  12. An analysis of 170 glioma patients and systematic review to investigate the association between IDH-1 mutations and preoperative glioma-related epilepsy.

    PubMed

    Yang, Yuan; Mao, Qing; Wang, Xiang; Liu, Yanhui; Mao, Yunhe; Zhou, Qiao; Luo, Jiewen

    2016-09-01

    Seizure is a common presenting symptom of glioma, and many biomarkers have been suggested to be associated with preoperative seizure; however, the relationships between IDH (isocitrate dehydrogenase) mutations and glioma-related epilepsy only recently been studied. The authors aimed to examine the correlations between IDH mutations in glioma patients with preoperative seizures and tumor location. A series of 170 glioma samples were analyzed for IDH1 R132H mutations (amino acid change from arginine to histidine at codon 132) with immunohistochemistry (IHC) staining and for IDH mutations with direct DNA sequencing when the IHC results were negative. If either the IHC or direct DNA sequencing result was positive, the IDH status was defined as mutated. The results of the IDH mutation examinations were used to analyze the relationship between mutations and glioma-related epilepsy. The study population consisted of 64 (37.6%) World Health Organization (WHO) grade II gliomas, 58 (34.1%) grade III, and 48 (28.3%) grade IV gliomas. A total of 84 samples with IDH1 mutations were observed in our study, and 54 of these presented with seizures as the initial symptoms, whereas 28 of the patients with wild-type IDH status presented with seizures (p=0.043 for the WHO grade II gliomas, p=0.002 for the grade III gliomas and p=0.942 for the grade IV gliomas, chi-squared tests). Among the WHO grade II and III gliomas, IDH1 mutations were significantly associated with preoperative seizures, but no significant relationship between IDH mutations and preoperative seizures was found with glioblastoma multiforme. PMID:27406953

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

    PubMed Central

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

    2016-01-01

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

  14. Glioma Association and Balancing Selection of ZFPM2.

    PubMed

    Tsang, Shui-Ying; Mei, Lingling; Wan, Weiqing; Li, Jun; Li, Yi; Zhao, Cunyou; Ding, Xiaofan; Pun, Frank W; Hu, Xiaoxia; Wang, Jianmin; Zhang, Junyi; Luo, Rongcheng; Cheung, Siu-Tim; Leung, Gilberto K K; Poon, Wai-Sang; Ng, Ho-Keung; Zhang, Liwei; Xue, Hong

    2015-01-01

    ZFPM2, encoding a zinc finger protein and abundantly expressed in the brain, uterus and smooth muscles, plays important roles in cardiac and gonadal development. Abnormal expression of ZFPM2 in ovarian tumors and neuroblastoma has been reported but hitherto its genetic association with cancer and effects on gliomas have not been studied. In the present study, the hexamer insertion-deletion polymorphism rs71305152, located within a large haplotype block spanning intron 1 to intron 3 of ZFPM2, was genotyped in Chinese cohorts of glioma (n = 350), non-glioma cancer (n = 354) and healthy control (n = 463) by direct sequencing and length polymorphism in gel electrophoresis, and ZFPM2 expression in glioma tissues (n = 69) of different grades was quantified by real-time RT-PCR. Moreover, potential natural selection pressure acting on the gene was investigated. Disease-association analysis showed that the overall genotype of rs71305152 was significantly associated with gliomas (P = 0.016), and the heterozygous genotype compared to the combined homozygous genotypes was less frequent in gliomas than in controls (P = 0.005) or non-glioma cancers (P = 0.020). ZFPM2 mRNA expression was negatively correlated with the grades of gliomas (P = 0.002), with higher expression levels in the low-grade gliomas. In the astrocytoma subtype, higher ZFPM2 expression was also correlated with the rs71305152 heterozygous genotype (P = 0.028). In addition, summary statistics tests gave highly positive values, demonstrating that the gene is under the influence of balancing selection. These findings suggest that ZFPM2 is a glioma susceptibility gene, its genotype and expression showing associations with incidence and severity, respectively. Moreover, the balancing selection acting on ZFPM2 may be related to the important roles it has to play in multiple organ development or associated disease etiology. PMID:26207917

  15. Glioma Association and Balancing Selection of ZFPM2

    PubMed Central

    Wan, Weiqing; Li, Jun; Li, Yi; Zhao, Cunyou; Ding, Xiaofan; Pun, Frank W.; Hu, Xiaoxia; Wang, Jianmin; Zhang, Junyi; Luo, Rongcheng; Cheung, Siu-Tim; Leung, Gilberto K. K.; Poon, Wai-Sang; Ng, Ho-Keung; Zhang, Liwei; Xue, Hong

    2015-01-01

    ZFPM2, encoding a zinc finger protein and abundantly expressed in the brain, uterus and smooth muscles, plays important roles in cardiac and gonadal development. Abnormal expression of ZFPM2 in ovarian tumors and neuroblastoma has been reported but hitherto its genetic association with cancer and effects on gliomas have not been studied. In the present study, the hexamer insertion-deletion polymorphism rs71305152, located within a large haplotype block spanning intron 1 to intron 3 of ZFPM2, was genotyped in Chinese cohorts of glioma (n = 350), non-glioma cancer (n = 354) and healthy control (n = 463) by direct sequencing and length polymorphism in gel electrophoresis, and ZFPM2 expression in glioma tissues (n = 69) of different grades was quantified by real-time RT-PCR. Moreover, potential natural selection pressure acting on the gene was investigated. Disease-association analysis showed that the overall genotype of rs71305152 was significantly associated with gliomas (P = 0.016), and the heterozygous genotype compared to the combined homozygous genotypes was less frequent in gliomas than in controls (P = 0.005) or non-glioma cancers (P = 0.020). ZFPM2 mRNA expression was negatively correlated with the grades of gliomas (P = 0.002), with higher expression levels in the low-grade gliomas. In the astrocytoma subtype, higher ZFPM2 expression was also correlated with the rs71305152 heterozygous genotype (P = 0.028). In addition, summary statistics tests gave highly positive values, demonstrating that the gene is under the influence of balancing selection. These findings suggest that ZFPM2 is a glioma susceptibility gene, its genotype and expression showing associations with incidence and severity, respectively. Moreover, the balancing selection acting on ZFPM2 may be related to the important roles it has to play in multiple organ development or associated disease etiology. PMID:26207917

  16. 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

  17. Nitrosoureas in the Management of Malignant Gliomas.

    PubMed

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

    2016-02-01

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

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

    PubMed Central

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

    2014-01-01

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

  19. Gap junctions modulate glioma invasion by direct transfer of microRNA.

    PubMed

    Hong, Xiaoting; Sin, Wun Chey; Harris, Andrew L; Naus, Christian C

    2015-06-20

    The invasiveness of high-grade glioma is the primary reason for poor survival following treatment. Interaction between glioma cells and surrounding astrocytes are crucial to invasion. We investigated the role of gap junction mediated miRNA transfer in this context. By manipulating gap junctions with a gap junction inhibitor, siRNAs, and a dominant negative connexin mutant, we showed that functional glioma-glioma gap junctions suppress glioma invasion while glioma-astrocyte and astrocyte-astrocyte gap junctions promote it in an in vitro transwell invasion assay. After demonstrating that glioma-astrocyte gap junctions are permeable to microRNA, we compared the microRNA profiles of astrocytes before and after co-culture with glioma cells, identifying specific microRNAs as candidates for transfer through gap junctions from glioma cells to astrocytes. Further analysis showed that transfer of miR-5096 from glioma cells to astrocytes is through gap junctions; this transfer is responsible, in part, for the pro-invasive effect. Our results establish a role for glioma-astrocyte gap junction mediated microRNA signaling in modulation of glioma invasive behavior, and that gap junction coupling among astrocytes magnifies the pro-invasive signaling. Our findings reveal the potential for therapeutic interventions based on abolishing alteration of stromal cells by tumor cells via manipulation of microRNA and gap junction channel activity. PMID:25978028

