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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

    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

  8. 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

  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

    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 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

  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 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

  2. 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

  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. 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

  4. 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

  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. 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

  6. 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

  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. 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

  4. 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

  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 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

  10. 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

  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

    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

  4. 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

  5. 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

  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. 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

  18. 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

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

    SciTech Connect

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

    2014-10-15

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

  20. 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. 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

  11. 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

  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. 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

  2. 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

  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. 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

  5. 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

  6. 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

  7. 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

  8. 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

  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. 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

  13. 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.

  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. 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

  16. 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

  17. 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

  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. 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

  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 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

  14. 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

  15. 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

  16. 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.

  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. 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

  8. 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

  9. 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

  10. 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

  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 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

  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

    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

  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. 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

  19. 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

  20. 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

  1. 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.

  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. 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.

  14. 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

  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. 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

  18. 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

  19. 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

  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. 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

  7. 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

  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