The transcription factor Olig2 is important for the biology of diffuse intrinsic pontine gliomas.

PubMed

Anderson, Jane L; Muraleedharan, Ranjithmenon; Oatman, Nicole; Klotter, Amanda; Sengupta, Satarupa; Waclaw, Ronald R; Wu, Jianqiang; Drissi, Rachid; Miles, Lili; Raabe, Eric H; Weirauch, Matthew L; Fouladi, Maryam; Chow, Lionel M; Hoffman, Lindsey; DeWire, Mariko; Dasgupta, Biplab

2017-08-01

Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. The transcription factor Olig2 is highly expressed in 70%-80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Brainstem angiocentric glioma: report of 2 cases.

PubMed

Weaver, Kristin J; Crawford, Lexi M; Bennett, Jeffrey A; Rivera-Zengotita, Marie L; Pincus, David W

2017-10-01

Angiocentric glioma is a rare tumor that was recognized by the WHO Classification of Tumours of the Central Nervous System as a distinct clinicopathological entity in 2007. Since this initial description, the vast majority of cases of angiocentric glioma reported in the literature have involved tumors of the cerebral hemispheres. To date, only 1 case of angiocentric glioma arising from the posterior midbrain has been reported. The authors present the cases of 2 pediatric patients who were found to have brainstem angiocentric gliomas. The clinical course, radiological and pathological features, treatment, and follow-up are described. The first case is one of a 5-year-old girl who presented with double vision, headache, and nausea and was found to have a midbrain lesion with pathological features consistent with angiocentric glioma. She was treated with resection and endoscopic third ventriculostomy (ETV), followed by close observation and serial neuroimaging. The second case is one of a 6-year-old boy who presented with progressive mouth drooping and problems with balance. He was found to have a pontine lesion with pathological features consistent with angiocentric glioma. This patient was treated with ETV, followed by close observation and serial neuroimaging. This report includes 6 and 1.5 years of follow-up of the patients, respectively. While there are limited data regarding the prognosis or long-term management of patients with brainstem angiocentric gliomas, the cases described in this report suggest an indolent course for this tumor, similar to the course of angiocentric gliomas located in the cerebral hemispheres.

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

PubMed

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

2017-01-01

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janssens, Geert O.R.J.; Gidding, Corrie E.M.; Lindert, Erik J. van

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

Convection enhanced delivery of carmustine to the murine brainstem: a feasibility study.

PubMed

Sewing, A Charlotte P; Caretti, Viola; Lagerweij, Tonny; Schellen, Pepijn; Jansen, Marc H A; van Vuurden, Dannis G; Idema, Sander; Molthoff, Carla F M; Vandertop, W Peter; Kaspers, Gertjan J L; Noske, David P; Hulleman, Esther

2014-12-30

Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients. The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol. Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors. Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals. CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG models. Copyright © 2014 Elsevier B.V. All rights reserved.

FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas.

PubMed

Picca, Alberto; Berzero, Giulia; Bielle, Franck; Touat, Mehdi; Savatovsky, Julien; Polivka, Marc; Trisolini, Elena; Meunier, Sheida; Schmitt, Yohann; Idbaih, Ahmed; Hoang-Xuan, Khe; Delattre, Jean-Yves; Mokhtari, Karima; Di Stefano, Anna Luisa; Sanson, Marc

2018-06-05

To characterize the prevalence and prognostic significance of major driver molecular alterations in adult midline diffuse gliomas (MLG). Adults with histologically proven MLG diagnosed between 1996 and 2017 were identified from our tumor bank, systematically reviewed, and reclassified according to WHO 2016. Targeted sequencing was performed, including determination of H3F3A , HIST1H3B , TERTp , IDH1/2 , FGFR1 , p16/CDKN2A , and EGFR status. A total of 116 adult patients (M/F 71/45, median age 46.5 years) with MLG (17 cerebellar, 8 spinal, 30 brainstem, 57 thalamic, and 4 diencephalic nonthalamic) were identified. Most patients had high-grade disease at presentation (grade II: 11%, grade III: 15%, grade IV: 75%). Median overall survival was 17.3 months (14.5-23.8 months). Main molecular alterations observed were TERT promoter, H3F3A , and hotspot FGFR1 (N546 and K656) mutations, in 37%, 34%, and 18% of patients, respectively. IDH1 mutations only affected brainstem gliomas (6/24 vs 0/78; p = 7.5 × 10 -5 ), were mostly non-R132H (contrasting with hemispheric gliomas, p = 0.0001), and were associated with longer survival (54 vs 12 months). TERT promoter mutation (9.1 vs 24.2 months), CDKN2A deletion (9.9 vs 23.8 months), and EGFR amplification (4.3 vs 23.8 months) were associated with shorter survival. Of interest, in contrast with pediatric MLG, H3K27M mutations were not associated with worse prognosis (23 vs 15 months). Patients with adult MLG present with unique clinical and molecular characteristics, differing from their pediatric counterparts. The identification of potentially actionable FGFR1 mutations in a subset of adult MLG highlights the importance of comprehensive genomic analysis in this rare affection. © 2018 American Academy of Neurology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org; Merchant, Thomas E.; Gajjar, Amar

Purpose: To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI). Methods and Materials: We analyzed 109 DTI studies from 20 brain tumor patients, aged 4 to 23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors (n = 10) received postoperative craniospinal irradiation (23.4-39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by four cycles of high-dose chemotherapy. Patients with high-grade gliomas (n = 10) received erlotinib during and after irradiation (54-59.4 Gy). Parametricmore » maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6 to 25 years, were included in the analysis. Results: The median DTI follow-up time was 3.5 years (range, 1.6-5.0 years). The median mean dose to the pons was 56 Gy (range, 7-59 Gy). Three patterns were seen in longitudinal FA and apparent diffusion coefficient changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns. Conclusions: Variations existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years after radiation therapy.« less

A Study of Pemetrexed in Children With Recurrent Cancer

ClinicalTrials.gov

2011-02-23

Osteosarcoma; Medulloblastoma; Sarcoma, Ewing's; Neuroblastoma (Measurable Disease); Neuroblastoma (Metaiodobenzylguanidine; Positive Evaluable); Rhabdomyosarcoma; Ependymoma; Non-brainstem High-grade Glioma

Extracellular diffusion quantified by magnetic resonance imaging during rat C6 glioma cell progression.

PubMed

Song, G; Luo, T; Dong, L; Liu, Q

2017-07-03

Solution reflux and edema hamper the convection-enhanced delivery of the standard treatment for glioma. Therefore, a real-time magnetic resonance imaging (MRI) method was developed to monitor the dosing process, but a quantitative analysis of local diffusion and clearance parameters has not been assessed. The objective of this study was to compare diffusion into the extracellular space (ECS) at different stages of rat C6 gliomas, and analyze the effects of the extracellular matrix (ECM) on the diffusion process. At 10 and 20 days, after successful glioma modeling, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) was introduced into the ECS of rat C6 gliomas. Diffusion parameters and half-life of the reagent were then detected using MRI, and quantified according to the mathematical model of diffusion. The main ECM components [chondroitin sulfate proteoglycans (CSPGs), collagen IV, and tenascin C] were detected by immunohistochemical and immunoblot analyses. In 20-day gliomas, Gd-DTPA diffused more slowly and derived higher tortuosity, with lower clearance rate and longer half-life compared to 10-day gliomas. The increased glioma ECM was associated with different diffusion and clearance parameters in 20-day rat gliomas compared to 10-day gliomas. ECS parameters were altered with C6 glioma progression from increased ECM content. Our study might help better understand the glioma microenvironment and provide benefits for interstitial drug delivery to treat brain gliomas.

Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

PubMed Central

Monje, Michelle; Mitra, Siddhartha S.; Freret, Morgan E.; Raveh, Tal B.; Kim, James; Masek, Marilyn; Attema, Joanne L.; Haddix, Terri; Edwards, Michael S. B.; Fisher, Paul G.; Weissman, Irving L.; Rowitch, David H.; Vogel, Hannes; Wong, Albert J.; Beachy, Philip A.

2011-01-01

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor. PMID:21368213

High-grade glioma diffusive modeling using statistical tissue information and diffusion tensors extracted from atlases.

PubMed

Roniotis, Alexandros; Manikis, Georgios C; Sakkalis, Vangelis; Zervakis, Michalis E; Karatzanis, Ioannis; Marias, Kostas

2012-03-01

Glioma, especially glioblastoma, is a leading cause of brain cancer fatality involving highly invasive and neoplastic growth. Diffusive models of glioma growth use variations of the diffusion-reaction equation in order to simulate the invasive patterns of glioma cells by approximating the spatiotemporal change of glioma cell concentration. The most advanced diffusive models take into consideration the heterogeneous velocity of glioma in gray and white matter, by using two different discrete diffusion coefficients in these areas. Moreover, by using diffusion tensor imaging (DTI), they simulate the anisotropic migration of glioma cells, which is facilitated along white fibers, assuming diffusion tensors with different diffusion coefficients along each candidate direction of growth. Our study extends this concept by fully exploiting the proportions of white and gray matter extracted by normal brain atlases, rather than discretizing diffusion coefficients. Moreover, the proportions of white and gray matter, as well as the diffusion tensors, are extracted by the respective atlases; thus, no DTI processing is needed. Finally, we applied this novel glioma growth model on real data and the results indicate that prognostication rates can be improved. © 2012 IEEE

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

PubMed

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

2015-12-08

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

Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

ClinicalTrials.gov

2018-06-28

Constitutional Mismatch Repair Deficiency Syndrome; Lynch Syndrome; Malignant Glioma; Progressive Ependymoma; Progressive Medulloblastoma; Recurrent Brain Neoplasm; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Brain Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Ependymoma; Refractory Medulloblastoma

Clinicopathological features and treatment outcomes of brain stem gliomas in Saudi population

PubMed Central

Bayoumi, Yasser; Sabbagh, Abdulrahman J; Mohamed, Reham; ElShokhaiby, Usama M; Maklad, Ahmed Marzouk; Tunio, Mutahir A; Balbaid, Ali Abdullah O

2014-01-01

AIM: To analyze experiences to identify treatment outcomes and prognostic factors in a Saudi population. METHODS: Medical records of patients with brainstem gliomas treated from July 2001 to December 2012 were reviewed to identify treatment outcomes of surgery, radiation therapy and chemotherapy and associated prognostic factors in a Saudi population. RESULTS: We analyzed 49 brain stem glioma (BSG) patients from July 2001 to December 2012; 31 of them were males (63.3%) with a median age of 12.6 years (range: 8-64 mo). Twenty-two patients (44.9%) had diffuse intrinsic pontine gliomas (DIPG) and 15 (30.6%) presented with focal/tectal BSG. Histopathology was available in 30 patients (61.2%). Median survival time for the whole cohort was 1.5 years. One and two year OS rates were 51.1% and 41.9% respectively. Two year OS rates for focal/tectal, dorsally exophytic, cervicomedullary and DIPG tumors were 60%, 33.3%, 33.3% and 13.6% respectively (P < 0.0001). Significant prognostic factors related to OS were age at diagnosis (worse for > 18 years) P = 0.01, KPS < 70 P = 0.02, duration of symptoms (< 60 d) P = 0.002, histology (better for favorable) P = 0.002, surgery (maximal resection) P = 0.002, and concurrent chemotherapy with radiation therapy in DIPG (better if given) P = 0.01. CONCLUSION: BSG, especially the DIPG subgroup, had a dismal prognosis, needing more aggressive neurosurgical, radiation and chemotherapy techniques, while focal and tectal tumors were found to have a better prognosis. PMID:25493242

Grading of Gliomas by Using Monoexponential, Biexponential, and Stretched Exponential Diffusion-weighted MR Imaging and Diffusion Kurtosis MR Imaging

PubMed Central

Bai, Yan; Lin, Yusong; Tian, Jie; Shi, Dapeng; Cheng, Jingliang; Haacke, E. Mark; Hong, Xiaohua; Ma, Bo; Zhou, Jinyuan

2016-01-01

Purpose To quantitatively compare the potential of various diffusion parameters obtained from monoexponential, biexponential, and stretched exponential diffusion-weighted imaging models and diffusion kurtosis imaging in the grading of gliomas. Materials and Methods This study was approved by the local ethics committee, and written informed consent was obtained from all subjects. Both diffusion-weighted imaging and diffusion kurtosis imaging were performed in 69 patients with pathologically proven gliomas by using a 3-T magnetic resonance (MR) imaging unit. An isotropic apparent diffusion coefficient (ADC), true ADC, pseudo-ADC, and perfusion fraction were calculated from diffusion-weighted images by using a biexponential model. A water molecular diffusion heterogeneity index and distributed diffusion coefficient were calculated from diffusion-weighted images by using a stretched exponential model. Mean diffusivity, fractional anisotropy, and mean kurtosis were calculated from diffusion kurtosis images. All values were compared between high-grade and low-grade gliomas by using a Mann-Whitney U test. Receiver operating characteristic and Spearman rank correlation analysis were used for statistical evaluations. Results ADC, true ADC, perfusion fraction, water molecular diffusion heterogeneity index, distributed diffusion coefficient, and mean diffusivity values were significantly lower in high-grade gliomas than in low-grade gliomas (U = 109, 56, 129, 6, 206, and 229, respectively; P < .05). Pseudo-ADC and mean kurtosis values were significantly higher in high-grade gliomas than in low-grade gliomas (U = 98 and 8, respectively; P < .05). Both water molecular diffusion heterogeneity index (area under the receiver operating characteristic curve [AUC] = 0.993) and mean kurtosis (AUC = 0.991) had significantly greater AUC values than ADC (AUC = 0.866), mean diffusivity (AUC = 0.722), and fractional anisotropy (AUC = 0.500) in the differentiation of low-grade and high-grade gliomas (P < .05). Conclusion Water molecular diffusion heterogeneity index and mean kurtosis values may provide additional information and improve the grading of gliomas compared with conventional diffusion parameters. © RSNA, 2015 Online supplemental material is available for this article. PMID:26230975

Meta-analysis of diffusion metrics for the prediction of tumor grade in gliomas.

PubMed

Miloushev, V Z; Chow, D S; Filippi, C G

2015-02-01

Diffusion tensor metrics are potential in vivo quantitative neuroimaging biomarkers for the characterization of brain tumor subtype. This meta-analysis analyzes the ability of mean diffusivity and fractional anisotropy to distinguish low-grade from high-grade gliomas in the identifiable tumor core and the region of peripheral edema. A meta-analysis of articles with mean diffusivity and fractional anisotropy data for World Health Organization low-grade (I, II) and high-grade (III, IV) gliomas, between 2000 and 2013, was performed. Pooled data were analyzed by using the odds ratio and mean difference. Receiver operating characteristic analysis was performed for patient-level data. The minimum mean diffusivity of high-grade gliomas was decreased compared with low-grade gliomas. High-grade gliomas had decreased average mean diffusivity values compared with low-grade gliomas in the tumor core and increased average mean diffusivity values in the peripheral region. High-grade gliomas had increased FA values compared with low-grade gliomas in the tumor core, decreased values in the peripheral region, and a decreased fractional anisotropy difference between the tumor core and peripheral region. The minimum mean diffusivity differs significantly with respect to the World Health Organization grade of gliomas. Statistically significant effects of tumor grade on average mean diffusivity and fractional anisotropy were observed, supporting the concept that high-grade tumors are more destructive and infiltrative than low-grade tumors. Considerable heterogeneity within the literature may be due to systematic factors in addition to underlying lesion heterogeneity. © 2015 by American Journal of Neuroradiology.

[A correlation between diffusion kurtosis imaging and the proliferative activity of brain glioma].

PubMed

Tonoyan, A S; Pronin, I N; Pitshelauri, D I; Shishkina, L V; Fadeeva, L M; Pogosbekyan, E L; Zakharova, N E; Shults, E I; Khachanova, N V; Kornienko, V N; Potapov, A A

2015-01-01

The aim of the study was to assess the capabilities of diffusion kurtosis imaging (DKI) in diagnosis of the glioma proliferative activity and to evaluate a relationship between the glioma proliferative activity index and diffusion parameters of the contralateral normal appearing white matter (CNAWM). The study included 47 patients with newly diagnosed brain gliomas (23 low grade, 13 grade III, and 11 grade IV gliomas). We determined a relationship between absolute and normalized parameters of the diffusion tensor (mean (MD), axial (AD), and radial (RD) diffusivities; fractional (FA) and relative (RA) anisotropies) and diffusion kurtosis (mean (MK), axial (AK), and radial (RK) kurtosis; kurtosis anisotropy (KA)) and the proliferative activity index in the most malignant glioma parts (p<0.05). We also established a relationship between the tensor and kurtosis parameters of CNAWM and the glioma proliferative activity index (p<0.05). The correlation between all the absolute and normalized diffusion parameters and the glioma proliferative activity index, except absolute and normalized FA and RA values, was found to be statistically significant (p<0.05). Kurtosis (MK, AK, and RK) and anisotropy (KA, FA, RA) values increased, and diffusivity (MD, AD, RD) values decreased as the glioma proliferative activity index increased. A strong correlation between the proliferative activity index and absolute RK (r=0,71; p=0.000001) and normalized values of MK (r=0.8; p=0.000001), AK (r=0.71; p=0.000001), RK (r=0.81; p=0.000001), and RD (r=-0.71; p=0.000001) was found. A weak, but statistically significant correlation between the glioma proliferative activity index and diffusion values RK (r=-0.36; p=0.014), KA (r=-0.39; p=0.007), RD (r=0.35; p=0.017), FA (r=-0.42; p=0.003), and RA (r=-0.41; p=0.004) of CNAWM was found. DKI has good capabilities to detect immunohistochemical changes in gliomas. DKI demonstrated a high sensitivity in detection of microstructural changes in the contralateral normal appearing white matter in patients with brain gliomas.

WEE1 Inhibitor AZD1775 and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

ClinicalTrials.gov

2018-06-11

Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; Glioblastoma; Gliosarcoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligoastrocytoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliosarcoma

Diffusion tensor imaging demonstrates brainstem and cerebellar abnormalities in congenital central hypoventilation syndrome.

PubMed

Kumar, Rajesh; Macey, Paul M; Woo, Mary A; Alger, Jeffry R; Harper, Ronald M

2008-09-01

Congenital central hypoventilation syndrome (CCHS) patients show reduced breathing drive during sleep, decreased hypoxic and hypercapnic ventilatory responses, and autonomic and affective deficits, suggesting both brainstem and forebrain injuries. Forebrain damage was previously described in CCHS, but methodological limitations precluded detection of brainstem injury, a concern because genetic mutations in CCHS target brainstem autonomic nuclei. To assess brainstem and cerebellar areas, we used diffusion tensor imaging-based measures, namely axial diffusivity, reflecting water diffusion parallel to fibers, and sensitive to axonal injury, and radial diffusivity, measuring diffusion perpendicular to fibers, and indicative of myelin injury. Diffusion tensor imaging was performed in 12 CCHS and 26 controls, and axial and radial diffusivity maps were compared between groups using analysis of covariance (covariates; age and gender). Increased axial diffusivity in CCHS appeared within the lateral medulla and clusters with injury extended from the dorsal midbrain through the periaqueductal gray, raphé, and superior cerebellar decussation, ventrally to the basal-pons. Cerebellar cortex and deep nuclei, and the superior and inferior cerebellar peduncles showed increased radial diffusivity. Midbrain, pontine, and lateral medullary structures, and the cerebellum and its fiber systems are injured in CCHS, likely contributing to the characteristics found in the syndrome.

Ribociclib and Everolimus in Treating Children With Recurrent or Refractory Malignant Brain Tumors

ClinicalTrials.gov

2018-03-09

Central Nervous System Embryonal Tumor, Not Otherwise Specified; Malignant Glioma; Recurrent Atypical Teratoid/Rhabdoid Tumor; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Diffuse Intrinsic Pontine Glioma

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

PubMed

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

2016-01-28

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

The use of fluorescein sodium in the biopsy and gross-total resection of a tectal plate glioma.

PubMed

Ung, Timothy H; Kellner, Christopher; Neira, Justin A; Wang, Shih-Hsiu J; D'Amico, Randy; Faust, Phyllis L; Canoll, Peter; Feldstein, Neil A; Bruce, Jeffrey N

2015-12-01

Intravenous administration of fluorescein sodium fluoresces glioma burden tissue and can be visualized using the surgical microscope with a specialized filter. Intraoperative guidance afforded through the use of fluorescein may enhance the fidelity of tissue sampling, and increase the ability to accomplish complete resection of tectal lesions. In this report the authors present the case of a 19-year-old man with a tectal anaplastic pilocytic astrocytoma in which the use of fluorescein sodium and a Zeiss Pentero surgical microscope equipped with a yellow 560 filter enabled safe complete resection. In conjunction with neurosurgical navigation, added intraoperative guidance provided by fluorescein may be beneficial in the resection of brainstem gliomas.

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

PubMed Central

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

2015-01-01

IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup. PMID:26314843

Re-evaluating TTF-1 immunohistochemistry in diffuse gliomas: Expression is clone-dependent and associated with tumor location.

PubMed

Pratt, Drew; Afsar, Nina; Allgauer, Michael; Fetsch, Patricia; Palisoc, Maryknoll; Pittaluga, Stefania; Quezado, Martha

TTF-1 is widely used as a marker in routine surgical pathology in the work-up of malignancy. Aberrant expression of TTF-1 in extrapulmonary and extrathyroidal malignancies is a frequently reported phenomenon. In addition to the recently characterized pituicyte-derived tumors of the sella, immunoreactivity has been reported in diffuse gliomas with the SPT24 clone. Here, we sought to evaluate TTF-1 expression with three commercially available clones in a large series of gliomas. Expression was compared across the newly defined diagnostic entities in the 2016 WHO Classification of CNS Tumors. Using tissue microarrays (TMA), 212 diffuse gliomas (WHO grades II - IV) were systematically evaluated with TTF-1 immunohistochemistry using three clones: SPT24, 8G7G3/1, and SP141, and results correlated with clinicopathologic features. 14 high-grade diffuse gliomas demonstrated nuclear staining with the SP141 and SPT24 clones. Two tumors showed weak positivity with the 8G7G3/1 clone. All tumors were high grade by histology (WHO grades III and IV). 86% (12/14) of TTF-1-positive gliomas involved the frontal lobes at diagnosis. No relationship with IDH R132H, ATRX, p53, H3K27M, or EGFR immunohistochemistry was identified. TTF-1 expression in gliomas was not independently prognostic of overall survival. TTF-1 expression in diffuse gliomas is a rare but potentially misleading occurrence. In our cohort, staining occurred with both the SPT24 and SP141 clones at equal intensity and frequency. Clustering of TTF-1-positive tumors in the frontal lobe(s) suggests lineage-specific expression. Due to clone-specific expression in diffuse gliomas, caution must be exercised in the work-up of intracranial tumors with TTF-1.
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Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial.

PubMed

Mackay, Alan; Burford, Anna; Molinari, Valeria; Jones, David T W; Izquierdo, Elisa; Brouwer-Visser, Jurriaan; Giangaspero, Felice; Haberler, Christine; Pietsch, Torsten; Jacques, Thomas S; Figarella-Branger, Dominique; Rodriguez, Daniel; Morgan, Paul S; Raman, Pichai; Waanders, Angela J; Resnick, Adam C; Massimino, Maura; Garrè, Maria Luisa; Smith, Helen; Capper, David; Pfister, Stefan M; Würdinger, Thomas; Tam, Rachel; Garcia, Josep; Thakur, Meghna Das; Vassal, Gilles; Grill, Jacques; Jaspan, Tim; Varlet, Pascale; Jones, Chris

2018-05-14

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8 + tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Anisotropy of anomalous diffusion improves the accuracy of differentiating low- and high-grade cerebral gliomas.

PubMed

Xu, Boyan; Su, Lu; Wang, Zhenxiong; Fan, Yang; Gong, Gaolang; Zhu, Wenzhen; Gao, Peiyi; Gao, Jia-Hong

2018-04-17

Anomalous diffusion model has been introduced and shown to be beneficial in clinical applications. However, only the directionally averaged values of anomalous diffusion parameters were investigated, and the anisotropy of anomalous diffusion remains unexplored. The aim of this study was to demonstrate the feasibility of using anisotropy of anomalous diffusion for differentiating low- and high-grade cerebral gliomas. Diffusion MRI images were acquired from brain tumor patients and analyzed using the fractional motion (FM) model. Twenty-two patients with histopathologically confirmed gliomas were selected. An anisotropy metric for the FM-related parameters, including the Noah exponent (α) and the Hurst exponent (H), was introduced and their values were statistically compared between the low- and high-grade gliomas. Additionally, multivariate logistic regression analysis was performed to assess the combination of the anisotropy metric and the directionally averaged value for each parameter. The diagnostic performances for grading gliomas were evaluated using a receiver operating characteristic (ROC) analysis. The Hurst exponent H was more anisotropic in high-grade than in low-grade gliomas (P = 0.015), while no significant difference was observed for the anisotropy of α. The ROC analysis revealed that larger areas under the ROC curves were produced for the combination of α (1) and the combination of H (0.813) compared with the directionally averaged α (0.979) and H (0.594), indicating an improved performance for tumor differentiation. The anisotropy of anomalous diffusion can provide distinctive information and benefit the differentiation of low- and high-grade gliomas. The utility of anisotropic anomalous diffusion may have an improved effect for investigating pathological changes in tissues. Copyright © 2018 Elsevier Inc. All rights reserved.

[Guidelines for adult diffuse gliomas WHO grade II, III and IV: pathology and biology. Société franc¸aise de neuropathologie . Réseau de neuro-oncologie pathologique].

PubMed

Figarella-Branger, Dominique; Labrousse, François; Mohktari, Karima

2012-10-01

Pathological diagnosis plays a major role in the therapeutic management of adult diffuse gliomas. It is based on the histopathological analysis of a representative specimen. Therefore pathologists might be aware of the neuroradiological features of the lesions. Pathologists play a major role in the management of biological resources. Pathologists should classify adult gliomas according to WHO 2007 classification (histological subtype and grade). In addition, in order to provide the histomolecular classification of adult gliomas, search for molecular markers of diagnostic, prognostic or predictive of therapeutic responses must be performed by appropriate and validated immunohistochemical and molecular techniques. In all diffuse gliomas, whatever their grade, search for IDH1 R132H and P53 expression is required. Search for IDH1 minor mutations and IDH2 mutations is required in grade II and III IDH1 R132H negative gliomas whereas 1p19q codeletion should be searched for in grade II and III gliomas with an oligodendroglial component. Search for EGFR amplification and MGMT promoter methylation is recommended. It is strongly recommended to fill the standardized form for pathology and molecular features (validated by the French Society of Neuropathology) in all adult diffuse gliomas. Copyright © 2012. Published by Elsevier Masson SAS.

Diffusion tensor imaging of the brainstem in children with achondroplasia

PubMed Central

BOSEMANI, THANGAMADHAN; ORMAN, GUNES; CARSON, KATHRYN A; MEODED, AVNER; HUISMAN, THIERRY A G M; PORETTI, ANDREA

2014-01-01

Aim The aims of this study were to compare, using diffusion tensor imaging (DTI) of the brainstem, microstructural integrity of the white matter in children with achondroplasia and age-matched participants and to correlate the severity of craniocervical junction (CCJ) narrowing and neurological findings with DTI scalars in children with achondroplasia. This study also aimed to assess the potential role of fibroblast growth factor receptor type 3 on white matter microstructure. Method Diffusion tensor imaging was performed using a 1.5T magnetic resonance scanner and balanced pairs of diffusion gradients along 20 non-collinear directions. Measurements were obtained from regions of interest, sampled in each pontine corticospinal tract (CST), medial lemniscus, and middle cerebellar peduncle, as well as in the lower brainstem and centrum semiovale, for fractional anisotropy and for mean, axial and radial diffusivity. In addition, a severity score for achondroplasia was assessed by measuring CCJ narrowing. Result Eight patients with achondroplasia (seven males, one female; mean age 5y 6mo, range 1y 1mo–15y 1mo) and eight age- and sex-matched comparison participants (mean age 5y 2mo, range 1y 1mo–14y 11mo) were included in this study. Fractional anisotropy was lower and mean diffusivity and radial diffusivity were higher in the lower brainstem of patients with achondroplasia than in age-matched comparison participants. The CST and middle cerebellar peduncle of the participants showed increases in mean, axial, and radial diffusivity. Fractional anisotropy in the lower brainstem was negatively correlated with the degree of CCJ narrowing. No differences in the DTI metrics of the centrum semiovale were observed between the two groups. Interpretation The reduction in fractional anisotropy and increase in diffusivities in the lower brainstem of participants with achondroplasia may reflect secondary encephalomalacic degeneration and cavitation of the affected white matter tracts as shown by histology. In children with achondroplasia, DTI may serve as a potential biomarker for brainstem white matter injury and aid in the care and management of these patients. PMID:24825324

Diffusion tensor imaging of the brainstem in children with achondroplasia.

PubMed

Bosemani, Thangamadhan; Orman, Gunes; Carson, Kathryn A; Meoded, Avner; Huisman, Thierry A G M; Poretti, Andrea

2014-11-01

The aims of this study were to compare, using diffusion tensor imaging (DTI) of the brainstem, microstructural integrity of the white matter in children with achondroplasia and age-matched participants and to correlate the severity of craniocervical junction (CCJ) narrowing and neurological findings with DTI scalars in children with achondroplasia. This study also aimed to assess the potential role of fibroblast growth factor receptor type 3 on white matter microstructure. Diffusion tensor imaging was performed using a 1.5T magnetic resonance scanner and balanced pairs of diffusion gradients along 20 non-collinear directions. Measurements were obtained from regions of interest, sampled in each pontine corticospinal tract (CST), medial lemniscus, and middle cerebellar peduncle, as well as in the lower brainstem and centrum semiovale, for fractional anisotropy and for mean, axial, and radial diffusivity. In addition, a severity score for achondroplasia was assessed by measuring CCJ narrowing. Eight patients with achondroplasia (seven males, one female; mean age 5y 6mo, range 1y 1mo-15y 1mo) and eight age- and sex-matched comparison participants (mean age 5y 2mo, range 1y 1mo-14y 11mo) were included in this study. Fractional anisotropy was lower and mean diffusivity and radial diffusivity were higher in the lower brainstem of patients with achondroplasia than in age-matched comparison participants. The CST and middle cerebellar peduncle of the participants showed increases in mean, axial, and radial diffusivity. Fractional anisotropy in the lower brainstem was negatively correlated with the degree of CCJ narrowing. No differences in the DTI metrics of the centrum semiovale were observed between the two groups. The reduction in fractional anisotropy and increase in diffusivities in the lower brainstem of participants with achondroplasia may reflect secondary encephalomalacic degeneration and cavitation of the affected white matter tracts as shown by histology. In children with achondroplasia, DTI may serve as a potential biomarker for brainstem white matter injury and aid in the care and management of these patients. © 2014 Mac Keith Press.

In Silico Neuro-Oncology: Brownian Motion-Based Mathematical Treatment as a Potential Platform for Modeling the Infiltration of Glioma Cells into Normal Brain Tissue.

PubMed

Antonopoulos, Markos; Stamatakos, Georgios

2015-01-01

Intensive glioma tumor infiltration into the surrounding normal brain tissues is one of the most critical causes of glioma treatment failure. To quantitatively understand and mathematically simulate this phenomenon, several diffusion-based mathematical models have appeared in the literature. The majority of them ignore the anisotropic character of diffusion of glioma cells since availability of pertinent truly exploitable tomographic imaging data is limited. Aiming at enriching the anisotropy-enhanced glioma model weaponry so as to increase the potential of exploiting available tomographic imaging data, we propose a Brownian motion-based mathematical analysis that could serve as the basis for a simulation model estimating the infiltration of glioblastoma cells into the surrounding brain tissue. The analysis is based on clinical observations and exploits diffusion tensor imaging (DTI) data. Numerical simulations and suggestions for further elaboration are provided.

TCGA_LowerGradeGliomas

Cancer.gov

TCGA researchers analyzed nearly 300 cases of diffuse low- and intermediate-grade gliomas, which together comprise lower-grade gliomas. LGGs occur mainly in adults and include astrocytomas, oligodendrogliomas and oligoastrocytomas.

Local image variance of 7 Tesla SWI is a new technique for preoperative characterization of diffusely infiltrating gliomas: correlation with tumour grade and IDH1 mutational status.

PubMed

Grabner, Günther; Kiesel, Barbara; Wöhrer, Adelheid; Millesi, Matthias; Wurzer, Aygül; Göd, Sabine; Mallouhi, Ammar; Knosp, Engelbert; Marosi, Christine; Trattnig, Siegfried; Wolfsberger, Stefan; Preusser, Matthias; Widhalm, Georg

2017-04-01

To investigate the value of local image variance (LIV) as a new technique for quantification of hypointense microvascular susceptibility-weighted imaging (SWI) structures at 7 Tesla for preoperative glioma characterization. Adult patients with neuroradiologically suspected diffusely infiltrating gliomas were prospectively recruited and 7 Tesla SWI was performed in addition to standard imaging. After tumour segmentation, quantification of intratumoural SWI hypointensities was conducted by the SWI-LIV technique. Following surgery, the histopathological tumour grade and isocitrate dehydrogenase 1 (IDH1)-R132H mutational status was determined and SWI-LIV values were compared between low-grade gliomas (LGG) and high-grade gliomas (HGG), IDH1-R132H negative and positive tumours, as well as gliomas with significant and non-significant contrast-enhancement (CE) on MRI. In 30 patients, 9 LGG and 21 HGG were diagnosed. The calculation of SWI-LIV values was feasible in all tumours. Significantly higher mean SWI-LIV values were found in HGG compared to LGG (92.7 versus 30.8; p < 0.0001), IDH1-R132H negative compared to IDH1-R132H positive gliomas (109.9 versus 38.3; p < 0.0001) and tumours with significant CE compared to non-significant CE (120.1 versus 39.0; p < 0.0001). Our data indicate that 7 Tesla SWI-LIV might improve preoperative characterization of diffusely infiltrating gliomas and thus optimize patient management by quantification of hypointense microvascular structures. • 7 Tesla local image variance helps to quantify hypointense susceptibility-weighted imaging structures. • SWI-LIV is significantly increased in high-grade and IDH1-R132H negative gliomas. • SWI-LIV is a promising technique for improved preoperative glioma characterization. • Preoperative management of diffusely infiltrating gliomas will be optimized.

A comprehensive review of paediatric low-grade diffuse glioma: pathology, molecular genetics and treatment.

PubMed

Ryall, Scott; Tabori, Uri; Hawkins, Cynthia

2017-04-01

Gliomas are the most common central nervous system neoplasms affecting children and can be both high- and low-grade. Paediatric low-grade glioma may be either World Health Organization grade I or grade II. Despite being classified as grade II diffuse astrocytoma, these neoplasms arising in children are distinct clinically and molecularly from their adult counterparts. They do not tend to progress to higher grade lesions and only rarely harbour an IDH mutation. Here, we review the clinical, histologic and molecular features of paediatric grade II diffuse glioma, highlighting their diagnostic criteria, prevalence across brain locations, their most common molecular features and how to test for them, and lastly the current status of therapeutic options available for their treatment.

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

PubMed

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

2016-08-01

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

Quantitative Magnetic Resonance Diffusion-Weighted Imaging Evaluation of the Supratentorial Brain Regions in Patients Diagnosed with Brainstem Variant of Posterior Reversible Encephalopathy Syndrome: A Preliminary Study.

PubMed

Chen, Tai-Yuan; Wu, Te-Chang; Ko, Ching-Chung; Feng, I-Jung; Tsui, Yu-Kun; Lin, Chien-Jen; Chen, Jeon-Hor; Lin, Ching-Po

2017-07-01

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity with several causes, characterized by rapid onset of symptoms and typical neuroimaging features, which usually resolve if promptly recognized and treated. Brainstem variant of PRES presents with vasogenic edema in brainstem regions on magnetic resonance (MR) images and there is sparing of the supratentorial regions. Because PRES is usually caused by a hypertensive crisis, which would likely have a systemic effect and global manifestations on the brain tissue, we thus proposed that some microscopic abnormalities of the supratentorial regions could be detected with diffusion-weighted imaging (DWI) using apparent diffusion coefficient (ADC) analysis in brainstem variant of PRES and hypothesized that "normal-looking" supratentorial regions will increase water diffusion. We retrospectively identified patients with PRES who underwent brain magnetic resonance imaging studies. We identified 11 brainstem variants of PRES patients, who formed the study cohort, and 11 typical PRES patients and 20 normal control subjects as the comparison cohorts for this study. Nineteen regions of interest were drawn and systematically placed. The mean ADC values were measured and compared among these 3 groups. ADC values of the typical PRES group were consistently elevated compared with those in normal control subjects. ADC values of the brainstem variant group were consistently elevated compared with those in normal control subjects. ADC values of the typical PRES group and brainstem variant group did not differ significantly, except for the pons area. Quantitative MR DWI may aid in the evaluation of supratentorial microscopic abnormalities in brainstem variant of PRES patients. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2017-01-24

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

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

PubMed Central

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

2013-01-01

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

Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas

ClinicalTrials.gov

2018-03-30

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

Global and Targeted Pathway Impact of Gliomas on White Matter Integrity Based on Lobar Localization.

PubMed

Ormond, David R; D'Souza, Shawn; Thompson, John A

2017-09-07

Primary brain tumors comprise 28% of all tumors and 80% of malignant tumors. Pathophysiology of high-grade gliomas includes significant distortion of white matter architecture, necrosis, the breakdown of the blood brain barrier, and increased intracranial pressure. Diffusion tensor imaging (DTI), a diffusion weighted imaging technique, can be used to assess white matter architecture. Use of DTI as a non-invasive pathophysiological tool to analyze glioma impact on white matter microstructure has yet to be fully explored. Preliminary assessment of DTI tractography was done as a measure of intracranial tumor impact on white matter architecture. Specifically, we addressed three questions: 1) whether glioma differentially affects local white matter structure compared to metastasis, 2) whether glioma affects tract integrity of major white matter bundles, 3) whether glioma lobe localization affects tract integrity of different white matter bundles. In this study, we retrospectively investigated preoperative DTI scans from 24 patients undergoing tumor resection. Fiber tractography was estimated using a deterministic fiber tracking algorithm in DSI (diffusion spectrum imaging) Studio. The automatic anatomical labeling (AAL) atlas was used to define the left and right (L/R)   hemisphere regions of interest (ROI). In addition, the John Hopkins University (JHU) White Matter Atlas was used to auto-segment major white matter bundle ROIs. For all tracts derived from ROI seed targets, we computed the following parameters: tract number, tract length, fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD). The DTI tractography analysis revealed that white matter integrity in the hemisphere ipsilateral to intracranial tumor was significantly compromised compared to the control contralateral hemisphere. No differences were observed between high vs low-grade gliomas, however, gliomas induced significantly greater white matter degradation than metastases. In addition, targeted analysis of major white matter bundles important for sensory/motor function (i.e., corticospinal tract and superior longitudinal fasciculus) revealed tract-parameter specific susceptibility due to the presence of the tumor. Finally, major tract bundles were differentially affected based on lobar localization of the glioma. These DTI-based tractographic analyses complement findings from gross histopathological examination of glioma impact on neural tissue. Global and focal white matter architecture, ipsilateral to glioma, shows higher rates of degradation or edema - based on DTI tractographic metrics - in comparison to normal brain or metastases. Gliomas, which arise in the parietal lobe, also have a higher negative impact (potentially due to increased edema) on white matter integrity of the superior longitudinal fasciculus(SLF) than those which arise in the frontal lobe. Future studies will focus on using preoperative and postoperative tractography to predict functional deficits following resective surgery.

Feasibility of creating a high-resolution 3D diffusion tensor imaging based atlas of the human brainstem: A case study at 11.7T

PubMed Central

Aggarwal, Manisha; Zhang, Jiangyang; Pletnikova, Olga; Crain, Barbara; Troncoso, Juan; Mori, Susumu

2013-01-01

A three-dimensional stereotaxic atlas of the human brainstem based on high resolution ex vivo diffusion tensor imaging (DTI) is introduced. The atlas consists of high resolution (125–255 μm isotropic) three-dimensional DT images of the formalin-fixed brainstem acquired at 11.7T. The DTI data revealed microscopic neuroanatomical details, allowing three-dimensional visualization and reconstruction of fiber pathways including the decussation of the pyramidal tract fibers, and interdigitating fascicles of the corticospinal and transverse pontine fibers. Additionally, strong grey-white matter contrasts in the apparent diffusion coefficient (ADC) maps enabled precise delineation of grey matter nuclei in the brainstem, including the cranial nerve and the inferior olivary nuclei. Comparison with myelin-stained histology shows that at the level of resolution achieved in this study, the structural details resolved with DTI contrasts in the brainstem were comparable to anatomical delineation obtained with histological sectioning. Major neural structures delineated from DTI contrasts in the brainstem are segmented and three-dimensionally reconstructed. Further, the ex vivo DTI data are nonlinearly mapped to a widely-used in vivo human brain atlas, to construct a high-resolution atlas of the brainstem in the Montreal Neurological Institute (MNI) stereotaxic coordinate space. The results demonstrate the feasibility of developing a 3D DTI based atlas for detailed characterization of brainstem neuroanatomy with high resolution and contrasts, which will be a useful resource for research and clinical applications. PMID:23384518

Histogram analysis of diffusion kurtosis imaging derived maps may distinguish between low and high grade gliomas before surgery.

PubMed

Qi, Xi-Xun; Shi, Da-Fa; Ren, Si-Xie; Zhang, Su-Ya; Li, Long; Li, Qing-Chang; Guan, Li-Ming

2018-04-01

To investigate the value of histogram analysis of diffusion kurtosis imaging (DKI) maps in the evaluation of glioma grading. A total of 39 glioma patients who underwent preoperative magnetic resonance imaging (MRI) were classified into low-grade (13 cases) and high-grade (26 cases) glioma groups. Parametric DKI maps were derived, and histogram metrics between low- and high-grade gliomas were analysed. The optimum diagnostic thresholds of the parameters, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were achieved using a receiver operating characteristic (ROC). Significant differences were observed not only in 12 metrics of histogram DKI parameters (P<0.05), but also in mean diffusivity (MD) and mean kurtosis (MK) values, including age as a covariate (F=19.127, P<0.001 and F=20.894, P<0.001, respectively), between low- and high-grade gliomas. Mean MK was the best independent predictor of differentiating glioma grades (B=18.934, 22.237 adjusted for age, P<0.05). The partial correlation coefficient between fractional anisotropy (FA) and kurtosis fractional anisotropy (KFA) was 0.675 (P<0.001). The AUC of the mean MK, sensitivity, and specificity were 0.925, 88.5% and 84.6%, respectively. DKI parameters can effectively distinguish between low- and high-grade gliomas. Mean MK is the best independent predictor of differentiating glioma grades. • DKI is a new and important method. • DKI can provide additional information on microstructural architecture. • Histogram analysis of DKI may be more effective in glioma grading.

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

ClinicalTrials.gov

2017-01-30

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

Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas.

PubMed

Wang, Huamin; Wang, Hua; Zhang, Wei; Huang, Helen J; Liao, Warren S L; Fuller, Gregory N

2004-08-01

Loss of phosphatase and tensin homolog (PTEN) and amplification of the epidermal growth factor receptor (EGFR) gene contribute to the progression of gliomas. As downstream targets of the PTEN and EGFR signaling pathways, Akt, NFkappaB, and signal transducer and activator of transcription-3 (Stat3) have been shown to play important roles in the control of cell proliferation, apoptosis, and oncogenesis. We examined the activation status of Akt, NFkappaB, and Stat3 in 259 diffuse gliomas using tissue microarrays and immunohistochemistry, and evaluated their association with glioma grade. We observed significant positive correlations between the activation status of Akt and NFkappaB and glioma grade. In contrast, only focal immunoreactivity for phospho-Stat3 was observed in < 9% of high-grade gliomas. In addition, we observed a significant correlation between the activation of Akt and NFkappaB. Functional correlation between Akt activation and the activation of NFkappaB was confirmed in U251MG GBM cells in which inhibition of Akt activation either by stable expression of PTEN or by the PI3-kinase inhibitors, wortmannin and LY294002, led to a concomitant decrease in NFkappaB-binding activity. Thus, our results demonstrate that constitutive activation of Akt and NFkappaB, but not Stat3, contributes significantly to the progression of diffuse gliomas, and activation of Akt may lead to NFkappaB activation in high-grade gliomas.

Diagnostic Accuracy of Centrally Restricted Diffusion in the Differentiation of Treatment-Related Necrosis from Tumor Recurrence in High-Grade Gliomas.

PubMed

Zakhari, N; Taccone, M S; Torres, C; Chakraborty, S; Sinclair, J; Woulfe, J; Jansen, G H; Nguyen, T B

2018-02-01

Centrally restricted diffusion has been demonstrated in recurrent high-grade gliomas treated with bevacizumab. Our purpose was to assess the accuracy of centrally restricted diffusion in the diagnosis of radiation necrosis in high-grade gliomas not treated with bevacizumab. In this prospective study, we enrolled patients with high-grade gliomas who developed a new ring-enhancing necrotic lesion and who underwent re-resection. The presence of a centrally restricted diffusion within the ring-enhancing lesion was assessed visually on diffusion trace images and by ADC measurements on 3T preoperative diffusion tensor examination. The percentage of tumor recurrence and radiation necrosis in each surgical specimen was defined histopathologically. The association between centrally restricted diffusion and radiation necrosis was assessed using the Fisher exact test. Differences in ADC and the ADC ratio between the groups were assessed via the Mann-Whitney U test, and receiver operating characteristic curve analysis was performed. Seventeen patients had re-resected ring-enhancing lesions: 8 cases of radiation necrosis and 9 cases of tumor recurrence. There was significant association between centrally restricted diffusion by visual assessment and radiation necrosis ( P = .015) with a sensitivity of 75% and a specificity of 88.9%, a positive predictive value 85.7%, and a negative predictive value of 80% for the diagnosis of radiation necrosis. There was a statistically significant difference in the ADC and ADC ratio between radiation necrosis and tumor recurrence ( P = .027). The presence of centrally restricted diffusion in a new ring-enhancing lesion might indicate radiation necrosis rather than tumor recurrence in high-grade gliomas previously treated with standard chemoradiation without bevacizumab. © 2018 by American Journal of Neuroradiology.

Combining Diffusion Tensor Metrics and DSC Perfusion Imaging: Can It Improve the Diagnostic Accuracy in Differentiating Tumefactive Demyelination from High-Grade Glioma?