  20. 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

  1. Cancer metabolism as a central driving force of glioma pathogenesis.

    PubMed

    Masui, Kenta; Cavenee, Webster K; Mischel, Paul S

    2016-07-01

    The recent identification of distinct genetic and epigenetic features in each glioma entity is leading to a multilayered, integrated diagnostic approach combining histologic features with molecular genetic information. Somatic mutations in isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways are key oncogenic events in diffuse gliomas, including lower grade (grade II and III) gliomas (LGG) and the highly lethal brain tumor glioblastoma (GBM), respectively, where they reprogram the epigenome, transcriptome, and metabolome to drive tumor growth. However, the mechanisms by which these genetic aberrations are translated into the aggressive nature of gliomas through metabolic reprogramming have just begun to be unraveled. The intricate interactions between the oncogenic signaling and cancer metabolism have also been recently demonstrated. Here, we describe a set of recent discoveries on cancer metabolism driven by IDH mutation and mutations in RTK pathways, highlighting the integration of genetic mutations, metabolic reprogramming, and epigenetic shifts, potentially providing new therapeutic opportunities. PMID:27295313

  2. 68Ga-PRGD2 PET/CT in the Evaluation of Glioma: A Prospective Study

    PubMed Central

    2015-01-01

    Integrin αvβ3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate 68gallium-BNOTA-PRGD2 (68Ga-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 68Ga-PRGD2 PET/CT and 18F-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 68Ga-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, 68Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than 18F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of 68Ga-PRGD2, rather than those of 18F-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 68Ga-PRGD2 seemed to be more superior to 18F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, 68Ga-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. PMID:25093246

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

    PubMed Central

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

    2015-01-01

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

  4. Description of selected characteristics of familial glioma patients – Results from the Gliogene Consortium

    PubMed Central

    Sadetzki, Siegal; Bruchim, Revital; Oberman, Bernice; Armstrong, Georgina N.; Lau, Ching C.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill S.; Il’yasova, Dora; Schildkraut, Joellen; Johansen, Christoffer; Houlston, Richard S.; Shete, Sanjay; Amos, Christopher I.; Bernstein, Jonine L.; Olson, Sara H.; Jenkins, Robert B.; Lachance, Daniel; Vick, Nicholas A.; Merrell, Ryan; Wrensch, Margaret; Davis, Faith G.; McCarthy, Bridget J.; Lai, Rose; Melin, Beatrice S.; Bondy, Melissa L.

    2012-01-01

    Background While certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained from 14 centres in the United States (US), Europe and Israel as part of the Gliogene Consortium. Methods Families with 2 or more verified gliomas were recruited between January 2007 and February 2011. Distributions of demographic characteristics and clinical variables of gliomas in the families were described based on information derived from personal questionnaires. Findings The study population comprised 841 glioma patients identified in 376 families (9797 individuals). There were more cases of glioma among males, with a male to female ratio of 1.25. In most families (83%), 2 gliomas were reported, with 3 and 4 gliomas in 13% and 3% of the families, respectively. For families with 2 gliomas, 57% were among 1st-degree relatives, and 31.5% among 2nd-degree relatives. Overall, the mean (±standard deviation [SD]) diagnosis age was 49.4 (±18.7) years. In 48% of families with 2 gliomas, at least one was diagnosed at <40 y, and in 12% both were diagnosed under 40 y of age. Most of these families (76%) had at least one grade IV glioblastoma multiforme (GBM), and in 32% both cases were grade IV gliomas. The most common glioma subtype was GBM (55%), followed by anaplastic astrocytoma (10%) and oligodendroglioma (8%). Individuals with grades I–II were on average 17 y younger than those with grades III–IV. Interpretation Familial glioma cases are similar to sporadic cases in terms of gender distribution, age, morphology and grade. Most familial gliomas appear to comprise clusters of two cases suggesting low penetrance, and that the risk of developing additional gliomas is probably low. These results should be useful in the counselling and clinical management of

  5. Chordoid Glioma with Intraventricular Dissemination: A Case Report with Perfusion MR Imaging Features

    PubMed Central

    Ki, So Yeon; Kim, Seul Kee; Heo, Tae Wook; Baek, Byung Hyun; Kim, Hyung Seok

    2016-01-01

    Chordoid glioma is a rare low grade tumor typically located in the third ventricle. Although a chordoid glioma can arise from ventricle with tumor cells having features of ependymal differentiation, intraventricular dissemination has not been reported. Here we report a case of a patient with third ventricular chordoid glioma and intraventricular dissemination in the lateral and fourth ventricles. We described the perfusion MR imaging features of our case different from a previous report. PMID:26798226

  6. Upregulation of p-Smad2 contributes to FAT10-induced oncogenic activities in glioma.

    PubMed

    Dai, Bin; Zhang, Yisong; Zhang, Peng; Pan, Changcun; Xu, Cheng; Wan, Weiqing; Wu, Zhen; Zhang, Junting; Zhang, Liwei

    2016-07-01

    The human leukocyte antigen f-associated transcript 10 (FAT10) has a similar structure and function with ubiquitin, which efficiently mediate proteasome degradation in an ubiquitin-independent manner. FAT10 expression is upregulated in many tumor tissues and plays a vital role in cell cycle regulation and tumor genesis. However, its role in glioma has not been illuminated. The aim of this study was to evaluate the prognostic value of FAT10 and investigate its functional roles in glioma. The expression of FAT10 in glioma patient samples was examined using quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry methods. Glioma cell lines with either FAT10 overexpression or knockdown were created. The effect of FAT10 on glioma cell migration and invasion was investigated using these cells. In the present study, we had shown that FAT10 was elevated significantly in glioma samples and correlated with tumor pathological grade. FAT10 high-expression glioma is associated with a poor clinical prognosis. Overexpression of FAT10 promoted proliferation, invasion, migration, and sphere formation of glioma cells, whereas downregulation of FAT10 had an opposite effect. Overexpression of FAT10 also promoted the growth of glioma cells in vivo. Moreover, FAT10 enhanced the phosphorylation of Smad2, which contributes to FAT10-induced oncogenic activities in glioma. In conclusion, these findings indicate that FAT10 is a critical regulator potential therapeutic target of glioma. PMID:26733179

  7. Expression of CDC5L is associated with tumor progression in gliomas.

    PubMed

    Chen, Wenjuan; Zhang, Li; Wang, Yan; Sun, Jie; Wang, Donglin; Fan, Shaochen; Ban, Na; Zhu, Junya; Ji, Bin; Wang, Yuchan

    2016-03-01

    Cell division cycle 5-like (CDC5L) protein is a cell cycle regulator of the G2/M transition and has been reported to participate in the catalytic step of pre-messenger RNA (mRNA) splicing and DNA damage repair. Recently, it was also found to act as a candidate oncogene in osteosarcoma and cervical tumors. However, the role of CDC5L expression in tumor biology was still unclear. Here, we analyzed the expression and clinical significance of CDC5L in gliomas. The expression of CDC5L in fresh glioma tissues and paraffin-embedded slices was evaluated by western blot and immunohistochemistry, respectively. We found that CDC5L was highly expressed in glioma tissues. The expression of CDC5L was significantly associated with glioma pathology grade and Ki-67 expression. Univariate and multivariate analyses showed that high CDC5L expression was an independent prognostic factor for glioma patients' survival. To determine whether CDC5L could regulate the proliferation of glioma cells, we transfected glioma cells with interfering RNA target CDC5L, then investigated cell proliferation with cell counting kit (CCK)-8, flow cytometry assays and colony formation analyses. Our results indicated that knockdown of CDC5L would inhibit proliferation of glioma cells. Besides, reduced expression of CDC5L could induce the apoptosis of glioma cells. These findings suggested that CDC5L might play an important role in glioma and thus be a promising therapeutic target of glioma. PMID:26490980

  8. Role of IL-6 in the invasiveness and prognosis of glioma

    PubMed Central

    Shan, Yongzhi; He, Xin; Song, Wei; Han, Dong; Niu, Jianxing; Wang, Jianzhen

    2015-01-01

    IL-6 is a cytokine secreted by glioma cells and plays an important role in the tumor growth. However, the impact of IL-6 on the invasiveness and prognosis of glioma is still unclear. In this study, immunohistochemistry was performed to determine the expression of IL-6 in 86 glioma tissues, and ELISA to measure IL-6 in the serum and cerebrospinal fluid (CSF) of these patients. Results showed, as ccompared with normal controls, the IL-6 in the glioma, CSF and serumincreased remarkably, and increased with the elevation of glioma grade. In addition, IL-6 in the supernatant was also detectable in glioma cell lines U251, U87, A172 and T98G. Transwell invasion assay showed that the invasiveness of glioma U87 cells and U251 cells increased remarkably after exogenous IL-6 treatment. Survival analysis indicated higher IL-6 before surgery and significantly reduction in IL-6 after operation in the serum and CSF predicted a poor prognosis. Thus, we speculate that, the poor prognosis of glioma is related to the IL-6 autocrine in the glioma and the IL-6 induced tumor growth and invasion. IL-6 may serve as a therapeutic target for glioma patients and IL-6 in the CSF and serum of glioma may be used to predict the prognosis of these patients. PMID:26309566

  9. 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

  10. Long-Term Survival of Children Less than Six Years of Age Enrolled on the CCG-945 Phase III Trial for Newly-Diagnosed High-Grade Glioma: A Report from the Children’s Oncology Group

    PubMed Central

    Batra, V; Sands, S; Holmes, E; Geyer, JR; Yates, A; Becker, L; Burger, P; Gilles, F; Wisoff, J; Allen, J; Pollack, IF; Finlay, JL

    2015-01-01

    Background We analyzed the long-term survival of children under six years of age (<6 yo) enrolled upon the Children’s Cancer Group (CCG)-945 high-grade glioma (HGG) study to determine the impact of intrinsic biological characteristics as well as treatment upon both survival and quality of life (QOL) in this younger age population. Procedure Analyses were undertaken on patients <6 yo with institutionally diagnosed HGG enrolled on the CCG-945 trial. Comparisons of survival were performed for patients less than three years of age (<3 yo) (treated with intent to avoid irradiation) versus those between three to six years of age (3–6 yo) (treated with irradiation and chemotherapy) at diagnosis. Discordance between the institutional diagnoses of HGG and consensus-reviewed diagnoses led us to perform further survival analyses for both groups. We compared the two groups of patients for biological markers, and evaluated the neuropsychological and QOL outcomes of long-term survivors. Results Patients <3 yo (n=49,19.5% of all enrolled patients) at diagnosis had a 10-year EFS and OS of 29± 6.5% and 37.5 ± 7% respectively while for patients 3–6 yo (n=34,13.5% of all enrolled patients) 10-year EFS and OS were 35± 8% and 36 ± 8% respectively. Molecular marker analysis showed that a smaller proportion of patients <3 yo harbored TP53 mutations (p=0.05). Analysis of QOL outcomes with a median length of follow up of 15.1 years (9.5–19.2) showed comparable results. Conclusions QOL and survival data were similar for the two groups. A larger prospective study is justified to study the efficacy of chemotherapy only regimens in younger children. PMID:24038913

  11. Re-irradiation or re-operation followed by dendritic cell vaccination? Comparison of two different salvage strategies for relapsed high-grade gliomas by means of a new prognostic model.

    PubMed

    Müller, Klaus; Henke, Guido; Pietschmann, Sophie; van Gool, Stefaan; De Vleeschouwer, Steven; von Bueren, André O; Compter, Inge; Friedrich, Carsten; Matuschek, Christiane; Klautke, Gunther; Kortmann, Rolf-Dieter; Hundsberger, Thomas; Baumert, Brigitta G

    2015-09-01

    We aimed to compare two different salvage treatment strategies for relapsed high-grade glioma (HGG) patients by means of a new prognostic model. A simplified version of the so-called HGG-Immuno RPA model estimates the prognosis of relapsed HGG patients and distinguishes three different prognostic classes (I = good, II = intermediate, III = poor). The model has been constructed with a cohort of 117 patients whose salvage treatment consisted of re-operation followed by dendritic cell vaccination (ReOP + DCV). However, using only the predictors histology, age and performance status, the simplified HGG-Immuno RPA model is basically independent from treatment. In the present study we applied the simplified model to the cohort used to construct the original HGG-Immuno RPA model and another cohort of 165 patients who underwent re-irradiation (ReRT) at relapse. Then, we compared the outcomes achieved by the two different salvage treatments in each prognostic class. The model predicted good, intermediate and poor prognosis for 11, 31 and 75 patients of the ReOP + DCV cohort and for 20, 39 and 106 patients of the ReRT cohort, respectively. Neither of the two strategies was superior to the other. In the groups with good, intermediate and poor prognosis 12-months survival rates were 73, 59 and 25 % after ReOP + DCV and 72, 36 and 23 % after ReRT, respectively. Being easy to handle and independent from treatment, the aforementioned model is useful for therapeutic decisions. ReRT and ReOP + DVC seem to be equally effective. The choice of salvage treatment should be based on the expected side effects. PMID:26070556

  12. Overexpression of tissue microRNA10b may help predict glioma prognosis.

    PubMed

    Zhang, Xinxin; Cheng, Jian; Fu, Ling; Li, Qingshui

    2016-07-01

    We investigated the relationship between microRNA-10b (miR-10b) expression and prognosis in human glioma patients. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to characterize the expression patterns of miR-10b in 128 glioma and 20 normal brain tissues. Clinical information - age, sex, Karnofsky Performance Status (KPS) and World Health Organization (WHO) grade - were also collected. The associations between miR-10b expression and the clinicopathological factors and outcome of glioma patients were statistically analyzed. Expression levels of miR-10b in glioma tissue were significantly higher than in normal brain tissue (P<0.001). High-grade glioma (WHO grade III and IV) had much higher miR-10b expression levels than low-grade tumors (WHO grade I and II). Additionally, the increased miR-10b expression in the glioma tissues was significantly associated with a low KPS (P=0.03). Kaplan-Meier survival curves and Cox regression analyses showed that overexpression of miR-10b (P=0.01) and high grade (P=0.02) were independent factors predicting poor outcome for glioma patients. Furthermore, subgroup analyses showed that the miR-10b expression level was significantly associated with poor overall survival in glioma patients with high grades (P<0.001). Up-regulation of miR-10b may have value in predicting clinical outcome in glioma patients, particularly for those with high pathological grades. PMID:26988656

  13. Distinct germline polymorphisms underlie glioma morphologic heterogeneity

    PubMed Central

    Jenkins, Robert B.; Wrensch, Margaret R.; Johnson, Derek; Fridley, Brooke L.; Decker, Paul A.; Xiao, Yuanyuan; Kollmeyer, Thomas M.; Rynearson, Amanda L.; Fink, Stephanie; Rice, Terri; McCoy, Lucie S.; Halder, Chandralekha; Kosel, Matthew L.; Giannini, Caterina; Tihan, Tarik; O’Neill, Brian P.; Lachance, Daniel H.; Yang, Ping; Wiemels, Joseph; Wiencke, John K.

    2010-01-01

    Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports it was not clear if the SNP associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case/control groups composed of the spectrum of infiltrating glioma subtypes, and stratified the analyses by type. We report that specific germline polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, OR=2.05, p=8.3*10−11), but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms which are significantly associated with glioblastoma (rs2297440, OR = 0.56, p= 4.6*10−10) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR=2.77, p=2.6*10-9). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development. PMID:21356187

  14. Proteomics of gliomas: Initial biomarker discovery and evolution of technology

    PubMed Central

    Kalinina, Juliya; Peng, Junmin; Ritchie, James C.; Van Meir, Erwin G.