PubMed

Hiremath, S B; Muraleedharan, A; Kumar, S; Nagesh, C; Kesavadas, C; Abraham, M; Kapilamoorthy, T R; Thomas, B

2017-04-01

Tumefactive demyelinating lesions with atypical features can mimic high-grade gliomas on conventional imaging sequences. The aim of this study was to assess the role of conventional imaging, DTI metrics ( p:q tensor decomposition), and DSC perfusion in differentiating tumefactive demyelinating lesions and high-grade gliomas. Fourteen patients with tumefactive demyelinating lesions and 21 patients with high-grade gliomas underwent brain MR imaging with conventional, DTI, and DSC perfusion imaging. Imaging sequences were assessed for differentiation of the lesions. DTI metrics in the enhancing areas and perilesional hyperintensity were obtained by ROI analysis, and the relative CBV values in enhancing areas were calculated on DSC perfusion imaging. Conventional imaging sequences had a sensitivity of 80.9% and specificity of 57.1% in differentiating high-grade gliomas ( P = .049) from tumefactive demyelinating lesions. DTI metrics ( p : q tensor decomposition) and DSC perfusion demonstrated a statistically significant difference in the mean values of ADC, the isotropic component of the diffusion tensor, the anisotropic component of the diffusion tensor, the total magnitude of the diffusion tensor, and rCBV among enhancing portions in tumefactive demyelinating lesions and high-grade gliomas ( P ≤ .02), with the highest specificity for ADC, the anisotropic component of the diffusion tensor, and relative CBV (92.9%). Mean fractional anisotropy values showed no significant statistical difference between tumefactive demyelinating lesions and high-grade gliomas. The combination of DTI and DSC parameters improved the diagnostic accuracy (area under the curve = 0.901). Addition of a heterogeneous enhancement pattern to DTI and DSC parameters improved it further (area under the curve = 0.966). The sensitivity increased from 71.4% to 85.7% after the addition of the enhancement pattern. DTI and DSC perfusion add profoundly to conventional imaging in differentiating tumefactive demyelinating lesions and high-grade gliomas. The combination of DTI metrics and DSC perfusion markedly improved diagnostic accuracy. © 2017 by American Journal of Neuroradiology.

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

PubMed

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

2015-06-01

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

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

PubMed

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

2012-08-01

Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild-type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG may help further distinguish this unique neoplasm from diffuse glioma. Copyright © 2012 Elsevier Inc. All rights reserved.

A high 18F-FDOPA uptake is associated with a slow growth rate in diffuse Grade II-III gliomas.

PubMed

Isal, Sibel; Gauchotte, Guillaume; Rech, Fabien; Blonski, Marie; Planel, Sophie; Chawki, Mohammad B; Karcher, Gilles; Marie, Pierre-Yves; Taillandier, Luc; Verger, Antoine

2018-04-01

In diffuse Grade II-III gliomas, a high 3,4-dihydroxy-6-( 18 F)-fluoro-L-phenylalanine ( 18 F-FDOPA) positron emission tomography (PET) uptake, with a standardized uptake value (SUV max )/contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. This pilot study was aimed to ascertain the prognostic value of this high 18 F-FDOPA uptake in diffuse Grade II-III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm per year. 20 patients (42 ± 10 years, 10 female) with newly-diagnosed diffuse Grade II-III gliomas (17 with IDH mutation) were retrospectively included. All had a 18 F-FDOPA PET, quantified with SUV max ratio, along with a serial MRI enabling VDE determination. SUV max ratio was above 1.8 in 5 patients (25%) all of whom had a VDE <4 mm/year (100%) and IDH mutation (100%). Moreover, a SUV max ratio above 1.8 was associated with higher rates of VDE <4 mm/year in the overall population (45 vs 0%, p = 0.04) and also in the subgroup of patients with IDH mutation (45 vs 0%, p = 0.10). This pilot study shows that in diffuse Grade II-III gliomas, a high 18 F-FDOPA uptake would be predictive of low tumour growth, with a different prognostic significance than IDH mutation. Advances in knowledge: 18 F-FDOPA PET in a single session imaging could have prognostic value in initial diagnosis of diffuse Grade II-III gliomas.

The Role of Molecular Diagnostics in the Management of Patients with Gliomas.

PubMed

Wirsching, Hans-Georg; Weller, Michael

2016-10-01

The revised World Health Organization (WHO) classification of tumors of the central nervous system of 2016 combines biology-driven molecular marker diagnostics with classical histological cancer diagnosis. Reclassification of gliomas by molecular similarity beyond histological boundaries improves outcome prediction and will increasingly guide treatment decisions. This change in paradigms implies more personalized and eventually more efficient therapeutic approaches, but the era of molecular targeted therapies for gliomas is yet at its onset. Promising results of molecularly targeted therapies in genetically less complex gliomas with circumscribed growth such as subependymal giant cell astrocytoma or pilocytic astrocytoma support further development of molecularly targeted therapies. In diffuse gliomas, several molecular markers that predict benefit from alkylating agent chemotherapy have been identified in recent years. For example, co-deletion of chromosome arms 1p and 19q predicts benefit from polychemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) in patients with anaplastic oligodendroglioma, and the presence of 1p/19q co-deletion was integrated as a defining feature of oligodendroglial tumors in the revised WHO classification. However, the tremendous increase in knowledge of molecular drivers of diffuse gliomas on genomic, epigenetic, and gene expression levels has not yet translated into effective molecular targeted therapies. Multiple reasons account for the failure of early clinical trials of molecularly targeted therapies in diffuse gliomas, including the lack of molecular entry controls as well as pharmacokinetic and pharmacodynamics issues, but the key challenge of specifically targeting the molecular backbone of diffuse gliomas is probably extensive clonal heterogeneity. A more profound understanding of clonal selection, alternative activation of oncogenic signaling pathways, and genomic instability is warranted to identify effective combination treatments and ultimately improve survival.

Tissue signature characterisation of diffusion tensor abnormalities in cerebral gliomas.

PubMed

Price, Stephen J; Peña, Alonso; Burnet, Neil G; Jena, Raj; Green, Hadrian A L; Carpenter, T Adrian; Pickard, John D; Gillard, Jonathan H

2004-10-01

The inherent invasiveness of malignant cells is a major determinant of the poor prognosis of cerebral gliomas. Diffusion tensor MRI (DTI) can identify white matter abnormalities in gliomas that are not seen on conventional imaging. By breaking down DTI into its isotropic (p) and anisotropic (q) components, we can determine tissue diffusion "signatures". In this study we have characterised these abnormalities in peritumoural white matter tracts. Thirty-five patients with cerebral gliomas and seven normal volunteers were imaged with DTI and T2-weighted sequences at 3 T. Displaced, infiltrated and disrupted white matter tracts were identified using fractional anisotropy (FA) maps and directionally encoded colour maps and characterised using tissue signatures. The diffusion tissue signatures were normal in ROIs where the white matter was displaced. Infiltrated white matter was characterised by an increase in the isotropic component of the tensor (p) and a less marked reduction of the anisotropic component (q). In disrupted white matter tracts, there was a marked reduction in q and increase in p. The direction of water diffusion was grossly abnormal in these cases. Diffusion tissue signatures may be a useful method of assessing occult white matter infiltration. Copyright 2004 Springer-Verlag

Evaluation of radiation necrosis and malignant glioma in rat models using diffusion tensor MR imaging

PubMed Central

Wang, Silun; Chen, Yifei; Lal, Bachchu; Ford, Eric; Tryggestad, Erik; Armour, Michael; Yan, Kun; Laterra, John; Zhou, Jinyuan

2011-01-01

Standard MRI cannot distinguish between radiation necrosis and tumor progression; however, this distinction is critical in the assessment of tumor response to therapy. In this study, one delayed radiation necrosis model (dose, 40 Gy; radiation field, 10 × 10 mm2; n = 13) and two orthotopic glioma models in rats (9L gliosarcoma, n = 8; human glioma xenografts, n = 5) were compared using multiple DTI indices. A visible isotropic apparent diffusion coefficient (ADC) pattern was observed in the lesion due to radiation necrosis, which consisted of a hypointense central zone and a hyperintense peripheral zone. There were significantly lower ADC, parallel diffusivity, and perpendicular diffusivity in the necrotic central zone than in the peripheral zone (all p < 0.001). When radiation-induced necrosis was compared with viable tumor, radiation necrosis had significantly lower ADC than 9L gliosarcoma and human glioma xenografts (both p < 0.01) in the central zone, and significantly lower FA than 9L gliosarcoma (p = 0.005) and human glioma xenografts (p = 0.012) in the peripheral zone. Histological analysis revealed parenchymal coagulative necrosis in the central zone, and damaged vessels and reactive astrogliosis in the peripheral zone. These data suggest that qualitative and quantitative analysis of the DTI maps can provide useful information by which to distinguish between radiation necrosis and viable glioma. PMID:21948114

Rapid Intraoperative Molecular Characterization of Glioma

PubMed Central

Shankar, Ganesh M.; Francis, Joshua M.; Rinne, Mikael L.; Ramkissoon, Shakti H.; Huang, Franklin W.; Venteicher, Andrew S.; Akama-Garren, Elliot H.; Kang, Yun Jee; Lelic, Nina; Kim, James C.; Brown, Loreal E.; Charbonneau, Sarah K.; Golby, Alexandra J.; Pedamallu, Chandra Sekhar; Hoang, Mai P.; Sullivan, Ryan J.; Cherniack, Andrew D.; Garraway, Levi A.; Stemmer-Rachamimov, Anat; Reardon, David A.; Wen, Patrick Y.; Brastianos, Priscilla K.; Curry, William T.; Barker, Fred G.; Hahn, William C.; Nahed, Brian V.; Ligon, Keith L.; Louis, David N.; Cahill, Daniel P.; Meyerson, Matthew

2016-01-01

IMPORTANCE Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%–99%) and 100% specificity (95% CI, 95%–100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations. PMID:26181761

Childhood Brain Stem Glioma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Childhood brain stem glioma presents as a diffuse intrinsic pontine glioma (DIPG; a fast-growing tumor that is difficult to treat and has a poor prognosis) or a focal glioma (grows more slowly, is easier to treat, and has a better prognosis). Learn about the diagnosis, cellular classification, staging, treatment, and clinical trials for pediatric brain stem glioma in this expert-reviewed summary.

Diffuse Gliomas for Nonneuropathologists: The New Integrated Molecular Diagnostics.

PubMed

Lee, Sunhee C

2018-05-18

Diffuse gliomas comprise the bulk of "brain cancer" in adults. The recent update to the 4th edition of the World Health Organization's classification of tumors of the central nervous system reflects an unprecedented change in the landscape of the diagnosis and management of diffuse gliomas that will affect all those involved in the management and care of patients. Of the recently discovered gene alterations, mutations in the Krebs cycle enzymes isocitrate dehydrogenases (IDHs) 1 and 2 have fundamentally changed the way the gliomas are understood and classified. Incorporating information on a few genetic parameters (IDH, ATRX and/or p53, and chromosome 1p19q codeletion), a relatively straightforward diagnostic algorithm has been generated with robust and reproducible results that correlate with patients' survival far better than relying on conventional histology alone. Evidence also supports the conclusion that the vast majority of diffuse gliomas without IDH mutations (IDH-wild-type astrocytomas) behave like IDH-wild-type glioblastomas ("molecular GBM"). Together, these changes reflect a big shift in the practice of diagnostic neuropathology in which tumor risk stratification aligns better with molecular information than histology/grading. The purpose of this review is to provide the readers with a brief synopsis of the changes in the 2016 World Health Organization update with an emphasis on diffuse gliomas and to summarize key gene abnormalities on which these classifications are based. Practical points involved in day-to-day diagnostic workup are also discussed, along with a comparison of the various diagnostic tests, including immunohistochemistry, with an emphasis on targeted next-generation sequencing panel technology as a future universal approach.

DNA methylation in adult diffuse gliomas.

PubMed

LeBlanc, Veronique G; Marra, Marco A

2016-11-01

Adult diffuse gliomas account for the majority of primary malignant brain tumours, and are in most cases lethal. Current therapies are often only marginally effective, and improved options will almost certainly benefit from further insight into the various processes contributing to gliomagenesis and pathology. While molecular characterization of these tumours classifies them on the basis of genetic alterations and chromosomal abnormalities, DNA methylation patterns are increasingly understood to play a role in glioma pathogenesis. Indeed, a subset of gliomas associated with improved survival is characterized by the glioma CpG island methylator phenotype (G-CIMP), which can be induced by the expression of mutant isocitrate dehydrogenase (IDH1/2). Aberrant methylation of particular genes or regulatory elements, within the context of G-CIMP-positive and/or negative tumours, has also been shown to be associated with differential survival. In this review, we provide an overview of the current knowledge regarding the role of DNA methylation in adult diffuse gliomas. In particular, we discuss IDH mutations and G-CIMP, MGMT promoter methylation, DNA methylation-mediated microRNA regulation and aberrant methylation of specific genes or groups of genes. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

[Immunotherapy in brain tumors].

PubMed

De Carli, Emilie; Delion, Matthieu; Rousseau, Audrey

2017-02-01

Diffuse gliomas represent the most common primary central nervous system (CNS) tumors in adults and children alike. Glioblastoma is the most frequent and malignant form of diffuse glioma with a median overall survival of 15 months despite aggressive treatments. New therapeutic approaches are needed to prolong survival in this always fatal disease. The CNS has been considered for a long time as an immune privileged organ, in part because of the existence of the blood-brain barrier. Nonetheless, immunotherapy is a novel approach in the therapeutic management of glioma patients, which has shown promising results in several clinical trials, especially in the adult population. Vaccination, with or without dendritic cells, blockade of the immune checkpoints, and adoptive T cell transfer are the most studied modalities of diffuse glioma immunotherapy. The future most likely resides in combinatorial approaches, with administration of conventional treatments (surgery, radiochemotherapy) and immunotherapy following yet to determine schedules. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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

Non-Gaussian diffusion MR imaging of glioma: comparisons of multiple diffusion parameters and correlation with histologic grade and MIB-1 (Ki-67 labeling) index.

PubMed

Yan, Ren; Haopeng, Pang; Xiaoyuan, Feng; Jinsong, Wu; Jiawen, Zhang; Chengjun, Yao; Tianming, Qiu; Ji, Xiong; Mao, Sheng; Yueyue, Ding; Yong, Zhang; Jianfeng, Luo; Zhenwei, Yao

2016-02-01

This study was conducted to compare the association of Gaussian and non-Gaussian magnetic resonance imaging (MRI)-derived parameters with histologic grade and MIB-1 (Ki-67 labeling) index (MI) in brain glioma. Sixty-five patients with pathologically confirmed glioma, who underwent diffusion-weighted MRI with 2 b values (0, 1000 s/mm(2)) and 22 b values (≤5000 s/mm(2)), respectively, were divided into three groups of grade II (n = 35), grade III (n = 8), and grade IV (n = 22). Comparisons by two groups were made for apparent diffusion coefficient (ADC), slow diffusion coefficient (Dslow), distributed diffusion coefficient (DDC), and heterogeneity index α. Analyses of receiver operating characteristic (ROC) curve were performed to maximize the area under the curve (AUC) for differentiating grade III + IV (high-grade glioma, HGG) from grade II (low-grade glioma, LGG) and grade IV (glioblastoma multiforme, GBM) from grade II + III (other grade glioma, OGG). Correlations with MI were analyzed for the MRI parameters. On tumor regions, the values of ADC, Dslow, DDC, and α were significantly higher in grade II [(1.37 ± 0.29, 0.70 ± 0.11, 1.39 ± 0.34) (×10(-3) mm(2)/s) and 0.88 ± 0.05, respectively] than in grade III [(0.99 ± 0.13, 0.55 ± 0.07, 1.04 ± 0.20) (×10(-3) mm(2)/s) and 0.80 ± 0.03, respectively] and grade IV [(1.03 ± 0.14, 0.50 ± 0.05, 1.02 ± 0.16) (×10(-3) mm(2)/s) and 0.76 ± 0.04, respectively] (all P < 0.001). The parameter α showed the highest AUCs of 0.950 and 0.922 in discriminating HGG from LGG and GBM from OGG, respectively. Significant correlations with histologic grade and MI were observed for the MRI parameters. The non-Gaussian MRI-derived parameters α and Dslow are superior to ADC in glioma grading, which are comparable with ADC as reliable biomarkers in noninvasively predicting the proliferation level of glioma malignancy.

Imaging White Matter in Human Brainstem

PubMed Central

Ford, Anastasia A.; Colon-Perez, Luis; Triplett, William T.; Gullett, Joseph M.; Mareci, Thomas H.; FitzGerald, David B.

2013-01-01

The human brainstem is critical for the control of many life-sustaining functions, such as consciousness, respiration, sleep, and transfer of sensory and motor information between the brain and the spinal cord. Most of our knowledge about structure and organization of white and gray matter within the brainstem is derived from ex vivo dissection and histology studies. However, these methods cannot be applied to study structural architecture in live human participants. Tractography from diffusion-weighted magnetic resonance imaging (MRI) may provide valuable insights about white matter organization within the brainstem in vivo. However, this method presents technical challenges in vivo due to susceptibility artifacts, functionally dense anatomy, as well as pulsatile and respiratory motion. To investigate the limits of MR tractography, we present results from high angular resolution diffusion imaging of an intact excised human brainstem performed at 11.1 T using isotropic resolution of 0.333, 1, and 2 mm, with the latter reflecting resolution currently used clinically. At the highest resolution, the dense fiber architecture of the brainstem is evident, but the definition of structures degrades as resolution decreases. In particular, the inferred corticopontine/corticospinal tracts (CPT/CST), superior (SCP) and middle cerebellar peduncle (MCP), and medial lemniscus (ML) pathways are clearly discernable and follow known anatomical trajectories at the highest spatial resolution. At lower resolutions, the CST/CPT, SCP, and MCP pathways are artificially enlarged due to inclusion of collinear and crossing fibers not inherent to these three pathways. The inferred ML pathways appear smaller at lower resolutions, indicating insufficient spatial information to successfully resolve smaller fiber pathways. Our results suggest that white matter tractography maps derived from the excised brainstem can be used to guide the study of the brainstem architecture using diffusion MRI in vivo. PMID:23898254

Imaging white matter in human brainstem.

PubMed

Ford, Anastasia A; Colon-Perez, Luis; Triplett, William T; Gullett, Joseph M; Mareci, Thomas H; Fitzgerald, David B

2013-01-01

The human brainstem is critical for the control of many life-sustaining functions, such as consciousness, respiration, sleep, and transfer of sensory and motor information between the brain and the spinal cord. Most of our knowledge about structure and organization of white and gray matter within the brainstem is derived from ex vivo dissection and histology studies. However, these methods cannot be applied to study structural architecture in live human participants. Tractography from diffusion-weighted magnetic resonance imaging (MRI) may provide valuable insights about white matter organization within the brainstem in vivo. However, this method presents technical challenges in vivo due to susceptibility artifacts, functionally dense anatomy, as well as pulsatile and respiratory motion. To investigate the limits of MR tractography, we present results from high angular resolution diffusion imaging of an intact excised human brainstem performed at 11.1 T using isotropic resolution of 0.333, 1, and 2 mm, with the latter reflecting resolution currently used clinically. At the highest resolution, the dense fiber architecture of the brainstem is evident, but the definition of structures degrades as resolution decreases. In particular, the inferred corticopontine/corticospinal tracts (CPT/CST), superior (SCP) and middle cerebellar peduncle (MCP), and medial lemniscus (ML) pathways are clearly discernable and follow known anatomical trajectories at the highest spatial resolution. At lower resolutions, the CST/CPT, SCP, and MCP pathways are artificially enlarged due to inclusion of collinear and crossing fibers not inherent to these three pathways. The inferred ML pathways appear smaller at lower resolutions, indicating insufficient spatial information to successfully resolve smaller fiber pathways. Our results suggest that white matter tractography maps derived from the excised brainstem can be used to guide the study of the brainstem architecture using diffusion MRI in vivo.

An adjoint-based method for a linear mechanically-coupled tumor model: application to estimate the spatial variation of murine glioma growth based on diffusion weighted magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Feng, Xinzeng; Hormuth, David A.; Yankeelov, Thomas E.

2018-06-01

We present an efficient numerical method to quantify the spatial variation of glioma growth based on subject-specific medical images using a mechanically-coupled tumor model. The method is illustrated in a murine model of glioma in which we consider the tumor as a growing elastic mass that continuously deforms the surrounding healthy-appearing brain tissue. As an inverse parameter identification problem, we quantify the volumetric growth of glioma and the growth component of deformation by fitting the model predicted cell density to the cell density estimated using the diffusion-weighted magnetic resonance imaging data. Numerically, we developed an adjoint-based approach to solve the optimization problem. Results on a set of experimentally measured, in vivo rat glioma data indicate good agreement between the fitted and measured tumor area and suggest a wide variation of in-plane glioma growth with the growth-induced Jacobian ranging from 1.0 to 6.0.

Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades.

PubMed

Togao, Osamu; Yoshiura, Takashi; Keupp, Jochen; Hiwatashi, Akio; Yamashita, Koji; Kikuchi, Kazufumi; Suzuki, Yuriko; Suzuki, Satoshi O; Iwaki, Toru; Hata, Nobuhiro; Mizoguchi, Masahiro; Yoshimoto, Koji; Sagiyama, Koji; Takahashi, Masaya; Honda, Hiroshi

2014-03-01

Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 ± 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets ω = -6 to +6 ppm (step 0.5 ppm). δB0 maps were acquired separately for a point-by-point δB0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)asym = (S[-3.5 ppm] - S[+3.5 ppm])/S0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density. The mean APT SI values were 2.1 ± 0.4% in grade II gliomas (n = 8), 3.2 ± 0.9% in grade III gliomas (n = 10), and 4.1 ± 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001). APT imaging can predict the histopathological grades of adult diffuse gliomas.

Sunitinib in Treating Patients With Recurrent Malignant Gliomas

ClinicalTrials.gov

2016-01-29

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

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

ClinicalTrials.gov

2018-06-19

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

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

ClinicalTrials.gov

2017-10-25

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

Validation of DWI pre-processing procedures for reliable differentiation between human brain gliomas.

PubMed

Vellmer, Sebastian; Tonoyan, Aram S; Suter, Dieter; Pronin, Igor N; Maximov, Ivan I

2018-02-01

Diffusion magnetic resonance imaging (dMRI) is a powerful tool in clinical applications, in particular, in oncology screening. dMRI demonstrated its benefit and efficiency in the localisation and detection of different types of human brain tumours. Clinical dMRI data suffer from multiple artefacts such as motion and eddy-current distortions, contamination by noise, outliers etc. In order to increase the image quality of the derived diffusion scalar metrics and the accuracy of the subsequent data analysis, various pre-processing approaches are actively developed and used. In the present work we assess the effect of different pre-processing procedures such as a noise correction, different smoothing algorithms and spatial interpolation of raw diffusion data, with respect to the accuracy of brain glioma differentiation. As a set of sensitive biomarkers of the glioma malignancy grades we chose the derived scalar metrics from diffusion and kurtosis tensor imaging as well as the neurite orientation dispersion and density imaging (NODDI) biophysical model. Our results show that the application of noise correction, anisotropic diffusion filtering, and cubic-order spline interpolation resulted in the highest sensitivity and specificity for glioma malignancy grading. Thus, these pre-processing steps are recommended for the statistical analysis in brain tumour studies. Copyright © 2017. Published by Elsevier GmbH.

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

PubMed

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

2017-08-01

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

Cerebral schistosomiasis: diffusion-weighted imaging helps to differentiate from brain glioma and metastasis.

PubMed

Huang, Jinbai; Luo, Jing; Peng, Jie; Yang, Tao; Zheng, Huanghua; Mao, Chunping

2017-11-01

Background Diffusion-weighted imaging (DWI) was introduced into clinical use some years ago. However, its use in the diagnosis of cerebral schistosomiasis has not been reported. Purpose To investigate the ability of the apparent diffusion coefficient (ADC) value of DWI in the diagnosis of cerebral schistosomiasis, and to differentiate it from brain high-grade gliomas and metastasis. Material and Methods Conventional brain MRI with pre-contrast, post-contrast, and DWI was performed on 50 cases of cerebral schistosomiasis, high-grade glioma, and brain metastasis. The ADC values of the three lesions, the proximal and the distal perifocal edema were measured. In order to remove the individual difference effect of ADC values, relative ADC (rADC) values were calculated through dividing the ADC value of the lesion area by that of the contralateral normal white matter. rADC values were used to evaluate the differences among cerebral schistosomiasis, brain high-grade gliomas, and metastasis. Results rADC of cerebral schistosomiasis was significantly lower than rADC of brain metastasis ( P < 0.05), without any significant differences when compared with high-grade gliomas. rADC of proximal perifocal edema in cerebral schistosomiasis was significantly higher than in high-grade gliomas ( P < 0.010), but not different compared with brain metastasis. Conclusion DWI examination with ADC values of lesions and proximal perifocal edema might be helpful in the exact diagnosis of cerebral schistosomiasis.

Dual-modality optical biopsy of glioblastomas multiforme with diffuse reflectance and fluorescence: ex vivo retrieval of optical properties

NASA Astrophysics Data System (ADS)

Du Le, Vinh Nguyen; Provias, John; Murty, Naresh; Patterson, Michael S.; Nie, Zhaojun; Hayward, Joseph E.; Farrell, Thomas J.; McMillan, William; Zhang, Wenbin; Fang, Qiyin

2017-02-01

Glioma itself accounts for 80% of all malignant primary brain tumors, and glioblastoma multiforme (GBM) accounts for 55% of such tumors. Diffuse reflectance and fluorescence spectroscopy have the potential to discriminate healthy tissues from abnormal tissues and therefore are promising noninvasive methods for improving the accuracy of brain tissue resection. Optical properties were retrieved using an experimentally evaluated inverse solution. On average, the scattering coefficient is 2.4 times higher in GBM than in low grade glioma (LGG), and the absorption coefficient is 48% higher. In addition, the ratio of fluorescence to diffuse reflectance at the emission peak of 460 nm is 2.6 times higher for LGG while reflectance at 650 nm is 2.7 times higher for GBM. The results reported also show that the combination of diffuse reflectance and fluorescence spectroscopy could achieve sensitivity of 100% and specificity of 90% in discriminating GBM from LGG during ex vivo measurements of 22 sites from seven glioma specimens. Therefore, the current technique might be a promising tool for aiding neurosurgeons in determining the extent of surgical resection of glioma and, thus, improving intraoperative tumor identification for guiding surgical intervention.

Dual-modality optical biopsy of glioblastomas multiforme with diffuse reflectance and fluorescence: ex vivo retrieval of optical properties.

PubMed

Du Le, Vinh Nguyen; Provias, John; Murty, Naresh; Patterson, Michael S; Nie, Zhaojun; Hayward, Joseph E; Farrell, Thomas J; McMillan, William; Zhang, Wenbin; Fang, Qiyin

2017-02-01

Glioma itself accounts for 80% of all malignant primary brain tumors, and glioblastoma multiforme (GBM) accounts for 55% of such tumors. Diffuse reflectance and fluorescence spectroscopy have the potential to discriminate healthy tissues from abnormal tissues and therefore are promising noninvasive methods for improving the accuracy of brain tissue resection. Optical properties were retrieved using an experimentally evaluated inverse solution. On average, the scattering coefficient is 2.4 times higher in GBM than in low grade glioma (LGG), and the absorption coefficient is 48% higher. In addition, the ratio of fluorescence to diffuse reflectance at the emission peak of 460 nm is 2.6 times higher for LGG while reflectance at 650 nm is 2.7 times higher for GBM. The results reported also show that the combination of diffuse reflectance and fluorescence spectroscopy could achieve sensitivity of 100% and specificity of 90% in discriminating GBM from LGG during ex vivo measurements of 22 sites from seven glioma specimens. Therefore, the current technique might be a promising tool for aiding neurosurgeons in determining the extent of surgical resection of glioma and, thus, improving intraoperative tumor identification for guiding surgical intervention.

A pragmatic clinicopathobiological grouping/staging system for gliomas: proposal of the Indian TNM subcommittee on brain tumors.

PubMed

Gupta, Tejpal; Sarin, Rajiv; Jalali, Rakesh; Sharma, Suash; Kurkure, Purna; Goel, Atul

2009-01-01

There is no universally accepted staging system for primary brain tumors wherein prognostication is mainly based on complex composite indices. To develop a simple, pragmatic, and widely applicable grouping/staging system for gliomas, the most common primary brain tumor. An expert neurooncology panel with representation from radiation oncology, neurosurgery, pathology, radiology, and medical oncology had several rounds of discussion on issues pertinent to brain tumor staging. The trade off was between the accuracy of prognostic categorization and a pragmatic, widely applicable approach. The Tumor-Node-Metastasis staging was considered irrelevant for gliomas that seldom metastasize to lymphatics or outside the neuraxis. Instead, a 4-point staging/grouping system is proposed, using histological grade as the main prognostic variable and at least one stage migration based on other unfavorable features such as tumor location (brainstem); age (<5 years for all grades, >50 years for high-grade, and >40 years for low-grade gliomas); poor neurological performance status (NPS 2-4); multicentricity and/or gliomatosis; and adverse biological parameters (proliferative index, angiogenesis markers, apoptotic index, cytogenetic abnormalities, and molecular markers). In absence of a grouping/staging system for primary brain tumors, prognostification is mostly based on complex composite indices. The proposed clinicopathobiological grouping/staging system for gliomas is a simple, pragmatic, and user-friendly tool with a potential to fulfill the objectives of staging classification.

Genomic underpinnings of brain tumors - TCGA

Cancer.gov

TCGA researchers analyzed nearly 300 cases of diffuse low- and intermediate-grade gliomas, which together comprise lower-grade gliomas. LGGs occur mainly in adults and include astrocytomas, oligodendrogliomas and oligoastrocytomas.

Erlotinib Hydrochloride and Isotretinoin in Treating Patients With Recurrent Malignant Glioma

ClinicalTrials.gov

2017-05-25

Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Recurrent Adult Brain Tumor

Contribution of diffusion tensor imaging to delineation of gliomas and glioblastomas.

PubMed

Tropine, A; Vucurevic, G; Delani, P; Boor, S; Hopf, N; Bohl, J; Stoeter, P

2004-12-01

To determine if the diffusion tensor imaging (DTI) parameters fractional anisotropy (FA) and mean diffusivity (MD) can differentiate between accompanying edema and tumor cell infiltration of white matter (WM) beyond the tumor edge as defined from conventional MRI in low- and high-grade gliomas. We examined 12 patients with high-grade gliomas/glioblastomas and eight patients with low-grade gliomas and compared them to 10 patients with meningiomas, in which no tumor infiltration is expected. The tumor was defined as the enhancing area in glioblastomas and meningiomas and as the area of increased T2-signal in low-grade gliomas. FA and MD were measured in the center of the tumor and in the adjacent WM. The contralateral WM and internal capsule were used as an internal standard. Comparing the WM areas of increased T2-signal adjacent to meningiomas and glioblastomas, we saw a trend (without significance) towards a reduction of FA, but not of MD, in glioblastomas. We found no changes of FA and MD in the WM adjacent to low-grade gliomas (without T2-signal increase) compared to the WM of the contralateral hemisphere. In meningiomas and high-grade gliomas/glioblastomas, a narrow rim of significantly (P < 0.01) increased FA and decreased MD values around the enhancing tumor area was seen, whereas in low-grade gliomas, such a rim could not be defined. There was no contribution of FA or MD to grading of gliomas. In glioblastomas, a reduction of FA in the edematous area surrounding the tumor may indicate tumor cell infiltration, but a reliable differentiation between infiltration and vasogenic edema is not yet possible on the basis of DTI. The additional finding of a narrow rim of increased FA and decreased MD at the edge of glioblastomas (as well as in meningiomas) may be caused by com-pressed WM fibers and/or increased vascularity, but does not contribute to exclude peripheral cellular infiltration. 2004 Wiley-Liss, Inc.

Clinical trial studies drug for pediatric diffuse intrinsic pontine glioma (DIPG) treatment | Center for Cancer Research

Cancer.gov

Diffuse intrinsic pontine gliomas (DIPGs) are difficult to treat and are the leading cause of brain tumor deaths in children. Katherine Warren, M.D., of the Pediatric Oncology Branch is leading a pediatric clinical trial to determine the safety and best dose of panobinostat, a histone deacetylase inhibitor, for slowing or stopping the growth of DIPGs. Read more…

Histopathologic response of the immature rat to diffuse traumatic brain injury.

PubMed

Adelson, P D; Jenkins, L W; Hamilton, R L; Robichaud, P; Tran, M P; Kochanek, P M

2001-10-01

The purpose of this study was to characterize the histopathologic response of rats at postnatal day (PND) 17 following an impact-acceleration diffuse traumatic brain injury (TBI) using a 150-g/2-meter injury as previously described. This injury produces acute neurologic and physiologic derangements as well as enduring motor and Morris water maze (MWM) functional deficits. Histopathologic studies of perfusion-fixed brains were performed by gross examination and light microscopy using hematoxylin and eosin, Bielschowsky silver stain, and glial fibrillary acidic protein (GFAP) immunohistochemistry at 1, 3, 7, 28, and 90 day after injury. Gross pathologic examination revealed diffuse subarachnoid hemorrhage (SAH) at 1-3 days but minimal supratentorial intraparenchymal hemorrhage. Petechial hemorrhages were noted in ventral brainstem segments and in the cerebellum. After 1-3-day survivals, light microscopy revealed diffuse SAH and intraventricular hemorrhage (IVH), mild edema, significant axonal injury, reactive astrogliosis, and localized midline cerebellar hemorrhage. Axonal injury most commonly occurred in the long ascending and descending fiber tracts of the brainstem and occasionally in the forebrain, and was maximal at 3 days, but present until 7 days after injury. Reactive astrocytes were similarly found both in location and timing, but were also significantly identified in the hippocampus, white matter tracts, and corpus callosum. Typically, TBI produced significant diffuse SAH accompanied by cerebral and brainstem astrogliosis and axonal injury without obvious neuronal loss. Since this injury produces some pathologic changes with sustained functional deficits similar to TBI in infants and children, it should be useful for the further study of the pathophysiology and therapy of diffuse TBI and brainstem injury in the immature brain.

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.

PubMed

Alli, Saira; Figueiredo, Carlyn A; Golbourn, Brian; Sabha, Nesrin; Wu, Megan Yijun; Bondoc, Andrew; Luck, Amanda; Coluccia, Daniel; Maslink, Colin; Smith, Christian; Wurdak, Heiko; Hynynen, Kullervo; O'Reilly, Meaghan; Rutka, James T

2018-05-15

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H&E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeng, Q.-S.; Li, C.-F.; Liu Hong

2007-05-01

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

Distinct molecular profile of diffuse cerebellar gliomas.

PubMed

Nomura, Masashi; Mukasa, Akitake; Nagae, Genta; Yamamoto, Shogo; Tatsuno, Kenji; Ueda, Hiroki; Fukuda, Shiro; Umeda, Takayoshi; Suzuki, Tomonari; Otani, Ryohei; Kobayashi, Keiichi; Maruyama, Takashi; Tanaka, Shota; Takayanagi, Shunsaku; Nejo, Takahide; Takahashi, Satoshi; Ichimura, Koichi; Nakamura, Taishi; Muragaki, Yoshihiro; Narita, Yoshitaka; Nagane, Motoo; Ueki, Keisuke; Nishikawa, Ryo; Shibahara, Junji; Aburatani, Hiroyuki; Saito, Nobuhito

2017-12-01

Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

A Patient-Specific Anisotropic Diffusion Model for Brain Tumour Spread.

PubMed

Swan, Amanda; Hillen, Thomas; Bowman, John C; Murtha, Albert D

2018-05-01

Gliomas are primary brain tumours arising from the glial cells of the nervous system. The diffuse nature of spread, coupled with proximity to critical brain structures, makes treatment a challenge. Pathological analysis confirms that the extent of glioma spread exceeds the extent of the grossly visible mass, seen on conventional magnetic resonance imaging (MRI) scans. Gliomas show faster spread along white matter tracts than in grey matter, leading to irregular patterns of spread. We propose a mathematical model based on Diffusion Tensor Imaging, a new MRI imaging technique that offers a methodology to delineate the major white matter tracts in the brain. We apply the anisotropic diffusion model of Painter and Hillen (J Thoer Biol 323:25-39, 2013) to data from 10 patients with gliomas. Moreover, we compare the anisotropic model to the state-of-the-art Proliferation-Infiltration (PI) model of Swanson et al. (Cell Prolif 33:317-329, 2000). We find that the anisotropic model offers a slight improvement over the standard PI model. For tumours with low anisotropy, the predictions of the two models are virtually identical, but for patients whose tumours show higher anisotropy, the results differ. We also suggest using the data from the contralateral hemisphere to further improve the model fit. Finally, we discuss the potential use of this model in clinical treatment planning.

Histogram analysis of diffusion kurtosis imaging estimates for in vivo assessment of 2016 WHO glioma grades: A cross-sectional observational study.

PubMed

Hempel, Johann-Martin; Schittenhelm, Jens; Brendle, Cornelia; Bender, Benjamin; Bier, Georg; Skardelly, Marco; Tabatabai, Ghazaleh; Castaneda Vega, Salvador; Ernemann, Ulrike; Klose, Uwe

2017-10-01

To assess the diagnostic performance of histogram analysis of diffusion kurtosis imaging (DKI) maps for in vivo assessment of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) integrated glioma grades. Seventy-seven patients with histopathologically-confirmed glioma who provided written informed consent were retrospectively assessed between 01/2014 and 03/2017 from a prospective trial approved by the local institutional review board. Ten histogram parameters of mean kurtosis (MK) and mean diffusivity (MD) metrics from DKI were independently assessed by two blinded physicians from a volume of interest around the entire solid tumor. One-way ANOVA was used to compare MK and MD histogram parameter values between 2016 CNS WHO-based tumor grades. Receiver operating characteristic analysis was performed on MK and MD histogram parameters for significant results. The 25th, 50th, 75th, and 90th percentiles of MK and average MK showed significant differences between IDH1/2 wild-type gliomas, IDH1/2 mutated gliomas, and oligodendrogliomas with chromosome 1p/19q loss of heterozygosity and IDH1/2 mutation (p<0.001). The 50th, 75th, and 90th percentiles showed a slightly higher diagnostic performance (area under the curve (AUC) range; 0.868-0.991) than average MK (AUC range; 0.855-0.988) in classifying glioma according to the integrated approach of 2016 CNS WHO. Histogram analysis of DKI can stratify gliomas according to the integrated approach of 2016 CNS WHO. The 50th (median), 75th , and the 90th percentiles showed the highest diagnostic performance. However, the average MK is also robust and feasible in routine clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed

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

2009-10-29

Malignant glioma cells are particularly motile and can travel diffusely through the brain parenchyma, apparently without following anatomical structures to guide their migration. The neural adhesion/recognition protein L1 (L1CAM; CD171) has been implicated in contributing to stimulation of motility and metastasis of several non-neural cancer types. We explored the expression and function of L1 protein as a stimulator of glioma cell motility using human high-grade glioma surgical specimens and established rat and human glioma cell lines. L1 protein expression was found in 17 out of 18 human high-grade glioma surgical specimens by western blotting. L1 mRNA was found to be present in human U-87/LacZ and rat C6 and 9L glioma cell lines. The glioma cell lines were negative for surface full length L1 by flow cytometry and high resolution immunocytochemistry of live cells. However, fixed and permeablized cells exhibited positive staining as numerous intracellular puncta. Western blots of cell line extracts revealed L1 proteolysis into a large soluble ectodomain (~180 kDa) and a smaller transmembrane proteolytic fragment (~32 kDa). Exosomal vesicles released by the glioma cell lines were purified and contained both full-length L1 and the proteolyzed transmembrane fragment. Glioma cell lines expressed L1-binding alphavbeta5 integrin cell surface receptors. Quantitative time-lapse analyses showed that motility was reduced significantly in glioma cell lines by 1) infection with an antisense-L1 retroviral vector and 2) L1 ectodomain-binding antibodies. Our novel results support a model of autocrine/paracrine stimulation of cell motility in glioma cells by a cleaved L1 ectodomain and/or released exosomal vesicles containing L1. This mechanism could explain the diffuse migratory behavior of high-grade glioma cancer cells within the brain.

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

PubMed Central

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

2009-01-01

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

MRI Evaluation of Non-Necrotic T2-Hyperintense Foci in Pediatric Diffuse Intrinsic Pontine Glioma.

PubMed

Clerk-Lamalice, O; Reddick, W E; Li, X; Li, Y; Edwards, A; Glass, J O; Patay, Z

2016-05-19

The conventional MR imaging appearance of diffuse intrinsic pontine glioma suggests intralesional histopathologic heterogeneity, and various distinct lesion components, including T2-hypointense foci, have been described. Here we report the prevalence, conventional MR imaging semiology, and advanced MR imaging features of non-necrotic T2-hyperintense foci in diffuse intrinsic pontine glioma. Twenty-five patients with diffuse intrinsic pontine gliomas were included in this study. MR imaging was performed at 3T by using conventional and advanced MR imaging sequences. Perfusion (CBV), vascular permeability (v e , K trans ), and diffusion (ADC) metrics were calculated and used to characterize non-necrotic T2-hyperintense foci in comparison with other lesion components, namely necrotic T2-hyperintense foci, T2-hypointense foci, peritumoral edema, and normal brain stem. Statistical analysis was performed by using Kruskal-Wallis and Wilcoxon rank sum tests. Sixteen non-necrotic T2-hyperintense foci were found in 12 tumors. In these foci, ADC values were significantly higher than those in either T2-hypointense foci (P = .002) or normal parenchyma (P = .0002), and relative CBV values were significantly lower than those in either T2-hypointense (P = .0002) or necrotic T2-hyperintense (P = .006) foci. Volume transfer coefficient values in T2-hyperintense foci were lower than those in T2-hypointense (P = .0005) or necrotic T2-hyperintense (P = .0348) foci. Non-necrotic T2-hyperintense foci are common, distinct lesion components within diffuse intrinsic pontine gliomas. Advanced MR imaging data suggest low cellularity and an early stage of angioneogenesis with leaky vessels resulting in expansion of the extracellular space. Because of the lack of biopsy validation, the underlying histoarchitectural and pathophysiologic changes remain unclear; therefore, these foci may correspond to a poorly understood biologic event in tumor evolution. © 2016 American Society of Neuroradiology.

Apparent diffusion coefficient for molecular subtyping of non-gadolinium-enhancing WHO grade II/III glioma: volumetric segmentation versus two-dimensional region of interest analysis.

PubMed

Thust, S C; Hassanein, S; Bisdas, S; Rees, J H; Hyare, H; Maynard, J A; Brandner, S; Tur, C; Jäger, H R; Yousry, T A; Mancini, L

2018-03-23

To investigate if quantitative apparent diffusion coefficient (ADC) measurements can predict genetic subtypes of non-gadolinium-enhancing gliomas, comparing whole tumour against single slice analysis. Volumetric T2-derived masks of 44 gliomas were co-registered to ADC maps with ADC mean (ADC mean ) calculated. For the slice analysis, two observers placed regions of interest in the largest tumour cross-section. The ratio (ADC ratio ) between ADC mean in the tumour and normal appearing white matter was calculated for both methods. Isocitrate dehydrogenase (IDH) wild-type gliomas showed the lowest ADC values throughout (p < 0.001). ADC mean in the IDH-mutant 1p19q intact group was significantly higher than in the IDH-mutant 1p19q co-deleted group (p < 0.01). A volumetric ADC mean threshold of 1201 × 10 -6 mm 2 /s identified IDH wild-type with a sensitivity of 83% and a specificity of 86%; a volumetric ADC ratio cut-off value of 1.65 provided a sensitivity of 80% and a specificity of 92% (area under the curve (AUC) 0.9-0.94). A slice ADC ratio threshold for observer 1 (observer 2) of 1.76 (1.83) provided a sensitivity of 80% (86%), specificity of 91% (100%) and AUC of 0.95 (0.96). The intraclass correlation coefficient was excellent (0.98). ADC measurements can support the distinction of glioma subtypes. Volumetric and two-dimensional measurements yielded similar results in this study. • Diffusion-weighted MRI aids the identification of non-gadolinium-enhancing malignant gliomas • ADC measurements may permit non-gadolinium-enhancing glioma molecular subtyping • IDH wild-type gliomas have lower ADC values than IDH-mutant tumours • Single cross-section and volumetric ADC measurements yielded comparable results in this study.

Glioma infiltration sign on high b-value diffusion-weighted imaging in gliomas and its prognostic value.

PubMed

Zeng, Qiang; Ling, Chenhan; Shi, Feina; Dong, Fei; Jiang, Biao; Zhang, Jianmin

2018-03-01

Glioma cells may infiltrate beyond the tumor margins revealed on conventional structural images. To investigate whether the presence of a glioma infiltration sign on high b-value diffusion-weighted imaging (DWI) can predict the prognosis of gliomas. Retrospective cohort. Fifty-two patients with gliomas (14 WHO grade II; 13 WHO grade III; 25 WHO grade IV). 3.0T, including a T 1 -weighted contrast-enhanced (T 1 w-CE) sequence, contrast-enhanced T 2 -flair sequence, and a DWI sequence. T 1 w-CE images and contrast-enhanced T 2 -flair images were used for identifying the tumor region for enhancing and nonenhancing gliomas, respectively. The glioma infiltration sign was defined as the presence of a peritumoral abnormal high signal region on DWI map, which was adjacent to the tumor region and had higher signal than surrounding areas. This sign was assessed on a high b-value DWI map with b = 3000 s/mm 2 . For patients with glioma infiltration sign, DWI3000 max , DWI1000 max , ADC3000 min , and ADC1000 min were measured by drawing a region of interest over the peritumoral abnormal high signal region. Survival analysis was conducted by using Cox regression. Glioma infiltration sign was observed in 28 (53.8%) patients. The occurrence rate of this sign was 92.0% in grade IV gliomas, 30.8% in grade III gliomas, and 7.1% in grade II gliomas. The glioma infiltration sign could independently predict both the progression-free survival (hazard ratio [HR], 95% confidence interval [CI] = 8.58 [3.19-23.03], P < 0.001) and overall survival (HR, 95% CI = 11.90 [3.41-41.55], P < 0.001) after adjustment. For patients with glioma infiltration sign, DWI3000 max (P = 0.005) and ADC3000 min (P = 0.008) were both independent predictors of overall survival after adjustment, while DWI1000 max and ADC1000 min were not. The glioma infiltration sign on high b-value DWI is an independent predictor of poor prognosis in glioma patients. High b-value DWI might be a convenient method to detect glioma infiltration. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

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

ClinicalTrials.gov

2018-04-30

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

Erlotinib and Temsirolimus in Treating Patients With Recurrent Malignant Glioma

ClinicalTrials.gov

2015-05-29

Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Recurrent Adult Brain Tumor

Lenalidomide and Radiation for Children with Brain Cancers

Cancer.gov

n this trial, patients up to age 18 who are newly diagnosed with diffuse intrinsic pontine gliomas (DIPG) or who have other incompletely resected high-grade gliomas will undergo radiation therapy and receive oral lenalidomide, followed by lenalidomide.

Advantages of high b-value diffusion-weighted imaging to diagnose pseudo-responses in patients with recurrent glioma after bevacizumab treatment.