    2011-01-01

    Gliomas are a group of aggressive brain tumors that diffusely infiltrate adjacent brain tissues, rendering them largely incurable, even with multiple treatment modalities and agents. Mostly asymptomatic at early stages, they present in several subtypes with astrocytic or oligodendrocytic features and invariably progress to malignant forms. Gliomas are difficult to classify precisely because of interobserver variability during histopathologic grading. Identifying biological signatures of each glioma subtype through protein biomarker profiling of tumor or tumor-proximal fluids is therefore of high priority. Such profiling not only may provide clues regarding tumor classification but may identify clinical biomarkers and pathologic targets for the development of personalized treatments. In the past decade, differential proteomic profiling techniques have utilized tumor, cerebrospinal fluid, and plasma from glioma patients to identify the first candidate diagnostic, prognostic, predictive, and therapeutic response markers, highlighting the potential for glioma biomarker discovery. The number of markers identified, however, has been limited, their reproducibility between studies is unclear, and none have been validated for clinical use. Recent technological advancements in methodologies for high-throughput profiling, which provide easy access, rapid screening, low sample consumption, and accurate protein identification, are anticipated to accelerate brain tumor biomarker discovery. Reliable tools for biomarker verification forecast translation of the biomarkers into clinical diagnostics in the foreseeable future. Herein we update the reader on the recent trends and directions in glioma proteomics, including key findings and established and emerging technologies for analysis, together with challenges we are still facing in identifying and verifying potential glioma biomarkers. PMID:21852429

  15. Spontaneously Arising Canine Glioma as a Potential Model for Human Glioma.

    PubMed

    Herranz, C; Fernández, F; Martín-Ibáñez, R; Blasco, E; Crespo, E; De la Fuente, C; Añor, S; Rabanal, R M; Canals, J M; Pumarola, M

    2016-01-01

    Human gliomas are malignant brain tumours that carry a poor prognosis and are composed of a heterogeneous population of cells. There is a paucity of animal models available for study of these tumours and most have been created by genetic modification. Spontaneously arising canine gliomas may provide a model for the characterization of the human tumours. The present study shows that canine gliomas form a range of immunohistochemical patterns that are similar to those described for human gliomas. The in-vitro sphere assay was used to analyze the expansion and differentiation potential of glioma cells taken from the periphery and centre of canine tumours. Samples from the subventricular zone (SVZ) and contralateral parenchyma were used as positive and negative controls, respectively. The expansion potential for all of these samples was low and cells from only three cultures were expanded for six passages. These three cultures were derived from high-grade gliomas and the cells had been cryopreserved. Most of the cells obtained from the centre of the tumours formed spheres and were expanded, in contrast to samples taken from the periphery of the tumours. Spheres were also formed and expanded from two areas of apparently unaffected brain parenchyma. The neurogenic SVZ contralateral samples also contained progenitor proliferating cells, since all of them were expanded for three to five passages. Differentiation analysis showed that all cultured spheres were multipotential and able to differentiate towards both neurons and glial cells. Spontaneously arising canine gliomas might therefore constitute an animal model for further characterization of these tumours. PMID:26804204

  16. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

    PubMed Central

    Eckel-Passow, Jeanette E.; Lachance, Daniel H.; Molinaro, Annette M.; Walsh, Kyle M.; Decker, Paul A.; Sicotte, Hugues; Pekmezci, Melike; Rice, Terri; Kosel, Matt L.; Smirnov, Ivan V.; Sarkar, Gobinda; Caron, Alissa A.; Kollmeyer, Thomas M.; Praska, Corinne E.; Chada, Anisha R.; Halder, Chandralekha; Hansen, Helen M.; McCoy, Lucie S.; Bracci, Paige M.; Marshall, Roxanne; Zheng, Shichun; Reis, Gerald F.; Pico, Alexander R.; O’Neill, Brian P.; Buckner, Jan C.; Giannini, Caterina; Huse, Jason T.; Perry, Arie; Tihan, Tarik; Berger, Mitchell S.; Chang, Susan M.; Prados, Michael D.; Wiemels, Joseph; Wiencke, John K.; Wrensch, Margaret R.; Jenkins, Robert B.

    2015-01-01

    BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triplepositive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. PMID:26061753

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

    SciTech Connect

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

    2012-01-01

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

  18. IDH1 mutation detection by droplet digital PCR in glioma.

    PubMed

    Wang, Jing; Zhao, Yi-ying; Li, Jian-feng; Guo, Cheng-cheng; Chen, Fu-rong; Su, Hong-kai; Zhao, Hua-fu; Long, Ya-kang; Shao, Jian-yong; To, Shing shun Tony; Chen, Zhong-ping

    2015-11-24

    Glioma is the most frequent central nervous system tumor in adults. The overall survival of glioma patients is disappointing, mostly due to the poor prognosis of glioblastoma (Grade IV glioma). Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma. As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients. The recently developed droplet digital PCR (ddPCR) technique generates a large amount of nanoliter-sized droplets, each of which carries out a PCR reaction on one template. Therefore, ddPCR provides high precision and absolute quantification of the nucleic acid target, with wide applications for both research and clinical diagnosis. In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR). With the results from Sanger direct sequencing as the standard, the characteristics of ddPCR were compared with qRT-PCR. The data indicated that ddPCR was much more sensitive and much easier to interpret than qRT-PCR. Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation. Therefore, ddPCR is able to applied clinically in predicting patient prognosis and selecting effective therapeutic strategies. Our data also supported that the prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation. PMID:26485760

  19. IDH1 mutation detection by droplet digital PCR in glioma

    PubMed Central

    Wang, Jing; Zhao, Yi-ying; Li, Jian-feng; Guo, Cheng-cheng; Chen, Fu-rong; Su, Hong-kai; Zhao, Hua-fu; Long, Ya-kang; Shao, Jian-yong; Tony To, Shing-shun; Chen, Zhong-ping

    2015-01-01

    Glioma is the most frequent central nervous system tumor in adults. The overall survival of glioma patients is disappointing, mostly due to the poor prognosis of glioblastoma (Grade IV glioma). Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma. As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients. The recently developed droplet digital PCR (ddPCR) technique generates a large amount of nanoliter-sized droplets, each of which carries out a PCR reaction on one template. Therefore, ddPCR provides high precision and absolute quantification of the nucleic acid target, with wide applications for both research and clinical diagnosis. In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR). With the results from Sanger direct sequencing as the standard, the characteristics of ddPCR were compared with qRT-PCR. The data indicated that ddPCR was much more sensitive and much easier to interpret than qRT-PCR. Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation. Therefore, ddPCR is able to applied clinically in predicting patient prognosis and selecting effective therapeutic strategies. Our data also supported that the prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation. PMID:26485760

  20. MYB-QKI rearrangements in Angiocentric Glioma drive tumorigenicity through a tripartite mechanism

    PubMed Central

    Bandopadhayay, Pratiti; Ramkissoon, Lori A.; Jain, Payal; Bergthold, Guillaume; Wala, Jeremiah; Zeid, Rhamy; Schumacher, Steven E.; Urbanski, Laura; O’Rourke, Ryan; Gibson, William J.; Pelton, Kristine; Ramkissoon, Shakti H.; Han, Harry J.; Zhu, Yuankun; Choudhari, Namrata; Silva, Amanda; Boucher, Katie; Henn, Rosemary E.; Kang, Yun Jee; Knoff, David; Paolella, Brenton R.; Gladden-Young, Adrianne; Varlet, Pascale; Pages, Melanie; Horowitz, Peleg M.; Federation, Alexander; Malkin, Hayley; Tracy, Adam; Seepo, Sara; Ducar, Matthew; Hummelen, Paul Van; Santi, Mariarita; Buccoliero, Anna Maria; Scagnet, Mirko; Bowers, Daniel C.; Giannini, Caterina; Puget, Stephanie; Hawkins, Cynthia; Tabori, Uri; Klekner, Almos; Bognar, Laszlo; Burger, Peter C.; Eberhart, Charles; Rodriguez, Fausto J.; Hill, D. Ashley; Mueller, Sabine; Haas-Kogan, Daphne A.; Phillips, Joanna J.; Santagata, Sandro; Stiles, Charles D.; Bradner, James E.; Jabado, Nada; Goren, Alon; Grill, Jacques; Ligon, Azra H.; Goumnerova, Liliana; Waanders, Angela J.; Storm, Phillip B.; Kieran, Mark W.; Ligon, Keith L.; Beroukhim, Rameen; Resnick, Adam C.

    2016-01-01

    Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs including 19 Angiocentric Gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in Angiocentric Gliomas. In vitro and in vivo functional studies show MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. This represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor. PMID:26829751

  1. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

    PubMed

    Bandopadhayay, Pratiti; Ramkissoon, Lori A; Jain, Payal; Bergthold, Guillaume; Wala, Jeremiah; Zeid, Rhamy; Schumacher, Steven E; Urbanski, Laura; O'Rourke, Ryan; Gibson, William J; Pelton, Kristine; Ramkissoon, Shakti H; Han, Harry J; Zhu, Yuankun; Choudhari, Namrata; Silva, Amanda; Boucher, Katie; Henn, Rosemary E; Kang, Yun Jee; Knoff, David; Paolella, Brenton R; Gladden-Young, Adrianne; Varlet, Pascale; Pages, Melanie; Horowitz, Peleg M; Federation, Alexander; Malkin, Hayley; Tracy, Adam A; Seepo, Sara; Ducar, Matthew; Van Hummelen, Paul; Santi, Mariarita; Buccoliero, Anna Maria; Scagnet, Mirko; Bowers, Daniel C; Giannini, Caterina; Puget, Stephanie; Hawkins, Cynthia; Tabori, Uri; Klekner, Almos; Bognar, Laszlo; Burger, Peter C; Eberhart, Charles; Rodriguez, Fausto J; Hill, D Ashley; Mueller, Sabine; Haas-Kogan, Daphne A; Phillips, Joanna J; Santagata, Sandro; Stiles, Charles D; Bradner, James E; Jabado, Nada; Goren, Alon; Grill, Jacques; Ligon, Azra H; Goumnerova, Liliana; Waanders, Angela J; Storm, Phillip B; Kieran, Mark W; Ligon, Keith L; Beroukhim, Rameen; Resnick, Adam C

    2016-03-01

    Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor. PMID:26829751

  2. Peritumoural glutamate correlates with post-operative seizures in supratentorial gliomas.

    PubMed

    Neal, Andrew; Yuen, Tanya; Bjorksten, Andrew R; Kwan, Patrick; O'Brien, Terence J; Morokoff, Andrew

    2016-09-01

    To examine the impact of glutamate on post-operative seizures and survival in a cohort of patients with grade II to IV supratentorial glioma. A retrospective analysis was performed on 216 patients who underwent surgery for supratentorial gliomas. Primary explanatory variables were peritumoural and/or tumoural glutamate concentrations, glutamate transporter expression (EAAT2 and SXC). Univariate and multivariate survival analysis was performed with primary outcomes of time to first post-operative seizure and overall survival. Subgroup analysis was performed in patients with de novo glioblastomas who received adjuvant chemoradiotherapy. 47 (21.8 %), 34 (15.8 %) and 135 (62.5 %) WHO grade II, III and IV gliomas respectively were followed for a median of 15.8 months. Following multivariate analysis, there was a non-significant association between higher peritumoural glutamate concentrations and time to first post-operative seizure (HR 2.07, CI 0.98-4.37, p = 0.06). In subgroup analysis of 81 glioblastoma patients who received adjunct chemoradiotherapy, peritumoural glutamate concentration was significantly associated with time to first post-operative seizure (HR 3.10, CI 1.20-7.97, p = 0.02). In both the overall cohort and subgroup analysis no glutamate cycle biomarkers were predictive of overall survival. Increased concentrations of peritumoural glutamate were significantly associated with shorter periods of post-operative seizure freedom in patients with de novo glioblastomas treated with adjuvant chemoradiotherapy. No glutamate cycle biomarkers were predictive of overall survival. These results suggest that therapies targeting glutamate may be beneficial in tumour associated epilepsy. PMID:27311724

  3. 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

  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. Silencing of R-Spondin1 increases radiosensitivity of glioma cells

    PubMed Central

    Ma, Guoda; Cui, Lili; Li, You; Zhou, Haihong; Liang, Wandong; Zhao, Bin; Li, Keshen

    2015-01-01

    Although radiation therapy is the most effective postoperative adjuvant treatment, it does not substantially improve the long-term outcomes of glioma patients because of the characteristic radioresistance of glioma. We found that R-Spondin1 (Rspo1) expression was elevated in high-grade gliomas and was associated with worse overall survival and disease-free survival. Rspo1 expression was also associated with reduced survival rates in glioma patients after treatment with radiotherapy and temozolomide (RT-TMZ). Importantly, Rspo1 was dramatically upregulated after radiation treatment in patients with glioma. Rspo1 silencing by shRNA potentiated glioma cell death upon radiation treatment. In a xenograft nude mouse model, combining radiation and silencing of Rspo1 potentiated tumor growth inhibition. Thus, combining radiotherapy with silencing of Rspo1 is a potential therapeutic approach. PMID:25865226

  6. Platelet-derived growth factor receptor (PDGFR) expression in primary spinal cord gliomas

    PubMed Central

    Canoll, Peter; McCormick, Paul C.; Feldstein, Neil A.; Anderson, Richard C.; Angevine, Peter D.; Kaiser, Michael G.; McCormick, Paul C.; Bruce, Jeffrey N.; Ogden, Alfred T.

    2013-01-01

    Abnormal signaling through the platelet-derived growth factor receptor (PDGFR) has been proposed as a possible mechanism of spinal cord glioma initiation and progression. However, the extent of PDGFR expression in human spinal cord gliomas remains unknown. In this study we perform immunohistochemical analysis of PDGFRα expression in a series of 33 primary intramedullary spinal cord gliomas of different types and grades. PDGFRα was seen to be expressed in a significant subset of these tumors across all major glioma types including ependymoma, oligodendroglioma, pilocytic astrocytoma, astrocytoma, and glioblastoma. These results support the hypothesis that growth factor signaling through the PDGFR may be important for the development of at least a subset of human spinal cord gliomas. Further studies investigating the prognostic significance of PDGFR expression as well as the role of PDGF signaling on the development of intramedullary spinal cord gliomas are warranted. PMID:21789698

  7. Single-frequency, dual-GNSS versus dual-frequency, single-GNSS: a low-cost and high-grade receivers GPS-BDS RTK analysis

    NASA Astrophysics Data System (ADS)

    Odolinski, Robert; Teunissen, Peter J. G.

    2016-06-01

    The concept of single-frequency, dual-system (SF-DS) real-time kinematic (RTK) positioning has become feasible since, for instance, the Chinese BeiDou Navigation Satellite System (BDS) has become operational in the Asia-Pacific region. The goal of the present contribution is to investigate the single-epoch RTK performance of such a dual-system and compare it to a dual-frequency, single-system (DF-SS). As the SF-DS we investigate the L1 GPS + B1 BDS model, and for DF-SS we take L1, L2 GPS and B1, B2 BDS, respectively. Two different locations in the Asia-Pacific region are analysed with varying visibility of the BDS constellation, namely Perth in Australia and Dunedin in New Zealand. To emphasize the benefits of such a model we also look into using low-cost ublox single-frequency receivers and compare such SF-DS RTK performance to that of a DF-SS, based on much more expensive survey-grade receivers. In this contribution a formal and empirical analysis is given. It will be shown that with the SF-DS higher elevation cut-off angles than the conventional 10° or 15° can be used. The experiment with low-cost receivers for the SF-DS reveals (for the first time) that it has the potential to achieve comparable ambiguity resolution performance to that of a DF-SS (L1, L2 GPS), based on the survey-grade receivers.