PubMed

Yamasaki, Fumiyuki; Kurisu, Kaoru; Aoki, Tomokazu; Yamanaka, Masami; Kajiwara, Yoshinori; Watanabe, Yosuke; Takayasu, Takeshi; Akiyama, Yuji; Sugiyama, Kazuhiko

2012-10-01

The diagnosis of pseudo-responses after bevacizumab treatment is difficult. Because diffusion-weighted imaging (DWI) is associated with cell density, it may facilitate the differentiation between true- and pseudo-responses. Furthermore, as high b-value DWI is even more sensitive to diffusion, it has been reported to be diagnostically useful in various clinical settings. Between September 2008 and May 2011, 10 patients (5 males, 5 females; age range 6-65 years) with recurrent glioma were treated with bevacizumab. All underwent pre- and post-treatment MRI including T2- or FLAIR imaging, post-gadolinium contrast T1-weighted imaging, and DWI with b-1000 and b-4000. Response rates were evaluated by MacDonald- and by response assessment in neuro-oncology working group (RANO) criteria. We also assessed the response rate by calculating the size of high intensity areas using high b-value diffusion-weighted criteria. Prognostic factors were evaluated using Kaplan-Meier survival curves (log-rank test). It was easier to identify pseudo-responses with RANO- than MacDonald criteria, however the reduction of edema by bevacizumab rendered the early diagnosis of tumor progression difficult by RANO criteria. In some patients with recurrent glioma treated with bevacizumab, high b-value diffusion-weighted criteria did, while MacDonald- and RANO criteria did not identify pseudo-responses at an early point after the start of therapy. High b-value DWI reflects cell density more accurately than regular b-value DWI. Our findings suggest that in patients with recurrent glioma, high b-value diffusion-weighted criteria are useful for the differentiation between pseudo- and true responses to treatment with bevacizumab. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location.

PubMed

Karremann, Michael; Gielen, Gerrit H; Hoffmann, Marion; Wiese, Maria; Colditz, Niclas; Warmuth-Metz, Monika; Bison, Brigitte; Claviez, Alexander; van Vuurden, Dannis G; von Bueren, André O; Gessi, Marco; Kühnle, Ingrid; Hans, Volkmar H; Benesch, Martin; Sturm, Dominik; Kortmann, Rolf-Dieter; Waha, Andreas; Pietsch, Torsten; Kramm, Christof M

2018-01-10

The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

A Novel Methodology for Applying Multivoxel MR Spectroscopy to Evaluate Convection-Enhanced Drug Delivery in Diffuse Intrinsic Pontine Gliomas.

PubMed

Guisado, D I; Singh, R; Minkowitz, S; Zhou, Z; Haque, S; Peck, K K; Young, R J; Tsiouris, A J; Souweidane, M M; Thakur, S B

2016-07-01

Diffuse intrinsic pontine gliomas are inoperable high-grade gliomas with a median survival of less than 1 year. Convection-enhanced delivery is a promising local drug-delivery technique that can bypass the BBB in diffuse intrinsic pontine glioma treatment. Evaluating tumor response is critical in the assessment of convection-enhanced delivery of treatment. We proposed to determine the potential of 3D multivoxel (1)H-MR spectroscopy to evaluate convection-enhanced delivery treatment effect in these tumors. We prospectively analyzed 3D multivoxel (1)H-MR spectroscopy data for 6 patients with nonprogressive diffuse intrinsic pontine gliomas who received convection-enhanced delivery treatment of a therapeutic antibody (Phase I clinical trial NCT01502917). To compare changes in the metabolite ratios with time, we tracked the metabolite ratios Cho/Cr and Cho/NAA at several ROIs: normal white matter, tumor within the convection-enhanced delivery infusion site, tumor outside of the infused area, and the tumor average. There was a comparative decrease in both Cho/Cr and Cho/NAA metabolite ratios at the tumor convection-enhanced delivery site versus tumor outside the infused area. We used MR spectroscopy voxels with dominant white matter as a reference. The difference between changes in metabolite ratios became more prominent with increasing time after convection-enhanced delivery treatment. The comparative change in metabolite ratios between the convection-enhanced delivery site and the tumor site outside the infused area suggests that multivoxel (1)H-MR spectroscopy, in combination with other imaging modalities, may provide a clinical tool to accurately evaluate local tumor response after convection-enhanced delivery treatment. © 2016 by American Journal of Neuroradiology.

The direct pathway from the brainstem reticular formation to the cerebral cortex in the ascending reticular activating system: A diffusion tensor imaging study.

PubMed

Jang, Sung Ho; Kwon, Hyeok Gyu

2015-10-08

Precise evaluation of the ascending reticular activating system (ARAS) is important for diagnosis, prediction of prognosis, and management of patients with disorders of impaired consciousness. In the current study, we attempted to reconstruct the direct neural pathway between the brainstem reticular formation (RF) and the cerebral cortex in normal subjects, using diffusion tensor imaging (DTI). Forty-one healthy subjects were recruited for this study. DTIs were performed using a sensitivity-encoding head coil at 1.5Tesla with FMRIB Software Library. For connectivity of the brainstem RF, we used two regions of interest (ROIs) for the brainstem RF (seed ROI) and the thalamus and hypothalamus (exclusion ROI). Connectivity was defined as the incidence of connection between the brainstem RF and target brain regions at the threshold of 5 and 50 streamlines. Regarding the thresholds of 5 and 50, the brainstem RF showed high connectivity to the lateral prefrontal cortex (lPFC, 67.1% and 20.7%) and ventromedial prefrontal cortex (vmPFC, 50.0% and 18.3%), respectively. In contrast, the brainstem RF showed low connectivity to the primary motor cortex (31.7% and 3.7%), premotor cortex (24.4% and 3.7%), primary somatosensory cortex (23.2% and 2.4%), orbitofrontal cortex (17.1% and 7.3%), and posterior parietal cortex (12.2% and 0%), respectively. The brainstem RF was mainly connected to the prefrontal cortex, particularly lPFC and vmPFC. We believe that the methodology and results of this study would be useful to clinicians involved in the care of patients with impaired consciousness and researchers in studies of the ARAS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

Brat, Daniel J; Verhaak, Roel G W; Aldape, Kenneth D; Yung, W K Alfred; Salama, Sofie R; Cooper, Lee A D; Rheinbay, Esther; Miller, C Ryan; Vitucci, Mark; Morozova, Olena; Robertson, A Gordon; Noushmehr, Houtan; Laird, Peter W; Cherniack, Andrew D; Akbani, Rehan; Huse, Jason T; Ciriello, Giovanni; Poisson, Laila M; Barnholtz-Sloan, Jill S; Berger, Mitchel S; Brennan, Cameron; Colen, Rivka R; Colman, Howard; Flanders, Adam E; Giannini, Caterina; Grifford, Mia; Iavarone, Antonio; Jain, Rajan; Joseph, Isaac; Kim, Jaegil; Kasaian, Katayoon; Mikkelsen, Tom; Murray, Bradley A; O'Neill, Brian Patrick; Pachter, Lior; Parsons, Donald W; Sougnez, Carrie; Sulman, Erik P; Vandenberg, Scott R; Van Meir, Erwin G; von Deimling, Andreas; Zhang, Hailei; Crain, Daniel; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Troy; Sherman, Mark; Yena, Peggy; Black, Aaron; Bowen, Jay; Dicostanzo, Katie; Gastier-Foster, Julie; Leraas, Kristen M; Lichtenberg, Tara M; Pierson, Christopher R; Ramirez, Nilsa C; Taylor, Cynthia; Weaver, Stephanie; Wise, Lisa; Zmuda, Erik; Davidsen, Tanja; Demchok, John A; Eley, Greg; Ferguson, Martin L; Hutter, Carolyn M; Mills Shaw, Kenna R; Ozenberger, Bradley A; Sheth, Margi; Sofia, Heidi J; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude; Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Jensen, Mark A; Liu, Jia; Pihl, Todd; Raman, Rohini; Wan, Yunhu; Wu, Ye; Ally, Adrian; Auman, J Todd; Balasundaram, Miruna; Balu, Saianand; Baylin, Stephen B; Beroukhim, Rameen; Bootwalla, Moiz S; Bowlby, Reanne; Bristow, Christopher A; Brooks, Denise; Butterfield, Yaron; Carlsen, Rebecca; Carter, Scott; Chin, Lynda; Chu, Andy; Chuah, Eric; Cibulskis, Kristian; Clarke, Amanda; Coetzee, Simon G; Dhalla, Noreen; Fennell, Tim; Fisher, Sheila; Gabriel, Stacey; Getz, Gad; Gibbs, Richard; Guin, Ranabir; Hadjipanayis, Angela; Hayes, D Neil; Hinoue, Toshinori; Hoadley, Katherine; Holt, Robert A; Hoyle, Alan P; Jefferys, Stuart R; Jones, Steven; Jones, Corbin D; Kucherlapati, Raju; Lai, Phillip H; Lander, Eric; Lee, Semin; Lichtenstein, Lee; Ma, Yussanne; Maglinte, Dennis T; Mahadeshwar, Harshad S; Marra, Marco A; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew L; Mieczkowski, Piotr A; Moore, Richard A; Mose, Lisle E; Mungall, Andrew J; Pantazi, Angeliki; Parfenov, Michael; Park, Peter J; Parker, Joel S; Perou, Charles M; Protopopov, Alexei; Ren, Xiaojia; Roach, Jeffrey; Sabedot, Thaís S; Schein, Jacqueline; Schumacher, Steven E; Seidman, Jonathan G; Seth, Sahil; Shen, Hui; Simons, Janae V; Sipahimalani, Payal; Soloway, Matthew G; Song, Xingzhi; Sun, Huandong; Tabak, Barbara; Tam, Angela; Tan, Donghui; Tang, Jiabin; Thiessen, Nina; Triche, Timothy; Van Den Berg, David J; Veluvolu, Umadevi; Waring, Scot; Weisenberger, Daniel J; Wilkerson, Matthew D; Wong, Tina; Wu, Junyuan; Xi, Liu; Xu, Andrew W; Yang, Lixing; Zack, Travis I; Zhang, Jianhua; Aksoy, B Arman; Arachchi, Harindra; Benz, Chris; Bernard, Brady; Carlin, Daniel; Cho, Juok; DiCara, Daniel; Frazer, Scott; Fuller, Gregory N; Gao, JianJiong; Gehlenborg, Nils; Haussler, David; Heiman, David I; Iype, Lisa; Jacobsen, Anders; Ju, Zhenlin; Katzman, Sol; Kim, Hoon; Knijnenburg, Theo; Kreisberg, Richard Bailey; Lawrence, Michael S; Lee, William; Leinonen, Kalle; Lin, Pei; Ling, Shiyun; Liu, Wenbin; Liu, Yingchun; Liu, Yuexin; Lu, Yiling; Mills, Gordon; Ng, Sam; Noble, Michael S; Paull, Evan; Rao, Arvind; Reynolds, Sheila; Saksena, Gordon; Sanborn, Zack; Sander, Chris; Schultz, Nikolaus; Senbabaoglu, Yasin; Shen, Ronglai; Shmulevich, Ilya; Sinha, Rileen; Stuart, Josh; Sumer, S Onur; Sun, Yichao; Tasman, Natalie; Taylor, Barry S; Voet, Doug; Weinhold, Nils; Weinstein, John N; Yang, Da; Yoshihara, Kosuke; Zheng, Siyuan; Zhang, Wei; Zou, Lihua; Abel, Ty; Sadeghi, Sara; Cohen, Mark L; Eschbacher, Jenny; Hattab, Eyas M; Raghunathan, Aditya; Schniederjan, Matthew J; Aziz, Dina; Barnett, Gene; Barrett, Wendi; Bigner, Darell D; Boice, Lori; Brewer, Cathy; Calatozzolo, Chiara; Campos, Benito; Carlotti, Carlos Gilberto; Chan, Timothy A; Cuppini, Lucia; Curley, Erin; Cuzzubbo, Stefania; Devine, Karen; DiMeco, Francesco; Duell, Rebecca; Elder, J Bradley; Fehrenbach, Ashley; Finocchiaro, Gaetano; Friedman, William; Fulop, Jordonna; Gardner, Johanna; Hermes, Beth; Herold-Mende, Christel; Jungk, Christine; Kendler, Ady; Lehman, Norman L; Lipp, Eric; Liu, Ouida; Mandt, Randy; McGraw, Mary; Mclendon, Roger; McPherson, Christopher; Neder, Luciano; Nguyen, Phuong; Noss, Ardene; Nunziata, Raffaele; Ostrom, Quinn T; Palmer, Cheryl; Perin, Alessandro; Pollo, Bianca; Potapov, Alexander; Potapova, Olga; Rathmell, W Kimryn; Rotin, Daniil; Scarpace, Lisa; Schilero, Cathy; Senecal, Kelly; Shimmel, Kristen; Shurkhay, Vsevolod; Sifri, Suzanne; Singh, Rosy; Sloan, Andrew E; Smolenski, Kathy; Staugaitis, Susan M; Steele, Ruth; Thorne, Leigh; Tirapelli, Daniela P C; Unterberg, Andreas; Vallurupalli, Mahitha; Wang, Yun; Warnick, Ronald; Williams, Felicia; Wolinsky, Yingli; Bell, Sue; Rosenberg, Mara; Stewart, Chip; Huang, Franklin; Grimsby, Jonna L; Radenbaugh, Amie J; Zhang, Jianan

2015-06-25

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. 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. 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. 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 codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

IDH mutation is paradoxically associated with higher 18F-FDOPA PET uptake in diffuse grade II and grade III gliomas.

PubMed

Verger, A; Metellus, Ph; Sala, Q; Colin, C; Bialecki, E; Taieb, D; Chinot, O; Figarella-Branger, D; Guedj, E

2017-08-01

The World Health Organization Classification of Tumors of the Central Nervous System has recently been updated by the integration of diagnostic and prognostic molecular parameters, giving pivotal attention to IDH mutation as a favourable factor. Amino acid PET is increasingly used in the management of gliomas, but its prognostic value is a matter of debate. The aim of this study was to assess the relationship between IDH mutation and 18 F-FDOPA uptake on PET in newly diagnosed gliomas. A total of 43 patients, presenting with diffuse astrocytic and oligodendroglial grade II and III gliomas, reclassified according to the 2016 WHO classification of tumours of the CNS, were retrospectively included. They had all undergone 18 F-FDOPA PET at an initial stage before surgery and histological diagnosis. 18 F-FDOPA uptake values were compared between patients with and without IDH mutation in terms of maximum standardized uptake value (SUVmax) ratios between tumour and normal contralateral brain (T/N), and between tumour and striatum (T/S). Patients with IDH mutation showed higher 18 F-FDOPA T/N SUVmax ratios (1.6 vs. 1.2) and T/S SUVmax ratios (0.9 vs. 0.6) than patients without IDH mutation (p < 0.05). This study showed paradoxically higher 18 F-FDOPA uptake in diffuse grade II and III gliomas with IDH mutation. Despite evident interest in the management of gliomas, and especially in relation to posttherapy evaluation, our findings raise the question of the prognostic value of 18 F-FDOPA uptake on PET uptake in this group of patients. This may be related to differences in amino acid integration, metabolism, or cell differentiation.

Linking late cognitive outcome with glioma surgery location using resection cavity maps.

PubMed

Hendriks, Eef J; Habets, Esther J J; Taphoorn, Martin J B; Douw, Linda; Zwinderman, Aeilko H; Vandertop, W Peter; Barkhof, Frederik; Klein, Martin; De Witt Hamer, Philip C

2018-05-01

Patients with a diffuse glioma may experience cognitive decline or improvement upon resective surgery. To examine the impact of glioma location, cognitive alteration after glioma surgery was quantified and related to voxel-based resection probability maps. A total of 59 consecutive patients (range 18-67 years of age) who had resective surgery between 2006 and 2011 for a supratentorial nonenhancing diffuse glioma (grade I-III, WHO 2007) were included in this observational cohort study. Standardized neuropsychological examination and MRI were obtained before and after surgery. Intraoperative stimulation mapping guided resections towards neurological functions (language, sensorimotor function, and visual fields). Maps of resected regions were constructed in standard space. These resection cavity maps were compared between patients with and without new cognitive deficits (z-score difference >1.5 SD between baseline and one year after resection), using a voxel-wise randomization test and calculation of false discovery rates. Brain regions significantly associated with cognitive decline were classified in standard cortical and subcortical anatomy. Cognitive improvement in any domain occurred in 10 (17%) patients, cognitive decline in any domain in 25 (42%), and decline in more than one domain in 10 (17%). The most frequently affected subdomains were attention in 10 (17%) patients and information processing speed in 9 (15%). Resection regions associated with decline in more than one domain were predominantly located in the right hemisphere. For attention decline, no specific region could be identified. For decline in information speed, several regions were found, including the frontal pole and the corpus callosum. Cognitive decline after resective surgery of diffuse glioma is prevalent, in particular, in patients with a tumor located in the right hemisphere without cognitive function mapping. © The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Possible structural abnormality of the brainstem in unipolar depressive illness: a transcranial ultrasound and diffusion tensor magnetic resonance imaging study.

PubMed

Steele, J D; Bastin, M E; Wardlaw, J M; Ebmeier, K P

2005-11-01

Most empirically derived antidepressants increase monoamine levels. The nuclei of cells synthesising these monoamines are located in the brainstem, and projection tracts such as the medial forebrain bundle reach virtually all other brain areas. Two studies of unipolar depressive illness using transcranial ultrasound have reported reduced echogenicity of the brainstem midline in unipolar depressed patients. This may be consistent with disruption of white matter tracts, including the medial forebrain bundle, and it has been suggested that the effect of such disruption could be reversed by antidepressants. To replicate these findings in a group of unipolar depressed patients and controls. Fifteen unipolar depressed patients and 15 controls were studied using transcranial ultrasound imaging and diffusion tensor magnetic resonance imaging (DT-MRI). No difference in echogenicity of the brainstem midline of unipolar depressed patients was found. A possible trend (Cohen's d = 0.39) in the direction of previous studies was found. Although the echogenicity of the brainstem midline of the control group was found to be similar to previous reports, there was no reduction in the patient group. Additionally, no structural abnormality of the brainstem was identified using DT-MRI. While these data do not replicate the findings of previous studies reporting a significant reduction in the echogenicity of the brainstem midline in unipolar depressed patients, the ultrasound investigation indicated that there may be a trend in this direction. Given the importance of identifying the causes of depressive illness, it is important that other groups attempt similar studies.

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

ClinicalTrials.gov

2018-03-16

Childhood Astrocytoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Diffuse Intrinsic Pontine Glioma; Glioma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Glioblastoma; Recurrent Childhood Medulloblastoma; Recurrent Primitive Neuroectodermal Tumor; Refractory Brain Neoplasm

Awake surgery for hemispheric low-grade gliomas: oncological, functional and methodological differences between pediatric and adult populations.

PubMed

Trevisi, Gianluca; Roujeau, Thomas; Duffau, Hugues

2016-10-01

Brain mapping through a direct cortical and subcortical electrical stimulation during an awake craniotomy has gained an increasing popularity as a powerful tool to prevent neurological deficit while increasing extent of resection of hemispheric diffuse low-grade gliomas in adults. However, few case reports or very limited series of awake surgery in children are currently available in the literature. In this paper, we review the oncological and functional differences between pediatric and adult populations, and the methodological specificities that may limit the use of awake mapping in pediatric low-grade glioma surgery. This could be explained by the fact that pediatric low-grade gliomas have a different epidemiology and biologic behavior in comparison to adults, with pilocytic astrocytomas (WHO grade I glioma) as the most frequent histotype, and with WHO grade II gliomas less prone to anaplastic transformation than their adult counterparts. In addition, aside from the issue of poor collaboration of younger children under 10 years of age, some anatomical and functional peculiarities of children developing brain (cortical and subcortical myelination, maturation of neural networks and of specialized cortical areas) can influence direct electrical stimulation methodology and sensitivity, limiting its use in children. Therefore, even though awake procedure with cortical and axonal stimulation mapping can be adapted in a specific subgroup of children with a diffuse glioma from the age of 10 years, only few pediatric patients are nonetheless candidates for awake brain surgery.

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

ClinicalTrials.gov

2017-04-27

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

IDH1 Mutation in Brain Stem Glioma: Case Report and Review of Literature.

PubMed

Javadi, Seyed Amirhossein; Hartmann, Christian; Walter, Gerhard Franz; Banan, Roozbeh; Samii, Amir

2018-01-01

The role of isocitrate dehydrogenase 1 (IDH1) mutation in brain stem glioma is not clear. To the best of our knowledge, six cases of brain stem gliomas carrying IDH1/2 mutations are currently reported in the literature. One case of diffuse brain stem glioma with IDH1 mutation, which was followed for 2 years, is presented and compared with IDH1 negative tumors. A 22-year-old lady was referred with diplopia and left arm palsy. Neuroimaging detected a nonenhancing, nonhomogeneous diffuse infiltrating brain stem tumor extending from pons to medulla. Microsurgical debulking was performed. Microscopic evaluation of the tissue specimen and immunohistochemistry revealed an astrocytoma WHO Grade II with proliferation rate of 3% and glial fibrillary acidic protein (GFAP)-positive tumor cells. Interestingly, the tumor cells expressed mutated IDH1 R132H protein. The patient underwent adjuvant radiation and chemotherapy. The primary and 2 years' clinical/radiological characteristics did not indicate any significant difference from other cases without IDH1 mutation. the prognostic value of IDH1/2 mutation in brain stem glioma is unclear. Brain stem biopsies may allow determination of a tissue-based tumor diagnosis for further investigations.

Immediate, irreversible, posttraumatic coma: a review indicating that bilateral brainstem injury rather than widespread hemispheric damage is essential for its production.

PubMed

Rosenblum, William I

2015-03-01

Traumatic brain injury may result in immediate long-lasting coma. Much attention has been given to predicting this outcome from the initial examination because these predictions can guide future treatment and interactions with the patient's family. Reports of diffuse axonal injury in these cases have ascribed the coma to widespread damage in the deep white matter that disconnects the hemispheres from the ascending arousal system (AAS). However, brainstem lesions are also present in such cases, and the AAS may be interrupted at the brainstem level. This review examines autopsy and imaging literature that assesses the presence, extent, and predictive value of lesions in both sites. The evidence suggests that diffuse injury to the deep white matter is not the usual cause of immediate long-lasting posttraumatic coma. Instead, brainstem lesions in the rostral pons or midbrain are almost always the cause but only if the lesions are bilateral. Moreover, recovery is possible if critical brainstem inputs to the AAS are spared. The precise localization of the latter is subject to ongoing investigation with advanced imaging techniques using magnets of very high magnetic gradients. Limited availability of this equipment plus the need to verify the findings continue to require meticulous autopsy examination.

Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.

PubMed

Hoffman, Lindsey M; Veldhuijzen van Zanten, Sophie E M; Colditz, Niclas; Baugh, Joshua; Chaney, Brooklyn; Hoffmann, Marion; Lane, Adam; Fuller, Christine; Miles, Lili; Hawkins, Cynthia; Bartels, Ute; Bouffet, Eric; Goldman, Stewart; Leary, Sarah; Foreman, Nicholas K; Packer, Roger; Warren, Katherine E; Broniscer, Alberto; Kieran, Mark W; Minturn, Jane; Comito, Melanie; Broxson, Emmett; Shih, Chie-Schin; Khatua, Soumen; Chintagumpala, Murali; Carret, Anne Sophie; Escorza, Nancy Yanez; Hassall, Timothy; Ziegler, David S; Gottardo, Nicholas; Dholaria, Hetal; Doughman, Renee; Benesch, Martin; Drissi, Rachid; Nazarian, Javad; Jabado, Nada; Boddaert, Nathalie; Varlet, Pascale; Giraud, Géraldine; Castel, David; Puget, Stephanie; Jones, Chris; Hulleman, Esther; Modena, Piergiorgio; Giagnacovo, Marzia; Antonelli, Manila; Pietsch, Torsten; Gielen, Gerrit H; Jones, David T W; Sturm, Dominik; Pfister, Stefan M; Gerber, Nicolas U; Grotzer, Michael A; Pfaff, Elke; von Bueren, André O; Hargrave, Darren; Solanki, Guirish A; Jadrijevic Cvrlje, Filip; Kaspers, Gertjan J L; Vandertop, William P; Grill, Jacques; Bailey, Simon; Biassoni, Veronica; Massimino, Maura; Calmon, Raphaël; Sanchez, Esther; Bison, Brigitte; Warmuth-Metz, Monika; Leach, James; Jones, Blaise; van Vuurden, Dannis G; Kramm, Christof M; Fouladi, Maryam

2018-05-10

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uh, Jinsoo, E-mail: jinsoo.uh@stjude.org; Merchant, Thomas E.; Li, Yimei

Purpose: To determine whether radiation-induced changes in white matter tracts are uniform across the brainstem. Methods and Materials: We analyzed serial diffusion tensor imaging data, acquired before radiation therapy and over 48 to 72 months of follow-up, from 42 pediatric patients (age 6-20 years) with medulloblastoma. FSL software (FMRIB, Oxford, UK) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivities. For a consistent identification of volumes of interest (VOIs), the parametric maps of each patient were transformed to a standard brain space (MNI152), on which we identified VOIs including corticospinal tract (CST), medial lemniscus (ML), transversemore » pontine fiber (TPF), and middle cerebellar peduncle (MCP) at the level of pons. Temporal changes of DTI parameters in VOIs were compared using a linear mixed effect model. Results: Radiation-induced white matter injury was marked by a decline in FA after treatment. The decline was often accompanied by decreased axial diffusivity, increased radial diffusivity, or both. This implied axonal damage and demyelination. We observed that the magnitude of the changes was not always uniform across substructures of the brainstem. Specifically, the changes in DTI parameters for TPF were more pronounced than in other regions (P<.001 for FA) despite similarities in the distribution of dose. We did not find a significant difference among CST, ML, and MCP in these patients (P>.093 for all parameters). Conclusions: Changes in the structural integrity of white matter tracts, assessed by DTI, were not uniform across the brainstem after radiation therapy. These results support a role for tract-based assessment in radiation treatment planning and determination of brainstem tolerance.« less

A probabilistic atlas of human brainstem pathways based on connectome imaging data.

PubMed

Tang, Yuchun; Sun, Wei; Toga, Arthur W; Ringman, John M; Shi, Yonggang

2018-04-01

The brainstem is a critical structure that regulates vital autonomic functions, houses the cranial nerves and their nuclei, relays motor and sensory information between the brain and spinal cord, and modulates cognition, mood, and emotions. As a primary relay center, the fiber pathways of the brainstem include efferent and afferent connections among the cerebral cortex, spinal cord, and cerebellum. While diffusion MRI has been successfully applied to map various brain pathways, its application for the in vivo imaging of the brainstem pathways has been limited due to inadequate resolution and large susceptibility-induced distortion artifacts. With the release of high-resolution data from the Human Connectome Project (HCP), there is increasing interest in mapping human brainstem pathways. Previous works relying on HCP data to study brainstem pathways, however, did not consider the prevalence (>80%) of large distortions in the brainstem even after the application of correction procedures from the HCP-Pipeline. They were also limited in the lack of adequate consideration of subject variability in either fiber pathways or region of interests (ROIs) used for bundle reconstruction. To overcome these limitations, we develop in this work a probabilistic atlas of 23 major brainstem bundles using high-quality HCP data passing rigorous quality control. For the large-scale data from the 500-Subject release of HCP, we conducted extensive quality controls to exclude subjects with severe distortions in the brainstem area. After that, we developed a systematic protocol to manually delineate 1300 ROIs on 20 HCP subjects (10 males; 10 females) for the reconstruction of fiber bundles using tractography techniques. Finally, we leveraged our novel connectome modeling techniques including high order fiber orientation distribution (FOD) reconstruction from multi-shell diffusion imaging and topography-preserving tract filtering algorithms to successfully reconstruct the 23 fiber bundles for each subject, which were then used to calculate the probabilistic atlases in the MNI152 space for public release. In our experimental results, we demonstrate that our method yielded anatomically faithful reconstruction of the brainstem pathways and achieved improved performance in comparison with an existing atlas of cerebellar peduncles based on HCP data. These atlases have been publicly released on NITRIC (https://www.nitrc.org/projects/brainstem_atlas/) and can be readily used by brain imaging researchers interested in studying brainstem pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Focal traumatic brain stem injury is a rare type of head injury resulting from assault: a forensic neuropathological study.

PubMed

Al-Sarraj, Safa; Fegan-Earl, Ashley; Ugbade, Antonia; Bodi, Istvan; Chapman, Rob; Poole, Simon; Swift, Ben; Jerreat, Peter; Cary, Nat

2012-04-01

Brainstem haemorrhage is common in cases of head injury when it is associated with space-occupying lesion and increases in the intracranial pressure (duret haemorrhage), in cases of diffuse axonal injury (in dorso-lateral quadrant) and diffuses vascular injury (in the periventricular tissue). However focal traumatic brainstem injury is rare. We identified 12 cases of focal traumatic brainstem injury from review of 319 case of head injury. The head trauma had been caused by different mechanisms of complex fall from height and assault. 10/12 are associated with skull fracture, 11/12 with contre coup contusions in the frontal and temporal lobes, 5/12 direct contusions to cerebellum, 5/12 haemorrhage in corpus callosum and 2/11 have gliding contusions. None of the cases had pathological evidence of increase in the intracranial pressure. The bleeding in the pons was at the edge in 2/12 and cross the section in 10/12. The majority of patients were unconscious immediately after the incident (10/12) and 9/12 died within one day. Focal traumatic brainstem injury occurs most likely due to direct impact at the back of the head or stretching forces affecting the brainstem in cases of complex fall from height and after assault, particularly those associated with kicks. It is a serious and commonly fatal brain damage, which needed to be differentiated from other causes of brainstem haemorrhages. Copyright © 2012 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

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

IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy.

PubMed

Neal, Andrew; Kwan, Patrick; O'Brien, Terence John; Buckland, Michael E; Gonzales, Michael; Morokoff, Andrew

2018-01-01

Isocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II-IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency. This was a retrospective study. Patients with grades II-IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A - postoperative seizure freedom; Group B - 1-11 seizures over 12months (less than one seizure per month); and Group C - greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data. One hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p=0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p=0.032) and Group B (RR 9.70, p=0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p=0.004). In patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez-Torres, Carlos J.; Engelbach, John A.; Cates, Jeremy

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

Impact of H3.3 K27M Mutation on Prognosis and Survival of Grade IV Spinal Cord Glioma on the Basis of New 2016 World Health Organization Classification of the Central Nervous System.

PubMed

Yi, Seong; Choi, Sunkyu; Shin, Dong Ah; Kim, Du Su; Choi, Junjeong; Ha, Yoon; Kim, Keung Nyun; Suh, Chang-Ok; Chang, Jong Hee; Kim, Se Hoon; Yoon, Do Heum

2018-05-01

Spinal cord glioma grade IV is a rare, diffuse midline glioma. H3 K27M-mutant was classified in a different entity in the 2016 World Health Organization (WHO) classification recently. No reports about prognosis of spinal cord glioma grade IV are available yet. To analyze the prognostic factors for spinal cord glioma grade IV. Twenty-five patients with spinal cord glioma of grade IV who underwent surgery in a single institute were selected. All grade IV spinal cord glioma histologically confirmed as glioblastoma or "diffuse midline glioma with H3 K27M-mutant" by the 2016 WHO classification of the central nervous system were included. Basic demographics, treatment modalities, and pathological tumor molecular profiles were investigated for prognosis. Mean age was 39.1 yr; male to female ratio was 18 : 7. Tumor was located in thoracic cord (53.3%), cervical cord (40%), and lumbar area (6.7%). Median overall survival was 37.1 mo; median disease-free survival was 18.5 mo. Treatment modality showed no statistical difference. Only K27M profile showed significant prognostic value, 20 patients (80%) showed K27M mutation positive, K27M mutation patients showed longer overall survival (40.07 mo) than K27M negative patients (11.63 mo, P < .0001), and disease-free survival (20.85 vs 8.72 mo, P = .0241). This study is the first and largest report of the prognosis of primary spinal cord grade IV glioma using the new WHO classification. This study reported survival analysis and prognostic factors, and revealed that H3.3 K27M mutation is not a major poor prognostic factor. Further studies to explore K27M mutations needed for risk stratification and therapy optimization.

Brain tumor modeling: glioma growth and interaction with chemotherapy

NASA Astrophysics Data System (ADS)

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

2011-10-01

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

Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.

PubMed

Li, Ningning; Zhang, Ying; Sidlauskas, Kastytis; Ellis, Matthew; Evans, Ian; Frankel, Paul; Lau, Joanne; El-Hassan, Tedani; Guglielmi, Loredana; Broni, Jessica; Richard-Loendt, Angela; Brandner, Sebastian

2018-05-03

To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.

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

ClinicalTrials.gov

2013-01-15

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

Changes in language white matter tract microarchitecture associated with cognitive deficits in patients with presumed low-grade glioma.

PubMed

Incekara, Fatih; Satoer, Djaina; Visch-Brink, Evy; Vincent, Arnaud; Smits, Marion

2018-06-08

OBJECTIVE The authors conducted a study to determine whether cognitive functioning of patients with presumed low-grade glioma is associated with white matter (WM) tract changes. METHODS The authors included 77 patients with presumed low-grade glioma who underwent awake surgery between 2005 and 2013. Diffusion tensor imaging with deterministic tractography was performed preoperatively to identify the arcuate, inferior frontooccipital, and uncinate fasciculi and to obtain the mean fractional anisotropy (FA) and mean diffusivity per tract. All patients were evaluated preoperatively using an extensive neuropsychological protocol that included assessments of the language, memory, and attention/executive function domains. Linear regression models were used to analyze each cognitive domain and each diffusion tensor imaging metric of the 3 WM tracts. RESULTS Significant correlations (corrected for multiple testing) were found between FA of the arcuate fasciculus and results of the repetition test for the language domain (β = 0.59, p < 0.0001) and between FA of the inferior frontooccipital fasciculus and results of the imprinting test for the memory domain (β = -0.55, p = 0.002) and the attention test for the attention and executive function domain (β = -0.62, p = 0.006). CONCLUSIONS In patients with glioma, language deficits in repetition of speech, imprinting, and attention deficits are associated with changes in the microarchitecture of the arcuate and inferior frontooccipital fasciculi.

7 Tesla 22-channel wrap-around coil array for cervical spinal cord and brainstem imaging.

PubMed

Zhang, Bei; Seifert, Alan C; Kim, Joo-Won; Borrello, Joseph; Xu, Junqian

2017-10-01

Increased signal-to-noise ratio and blood oxygenation level-dependent sensitivity at 7 Tesla (T) have the potential to enable high-resolution imaging of the human cervical spinal cord and brainstem. We propose a new two-panel radiofrequency coil design for these regions to fully exploit the advantages of ultra-high field. A two-panel array, containing four transmit/receive and 18 receive-only elements fully encircling the head and neck, was constructed following simulations demonstrating the B1+ and specific absorption rate (SAR) benefits of two-panel over one-panel arrays. This array was compared with a previously reported posterior-only array and tested for safety using a phantom. Its anatomical, functional, and diffusion MRI performance was demonstrated in vivo. The two-panel array produced more uniform B1+ across the brainstem and cervical spinal cord without compromising SAR, and achieved 70% greater receive sensitivity than the posterior-only array. The two-panel design enabled acceleration of R = 2 × 2 in two dimensions or R = 3 in a single dimension. High quality in vivo anatomical, functional, and diffusion images of the human cervical spinal cord and brainstem were acquired. We have designed and constructed a wrap-around coil array with excellent performance for cervical spinal cord and brainstem MRI at 7T, which enables simultaneous human cervical spinal cord and brainstem functional MRI. Magn Reson Med 78:1623-1634, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Preoperative grading of supratentorial gliomas using high or standard b-value diffusion-weighted MR imaging at 3T.

PubMed

Cihangiroglu, M M; Ozturk-Isik, E; Firat, Z; Kilickesmez, O; Ulug, A M; Ture, U

2017-03-01

The goal of this study was to compare diffusion-weighted magnetic resonance imaging (DW-MRI) using high b-value (b=3000s/mm 2 ) to DW-MRI using standard b-value (b=1000s/mm 2 ) in the preoperative grading of supratentorial gliomas. Fifty-three patients with glioma had brain DW-MRI at 3T using two different b-values (b=1000s/mm 2 and b=3000s/mm 2 ). There were 35 men and 18 women with a mean age of 40.5±17.1 years (range: 18-79 years). Mean, minimum, maximum, and range of apparent diffusion coefficient (ADC) values for solid tumor ROIs (ADC mean , ADC min , ADC max , and ADC diff ), and the normalized ADC (ADC ratio ) were calculated. A Kruskal-Wallis statistic with Bonferroni correction for multiple comparisons was applied to detect significant ADC parameter differences between tumor grades by including or excluding 19 patients with an oligodendroglioma. Receiver operating characteristic curve analysis was conducted to define appropriate cutoff values for grading gliomas. No differences in ADC derived parameters were found between grade II and grade III gliomas. Mean ADC values using standard b-value were 1.17±0.27×10 -3 mm 2 /s [range: 0.63-1.61], 1.05±0.22×10 -3 mm 2 /s [range: 0.73-1.33], and 0.86±0.23×10 -3 mm 2 /s [range: 0.52-1.46] for grades II, III and IV gliomas, respectively. Using high b-value, mean ADC values were 0.89±0.24×10 -3 mm 2 /s [range: 0.42-1.25], 0.82±0.20×10 -3 mm 2 /s [range: 0.56-1.10], and 0.59±0.17×10 -3 mm 2 /s [range: 0.40-1.01] for grades II, III and IV gliomas, respectively. ADC mean , ADC ratio , ADC max , and ADC min were different between grade II and grade IV gliomas at both standard and high b-values. Differences in ADC mean , ADC max , and ADC diff were found between grade III and grade IV only using high b-value. ADC parameters derived from DW-MRI using a high b-value allows a better differential diagnosis of gliomas, especially for differentiating grades III and IV, than those derived from DW-MRI using a standard b-value. Copyright © 2016 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

[New opportunities of magnetic-resonance imaging: an algorithm of CSD-HARDI tractography in reconstruction of the brainstem reticular formation fibers].

PubMed

Aleksandrova, E V; Batalov, A I; Pogosbekyan, E L; Zakharova, N E; Fadeeva, L M; Kravchuk, A D; Pronin, I N; Potapov, A A

2018-01-01

The study purpose was to develop a technique for intravital visualization of the brainstem reticular formation fibers in healthy volunteers using magnetic resonance imaging (MRI). The study included 21 subjects (13 males and 8 females) aged 21 to 62 years. The study was performed on a magnetic resonance imaging scanner with a magnetic field strength of 3 T in T1, T2, T2-FLAIR, DWI, and SWI modes. A CSD-HARDI algorithm was used to identify thin intersecting fibers of the reticular formatio. We developed a technique for reconstructing the reticular formation pathways, tested it in healthy volunteers, and obtained standard quantitative indicators (fractional anisotropy (FA), apparent diffusion coefficient (ACD), fiber length and density, and axial and radial diffusion). We performed a comparative analysis of these indicators in males and females. There was no difference between these groups and between indicators for the right and left brainstem. Our findings will enable comparative analysis of examination results in patients with brain pathology accompanied by brainstem injury, which may help predict the outcome. This work was supported by a grant of the Russian Foundation for Basic Research (#16-04-01472).

Brainstem ischemic lesions on MRI in children with tuberculous meningitis: with diffusion weighted confirmation.

PubMed

van der Merwe, Dirk Johannes; Andronikou, Savvas; Van Toorn, Ronald; Pienaar, Manana

2009-08-01

The Western Cape in South Africa has one of the highest incidences of tuberculous meningitis (TBM) in the world. Despite therapy, the outcome in children with advanced TBM remains dismal. Magnetic resonance imaging (MRI) has been shown to be superior to computed tomography (CT) in demonstrating ischemia in TBM, especially of the brainstem. The objective of this study was to characterize brainstem lesions and association with clinical findings in children with TBM by using MRI. CT and multiplanar MRI scans were performed in 30 children with proven TBM. From this group, a subgroup with radiological ischemic changes of the brainstem were identified. Radiological findings in these patients were then correlated with severity of disease, motor deficit, and outcome after 6 months. Radiological brainstem abnormalities were identified in 14 out of 30 children. Thirty-eight brainstem lesions were confirmed to be ischemic. The severity of disease at presentation, degree of motor deficit, and developmental outcome after 6 months of the children with ischemic brainstem lesions was poorer compared to those children without brainstem involvement. However, both sensitivity and specificity of the MRI brainstem lesion detection for clinical outcome proved low. A significant percentage of children with TBM have ischemic brainstem lesions. These are poorly visualized on conventional CT. MRI scanning is more sensitive in detecting these lesions and localizing them. There appears to be some association between MRI-detected brainstem lesions and clinical outcome. The exact meaning of these lesions and their implication for the patient's management require further clarification.

Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma.

PubMed

Bredlau, Amy Lee; Dixit, Suraj; Chen, Chao; Broome, Ann-Marie

2017-01-01

Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs. Multiple nanoparticle formulations are currently being investigated for the treatment of DIPGs. Nanoparticles based upon stable elements, polymer nanoparticles, and organic nanoparticles are under development for the treatment of brain tumors, including DIPGs. Targeting of nanoparticles is now possible as delivery techniques that address the difficulty in crossing the blood brain barrier (BBB) are developed. Theranostic nanoparticles, a combination of therapeutics and diagnostic nanoparticles, improve imaging of the cancerous tissue while delivering therapy to the local region. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG.

[Imaging of gliomas].

PubMed

Martin-Duverneuil, N; Guillevin, R; Chiras, J

2008-11-01

The imaging of gliomas, as well as diffuse infiltrative gliomas or as more recently individualized entities, has been profoundly modified these last years. Correlated with the classic morphological MRI, numerous new sequences have appeared that allowed a more metabolic approach of the tumors, such as diffusion, perfusion--related to angiogenesis--and spectroscopy--reflecting metabolic data. Their development in daily practice allows to precise the diagnostic, to definite the more active areas (correlated with the hyperperfused or more metabolic active areas in relation with the Ki67 index) and so optimize the biopsy and/or evaluate the evolution of the lesion. When associated, they allow also and perhaps especially to precise the diagnostic, particularly with other tumoral masses such as lymphomas or metastases that can present misleading patterns, but also with other more benign lesions such as abcesses. Always critically analysed, and reevaluated along the time if necessary, they can sometimes help the histological diagnosis, but never can be used in place of it.

Palliative Care Options for a Young Adult Patient with a Diffuse Intrinsic Pontine Glioma.

PubMed

Sison, Julian; Tran, Hung; Margol, Ashley; Tiwari, Nishant; Garcia, Karla M; Cotter, Jennifer; Kiehna, Erin; Olch, Arthur J; Wong, Kenneth

2017-08-18

Diffuse intrinsic pontine gliomas (DIPGs) are rare but devastating brain tumors that occur primarily in children. These gliomas have poor prognoses and present options focus on palliation of symptoms and prolongation of life. Here, we present a case of a 16-year-old female diagnosed with a DIPG whose age group has been mostly left out of discussions regarding psychosocial support options. This report is meant to start a conversation about the different support options available at our institution that have shown promising results in the literature for palliative care applications. These options can include camps for patients with brain tumors, psychological counseling, the Ronald McDonald House, and other psychosocial programs. Many of these programs can be tailored to meet the specific needs of adolescent and young adult (AYA) patients and will hopefully be integrated into a comprehensive palliative care regimen in future studies.

Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma

PubMed Central

Bredlau, Amy Lee; Dixit, Suraj; Chen, Chao; Broome, Ann-Marie

2017-01-01

Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs. Multiple nanoparticle formulations are currently being investigated for the treatment of DIPGs. Nanoparticles based upon stable elements, polymer nanoparticles, and organic nanoparticles are under development for the treatment of brain tumors, including DIPGs. Targeting of nanoparticles is now possible as delivery techniques that address the difficulty in crossing the blood brain barrier (BBB) are developed. Theranostic nanoparticles, a combination of therapeutics and diagnostic nanoparticles, improve imaging of the cancerous tissue while delivering therapy to the local region. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG. PMID:26903150

Outcomes of Pediatric Low-grade Gliomas Treated With Radiation Therapy: A Single-institution Study

PubMed Central

Raikar, Sunil S.; Halloran, Donna R.; Elliot, Michael; McHugh, Michele; Patel, Shaun; Gauvain, Karen M.

2014-01-01

Summary Radiation therapy is often considered the treatment of choice for low-grade gliomas. However, given the long-term effects of radiation on the developing brain, the appropriate use of radiation therapy in pediatric patients remains controversial. The purpose of this study was to evaluate progression-free survival (PFS) of pediatric low-grade glioma patients treated with radiation therapy. Data were obtained through a retrospective chart review of patients treated between 1991 and 2008 from a single tertiary care center in the midwest. The study population consisted of 17 patients, of whom 8 (47%) had tumor recurrence after radiation therapy. The median follow-up time was 8.2 years, with a range of 2.3 to 17.2 years. The median age at diagnosis was 5.4 years, and the median age at radiation therapy was 9.4 years. The 3- and the 10-year PFS were 69% ± 11.7% and 46% ± 13.3%, respectively. A significant difference in PFS was seen when comparing brainstem tumors with hypothalamic/optic pathway tumors (P = 0.019). Differences in PFS based on the age at diagnosis, the extent of initial surgery, and indication for radiation therapy were not significant. A larger multicenter study is needed to better assess PFS in these patients. PMID:24714505

Recapitulating in vivo-like plasticity of glioma cell invasion along blood vessels and in astrocyte-rich stroma.

PubMed

Gritsenko, Pavlo; Leenders, William; Friedl, Peter

2017-10-01

Diffuse invasion of glioma cells into the brain parenchyma leads to nonresectable brain tumors and poor prognosis of glioma disease. In vivo, glioma cells can adopt a range of invasion strategies and routes, by moving as single cells, collective strands and multicellular networks along perivascular, perineuronal and interstitial guidance cues. Current in vitro assays to probe glioma cell invasion, however, are limited in recapitulating the modes and adaptability of glioma invasion observed in brain parenchyma, including collective behaviours. To mimic in vivo-like glioma cell invasion in vitro, we here applied three tissue-inspired 3D environments combining multicellular glioma spheroids and reconstituted microanatomic features of vascular and interstitial brain structures. Radial migration from multicellular glioma spheroids of human cell lines and patient-derived xenograft cells was monitored using (1) reconstituted basement membrane/hyaluronan interfaces representing the space along brain vessels; (2) 3D scaffolds generated by multi-layered mouse astrocytes to reflect brain interstitium; and (3) freshly isolated mouse brain slice culture ex vivo. The invasion patterns in vitro were validated using histological analysis of brain sections from glioblastoma patients and glioma xenografts infiltrating the mouse brain. Each 3D assay recapitulated distinct aspects of major glioma invasion patterns identified in mouse xenografts and patient brain samples, including individually migrating cells, collective strands extending along blood vessels, and multicellular networks of interconnected glioma cells infiltrating the neuropil. In conjunction, these organotypic assays enable a range of invasion modes used by glioma cells and will be applicable for mechanistic analysis and targeting of glioma cell dissemination.

Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma.