  8. Selective Targeting to Glioma with Nucleic Acid Aptamers

    PubMed Central

    Aptekar, Shraddha; Arora, Mohit; Lawrence, Clare Louise; Lea, Robert William; Ashton, Katherine; Dawson, Tim; Alder, Jane Elizabeth; Shaw, Lisa

    2015-01-01

    Malignant glioma is characterised by a rapid growth rate and high capacity for invasive infiltration to surrounding brain tissue; hence, diagnosis and treatment is difficult and patient survival is poor. Aptamers contribute a promising and unique technology for the in vitro imaging of live cells and tissues, with a potentially bright future in clinical diagnostics and therapeutics for malignant glioma. The binding selectivity, uptake capacity and binding target of two DNA aptamers, SA43 and SA44, were investigated in glioma cells and patient tissues. The binding assay showed that SA43 and SA44 bound with strong affinity (Kd, 21.56 ± 4.60 nM and Kd, 21.11 ± 3.30 nM respectively) to the target U87MG cells. Quantitative analysis by flow cytometry showed that the aptamers were able to actively internalise in U87MG and 1321N1 glioma cells compared to the non-cancerous and non-glioma cell types. Confocal microscopy confirmed staining in the cytoplasm, and co-localisation studies with endoplasmic reticulum, Golgi apparatus and lysosomal markers suggested internalisation and compartmentalisation within the endomembrane system. Both aptamers selectively bound to Ku 70 and Ku 80 DNA repair proteins as determined by aptoprecipitation (AP) followed by mass spectrometry analysis and confirmation by Western blot. In addition, aptohistochemical (AHC) staining on paraffin embedded, formalin fixed patient tissues revealed that the binding selectivity was significantly higher for SA43 aptamer in glioma tissues (grade I, II, III and IV) compared to the non-cancerous tissues, whereas SA44 did not show selectivity towards glioma tissues. The results indicate that SA43 aptamer can differentiate between glioma and non-cancerous cells and tissues and therefore, shows promise for histological diagnosis of glioma. PMID:26252900

  9. Radiation-induced gliomas

    PubMed Central

    Prasad, Gautam; Haas-Kogan, Daphne A.

    2013-01-01

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

  10. Galectins and Gliomas

    PubMed Central

    Le Mercier, Marie; Fortin, Shannon; Mathieu, Véronique; Kiss, Robert; Lefranc, Florence

    2010-01-01

    Malignant gliomas, especially glioblastomas, are associated with a dismal prognosis. Despite advances in diagnosis and treatment, glioblastoma patients still have a median survival expectancy of only 14 months. This poor prognosis can be at least partly explained by the fact that glioma cells diffusely infiltrate the brain parenchyma and exhibit decreased levels of apoptosis, and thus resistance to cytotoxic drugs. Galectins are a family of mammalian beta-galactoside-binding proteins characterized by a shared characteristic amino acid sequence. They are expressed differentially in normal vs. neoplastic tissues and are known to play important roles in several biological processes such as cell proliferation, death and migration. This review focuses on the role played by galectins, especially galectin-1 and galectin-3, in glioma biology. The involvement of these galectins in different steps of glioma malignant progression such as migration, angiogenesis or chemoresistance makes them potentially good targets for the development of new drugs to combat these malignant tumors. PMID:19371355

  11. Ki-67/MIB-1 immunostaining in a cohort of human gliomas

    PubMed Central

    Skjulsvik, Anne J; Mørk, Jørgen N; Torp, Morten O; Torp, Sverre H

    2014-01-01

    Histopathological malignancy grading of human gliomas is limited by subjective interpretation of the morphological criteria. Assessment of mitotic activity is a cornerstone of grading these tumours, but mitotic figures can be hard to identify in haematoxylin-eosin stained sections. Thus, determining proliferative activity by means of Ki-67/MIB-1 immunostaining has become a useful supplement. However, this method has drawbacks, so continuous testing and evaluation are required for optimization and standardization. The aim of this study was to analyse and evaluate the Ki-67/MIB-1 proliferative indices (PIs) in a series of gliomas. We found that Ki-67/MIB-1 PIs correlated well with histological malignancy grade in all glioma subtypes, but a considerable overlap of PIs was observed between the malignancy groups. Consequently, Ki-67/MIB-1 immunostaining alone is not sufficient to adequately determine the malignancy grade. Therefore, future work is necessary to clarify the role of this immunostaining in the histopathological diagnosis of human gliomas. PMID:25674263

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

    PubMed

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

    2016-01-01

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

  13. The role of Alix in the proliferation of human glioma cells.

    PubMed

    Zhao, Chengjin; Ban, Na; Dai, Shirong; Zhang, Xiubing; Zhang, Li; Xu, Peng; Chen, Wenjuan; Sun, Jie; Bao, Zhen; Chang, Hao; Wang, Donglin; Ren, Jianbing

    2016-06-01

    Apoptosis-linked-gene-2-interacting protein 1 (Alix) is involved in the endosome-lysosome system in the cytoplasm. The normal function of Alix may be altered by ALG-2 toward a destructive role during active cell death. Alix also may play a role in regulation of cell proliferation. However, the role of Alix in human glioma has not been elucidated yet. This study intended to clarify the relationship between Alix and glioma pathologic grades and its role in the proliferation of glioma cells. Our findings showed that Alix protein concentrations were significantly elevated in high-grade glioma tissue compared with low-grade glioma (P < .0001). Immunohistochemical study revealed that Alix was overexpressed in 75 resected glioma tissues and may forecast poor survival. Alix expression was increased in resting serum-stimulated glioma cells. Additionally, we reduced Alix expression in U251MG cells and then found that cell viability was decreased significantly when p21 expression increased. Colony formation assay and flow cytometry analysis demonstrated that reduced Alix expression may lead to growth inhibition and cell cycle arrest. In summary, our findings suggest that Alix plays an important role in the proliferation of glioma cells and may be a novel therapeutic target. PMID:26980041

  14. 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

  15. Upregulation of miR-183 expression and its clinical significance in human brain glioma.

    PubMed

    Ye, Zhennan; Zhang, Zihuan; Wu, Lingyun; Liu, Cegang; Chen, Qiang; Liu, Jingpeng; Wang, Xiaoliang; Zhuang, Zong; Li, Wei; Xu, Shanshui; Hang, Chunhua

    2016-08-01

    Glioma is the most common type of primary malignant tumor in the central nervous system (CNS) with a high incidence and a high mortality rate, as well as an extremely low 5-year survival rate. As a class of small non-coding RNAs, microRNAs (miRNAs) may be closely involved in carcinogenesis and might also be connected with glioma diagnosis and prognosis. In this study, we aimed at investigating the expression level of microRNA-183 (miR-183) in 105 cases of glioma tissues of four World Health Organization (WHO) grades and 10 cases of normal brain tissues and its potential predictive and prognostic values in glioma. We found that the expression levels of miR-183 were significantly higher in glioma tissues than that in normal brain tissues, and also higher in high-grade gliomas (WHO grade III and IV) compared with low-grade gliomas (WHO grade I and II). The miR-183 expression level was classified as low or high according to the median value. High expression of miR-183 was found to significantly correlate with larger tumor size, higher WHO grade, and worse Karnofsky performance score (KPS). Kaplan-Meier survival analysis showed that patients with high miR-183 expression had worse overall survival (OS) and progression-free survival (PFS) than patients with low miR-183 expression. Moreover, univariate and multivariate analyses indicated that miR-183 expression level was an independent prognostic parameter of a patient's OS and PFS. In conclusion, our study indicated that miR-183 was upregulated in glioma, and that it may be used as a potential biomarker of poor prognosis in patients with glioma. PMID:27215622

  16. 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

  17. The role of ventriculoperitoneal shunting in patients with supratentorial glioma

    PubMed Central

    de la Fuente, Macarena I; DeAngelis, Lisa M

    2014-01-01

    Objectives To assess the impact of ventriculoperitoneal (VPS) in patients with glioma. Methods Retrospective review of patients with grade II-IV glioma who had VPS placement from January 1995 to November 2012. Results We identified 62 patients. At time of VPS, 41 had gait disturbance, 40 cognitive impairment and 16 urinary incontinence; 10 had the classic triad. Thirty-eight (61%) improved after VPS. Median overall survival from VPS was 7 months for all patients, but 11 months for those who improved and 2 months for non-responders. Leptomeningeal disease, glioma grade or radiographic ventricular decompression did not predict benefit. Conclusions VPS can improve functional status in some patients with symptoms suggestive of hydrocephalus. PMID:25356380

  18. Atypical nuclear localization of VIP receptors in glioma cell lines and patients

    SciTech Connect

    Barbarin, Alice; Séité, Paule; Godet, Julie; Bensalma, Souheyla; Muller, Jean-Marc; Chadéneau, Corinne

    2014-11-28

    Highlights: • The VIP receptor VPAC1 contains a putative NLS signal. • VPAC1 is predominantly nuclear in GBM cell lines but not VPAC2. • Non-nuclear VPAC1/2 protein expression is correlated with glioma grade. • Nuclear VPAC1 is observed in 50% of stage IV glioma (GBM). - Abstract: An increasing number of G protein-coupled receptors, like receptors for vasoactive intestinal peptide (VIP), are found in cell nucleus. As VIP receptors are involved in the regulation of glioma cell proliferation and migration, we investigated the expression and the nuclear localization of the VIP receptors VPAC1 and VPAC2 in this cancer. First, by applying Western blot and immunofluorescence detection in three human glioblastoma (GBM) cell lines, we observed a strong nuclear staining for the VPAC1 receptor and a weak nuclear VPAC2 receptor staining. Second, immunohistochemical staining of VPAC1 and VPAC2 on tissue microarrays (TMA) showed that the two receptors were expressed in normal brain and glioma tissues. Expression in the non-nuclear compartment of the two receptors significantly increased with the grade of the tumors. Analysis of nuclear staining revealed a significant increase of VPAC1 staining with glioma grade, with up to 50% of GBM displaying strong VPAC1 nuclear staining, whereas nuclear VPAC2 staining remained marginal. The increase in VPAC receptor expression with glioma grades and the enhanced nuclear localization of the VPAC1 receptors in GBM might be of importance for glioma progression.

  19. 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

  20. 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

  1. Trends in Malignant Glioma Monoclonal Antibody Therapy

    PubMed Central

    Chekhonin, Ivan; Gurina, Olga

    2015-01-01

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

  2. Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes

    PubMed Central

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

    2016-01-01

    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. PMID:26976322

  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

    2016-01-01

    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. PMID:26976322

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

    PubMed Central

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

    2009-01-01

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

  5. Molecular Neuropathology of Gliomas

    PubMed Central

    Riemenschneider, Markus J.; Reifenberger, Guido

    2009-01-01

    Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified according to the World Health Organization (WHO) classification of tumors of the nervous system. Over the past 20 years the cytogenetic and molecular genetic alterations associated with glioma formation and progression have been intensely studied and genetic profiles as additional aids to the definition of brain tumors have been incorporated in the WHO classification. In fact, first steps have been undertaken in supplementing classical histopathological diagnosis by the use of molecular tests, such as MGMT promoter hypermethylation in glioblastomas or detection of losses of chromosome arms 1p and 19q in oligodendroglial tumors. The tremendous progress that has been made in the use of array-based profiling techniques will likely contribute to a further molecular refinement of glioma classification and lead to the identification of glioma core pathways that can be specifically targeted by more individualized glioma therapies. PMID:19333441

  6. 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

  7. Phase I Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Intratumoral Infusions of GRm13Z40-2, An Allogeneic CD8+ Cytolitic T-Cell Line Genetically Modified to Express the IL 13-Zetakine and HyTK and to be Resistant to Glucocorticoids, in Combination With Interleukin-2

    ClinicalTrials.gov

    2015-06-03

    Anaplastic Astrocytoma; Anaplastic Ependymoma; Anaplastic Meningioma; Anaplastic Oligodendroglioma; Brain Stem Glioma; Ependymoblastoma; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Grade III Meningioma; Meningeal Hemangiopericytoma; Mixed Glioma; Pineal Gland Astrocytoma; Brain Tumor

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

    PubMed Central

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

    2015-01-01

    Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes. PMID:26517124

  9. 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. PMID:26517124

  10. 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

  11. 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

  12. 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

  13. CHD1L Regulates Cell Cycle, Apoptosis, and Migration in Glioma.

    PubMed

    Sun, Jie; Zhang, Li; Zhao, Hongyu; Qiu, Xiaojun; Chen, Wenjuan; Wang, Donglin; Ban, Na; Fan, Shaochen; Shen, Chaoyan; Xia, Xiaojie; Ji, Bin; Wang, Yuchan

    2016-05-01

    Chromodomain helicase/ATPase DNA binding protein 1-like (CHD1L) gene is a newly identified oncogene located at Chr1q21 and it is amplified in many solid tumors. In this study, we intended to investigate the clinical significance of CHD1L expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that CHD1L was overexpressed in glioma tissues and glioma cell lines. In addition, the expression level of CHD1L was positively correlated with glioma pathological grade and Ki-67 expression. Kaplan-Meier curve indicated that high expression of CHD1L may result in poor prognosis of glioma patients. Accordingly, suppression of CHD1L in glioma cells was shown to induce cell cycle arrest and increase apoptosis. In addition, knockdown of CHD1L significantly accelerated migration and invasion ability of glioma cells. Together our findings suggest that CHD1L is involved in the progression of glioma and may be a novel target for further therapy. PMID:26162969

  14. Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas.

    PubMed

    Siegal, Tali

    2016-01-01

    Sorting and grading of glial tumors by the WHO classification provide clinicians with guidance as to the predicted course of the disease and choice of treatment. Nonetheless, histologically identical tumors may have very different outcome and response to treatment. Molecular markers that carry both diagnostic and prognostic information add useful tools to traditional classification by redefining tumor subtypes within each WHO category. Therefore, molecular markers have become an integral part of tumor assessment in modern neuro-oncology and biomarker status now guides clinical decisions in some subtypes of gliomas. The routine assessment of IDH status improves histological diagnostic accuracy by differentiating diffuse glioma from reactive gliosis. It carries a favorable prognostic implication for all glial tumors and it is predictive for chemotherapeutic response in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q are defined as tumors of oligodendroglial lineage and have favorable prognosis. MGMT promoter methylation is a favorable prognostic marker in astrocytic high-grade gliomas and it is predictive for chemotherapeutic response in anaplastic gliomas with wild-type IDH1/2 and in glioblastoma of the elderly. The clinical implication of other molecular markers of gliomas like mutations of EGFR and ATRX genes and BRAF fusion or point mutation is highlighted. The potential of molecular biomarker-based classification to guide future therapeutic approach is discussed and accentuated. PMID:26508407

  15. 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

  16. HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation.

    PubMed

    Haapa-Paananen, S; Kiviluoto, S; Waltari, M; Puputti, M; Mpindi, J P; Kohonen, P; Tynninen, O; Haapasalo, H; Joensuu, H; Perälä, M; Kallioniemi, O

    2012-03-01

    Malignant glioma is the most common brain tumor with 16,000 new cases diagnosed annually in the United States. We performed a systematic large-scale transcriptomics data mining study of 9783 tissue samples from the GeneSapiens database to systematically identify genes that are most glioma-specific. We searched for genes that were highly expressed in 322 glioblastoma multiforme tissue samples and 66 anaplastic astrocytomas as compared with 425 samples from histologically normal central nervous system. Transcription cofactor HES6 (hairy and enhancer of split 6) emerged as the most glioma-specific gene. Immunostaining of a tissue microarray showed HES6 expression in 335 (98.8%) out of the 339 glioma samples. HES6 was expressed in endothelial cells of the normal brain and glioma tissue. Recurrent grade 2 astrocytomas and grade 2 or 3 oligodendrogliomas showed higher levels of HES6 immunoreactivity than the corresponding primary tumors. High HES6 mRNA expression correlated with the proneural subtype that generally has a favorable outcome but is prone to recur. Functional studies suggested an important role for HES6 in supporting survival of glioma cells, as evidenced by reduction of cancer cell proliferation and migration after HES6 silencing. The biological role and consequences of HES6 silencing and overexpression was explored with genome-wide analyses, which implicated a role for HES6 in p53, c-myc and nuclear factor-κB transcriptional networks. We conclude that HES6 is important for glioma cell proliferation and migration, and may have a role in angiogenesis. PMID:21785461