PubMed

Hu, Xin; Martinez-Ledesma, Emmanuel; Zheng, Siyuan; Kim, Hoon; Barthel, Floris; Jiang, Tao; Hess, Kenneth R; Verhaak, Roel G W

2017-06-01

Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. We assembled gene expression profiles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A first cohort was randomly split into training (n = 170) and a validation dataset (n = 163). A second validation set consisted of 41 expression profiles. An elastic-net penalized Cox proportional hazards model was applied to build a classifier model through cross-validation within the training dataset. The selected 35-gene signature was used to identify high-risk and low-risk groups in the validation set, which showed significantly different overall survival (P = .00058, log-rank test). For time-to-death events, the high-risk group predicted by the gene signature yielded a hazard ratio of 1.78 (95% confidence interval, 1.02-3.11). The signature was also significantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDH-mutant 1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be significantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH-wild-type lower grade or IDH-mutant, non-co-deleted gliomas. We identified a 35-gene signature that identifies high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratification. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

PubMed

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

2012-11-01

KIAA1549-BRAF fusion gene and isocitrate dehydrogenase (IDH) mutations are considered two mutually exclusive genetic events in pilocytic astrocytomas and diffuse gliomas, respectively. We investigated the presence of the KIAA1549-BRAF fusion gene in conjunction with IDH mutations and 1p/19q loss in 185 adult diffuse gliomas. Moreover BRAF(v600E) mutation was also screened. The KIAA1549-BRAF fusion gene was evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and sequencing. We found IDH mutations in 125 out 175 cases (71.4%). There were KIAA1549-BRAF fusion gene in 17 out of 180 (9.4%) cases and BRAF(v600E) in 2 out of 133 (1.5%) cases. In 11 of these 17 cases, both IDH mutations and the KIAA1549-BRAF fusion were present, as independent molecular events. Moreover, 6 of 17 cases showed co-presence of 1p/19q loss, IDH mutations and KIAA1549-BRAF fusion. Among the 17 cases with KIAA1549-BRAF fusion gene 15 (88.2%) were oligodendroglial neoplasms. Similarly, the two cases with BRAF(v600E) mutation were both oligodendroglioma and one had IDH mutations and 1p/19q co-deletion. Our results suggest that in a small fraction of diffuse gliomas, KIAA1549-BRAF fusion gene and BRAF(v600E) mutation may be responsible for deregulation of the Ras-RAF-ERK signaling pathway. Such alterations are more frequent in oligodendroglial neoplasm and may be co-present with IDH mutations and 1p/19q loss. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

Imaging growth and isocitrate dehydrogenase 1 mutation are independent predictors for diffuse low-grade gliomas

PubMed Central

Gozé, Catherine; Blonski, Marie; Le Maistre, Guillaume; Bauchet, Luc; Dezamis, Edouard; Page, Philippe; Varlet, Pascale; Capelle, Laurent; Devaux, Bertrand; Taillandier, Luc; Duffau, Hugues; Pallud, Johan

2014-01-01

Background We explored whether spontaneous imaging tumor growth (estimated by the velocity of diametric expansion) and isocitrate dehydrogenase 1 (IDH1) mutation (estimated by IDH1 immunoexpression) were independent predictors of long-term outcomes of diffuse low-grade gliomas in adults. Methods One hundred thirty-one adult patients with newly diagnosed supratentorial diffuse low-grade gliomas were retrospectively studied. Results Isocitrate dehydrogenase 1 mutations were present in 107 patients. The mean spontaneous velocity of diametric expansion was 5.40 ± 5.46 mm/y. During follow-up (mean, 70 ± 54.7 mo), 56 patients presented a malignant transformation and 23 died. The median malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (149 and 198 mo, respectively) than in cases of fast velocity of diametric expansion (46 and 82 mo; P < .001 and P < .001, respectively) and in cases with IDH1 mutation (100 and 198 mo, respectively) than in cases without IDH1 mutation (72 mo and not reached; P = .028 and P = .001, respectively). In multivariate analyses, spontaneous velocity of diametric expansion and IDH1 mutation were independent prognostic factors for malignant progression-free survival (P < .001; hazard ratio, 4.23; 95% CI, 1.81–9.40 and P = .019; hazard ratio, 2.39; 95% CI, 1.19–4.66, respectively) and for overall survival (P < .001; hazard ratio, 26.3; 95% CI, 5.42–185.2 and P = .007; hazard ratio, 17.89; 95% CI, 2.15–200.1, respectively). Conclusions The spontaneous velocity of diametric expansion and IDH1 mutation status are 2 independent prognostic values that should be obtained at the beginning of the management of diffuse low-grade gliomas in adults. PMID:24847087

Molecular Classification of Low-Grade Diffuse Gliomas

PubMed Central

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

2010-01-01

The current World Health Organization classification recognizes three histological types of grade II low-grade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ± IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ± IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P = 0.0037). Multivariate analysis with adjustment for age and treatment confirmed these results (P = 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P = 0.0005) and 1p/19q loss for longer survival (P = 0.0002), while IDH1/2 mutations are not prognostic (P = 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma. PMID:21075857

HGG-22. TARGETING NEURONAL ACTIVITY-REGULATED NEUROLIGIN-3 DEPENDENCY FOR HIGH-GRADE GLIOMA THERAPY

PubMed Central

Venkatesh, Humsa S; Tam, Lydia T; Woo, Pamelyn J; Monje, Michelle

2017-01-01

Abstract Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. Here, we demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) fail to grow in Nlgn3 knockout mice. Using genetic mouse models, we illustrate that Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of an ADAM10 inhibitor robustly blocks pGBM and DIPG xenograft growth via modulation of the tumor microenvironment. This work defines the therapeutic potential of and a promising strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG.

Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: facilitating analysis of archival gliomas.

PubMed

Mohapatra, Gayatry; Engler, David A; Starbuck, Kristen D; Kim, James C; Bernay, Derek C; Scangas, George A; Rousseau, Audrey; Batchelor, Tracy T; Betensky, Rebecca A; Louis, David N

2011-04-01

Array comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA). Because diffuse malignant gliomas are often sampled by small biopsies, formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis; FFPE tissues are also needed to study the intratumoral heterogeneity that characterizes these neoplasms. In this paper, we present a combination of evaluations and technical advances that provide strong support for the ready use of oligonucleotide aCGH on FFPE diffuse gliomas. We first compared aCGH using bacterial artificial chromosome (BAC) arrays in 45 paired frozen and FFPE gliomas, and demonstrate a high concordance rate between FFPE and frozen DNA in an individual clone-level analysis of sensitivity and specificity, assuring that under certain array conditions, frozen and FFPE DNA can perform nearly identically. However, because oligonucleotide arrays offer advantages to BAC arrays in genomic coverage and practical availability, we next developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. To demonstrate utility in FFPE tissues, we applied this approach to biphasic anaplastic oligoastrocytomas and demonstrate CNA differences between DNA obtained from the two components. Therefore, BAC and oligonucleotide aCGH can be sensitive and specific tools for detecting CNAs in FFPE DNA, and novel labeling techniques enable the routine use of oligonucleotide arrays for FFPE DNA. In combination, these advances should facilitate genome-wide analysis of rare, small and/or histologically heterogeneous gliomas from FFPE tissues.

Proton magnetic resonance spectroscopy predicts proliferative activity in diffuse low-grade gliomas.

PubMed

Guillevin, Remy; Menuel, Carole; Duffau, Hugues; Kujas, Michel; Capelle, Laurent; Aubert, Agnès; Taillibert, Sophie; Idbaih, Ahmed; Pallud, Joan; Demarco, Giovanni; Costalat, Robert; Hoang-Xuan, Khê; Chiras, Jacques; Vallée, Jean-Noel

2008-04-01

The aim of the study was to investigate the ability of (1)HMRS to reflect proliferative activity of diffuse low-grade gliomas (WHO grade II). Between November 2002 and March 2007, a prospective study was performed on consecutive patients with suspected supratentorial hemispheric diffuse low-grade tumors. All the patients underwent MR examination using uniform procedures, and then surgical resection or biopsy within 2 weeks of the MR examination. Proliferative activity of the tumors was assessed by Ki-67 immunochemistry (Mb-1) on paraffin embedded tumor sections. Spectroscopic data was compared with Ki-67 labeling index and other histologic data such as histological subtype, cellular atypia, cellular density using univariate and multivariate analysis. 82 of 97 consecutive patients had histologically confirmed WHO grade 2 gliomas. Ki-67 proliferation index (PI) was correlated with specific spectral patterns: (1) low PI (<4%) was associated with increased Cho/Cr and absence of both free lipids or lactates; (2) intermediate PI (4-8%) was associated with resonance of lactates; and (3) high PI (>8%) was characterized by a resonance of free lipids. On multivariate analysis, resonance of lactates and resonance of free lipids appeared as independent predictors of intermediate PI (P < 0.001) and high PI (P < 0.001), respectively; moreover, free lipids resonance was correlated with cellular atypia (P < 0.05). This study suggests that (1)HMRS is a reliable tool to evaluate the proliferation activity of WHO grade 2 glioma and to identify potentially more aggressive clinical behavior.

Loss of pons-to-hypothalamic white matter tracks in brainstem obesity.

PubMed

Purnell, J Q; Lahna, D L; Samuels, M H; Rooney, W D; Hoffman, W F

2014-12-01

Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in <1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of 'brainstem obesity' and adds to the brain regions that can determine the long-term body weight set point in humans.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy.

PubMed

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue; Wu, Yuan-Hung

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy

PubMed Central

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting. PMID:28662135

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

ClinicalTrials.gov

2015-09-28

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

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

ClinicalTrials.gov

2017-03-22

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

Extent of resection and timing of surgery in adult low grade glioma.

PubMed

A Mirza, Farhan; Shamim, Muhammad Shahzad

2017-06-01

Low grade glioma is a group of WHO grade II tumours including diffuse astrocytoma, oligodendroglioma, and oligoastrocytoma. Strong evidence exists in literature now to support early surgery and higher extent of safe resection in improving outcomes. In this review, we are highlighting some of the important studies done in the last few years specifically addressing timing of surgery and extent of resection.

Influence of region-of-interest designs on quantitative measurement of multimodal imaging of MR non-enhancing gliomas.

PubMed

Takano, Koji; Kinoshita, Manabu; Arita, Hideyuki; Okita, Yoshiko; Chiba, Yasuyoshi; Kagawa, Naoki; Watanabe, Yoshiyuki; Shimosegawa, Eku; Hatazawa, Jun; Hashimoto, Naoya; Fujimoto, Yasunori; Kishima, Haruhiko

2018-05-01

A number of studies have revealed the usefulness of multimodal imaging in gliomas. Although the results have been heavily affected by the method used for region of interest (ROI) design, the most discriminatory method for setting the ROI remains unclear. The aim of the present study was to determine the most suitable ROI design for 18 F-fluorodeoxyglucose (FDG) and 11 C-methionine (MET) positron emission tomography (PET), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) obtained by diffusion tensor imaging (DTI) from the viewpoint of grades of non-enhancing gliomas. A total of 31 consecutive patients with newly diagnosed, histologically confirmed magnetic resonance (MR) non-enhancing gliomas who underwent FDG-PET, MET-PET and DTI were retrospectively investigated. Quantitative measurements were performed using four different ROIs; hotspot/tumor center and whole tumor, constructed in either two-dimensional (2D) or three-dimensional (3D). Histopathological grading of the tumor was considered as empirical truth and the quantitative measurements obtained from each ROI was correlated with the grade of the tumor. The most discriminating ROI for non-enhancing glioma grading was different according to the different imaging modalities. 2D-hotspot/center ROI was most discriminating for FDG-PET (P=0.087), ADC map (P=0.0083), and FA map (P=0.25), whereas 3D-whole tumor ROI was best for MET-PET (P=0.0050). In the majority of scenarios, 2D-ROIs performed better than 3D-ROIs. Results from the image analysis using FDG-PET, MET-PET, ADC and FA may be affected by ROI design and the most discriminating ROI for non-enhancing glioma grading was different according to the imaging modality.

Functional Connectivity in Frontoparietal Network: Indicator of Preoperative Cognitive Function and Cognitive Outcome Following Surgery in Patients with Glioma.

PubMed

Lang, Stefan; Gaxiola-Valdez, Ismael; Opoku-Darko, Michael; Partlo, Lisa A; Goodyear, Bradley G; Kelly, John J P; Federico, Paolo

2017-09-01

Patients with diffuse glioma are known to have impaired cognitive functions preoperatively. However, the mechanism of these cognitive deficits remains unclear. Resting-state functional connectivity in the frontoparietal network (FPN) is associated with cognitive performance in healthy subjects. For this reason, it was hypothesized that functional connectivity of the FPN would be related to cognitive functioning in patients with glioma. To assess this relationship, preoperative cognitive status was correlated to patient-specific connectivity within the FPN. Further, we assessed whether connectivity could predict neuropsychologic outcome following surgery. Sixteen patients with diffuse glioma underwent neuropsychologic assessment and preoperative functional magnetic resonance imaging using task (n-back) and resting-state scans. Thirteen patients had postoperative cognitive assessment. An index of patient-specific functional connectivity in the FPN was derived by averaging connectivity values between 2 prefrontal and 2 parietal cortex regions defined by activation during the n-back task. The relationship of these indices with cognitive performance was assessed. Higher average connectivity within the FPN is associated with lower composite cognitive scores. Higher connectivity of the parietal region of the tumor-affected hemisphere is associated specifically with lower fluid cognition. Lower connectivity of the parietal region of the nontumor hemisphere is associated with worse neuropsychologic outcome 1 month after surgery. Resting-state functional connectivity between key regions of the FPN is associated with cognitive performance in patients with glioma and is related to cognitive outcome following surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study

PubMed Central

Rudà, Roberta; Magliola, Umberto; Bertero, Luca; Trevisan, Elisa; Bosa, Chiara; Mantovani, Cristina; Ricardi, Umberto; Castiglione, Anna; Monagheddu, Chiara; Soffietti, Riccardo

2013-01-01

Background Little information is available regarding the effect of conventional radiotherapy on glioma-related seizures. Methods In this retrospective study, we analyzed the seizure response and outcome following conventional radiotherapy in a cohort of 43 patients with glioma (33 grade II, 10 grade III) and medically intractable epilepsy. Results At 3 months after radiotherapy, seizure reduction was significant (≥50% reduction of frequency compared with baseline) in 31/43 patients (72%) of the whole series and in 25/33 patients (76%) with grade II gliomas, whereas at 12 months seizure reduction was significant in 26/34 (76%) and in 19/25 (76%) patients, respectively. Seizure reduction was observed more often among patients displaying an objective tumor response on MRI, but patients with no change on MRI also had a significant seizure reduction. Seizure freedom (Engel class I) was achieved at 12 months in 32% of all patients and in 38% of patients with grade II tumors. Timing of radiotherapy and duration of seizures prior to radiotherapy were significantly associated with seizure reduction. Conclusions This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy. PMID:23897633

Survival Associations Using Perfusion and Diffusion Magnetic Resonance Imaging in Patients With Histologic and Genetic Defined Diffuse Glioma World Health Organization Grades II and III.

PubMed

Latysheva, Anna; Eeg Emblem, Kyrre; Server, Andrés; Brandal, Petter; Meling, Torstein R; Pahnke, Jens; Hald, John K

2018-06-12

According to the new World Health Organization 2016 classification for tumors of the central nervous system, 1p/19q codeletion defines the genetic hallmark that differentiates oligodendrogliomas from diffuse astrocytomas. The aim of our study was to evaluate whether relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) histogram analysis can stratify survival in adult patients with genetic defined diffuse glioma grades II and III. Sixty-seven patients with untreated diffuse gliomas World Health Organization grades II and III and known 1p/19q codeletion status were included retrospectively and analyzed using ADC and rCBV maps based on whole-tumor volume histograms. Overall survival and progression-free survival (PFS) were analyzed by using Kaplan-Meier and Cox survival analyses adjusted for known survival predictors. Significant longer PFS was associated with homogeneous rCBV distribution-higher rCBVpeak (median, 37 vs 26 months; hazard ratio [HR], 3.2; P = 0.02) in patients with astrocytomas, and heterogeneous rCBV distribution-lower rCBVpeak (median, 46 vs 37 months; HR, 5.3; P < 0.001) and higher rCBVmean (median, 44 vs 39 months; HR, 7.9; P = 0.003) in patients with oligodendrogliomas. Apparent diffusion coefficient parameters (ADCpeak, ADCmean) did not stratify PFS and overall survival. Tumors with heterogeneous perfusion signatures and high average values were associated with longer PFS in patients with oligodendrogliomas. On the contrary, heterogeneous perfusion distribution was associated with poor outcome in patients with diffuse astrocytomas.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

The pathobiology of collagens in glioma

PubMed Central

Payne, Leo S.; Huang, Paul H.

2013-01-01

Malignant gliomas are characterised by diffuse infiltration into the surrounding brain parenchyma. Infiltrating glioma cells exist in close proximity with components of the tumour microenvironment, including the extracellular matrix (ECM). While levels of collagens in the normal adult brain are low, in glioma, collagen levels are elevated and play an important role in driving the tumor progression. In this review, we provide a comprehensive overview of the nature of collagens found in gliomas and offer insights into the mechanisms by which cancer cells interact with this ECM via receptors including the integrins, discoidin domain receptors and Endo180. We further describe the major remodelling pathways of brain tumour collagen mediated by the matrix metalloproteinases and highlight the reciprocal relationship between these enzymes and the collagen receptors. Finally, we conclude by offering a perspective on how the biophysical properties of the collagen ECM, in particular, mechanical stiffness and compliance may influence malignant outcome. Understanding the complex interactions between glioma cells and the collagen ECM may provide new avenues to combat the rampant tumor progression and chemoresistance in brain cancer patients. PMID:23861322

Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing.

PubMed

Agarwal, Shipra; Sharma, Mehar Chand; Jha, Prerana; Pathak, Pankaj; Suri, Vaishali; Sarkar, Chitra; Chosdol, Kunzang; Suri, Ashish; Kale, Shashank Sharad; Mahapatra, Ashok Kumar; Jha, Pankaj

2013-06-01

Mutations involving isocitrate dehydrogenase 1 (IDH 1) occur in a high proportion of diffuse gliomas, with implications on diagnosis and prognosis. About 90% involve exon 4 at codon 132, replacing amino acid arginine with histidine (R132H). Rarer ones include R132C, R132S, R132G, R132L, R132V, and R132P. Most authors have used DNA-based methods to assess IDH1 status. Preliminary studies comparing imunohistochemistry (IHC) with IDH1-R132H mutation-specific antibodies have shown concordance with DNA sequencing and no cross-reactivity with wild-type IDH1 or other mutant proteins. The present study compares results of IHC with DNA sequencing in diffuse gliomas. Fifty diffuse gliomas with frozen tissue samples for DNA sequencing and adequate tissue in paraffin blocks for IHC using IDH1-R132H specific antibody were assessed for IDH1 mutations. Concordance of findings between IHC and DNA sequencing was noted in 88% (44/50) cases. All 6 cases with discrepancy were immunopositive with DIA-H09 antibody. While in 3 of these 6 cases, DNA sequencing failed to reveal any mutations, R132L (arginine replaced by leucine) mutation was found in the rest 3 cases. Interestingly, of the immunopositive cases, 46.6% (14/30) showed immunostaining in only a fraction of tumor cells. IHC is an easy and quick method of detecting IDH1-R132H mutations, but there may be some discrepancies between IHC and DNA sequencing. Although there were no false-negative cases, cross-reactivity with IDH1-R132L was seen in 3, a finding not reported thus far. Because of more universal availability of IHC over genetic testing, cross-reactivity and staining heterogeneity may have bearing over its use in detecting IDH1-R132H mutation in gliomas.

Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing

PubMed Central

Agarwal, Shipra; Sharma, Mehar Chand; Jha, Prerana; Pathak, Pankaj; Suri, Vaishali; Sarkar, Chitra; Chosdol, Kunzang; Suri, Ashish; Kale, Shashank Sharad; Mahapatra, Ashok Kumar; Jha, Pankaj

2013-01-01

Background Mutations involving isocitrate dehydrogenase 1 (IDH 1) occur in a high proportion of diffuse gliomas, with implications on diagnosis and prognosis. About 90% involve exon 4 at codon 132, replacing amino acid arginine with histidine (R132H). Rarer ones include R132C, R132S, R132G, R132L, R132V, and R132P. Most authors have used DNA-based methods to assess IDH1 status. Preliminary studies comparing imunohistochemistry (IHC) with IDH1-R132H mutation-specific antibodies have shown concordance with DNA sequencing and no cross-reactivity with wild-type IDH1 or other mutant proteins. The present study compares results of IHC with DNA sequencing in diffuse gliomas. Materials and methods Fifty diffuse gliomas with frozen tissue samples for DNA sequencing and adequate tissue in paraffin blocks for IHC using IDH1-R132H specific antibody were assessed for IDH1 mutations. Results Concordance of findings between IHC and DNA sequencing was noted in 88% (44/50) cases. All 6 cases with discrepancy were immunopositive with DIA-H09 antibody. While in 3 of these 6 cases, DNA sequencing failed to reveal any mutations, R132L (arginine replaced by leucine) mutation was found in the rest 3 cases. Interestingly, of the immunopositive cases, 46.6% (14/30) showed immunostaining in only a fraction of tumor cells. Conclusions IHC is an easy and quick method of detecting IDH1-R132H mutations, but there may be some discrepancies between IHC and DNA sequencing. Although there were no false-negative cases, cross-reactivity with IDH1-R132L was seen in 3, a finding not reported thus far. Because of more universal availability of IHC over genetic testing, cross-reactivity and staining heterogeneity may have bearing over its use in detecting IDH1-R132H mutation in gliomas. PMID:23486690

Yoga Therapy in Treating Patients With Malignant Brain Tumors

ClinicalTrials.gov

2017-07-27

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

Management of diffuse low-grade gliomas in adults - use of molecular diagnostics.

PubMed

Buckner, Jan; Giannini, Caterina; Eckel-Passow, Jeanette; Lachance, Daniel; Parney, Ian; Laack, Nadia; Jenkins, Robert

2017-06-01

Diffuse WHO grade II gliomas are histologically and genetically heterogeneous. The 2016 WHO classification redefines grade II gliomas with respect to morphological and molecular tumour alterations: grade II oligodendrogliomas are defined by the presence of whole-arm codeletion in chromosomal arms 1p/19q, whereas isocitrate dehydrogenase (IDH) mutations define subclasses of astrocytoma. Although histological grade remains useful, the prognoses of patients with glioma are more tightly associated with molecular alterations than with grade, and chromosomal and gene array technologies are becoming increasingly beneficial in understanding tumour genetic heterogeneity. The indolent nature of the disease often creates subtle neurological symptoms that can be overlooked or misunderstood, resulting in delayed diagnosis. Seizures often herald the diagnosis, especially in patients who have IDH mutations, which are associated with an increased production of 2-hydroxyglutarate. Treatment paradigms have shifted, owing to new diagnostic criteria and new clinical trial evidence. Patients benefit more from chemoradiation than radiation alone, especially those with tumour IDH1 Arg132His mutations; gross total resection of the tumour, including tumours with IDH mutations, is associated with prolonged survival. Initial observation remains appropriate in patients whose rate of disease growth is not yet completely defined; such patients could include those with completely resected disease and those with 1p/19q codeleted tumours.

Functional-Based Resection Does Not Worsen Quality of Life in Patients with a Diffuse Low-Grade Glioma Involving Eloquent Brain Regions: A Prospective Cohort Study.

PubMed

Muto, Jun; Dezamis, Edouard; Rigaux-Viode, Odile; Peeters, Sophie; Roux, Alexandre; Zanello, Marc; Mellerio, Charles; Sauvageon, Xavier; Varlet, Pascale; Oppenheim, Catherine; Pallud, Johan

2018-05-01

We assessed the impact of surgery on postoperative cognitive function and ability to work in adult patients with a diffuse low-grade glioma involving eloquent brain regions and having a functional-based maximal surgical resection using intraoperative corticosubcortical mapping under awake conditions. We prospectively included 39 consecutive patients with diffuse isocitrate dehydrogenase-mutant low-grade glioma without preoperative and adjuvant oncologic treatment and assessed preoperative (mean, 24.1 ± 21.2 days before surgery) and postoperative (mean, 14.6 ± 13.2 months after surgery) cognitive evaluations and ability to work together with clinical, imaging, therapeutic, and follow-up characteristics before tumor progression. None of the 3 patients without preoperative cognitive deficit had postoperative worsening. We observed a significant inverse interaction between worsened postoperative cognitive function and extent of resection: 80.0%, 18.8%, and 16.7% of worsening after partial, subtotal, and total resection, respectively (P = 0.020). We observed an independent interaction between improved postoperative cognitive function and extent of resection: 20.0%, 43.7%, and 44.4% of improvement after partial, subtotal, and total resection, respectively (P = 0.022). Of the employed patients, 61.8% were unable to work preoperatively and 82.4% resumed their employment postoperatively (mean, 6.9 ± 5.5 months). We observed an independent interaction between postoperative ability to work, similar or superior to preoperative work capacity and extent of resection (P < 0.001): 20.0%, 87.5%, and 100% ability to work after partial, subtotal resection, and total resection. The extent of the functional-based surgical resection and the residual tumor for diffuse low-grade gliomas involving eloquent brain regions correlate with postoperative cognitive outcomes and return to work rates. Copyright © 2018 Elsevier Inc. All rights reserved.

The impact of body mass index and height on the risk for glioblastoma and other glioma subgroups: a large prospective cohort study.

PubMed

Wiedmann, Markus K H; Brunborg, Cathrine; Di Ieva, Antonio; Lindemann, Kristina; Johannesen, Tom B; Vatten, Lars; Helseth, Eirik; Zwart, John A

2017-07-01

Glioma comprises a heterogeneous group of mostly malignant brain tumors, whereof glioblastoma (GBM) represents the largest and most lethal subgroup. Body height and body mass index (BMI) are risk factors for other cancers, but no previous study has examined anthropometric data in relation to different glioma subgroups. This prospective cohort study includes 1.8 million Norwegian women and men between ages 14 and 80 years at baseline. Body weight and height were measured, and incident cases of glioma were identified by linkage to the National Cancer Registry. Cox regression analyses were performed to evaluate risk for different glioma subgroups in relation to anthropometric measures. During 54 million person-years of follow-up, 4,382 gliomas were identified. Overweight and obesity were not associated with risk for any glioma subgroup. Height was positively associated with risk for GBM and all other gliomas (hazard ratio [HR] per 10 cm increase: 1.24; 95% confidence interval [CI], 1.17-1.31 and 1.18; 95% CI, 1.09-1.29) but not with the proxy for isocitrate dehydrogenase (IDH)-mutant glioma (HR, 1.09; 95% CI, 0.98-1.21). In further subgroup analyses, the effect of height on glioma risk varied significantly with positive associations for oligoastrocytoma (HR, 1.74; 95% CI, 1.20-2.53) and malignant glioma not otherwise specified (NOS) (HR, 1.42; 95% CI, 1.16-1.76, but not with diffuse astrocytoma (WHO grades II and III) or oligodendroglioma. This epidemiologic study consolidates height as a risk factor for GBM and other gliomas. It further indicates that this association is not universal for gliomas but may differ between different glioma subgroups. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Structural Connectome of the Human Central Homeostatic Network.

PubMed

Edlow, Brian L; McNab, Jennifer A; Witzel, Thomas; Kinney, Hannah C

2016-04-01

Homeostatic adaptations to stress are regulated by interactions between the brainstem and regions of the forebrain, including limbic sites related to respiratory, autonomic, affective, and cognitive processing. Neuroanatomic connections between these homeostatic regions, however, have not been thoroughly identified in the human brain. In this study, we perform diffusion spectrum imaging tractography using the MGH-USC Connectome MRI scanner to visualize structural connections in the human brain linking autonomic and cardiorespiratory nuclei in the midbrain, pons, and medulla oblongata with forebrain sites critical to homeostatic control. Probabilistic tractography analyses in six healthy adults revealed connections between six brainstem nuclei and seven forebrain regions, several over long distances between the caudal medulla and cerebral cortex. The strongest evidence for brainstem-homeostatic forebrain connectivity in this study was between the brainstem midline raphe and the medial temporal lobe. The subiculum and amygdala were the sampled forebrain nodes with the most extensive brainstem connections. Within the human brainstem-homeostatic forebrain connectome, we observed that a lateral forebrain bundle, whose connectivity is distinct from that of rodents and nonhuman primates, is the primary conduit for connections between the brainstem and medial temporal lobe. This study supports the concept that interconnected brainstem and forebrain nodes form an integrated central homeostatic network (CHN) in the human brain. Our findings provide an initial foundation for elucidating the neuroanatomic basis of homeostasis in the normal human brain, as well as for mapping CHN disconnections in patients with disorders of homeostasis, including sudden and unexpected death, and epilepsy.

Optimizing a machine learning based glioma grading system using multi-parametric MRI histogram and texture features

PubMed Central

Hu, Yu-Chuan; Li, Gang; Yang, Yang; Han, Yu; Sun, Ying-Zhi; Liu, Zhi-Cheng; Tian, Qiang; Han, Zi-Yang; Liu, Le-De; Hu, Bin-Quan; Qiu, Zi-Yu; Wang, Wen; Cui, Guang-Bin

2017-01-01

Current machine learning techniques provide the opportunity to develop noninvasive and automated glioma grading tools, by utilizing quantitative parameters derived from multi-modal magnetic resonance imaging (MRI) data. However, the efficacies of different machine learning methods in glioma grading have not been investigated.A comprehensive comparison of varied machine learning methods in differentiating low-grade gliomas (LGGs) and high-grade gliomas (HGGs) as well as WHO grade II, III and IV gliomas based on multi-parametric MRI images was proposed in the current study. The parametric histogram and image texture attributes of 120 glioma patients were extracted from the perfusion, diffusion and permeability parametric maps of preoperative MRI. Then, 25 commonly used machine learning classifiers combined with 8 independent attribute selection methods were applied and evaluated using leave-one-out cross validation (LOOCV) strategy. Besides, the influences of parameter selection on the classifying performances were investigated. We found that support vector machine (SVM) exhibited superior performance to other classifiers. By combining all tumor attributes with synthetic minority over-sampling technique (SMOTE), the highest classifying accuracy of 0.945 or 0.961 for LGG and HGG or grade II, III and IV gliomas was achieved. Application of Recursive Feature Elimination (RFE) attribute selection strategy further improved the classifying accuracies. Besides, the performances of LibSVM, SMO, IBk classifiers were influenced by some key parameters such as kernel type, c, gama, K, etc. SVM is a promising tool in developing automated preoperative glioma grading system, especially when being combined with RFE strategy. Model parameters should be considered in glioma grading model optimization. PMID:28599282

Optimizing a machine learning based glioma grading system using multi-parametric MRI histogram and texture features.

PubMed

Zhang, Xin; Yan, Lin-Feng; Hu, Yu-Chuan; Li, Gang; Yang, Yang; Han, Yu; Sun, Ying-Zhi; Liu, Zhi-Cheng; Tian, Qiang; Han, Zi-Yang; Liu, Le-De; Hu, Bin-Quan; Qiu, Zi-Yu; Wang, Wen; Cui, Guang-Bin

2017-07-18

Current machine learning techniques provide the opportunity to develop noninvasive and automated glioma grading tools, by utilizing quantitative parameters derived from multi-modal magnetic resonance imaging (MRI) data. However, the efficacies of different machine learning methods in glioma grading have not been investigated.A comprehensive comparison of varied machine learning methods in differentiating low-grade gliomas (LGGs) and high-grade gliomas (HGGs) as well as WHO grade II, III and IV gliomas based on multi-parametric MRI images was proposed in the current study. The parametric histogram and image texture attributes of 120 glioma patients were extracted from the perfusion, diffusion and permeability parametric maps of preoperative MRI. Then, 25 commonly used machine learning classifiers combined with 8 independent attribute selection methods were applied and evaluated using leave-one-out cross validation (LOOCV) strategy. Besides, the influences of parameter selection on the classifying performances were investigated. We found that support vector machine (SVM) exhibited superior performance to other classifiers. By combining all tumor attributes with synthetic minority over-sampling technique (SMOTE), the highest classifying accuracy of 0.945 or 0.961 for LGG and HGG or grade II, III and IV gliomas was achieved. Application of Recursive Feature Elimination (RFE) attribute selection strategy further improved the classifying accuracies. Besides, the performances of LibSVM, SMO, IBk classifiers were influenced by some key parameters such as kernel type, c, gama, K, etc. SVM is a promising tool in developing automated preoperative glioma grading system, especially when being combined with RFE strategy. Model parameters should be considered in glioma grading model optimization.

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.

PubMed

Shirahata, Mitsuaki; Ono, Takahiro; Stichel, Damian; Schrimpf, Daniel; Reuss, David E; Sahm, Felix; Koelsche, Christian; Wefers, Annika; Reinhardt, Annekathrin; Huang, Kristin; Sievers, Philipp; Shimizu, Hiroaki; Nanjo, Hiroshi; Kobayashi, Yusuke; Miyake, Yohei; Suzuki, Tomonari; Adachi, Jun-Ichi; Mishima, Kazuhiko; Sasaki, Atsushi; Nishikawa, Ryo; Bewerunge-Hudler, Melanie; Ryzhova, Marina; Absalyamova, Oksana; Golanov, Andrey; Sinn, Peter; Platten, Michael; Jungk, Christine; Winkler, Frank; Wick, Antje; Hänggi, Daniel; Unterberg, Andreas; Pfister, Stefan M; Jones, David T W; van den Bent, Martin; Hegi, Monika; French, Pim; Baumert, Brigitta G; Stupp, Roger; Gorlia, Thierry; Weller, Michael; Capper, David; Korshunov, Andrey; Herold-Mende, Christel; Wick, Wolfgang; Louis, David N; von Deimling, Andreas

2018-04-23

According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII IDHmut ), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII IDHmut ), and WHO grade IV glioblastoma, IDH-mutant (GBM IDHmut ). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII IDHmut and AAIII IDHmut have lost their significance. In contrast, GBM IDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.

Evaluation of IDH1 status in diffusely infiltrating gliomas by immunohistochemistry using anti-mutant and wild type IDH1 antibodies.

PubMed

Ikota, Hayato; Nobusawa, Sumihito; Arai, Hideo; Kato, Yukinari; Ishizawa, Keisuke; Hirose, Takanori; Yokoo, Hideaki

2015-10-01

Glioma cells with the isocitrate dehydrogenase (IDH) 1 G395A mutation are strongly immunopositive for mIDH1(R132H), an antibody against mutant IDH1(R132H) (clone H09). However, we encountered some gliomas which were ambiguously positive for mIDH1(R132H) despite having the IDH1 G395A mutation. The aim of this study was to establish an evaluation procedure of IDH1 status by immunohistochemistry. Forty-three diffusely infiltrating gliomas were studied, and four of eight anaplastic oligoastrocytomas with the IDH1 G395A mutation were modestly or weakly positive for both the mIDH1(R132H) and an antibody against wild type IDH1, RcMab-1. Based on our staining results, the IDH1 expression of both wild and mutated types seemed to be codominant and also to be evenly suppressed under a certain condition. We propose a procedure for determining IDH1 status. If a glioma is weakly positive for mIDH1(R132H), immunohistochemistry for RcMab-1 should be performed. If the tumor cells are strongly positive for RcMab-1, the IDH1 G395A mutation is judged to be absent on the grounds that IDH1 expression is not suppressed. If the tumor cells are weakly positive for both mIDH1(R132H) and RcMab-1, then a conclusion should be made after DNA sequencing. This procedure is useful for practical evaluation of IDH1 status.

Measurable Supratentorial White Matter Volume Changes in Patients with Diffuse Intrinsic Pontine Glioma Treated with an Anti-Vascular Endothelial Growth Factor Agent, Steroids, and Radiation.

PubMed

Svolos, P; Reddick, W E; Edwards, A; Sykes, A; Li, Y; Glass, J O; Patay, Z

2017-06-01

Assessing the response to treatment in infiltrative brain tumors by using lesion volume-based response criteria is challenging. We hypothesized that in such tumors, volume measurements alone may not accurately capture changes in actual tumor burden during treatment. We longitudinally evaluated volume changes in both normal-appearing supratentorial white matter and the brain stem lesions in patients treated for diffuse intrinsic pontine glioma to determine to what extent adjuvant systemic therapies may skew the accuracy of tumor response assessments based on volumetric analysis. The anatomic MR imaging and diffusion tensor imaging data of 26 patients with diffuse intrinsic pontine glioma were retrospectively analyzed. Treatment included conformal radiation therapy in conjunction with vandetanib and dexamethasone. Volumetric and diffusion data were analyzed with time, and differences between time points were evaluated statistically. Normalized brain stem lesion volume decreased during combined treatment (slope = -0.222, P < .001) and increased shortly after completion of radiation therapy (slope = 0.422, P < .001). Supratentorial white matter volume steadily and significantly decreased with time (slope = -0.057, P < .001). Longitudinal changes in brain stem lesion volume are robust; less pronounced but measurable changes occur in the supratentorial white matter. Volume changes in nonirradiated supratentorial white matter during the disease course reflect the effects of systemic medication on the water homeostasis of normal parenchyma. Our data suggest that adjuvant nontumor-targeted therapies may have a more substantial effect on lesion volume changes than previously thought; hence, an apparent volume decrease in infiltrative tumors receiving combined therapies may lead to overestimation of the actual response and tumor control. © 2017 by American Journal of Neuroradiology.

Application of a Simplified Method for Estimating Perfusion Derived from Diffusion-Weighted MR Imaging in Glioma Grading.

PubMed

Cao, Mengqiu; Suo, Shiteng; Han, Xu; Jin, Ke; Sun, Yawen; Wang, Yao; Ding, Weina; Qu, Jianxun; Zhang, Xiaohua; Zhou, Yan

2017-01-01

Purpose : To evaluate the feasibility of a simplified method based on diffusion-weighted imaging (DWI) acquired with three b -values to measure tissue perfusion linked to microcirculation, to validate it against from perfusion-related parameters derived from intravoxel incoherent motion (IVIM) and dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging, and to investigate its utility to differentiate low- from high-grade gliomas. Materials and Methods : The prospective study was approved by the local institutional review board and written informed consent was obtained from all patients. From May 2016 and May 2017, 50 patients confirmed with glioma were assessed with multi- b -value DWI and DCE MR imaging at 3.0 T. Besides conventional apparent diffusion coefficient (ADC 0,1000 ) map, perfusion-related parametric maps for IVIM-derived perfusion fraction ( f ) and pseudodiffusion coefficient (D*), DCE MR imaging-derived pharmacokinetic metrics, including K trans , v e and v p , as well as a metric named simplified perfusion fraction (SPF), were generated. Correlation between perfusion-related parameters was analyzed by using the Spearman rank correlation. All imaging parameters were compared between the low-grade ( n = 19) and high-grade ( n = 31) groups by using the Mann-Whitney U test. The diagnostic performance for tumor grading was evaluated with receiver operating characteristic (ROC) analysis. Results : SPF showed strong correlation with IVIM-derived f and D* ( ρ = 0.732 and 0.716, respectively; both P < 0.001). Compared with f , SPF was more correlated with DCE MR imaging-derived K trans ( ρ = 0.607; P < 0.001) and v p ( ρ = 0.397; P = 0.004). Among all parameters, SPF achieved the highest accuracy for differentiating low- from high-grade gliomas, with an area under the ROC curve value of 0.942, which was significantly higher than that of ADC 0,1000 ( P = 0.004). By using SPF as a discriminative index, the diagnostic sensitivity and specificity were 87.1% and 94.7%, respectively, at the optimal cut-off value of 19.26%. Conclusion : The simplified method to measure tissue perfusion based on DWI by using three b -values may be helpful to differentiate low- from high-grade gliomas. SPF may serve as a valuable alternative to measure tumor perfusion in gliomas in a noninvasive, convenient and efficient way.

The role of radiotherapy in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

PubMed

Ryken, Timothy C; Parney, Ian; Buatti, John; Kalkanis, Steven N; Olson, Jeffrey J

2015-12-01

(1) What is the optimal role of external beam radiotherapy in the management of adult patients with newly diagnosed low-grade glioma (LGG) in terms of improving outcome (i.e., survival, complications, seizure control or other reported outcomes of interest)? (2) Which radiation strategies (dose, timing, fractionation, stereotactic radiation, brachytherapy, chemotherapy) improve outcomes compared to standard external beam radiation therapy in the initial management of low grade gliomas in adults? (3) Do specific factors (e.g., age, volume, extent of resection, genetic subtype) identify subgroups with better outcomes following radiation therapy than the general population of adults with newly diagnosed low-grade gliomas? These recommendations apply to adults with newly diagnosed diffuse LGG. OUTCOMES IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level I Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong progression free survival, irrespective of extent of resection. Level II Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults as an equivalent alternative to observation in preserving cognitive function, irrespective of extent of resection. Level III Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults to improve seizure control in patients with epilepsy and subtotal resection. Level III Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong overall survival in patients with subtotal resection. Level III Consideration of the risk of radiation induced morbidity, including cognitive decline, imaging abnormalities, metabolic dysfunction and malignant transformation, is recommended when the delivery of radiotherapy is selected in the management of newly diagnosed low-grade glioma in adults. STRATEGIES OF RADIOTHERAPY IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA: Level I Lower dose radiotherapy is recommended as an equivalent alternative to higher dose immediate postoperative radiotherapy (45-50.4 vs. 59.4-64.8 Gy) in the management of newly diagnosed low-grade glioma in adults with reduced toxicity. Level III Delaying radiotherapy until recurrence or progression is recommended as an equivalent alternative to immediate postoperative radiotherapy in the management of newly diagnosed low-grade glioma in adults but may result in shorter time to progression. Level III The addition of chemotherapy to radiotherapy is not recommended over whole brain radiotherapy alone in the management of low-grade glioma, as it provides no additional survival benefit. Level III Limited-field radiotherapy is recommended over whole brain radiotherapy in the management of low-grade glioma. Level III Either stereotactic radiosurgery or brachytherapy are recommended as acceptable alternatives to external radiotherapy in selected patients. PROGNOSTIC FACTORS IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level II It is recommended that age greater than 40 years, astrocytic pathology, diameter greater than 6 cm, tumor crossing the midline and preoperative neurological deficit be considered as negative prognostic indicators when predicting overall survival in adult low grade glioma patients treated with radiotherapy. Level II It is recommended that smaller tumor size, extent of surgical resection and higher mini-mental status exam be considered as positive prognostic indicators when predicting overall survival and progression free survival in patients in adult low grade glioma patients treated with radiotherapy. Level III It is recommended that seizures at presentation, presence of oligodendroglial histological component and 1p19q deletion (along with additional relevant factors-see Table 1) be considered as positive prognostic indicators when predicting response to radiotherapy in adults with low grade gliomas. Level III It is recommended that increasing age, decreasing performance status, decreasing cognition, presence of astrocytic histological component (along with additional relevant factors (see Tables 1, 2) be considered as negative prognostic indicators when predicting response to radiotherapy.

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma.

PubMed

Venkatesh, Humsa S; Tam, Lydia T; Woo, Pamelyn J; Lennon, James; Nagaraja, Surya; Gillespie, Shawn M; Ni, Jing; Duveau, Damien Y; Morris, Patrick J; Zhao, Jean J; Thomas, Craig J; Monje, Michelle

2017-09-28

High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

PubMed Central

Venkatesh, Humsa S.; Tam, Lydia T.; Woo, Pamelyn J.; Lennon, James; Nagaraja, Surya; Gillespie, Shawn M.; Ni, Jing; Duveau, Damien Y.; Morris, Patrick J.; Zhao, Jean J.; Thomas, Craig J.; Monje, Michelle

2017-01-01

Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy. PMID:28959975

A fuzzy feature fusion method for auto-segmentation of gliomas with multi-modality diffusion and perfusion magnetic resonance images in radiotherapy.

PubMed

Guo, Lu; Wang, Ping; Sun, Ranran; Yang, Chengwen; Zhang, Ning; Guo, Yu; Feng, Yuanming

2018-02-19

The diffusion and perfusion magnetic resonance (MR) images can provide functional information about tumour and enable more sensitive detection of the tumour extent. We aimed to develop a fuzzy feature fusion method for auto-segmentation of gliomas in radiotherapy planning using multi-parametric functional MR images including apparent diffusion coefficient (ADC), fractional anisotropy (FA) and relative cerebral blood volume (rCBV). For each functional modality, one histogram-based fuzzy model was created to transform image volume into a fuzzy feature space. Based on the fuzzy fusion result of the three fuzzy feature spaces, regions with high possibility belonging to tumour were generated automatically. The auto-segmentations of tumour in structural MR images were added in final auto-segmented gross tumour volume (GTV). For evaluation, one radiation oncologist delineated GTVs for nine patients with all modalities. Comparisons between manually delineated and auto-segmented GTVs showed that, the mean volume difference was 8.69% (±5.62%); the mean Dice's similarity coefficient (DSC) was 0.88 (±0.02); the mean sensitivity and specificity of auto-segmentation was 0.87 (±0.04) and 0.98 (±0.01) respectively. High accuracy and efficiency can be achieved with the new method, which shows potential of utilizing functional multi-parametric MR images for target definition in precision radiation treatment planning for patients with gliomas.

A Sensitive and Specific Diagnostic Panel to Distinguish Diffuse Astrocytoma from Astrocytosis: Chromosome 7 Gain with Mutant Isocitrate Dehydrogenase 1 and p53

PubMed Central

Camelo-Piragua, Sandra; Jansen, Michael; Ganguly, Aniruddha; Kim, J. ChulMin; Cosper, Arjola K.; Dias-Santagata, Dora; Nutt, Catherine L.; Iafrate, A. John; Louis, David N.

2011-01-01

One of the major challenges of surgical neuropathology is the distinction of diffuse astrocytoma (World Health Organization [WHO] grade II) from astrocytosis. The most commonly used ancillary tool to solve this problem is p53 immunohistochemistry (IHC), but this is neither sensitive nor specific. Isocitrate dehydrogenase 1 (IDH1) mutations are common in lower grade gliomas, with most causing a specific amino acid change (R132H) that can be detected with a monoclonal antibody. IDH2 mutations are rare, but also occur in gliomas. In addition, gains of chromosome 7 are common in gliomas. In this study we assessed the status of p53, IDH1/2 and chromosome 7 to determine the most useful panel to distinguish astrocytoma from astrocytosis. We studied biopsy specimens from 21 WHO grade II diffuse astrocytomas and 20 reactive conditions. The single most sensitive test to identify astrocytoma is fluorescence in situ hybridization (FISH) for chromosome 7 gain (76.2%). The combination of p53 and mutant IDH1 IHC provides a higher sensitivity (71.4%) than either test alone (47.8%); this combination offers a practical initial approach for the surgical pathologist. The best overall sensitivity (95%) is achieved when FISH for chromosome 7 gain is added to the p53-mutant IDH1 IHC panel. PMID:21343879

Proteomics of gliomas: Initial biomarker discovery and evolution of technology

PubMed Central

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

2011-01-01

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

Pulsed and oscillating gradient MRI for assessment of cell size and Extracellular space (POMACE) in mouse gliomas

PubMed Central

Reynaud, Olivier; Winters, Kerryanne Veronica; Hoang, Dung Minh; Wadghiri, Youssef Zaim; Novikov, Dmitry S.; Kim, Sungheon Gene

2016-01-01

Solid tumor microstructure is related to aggressiveness of tumor, interstitial pressure and drug delivery pathways that are closely associated with treatment response, metastatic spread and prognosis. In this study, we introduce a novel diffusion MRI data analysis framework, Pulsed and Oscillating gradient MRI for Assessment of Cell size and Extracellular space (POMACE), and demonstrate its feasibility in a mouse tumor model. In vivo and ex vivo POMACE experiments were performed on mice bearing the GL261 murine glioma model (n=8). Since the complete diffusion time-dependence is in general non-analytical, the tumor microstructure was modeled in an appropriate time/frequency regime by impermeable spheres (radius Rcell, intracellular diffusivity Dics) surrounded by extracellular space (approximated by constant apparent diffusivity Decs in volume fraction ECS). POMACE parametric maps (ECS, Rcell, Dics, Decs) were compared with conventional diffusion weighted imaging metrics, electron microscopy (EM), alternative ECS determination based on effective medium theory (EMT), and optical microscopy performed on the same samples. It was shown that Decs can be approximated by its long-time tortuosity limit in the range [1/(88 Hz) - 31 ms]. ECS estimations (44±7% in vivo and 54±11% ex vivo) were in agreement with EMT-based ECS and literature on brain gliomas. Ex vivo, ECS maps correlated well with optical microscopy. Cell sizes (Rcell=4.8±1.3 in vivo and 4.3±1.4 μm ex vivo) were consistent with EM measurements (4.7±1.8 μm). In conclusion, Rcell and ECS can be quantified and mapped in vivo and ex vivo in brain tumors using the proposed POMACE method. Our experimental results support that POMACE provides a way to interpret the frequency- or time-dependence of the diffusion coefficient in tumors in terms of objective biophysical parameters of neuronal tissue, which can be used for non-invasive monitoring of preclinical cancer studies and treatment efficacy. PMID:27448059

Lentiviral-induced high-grade gliomas in rats: the effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H.