  17. Elevated expression of chloride intracellular channel 1 is correlated with poor prognosis in human gliomas

    PubMed Central

    2012-01-01

    Background Chloride intracellular channel 1 (CLIC1) is expressed ubiquitously in human tissues and is involved in the regulation of cell cycle, cell proliferation and differentiation. Recent studies have shown that CLIC1 is highly expressed in several human malignant tumors. However, its roles in human gliomas are still unclear. The aim of this study was to investigate the clinicopathological significance and prognostic value of CLIC1 expression in human gliomas. Methods CLIC1 expression in human gliomas and nonneoplastic brain tissues was measured by real-time quantitative RT-PCR assay and immunohistochemistry. Its association with clinicopathological factors or prognosis in patients with gliomas was statistically analyzed. Results The expression of CLIC1 at both mRNA and protein levels was significantly increased in high-grade (Grade III~IV) glioma tissues compared with that in low-grade (Grade I~II) and nonneoplastic brain tissues, and was up-regulated with ascending tumor World Health Organization (WHO) grades. The elevated expression of CLIC1 protein was also significantly correlated with low Karnofsky performance score (KPS) (P=0.008). Moreover, both univariate and multivariate analysis shown that high CLIC1 expression was significantly associated with poor prognosis in patients with gliomas (P<0.001 and P=0.01, respectively). In particular, the elevated CLIC1 expression also correlated with shorter overall survival in different glioma subgroups stratified according to the WHO grading. Conclusions Our data provide the first evidence that CLIC1 expression might play an important role in the regulation of aggressiveness in human gliomas. The elevated expression of CLIC1 might represent a valuable prognostic marker for this disease. PMID:22578365

  18. 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

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

    PubMed

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

    2015-01-01

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

  20. Germline mutations in shelterin complex genes are associated with familial glioma.

    PubMed

    Bainbridge, Matthew N; Armstrong, Georgina N; Gramatges, M Monica; Bertuch, Alison A; Jhangiani, Shalini N; Doddapaneni, Harsha; Lewis, Lora; Tombrello, Joseph; Tsavachidis, Spyros; Liu, Yanhong; Jalali, Ali; Plon, Sharon E; Lau, Ching C; Parsons, Donald W; Claus, Elizabeth B; Barnholtz-Sloan, Jill; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S; Jenkins, Robert B; Lachance, Daniel; Olson, Sara H; Bernstein, Jonine L; Merrell, Ryan T; Wrensch, Margaret R; Walsh, Kyle M; Davis, Faith G; Lai, Rose; Shete, Sanjay; Aldape, Kenneth; Amos, Christopher I; Thompson, Patricia A; Muzny, Donna M; Gibbs, Richard A; Melin, Beatrice S; Bondy, Melissa L

    2015-01-01

    Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma. PMID:25482530

  1. Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas.

    PubMed

    Sugahara, T; Korogi, Y; Kochi, M; Ikushima, I; Shigematu, Y; Hirai, T; Okuda, T; Liang, L; Ge, Y; Komohara, Y; Ushio, Y; Takahashi, M

    1999-01-01

    The purpose of this study was to evaluate the utility of diffusion-weighted magnetic resonance imaging (MRI) with echo-planar imaging (EPI) technique in depicting the tumor cellularity and grading of gliomas. Twenty consecutive patients (13 men and 7 women, ranging in age from 13 to 69 years) with histologically proven gliomas were examined using a 1.5 T superconducting imager. Tumor cellularity, analyzed with National Institutes of Health Image 1.60 software on a Macintosh computer, was compared with the minimum apparent diffusion coefficient (ADC) and the signal intensity on the T2-weighted images. The relationship of the minimum ADC to the tumor grade was also evaluated. Tumor cellularity correlated well with the minimum ADC value of the gliomas (P = 0.007), but not with the signal intensity on the T2-weighted images. The minimum ADC of the high-grade gliomas was significantly higher than that of the low-grade gliomas. Diffusion-weighted MRI with EPI is a useful technique for assessing the tumor cellularity and grading of gliomas. This information is not obtained with conventional MRI and is useful for the diagnosis and characterization of gliomas. PMID:10030650

  2. DDX3X Biomarker Correlates with Poor Survival in Human Gliomas

    PubMed Central

    Hueng, Dueng-Yuan; Tsai, Wen-Chiuan; Chiou, Hsin-Ying Clair; Feng, Shao-Wei; Lin, Chin; Li, Yao-Feng; Huang, Li-Chun; Lin, Ming-Hong

    2015-01-01

    Primary high-grade gliomas possess invasive growth and lead to unfavorable survival outcome. The investigation of biomarkers for prediction of survival outcome in patients with gliomas is important for clinical assessment. The DEAD (Asp-Glu-Ala-Asp) box helicase 3, X-linked (DDX3X) controls tumor migration, proliferation, and progression. However, the role of DDX3X in defining the pathological grading and survival outcome in patients with human gliomas is not yet clarified. We analyzed the DDX3X gene expression, WHO pathological grading, and overall survival from de-linked data. Further validation was done using quantitative RT-PCR of cDNA from normal brain and glioma, and immunohistochemical (IHC) staining of tissue microarray. Statistical analysis of GEO datasets showed that DDX3X mRNA expression demonstrated statistically higher in WHO grade IV (n = 81) than in non-tumor controls (n = 23, p = 1.13 × 10−10). Moreover, DDX3X level was also higher in WHO grade III (n = 19) than in non-tumor controls (p = 2.43 × 10−5). Kaplan–Meier survival analysis showed poor survival in patients with high DDX3X mRNA levels (n = 24) than in those with low DDX3X expression (n = 53) (median survival, 115 vs. 58 weeks, p = 0.0009, by log-rank test, hazard ratio: 0.3507, 95% CI: 0.1893–0.6496). Furthermore, DDX3X mRNA expression and protein production significantly increased in glioma cells compared with normal brain tissue examined by quantitative RT-PCR, and Western blot. IHC staining showed highly staining of high-grade glioma in comparison with normal brain tissue. Taken together, DDX3X expression level positively correlates with WHO pathologic grading and poor survival outcome, indicating that DDX3X is a valuable biomarker in human gliomas. PMID:26184164

  3. Motexafin-Gadolinium and Involved Field Radiation Therapy for Intrinsic Pontine Glioma of Childhood: A Children's Oncology Group Phase 2 Study

    SciTech Connect

    Bradley, Kristin A.; Zhou Tianni; McNall-Knapp, Rene Y.; Jakacki, Regina I.; Pollack, Ian F.

    2013-01-01

    Purpose: To evaluate the effects on 1-year event-free survival (EFS) and overall survival (OS) of combining motexafin and gadolinium (MGd), a potent radiosensitizer, with daily fractionated radiation therapy in children with newly diagnosed intrinsic pontine gliomas. Methods and Materials: Patients with newly diagnosed intrinsic pontine glioma were treated with MGd daily for 5 consecutive days each week, for a total of 30 doses. Patients received a 5- to 10-min intravenous bolus of MGd, 4.4 mg/kg/day, given 2 to 5 h prior to standard dose irradiation. Radiation therapy was administered at a daily dose of 1.8 Gy for 30 treatments over 6 weeks. The total dose was 54 Gy. Results: Sixty eligible children received MGd daily, concurrent with 6 weeks of radiation therapy. The estimated 1-year EFS was 18% {+-} 5%, and the estimated 1-year OS was 53% {+-} 6.5%. The most common grade 3 to 4 toxicities were lymphopenia, transient elevation of liver transaminases, and hypertension. Conclusions: Compared to historical controls, the addition of MGd to a standard 6-week course of radiation did not improve the survival of pediatric patients with newly diagnosed intrinsic pontine gliomas.

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

    PubMed

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

    2016-05-01

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

  5. Identification of microRNAs in the cerebrospinal fluid as biomarker for the diagnosis of glioma.

    PubMed

    Baraniskin, Alexander; Kuhnhenn, Jan; Schlegel, Uwe; Maghnouj, Abdelouahid; Zöllner, Hannah; Schmiegel, Wolf; Hahn, Stephan; Schroers, Roland

    2012-01-01

    Malignant gliomas are the most common and lethal primary intracranial tumors. To date, no reliable biomarkers for the detection and risk stratification of gliomas have been identified. Recently, we demonstrated significant levels of microRNAs (miRNAs) to be present in cerebrospinal fluid (CSF) samples from patients with primary CNS lymphoma. Because of the involvement of miRNA in carcinogenesis, miRNAs in CSF may serve as unique biomarkers for minimally invasive diagnosis of glioma. The objective of this pilot study was to identify differentially expressed microRNAs in CSF samples from patients with glioma as potential novel glioma biomarkers. With use of a candidate approach of miRNA quantification by reverse-transcriptase polymerase chain reaction (qRT-PCR), miRNAs with significant leve