PubMed

Lynes, John; Wibowo, Mia; Koschmann, Carl; Baker, Gregory J; Saxena, Vandana; Muhammad, A K M G; Bondale, Niyati; Klein, Julia; Assi, Hikmat; Lieberman, Andrew P; Castro, Maria G; Lowenstein, Pedro R

2014-07-01

In human gliomas, the RTK/RAS/PI(3)K signaling pathway is nearly always altered. We present a model of experimental gliomagenesis that elucidates the contributions of genes involved in this pathway (PDGF-B ligand, HRAS-G12V, and AKT). We also examine the effect on gliomagenesis by the potential modifier gene, IDH1-R132H. Injections of lentiviral-encoded oncogenes induce de novo gliomas of varying penetrance, tumor progression, and histological grade depending on the specific oncogenes used. Our model mimics hallmark histological structures of high-grade glioma, such as pseudopalisades, glomeruloid microvascular proliferation, and diffuse tumor invasion. We use our model of gliomagenesis to test the efficacy of an experimental brain tumor gene therapy. Our model allowed us to test the contributions of oncogenes in the RTK/RAS/PI(3)K pathway, and their potential modification by over-expression of mutated IDH1, in glioma development and progression in rats. Our model constitutes a clinically relevant system to study gliomagenesis, the effects of modifier genes, and the efficacy of experimental therapeutics.

Extent of BOLD Vascular Dysregulation Is Greater in Diffuse Gliomas without Isocitrate Dehydrogenase 1 R132H Mutation.

PubMed

Englander, Zachary K; Horenstein, Craig I; Bowden, Stephen G; Chow, Daniel S; Otten, Marc L; Lignelli, Angela; Bruce, Jeffrey N; Canoll, Peter; Grinband, Jack

2018-06-01

Purpose To determine the effect that R132H mutation status of diffuse glioma has on extent of vascular dysregulation and extent of residual blood oxygen level-dependent (BOLD) abnormality after surgical resection. Materials and Methods This study was an institutional review board-approved retrospective analysis of an institutional database of patients, and informed consent was waived. From 2010 to 2017, 39 treatment-naïve patients with diffuse glioma underwent preoperative echo-planar imaging and BOLD functional magnetic resonance imaging. BOLD vascular dysregulation maps were made by identifying voxels with time series similar to tumor and dissimilar to healthy brain. The spatial overlap between tumor and vascular dysregulation was characterized by using the Dice coefficient, and areas of BOLD abnormality outside the tumor margins were quantified as BOLD-only fraction (BOF). Linear regression was used to assess effects of R132H status on the Dice coefficient, BOF, and residual BOLD abnormality after surgical resection. Results When compared with R132H wild-type (R132H-) gliomas, R132H-mutated (R132H+) gliomas showed greater spatial overlap between BOLD abnormality and tumor (mean Dice coefficient, 0.659 ± 0.02 [standard error] for R132H+ and 0.327 ± 0.04 for R132H-; P < .001), less BOLD abnormality beyond the tumor margin (mean BOF, 0.255 ± 0.03 for R132H+ and 0.728 ± 0.04 for R132H-; P < .001), and less postoperative BOLD abnormality (residual fraction, 0.046 ± 0.0047 for R132H+ and 0.397 ± 0.045 for R132H-; P < .001). Receiver operating characteristic curve analysis showed high sensitivity and specificity in the discrimination of R132H+ tumors from R132H- tumors with calculation of both Dice coefficient and BOF (area under the receiver operating characteristic curve, 0.967 and 0.977, respectively). Conclusion R132H mutation status is an important variable affecting the extent of tumor-associated vascular dysregulation and the residual vascular dysregulation after surgical resection. © RSNA, 2018 Online supplemental material is available for this article.

A case report of adult cerebellar high-grade glioma with H3.1 K27M mutation: a rare example of an H3 K27M mutant cerebellar tumor.

PubMed

Funata, Nobuaki; Nobusawa, Sumihito; Nakata, Satoshi; Yamazaki, Tatsuya; Takabagake, Kazuhiko; Koike, Tsukasa; Maegawa, Tatsuya; Yamada, Ryoji; Shinoura, Nobusada; Mine, Yutaka

2018-01-01

Diffuse midline glioma, H3 K27M mutant, is newly recognized as a distinct category, which usually arises in the brain stem, thalamus or spinal cord of children, and young adults. The oncogenic H3 K27M mutation involves H3.3 (encoded by H3F3A) or H3.1 (encoded by HIST1H3B/HIST1H3C), and the incidence of each mutation differs among the primary sites. Recently, several papers have reported that cerebellar high-grade gliomas in both children and adults also harbor H3 K27 mutation. With the exception of one pediatric case, all of the cases carried the mutation in H3.3. We herein present the case of an adult cerebellar high-grade astrocytic tumor with H3.1 K27M mutation in a 45-year-old man, which also involvedTP53 mutation and was immunonegative for ATRX. Some groups have reported that H3.3 and H3.1 K27M mutations define subgroups of diffuse intrinsic pontine gliomas (DIPGs) with different phenotypes as well as genetic alterations. On comparing the findings of the present case, particularly TP53 mutation status and ATRX expression, to the findings of the previous studies on DIPGs, our case seems unusual among the H3.1 K27M mutant subgroup. Further studies are needed to clarify the exact frequency, clinicopathological characteristics, and genomic alterations of cerebellar gliomas harboring H3 K27M mutation.

Machine-learning in grading of gliomas based on multi-parametric magnetic resonance imaging at 3T.

PubMed

Citak-Er, Fusun; Firat, Zeynep; Kovanlikaya, Ilhami; Ture, Ugur; Ozturk-Isik, Esin

2018-06-15

The objective of this study was to assess the contribution of multi-parametric (mp) magnetic resonance imaging (MRI) quantitative features in the machine learning-based grading of gliomas with a multi-region-of-interests approach. Forty-three patients who were newly diagnosed as having a glioma were included in this study. The patients were scanned prior to any therapy using a standard brain tumor magnetic resonance (MR) imaging protocol that included T1 and T2-weighted, diffusion-weighted, diffusion tensor, MR perfusion and MR spectroscopic imaging. Three different regions-of-interest were drawn for each subject to encompass tumor, immediate tumor periphery, and distant peritumoral edema/normal. The normalized mp-MRI features were used to build machine-learning models for differentiating low-grade gliomas (WHO grades I and II) from high grades (WHO grades III and IV). In order to assess the contribution of regional mp-MRI quantitative features to the classification models, a support vector machine-based recursive feature elimination method was applied prior to classification. A machine-learning model based on support vector machine algorithm with linear kernel achieved an accuracy of 93.0%, a specificity of 86.7%, and a sensitivity of 96.4% for the grading of gliomas using ten-fold cross validation based on the proposed subset of the mp-MRI features. In this study, machine-learning based on multiregional and multi-parametric MRI data has proven to be an important tool in grading glial tumors accurately even in this limited patient population. Future studies are needed to investigate the use of machine learning algorithms for brain tumor classification in a larger patient cohort. Copyright © 2018. Published by Elsevier Ltd.

Right-sided dominance of the bilateral vestibular system in the upper brainstem and thalamus.

PubMed

Dieterich, Marianne; Kirsch, V; Brandt, T

2017-10-01

MRI diffusion tensor imaging tractography was performed on the bilateral vestibular brainstem pathways, which run from the vestibular nuclei via the paramedian and posterolateral thalamic subnuclei to the parieto-insular vestibular cortex. Twenty-one right-handed healthy subjects participated. Quantitative analysis revealed a rope-ladder-like system of vestibular pathways in the brainstem with crossings at pontine and mesencephalic levels. Three structural types of right-left fiber distributions could be delineated: (1) evenly distributed pathways at the lower pontine level from the vestibular nuclei to the pontine crossing, (2) a moderate, pontomesencephalic right-sided lateralization between the pontine and mesencephalic crossings, and (3) a further increase of the right-sided lateralization above the mesencephalic crossing leading to the thalamic vestibular subnuclei. The increasing lateralization along the brainstem was the result of an asymmetric number of pontine and mesencephalic crossing fibers which was higher for left-to-right crossings. The dominance of the right vestibular meso-diencephalic circuitry in right-handers corresponds to the right-hemispheric dominance of the vestibular cortical network. The structural asymmetry apparent in the upper brainstem might be interpreted in relation to the different functions of the vestibular system depending on their anatomical level: a symmetrical sensorimotor reflex control of eye, head, and body mediated by the lower brainstem; a lateralized right-sided upper brainstem-thalamic function as part of the dominant right-sided cortical/subcortical vestibular system that enables a global percept of body motion and orientation in space.

Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation.

PubMed

Badie, Behnam; Schartner, Jill M; Hagar, Aaron R; Prabakaran, Sakthivel; Peebles, Todd R; Bartley, Becky; Lapsiwala, Samir; Resnick, Daniel K; Vorpahl, Jessica

2003-02-01

Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. To examine the role of inflammatory cells in brain edema formation, we studied the expression cyclooxygenase (COX)-2, a key enzyme in arachidonic acid metabolism, by microglia in the C6 rodent glioma model. The expression of COX-2 in primary microglia cultures obtained from intracranial rat C6 gliomas was examined using reverse transcription-PCR, Western analysis, and prostaglandin E(2) (PGE(2)) enzyme immunoassay. Blood-tumor barrier permeability was studied in the same tumor model using magnetic resonance imaging. In contrast to C6 glioma cells, microglia isolated from intracranial C6 tumors produced high levels of PGE(2) through a COX-2-dependent pathway. To test whether the observed microglia COX-2 activity played a role in brain edema formation in gliomas, tumor-bearing rats were treated with rofecoxib, a selective COX-2 inhibitor. Rofecoxib was as effective as dexamethasone in decreasing the diffusion of contrast material into the brain parenchyma (P = 0.01, rofecoxib versus control animals), suggesting a reduction in blood-tumor barrier permeability. These findings suggest that glioma-infiltrating microglia are a major source of PGE(2) production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors.

Remote intracranial recurrence of IDH mutant gliomas is associated with TP53 mutations and an 8q gain

PubMed Central

Nakae, Shunsuke; Kato, Takema; Murayama, Kazuhiro; Sasaki, Hikaru; Abe, Masato; Kumon, Masanobu; Kumai, Tadashi; Yamashiro, Kei; Inamasu, Joji; Hasegawa, Mitsuhiro; Kurahashi, Hiroki; Hirose, Yuichi

2017-01-01

Most IDH mutant gliomas harbor either 1p/19q co-deletions or TP53 mutation; 1p/19q co-deleted tumors have significantly better prognoses than tumors harboring TP53 mutations. To investigate the clinical factors that contribute to differences in tumor progression of IDH mutant gliomas, we classified recurrent tumor patterns based on MRI and correlated these patterns with their genomic characterization. Accordingly, in IDH mutant gliomas (N = 66), 1p/19 co-deleted gliomas only recurred locally, whereas TP53 mutant gliomas recurred both locally and in remote intracranial regions. In addition, diffuse tensor imaging suggested that remote intracranial recurrence in the astrocytomas, IDH-mutant with TP53 mutations may occur along major fiber bundles. Remotely recurrent tumors resulted in a higher mortality and significantly harbored an 8q gain; astrocytomas with an 8q gain resulted in significantly shorter overall survival than those without an 8q gain. OncoScan® arrays and next-generation sequencing revealed specific 8q regions (i.e., between 8q22 and 8q24) show a high copy number. In conclusion, only tumors with TP53 mutations showed patterns of remote recurrence in IDH mutant gliomas. Furthermore, an 8q gain was significantly associated with remote intracranial recurrence and can be considered a poor prognostic factor in astrocytomas, IDH-mutant. PMID:29156679

Three-Dimensional Printed Modeling of Diffuse Low-Grade Gliomas and Associated White Matter Tract Anatomy.

PubMed

Thawani, Jayesh P; Singh, Nickpreet; Pisapia, Jared M; Abdullah, Kalil G; Parker, Drew; Pukenas, Bryan A; Zager, Eric L; Verma, Ragini; Brem, Steven

2017-04-01

Diffuse low-grade gliomas (DLGGs) represent several pathological entities that infiltrate and invade cortical and subcortical structures in the brain. To describe methods for rapid prototyping of DLGGs and surgically relevant anatomy. Using high-definition imaging data and rapid prototyping technologies, we were able to generate 3 patient DLGGs to scale and represent the associated white matter tracts in 3 dimensions using advanced diffusion tensor imaging techniques. This report represents a novel application of 3-dimensional (3-D) printing in neurosurgery and a means to model individualized tumors in 3-D space with respect to subcortical white matter tract anatomy. Faculty and resident evaluations of this technology were favorable at our institution. Developing an understanding of the anatomic relationships existing within individuals is fundamental to successful neurosurgical therapy. Imaging-based rapid prototyping may improve on our ability to plan for and treat complex neuro-oncologic pathology. Copyright © 2017 by the Congress of Neurological Surgeons

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

NASA Astrophysics Data System (ADS)

Ewell, Lars

2006-03-01

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

Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors

ClinicalTrials.gov

2017-07-14

Diffuse Intrinsic Pontine Glioma; Brain Tumor, Recurrent; Solid Tumor, Recurrent; Neuroblastoma, Recurrent, Refractory; Ewing Sarcoma, Recurrent, Refractory; Rhabdomyosarcoma, Recurrent, Refractory; Osteosarcoma, Recurrent, Refractory; Rhabdoid Tumor, Recurrent, Refractory

Paediatric brain tumours: A review of radiotherapy, state of the art and challenges for the future regarding protontherapy and carbontherapy.

PubMed

Laprie, A; Hu, Y; Alapetite, C; Carrie, C; Habrand, J-L; Bolle, S; Bondiau, P-Y; Ducassou, A; Huchet, A; Bertozzi, A-I; Perel, Y; Moyal, É; Balosso, J

2015-12-01

Brain tumours are the most frequent solid tumours in children and the most frequent radiotherapy indications in paediatrics, with frequent late effects: cognitive, osseous, visual, auditory and hormonal. A better protection of healthy tissues by improved beam ballistics, with particle therapy, is expected to decrease significantly late effects without decreasing local control and survival. This article reviews the scientific literature to advocate indications of protontherapy and carbon ion therapy for childhood central nervous system cancer, and estimate the expected therapeutic benefits. A systematic review was performed on paediatric brain tumour treatments using Medline (from 1966 to March of 2014). To be included, clinical trials had to meet the following criteria: age of patients 18 years or younger, treated with radiation, and report of survival. Studies were also selected according to the evidence level. A secondary search of cited references found other studies about cognitive functions, quality of life, the comparison of photon and proton dosimetry showing potential dose escalation and/or sparing of organs at risk with protontherapy; and studies on dosimetric and technical issues related to protontherapy. A total of 7051 primary references published were retrieved, among which 40 clinical studies and 60 papers about quality of life, dose distribution and dosimetry were analysed, as well as the ongoing clinical trials. These papers have been summarized and reported in a specific document made available to the participants of a final 1-day workshop. Tumours of the meningeal envelop and bony cranial structures were excluded from the analysis. Protontherapy allows outstanding ballistics to target the tumour area, while substantially decreasing radiation dose to the normal tissues. There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas. Carbon ion therapy is just emerging and may be studied for highly aggressive and radioresistant tumours, as an initial treatment for diffuse brainstem gliomas, and for relapse of high-grade gliomas. Both protontherapy and carbon ion therapy are promising for paediatric brain tumours. The benefit of decreasing late effects without altering survival has been described for most paediatric brain tumours with protontherapy and is currently assessed in ongoing clinical trials with up-to-date proton devices. Unfortunately, in 2015, only a minority of paediatric patients in France can receive protontherapy due to the lack of equipment. Copyright © 2015. Published by Elsevier SAS.

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

PubMed

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

2016-11-23

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

SJDAWN: St. Jude Children's Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors

ClinicalTrials.gov

2018-04-09

Anaplastic Astrocytoma; Anaplastic Ependymoma; Anaplastic Ganglioglioma; Anaplastic Meningioma; Anaplastic Oligodendroglioma; Pleomorphic Xanthoastrocytoma, Anaplastic; Atypical Teratoid/Rhabdoid Tumor; Brain Cancer; Brain Tumor; Central Nervous System Neoplasms; Choroid Plexus Carcinoma; CNS Embryonal Tumor With Rhabdoid Features; Ganglioneuroblastoma of Central Nervous System; CNS Tumor; Embryonal Tumor of CNS; Ependymoma; Glioblastoma; Glioma; Glioma, Malignant; Medulloblastoma; Medulloblastoma; Unspecified Site; Medulloepithelioma; Neuroepithelial Tumor; Neoplasms; Neoplasms, Neuroepithelial; Papillary Tumor of the Pineal Region (High-grade Only); Pediatric Brain Tumor; Pineal Parenchymal Tumor of Intermediate Differentiation (High-grade Only); Pineoblastoma; Primitive Neuroectodermal Tumor; Recurrent Medulloblastoma; Refractory Brain Tumor; Neuroblastoma. CNS; Glioblastoma, IDH-mutant; Glioblastoma, IDH-wildtype; Medulloblastoma, Group 3; Medulloblastoma, Group 4; Glioma, High Grade; Neuroepithelial Tumor, High Grade; Medulloblastoma, SHH-activated and TP53 Mutant; Medulloblastoma, SHH-activated and TP53 Wildtype; Medulloblastoma, Chromosome 9q Loss; Medulloblastoma, Non-WNT Non-SHH, NOS; Medulloblastoma, Non-WNT/Non-SHH; Medulloblastoma, PTCH1 Mutation; Medulloblastoma, WNT-activated; Ependymoma, Recurrent; Glioma, Recurrent High Grade; Glioma, Recurrent Malignant; Embryonal Tumor, NOS; Glioma, Diffuse Midline, H3K27M-mutant; Embryonal Tumor With Multilayered Rosettes (ETMR); Ependymoma, NOS, WHO Grade III; Ependymoma, NOS, WHO Grade II; Medulloblastoma, G3/G4; Ependymoma, RELA Fusion Positive

Glioma Indian scenario: Is there a human leucocyte antigen association?

PubMed

Shankarkumar, U; Sridharan, B

2011-07-01

The central nervous system tumors are a rare neoplasm with little knowledge with Human Leukocyte Antigen (HLA) involvement. Primary brain tumors are cancers that originate in brain classified according to their appearance under a microscope as low grade (grade I and II) with diffuse astrocytomas, pliocytic astrocytomas, oligodendrogliomas, gangliogliomas, and mixed gliomas as common subtypes and high grade (grade III and IV). HLA associations in common glioma are reported from other parts of the world. The normal cancer treatment is surgery, followed by radiotherapy, and chemotherapy; nowadays immunotherapy is advised. HLA distribution in a Glioma patient was done based on serology and molecular techniques. The immune response gene studies have implicated the HLA allele association in most of the common diseases from India. Considerable variations are noted in HLA association with cancers; hence, we have summarized the HLA involvement in Glioma with respect to the literature. HLA A*030101, A*310102, B*350101, B*4406, Cw*040101, Cw*070101, DRB1*070101, and DRB1*1001. Ethnic diversity and HLA polymorphism precipitate differential immune response genes involved in variable disease manifestations. Therefore, caste-specific HLA allelic specificity needs to be identified, which may help in early identification of the associated HLA allele and establishing clinical practices among glioma patients.

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

NASA Astrophysics Data System (ADS)

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

2016-11-01

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

Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets

PubMed Central

Miranda-Gonçalves, Vera; Honavar, Mrinalini; Pinheiro, Céline; Martinho, Olga; Pires, Manuel M.; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Palmeirim, Isabel; Reis, Rui M.; Baltazar, Fátima

2013-01-01

Background Gliomas exhibit high glycolytic rates, and monocarboxylate transporters (MCTs) play a major role in the maintenance of the glycolytic metabolism through the proton-linked transmembrane transport of lactate. However, their role in gliomas is poorly studied. Thus, we aimed to characterize the expression of MCT1, MCT4, and their chaperone CD147 and to assess the therapeutic impact of MCT inhibition in gliomas. Methods MCTs and CD147 expressions were characterized by immunohistochemistry in nonneoplastic brain and glioma samples. The effect of CHC (MCT inhibitor) and MCT1 silencing was assessed in in vitro and in vivo glioblastoma models. Results MCT1, MCT4, and CD147 were overexpressed in the plasma membrane of glioblastomas, compared with diffuse astrocytomas and nonneoplastic brain. CHC decreased glycolytic metabolism, migration, and invasion and induced cell death in U251 cells (more glycolytic) but only affected proliferation in SW1088 (more oxidative). The effectiveness of CHC in glioma cells appears to be dependent on MCT membrane expression. MCT1 downregulation showed similar effects on different glioma cells, supporting CHC as an MCT1 inhibitor. There was a synergistic effect when combining CHC with temozolomide treatment in U251 cells. In the CAM in vivo model, CHC decreased the size of tumors and the number of blood vessels formed. Conclusions This is the most comprehensive study reporting the expression of MCTs and CD147 in gliomas. The MCT1 inhibitor CHC exhibited anti-tumoral and anti-angiogenic activity in gliomas and, of importance, enhanced the effect of temozolomide. Thus, our results suggest that development of therapeutic approaches targeting MCT1 may be a promising strategy in glioblastoma treatment. PMID:23258846

Grading of Gliomas by Using Radiomic Features on Multiple Magnetic Resonance Imaging (MRI) Sequences.

PubMed

Qin, Jiang-Bo; Liu, Zhenyu; Zhang, Hui; Shen, Chen; Wang, Xiao-Chun; Tan, Yan; Wang, Shuo; Wu, Xiao-Feng; Tian, Jie

2017-05-07

BACKGROUND Gliomas are the most common primary brain neoplasms. Misdiagnosis occurs in glioma grading due to an overlap in conventional MRI manifestations. The aim of the present study was to evaluate the power of radiomic features based on multiple MRI sequences - T2-Weighted-Imaging-FLAIR (FLAIR), T1-Weighted-Imaging-Contrast-Enhanced (T1-CE), and Apparent Diffusion Coefficient (ADC) map - in glioma grading, and to improve the power of glioma grading by combining features. MATERIAL AND METHODS Sixty-six patients with histopathologically proven gliomas underwent T2-FLAIR and T1WI-CE sequence scanning with some patients (n=63) also undergoing DWI scanning. A total of 114 radiomic features were derived with radiomic methods by using in-house software. All radiomic features were compared between high-grade gliomas (HGGs) and low-grade gliomas (LGGs). Features with significant statistical differences were selected for receiver operating characteristic (ROC) curve analysis. The relationships between significantly different radiomic features and glial fibrillary acidic protein (GFAP) expression were evaluated. RESULTS A total of 8 radiomic features from 3 MRI sequences displayed significant differences between LGGs and HGGs. FLAIR GLCM Cluster Shade, T1-CE GLCM Entropy, and ADC GLCM Homogeneity were the best features to use in differentiating LGGs and HGGs in each MRI sequence. The combined feature was best able to differentiate LGGs and HGGs, which improved the accuracy of glioma grading compared to the above features in each MRI sequence. A significant correlation was found between GFAP and T1-CE GLCM Entropy, as well as between GFAP and ADC GLCM Homogeneity. CONCLUSIONS The combined radiomic feature had the highest efficacy in distinguishing LGGs from HGGs.

Prospective longitudinal MRI study of brain volumes and diffusion changes during the first year after moderate to severe traumatic brain injury

PubMed Central

Brezova, Veronika; G⊘ran Moen, Kent; Skandsen, Toril; Vik, Anne; Brewer, James B.; Salvesen, Øyvind; Håberg, Asta K.

2014-01-01

The objectives of this prospective study in 62 moderate–severe TBI patients were to investigate volume change in cortical gray matter (GM), hippocampus, lenticular nucleus, lobar white matter (WM), brainstem and ventricles using a within subject design and repeated MRI in the early phase (1–26 days) and 3 and 12 months postinjury and to assess changes in GM apparent diffusion coefficient (ADC) in normal appearing tissue in the cortex, hippocampus and brainstem. The impact of Glasgow Coma Scale (GCS) score at admission, duration of post-traumatic amnesia (PTA), and diffusion axonal injury (DAI) grade on brain volumes and ADC values over time was assessed. Lastly, we determined if MRI-derived brain volumes from the 3-month scans provided additional, significant predictive value to 12-month outcome classified with the Glasgow Outcome Scale—Extended after adjusting for GCS, PTA and age. Cortical GM loss was rapid, largely finished by 3 months, but the volume reduction was unrelated to GCS score, PTA, or presence of DAI. However, cortical GM volume at 3 months was a significant independent predictor of 12-month outcome. Volume loss in the hippocampus and lenticular nucleus was protracted and statistically significant first at 12 months. Slopes of volume reduction over time for the cortical and subcortical GGM were significantly different. Hippocampal volume loss was most pronounced and rapid in individuals with PTA > 2 weeks. The 3-month volumes of the hippocampus and lentiform nucleus were the best independent predictors of 12-month outcome after adjusting for GCS, PTA and age. In the brainstem, volume loss was significant at both 3 and 12 months. Brainstem volume reduction was associated with lower GCS score and the presence of DAI. Lobar WM volume was significantly decreased first after 12 months. Surprisingly DAI grade had no impact on lobar WM volume. Ventricular dilation developed predominantly during the first 3 months, and was strongly associated with volume changes in the brainstem and cortical GM, but not lobar WM volume. Higher ADC values were detected in the cortex in individuals with severe TBI, DAI and PTA > 2 weeks, from 3 months. There were no associations between ADC values and brain volumes, and ADC values did not predict outcome. PMID:25068105

Inter- and intrapatient variability of facial nerve response areas in the floor of the fourth ventricle.

PubMed

Bertalanffy, Helmut; Tissira, Nadir; Krayenbühl, Niklaus; Bozinov, Oliver; Sarnthein, Johannes

2011-03-01

Surgical exposure of intrinsic brainstem lesions through the floor of the 4th ventricle requires precise identification of facial nerve (CN VII) fibers to avoid damage. To assess the shape, size, and variability of the area where the facial nerve can be stimulated electrophysiologically on the surface of the rhomboid fossa. Over a period of 18 months, 20 patients were operated on for various brainstem and/or cerebellar lesions. Facial nerve fibers were stimulated to yield compound muscle action potentials (CMAP) in the target muscles. Using the sites of CMAP yield, a detailed functional map of the rhomboid fossa was constructed for each patient. Lesions resected included 14 gliomas, 5 cavernomas, and 1 epidermoid cyst. Of 40 response areas mapped, 19 reached the median sulcus. The distance from the obex to the caudal border of the response area ranged from 8 to 27 mm (median, 17 mm). The rostrocaudal length of the response area ranged from 2 to 15 mm (median, 5 mm). Facial nerve response areas showed large variability in size and position, even in patients with significant distance between the facial colliculus and underlying pathological lesion. Lesions located close to the facial colliculus markedly distorted the response area. This is the first documentation of variability in the CN VII response area in the rhomboid fossa. Knowledge of this remarkable variability may facilitate the assessment of safe entry zones to the brainstem and may contribute to improved outcome following neurosurgical interventions within this sensitive area of the brain.

Quantitative characterization of the imaging limits of diffuse low-grade oligodendrogliomas.

PubMed

Gerin, Chloé; Pallud, Johan; Deroulers, Christophe; Varlet, Pascale; Oppenheim, Catherine; Roux, Francois-Xavier; Chrétien, Fabrice; Thomas, Stephen R; Grammaticos, Basile; Badoual, Mathilde

2013-10-01

Supratentorial diffuse low-grade gliomas in adults extend beyond maximal visible MRI-defined abnormalities, and a gap exists between the imaging signal changes and the actual tumor margins. Direct quantitative comparisons between imaging and histological analyses are lacking to date. However, they are of the utmost importance if one wishes to develop realistic models for diffuse glioma growth. In this study, we quantitatively compared the cell concentration and the edema fraction from human histological biopsy samples (BSs) performed inside and outside imaging abnormalities during serial imaging-based stereotactic biopsy of diffuse low-grade gliomas. The cell concentration was significantly higher in BSs located inside (1189 ± 378 cell/mm(2)) than outside (740 ± 124 cell/mm(2)) MRI-defined abnormalities (P = .0003). The edema fraction was significantly higher in BSs located inside (mean, 45% ± 23%) than outside (mean, 5 %± 9%) MRI-defined abnormalities (P < .0001). At borders of the MRI-defined abnormalities, 20% of the tissue surface area was occupied by edema and only 3% by tumor cells. The cycling cell concentration was significantly higher in BSs located inside (10 ± 12 cell/mm(2)), compared with outside (0.5 ± 0.9 cell/mm(2)), MRI-defined abnormalities (P = .0001). We showed that the margins of T2-weighted signal changes are mainly correlated with the edema fraction. In 62.5% of patients, the cycling tumor cell fraction (defined as the ratio of the cycling tumor cell concentration to the total number of tumor cells) was higher at the limits of the MRI-defined abnormalities than closer to the center of the tumor. In the remaining patients, the cycling tumor cell fraction increased towards the center of the tumor.

Passive antibody-mediated immunotherapy for the treatment of malignant gliomas.

PubMed

Mitra, Siddhartha; Li, Gordon; Harsh, Griffith R

2010-01-01

Despite advances in understanding the molecular mechanisms of brain cancer, the outcome of patients with malignant gliomas treated according to the current standard of care remains poor. Novel therapies are needed, and immunotherapy has emerged with great promise. The diffuse infiltration of malignant gliomas is a major challenge to effective treatment; immunotherapy has the advantage of accessing the entire brain with specificity for tumor cells. Therapeutic immune approaches include cytokine therapy, passive immunotherapy, and active immunotherapy. Cytokine therapy involves the administration of immunomodulatory cytokines to activate the immune system. Active immunotherapy is the generation or augmentation of an immune response, typically by vaccination against tumor antigens. Passive immunotherapy connotes either adoptive therapy, in which tumor-specific immune cells are expanded ex vivo and reintroduced into the patient, or passive antibody-mediated therapy. In this article, the authors discuss the preclinical and clinical studies that have used passive antibody-mediated immunotherapy, otherwise known as serotherapy, for the treatment of malignant gliomas.

Diffusion tensor imaging of the inferior colliculus and brainstem auditory-evoked potentials in preterm infants.

PubMed

Reiman, Milla; Parkkola, Riitta; Johansson, Reijo; Jääskeläinen, Satu K; Kujari, Harry; Lehtonen, Liisa; Haataja, Leena; Lapinleimu, Helena

2009-08-01

Preterm and low-birth-weight infants have an increased risk of sensorineural hearing loss. Brainstem auditory-evoked potentials (BAEP) are an effective method to detect subtle deficits in impulse conduction in the auditory pathway. Abnormalities on diffusion tensor imaging (DTI) have been shown to be associated with perinatal white-matter injury and reduced fractional anisotropy (FA) has been reported in patients with sensorineural hearing loss. To evaluate the possibility of a correlation between BAEP and DTI of the inferior colliculus in preterm infants. DTI at term age and BAEP measurements were performed on all very-low-birth-weight or very preterm study infants (n=56). FA and apparent diffusion coefficient (ADC) of the inferior colliculus were measured from the DTI. Shorter BAEP wave I, III, and V latencies and I-III and I-V intervals and higher wave V amplitude correlated with higher FA of the inferior colliculus. The association between the DTI findings of the inferior colliculus and BAEP responses suggests that DTI can be used to assess the integrity of the auditory pathway in preterm infants.

A clinical perspective on the 2016 WHO brain tumor classification and routine molecular diagnostics.

PubMed

van den Bent, Martin J; Weller, Michael; Wen, Patrick Y; Kros, Johan M; Aldape, Ken; Chang, Susan

2017-05-01

The 2007 World Health Organization (WHO) classification of brain tumors did not use molecular abnormalities as diagnostic criteria. Studies have shown that genotyping allows a better prognostic classification of diffuse glioma with improved treatment selection. This has resulted in a major revision of the WHO classification, which is now for adult diffuse glioma centered around isocitrate dehydrogenase (IDH) and 1p/19q diagnostics. This revised classification is reviewed with a focus on adult brain tumors, and includes a recommendation of genes of which routine testing is clinically useful. Apart from assessment of IDH mutational status including sequencing of R132H-immunohistochemistry negative cases and testing for 1p/19q, several other markers can be considered for routine testing, including assessment of copy number alterations of chromosome 7 and 10 and of TERT promoter, BRAF, and H3F3A mutations. For "glioblastoma, IDH mutated" the term "astrocytoma grade IV" could be considered. It should be considered to treat IDH wild-type grades II and III diffuse glioma with polysomy of chromosome 7 and loss of 10q as glioblastoma. New developments must be more quickly translated into further revised diagnostic categories. Quality control and rapid integration of molecular findings into the final diagnosis and the communication of the final diagnosis to clinicians require systematic attention. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma.

PubMed

Lober, Robert M; Cho, Yoon-Jae; Tang, Yujie; Barnes, Patrick D; Edwards, Michael S; Vogel, Hannes; Fisher, Paul G; Monje, Michelle; Yeom, Kristen W

2014-03-01

While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-naïve DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295 × 10(-6) mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13 months, respectively (log-rank p < 0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG.

EG-07CELL CYCLE SIGNATURE AND TUMOR PHYLOGENY ARE ENCODED IN THE EVOLUTIONARY DYNAMICS OF DNA METHYLATION IN GLIOMA

PubMed Central

Mazor, Tali; Pankov, Aleksandr; Johnson, Brett E.; Hong, Chibo; Bell, Robert J.A.; Smirnov, Ivan V.; Reis, Gerald F.; Phillips, Joanna J.; Barnes, Michael; Bollen, Andrew W.; Taylor, Barry S.; Molinaro, Annette M.; Olshen, Adam B.; Song, Jun S.; Berger, Mitchel S.; Chang, Susan M.; Costello, Joseph F.

2014-01-01

The clonal evolution of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast, tumor epigenetic states, including DNA methylation, are reversible and sensitive to the tumor microenvironment, presumably precluding the use of epigenetics to discover tumor phylogeny. Here we examined the spatial and temporal dynamics of DNA methylation in a clinically and genetically characterized cohort of IDH1-mutant low-grade gliomas and their patient-matched recurrences. WHO grade II gliomas are diffuse, infiltrative tumors that frequently recur and may undergo malignant progression to a higher grade with a worse prognosis. The extent to which epigenetic alterations contribute to the evolution of low-grade gliomas, including malignant progression, is unknown. While all gliomas in the cohort exhibited the hypermethylation signature associated with IDH1 mutation, low-grade gliomas that underwent malignant progression to high-grade glioblastoma (GBM) had a unique signature of DNA hypomethylation enriched for active enhancers, as well as sites of age-related hypermethylation in the brain. Genes with promoter hypomethylation and concordant transcriptional upregulation during evolution to GBM were enriched in cell cycle function, evolving in concert with genetic alterations that deregulate the G1/S cell cycle checkpoint. Despite the plasticity of tumor epigenetic states, phyloepigenetic trees robustly recapitulated phylogenetic trees derived from somatic mutations in the same patients. These findings highlight widespread co-dependency of genetic and epigenetic events throughout the clonal evolution of initial and recurrent glioma.

Glioma-secreted soluble factors stimulate microglial activation: The role of interleukin-1β and tumor necrosis factor-α.

PubMed

Hwang, Ji-Sun; Jung, Eun-Hye; Kwon, Mi-Youn; Han, Inn-Oc

2016-09-15

We aimed to elucidate the effect of soluble factors secreted by glioma on microglial activation. Conditioned medium (CM) from glioma cells, CRT-MG and C6, significantly induced nitric oxide (NO) production and stimulated the mRNA expression of inducible NO synthase (iNOS), interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-α) and cyclooxygenase 2 (COX-2) in BV2 cells. Glioma CM stimulated p38 mitogen-activated protein kinase (MAPK) phosphorylation, and a p38 MAPK inhibitor, SB203580, suppressed CM-induced NO production in BV2 cells. In addition, CM stimulated nuclear factor-kappaB (NF-κB) DNA binding and transcriptional activity, which was repressed by SB203580. Gliomas displayed higher mRNA expression and release of TNF-α and IL-1β than primary astrocyte cells. Neutralization of TNF-α and IL-1β in C6-CM using a neutralizing antibody inhibited NO/iNOS expression in BV-2 cells. These results indicate potential contribution of diffusible tumor-derived factors to regulate microglial activation and subsequent tumor microenvironment. Copyright © 2016. Published by Elsevier B.V.

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence.

PubMed

de Souza, Camila Ferreira; Sabedot, Thais S; Malta, Tathiane M; Stetson, Lindsay; Morozova, Olena; Sokolov, Artem; Laird, Peter W; Wiznerowicz, Maciej; Iavarone, Antonio; Snyder, James; deCarvalho, Ana; Sanborn, Zachary; McDonald, Kerrie L; Friedman, William A; Tirapelli, Daniela; Poisson, Laila; Mikkelsen, Tom; Carlotti, Carlos G; Kalkanis, Steven; Zenklusen, Jean; Salama, Sofie R; Barnholtz-Sloan, Jill S; Noushmehr, Houtan

2018-04-10

Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Contralateral Anterior Interhemispheric Transparaterminal Gyrus Approach for Thalamopeduncular Pilocytic Astrocytoma in an Adult: Technical Report.

PubMed

Kumar, Amandeep; Sharma, Raghavendra; Garg, Ajay; Sharma, Bhawani S

2016-03-01

Thalamopeduncular gliomas arise at the junction of the thalamus and cerebral peduncle and constitute a subgroup of thalamic gliomas. These are surgically challenging lesions because of close proximity to important neural structures including corticospinal tracts (CSTs) and the thalamus. These tumors usually displace CSTs anterolaterally or extend to the lateral ventricular surface. Such tumors can be removed by either temporal or transventricular approaches. However, if CSTs cover the entire lateral surface of tumor and tumor does not extend to the ventricular surface, temporal and transventricular approaches cannot be used because the trajectories of both approaches would pass through normal eloquent structures (CSTs and thalamus), and consequently there would be a very high risk of postoperative neurologic deficits developing. A 50-year-old woman presented with contralateral hemiparesis. Radiologic evaluation revealed a right Thalamopeduncular glioma that displaced CSTs laterally and was covered by normal thalamus superiorly. Some CST fibers passed through the tumor. Because both lateral and superior surfaces were covered by eloquent structures, we used an anterior interhemispheric transparaterminal gyrus approach to access the tumor successfully and achieved subtotal excision. The patient had transient neurologic deterioration postoperatively that recovered to preoperative level within 2 weeks. The anterior interhemispheric transparaterminal gyrus approach has not been described previously for accessing brainstem lesions. This approach can be used to access tumors of the cerebral peduncle that displace CSTs laterally and are covered by normal thalamus superiorly. The anterior interhemispheric transparaterminal gyrus approach adds to the armamentarium of neurosurgeons for treatment of cerebral peduncular lesions. Copyright © 2016 Elsevier Inc. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2005-11-01

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

Tectal gliomas: assessment of malignant progression, clinical management, and quality of life in a supposedly benign neoplasm.

PubMed

Mohme, Malte; Fritzsche, Friederike S; Mende, Klaus C; Matschke, Jakob; Löbel, Ulrike; Kammler, Gertrud; Westphal, Manfred; Emami, Pedram; Martens, Tobias

2018-06-01

OBJECTIVE Tectal gliomas constitute a rare and inhomogeneous group of lesions with an uncertain clinical course. Because these supposedly benign tumors are frequently followed up by observation over many years, the authors undertook this analysis of their own case series in an effort to demonstrate that the clinical course is highly variable and that there is a potential for a progressive biology. METHODS Clinical data analysis of 23 cases of tectal glioma (involving 9 children and 14 adults) was performed retrospectively. Radiographic data were analyzed longitudinally and MR images were evaluated for tumor volume, contrast enhancement, and growth progression. Quality of life was assessed using the EORTC BN20 and C30 questionnaires during follow-up in a subgroup of patients. RESULTS The patients' mean age at diagnosis was 29.2 years. The main presenting symptom at diagnosis was hydrocephalus (80%). Six patients were treated by primary tumor resection (26.1%), 3 patients underwent biopsy followed by resection (13.1%), and 3 patients underwent biopsy only (13.1%). For additional treatment of hydrocephalus, 14 patients (60.9%) received shunts and/or endoscopic third ventriculostomy. Radiographic tumor progression was observed in 47.9% of the 23 cases. The mean time between diagnosis and growth progression was 51.5 months, and the mean time to contrast enhancement was 69.7 months. Histopathological analysis was obtained in 12 cases (52.2%), resulting in 5 cases of high-grade glioma (3 cases of glioblastoma multiforme [GBM], grade IV, and 2 of anaplastic astrocytoma, grade III), 5 cases of pilocytic astrocytoma, 1 diffuse astrocytoma, and 1 ganglioglioma. Malignant progression was observed in 2 cases, with 1 case progressing from a diffuse astrocytoma (grade II) to a GBM (grade IV) within a period of 13 years. Quality-of-life measurements demonstrated distinct functional deficits compared to a healthy sample as well as glioma control cohorts. CONCLUSIONS Analysis of this case series shows that a major subpopulation of tectal gliomas show progression and malignant transformation in children as well as in adolescents. These tumors therefore cannot be considered inert lesions and require histological confirmation and close follow-up. Quality-of-life questionnaires show that tectal glioma patients might benefit from special psychological support in emotional, social, and cognitive functionality.

Relation between cognition and neural connection from injured cingulum to brainstem cholinergic nuclei in chronic patients with traumatic brain injury.

PubMed

Yoo, Jin-Sun; Kim, Oh Lyong; Kim, Seong Ho; Kim, Min Su; Jang, Sung Ho

2014-01-01

This study investigated the relation between cognition and the neural connection from injured cingulum to brainstem cholinergic nuclei in patients with traumatic brain injury (TBI), using diffusion tensor tractography (DTT). Among 353 patients with TBI, 20 chronic patients who showed discontinuation of both anterior cingulums from the basal forebrain on DTT were recruited for this study. The Wechsler Intelligence Scale and the Memory Assessment Scale (MAS; short-term, verbal, visual and total memory) were used for assessment of cognition. Patients were divided into two groups according to the presence of a neural connection between injured cingulum and brainstem cholinergic nuclei. Eight patients who had a neural connection between injured cingulum and brainstem cholinergic nuclei showed better short-term memory on MAS than 12 patients who did not (p < 0.05). However, other results of neuropsychological testing showed no significant difference (p > 0.05). Better short-term memory in patients who had the neural connection between injured cingulum and brainstem cholinergic nuclei appears to have been attributed to the presence of cholinergic innervation to the cerebral cortex through the neural connection instead of the injured anterior cingulum. The neural connection appears to compensate for the injured anterior cingulum in obtaining cholinergic innervation.

Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas.

PubMed

Siegal, Tali

2016-01-01

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

Tumor-related neurocognitive dysfunction in patients with diffuse glioma: a systematic review of neurocognitive functioning prior to anti-tumor treatment.

PubMed

van Kessel, Emma; Baumfalk, Anniek E; van Zandvoort, Martine J E; Robe, Pierre A; Snijders, Tom J

2017-08-01

Deficits in neurocognitive functioning (NCF) frequently occur in glioma patients. Both treatment and the tumor itself contribute to these deficits. Data about the role of the tumor are scarce, because NCF has mostly been studied postoperatively. We aimed to summarize data on pre-treatment NCF in glioma patients and to determine the overall and domain-specific prevalence of neurocognitive dysfunction. We searched PubMed and Embase according to PRISMA-P protocol for studies that evaluated pre-treatment NCF in glioma patients (1995-November 2016) and extracted information about NCF. We performed analysis of data for two main outcome measures; mean cognitive functioning of the study sample (at group level) and the percentage of impaired patients (at individual level). We included 23 studies. Most studies were small observational prospective cohort studies. In 11 (47.5%) studies, patient selection was based on tumor location. NCF was analyzed at the group level in 14 studies, of which 13 (92.9%) found decreased NCF at group level, compared to normative data or matched controls. The proportion of individuals with decreased NCF was reported in 15 studies. NCF was impaired (in any domain) in 62.6% of the individuals (median; interquartile range 31.0-79.0). Cognitive impairments were more common in patients with high-grade glioma than with low-grade glioma (OR 2.50; 95% CI 1.71-3.66). Cognitive impairment occurs in the majority of treatment-naive glioma patients, suggesting that neurocognitive dysfunction is related to the tumor. However, the literature about pre-treatment NCF in glioma patients is characterized by small-scale studies and strong heterogeneity in patient selection, resulting in high risk of bias.

A pro-invasive role for the Ca2+-activated K+ channel KCa3.1 in malignant glioma

PubMed Central

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

2014-01-01

Glioblastoma multiforme (GBM) are highly motile primary brain tumors. Diffuse tissue invasion hampers surgical resection leading to poor patient prognosis. Recent studies suggest that intracellular Ca2+ acts as a master regulator for cell motility and engages a number of downstream signals including Ca2+-activated ion channels. Querying the REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT), an annotated patient gene database maintained by the National Cancer Institute, we identified the intermediate conductance Ca2+-activated K+ channels, KCa3.1, being overexpressed in 32% of glioma patients where protein expression significantly correlated with poor patient survival. To mechanistically link KCa3.1 expression to glioma invasion, we selected patient gliomas that, when propagated as xenolines in vivo, present with either high or low KCa3.1 expression. In addition we generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression. Subjecting these cells to a combination of in vitro and in situ invasion assays, we demonstrate that KCa3.1 expression significantly enhances glioma invasion and that either specific pharmacological inhibition with TRAM-34 or elimination of the channel impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA resulted in a significant reduction in tumor invasion into surrounding brain in vivo. These results show that KCa3.1 confers an invasive phenotype that significantly worsens a patient’s outlook, and suggests that KCa3.1 represents a viable therapeutic target to reduce glioma invasion. PMID:24585442

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

PubMed

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

2011-05-01

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

Diffuse gliomas with FGFR3-TACC3 fusion have characteristic histopathological and molecular features.

PubMed

Bielle, Franck; Di Stefano, Anna-Luisa; Meyronet, David; Picca, Alberto; Villa, Chiara; Bernier, Michèle; Schmitt, Yohann; Giry, Marine; Rousseau, Audrey; Figarella-Branger, Dominique; Maurage, Claude-Alain; Uro-Coste, Emmanuelle; Lasorella, Anna; Iavarone, Antonio; Sanson, Marc; Mokhtari, Karima

2017-10-04

Adult glioblastomas, IDH-wildtype represent a heterogeneous group of diseases. They are resistant to conventional treatment by concomitant radiochemotherapy and carry a dismal prognosis. The discovery of oncogenic gene fusions in these tumors has led to prospective targeted treatments, but identification of these rare alterations in practice is challenging. Here, we report a series of 30 adult diffuse gliomas with an in frame FGFR3-TACC3 oncogenic fusion (n = 27 WHO grade IV and n = 3 WHO grade II) as well as their histological and molecular features. We observed recurrent morphological features (monomorphous ovoid nuclei, nuclear palisading and thin parallel cytoplasmic processes, endocrinoid network of thin capillaries) associated with frequent microcalcifications and desmoplasia. We report a constant immunoreactivity for FGFR3, which is a valuable method for screening for the FGFR3-TACC3 fusion with 100% sensitivity and 92% specificity. We confirmed the associated molecular features (typical genetic alterations of glioblastoma, except the absence of EGFR amplification, and an increased frequency of CDK4 and MDM2 amplifications). FGFR3 immunopositivity is a valuable tool to identify gliomas that are likely to harbor the FGFR3-TACC3 fusion for inclusion in targeted therapeutic trials. © 2017 International Society of Neuropathology.

FTIR spectro-imaging of collagen scaffold formation during glioma tumor development.

PubMed

Noreen, Razia; Chien, Chia-Chi; Chen, Hsiang-Hsin; Bobroff, Vladimir; Moenner, Michel; Javerzat, Sophie; Hwu, Yeukuang; Petibois, Cyril

2013-11-01

Evidence has recently emerged that solid and diffuse tumors produce a specific extracellular matrix (ECM) for division and diffusion, also developing a specific interface with microvasculature. This ECM is mainly composed of collagens and their scaffolding appears to drive tumor growth. Although collagens are not easily analyzable by UV-fluorescence means, FTIR imaging has appeared as a valuable tool to characterize collagen contents in tissues, specially the brain, where ECM is normally devoid of collagen proteins. Here, we used FTIR imaging to characterize collagen content changes in growing glioma tumors. We could determine that C6-derived solid tumors presented high content of triple helix after 8-11 days of growth (typical of collagen fibrils formation; 8/8 tumor samples; 91 % of total variance), and further turned to larger α-helix (days 12-15; 9/10 of tumors; 94 % of variance) and β-turns (day 18-21; 7/8 tumors; 97 % of variance) contents, which suggest the incorporation of non-fibrillar collagen types in ECM, a sign of more and more organized collagen scaffold along tumor progression. The growth of tumors was also associated to the level of collagen produced (P < 0.05). This study thus confirms that collagen scaffolding is a major event accompanying the angiogenic shift and faster tumor growth in solid glioma phenotypes.

Methods to Differentiate Radiation Necrosis and Recurrent Disease in Gliomas

NASA Astrophysics Data System (ADS)

Ewell, Lars

2007-03-01

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

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. © 2014 International Society of Neuropathology.

Absence of IDH1-R132H mutation predicts rapid progression of nonenhancing diffuse glioma in older adults.

PubMed

Olar, Adriana; Raghunathan, Aditya; Albarracin, Constance T; Aldape, Kenneth D; Cahill, Daniel P; Powell, Suzanne Z; Goodman, J Clay; Fuller, Gregory N

2012-06-01

Advanced age and contrast enhancement portend a poor prognosis in diffuse glioma (DG). Diffuse glioma may present as nonenhancing tumors that rapidly progress in weeks to months to a pattern of ring enhancement, characteristic of glioblastoma (GBM). Mutations involving isocitrate dehydrogenase 1 (IDH1) have recently emerged as important diagnostic and prognostic markers in DG. R132H is the most common mutation, expressed in more than 80% of DG and secondary GBM but in less than 10% of primary GBM. Adults older than 50 years with nonenhancing, rapidly progressing DG were identified. A comparison group comprised randomly selected, age-matched patients with nonenhancing, nonprogressing DG. Isocitrate dehydrogenase 1 status was evaluated using anti-IDH1-R132H antibodies (Dianova, Hamburg, Germany). The results were correlated with the clinical outcomes. We identified 4 patients who presented with nonenhancing DG that rapidly progressed to ring-enhancing lesions that were subsequently diagnosed on surgical resection as GBM. This group showed absent IDH1-R132H expression, which is characteristic of primary GBM. The comparison group of 5 patients presented with nonenhancing, nonprogressing DG, and all 5 tumors showed IDH1-R132H expression. In conclusion, negative IDH1-R132H mutation status in nonenhancing DG of older adults is a poor prognostic factor associated with rapid progression to ring-enhancing GBM. The shorter interval of progression and negative IDH1-R132H mutation status suggest a similar molecular pathway as seen in primary GBM. Copyright © 2012 Elsevier Inc. All rights reserved.

Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

ClinicalTrials.gov

2013-07-01

Childhood Burkitt Lymphoma; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Medulloepithelioma; Childhood Meningioma; Childhood Mixed Glioma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Oligodendroglioma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate.

PubMed

Andronesi, Ovidiu C; Arrillaga-Romany, Isabel C; Ly, K Ina; Bogner, Wolfgang; Ratai, Eva M; Reitz, Kara; Iafrate, A John; Dietrich, Jorg; Gerstner, Elizabeth R; Chi, Andrew S; Rosen, Bruce R; Wen, Patrick Y; Cahill, Daniel P; Batchelor, Tracy T

2018-04-16

Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to the reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. An inverse correlation between metabolic changes and diffusion MRI indicates an effect on the tumor-cell density. We demonstrate a feasible radiopharmacodynamics approach to support the rapid clinical translation of rationally designed drugs targeting IDH1/2 mutations for personalized and precision medicine of glioma patients.

Paclitaxel loaded phospholipid-based gel as a drug delivery system for local treatment of glioma.

PubMed

Chen, Tijia; Gong, Ting; Zhao, Ting; Liu, Xing; Fu, Yao; Zhang, Zhirong; Gong, Tao

2017-08-07

Paclitaxel (PTX) is a chemotherapeutic agent and has been widely used in clinic against human cancer. However, it has limited application in brain tumor treatment due to the poor penetration of blood brain barrier. Local delivery system is a promising carrier of PTX in the treatment of glioma. A biodegradable phospholipid-based gel (PG) system was developed for intratumoral injection and evaluated in brain glioma-bearing mice model. PTX loaded PG was composed of phospholipid, ethanol, medium chain triglyceride, triacetin and PTX. It was prepared by a very simple method. The system was a transparent solution with good fluidity, while turned into a gel after phase-transition when ethanol diffused. Both in vitro dissolution and in vivo imaging study proved the sustained release effect of PG system. In vivo tolerability study showed a better tolerability after mice treated with PTX PG compared with free PTX. The survival time of brain glioma-bearing mice after treatment with PTX PG was significantly prolonged compared with mice treated by free PTX (P<0.05). In conclusion, this study developed a novel PG based local PTX delivery system with simple preparation method, good tolerability and high therapeutic efficacy. It has a great potential to improve the clinical management of glioma. Copyright © 2017 Elsevier B.V. All rights reserved.

Expression and role of the cell surface protease seprase/fibroblast activation protein-α (FAP-α) in astroglial tumors.

PubMed

Mentlein, Rolf; Hattermann, Kirsten; Hemion, Charles; Jungbluth, Achim A; Held-Feindt, Janka

2011-03-01

Seprase or fibroblast activation protein-α (FAP-α) is a cell-surface serine protease that was previously described nearly exclusively on reactive and tumor stromal fibroblasts and thought to be involved in tissue remodeling. We investigated the expression and significance of FAP-α in astrocytomas/glioblastomas. As shown by quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, FAP-α was elevated in whole glioblastoma tissues and in particular in most glioma cells in situ and in vitro. In glioma stem-like cells (gliospheres), FAP-α was detected at low levels; however, FAP-α was considerably induced upon differentiation with 10% fetal calf serum. To explore its functional role, FAP-α was silenced by siRNA transfection. In Boyden chamber assays, FAP-α silenced cells migrated similar as control cells through non-coated or Matrigel (basal lamina)-coated porous membranes, but significantly slower through membranes coated with gelatin or brevican, a major component of brain extracellular matrix. Furthermore, FAP-α-silenced glioma cells migrated through murine brain slices much slower under the conditions tested than differentially fluorescent-labeled control cells. Thus, FAP-α is highly expressed on the surface of glioma cells and contributes to diffuse glioma invasion through extracellular matrix components.

Longitudinal evaluation of corticospinal tract in patients with resected brainstem cavernous malformations using high-definition fiber tractography and diffusion connectometry analysis: preliminary experience.

PubMed

Faraji, Amir H; Abhinav, Kumar; Jarbo, Kevin; Yeh, Fang-Cheng; Shin, Samuel S; Pathak, Sudhir; Hirsch, Barry E; Schneider, Walter; Fernandez-Miranda, Juan C; Friedlander, Robert M

2015-11-01

Brainstem cavernous malformations (CMs) are challenging due to a higher symptomatic hemorrhage rate and potential morbidity associated with their resection. The authors aimed to preoperatively define the relationship of CMs to the perilesional corticospinal tracts (CSTs) by obtaining qualitative and quantitative data using high-definition fiber tractography. These data were examined postoperatively by using longitudinal scans and in relation to patients' symptomatology. The extent of involvement of the CST was further evaluated longitudinally using the automated "diffusion connectometry" analysis. Fiber tractography was performed with DSI Studio using a quantitative anisotropy (QA)-based generalized deterministic tracking algorithm. Qualitatively, CST was classified as being "disrupted" and/or "displaced." Quantitative analysis involved obtaining mean QA values for the CST and its perilesional and nonperilesional segments. The contralateral CST was used for comparison. Diffusion connectometry analysis included comparison of patients' data with a template from 90 normal subjects. Three patients (mean age 22 years) with symptomatic pontomesencephalic hemorrhagic CMs and varying degrees of hemiparesis were identified. The mean follow-up period was 37.3 months. Qualitatively, CST was partially disrupted and displaced in all. Direction of the displacement was different in each case and progressively improved corresponding with the patient's neurological status. No patient experienced neurological decline related to the resection. The perilesional mean QA percentage decreases supported tract disruption and decreased further over the follow-up period (Case 1, 26%-49%; Case 2, 35%-66%; and Case 3, 63%-78%). Diffusion connectometry demonstrated rostrocaudal involvement of the CST consistent with the quantitative data. Hemorrhagic brainstem CMs can disrupt and displace perilesional white matter tracts with the latter occurring in unpredictable directions. This requires the use of tractography to accurately define their orientation to optimize surgical entry point, minimize morbidity, and enhance neurological outcomes. Observed anisotropy decreases in the perilesional segments are consistent with neural injury following hemorrhagic insults. A model using these values in different CST segments can be used to longitudinally monitor its craniocaudal integrity. Diffusion connectometry is a complementary approach providing longitudinal information on the rostrocaudal involvement of the CST.

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

ClinicalTrials.gov

2013-01-15

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

Postmortem diffusion MRI of the human brainstem and thalamus for deep brain stimulator electrode localization

PubMed Central

Calabrese, Evan; Hickey, Patrick; Hulette, Christine; Zhang, Jingxian; Parente, Beth; Lad, Shivanand P.; Johnson, G. Allan

2015-01-01

Deep brain stimulation (DBS) is an established surgical therapy for medically refractory tremor disorders including essential tremor (ET) and is currently under investigation for use in a variety of other neurologic and psychiatric disorders. There is growing evidence that the anti-tremor effects of DBS for ET are directly related to modulation of the dentatorubrothalamic tract (DRT), a white matter pathway that connects the cerebellum, red nucleus, and ventral intermediate nucleus of the thalamus. Emerging white matter targets for DBS, like the DRT, will require improved 3D reference maps of deep brain anatomy and structural connectivity for accurate electrode targeting. High-resolution diffusion MRI of postmortem brain specimens can provide detailed volumetric images of important deep brain nuclei and 3D reconstructions of white matter pathways with probabilistic tractography techniques. We present a high spatial and angular resolution diffusion MRI template of the postmortem human brainstem and thalamus with 3D reconstructions of the nuclei and white matter tracts involved in ET circuitry. We demonstrate accurate registration of these data to in vivo, clinical images from patients receiving DBS therapy, and correlate electrode proximity to tractography of the DRT with improvement of ET symptoms. PMID:26043869

Cortical GABAergic excitation contributes to epileptic activities around human glioma

PubMed Central

Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

2015-01-01

Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

Analysis of 11C-methionine uptake in low-grade gliomas and correlation with proliferative activity.

PubMed

Kato, T; Shinoda, J; Oka, N; Miwa, K; Nakayama, N; Yano, H; Maruyama, T; Muragaki, Y; Iwama, T

2008-11-01

The relationship of (11)C-methionine (MET) uptake and tumor activity in low-grade gliomas (those meeting the criteria for World Health Organization [WHO] grade II gliomas) remains uncertain. The aim of this study was to compare MET uptake in low-grade gliomas and to analyze whether MET positron-emission tomography (PET) can estimate tumor viability and provide evidence of malignant transformation. We studied glioma metabolic activity in 49 consecutive patients with newly diagnosed grade II gliomas by using MET PET before surgical resection. On MET PET, we measured tumor/normal brain uptake ratio (T/N ratio) in 21 diffuse astrocytomas (DAs), 12 oligodendrogliomas (ODs), and 16 oligoastrocytomas (OAs). We compared MET T/N ratio among these 3 tumors and investigated possible correlation with proliferative activity, as measured by Mib-1 labeling index (LI). MET T/N ratios of DA, OD, and OA were 2.11 +/- 0.87, 3.75 +/- 1.43, and 2.76 +/- 1.27, respectively. The MET T/N ratio of OD was significantly higher than that of DA (P < .005). In comparison of MET T/N ratios with the Mib-1 LI, a significant correlation was shown in DA (r = 0.63; P < .005) but not in OD and OA. MET uptake in DAs may be closely associated with tumor viability, which depends on increased amino acid transport by an activated carrier-mediated system. DAs with lower MET uptake were considered more quiescent lesions, whereas DA with higher MET uptake may act more aggressively.

Expression and prognostic role of orphan receptor GPR110 in glioma.

PubMed

Shi, Haiping; Zhang, Shiyuan

2017-09-16

Glioma is the most common type of malignancy in the central nervous system, which has a poor prognosis due to its rapid progression and diffuse invasion. Identification of novel biomarkers for glioma would be invaluable for studying disease mechanism and improving prognosis. Orphan G protein-coupled receptor 110 (GPR110) belongs to the subfamily VI of adhesion GPCR. The knowledge of the ligand, signaling pathway or physiology function of GPR110 is poorly elucidated. The potential role of GPR110 as an oncogene in mouse has been recently reported by mutagenesis screen. However, its expression and role in human glioma hasn't been identified. Here in the current study, we initially explored the RNA and protein expression of GPR110 in patients with glioma. Statistical analysis proved that GPR110 was highly expressed in some patients, which was correlated with advanced disease stages. Furthermore, univariate and multivariate analyses revealed its role as an independent prognostic biomarker for the overall survival of glioma patients. Interestingly, cellular studies showed that overexpression or knockdown of GPR110 in U87 cells didn't affect cell proliferation and migration. However, the invasion of U87 cells was significantly enhanced by GPR110-overepxression, while inhibited by GPR110-knockdown. The detailed mechanisms remain further investigation although our results suggested the possible participation of STAT3 instead of ERK in the GPR110 signaling pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Severe cerebral white matter involvement in a case of dentatorubropallidoluysian atrophy studied at autopsy.

PubMed

Muñoz, Esteban; Campdelacreu, Jaume; Ferrer, Isidre; Rey, María J; Cardozo, Adriana; Gómez, Beatriz; Tolosa, Eduardo

2004-06-01

The pathophysiology of white matter involvement in dentatorubropallidoluysian atrophy (DRPLA) is controversial. Moreover, the clinical repercussions and evolution of these lesions have not been well documented. To describe a case of DRPLA with severe cerebellar white matter involvement. Case report. Patient A 62-year-old woman with DRPLA. When the genetic diagnosis was made, the patient manifested severe ataxia, slight dysarthria, and subcortical cognitive impairment. Cranial magnetic resonance imaging showed atrophy of the cerebellum and brainstem and moderate high-intensity signal alterations in the periventricular cerebral white matter in T2-weighted sequences. In the following 5 years, she developed uncontrolled head movements associated with severe bruxism and tetraparesis, and became deeply demented. New magnetic resonance imaging showed severe diffuse cerebral white matter alterations in T2 sequences with only slight progression of brainstem and cerebellar atrophy. After her death at 67 years of age, the autopsy study showed diffuse myelin pallor, axonal preservation, and reactive astrogliosis in the cerebral white matter, with only mild atherosclerotic changes, and moderate neuronal loss in the cerebellum and brainstem. Leukoencephalopathy could be a prominent finding in some patients with DRPLA, explaining, at least in part, their clinical evolution. In our case, the disproportion between the severity of white matter damage and vascular changes does not support a cardinal role for ischemic mechanisms in leukoencephalopathy.

Long-term recovery of motor function in a quadriplegic patient with diffuse axonal injury and traumatic hemorrhage: a case report.

PubMed

Kim, Dong Gyu; Kim, Seong Ho; Kim, Oh Lyong; Cho, Yun Woo; Son, Su Min; Jang, Sung Ho

2009-01-01

There have been no studies on motor recovery in severe quadriplegic patients with traumatic brain injury (TBI) resulting from combined causes of weakness; this type of patient is often seen in rehabilitation clinics. We report on a quadriplegic patient who showed long-term motor recovery from severe weakness caused by a diffuse axonal injury (DAI) on the brainstem and a traumatic intracerebral hemorrhage (ICH) on left cerebral peduncle, as evaluated by diffuse tensor imaging (DTI) and functional MRI (fMRI). A 17-year-old male patient presented with quadriparesis at the onset of TBI. Over the 28-month period following the onset of the injury, the motor function of the four extremities slowly recovered to a range that was nearly normal. Two longitudinal DTIs (at 11 and 28 months from onset) and fMRI (at 28 months) were performed. Fractional anisotropy and an apparent diffusion coefficient were measured using the region of interest method, and diffusion tensor tractography was conducted using a DTI/fMRI combination. Fractional anisotrophy values in the brainstem, which were markedly decreased on the 11-month DTI, were increased on the 28-month DTI. On the fMRI performed at 28 months, the contralateral primary sensori-motor cortex was activated by the movement of either the right or left hand. Diffusion tensor tractography showed that fiber tracts originating from the motor-sensory cortex passed through the known corticospinal tract pathway to the pons. It seems that the weakness of this patient recovered due to the recovery of the damaged corticospinal tracts.

Three-dimensional anisotropy contrast periodically rotated overlapping parallel lines with enhanced reconstruction (3DAC PROPELLER) on a 3.0T system: a new modality for routine clinical neuroimaging.

PubMed

Nakada, Tsutomu; Matsuzawa, Hitoshi; Fujii, Yukihiko; Takahashi, Hitoshi; Nishizawa, Masatoyo; Kwee, Ingrid L

2006-07-01

Clinical magnetic resonance imaging (MRI) has recently entered the "high-field" era, and systems equipped with 3.0-4.0T superconductive magnets are becoming the gold standard for diagnostic imaging. While higher signal-to-noise ratio (S/N) is a definite advantage of higher field systems, higher susceptibility effect remains to be a significant trade-off. To take advantage of a higher field system in performing routine clinical images of higher anatomical resolution, we implemented a vector contrast image technique to 3.0T imaging, three-dimensional anisotropy contrast (3DAC), with a PROPELLER (Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction) sequence, a method capable of effectively eliminating undesired artifacts on rapid diffusion imaging sequences. One hundred subjects (20 normal volunteers and 80 volunteers with various central nervous system diseases) participated in the study. Anisotropic diffusion-weighted PROPELLER images were obtained on a General Electric (Waukesha, WI, USA) Signa 3.0T for each axis, with b-value of 1100 sec/mm(2). Subsequently, 3DAC images were constructed using in-house software written on MATLAB (MathWorks, Natick, MA, USA). The vector contrast allows for providing exquisite anatomical detail illustrated by clear identification of all major tracts through the entire brain. 3DAC images provide better anatomical resolution for brainstem glioma than higher-resolution T2 reversed images. Degenerative processes of disease-specific tracts were clearly identified as illustrated in cases of multiple system atrophy and Joseph-Machado disease. Anatomical images of significantly higher resolution than the best current standard, T2 reversed images, were successfully obtained. As a technique readily applicable under routine clinical setting, 3DAC PROPELLER on a 3.0T system will be a powerful addition to diagnostic imaging.

Introduction of a standardized multimodality image protocol for navigation-guided surgery of suspected low-grade gliomas.

PubMed

Mert, Aygül; Kiesel, Barbara; Wöhrer, Adelheid; Martínez-Moreno, Mauricio; Minchev, Georgi; Furtner, Julia; Knosp, Engelbert; Wolfsberger, Stefan; Widhalm, Georg

2015-01-01

OBJECT Surgery of suspected low-grade gliomas (LGGs) poses a special challenge for neurosurgeons due to their diffusely infiltrative growth and histopathological heterogeneity. Consequently, neuronavigation with multimodality imaging data, such as structural and metabolic data, fiber tracking, and 3D brain visualization, has been proposed to optimize surgery. However, currently no standardized protocol has been established for multimodality imaging data in modern glioma surgery. The aim of this study was therefore to define a specific protocol for multimodality imaging and navigation for suspected LGG. METHODS Fifty-one patients who underwent surgery for a diffusely infiltrating glioma with nonsignificant contrast enhancement on MRI and available multimodality imaging data were included. In the first 40 patients with glioma, the authors retrospectively reviewed the imaging data, including structural MRI (contrast-enhanced T1-weighted, T2-weighted, and FLAIR sequences), metabolic images derived from PET, or MR spectroscopy chemical shift imaging, fiber tracking, and 3D brain surface/vessel visualization, to define standardized image settings and specific indications for each imaging modality. The feasibility and surgical relevance of this new protocol was subsequently prospectively investigated during surgery with the assistance of an advanced electromagnetic navigation system in the remaining 11 patients. Furthermore, specific surgical outcome parameters, including the extent of resection, histological analysis of the metabolic hotspot, presence of a new postoperative neurological deficit, and intraoperative accuracy of 3D brain visualization models, were assessed in each of these patients. RESULTS After reviewing these first 40 cases of glioma, the authors defined a specific protocol with standardized image settings and specific indications that allows for optimal and simultaneous visualization of structural and metabolic data, fiber tracking, and 3D brain visualization. This new protocol was feasible and was estimated to be surgically relevant during navigation-guided surgery in all 11 patients. According to the authors' predefined surgical outcome parameters, they observed a complete resection in all resectable gliomas (n = 5) by using contour visualization with T2-weighted or FLAIR images. Additionally, tumor tissue derived from the metabolic hotspot showed the presence of malignant tissue in all WHO Grade III or IV gliomas (n = 5). Moreover, no permanent postoperative neurological deficits occurred in any of these patients, and fiber tracking and/or intraoperative monitoring were applied during surgery in the vast majority of cases (n = 10). Furthermore, the authors found a significant intraoperative topographical correlation of 3D brain surface and vessel models with gyral anatomy and superficial vessels. Finally, real-time navigation with multimodality imaging data using the advanced electromagnetic navigation system was found to be useful for precise guidance to surgical targets, such as the tumor margin or the metabolic hotspot. CONCLUSIONS In this study, the authors defined a specific protocol for multimodality imaging data in suspected LGGs, and they propose the application of this new protocol for advanced navigation-guided procedures optimally in conjunction with continuous electromagnetic instrument tracking to optimize glioma surgery.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Korinthenberg, Rudolf, E-mail: rudolf.korinthenberg@uniklinik-freiburg.d; Neuburger, Daniela; Trippel, Michael

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- andmore » 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.« less

Contemporary management of low--grade glioma: a paradigm shift in neuro-oncology.

PubMed

Hayhurst, Caroline

2017-06-01

Supratentorial diffuse intrinsic low-grade gliomas represent a distinct but heterogenous group of tumours, with the propensity to grow and to differentiate into malignant tumours. They have been historically viewed in the 'benign' spectrum of intrinsic brain tumours, so a watch-and-wait policy was often adopted. With recent advances in our understanding of the natural history of these tumours, combined with advances in surgical technique, an aggressive approach is now recommended. Increasing quality evidence of the impact of tumour resection and multicentre trials of adjuvant radiotherapy and chemotherapy have led to a new algorithm for low-grade glioma management. This review aims to outline the emerging evidence that has shifted neuro-oncology practice. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A method for safely resecting anterior butterfly gliomas: the surgical anatomy of the default mode network and the relevance of its preservation.

PubMed

Burks, Joshua D; Bonney, Phillip A; Conner, Andrew K; Glenn, Chad A; Briggs, Robert G; Battiste, James D; McCoy, Tressie; O'Donoghue, Daniel L; Wu, Dee H; Sughrue, Michael E

2017-06-01

OBJECTIVE Gliomas invading the anterior corpus callosum are commonly deemed unresectable due to an unacceptable risk/benefit ratio, including the risk of abulia. In this study, the authors investigated the anatomy of the cingulum and its connectivity within the default mode network (DMN). A technique is described involving awake subcortical mapping with higher attention tasks to preserve the cingulum and reduce the incidence of postoperative abulia for patients with so-called butterfly gliomas. METHODS The authors reviewed clinical data on all patients undergoing glioma surgery performed by the senior author during a 4-year period at the University of Oklahoma Health Sciences Center. Forty patients were identified who underwent surgery for butterfly gliomas. Each patient was designated as having undergone surgery either with or without the use of awake subcortical mapping and preservation of the cingulum. Data recorded on these patients included the incidence of abulia/akinetic mutism. In the context of the study findings, the authors conducted a detailed anatomical study of the cingulum and its role within the DMN using postmortem fiber tract dissections of 10 cerebral hemispheres and in vivo diffusion tractography of 10 healthy subjects. RESULTS Forty patients with butterfly gliomas were treated, 25 (62%) with standard surgical methods and 15 (38%) with awake subcortical mapping and preservation of the cingulum. One patient (1/15, 7%) experienced postoperative abulia following surgery with the cingulum-sparing technique. Greater than 90% resection was achieved in 13/15 (87%) of these patients. CONCLUSIONS This study presents evidence that anterior butterfly gliomas can be safely removed using a novel, attention-task based, awake brain surgery technique that focuses on preserving the anatomical connectivity of the cingulum and relevant aspects of the cingulate gyrus.

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

PubMed

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

2013-04-01

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

Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

PubMed Central

El-Khouly, Fatma E.; van Vuurden, Dannis G.; Stroink, Thom; Hulleman, Esther; Kaspers, Gertjan J. L.; Hendrikse, N. Harry; Veldhuijzen van Zanten, Sophie E. M.

2017-01-01

Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG. PMID:29164054

Apparent diffusion coefficient histogram metrics correlate with survival in diffuse intrinsic pontine glioma: a report from the Pediatric Brain Tumor Consortium

PubMed Central

Poussaint, Tina Young; Vajapeyam, Sridhar; Ricci, Kelsey I.; Panigrahy, Ashok; Kocak, Mehmet; Kun, Larry E.; Boyett, James M.; Pollack, Ian F.; Fouladi, Maryam

2016-01-01

Background Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT). Methods Baseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis. Results Based on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement. Conclusions ADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials. PMID:26487690

The Integration of Biology Into the Treatment of Diffuse Intrinsic Pontine Glioma: A Review of the North American Clinical Trial Perspective.

PubMed

Clymer, Jessica; Kieran, Mark W

2018-01-01

Dramatic advances in the molecular analysis of diffuse intrinsic pontine glioma have occurred over the last decade and resulted in the identification of potential therapeutic targets. In spite of these advances, no significant improvement in the outcome has been achieved and median survival remains approximately 10 months. An understanding of the approaches that have been taken to date, why they failed, and how that information can lead the field forward is critical if we are to change the status quo . In this review, we will discuss the clinical trial landscape in North America with an overview of historical approaches that failed and what might account for this failure. We will then provide a discussion of how our understanding of the genotype of this disease has led to the development of a number of trials targeting the mutations and epigenome of diffuse intrinsic pontine gliomas and the issues related to these trials. Similarly, the introduction of methodologies to address penetration across the blood-brain barrier will be considered in the context of both targeted approaches, epigenetic modification, and immune surveillance of these tumors. The comprehensive analysis of these data, generated through cooperative groups, collaborative clinical trials, and pilot studies in North America will be the focus of the IVth Memorial Alicia Pueyo international symposium in Barcelona on March 12th, 2018 and will be compared and contrasted with a similar comprehensive analysis of the European data with the goal of bringing all of these data together to develop a uniform platform on which new rational trials can be based.

Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas

PubMed Central

Annala, Matti; Lehtinen, Birgitta; Kesseli, Juha; Haapasalo, Joonas; Ruusuvuori, Pekka; Yli-Harja, Olli; Visakorpi, Tapio; Haapasalo, Hannu; Nykter, Matti; Zhang, Wei

2017-01-01

Abstract Background Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled-coil protein 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well to FGFR inhibition. As high FGFR3 expression has been detected in fusion-positive tumors, we sought to determine the clinical significance of FGFR3 protein expression level as well as its potential for indicating FGFR3 fusions. Methods We performed FGFR3 immunohistochemistry on tissue microarrays containing 676 grades II–IV astrocytomas and 116 grades II–III oligodendroglial tumor specimens. Fifty-one cases were further analyzed using targeted sequencing. Results Moderate to strong FGFR3 staining was detected in gliomas of all grades, was more common in females, and was associated with poor survival in diffuse astrocytomas. Targeted sequencing identified FGFR3-TACC3 fusions and an FGFR3-CAMK2A fusion in 10 of 15 strongly stained cases, whereas no fusions were found in 36 negatively to moderately stained cases. Fusion-positive cases were predominantly female and negative for IDH and EGFR/PDGFRA/MET alterations. These and moderately stained cases show lower MIB-1 proliferation index than negatively to weakly stained cases. Furthermore, stronger FGFR3 expression was commonly observed in malignant tissue regions of lower cellularity in fusion-negative cases. Importantly, subregional negative FGFR3 staining was also observed in a few fusion-positive cases. Conclusions Strong FGFR3 protein expression is indicative of FGFR3 fusions and may serve as a clinically applicable predictive marker for treatment regimens based on FGFR inhibitors. PMID:28379477

Amino acid tracers in PET imaging of diffuse low-grade gliomas: a systematic review of preoperative applications.

PubMed

Näslund, Olivia; Smits, Anja; Förander, Petter; Laesser, Mats; Bartek, Jiri; Gempt, Jens; Liljegren, Ann; Daxberg, Eva-Lotte; Jakola, Asgeir Store

2018-05-24

Positron emission tomography (PET) imaging using amino acid tracers has in recent years become widely used in the diagnosis and prediction of disease course in diffuse low-grade gliomas (LGG). However, implications of preoperative PET for treatment and prognosis in this patient group have not been systematically studied. The aim of this systematic review was to evaluate the preoperative diagnostic and prognostic value of amino acid PET in suspected diffuse LGG. Medline, Cochrane Library, and Embase databases were systematically searched using keywords "PET," "low-grade glioma," and "amino acids tracers" with their respective synonyms. Out of 2137 eligible studies, 28 met the inclusion criteria. Increased amino acid uptake (lesion/brain) was consistently reported among included studies; in 25-92% of subsequently histopathology-verified LGG, in 83-100% of histopathology-verified HGG, and also in some non-neoplastic lesions. No consistent results were found in studies reporting hot spot areas on PET in MRI-suspected LGG. Thus, the diagnostic value of amino acid PET imaging in suspected LGG has proven difficult to interpret, showing clear overlap and inconsistencies among reported results. Similarly, the results regarding the prognostic value of PET in suspected LGG and the correlation between uptake ratios and the molecular tumor status of LGG were conflicting. This systematic review illustrates the difficulties with prognostic studies presenting data on group-level without adjustment for established clinical prognostic factors, leading to a loss of additional prognostic information. We conclude that the prognostic value of PET is limited to analysis of histological subgroups of LGG and is probably strongest when using kinetic analysis of dynamic FET uptake parameters.

The 2016 revision of the WHO Classification of Central Nervous System Tumours: retrospective application to a cohort of diffuse gliomas.

PubMed

Rogers, Te Whiti; Toor, Gurvinder; Drummond, Katharine; Love, Craig; Field, Kathryn; Asher, Rebecca; Tsui, Alpha; Buckland, Michael; Gonzales, Michael

2018-03-01

The classification of central nervous system tumours has more recently been shaped by a focus on molecular pathology rather than histopathology. We re-classified 82 glial tumours according to the molecular-genetic criteria of the 2016 revision of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System. Initial diagnoses and grading were based on the morphological criteria of the 2007 WHO scheme. Because of the impression of an oligodendroglial component on initial histological assessment, each tumour was tested for co-deletion of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH-1 and 2) genes. Additionally, expression of proteins encoded by alpha-thalassemia X-linked mental retardation (ATRX) and TP53 genes was assessed by immunohistochemistry. We found that all but two tumours could be assigned to a specific category in the 2016 revision. The most common change in diagnosis was from oligoastrocytoma to specifically astrocytoma or oligodendroglioma. Analysis of progression free survival (PFS) for WHO grade II and III tumours showed that the objective criteria of the 2016 revision separated diffuse gliomas into three distinct molecular categories: chromosome 1p/19q co-deleted/IDH mutant, intact 1p/19q/IDH mutant and IDH wild type. No significant difference in PFS was found when comparing IDH mutant grade II and III tumours suggesting that IDH status is more informative than tumour grade. The segregation into distinct molecular sub-types that is achieved by the 2016 revision provides an objective evidence base for managing patients with grade II and III diffuse gliomas based on prognosis.

Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens.

PubMed

Preusser, Matthias; Wöhrer, Adelheid; Stary, Susanne; Höftberger, Romana; Streubel, Berthold; Hainfellner, Johannes A

2011-08-01

To assess the value of anti-isocitrate dehydrogenase 1 (IDH1) immunohistochemistry for evaluating diffuse gliomas, we analyzed anti-IDH1-R132H immunohistochemistry using monoclonal antibodies DIA-H09 and IMab-1 and IDH1 gene sequencing in formalin-fixed and paraffin-embedded biopsy samples of 95 diffuse gliomas. We found concordant immunostaining results using the 2 antibodies in 94 (98.9%) of the 95 cases, but DIA-H09 generally showed a higher signal-to-background ratio than IMab-1 did. Fifty-five percent of cases showed anti-IDH1-R132H immunostaining of virtually all tumor cells and 15% of only a fraction of tumor cells. All cases with complete or partial immunostaining of the tumor tissue carried the IDH1-R132H mutation. In all cases with negative immunostaining results (approximately 30%), genetic analysis showed IDH1 wild-type or non-R132H-IDH1 mutations. In a single tiny biopsy, both anti-IDH1-R132H antibodies showed immunoreactivity, but genetic testing was inconclusive. Our data confirm anti-IDH1-R132H immunostaining as a reliable method for evaluation of IDH1 gene mutation status. They also suggest the following: (i) in some cases, nonspecific background staining or regional heterogeneity of IDH1-R132H protein expression may necessitate confirmatory genetic analysis; (ii) for individual cases, anti-IDH1-R132H immunostaining may not reliably identify infiltrating tumor cells admixed with preexisting or reactive glial cells; and (iii) in tiny biopsies, immunohistochemistry may be more sensitive for detection of IDH1-R132H mutation than genetic analysis.

Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma

PubMed Central

Tsoli, Maria; Liu, Jie; Franshaw, Laura; Shen, Han; Cheng, Cecilia; Jung, MoonSun; Joshi, Swapna; Ehteda, Anahid; Khan, Aaminah; Montero-Carcabosso, Angel; Dilda, Pierre J.; Hogg, Philip; Ziegler, David S.

2018-01-01

Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK. In vivo experiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor penetration of the inhibitors into the brain. Further testing of this anti-DIPG strategy with compounds that penetrate the BBB is warranted. PMID:29484131

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Arthur K., E-mail: arthur.liu@ucdenver.ed; Macy, Margaret E.; Foreman, Nicholas K.

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

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

PubMed

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

2016-07-01

Spontaneous gliomas in dogs occur at a frequency similar to that in humans and may provide a translational model for therapeutic development and comparative biological investigations. Copy number alterations in 38 canine gliomas, including diffuse astrocytomas, glioblastomas, oligodendrogliomas, and mixed oligoastrocytomas, were defined using an Illumina 170K single nucleotide polymorphism array. Highly recurrent alterations were seen in up to 85% of some tumor types, most notably involving chromosomes 13, 22, and 38, and gliomas clustered into 2 major groups consisting of high-grade IV astrocytomas, or oligodendrogliomas and other tumors. Tumor types were characterized by specific broad and focal chromosomal events including focal loss of the INK4A/B locus in glioblastoma and loss of the RB1 gene and amplification of the PDGFRA gene in oligodendrogliomas. Genes associated with the 3 critical pathways in human high-grade gliomas (TP53, RB1, and RTK/RAS/PI3K) were frequently associated with canine aberrations. Analysis of oligodendrogliomas revealed regions of chromosomal losses syntenic to human 1p involving tumor suppressor genes, such as CDKN2C, as well as genes associated with apoptosis, autophagy, and response to chemotherapy and radiation. Analysis of high frequency chromosomal aberrations with respect to human orthologues may provide insight into both novel and common pathways in gliomagenesis and response to therapy. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

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

PubMed Central

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

2016-01-01

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

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

PubMed

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)-TERTp(mut)) (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)-TERTp(wt)) (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.

Upfront chemotherapy and subsequent resection for molecularly defined gliomas.

PubMed

Sasaki, Hikaru; Hirose, Yuichi; Yazaki, Takahito; Kitamura, Yohei; Katayama, Makoto; Kimura, Tokuhiro; Fujiwara, Hirokazu; Toda, Masahiro; Ohira, Takayuki; Yoshida, Kazunari

2015-08-01

Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression-free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB-1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy.

Impact of Virtual and Augmented Reality Based on Intraoperative Magnetic Resonance Imaging and Functional Neuronavigation in Glioma Surgery Involving Eloquent Areas.

PubMed

Sun, Guo-Chen; Wang, Fei; Chen, Xiao-Lei; Yu, Xin-Guang; Ma, Xiao-Dong; Zhou, Ding-Biao; Zhu, Ru-Yuan; Xu, Bai-Nan

2016-12-01

The utility of virtual and augmented reality based on functional neuronavigation and intraoperative magnetic resonance imaging (MRI) for glioma surgery has not been previously investigated. The study population consisted of 79 glioma patients and 55 control subjects. Preoperatively, the lesion and related eloquent structures were visualized by diffusion tensor tractography and blood oxygen level-dependent functional MRI. Intraoperatively, microscope-based functional neuronavigation was used to integrate the reconstructed eloquent structure and the real head and brain, which enabled safe resection of the lesion. Intraoperative MRI was used to verify brain shift during the surgical process and provided quality control during surgery. The control group underwent surgery guided by anatomic neuronavigation. Virtual and augmented reality protocols based on functional neuronavigation and intraoperative MRI provided useful information for performing tailored and optimized surgery. Complete resection was achieved in 55 of 79 (69.6%) glioma patients and 20 of 55 (36.4%) control subjects, with average resection rates of 95.2% ± 8.5% and 84.9% ± 15.7%, respectively. Both the complete resection rate and average extent of resection differed significantly between the 2 groups (P < 0.01). Postoperatively, the rate of preservation of neural functions (motor, visual field, and language) was lower in controls than in glioma patients at 2 weeks and 3 months (P < 0.01). Combining virtual and augmented reality based on functional neuronavigation and intraoperative MRI can facilitate resection of gliomas involving eloquent areas. Copyright © 2016 Elsevier Inc. All rights reserved.

Pericytes/vessel-associated mural cells (VAMCs) are the major source of key epithelial-mesenchymal transition (EMT) factors SLUG and TWIST in human glioma.

PubMed

Mäder, Lisa; Blank, Anna E; Capper, David; Jansong, Janina; Baumgarten, Peter; Wirsik, Naita M; Zachskorn, Cornelia; Ehlers, Jakob; Seifert, Michael; Klink, Barbara; Liebner, Stefan; Niclou, Simone; Naumann, Ulrike; Harter, Patrick N; Mittelbronn, Michel

2018-05-08

Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas. We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR -amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed. Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis. In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.

Intraparenchymal epidermoid cyst: proper surgical management may lead to satisfactory outcome.

PubMed

Zheng, Jian; Wang, Chun; Liu, Fengqiang

2018-03-12

Intraparenchymal epidermoid cysts (IECs) are rare lesions, thus the preoperative diagnosis and proper surgical management are still a challenge. We searched the database at our institution and performed a search of English literature in PubMed and Google Scholar. Keywords used were as follows: "intraparenchymal"; "intracerebral"; "intraaxial"; "epidermoid cyst"; "brainstem"; "cholesteatoma"; "pearly tumor". Only cases that were true intraparenchymally located and contained adequate clinical information were included. Six cases of IECs were recorded at our institution. Total removal was achieved in all the six patients with good outcomes. 29 cases meeting the above criteria were found in the literature. Including ours, a total of 35 patients were analyzed. Females were more frequently affected (F/M ratio, 1.9:1). Most of them were located in the brainstem (42.9%) and temporal lobe (22.9%). While in children, all were located in the brainstem. 45.2% showed subtle peripheral enhancement on Magnetic Resonance Imaging (MRI), and all appeared hyperintense on Diffusion Weighted Imaging (DWI). In the subgroup of cerebral lobes and cerebellums, total resection was achieved in 89.5%, and they all showed good outcomes. While in the subgroup of brainstem, 46.7% (seven cases) underwent total resection and 50% (three cases) of them died postoperatively. MRI with DWI is helpful in the preoperative diagnosis. Total resection should be achieved for the IECs located in cerebral lobes and cerebellums, while subtotal resection is a wise and safe strategy for the IECs located in the brainstem.

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

The Usefulness of Diffusion Tensor Imaging and Tractography in Surgery of Brainstem Cavernous Malformations.

PubMed

Januszewski, Jacob; Albert, Lauren; Black, Karen; Dehdashti, Amir R

2016-09-01

Diffusion tensor imaging (DTI) estimates the course and connectivity patterns of white matter tracts. The objective of this study is to evaluate whether findings in the brain stem modify the preoperative surgical trajectory planning or postoperative outcome in patients with brain stem cavernous malformations. Ten patients with symptomatic brainstem cavernous malformation underwent surgical resection. Five patients received preoperative DTI evaluation and the remaining 5 did not. Reconstructed DTI tracts consisted of corticospinal, medial lemnisci, and cerebellar peduncles. The surgical planning and postoperative outcome were evaluated. In 5 patients with no preoperative DTI evaluation, surgical planning was based on anatomic landmark and the 2-point technique. The other 5 patients underwent preoperative DTI, and findings were factored into the selection of the surgical approach. In 3 of the 5 cases with DTI evaluation, the 2-point technique suggested a similar trajectory. In the other 2, the DTI findings suggested a different approach to avoid damage to the white matter tract. Two patients in the group with no DTI had immediate postoperative new or worsened deficit, which improved at long-term follow-up. No patient in the DTI group had a new neurologic deficit. Compared with the standard magnetic resonance imaging, DTI provided improved visualization of cavernous malformation involvement in eloquent fiber tracts of the brainstem. This additional information might help in selecting a more appropriate surgical trajectory in selected lesions. Larger patient cohorts are needed to assess the effect of this modality in patients' outcome. Published by Elsevier Inc.

Postmortem diffusion MRI of the human brainstem and thalamus for deep brain stimulator electrode localization.

PubMed

Calabrese, Evan; Hickey, Patrick; Hulette, Christine; Zhang, Jingxian; Parente, Beth; Lad, Shivanand P; Johnson, G Allan

2015-08-01

Deep brain stimulation (DBS) is an established surgical therapy for medically refractory tremor disorders including essential tremor (ET) and is currently under investigation for use in a variety of other neurologic and psychiatric disorders. There is growing evidence that the anti-tremor effects of DBS for ET are directly related to modulation of the dentatorubrothalamic tract (DRT), a white matter pathway that connects the cerebellum, red nucleus, and ventral intermediate nucleus of the thalamus. Emerging white matter targets for DBS, like the DRT, will require improved three-dimensional (3D) reference maps of deep brain anatomy and structural connectivity for accurate electrode targeting. High-resolution diffusion MRI of postmortem brain specimens can provide detailed volumetric images of important deep brain nuclei and 3D reconstructions of white matter pathways with probabilistic tractography techniques. We present a high spatial and angular resolution diffusion MRI template of the postmortem human brainstem and thalamus with 3D reconstructions of the nuclei and white matter tracts involved in ET circuitry. We demonstrate registration of these data to in vivo, clinical images from patients receiving DBS therapy, and correlate electrode proximity to tractography of the DRT with improvement of ET symptoms. © 2015 Wiley Periodicals, Inc.

Prevalence and impact of diffuse axonal injury in patients with moderate and severe head injury: a cohort study of early magnetic resonance imaging findings and 1-year outcome.

PubMed

Skandsen, Toril; Kvistad, Kjell Arne; Solheim, Ole; Strand, Ingrid Haavde; Folvik, Mari; Vik, Anne

2010-09-01

In this prospective cohort study the authors examined patients with moderate to severe head injuries using MR imaging in the early phase. The objective was to explore the occurrence of diffuse axonal injury (DAI) and determine whether DAI was related to level of consciousness and patient outcome. One hundred and fifty-nine patients (age range 5-65 years) with traumatic brain injury, who survived the acute phase, and who had a Glasgow Coma Scale (GCS) score of 3-13 were admitted between October 2004 and August 2008. Of these 159 patients, 106 were examined using MR imaging within 4 weeks postinjury. Patients were classified into 1 of 3 stages of DAI: Stage 1, in which lesions were confined to the lobar white matter; Stage 2, in which there were callosal lesions; and Stage 3, in which lesions occurred in the dorsolateral brainstem. The outcome measure used 12 months postinjury was the Glasgow Outcome Scale-Extended (GOSE). Diffuse axonal injury was detected in 72% of the patients and a combination of DAI and contusions or hematomas was found in 50%. The GCS score was significantly lower in patients with "pure DAI" (median GCS Score 9) than in patients without DAI (median GCS Score 12; p < 0.001). The GCS score was related to outcome only in those patients with DAI (r = 0.47; p = 0.001). Patients with DAI had a median GOSE score of 7, and patients without DAI had a median GOSE score of 8 (p = 0.10). Outcome was better in patients with DAI Stage 1 (median GOSE Score 8) and DAI Stage 2 (median GOSE Score 7.5) than in patients with DAI Stage 3 (median GOSE Score 4; p < 0.001). Thus, in patients without any brainstem injury, there was no difference in good recovery between patients with DAI (67%) and patients without DAI (66%). Diffuse axonal injury was found in almost three-quarters of the patients with moderate and severe head injury who survived the acute phase. Diffuse axonal injury influenced the level of consciousness, and only in patients with DAI was GCS score related to outcome. Finally, DAI was a negative prognostic sign only when located in the brainstem.

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

PubMed Central

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

2015-01-01

Conventional white matter (WM) imaging approaches, such as diffusion tensor imaging (DTI), have been used to preoperatively identify the location of affected WM tracts in patients with intracranial tumors in order to maximize the extent of resection and potentially reduce postoperative morbidity. DTI, however, has limitations that include its inability to resolve multiple crossing fibers and its susceptibility to partial volume effects. Therefore, recent focus has shifted to more advanced WM imaging techniques such as high-definition fiber tractography (HDFT). In this paper, we illustrate the application of HDFT, which in our preliminary experience has enabled accurate depiction of perilesional tracts in a 3-dimensional manner in multiple anatomical compartments including edematous zones around high-grade gliomas. This has facilitated accurate surgical planning. This is illustrated by using case examples of patients with glioblastoma multiforme. We also discuss future directions in the role of these techniques in surgery for gliomas. PMID:26117712

Application of Awake Craniotomy and Intraoperative Brain Mapping for Surgical Resection of Insular Gliomas of the Dominant Hemisphere.

PubMed

Alimohamadi, Maysam; Shirani, Mohammad; Shariat Moharari, Reza; Pour-Rashidi, Ahmad; Ketabchi, Mehdi; Khajavi, Mohammadreza; Arami, Mohamadali; Amirjamshidi, Abbas

2016-08-01

Radical resection of dominant insular gliomas is difficult because of their close vicinity with internal capsule, basal ganglia, and speech centers. Brain mapping techniques can be used to maximize the extent of tumor removal and to minimize postoperative morbidities by precise localization of eloquent cortical and subcortical areas. Patients with newly diagnosed gliomas of dominant insula were enrolled. The exclusion criteria were severe cognitive disturbances, communication difficulty, age greater than 75 years, severe obesity, difficult airways for intubation and severe cardiopulmonary diseases. All were evaluated preoperatively with contrast-enhanced brain magnetic resonance imaging (MRI), functional brain MRI, and diffusion tensor tractography of language and motor systems. All underwent awake craniotomy with the same anesthesiology protocol. Intraoperative monitoring included continuous motor-evoked potential, electromyography, electrocorticography, direct electrical stimulation of cortex, and subcortical tracts. The patients were followed with serial neurologic examination and imaging. Ten patients were enrolled (4 men, 6 women) with a mean age of 43.6 years. Seven patients suffered from low-grade glioma, and 3 patients had high-grade glioma. The most common clinical presentation was seizure followed by speech disturbance, hemiparesis, and memory loss. Extent of tumor resection ranged from 73% to 100%. No mortality or new major postoperative neurologic deficit was encountered. Seizure control improved in three fourths of patients with medical refractory epilepsy. In one patient with speech disorder at presentation, the speech problem became worse after surgery. Brain mapping during awake craniotomy helps to maximize extent of tumor resection while preserving neurologic function in patients with dominant insular lobe glioma. Copyright © 2016. Published by Elsevier Inc.

Quantitative correlational study of microbubble-enhanced ultrasound imaging and magnetic resonance imaging of glioma and early response to radiotherapy in a rat model.

PubMed

Yang, Chen; Lee, Dong-Hoon; Mangraviti, Antonella; Su, Lin; Zhang, Kai; Zhang, Yin; Zhang, Bin; Li, Wenxiao; Tyler, Betty; Wong, John; Wang, Ken Kang-Hsin; Velarde, Esteban; Zhou, Jinyuan; Ding, Kai

2015-08-01

Radiotherapy remains a major treatment method for malignant tumors. Magnetic resonance imaging (MRI) is the standard modality for assessing glioma treatment response in the clinic. Compared to MRI, ultrasound imaging is low-cost and portable and can be used during intraoperative procedures. The purpose of this study was to quantitatively compare contrast-enhanced ultrasound (CEUS) imaging and MRI of irradiated gliomas in rats and to determine which quantitative ultrasound imaging parameters can be used for the assessment of early response to radiation in glioma. Thirteen nude rats with U87 glioma were used. A small thinned skull window preparation was performed to facilitate ultrasound imaging and mimic intraoperative procedures. Both CEUS and MRI with structural, functional, and molecular imaging parameters were performed at preradiation and at 1 day and 4 days postradiation. Statistical analysis was performed to determine the correlations between MRI and CEUS parameters and the changes between pre- and postradiation imaging. Area under the curve (AUC) in CEUS showed significant difference between preradiation and 4 days postradiation, along with four MRI parameters, T2, apparent diffusion coefficient, cerebral blood flow, and amide proton transfer-weighted (APTw) (all p < 0.05). The APTw signal was correlated with three CEUS parameters, rise time (r = - 0.527, p < 0.05), time to peak (r = - 0.501, p < 0.05), and perfusion index (r = 458, p < 0.05). Cerebral blood flow was correlated with rise time (r = - 0.589, p < 0.01) and time to peak (r = - 0.543, p < 0.05). MRI can be used for the assessment of radiotherapy treatment response and CEUS with AUC as a new technique and can also be one of the assessment methods for early response to radiation in glioma.

Diagnostic accuracy of magnetic resonance imaging techniques for treatment response evaluation in patients with high-grade glioma, a systematic review and meta-analysis.

PubMed

van Dijken, Bart R J; van Laar, Peter Jan; Holtman, Gea A; van der Hoorn, Anouk

2017-10-01

Treatment response assessment in high-grade gliomas uses contrast enhanced T1-weighted MRI, but is unreliable. Novel advanced MRI techniques have been studied, but the accuracy is not well known. Therefore, we performed a systematic meta-analysis to assess the diagnostic accuracy of anatomical and advanced MRI for treatment response in high-grade gliomas. Databases were searched systematically. Study selection and data extraction were done by two authors independently. Meta-analysis was performed using a bivariate random effects model when ≥5 studies were included. Anatomical MRI (five studies, 166 patients) showed a pooled sensitivity and specificity of 68% (95%CI 51-81) and 77% (45-93), respectively. Pooled apparent diffusion coefficients (seven studies, 204 patients) demonstrated a sensitivity of 71% (60-80) and specificity of 87% (77-93). DSC-perfusion (18 studies, 708 patients) sensitivity was 87% (82-91) with a specificity of 86% (77-91). DCE-perfusion (five studies, 207 patients) sensitivity was 92% (73-98) and specificity was 85% (76-92). The sensitivity of spectroscopy (nine studies, 203 patients) was 91% (79-97) and specificity was 95% (65-99). Advanced techniques showed higher diagnostic accuracy than anatomical MRI, the highest for spectroscopy, supporting the use in treatment response assessment in high-grade gliomas. • Treatment response assessment in high-grade gliomas with anatomical MRI is unreliable • Novel advanced MRI techniques have been studied, but diagnostic accuracy is unknown • Meta-analysis demonstrates that advanced MRI showed higher diagnostic accuracy than anatomical MRI • Highest diagnostic accuracy for spectroscopy and perfusion MRI • Supports the incorporation of advanced MRI in high-grade glioma treatment response assessment.

Molecular Alterations of KIT Oncogene in Gliomas

PubMed Central

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

2007-01-01

Gliomas are the most common and devastating primary brain tumours. Despite therapeutic advances, the majority of gliomas do not respond either to chemo or radiotherapy. KIT, a class III receptor tyrosine kinase (RTK), is frequently involved in tumourigenic processes. Currently, KIT constitutes an attractive therapeutic target. In the present study we assessed the frequency of KIT overexpression in gliomas and investigated the genetic mechanisms underlying KIT overexpression. KIT (CD117) immunohistochemistry was performed in a series of 179 gliomas of various grades. KIT activating gene mutations (exons 9, 11, 13 and 17) and gene amplification analysis, as defined by chromogenic in situ hybridization (CISH) and quantitative real-time PCR (qRT-PCR) were performed in CD117 positive cases. Tumour cell immunopositivity was detected in 15.6% (28/179) of cases, namely in 25% (1/4) of pilocytic astrocytomas, 25% (5/20) of diffuse astrocytomas, 20% (1/5) of anaplastic astrocytomas, 19.5% (15/77) of glioblastomas and one third (3/9) of anaplastic oligoastrocytomas. Only 5.7% (2/35) of anaplastic oligodendrogliomas showed CD117 immunoreactivity. No association was found between tumour CD117 overexpression and patient survival. In addition, we also observed CD117 overexpression in endothelial cells, which varied from 0–22.2% of cases, being more frequent in high-grade lesions. No KIT activating mutations were identified. Interestingly, CISH and/or qRT-PCR analysis revealed the presence of KIT gene amplification in 6 glioblastomas and 2 anaplastic oligoastrocytomas, corresponding to 33% (8/24) of CD117 positive cases. In conclusion, our results demonstrate that KIT gene amplification rather than gene mutation is a common genetic mechanism underlying KIT expression in subset of malignant gliomas. Further studies are warranted to determine whether glioma patients exhibiting KIT overexpression and KIT gene amplification may benefit from therapy with anti-KIT RTK inhibitors. PMID:17726262

Relationship of In Vivo MR Parameters to Histopathological and Molecular Characteristics of Newly Diagnosed, Nonenhancing Lower-Grade Gliomas.

PubMed

Luks, Tracy L; McKnight, Tracy Richmond; Jalbert, Llewellyn E; Williams, Aurelia; Neill, Evan; Lobo, Khadjia A; Persson, Anders I; Perry, Arie; Phillips, Joanna J; Molinaro, Annette M; Chang, Susan M; Nelson, Sarah J

2018-06-05

The goal of this research was to elucidate the relationship between WHO 2016 molecular classifications of newly diagnosed, nonenhancing lower grade gliomas (LrGG), tissue sample histopathology, and magnetic resonance (MR) parameters derived from diffusion, perfusion, and 1 H spectroscopic imaging from the tissue sample locations and the entire tumor. A total of 135 patients were scanned prior to initial surgery, with tumor cellularity scores obtained from 88 image-guided tissue samples. MR parameters were obtained from corresponding sample locations, and histograms of normalized MR parameters within the T2 fluid-attenuated inversion recovery lesion were analyzed in order to evaluate differences between subgroups. For tissue samples, higher tumor scores were related to increased normalized apparent diffusion coefficient (nADC), lower fractional anisotropy (nFA), lower cerebral blood volume (nCBV), higher choline (nCho), and lower N-acetylaspartate (nNAA). Within the T2 lesion, higher tumor grade was associated with higher nADC, lower nFA, and higher Cho to NAA index. Pathological analysis confirmed that diffusion and metabolic parameters increased and perfusion decreased with tumor cellularity. This information can be used to select targets for tissue sampling and to aid in making decisions about treating residual disease. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Identifying the association between contrast enhancement pattern, surgical resection, and prognosis in anaplastic glioma patients.

PubMed

Wang, Yinyan; Wang, Kai; Wang, Jiangfei; Li, Shaowu; Ma, Jun; Dai, Jianping; Jiang, Tao

2016-04-01

Contrast enhancement observable on magnetic resonance (MR) images reflects the destructive features of malignant gliomas. This study aimed to investigate the relationship between radiologic patterns of tumor enhancement, extent of resection, and prognosis in patients with anaplastic gliomas (AGs). Clinical data from 268 patients with histologically confirmed AGs were retrospectively analyzed. Contrast enhancement patterns were classified based on preoperative T1-contrast MR images. Univariate and multivariate analyses were performed to evaluate the prognostic value of MR enhancement patterns on progression-free survival (PFS) and overall survival (OS). The pattern of tumor contrast enhancement was associated with the extent of surgical resection in AGs. A gross total resection was more likely to be achieved for AGs with focal enhancement than those with diffuse (p = 0.001) or ring-like (p = 0.024) enhancement. Additionally, patients with focal-enhanced AGs had a significantly longer PFS and OS than those with diffuse (log-rank, p = 0.025 and p = 0.031, respectively) or ring-like (log-rank, p = 0.008 and p = 0.011, respectively) enhanced AGs. Furthermore, multivariate analysis identified the pattern of tumor enhancement as a significant predictor of PFS (p = 0.016, hazard ratio [HR] = 1.485) and OS (p = 0.030, HR = 1.446). Our results suggested that the contrast enhancement pattern on preoperative MR images was associated with the extent of resection and predictive of survival outcomes in AG patients.

Novel internal regulators and candidate miRNAs within miR-379/miR-656 miRNA cluster can alter cellular phenotype of human glioblastoma.

PubMed

Nayak, Subhashree; Aich, Meghali; Kumar, Anupam; Sengupta, Suman; Bajad, Prajakta; Dhapola, Parashar; Paul, Deepanjan; Narta, Kiran; Purkrait, Suvendu; Mehani, Bharati; Suri, Ashish; Chakraborty, Debojyoti; Mukhopadhyay, Arijit; Sarkar, Chitra

2018-05-16

Clustered miRNAs can affect functioning of downstream pathways due to possible coordinated function. We observed 78-88% of the miR-379/miR-656 cluster (C14MC) miRNAs were downregulated in three sub-types of diffuse gliomas, which was also corroborated with analysis from The Cancer Genome Atlas (TCGA) datasets. The miRNA expression levels decreased with increasing tumor grade, indicating this downregulation as an early event in gliomagenesis. Higher expression of the C14MC miRNAs significantly improved glioblastioma prognosis (Pearson's r = 0.62; p < 3.08e-22). ENCODE meta-data analysis, followed by reporter assays validated existence of two novel internal regulators within C14MC. CRISPR activation of the most efficient internal regulator specifically induced members of the downstream miRNA sub-cluster and apoptosis in glioblastoma cells. Luciferase assays validated novel targets for miR-134 and miR-485-5p, two miRNAs from C14MC with the most number of target genes relevant for glioma. Overexpression of miR-134 and miR-485-5p in human glioblastoma cells suppressed invasion and proliferation, respectively. Furthermore, apoptosis was induced by both miRs, individually and in combination. The results emphasize the tumor suppressive role of C14MC in diffuse gliomas, and identifies two specific miRNAs with potential therapeutic value and towards better disease management and therapy.

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

PubMed Central

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

2017-01-01

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

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

PubMed

Duffau, Hugues; Taillandier, Luc

2015-03-01

Diffuse low-grade glioma grows, migrates along white matter tracts, and progresses to high-grade glioma. Rather than a "wait and see" policy, an aggressive attitude is now recommended, with early surgery as the first therapy. Intraoperative mapping, with maximal resection according to functional boundaries, is associated with a longer overall survival (OS) while minimizing morbidity. However, most studies have investigated the role of only one specific treatment (surgery, radiotherapy, chemotherapy) without taking a global view of managing the cumulative time while preserving quality of life (QoL) versus time to anaplastic transformation. Our aim is to switch towards a more holistic concept based upon the anticipation of a personalized and long-term multistage therapeutic approach, with online adaptation of the strategy over the years using feedback from clinical, radiological, and histomolecular monitoring. This dynamic strategy challenges the traditional approach by proposing earlier therapy, by repeating treatments, and by reversing the classical order of therapies (eg, neoadjuvant chemotherapy when maximal resection is impossible, no early radiotherapy) to improve OS and QoL. New individualized management strategies should deal with the interactions between the course of this chronic disease, reaction brain remapping, and oncofunctional modulation elicited by serial treatments. This philosophy supports a personalized, functional, and preventive neuro-oncology. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

White matter damage is related to ataxia severity in SCA3.

PubMed

Kang, J-S; Klein, J C; Baudrexel, S; Deichmann, R; Nolte, D; Hilker, R

2014-02-01

Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.

Apparent diffusion coefficient measurement in glioma: Influence of region-of-interest determination methods on apparent diffusion coefficient values, interobserver variability, time efficiency, and diagnostic ability.

PubMed

Han, Xu; Suo, Shiteng; Sun, Yawen; Zu, Jinyan; Qu, Jianxun; Zhou, Yan; Chen, Zengai; Xu, Jianrong

2017-03-01

To compare four methods of region-of-interest (ROI) placement for apparent diffusion coefficient (ADC) measurements in distinguishing low-grade gliomas (LGGs) from high-grade gliomas (HGGs). Two independent readers measured ADC parameters using four ROI methods (single-slice [single-round, five-round and freehand] and whole-volume) on 43 patients (20 LGGs, 23 HGGs) who had undergone 3.0 Tesla diffusion-weighted imaging and time required for each method of ADC measurements was recorded. Intraclass correlation coefficients (ICCs) were used to assess interobserver variability of ADC measurements. Mean and minimum ADC values and time required were compared using paired Student's t-tests. All ADC parameters (mean/minimum ADC values of three single-slice methods, mean/minimum/standard deviation/skewness/kurtosis/the10 th and 25 th percentiles/median/maximum of whole-volume method) were correlated with tumor grade (low versus high) by unpaired Student's t-tests. Discriminative ability was determined by receiver operating characteristic curves. All ADC measurements except minimum, skewness, and kurtosis of whole-volume ROI differed significantly between LGGs and HGGs (all P < 0.05). Mean ADC value of single-round ROI had the highest effect size (0.72) and the greatest areas under the curve (0.872). Three single-slice methods had good to excellent ICCs (0.67-0.89) and the whole-volume method fair to excellent ICCs (0.32-0.96). Minimum ADC values differed significantly between whole-volume and single-round ROI (P = 0.003) and, between whole-volume and five-round ROI (P = 0.001). The whole-volume method took significantly longer than all single-slice methods (all P < 0.001). ADC measurements are influenced by ROI determination methods. Whole-volume histogram analysis did not yield better results than single-slice methods and took longer. Mean ADC value derived from single-round ROI is the most optimal parameter for differentiating LGGs from HGGs. 3 J. Magn. Reson. Imaging 2017;45:722-730. © 2016 International Society for Magnetic Resonance in Medicine.

Establishment of Anti-Human ATRX Monoclonal Antibody AMab-6

PubMed Central

Ogasawara, Satoshi; Fujii, Yuki; Kaneko, Mika K.; Oki, Hiroharu; Sabit, Hemragul; Nakada, Mitsutoshi; Suzuki, Hiroyoshi; Ichimura, Koichi; Komori, Takashi

2016-01-01

Gliomas are the most frequently occurring brain tumors with a heterogeneous molecular background. The molecular subgrouping of gliomas more prognostically stratifies patients into distinct groups compared with conventional histological classification. The most important molecules for the subtype diagnosis of diffuse gliomas are mutations of isocitrate dehydrogenase (IDH), TERT promoter, and α-thalassemia/mental-retardation-syndrome-X-linked (ATRX) and the codeletion of 1p/19q. Among them, IDH and ATRX mutations can be diagnosed using specific monoclonal antibodies (mAbs). We have developed many mAbs against IDH mutants, including HMab-1/HMab-2 against IDH1-R132H and multispecific mAbs MsMab-1/MsMab-2 against IDH1/2 mutations. In contrast, highly sensitive mAbs against ATRX remain to be established. In this study, we immunized mice with recombinant human ATRX and developed a novel mAb, AMab-6. The dissociation constant of AMab-6 was determined to be 9.7 × 10−10 M, indicating that the binding affinity of AMab-6 is very high. Furthermore, AMab-6 sensitively detects ATRX in Western blot and immunohistochemical analyses, indicating that AMab-6 could become the standard marker to determine the ATRX mutation status of gliomas in immunohistochemical analyses. PMID:27788029

Establishment of Anti-Human ATRX Monoclonal Antibody AMab-6.

PubMed

Ogasawara, Satoshi; Fujii, Yuki; Kaneko, Mika K; Oki, Hiroharu; Sabit, Hemragul; Nakada, Mitsutoshi; Suzuki, Hiroyoshi; Ichimura, Koichi; Komori, Takashi; Kato, Yukinari

2016-10-01

Gliomas are the most frequently occurring brain tumors with a heterogeneous molecular background. The molecular subgrouping of gliomas more prognostically stratifies patients into distinct groups compared with conventional histological classification. The most important molecules for the subtype diagnosis of diffuse gliomas are mutations of isocitrate dehydrogenase (IDH), TERT promoter, and α-thalassemia/mental-retardation-syndrome-X-linked (ATRX) and the codeletion of 1p/19q. Among them, IDH and ATRX mutations can be diagnosed using specific monoclonal antibodies (mAbs). We have developed many mAbs against IDH mutants, including HMab-1/HMab-2 against IDH1-R132H and multispecific mAbs MsMab-1/MsMab-2 against IDH1/2 mutations. In contrast, highly sensitive mAbs against ATRX remain to be established. In this study, we immunized mice with recombinant human ATRX and developed a novel mAb, AMab-6. The dissociation constant of AMab-6 was determined to be 9.7 × 10 -10 M, indicating that the binding affinity of AMab-6 is very high. Furthermore, AMab-6 sensitively detects ATRX in Western blot and immunohistochemical analyses, indicating that AMab-6 could become the standard marker to determine the ATRX mutation status of gliomas in immunohistochemical analyses.

Optical-sectioning microscopy of protoporphyrin IX fluorescence in human gliomas: standardization and quantitative comparison with histology

NASA Astrophysics Data System (ADS)

Wei, Linpeng; Chen, Ye; Yin, Chengbo; Borwege, Sabine; Sanai, Nader; Liu, Jonathan T. C.

2017-04-01

Systemic delivery of 5-aminolevulinic acid leads to enhanced fluorescence image contrast in many tumors due to the increased accumulation of protoporphyrin IX (PpIX), a fluorescent porphyrin that is associated with tumor burden and proliferation. The value of PpIX-guided resection of malignant gliomas has been demonstrated in prospective randomized clinical studies in which a twofold greater extent of resection and improved progression-free survival have been observed. In low-grade gliomas and at the diffuse infiltrative margins of all gliomas, PpIX fluorescence is often too weak to be detected with current low-resolution surgical microscopes that are used in operating rooms. However, it has been demonstrated that high-resolution optical-sectioning microscopes are capable of detecting the sparse and punctate accumulations of PpIX that are undetectable via conventional low-power surgical fluorescence microscopes. To standardize the performance of high-resolution optical-sectioning devices for future clinical use, we have developed an imaging phantom and methods to ensure that the imaging of PpIX-expressing brain tissues can be performed reproducibly. Ex vivo imaging studies with a dual-axis confocal microscope demonstrate that these methods enable the acquisition of images from unsectioned human brain tissues that quantitatively and consistently correlate with images of histologically processed tissue sections.

Robust detection of EGFR copy number changes and EGFR variant III: technical aspects and relevance for glioma diagnostics.

PubMed

Jeuken, Judith; Sijben, Angelique; Alenda, Cristina; Rijntjes, Jos; Dekkers, Marieke; Boots-Sprenger, Sandra; McLendon, Roger; Wesseling, Pieter

2009-10-01

Epidermal growth factor receptor (EGFR) is commonly affected in cancer, generally in the form of an increase in DNA copy number and/or as mutation variants [e.g., EGFR variant III (EGFRvIII), an in-frame deletion of exons 2-7]. While detection of EGFR aberrations can be expected to be relevant for glioma patients, such analysis has not yet been implemented in a routine setting, also because feasible and robust assays were lacking. We evaluated multiplex ligation-dependent probe amplification (MLPA) for detection of EGFR amplification and EGFRvIII in DNA of a spectrum of 216 diffuse gliomas. EGFRvIII detection was verified at the protein level by immunohistochemistry and at the RNA level using the conventionally used endpoint RT-PCR as well as a newly developed quantitative RT-PCR. Compared to these techniques, the DNA-based MLPA assay for EGFR/EGFRvIII analysis tested showed 100% sensitivity and specificity. We conclude that MLPA is a robust assay for detection of EGFR/EGFRvIII aberrations. While the exact diagnostic, prognostic and predictive value of such EGFR testing remains to be seen, MLPA has great potential as it can reliably and relatively easily be performed on routinely processed (formalin-fixed, paraffin-embedded) tumor tissue in combination with testing for other relevant glioma markers.

Photo-activated Cancer Therapy: Potential for Treatment of Brain Tumors

NASA Astrophysics Data System (ADS)

Hirschberg, Henry

The diffuse and infiltrative nature of high grade gliomas, such as glioblastoma multiforme (GBM), makes complete surgical resection virtually impossible. The propensity of glioma cells to migrate along white matter tracts suggests that a cure is possible only if these migratory cells can be eradicated. Approximately 80% of GBMs recur within 2 cm of the resection margin, suggesting that a reasonable approach for improving the prognosis of GBM patients would be the development of improved local therapies capable of eradicating glioma cells in the brain-adjacent-to-tumor (BAT). An additional complicating factor for the development of successful therapies is the presence of the blood-brain barrier (BBB) which is highly variable throughout the BAT—it is intact in some regions, while leaky in others. This variance in BBB patency has significant implications for the delivery of therapeutic agents. The results of a number of studies have shown that experimental light-based therapeutic modalities such as photochemical internalization (PCI) and photothermal therapy (PTT) may be useful in the treatment of gliomas. This chapter summarizes recent findings illustrating the potential of: (1) PCI for the delivery of therapeutic macromolecules such as chemotherapeutic agents and tumor suppressor genes, and (2) nanoshell-mediated PTT, including nanoparticle delivery approaches via macrophages.

Distribution of MCH-containing fibers in the feline brainstem: Relevance for REM sleep regulation.

PubMed

Costa, Alicia; Castro-Zaballa, Santiago; Lagos, Patricia; Chase, Michael H; Torterolo, Pablo

2018-06-01

Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes, such as sleep. Unlike rodents, in the order carnivora as well as in humans, MCH exerts its biological functions through two receptors: MCHR-1 and MCHR-2. Hence, the cat is an optimal animal to model MCHergic functions in humans. In the present study, we examined the distribution of MCH-positive fibers in the brainstem of the cat. MCHergic axons with distinctive varicosities and boutons were heterogeneously distributed, exhibiting different densities in distinct regions of the brainstem. High density of MCHergic fibers was found in the dorsal raphe nucleus, the laterodorsal tegmental nucleus, the periaqueductal gray, the pendunculopontine tegmental nucleus, the locus coeruleus and the prepositus hypoglossi. Because these areas are involved in the control of REM sleep, the present anatomical data support the role of this neuropeptidergic system in the control of this behavioral state. Copyright © 2018 Elsevier Inc. All rights reserved.

Correction to: Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood.

PubMed

Massimino, Maura; Biassoni, Veronica; Miceli, Rosalba; Schiavello, Elisabetta; Warmuth-Metz, Monika; Modena, Piergiorgio; Casanova, Michela; Pecori, Emilia; Giangaspero, Felice; Antonelli, Manila; Buttarelli, Francesca Romana; Potepan, Paolo; Pollo, Bianca; Nunziata, Raffaele; Spreafico, Filippo; Podda, Marta; Anichini, Andrea; Clerici, Carlo Alfredo; Sardi, Iacopo; De Cecco, Loris; Bode, Udo; Bach, Ferdinand; Gandola, Lorenza

2018-05-16

The therapeutic experience reported in the paper was conceived after the use of nimotuzumab and radiotherapy (BSCPED-05 international multicentric trial, EUDRACT 2005-003100-11) in 2009 when we decided to explore the activity of the same combination plus vinorelbine (see the paper for the rationale).

An attempt to conceptualize the individual onco-functional balance: Why a standardized treatment is an illusion for diffuse low-grade glioma patients.

PubMed

Mandonnet, Emmanuel; Duffau, Hugues

2018-02-01

In the era of evidence-based medicine, clinicians aim to establish standards of care from randomized studies. Following, personalized medicine has emerged, as new individualized biomarkers could help to predict sensitivity to specific treatment. In this paper, we show that, for diffuse low-grade glioma, some specificities - dual goal of both survival and functional gain, long duration of the disease with multistep treatments, multiparametric evaluation of the onco-functional balance of each treatment modality - call for a change of paradigm. After summarizing how to weight the benefits and risks of surgery, chemotherapy and radiotherapy, we show that the overall efficacy of a treatment modality cannot be assessed per se, as it depends on its integration in the whole sequence. Then, we revisit the notion of personalized medicine: instead of decision-making based solely on molecular profile, we plead for a recursive algorithm, allowing a dynamic evaluation of the onco-functional balance, integrating many individual characteristics of the patient's tumor and brain function. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Immunization against GAD Induces Antibody Binding to GAD-Independent Antigens and Brainstem GABAergic Neuronal Loss

PubMed Central

Chang, Thashi; Alexopoulos, Harry; Pettingill, Philippa; McMenamin, Mary; Deacon, Robert; Erdelyi, Ferenc; Szabó, Gabor; Buckley, Camilla J.; Vincent, Angela

2013-01-01

Stiff person syndrome (SPS) is a highly-disabling neurological disorder of the CNS characterized by progressive muscular rigidity and spasms. In approximately 60–80% of patients there are autoantibodies to glutamic acid decarboxylase (GAD), the enzyme that synthesizes gamma-amino butyric acid (GABA), the predominant inhibitory neurotransmitter of the CNS. Although GAD is intracellular, it is thought that autoimmunity to GAD65 may play a role in the development of SPS. To test this hypothesis, we immunized mice, that expressed enhanced green fluorescent protein (EGFP) under the GAD65 promoter, with either GAD65 (n = 13) or phosphate buffered saline (PBS) (n = 13). Immunization with GAD65 resulted in autoantibodies that immunoprecipitated GAD, bound to CNS tissue in a highly characteristic pattern, and surprisingly bound not only to GAD intracellularly but also to the surface of cerebellar neurons in culture. Moreover, immunization resulted in immunoglobulin diffusion into the brainstem, and a partial loss of GAD-EGFP expressing cells in the brainstem. Although immunization with GAD65 did not produce any behavioral abnormality in the mice, the induction of neuronal-surface antibodies and the trend towards loss of GABAergic neurons in the brainstem, supports a role for humoral autoimmunity in the pathogenesis of SPS and suggests that the mechanisms may involve spread to antigens expressed on the surface of these neurons. PMID:24058450

The Influence of Traumatic Axonal Injury in Thalamus and Brainstem on Level of Consciousness at Scene or Admission: A Clinical Magnetic Resonance Imaging Study

PubMed Central

Moen, Kent Gøran; Skandsen, Toril; Kvistad, Kjell Arne; Laureys, Steven; Håberg, Asta; Vik, Anne

2018-01-01

Abstract The aim of this study was to investigate how traumatic axonal injury (TAI) lesions in the thalamus, basal ganglia, and brainstem on clinical brain magnetic resonance imaging (MRI) are associated with level of consciousness in the acute phase in patients with moderate to severe traumatic brain injury (TBI). There were 158 patients with moderate to severe TBI (7–70 years) with early 1.5T MRI (median 7 days, range 0–35) without mass lesion included prospectively. Glasgow Coma Scale (GCS) scores were registered before intubation or at admission. The TAI lesions were identified in T2*gradient echo, fluid attenuated inversion recovery, and diffusion weighted imaging scans. In addition to registering TAI lesions in hemispheric white matter and the corpus callosum, TAI lesions in the thalamus, basal ganglia, and brainstem were classified as uni- or bilateral. Twenty percent of patients had TAI lesions in the thalamus (7% bilateral), 18% in basal ganglia (2% bilateral), and 29% in the brainstem (9% bilateral). One of 26 bilateral lesions in the thalamus or brainstem was found on computed tomography. The GCS scores were lower in patients with bilateral lesions in the thalamus (median four) and brainstem (median five) than in those with corresponding unilateral lesions (median six and eight, p = 0.002 and 0.022). The TAI locations most associated with low GCS scores in univariable ordinal regression analyses were bilateral TAI lesions in the thalamus (odds ratio [OR] 35.8; confidence interval [CI: 10.5−121.8], p < 0.001), followed by bilateral lesions in basal ganglia (OR 13.1 [CI: 2.0–88.2], p = 0.008) and bilateral lesions in the brainstem (OR 11.4 [CI: 4.0–32.2], p < 0.001). This Trondheim TBI study showed that patients with bilateral TAI lesions in the thalamus, basal ganglia, or brainstem had particularly low consciousness at admission. We suggest these bilateral lesions should be evaluated further as possible biomarkers in a new TAI-MRI classification as a worst grade, because they could explain low consciousness in patients without mass lesions. PMID:29334825

TH-EF-BRB-01: BEST IN PHYSICS (THERAPY): Dosimetric Comparison of 4π and Clinical IMRT for Cortex-Sparing High-Grade Glioma Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woods, K; Tran, A; Yu, V

Purpose: Thinning of the cerebral cortex has been observed in patients treated with fractionated partial brain radiation therapy and may contribute to cognitive decline following treatment. The extent of this thinning is dose-dependent, and was shown comparable to that of neurodegenerative diseases such as Alzheimer’s disease at one year post-therapy. This study investigates whether 4π radiotherapy can enable better sparing of the cortex and other critical structures when compared to conventional clinical IMRT plans. Methods: Clinical cortex-sparing IMRT plans for 15 high-grade glioma patients were included in this study. 4π radiotherapy plans were created for each patient with 20 intensity-modulatedmore » non-coplanar fields selected with a greedy column-generation optimization. All plans were normalized to deliver 100% of the prescribed dose to 95% of the planning target volume (PTV). The mean and maximum dose to the cerebral cortex and other organs at risk (OARs) were compared for the two plan types, as well as the conformity index (CI), homogeneity index (HI), and 50% dose spillage volume (R50). Results: The 4π plans significantly reduced the mean cortex dose by an average of 16% (range 6% to 27%) compared to the clinical plans. The mean dose to every other OAR compared was also reduced by 15% to 43%, with statistically significant reductions to the brainstem, chiasm, eyes, optic nerves, subcortical whit, and hippocampus. The average maximum doses were also reduced for 10/12 OARs. The R50 was significantly reduced with the 4π plans (>14%) and the homogeneity index was significantly improved. Conclusion: 4π enables significant sparing of the cerebral cortex when treating high-grade gliomas with fractionated partial brain radiation therapy, potentially reducing the risk of harmful dose-dependent cortical thinning. NIH R43CA183390, NIH R01CA188300, Varian Medical Systems.« less

Identification of early and distinct glioblastoma response patterns treated by boron neutron capture therapy not predicted by standard radiographic assessment using functional diffusion map

PubMed Central

2013-01-01

Background Radiologic response of brain tumors is traditionally assessed according to the Macdonald criteria 10 weeks from the start of therapy. Because glioblastoma (GB) responds in days rather than weeks after boron neutron capture therapy (BNCT) that is a form of tumor-selective particle radiation, it is inconvenient to use the Macdonald criteria to assess the therapeutic efficacy of BNCT by gadolinium-magnetic resonance imaging (Gd-MRI). Our study assessed the utility of functional diffusion map (fDM) for evaluating response patterns in GB treated by BNCT. Methods The fDM is an image assessment using time-dependent changes of apparent diffusion coefficient (ADC) in tumors on a voxel-by-voxel approach. Other than time-dependent changes of ADC, fDM can automatically assess minimum/maximum ADC, Response Evaluation Criteria In Solid Tumors (RECIST), and the volume of enhanced lesions on Gd-MRI over time. We assessed 17 GB patients treated by BNCT using fDM. Additionally, in order to verify our results, we performed a histopathological examination using F98 rat glioma models. Results Only the volume of tumor with decreased ADC by fDM at 2 days after BNCT was a good predictor for GB patients treated by BNCT (P value = 0.022 by log-rank test and 0.033 by wilcoxon test). In a histopathological examination, brain sections of F98 rat glioma models treated by BNCT showed cell swelling of both the nuclei and the cytoplasm compared with untreated rat glioma models. Conclusions The fDM could identify response patterns in BNCT-treated GB earlier than a standard radiographic assessment. Early detection of treatment failure can allow a change or supplementation before tumor progression and might lead to an improvement of GB patients’ prognosis. PMID:23915330

Distributed abnormalities of brain white matter architecture in patients with dominant optic atrophy and OPA1 mutations.

PubMed

Rocca, Maria A; Bianchi-Marzoli, Stefania; Messina, Roberta; Cascavilla, Maria Lucia; Zeviani, Massimo; Lamperti, Costanza; Milesi, Jacopo; Carta, Arturo; Cammarata, Gabriella; Leocani, Letizia; Lamantea, Eleonora; Bandello, Francesco; Comi, Giancarlo; Falini, Andrea; Filippi, Massimo

2015-05-01

Using advanced MRI techniques, we investigated the presence and topographical distribution of brain grey matter (GM) and white matter (WM) alterations in dominant optic atrophy (DOA) patients with genetically proven OPA1 mutation as well as their correlation with clinical and neuro-ophthalmologic findings. Nineteen DOA patients underwent neurological, neuro-ophthalmologic and brainstem auditory evoked potentials (BAEP) evaluations. Voxel-wise methods were applied to assess regional GM and WM abnormalities in patients compared to 20 healthy controls. Visual acuity was reduced in 16 patients. Six DOA patients (4 with missense mutations) had an abnormal I peripheral component (auditory nerve) at BAEP. Compared to controls, DOA patients had significant atrophy of the optic nerves (p < 0.0001). Voxel-based morphometry (VBM) analysis showed that, compared to controls, DOA patients had significant WM atrophy of the chiasm and optic tracts; whereas no areas of GM atrophy were found. Tract-based spatial statistics (TBSS) analysis showed that compared to controls, DOA patients had significantly lower mean diffusivity, axial and radial diffusivity in the WM of the cerebellum, brainstem, thalamus, fronto-occipital-temporal lobes, including the cingulum, corpus callosum, corticospinal tract and optic radiation bilaterally. No abnormalities of fractional anisotropy were detected. No correlations were found between volumetric and diffusivity abnormalities quantified with MRI and clinical and neuro-ophthalmologic measures of disease severity. Consistently with pathological studies, tissue loss in DOA patients is limited to anterior optic pathways reflecting retinal ganglion cell degeneration. Distributed abnormalities of diffusivity indexes might reflect abnormal intracellular mitochondrial morphology as well as alteration of protein levels due to OPA1 mutations.

Depressive disorder may be associated with raphe nuclei lesions in patients with brainstem infarction.

PubMed

Numasawa, Yoshiyuki; Hattori, Takaaki; Ishiai, Sumio; Kobayashi, Zen; Kamata, Tomoyuki; Kotera, Minoru; Ishibashi, Satoru; Sanjo, Nobuo; Mizusawa, Hidehiro; Yokota, Takanori

2017-04-15

Depression is a common symptom after stroke, but its neural substrates remain unclear. The ascending serotonergic system originates from the raphe nuclei in the brainstem. We hypothesized that depressive disorder due to brainstem infarction is associated with damage to the raphe nuclei. We prospectively enrolled 19 patients who had the first-ever acute isolated brainstem infarction in an observational cross-sectional study. All patients were evaluated by using the Montgomery Åsberg Depression Rating Scale (MADRS), the clinician-rated version of Apathy Evaluation Scale (AES-C) and Mini-Mental State Examination (MMSE). Depressive disorder was diagnosed according to DSM-5 and MADRS score of 12 or greater. Diffusion tensor imaging and proton density-weighted images were used to identify damage in the raphe nuclei. Accordingly, patients were classified into either the raphe-nuclei-damaged or intact group. Prevalence of depressive disorder and the MADRS, AES-C, and MMSE scores were compared between the two groups. Depressive disorder was more frequent in the damaged group (n=6) than in the intact group (n=13) (83% vs. 15%; P=0.01). MADRS scores were higher in the damaged group than in the intact group (mean±1 SD, 17.5±7.9 vs. 7.0±4.4; P=0.002), whereas the AES-C and MMSE scores did not differ between groups. We did not assess the damage to the ascending projection fibers from the raphe nuclei. Our results suggest that damage to the raphe nuclei underlies depressive disorder due to brainstem infarction, possibly via serotonergic denervation. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed

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

2015-09-01

Conventional white matter (WM) imaging approaches, such as diffusion tensor imaging (DTI), have been used to preoperatively identify the location of affected WM tracts in patients with intracranial tumors in order to maximize the extent of resection and potentially reduce postoperative morbidity. DTI, however, has limitations that include its inability to resolve multiple crossing fibers and its susceptibility to partial volume effects. Therefore, recent focus has shifted to more advanced WM imaging techniques such as high-definition fiber tractography (HDFT). In this paper, we illustrate the application of HDFT, which in our preliminary experience has enabled accurate depiction of perilesional tracts in a 3-dimensional manner in multiple anatomical compartments including edematous zones around high-grade gliomas. This has facilitated accurate surgical planning. This is illustrated by using case examples of patients with glioblastoma multiforme. We also discuss future directions in the role of these techniques in surgery for gliomas. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cerebral Proliferative Angiopathy (CPA): Imaging Findings and Response to Therapy.

PubMed

Lopci, Egesta; Olivari, Laura; Bello, Lorenzo; Navarria, Pierina; Chiti, Arturo

2016-12-01

We report the case of a 55-year-old woman with cerebral proliferative angiopathy (CPA). Her medical history included brain surgery for small vascular lesions and suspicion of cerebral malignancy. C methionine PET (C-METH PET) demonstrated a diffusely increased uptake on the right hemisphere. Contrast-enhanced MRI documented a massive lesion with a diffuse "nidus" appearance, involving the right cerebral hemisphere (sparing the inferior frontal gyrus and the anterior frontal lobe), the brainstem, and the middle cerebellar peduncle. Pathology confirmed the diagnosis of CPA and, after radiation treatment, the patient presented with clinical and radiological response.

HINTS to diagnose stroke in the acute vestibular syndrome: three-step bedside oculomotor examination more sensitive than early MRI diffusion-weighted imaging.

PubMed

Kattah, Jorge C; Talkad, Arun V; Wang, David Z; Hsieh, Yu-Hsiang; Newman-Toker, David E

2009-11-01

Acute vestibular syndrome (AVS) is often due to vestibular neuritis but can result from vertebrobasilar strokes. Misdiagnosis of posterior fossa infarcts in emergency care settings is frequent. Bedside oculomotor findings may reliably identify stroke in AVS, but prospective studies have been lacking. The authors conducted a prospective, cross-sectional study at an academic hospital. Consecutive patients with AVS (vertigo, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with >or=1 stroke risk factor underwent structured examination, including horizontal head impulse test of vestibulo-ocular reflex function, observation of nystagmus in different gaze positions, and prism cross-cover test of ocular alignment. All underwent neuroimaging and admission (generally <72 hours after symptom onset). Strokes were diagnosed by MRI or CT. Peripheral lesions were diagnosed by normal MRI and clinical follow-up. One hundred one high-risk patients with AVS included 25 peripheral and 76 central lesions (69 ischemic strokes, 4 hemorrhages, 3 other). The presence of normal horizontal head impulse test, direction-changing nystagmus in eccentric gaze, or skew deviation (vertical ocular misalignment) was 100% sensitive and 96% specific for stroke. Skew was present in 17% and associated with brainstem lesions (4% peripheral, 4% pure cerebellar, 30% brainstem involvement; chi(2), P=0.003). Skew correctly predicted lateral pontine stroke in 2 of 3 cases in which an abnormal horizontal head impulse test erroneously suggested peripheral localization. Initial MRI diffusion-weighted imaging was falsely negative in 12% (all <48 hours after symptom onset). Skew predicts brainstem involvement in AVS and can identify stroke when an abnormal horizontal head impulse test falsely suggests a peripheral lesion. A 3-step bedside oculomotor examination (HINTS: Head-Impulse-Nystagmus-Test-of-Skew) appears more sensitive for stroke than early MRI in AVS.

Quantitative correlational study of microbubble-enhanced ultrasound imaging and magnetic resonance imaging of glioma and early response to radiotherapy in a rat model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Chen; Lee, Dong-Hoon; Zhang, Kai

Purpose: Radiotherapy remains a major treatment method for malignant tumors. Magnetic resonance imaging (MRI) is the standard modality for assessing glioma treatment response in the clinic. Compared to MRI, ultrasound imaging is low-cost and portable and can be used during intraoperative procedures. The purpose of this study was to quantitatively compare contrast-enhanced ultrasound (CEUS) imaging and MRI of irradiated gliomas in rats and to determine which quantitative ultrasound imaging parameters can be used for the assessment of early response to radiation in glioma. Methods: Thirteen nude rats with U87 glioma were used. A small thinned skull window preparation was performedmore » to facilitate ultrasound imaging and mimic intraoperative procedures. Both CEUS and MRI with structural, functional, and molecular imaging parameters were performed at preradiation and at 1 day and 4 days postradiation. Statistical analysis was performed to determine the correlations between MRI and CEUS parameters and the changes between pre- and postradiation imaging. Results: Area under the curve (AUC) in CEUS showed significant difference between preradiation and 4 days postradiation, along with four MRI parameters, T{sub 2}, apparent diffusion coefficient, cerebral blood flow, and amide proton transfer-weighted (APTw) (all p < 0.05). The APTw signal was correlated with three CEUS parameters, rise time (r = − 0.527, p < 0.05), time to peak (r = − 0.501, p < 0.05), and perfusion index (r = 458, p < 0.05). Cerebral blood flow was correlated with rise time (r = − 0.589, p < 0.01) and time to peak (r = − 0.543, p < 0.05). Conclusions: MRI can be used for the assessment of radiotherapy treatment response and CEUS with AUC as a new technique and can also be one of the assessment methods for early response to radiation in glioma.« less

A pilot cost-effectiveness analysis of treatments in newly diagnosed high-grade gliomas: the example of 5-aminolevulinic Acid compared with white-light surgery.

PubMed

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

2015-05-01

High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. The incremental cost-effectiveness ratios are below &OV0556;10 000 in all evaluated outcomes, being around &OV0556;9100 per quality-adjusted life-year gained, &OV0556;6700 per life-year gained, and &OV0556;8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of &OV0556;20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on the basis of existing data.

5-Aminolevulinic Acid Induced Fluorescence Is a Powerful Intraoperative Marker for Precise Histopathological Grading of Gliomas with Non-Significant Contrast-Enhancement

PubMed Central

Widhalm, Georg; Kiesel, Barbara; Woehrer, Adelheid; Traub-Weidinger, Tatjana; Preusser, Matthias; Marosi, Christine; Prayer, Daniela; Hainfellner, Johannes A.; Knosp, Engelbert; Wolfsberger, Stefan

2013-01-01

Background Intraoperative identification of anaplastic foci in diffusely infiltrating gliomas (DIG) with non-significant contrast-enhancement on MRI is indispensible to avoid histopathological undergrading and subsequent treatment failure. Recently, we found that 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence can visualize areas with increased proliferative and metabolic activity in such gliomas intraoperatively. As treatment of DIG is predominantely based on histopathological World Health Organisation (WHO) parameters, we analyzed whether PpIX fluorescence can detect anaplastic foci according to these criteria. Methods We prospectively included DIG patients with non-significant contrast-enhancement that received 5-ALA prior to resection. Intraoperatively, multiple samples from PpIX positive and negative intratumoral areas were collected using a modified neurosurgical microscope. In all samples, histopathological WHO criteria and proliferation rate were assessed and correlated to the PpIX fluorescence status. Results A total of 215 tumor specimens were collected in 59 patients. Of 26 WHO grade III gliomas, 23 cases (85%) showed focal PpIX fluorescence, whereas 29 (91%) of 33 WHO grade II gliomas were PpIX negative. In intratumoral areas with focal PpIX fluorescence, mitotic rate, cell density, nuclear pleomorphism, and proliferation rate were significantly higher than in non-fluorescing areas. The positive predictive value of focal PpIX fluorescence for WHO grade III histology was 85%. Conclusions Our study indicates that 5-ALA induced PpIX fluorescence is a powerful marker for intraoperative identification of anaplastic foci according to the histopathological WHO criteria in DIG with non-significant contrast-enhancement. Therefore, application of 5-ALA optimizes tissue sampling for precise histopathological diagnosis independent of brain-shift. PMID:24204718

Multimodal 18F-Fluciclovine PET/MRI and Ultrasound-Guided Neurosurgery of an Anaplastic Oligodendroglioma.

PubMed

Karlberg, Anna; Berntsen, Erik Magnus; Johansen, Håkon; Myrthue, Mariane; Skjulsvik, Anne Jarstein; Reinertsen, Ingerid; Esmaeili, Morteza; Dai, Hong Yan; Xiao, Yiming; Rivaz, Hassan; Borghammer, Per; Solheim, Ole; Eikenes, Live

2017-12-01

Structural magnetic resonance imaging (MRI) and histopathologic tissue sampling are routinely performed as part of the diagnostic workup for patients with glioma. Because of the heterogeneous nature of gliomas, there is a risk of undergrading caused by histopathologic sampling errors. MRI has limitations in identifying tumor grade and type, detecting diffuse invasive growth, and separating recurrences from treatment induced changes. Positron emission tomography (PET) can provide quantitative information of cellular activity and metabolism, and may therefore complement MRI. In this report, we present the first patient with brain glioma examined with simultaneous PET/MRI using the amino acid tracer 18 F-fluciclovine ( 18 F-FACBC) for intraoperative image-guided surgery. A previously healthy 60-year old woman was admitted to the emergency care with speech difficulties and a mild left-sided hemiparesis. MRI revealed a tumor that was suggestive of glioma. Before surgery, the patient underwent a simultaneous PET/MRI examination. Fused PET/MRI, T1, FLAIR, and intraoperative three-dimensional ultrasound images were used to guide histopathologic tissue sampling and surgical resection. Navigated, image-guided histopathologic samples were compared with PET/MRI image data to assess the additional value of the PET acquisition. Histopathologic analysis showed anaplastic oligodendroglioma in the most malignant parts of the tumor, while several regions were World Health Organization (WHO) grade II. 18 F-Fluciclovine uptake was found in parts of the tumor where regional WHO grade, cell proliferation, and cell densities were highest. This finding suggests that PET/MRI with this tracer could be used to improve accuracy in histopathologic tissue sampling and grading, and possibly for guiding treatments targeting the most malignant part of extensive and eloquent gliomas. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement.

PubMed

Widhalm, Georg; Kiesel, Barbara; Woehrer, Adelheid; Traub-Weidinger, Tatjana; Preusser, Matthias; Marosi, Christine; Prayer, Daniela; Hainfellner, Johannes A; Knosp, Engelbert; Wolfsberger, Stefan

2013-01-01

Intraoperative identification of anaplastic foci in diffusely infiltrating gliomas (DIG) with non-significant contrast-enhancement on MRI is indispensible to avoid histopathological undergrading and subsequent treatment failure. Recently, we found that 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence can visualize areas with increased proliferative and metabolic activity in such gliomas intraoperatively. As treatment of DIG is predominantely based on histopathological World Health Organisation (WHO) parameters, we analyzed whether PpIX fluorescence can detect anaplastic foci according to these criteria. We prospectively included DIG patients with non-significant contrast-enhancement that received 5-ALA prior to resection. Intraoperatively, multiple samples from PpIX positive and negative intratumoral areas were collected using a modified neurosurgical microscope. In all samples, histopathological WHO criteria and proliferation rate were assessed and correlated to the PpIX fluorescence status. A total of 215 tumor specimens were collected in 59 patients. Of 26 WHO grade III gliomas, 23 cases (85%) showed focal PpIX fluorescence, whereas 29 (91%) of 33 WHO grade II gliomas were PpIX negative. In intratumoral areas with focal PpIX fluorescence, mitotic rate, cell density, nuclear pleomorphism, and proliferation rate were significantly higher than in non-fluorescing areas. The positive predictive value of focal PpIX fluorescence for WHO grade III histology was 85%. Our study indicates that 5-ALA induced PpIX fluorescence is a powerful marker for intraoperative identification of anaplastic foci according to the histopathological WHO criteria in DIG with non-significant contrast-enhancement. Therefore, application of 5-ALA optimizes tissue sampling for precise histopathological diagnosis independent of brain-shift.

Machine learning: a useful radiological adjunct in determination of a newly diagnosed glioma's grade and IDH status.

PubMed

De Looze, Céline; Beausang, Alan; Cryan, Jane; Loftus, Teresa; Buckley, Patrick G; Farrell, Michael; Looby, Seamus; Reilly, Richard; Brett, Francesca; Kearney, Hugh

2018-05-16

Machine learning methods have been introduced as a computer aided diagnostic tool, with applications to glioma characterisation on MRI. Such an algorithmic approach may provide a useful adjunct for a rapid and accurate diagnosis of a glioma. The aim of this study is to devise a machine learning algorithm that may be used by radiologists in routine practice to aid diagnosis of both: WHO grade and IDH mutation status in de novo gliomas. To evaluate the status quo, we interrogated the accuracy of neuroradiology reports in relation to WHO grade: grade II 96.49% (95% confidence intervals [CI] 0.88, 0.99); III 36.51% (95% CI 0.24, 0.50); IV 72.9% (95% CI 0.67, 0.78). We derived five MRI parameters from the same diagnostic brain scans, in under two minutes per case, and then supplied these data to a random forest algorithm. Machine learning resulted in a high level of accuracy in prediction of tumour grade: grade II/III; area under the receiver operating characteristic curve (AUC) = 98%, sensitivity = 0.82, specificity = 0.94; grade II/IV; AUC = 100%, sensitivity = 1.0, specificity = 1.0; grade III/IV; AUC = 97%, sensitivity = 0.83, specificity = 0.97. Furthermore, machine learning also facilitated the discrimination of IDH status: AUC of 88%, sensitivity = 0.81, specificity = 0.77. These data demonstrate the ability of machine learning to accurately classify diffuse gliomas by both WHO grade and IDH status from routine MRI alone-without significant image processing, which may facilitate usage as a diagnostic adjunct in clinical practice.

Sox11 expression in astrocytic gliomas: correlation with nestin/c-Met/IDH1-R132H expression phenotypes, p-Stat-3 and survival

PubMed Central

Korkolopoulou, P; Levidou, G; El-Habr, E A; Adamopoulos, C; Fragkou, P; Boviatsis, E; Themistocleous, M S; Petraki, K; Vrettakos, G; Sakalidou, M; Samaras, V; Zisakis, A; Saetta, A; Chatziandreou, I; Patsouris, E; Piperi, C

2013-01-01

Background: Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. Methods: We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. Results: Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. Conclusions: We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma. PMID:23619925

Sox11 expression in astrocytic gliomas: correlation with nestin/c-Met/IDH1-R132H expression phenotypes, p-Stat-3 and survival.

PubMed

Korkolopoulou, P; Levidou, G; El-Habr, E A; Adamopoulos, C; Fragkou, P; Boviatsis, E; Themistocleous, M S; Petraki, K; Vrettakos, G; Sakalidou, M; Samaras, V; Zisakis, A; Saetta, A; Chatziandreou, I; Patsouris, E; Piperi, C

2013-05-28

Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma.

Diffusion Tensor Imaging Tractography Detecting Isolated Oculomotor Nerve Damage After Traumatic Brain Injury.

PubMed

Jacquesson, Timothée; Frindel, Carole; Cotton, Francois

2017-04-01

A 24-year-old woman was hit by a bus and suffered an isolated complete oculomotor nerve palsy. Computed tomography scan did not show a skull base fracture. T2*-weighted magnetic resonance imaging revealed petechial cerebral hemorrhages sparing the brainstem. T2 constructive interference in steady state suggested a partial sectioning of the left oculomotor nerve just before entering the superior orbital fissure. Diffusion tensor imaging fiber tractography confirmed a sharp arrest of the left oculomotor nerve. This recent imaging technique could be of interest to assess white fiber damage and help make a diagnosis or prognosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Preoperative grading of supratentorial nonenhancing gliomas by high b-value diffusion-weighted 3 T magnetic resonance imaging.

PubMed

Han, Haiwei; Han, Chengkun; Wu, Xiurong; Zhong, Shan; Zhuang, Xiongjie; Tan, Guowei; Wu, Hua

2017-05-01

The purpose of this study was to determine the difference in discrimination between high- and low-grade supratentorial nonenhancing gliomas (HGGs and LGGs, respectively) when using apparent diffusion coefficient (ADC) values with high or standard b-value. Thirty-nine patients underwent conventional magnetic resonance imaging and diffusion-weighted imaging (DWI) with standard and high b-values (b = 1000 and 3000 s/mm 2 , respectively). Minimum, maximum, and mean ADC values (ADC MIN , ADC MAX , and ADC MEAN , respectively) were measured from ADC maps with both b-values. Receiver operating curve analysis was used to determine the cutoff ADC values for distinguishing between nonenhancing HGGs and LGGs. ADC MIN , ADC MAX , and ADC MEAN values for the nonenhancing HGGs were lower than those for LGGs. These differences were much larger when a high b-value was used (all P < 0.0001) than when a standard b-value was used (P = 0.0001, <0.0001, and <0.0001, respectively). Discriminant analysis indicated that the greatest likelihood for discriminating HGGs and LGGs when ADC MEAN was obtained with a high b-value, with cutoff value of 0.814 × 10 -3  mm 2 /s. ADC values obtained with a high b-value can be useful for grading and surgical management of nonenhancing HGGs and LGGs. The lowest degree of overlap was obtained when ADC MEAN was determined with a b-value of 3000 s/mm 2 .

Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas.

PubMed

Hayes, Josie; Yu, Yao; Jalbert, Llewellyn E; Mazor, Tali; Jones, Lindsey E; Wood, Matthew D; Walsh, Kyle M; Bengtsson, Henrik; Hong, Chibo; Oberndorfer, Stefan; Roetzer, Thomas; Smirnov, Ivan V; Clarke, Jennifer L; Aghi, Manish K; Chang, Susan M; Nelson, Sarah J; Woehrer, Adelheid; Phillips, Joanna J; Solomon, David A; Costello, Joseph F

2018-04-09

Rare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution. In this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions. One patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second. Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note.

PubMed

Coca, H A; Cebula, H; Benmekhbi, M; Chenard, M P; Entz-Werle, N; Proust, F

2016-12-01

Diffuse intrinsic pontine gliomas (DIPG) constitute 10-15% of all brain tumors in the pediatric population; currently prognosis remains poor, with an overall survival of 7-14 months. Recently the indication of DIPG biopsy has been enlarged due to the development of molecular biology and various ongoing clinical and therapeutic trials. Classically a biopsy is performed using a stereotactic frame assisted procedure but the workflow may sometimes be heavy and more complex especially in children. In this study the authors present their experience with frameless robotic-guided biopsy of DIPG in a pediatric population. Retrospective study on a series of five consecutive pediatric patients harboring DIPG treated over a 4-year period. All patients underwent frameless robotic-guided biopsy via a transcerebellar approach. Among the 5 patients studied 3 were male and 2 female with a median age of 8.6 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy in all patients. MRI imaging of the lesion showed typical DIPG features (3 of them located in the pons) with hypo-intensity on T1 and hyper-intensity signal on T2 sequences and diffuse gadolinium enhancement. The mean procedure time was 56minutes (range 45 to 67minutes). No new postoperative neurological deficits were recorded. Histological diagnosis was achieved in all cases as follows: two anaplastic astrocytomas (grade III), two glioblastomas, and one diffuse astrocytoma (grade III). Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

MR-monitored LITT as a palliative concept in patients with high grade gliomas: preliminary clinical experience.

PubMed

Reimer, P; Bremer, C; Horch, C; Morgenroth, C; Allkemper, T; Schuierer, G

1998-01-01

The purpose of this study was to evaluate the clinical utility of laser-induced thermotherapy (LITT) as a palliative treatment for patients with high-grade gliomas. Four consenting patients with recurrent high grade III/IV gliomas near the primary language or motor areas were palliatively treated with LITT (2-5 W, 3-13 minutes; Neodym YAG Laser, Dornier, Friedrichshafen, Germany). Temperature monitoring was performed by T1-weighted turbo-fast low-angle shot (FLASH) imaging at 1.5 T (Siemens Magnetom SP 4000, Siemens, Erlangen, Germany). MRI studies before LITT included contrast-enhanced conventional scans and functional activation studies to localize the primary motor cortex or language areas using an echo-planar imaging (EPI) spin-echo (SE) sequence. Follow-up studies consisted of contrast-enhanced conventional scans as well as diffusion studies (contrast-enhanced Fourier-acquired steady-state technique and EPI-SE) and perfusion studies (EPI-SE with .2 mmol of gadolinium (Gd)/kg body weight) to differentiate post-therapeutic effects from residual or recurrent tumor growth. Local tumor control was achieved in areas with laser energy deposition with clinically stable conditions > or = 6 months. Conventional contrast-enhanced scans demonstrated strong enhancement surrounding ablated tumor components, which showed a reduction in CBV/CBF. Perfusion studies were useful to discriminate granulomatous tissue enhancement from residual or recurrent tumor growth. Careful application of LITT may evolve as an alternative palliative concept for patients with end-stage high-grade cerebral gliomas reducing clinical symptoms from circumscribed areas of pathology.

OP17MICRORNA PROFILING USING SMALL RNA-SEQ IN PAEDIATRIC LOW GRADE GLIOMAS

PubMed Central

Jeyapalan, Jennie N.; Jones, Tania A.; Tatevossian, Ruth G.; Qaddoumi, Ibrahim; Ellison, David W.; Sheer, Denise

2014-01-01

INTRODUCTION: MicroRNAs regulate gene expression by targeting mRNAs for translational repression or degradation at the post-transcriptional level. In paediatric low-grade gliomas a few key genetic mutations have been identified, including BRAF fusions, FGFR1 duplications and MYB rearrangements. Our aim in the current study is to profile aberrant microRNA expression in paediatric low-grade gliomas and determine the role of epigenetic changes in the aetiology and behaviour of these tumours. METHOD: MicroRNA profiling of tumour samples (6 pilocytic, 2 diffuse, 2 pilomyxoid astrocytomas) and normal brain controls (4 adult normal brain samples and a primary glial progenitor cell-line) was performed using small RNA sequencing. Bioinformatic analysis included sequence alignment, analysis of the number of reads (CPM, counts per million) and differential expression. RESULTS: Sequence alignment identified 695 microRNAs, whose expression was compared in tumours v. normal brain. PCA and hierarchical clustering showed separate groups for tumours and normal brain. Computational analysis identified approximately 400 differentially expressed microRNAs in the tumours compared to matched location controls. Our findings will then be validated and integrated with extensive genetic and epigenetic information we have previously obtained for the full tumour cohort. CONCLUSION: We have identified microRNAs that are differentially expressed in paediatric low-grade gliomas. As microRNAs are known to target genes involved in the initiation and progression of cancer, they provide critical information on tumour pathogenesis and are an important class of biomarkers.

Oxaliplatin and Irinotecan in Treating Young Patients With Refractory Solid Tumors or Lymphomas

ClinicalTrials.gov

2013-06-04

Childhood Burkitt Lymphoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway Glioma; Recurrent Colon Cancer; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Melanoma; Recurrent Nasopharyngeal Cancer; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

Expression of amyloid-β protein and amyloid-β precursor protein after primary brain-stem injury in rats.

PubMed

Yang, Shudong; Sun, Rongchao; Zhou, Zhiyi; Zhou, Jing; Liang, Jiabei; Mu, Huijun

2014-09-01

Amyloid-β (Aβ) protein and its precursor, amyloid-β precursor protein (β-APP), have traditionally been used in the diagnosis of Alzheimer disease. Their use in diagnosis of traumatic brain injury by forensic analysis is becoming more widespread. However, to date, no reliable small animal model exists to evaluate these brain injury indicators. To address this, we have studied primary brain-stem injury in rats to assess the appearance of diffuse axonal injury in brain sections and correlate these findings with appearance of Aβ and relative β-APP mRNA levels. Using an EnVision 2-step immunohistochemical staining method to measure axon diameter, we found that there was significant difference in axon diameters within the medulla oblongata and several time points after brain injury, ranging from 3 to 24 hours. In addition, mRNA expression levels of β-APP increased following brain injury, peaking 3 hours following injury and decreasing back to baseline levels by 24 hours after injury. These results suggest that using immunohistochemistry and reverse transcription-polymerase chain reaction to detect changes in Aβ-associated axonal changes and β-APP mRNA levels, respectively, can be useful for the diagnosis of diffuse axonal injury during autopsy at early time points following fatal brain injury.

Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders.

PubMed

Edlow, Brian L; Takahashi, Emi; Wu, Ona; Benner, Thomas; Dai, Guangping; Bu, Lihong; Grant, Patricia Ellen; Greer, David M; Greenberg, Steven M; Kinney, Hannah C; Folkerth, Rebecca D

2012-06-01

The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

Interhemispheric Difference Images from Postoperative Diffusion Tensor Imaging of Gliomas

PubMed Central

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

2016-01-01

Introduction Determining the full extent of gliomas during radiotherapy planning can be challenging with conventional T1 and T2 magnetic resonance imaging (MRI). The purpose of this study was to develop a method to automatically calculate differences in the fractional anisotropy (FA) and mean diffusivity (MD) values in target volumes obtained with diffusion tensor imaging (DTI) by comparing with values from anatomically homologous voxels on the contralateral side of the brain. Methods Seven patients with a histologically confirmed glioma underwent postoperative radiotherapy planning with 1.5 T MRI and computed tomography. DTI was acquired using echo planar imaging for 20 noncolinear directions with b = 1000 s/mm2 and one additional image with b = 0, repeated four times for signal averaging. The distribution of FA and MD was calculated in the gross tumor volume (GTV), shells 0-5 mm, 5-10 mm, 10-15 mm, 15-20 mm, and 20-25 mm outside the GTV, and the GTV mirrored in the left-right direction (mirGTV). All images were aligned to a template image, and FA and MD interhemispheric difference images were calculated. The difference in mean FA and MD between the regions of interest was statistically tested using two-sided paired t-tests with α = 0.05. Results The mean FA in mirGTV was 0.20 ± 0.04, which was larger than the FA in the GTV (0.12 ± 0.03) and shells 0-5 mm (0.15 ± 0.03) and 5-10 mm (0.17 ± 0.03) outside the GTV. The mean MD (×10-3 mm2/s) in mirGTV was 0.93 ± 0.09, which was smaller than the MD in the GTV (1.48 ± 0.19) and the peritumoral shells. The distribution of FA and MD interhemispheric differences followed the same trends as FA and MD values. Conclusions This study successfully implemented a method for calculation of FA and MD differences by comparison of voxel values with anatomically homologous voxels on the contralateral side of the brain. Further research is warranted to determine if radiotherapy planning using these images can be used to improve target delineation. PMID:27843735

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

PubMed

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

2015-01-01

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

Evaluation of TgH(CX3CR1-EGFP) mice implanted with mCherry-GL261 cells as an in vivo model for morphometrical analysis of glioma-microglia interaction.

PubMed

Resende, Fernando F B; Bai, Xianshu; Del Bel, Elaine Aparecida; Kirchhoff, Frank; Scheller, Anja; Titze-de-Almeida, Ricardo

2016-02-08

Glioblastoma multiforme is the most aggressive brain tumor. Microglia are prominent cells within glioma tissue and play important roles in tumor biology. This work presents an animal model designed for the study of microglial cell morphology in situ during gliomagenesis. It also allows a quantitative morphometrical analysis of microglial cells during their activation by glioma cells. The animal model associates the following cell types: 1- mCherry red fluorescent GL261 glioma cells and; 2- EGFP fluorescent microglia, present in the TgH(CX3CR1-EGFP) mouse line. First, mCherry-GL261 glioma cells were implanted in the brain cortex of TgH(CX3CR1-EGFP) mice. Epifluorescence - and confocal laser-scanning microscopy were employed for analysis of fixed tissue sections, whereas two-photon laser-scanning microscopy (2P-LSM) was used to track tumor cells and microglia in the brain of living animals. Implanted mCherry-GL261 cells successfully developed brain tumors. They mimic the aggressive behavior found in human disease, with a rapid increase in size and the presence of secondary tumors apart from the injection site. As tumor grows, mCherry-GL261 cells progressively lost their original shape, adopting a heterogeneous and diffuse morphology at 14-18 d. Soma size increased from 10-52 μm. At this point, we focused on the kinetics of microglial access to glioma tissues. 2P-LSM revealed an intense microgliosis in brain areas already shortly after tumor implantation, i.e. at 30 min. By confocal microscopy, we found clusters of microglial cells around the tumor mass in the first 3 days. Then cells infiltrated the tumor area, where they remained during all the time points studied, from 6-18 days. Microglia in contact with glioma cells also present changes in cell morphology, from a ramified to an amoeboid shape. Cell bodies enlarged from 366 ± 0.0 μm(2), in quiescent microglia, to 1310 ± 146.0 μm(2), and the cell processes became shortened. The GL261/CX3CR1 mouse model reported here is a valuable tool for imaging of microglial cells during glioma growth, either in fixed tissue sections or living animals. Remarkable advantages are the use of immunocompetent animals and the simplified imaging method without the need of immunohistochemical procedures.

Brainstem Involvement as a Cause of Central Sleep Apnea: Pattern of Microstructural Cerebral Damage in Patients with Cerebral Microangiopathy

PubMed Central

Duning, Thomas; Deppe, Michael; Brand, Eva; Stypmann, Jörg; Becht, Charlotte; Heidbreder, Anna; Young, Peter

2013-01-01

Background The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea. Patients and Methods Genetically proven FD patients (n = 23) and age-matched healthy controls (n = 44) underwent a cardio-respiratory polysomnography and brain MRI at 3.0 Tesla. We applied different MR-imaging techniques, ranging from semiquantitative measurement of white matter lesion (WML) volumes and automated calculation of brain tissue volumes to VBM of gray matter and voxel-based diffusion tensor imaging (DTI) analysis. Results In 5 of 23 Fabry patients (22%) CSA-CSR was detected. Voxel-based DTI analysis revealed widespread structural changes in FD patients when compared to the healthy controls. When calculated as a separate group, DTI changes of CSA-CSR patients were most prominent in the brainstem. Voxel-based regression analysis revealed a significant association between CSR severity and microstructural DTI changes within the brainstem. Conclusion Subtle microstructural changes in the brainstem might be a neuroanatomical correlate of CSA-CSR in patients at risk of WML. DTI is more sensitive and specific than conventional structural MRI and other advanced MR analyses tools in demonstrating these abnormalities. PMID:23637744

Altered functional connectivity in lesional peduncular hallucinosis with REM sleep behavior disorder.

PubMed

Geddes, Maiya R; Tie, Yanmei; Gabrieli, John D E; McGinnis, Scott M; Golby, Alexandra J; Whitfield-Gabrieli, Susan

2016-01-01

Brainstem lesions causing peduncular hallucinosis (PH) produce vivid visual hallucinations occasionally accompanied by sleep disorders. Overlapping brainstem regions modulate visual pathways and REM sleep functions via gating of thalamocortical networks. A 66-year-old man with paroxysmal atrial fibrillation developed abrupt-onset complex visual hallucinations with preserved insight and violent dream enactment behavior. Brain MRI showed restricted diffusion in the left rostrodorsal pons suggestive of an acute ischemic stroke. REM sleep behavior disorder (RBD) was diagnosed on polysomnography. We investigated the integrity of ponto-geniculate-occipital circuits with seed-based resting-state functional connectivity MRI (rs-fcMRI) in this patient compared to 46 controls. Rs-fcMRI revealed significantly reduced functional connectivity between the lesion and lateral geniculate nuclei (LGN), and between LGN and visual association cortex compared to controls. Conversely, functional connectivity between brainstem and visual association cortex, and between visual association cortex and prefrontal cortex (PFC) was significantly increased in the patient. Focal damage to the rostrodorsal pons is sufficient to cause RBD and PH in humans, suggesting an overlapping mechanism in both syndromes. This lesion produced a pattern of altered functional connectivity consistent with disrupted visual cortex connectivity via de-afferentation of thalamocortical pathways. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Disconnection of the Ascending Arousal System in Traumatic Coma

PubMed Central

Edlow, Brian L.; Haynes, Robin L.; Takahashi, Emi; Klein, Joshua P.; Cummings, Peter; Benner, Thomas; Greer, David M.; Greenberg, Steven M.; Wu, Ona; Kinney, Hannah C.; Folkerth, Rebecca D.

2013-01-01

Traumatic coma is associated with disruption of axonal pathways throughout the brain but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging (HARDI) to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness – arousal and awareness – in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. HARDI tractography guided tissue sampling in the neuropathological analysis. HARDI tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical “awareness pathways.” Neuropathologic examination, which utilized β-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of HARDI tract disruption. Axonal injury was also present within the grey matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain. PMID:23656993

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

PubMed Central

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

2015-01-01

BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratios are below €10 000 in all evaluated outcomes, being around €9100 per quality-adjusted life-year gained, €6700 per life-year gained, and €8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of €20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on the basis of existing data. ABBREVIATIONS: 5-ALA, 5-aminolevulinic acid ICER, incremental cost-effectiveness ratio LY, life-year PFLY, progression-free life-year QALY, quality-adjusted life-year PMID:25714513

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

DTIC Science & Technology

2012-09-01

Hydrocephalus mice were excluded from this calculation. With this particular experiment the hydrocephalus rate is 57% (due to the formation of...is completed. We have generated 10 tumors by injecting 14 mice and an example of one is described in the figure below. Hydrocephalus mice were...excluded from the 4 analysis. The hydrocephalus rate was 51% for this experiment due to the formation of leptomeningeal tumor

Diffuse intrinsic pontine glioma in children and adolescents: a single-center experience.

PubMed

Vallero, Stefano Gabriele; Bertin, Daniele; Basso, Maria Eleonora; Pittana, Laura Stefania; Mussano, Anna; Fagioli, Franca

2014-06-01

Patients with diffuse intrinsic pontine glioma (DIPG) have a very poor prognosis. Only radiotherapy (XRT) has proven to be effective in delaying the disease progression. Several chemotherapy schedules have been applied so far, but none demonstrated significant improvements in progression and survival. We retrospectively analyzed the clinical data of children diagnosed with DIPG at our center (Pediatric Hospital "Regina Margherita," Turin, Italy) between 1999 and 2013. Progression-free survival (PFS) and overall survival (OS) were used to describe the outcomes. Twenty-four children were included in our report. Patients diagnosed before March 2003 (n = 12) were treated with XRT and vincristine (VCR); the remaining 12 patients received XRT and temozolomide (TMZ). Progression-free survival was 18.8 % at 1 year (SE = 7.6 %), while overall survival was 44.1 % at 1 year (SE = 9.9 %). Median PFS was 8.1 months, whereas median OS was 11.2 months. No statistically significant difference in PFS or OS was evidenced between the two treatment groups. Radiotherapy followed by VCR or TMZ allows obtaining results that are in line with previous reports, with no advantages over other similar treatment schedules. DIPGs are challenging tumors with a dismal outcome. Further research and newer therapies are urgently needed in order to achieve improvements in survival.

Diffuse intrinsic pontine glioma: is MRI surveillance improved by region of interest volumetry?

PubMed

Riley, Garan T; Armitage, Paul A; Batty, Ruth; Griffiths, Paul D; Lee, Vicki; McMullan, John; Connolly, Daniel J A

2015-02-01

Paediatric diffuse intrinsic pontine glioma (DIPG) is noteworthy for its fibrillary infiltration through neuroparenchyma and its resultant irregular shape. Conventional volumetry methods aim to approximate such irregular tumours to a regular ellipse, which could be less accurate when assessing treatment response on surveillance MRI. Region-of-interest (ROI) volumetry methods, using manually traced tumour profiles on contiguous imaging slices and subsequent computer-aided calculations, may prove more reliable. To evaluate whether the reliability of MRI surveillance of DIPGs can be improved by the use of ROI-based volumetry. We investigated the use of ROI- and ellipsoid-based methods of volumetry for paediatric DIPGs in a retrospective review of 22 MRI examinations. We assessed the inter- and intraobserver variability of the two methods when performed by four observers. ROI- and ellipsoid-based methods strongly correlated for all four observers. The ROI-based volumes showed slightly better agreement both between and within observers than the ellipsoid-based volumes (inter-[intra-]observer agreement 89.8% [92.3%] and 83.1% [88.2%], respectively). Bland-Altman plots show tighter limits of agreement for the ROI-based method. Both methods are reproducible and transferrable among observers. ROI-based volumetry appears to perform better with greater intra- and interobserver agreement for complex-shaped DIPG.

Clinical indications for high-field 1.5 T intraoperative magnetic resonance imaging and neuro-navigation for neurosurgical procedures. Review of initial 100 cases.

PubMed

Maesawa, Satoshi; Fujii, Masazumi; Nakahara, Norimoto; Watanabe, Tadashi; Saito, Kiyoshi; Kajita, Yasukazu; Nagatani, Tetsuya; Wakabayashi, Toshihiko; Yoshida, Jun

2009-08-01

Initial experiences are reviewed in an integrated operation theater equipped with an intraoperative high-field (1.5 T) magnetic resonance (MR) imager and neuro-navigation (BrainSUITE), to evaluate the indications and limitations. One hundred consecutive cases were treated, consisting of 38 gliomas, 49 other tumors, 11 cerebrovascular diseases, and 2 functional diseases. The feasibility and usefulness of the integrated theater were evaluated for individual diseases, focusing on whether intraoperative images (including diffusion tensor imaging) affected the surgical strategy. The extent of resection and outcomes in each histological category of brain tumors were examined. Intraoperative high-field MR imaging frequently affected or modified the surgical strategy in the glioma group (27/38 cases, 71.1%), but less in the other tumor group (13/49 cases, 26.5%). The surgical strategy was not modified in cerebrovascular or functional diseases, but the success of procedures and the absence of complications could be confirmed. In glioma surgery, subtotal or greater resection was achieved in 22 of the 31 patients (71%) excluding biopsies, and intraoperative images revealed tumor remnants resulting in the extension of resection in 21 of the 22 patients (95.4%), the highest rate of extension among all types of pathologies. The integrated neuro-navigation improved workflow. The best indication for intraoperative high-field MR imaging and integrated neuro-navigation is brain tumors, especially gliomas, and is supplementary in assuring quality in surgery for cerebrovascular or functional diseases. Immediate quality assurance is provided in several types of neurosurgical procedures.

Diffusion-weighted imaging determinants for acute ischemic stroke diagnosis in the emergency room.

PubMed

Brunser, Alejandro M; Cavada, Gabriel; Venturelli, Paula Muñoz; Olavarría, Verónica; Rojo, Alexis; Almeida, Juan; Díaz, Violeta; Hoppe, Arnold; Lavados, Pablo

2018-05-22

The aim of this study was to investigate the clinical-radiological determinants of diffusion-weighted image (DWI) abnormalities in patients with suspected acute ischemic stroke (AIS) seen at the emergency room (ER). During the study period, 882 consecutive patients were screened at Clínica Alemana de Santiago, Chile; 786 had AIS and 711 (90.4%) were included. DWI demonstrated 87.3% sensitivity and 99.0% specificity, with a positive likelihood ratio of 79 and a negative likelihood ratio of 0.13 for the detection of AIS. In the univariate analysis, a positive DWI in AIS was associated with admission National Institute of Health Stroke Scale (NIHSS) score (OR 1.09, 95% CI 1.04-1.1%), time from symptom onset to DWI (OR 1.03, 95% CI 1.01-1.05), presence of a relevant intracranial artery occlusion (OR 3.18, 95% CI 1.75-5.76), posterior circulation ischemia (OR 0.44, 95% CI 0.28-0.7), brainstem location of the AIS (OR 0.16, 95% CI 0.093-0.27), infratentorial location of AIS (OR 0.44, 95% CI 0.28-0.70), and lacunar (OR 0.27, 95% CI 0.11-0.68) or undetermined stroke etiology (OR 0.12, 95% CI 0.3-0.31). In multivariate analysis, only admission NIHSS score (OR 1.07, 95% CI 1.01-1.13), time from symptom onset to DWI (OR 1.04, 95% CI 1.01-1.13), brainstem location (OR 0.13, 95% CI 0.051-0.37), and lacunar (OR: 0.4, 95% CI 0.21-0.78) or undetermined etiology (OR: 0.4, 95% CI 0.22-0.78) remained independently associated. DWI detects AIS accurately; the positivity of these evaluations in the ER is associated only with NIHSS on admission, time to DWI, brainstem location, and AIS etiology.

Immunohistochemical comparative analysis of GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 expression in WHO 2016 classified neuroepithelial tumours and their prognostic value.

PubMed

Schwab, David Emanuel; Lepski, Guilherme; Borchers, Christian; Trautmann, Katrin; Paulsen, Frank; Schittenhelm, Jens

2018-01-01

Immunohistochemistry is routinely used in differential diagnosis of tumours of the central nervous system (CNS). The latest 2016 WHO 2016 revision now includes molecular data such as IDH mutation and 1p/19q codeletion thus restructuring glioma classification. Direct comparative information between commonly used immunohistochemical markers for glial tumours GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 concerning quality and quantity of expression and their relation to the new molecular markers are lacking. We therefore compared the immunohistochemical staining results of all five antibodies in 34 oligodendrogliomas, 106 ependymomas and 423 astrocytic tumours. GFAP expression was reduced in cases with higher WHO grade, oligodendroglial differentiation and in IDH wildtype diffuse astrocytomas. By contrast MAP - 2 expression was significantly increased in diffuse astrocytomas with IDH mutation, while NOGO - A expression was not associated with any molecular marker. WT - 1 expression was significantly decreased in tumours with IDH mutation and ATRX loss. OLIG - 2 was increased in IDH-mutant grade II astrocytomas and in cases with higher proliferation rate. In univariate survival analysis high WT - 1 expression was significantly associated with worse outcome in diffuse astrocytic tumours (log rank p < 0.0001; n = 211; median time: 280 days vs 562 days). None of the markers was prognostic in multivariate survival analysis. Among the evaluated markers MAP - 2, OLIG - 2 and WT - 1 showed the best potential to separate between glioma entities and can be recommended for a standardized immunohistochemical panel. Copyright © 2017 Elsevier GmbH. All rights reserved.

EG-01EPIGENETIC INACTIVATION OF ARGININE BIOSYNTHESIS PATHWAY IN PAEDIATRIC HIGH GRADE GLIOMA

PubMed Central

Channathodiyil, Prasanna; Kardooni, Hoda; Khozoie, Combiz; Nelofer, Syed; Darling, John; Morris, Mark; Warr, Tracy

2014-01-01

Aberrant cellular metabolism contributes significantly to the growth and proliferation of several tumour types. Identification of genes that control critical metabolic pathways is a major factor in the development of novel therapies that target metabolic defects in tumour cells. Our aim is to identify such genes in paediatric high grade glioma that are altered due to promoter hyper-methylation of cytosine residues in CpG dinucleotides. Genome wide DNA methylation profiling using Illumina infinium methylation 450K bead chip array was performed on 18 well-characterised short term cultures derived from paediatric high grade astrocytoma including 3 from diffuse intrinsic pontine glioma. Data analyses were based on beta scores of probes for each gene as measures of intensities of methylation. Genes were selected with beta scores of tumour > =0.70 and that of normal human astrocytes < =0.30. We identified that two vital genes involved in the regulation of arginine biosynthetic pathway, argininosuccinate synthetase 1(ASS1) and argininosuccinate lyase (ASL) were methylated in 9/18 (50%) cases. Hyper methylation was confirmed by methylation-specific PCR and up-regulation of gene expression following treatment with 2 µM 5-aza-2'-deoxyctidine. Down-regulation of ASS1 in hyper methylated samples was confirmed by Western blot analysis. Our findings report epigenetic deregulation of ASS1 and ASL in a subset of paediatric high grade glioma. The enzymes encoded by these genes are essential elements of urea cycle that function together in the de novo synthesis of arginine from citrulline. Tumour cells with deficient ASS1/ASL depend on external sources of arginine for survival and have been reported to be sensitive to autophagic cell death induced by arginine starvation. Therefore, further investigation may render the possibility of arginine-deprivation therapy in such sub type of paediatric high grade glioma. This therapeutic approach is of interest as tumour cells with abnormal expression of ASS1/ASL can be specifically targeted, while the normal cells can be spared.

Feasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Narayana, Ashwatha; Golfinos, John G.; Fischer, Ingeborg

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.more » 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.« less

Topological analysis of the brainstem of the bowfin, Amia calva.

PubMed

Heijdra, Y F; Nieuwenhuys, R

1994-01-01

This paper presents a survey of the cell masses in the brainstem of the generalized actinopterygian fish Amia calva, based on transversely cut Nissl-, Klüver-Barrera-, and Bodian-stained serial sections. This study is intended to serve a double purpose. First it forms part of a now almost complete series of publications on the structure of the brainstem in representative species of all groups of vertebrates. Within the framework of this comparative program the cell masses in the brainstem and their positional relations are analyzed in the light of the Herrick-Johnston concept; according to this the brainstem nuclei are arranged in four longitudinal, functional zones or columns, the boundaries of which are marked by ventricular sulci. The procedure employed in this analysis essentially involves two steps: first, the cell masses and large individual cells are projected upon the ventricular surface, and next, the ventricular surface is flattened out, that is, subjected to a one-to-one continuous topological transformation (Nieuwenhuys [1974] J. Comp. Neurol. 156:255-267). The second purpose of the present paper is to provide a cytoarchitectonic basis for experimental analysis of the fiber connectivity in the brainstem of Amia. Five longitudinal sulci--the sulcus medianus inferior, the sulcus intermedius ventralis, the sulcus limitans, the sulcus intermedius dorsalis, and the sulcus lateralis mesencephali--could be distinguished. Some shorter grooves, present in the isthmal region, clearly deviate from the overall longitudinal pattern of the other sulci. Although in Amia most neuronal perikarya are contained within a diffuse periventricular gray, 40 cell masses could be delineated: Eight of these are primary efferent or motor nuclei, 10 are primary afferent or sensory centers, seven are considered to be components of the reticular formation, and the remaining 15 may be interpreted as "relay" nuclei. The topological analysis yielded the following results. In the rhombencephalon the gray matter is arranged in four longitudinal columns or areas, termed area ventralis, area intermedioventralis, area intermediodorsalis, and area dorsalis. The sulcus intermedius ventralis, the sulcus limitans, and the sulcus intermedius dorsalis mark the boundaries between these morphological entities. These longitudinal areas coincide largely, but not entirely, with the functional columns of Herrick and Johnston. The most obvious incongruity is that the area intermediodorsalis contains, in addition to the viscerosensory nucleus of the solitary tract, several general somatosensory and special somatosensory nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitative morphological magnetic resonance imaging follow-up of low-grade glioma: a plea for systematic measurement of growth rates.

PubMed

Pallud, Johan; Taillandier, Luc; Capelle, Laurent; Fontaine, Denys; Peyre, Matthieu; Ducray, François; Duffau, Hugues; Mandonnet, Emmanuel

2012-09-01

Supratentorial hemispheric diffuse low-grade gliomas (LGGs), i.e., World Health Organization grade II gliomas, are a heterogeneous group of tumors. During their natural course, LGGs tend to progress to a higher grade of malignancy, leading to neurological disability and ultimately to death. In this review, we will show, that during their low-grade period, these tumors exhibit systematically a spontaneous and continuous radiological growth, whatever their histological subtypes. The radiological tumor growth is easily quantified by measuring the evolution of the equivalent tumor diameter (calculated from the tumor volume), obtaining the velocity of diametric expansion (VDE). The spontaneous VDE of LGGs varies markedly with an average VDE of about 4 mm/year. It depends on intrinsic factors (1p19q codeletion status, P53 overexpression status) and can be modified by extrinsic factors (pregnancy). The spontaneous VDE carries a strong prognostic significance regarding progression-free and overall survivals. As a consequence, VDE should be integrated along with the other "static" parameters (multimodal imaging, histological and molecular analyses) in the initial investigations. In addition, the assessment of VDE obtained before, during, and after a particular oncological treatment helps in analyzing their effects on LGGs on an individual basis, helping to guide the decision making.

Anatomic Location of Tumor Predicts the Accuracy of Motor Function Localization in Diffuse Lower-Grade Gliomas Involving the Hand Knob Area.

PubMed

Fang, S; Liang, J; Qian, T; Wang, Y; Liu, X; Fan, X; Li, S; Wang, Y; Jiang, T

2017-10-01

The accuracy of preoperative blood oxygen level-dependent fMRI remains controversial. This study assessed the association between the anatomic location of a tumor and the accuracy of fMRI-based motor function mapping in diffuse lower-grade gliomas. Thirty-five patients with lower-grade gliomas involving motor areas underwent preoperative blood oxygen level-dependent fMRI scans with grasping tasks and received intraoperative direct cortical stimulation. Patients were classified into an overlapping group and a nonoverlapping group, depending on the extent to which blood oxygen level-dependent fMRI and direct cortical stimulation results concurred. Tumor location was quantitatively measured, including the shortest distance from the tumor to the hand knob and the deviation distance of the midpoint of the hand knob in the lesion hemisphere relative to the midline compared with the normal contralateral hemisphere. A 4-mm shortest distance from the tumor to the hand knob value was identified as optimal for differentiating the overlapping and nonoverlapping group with the receiver operating characteristic curve (sensitivity, 84.6%; specificity, 77.8%). The shortest distances from the tumor to the hand knob of ≤4 mm were associated with inaccurate fMRI-based localizations of the hand motor cortex. The shortest distances from the tumor to the hand knob were larger ( P = .002), and the deviation distances for the midpoint of the hand knob in the lesion hemisphere were smaller ( P = .003) in the overlapping group than in the nonoverlapping group. This study suggests that the shortest distance from the tumor to the hand knob and the deviation distance for the midpoint of the hand knob on the lesion hemisphere are predictive of the accuracy of blood oxygen level-dependent fMRI results. Smaller shortest distances from the tumor to the hand knob and larger deviation distances for the midpoint of hand knob on the lesion hemisphere are associated with less accuracy of motor cortex localization with blood oxygen level-dependent fMRI. Preoperative fMRI data for surgical planning should be used cautiously when the shortest distance from the tumor to the hand knob is ≤4 mm, especially for lower-grade gliomas anterior to the central sulcus. © 2017 by American Journal of Neuroradiology.

Dementia After Moderate-Severe Traumatic Brain Injury: Coexistence of Multiple Proteinopathies.

PubMed

Kenney, Kimbra; Iacono, Diego; Edlow, Brian L; Katz, Douglas I; Diaz-Arrastia, Ramon; Dams-O'Connor, Kristen; Daneshvar, Daniel H; Stevens, Allison; Moreau, Allison L; Tirrell, Lee S; Varjabedian, Ani; Yendiki, Anastasia; van der Kouwe, Andre; Mareyam, Azma; McNab, Jennifer A; Gordon, Wayne A; Fischl, Bruce; McKee, Ann C; Perl, Daniel P

2018-01-01

We report the clinical, neuroimaging, and neuropathologic characteristics of 2 patients who developed early onset dementia after a moderate-severe traumatic brain injury (TBI). Neuropathological evaluation revealed abundant β-amyloid neuritic and cored plaques, diffuse β-amyloid plaques, and frequent hyperphosphorylated-tau neurofibrillary tangles (NFT) involving much of the cortex, including insula and mammillary bodies in both cases. Case 1 additionally showed NFTs in both the superficial and deep cortical layers, occasional perivascular and depth-of-sulci NFTs, and parietal white matter rarefaction, which corresponded with decreased parietal fiber tracts observed on ex vivo MRI. Case 2 additionally showed NFT predominance in the superficial layers of the cortex, hypothalamus and brainstem, diffuse Lewy bodies in the cortex, amygdala and brainstem, and intraneuronal TDP-43 inclusions. The neuropathologic diagnoses were atypical Alzheimer disease (AD) with features of chronic traumatic encephalopathy and white matter loss (Case 1), and atypical AD, dementia with Lewy bodies and coexistent TDP-43 pathology (Case 2). These findings support an epidemiological association between TBI and dementia and further characterize the variety of misfolded proteins that may accumulate after TBI. Analyses with comprehensive clinical, imaging, genetic, and neuropathological data are required to characterize the full clinicopathological spectrum associated with dementias occurring after moderate-severe TBI. 2017 American Association of Neuropathologists, Inc. This work is written by US Government employees and is in the public domain in the US.

Dengue fever with diffuse cerebral hemorrhages, subdural hematoma and cranial diabetes insipidus.

PubMed

Jayasinghe, Nayomi Shermila; Thalagala, Eranga; Wattegama, Milanka; Thirumavalavan, Kanapathipillai

2016-05-10

Neurological manifestations in dengue fever occur in <1 % of the patients and known to be due to multisystem dysfunction secondary to vascular leakage. Occurrence of wide spread cerebral haemorrhages with subdural hematoma during the leakage phase without profound thrombocytopenia and occurrence of cranial diabetes insipidus are extremely rare and had not been reported in published literature earlier, thus we report the first case. A 24 year old previously healthy lady was admitted on third day of fever with thrombocytopenia. Critical phase started on fifth day with evidence of pleural effusion and moderate ascites. Thirty one hours into critical phase she developed headache, altered level of consciousness, limb rigidity and respiratory depression without definite seizures. Non-contrast CT brain done at tertiary care level revealed diffuse intracranial haemorrhages and sub arachnoid haemorrhages in right frontal, parietal, occipital lobes and brainstem, cerebral oedema with an acute subdural hematoma in right temporo- parietal region. Her platelet count was 40,000 at this time with signs of vascular leakage. She was intubated and ventilated with supportive care. Later on she developed features of cranial diabetes insipidus and it responded to intranasal desmopressin therapy. In spite of above measures signs of brainstem herniation developed and she succumbed to the illness on day 8. Dengue was confirmed serologically. Exact pathophysiological mechanism of diffuse cerebral haemorrhages without profound thrombocytopenia is not well understood. Increased awareness and high degree of clinical suspicion is needed among clinicians for timely diagnosis of this extremely rare complication of dengue fever. We postulate that immunological mechanisms may play a role in pathogenesis. However further comprehensive research and studies are needed to understand the pathophysiological mechanisms leading to this complication.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brynolfsson, Patrik; Hauksson, Jón; Karlsson, Mikael

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 treatedmore » 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 to hold pretreatment prognostic information, independent of known prognostic factors such as age, stage, and surgical procedure. These findings encourage further studies with a larger patient cohort.« less

Somatotopic arrangement and location of the corticospinal tract in the brainstem of the human brain.

PubMed

Jang, Sung Ho

2011-07-01

The corticospinal tract (CST) is the most important motor pathway in the human brain. Detailed knowledge of CST somatotopy is important in terms of rehabilitative management and invasive procedures for patients with brain injuries. In this study, I conducted a review of nine previous studies of the somatotopical location and arrangement at the brainstem in the human brain. The results of this review indicated that the hand and leg somatotopies of the CST are arranged medio-laterally in the mid to lateral portion of the cerebral peduncle, ventromedial-dorsolaterally in the pontine basis, and medio-laterally in the medullary pyramid. However, few diffusion tensor imaging (DTI) studies have been conducted on this topic, and only nine have been reported: midbrain (2 studies), pons (4 studies), and medulla (1 study). Therefore, further DTI studies should be conducted in order to expand the literature on this topic. In particular, research on midbrain and medulla should be encouraged.

Automatic Semantic Segmentation of Brain Gliomas from MRI Images Using a Deep Cascaded Neural Network.

PubMed

Cui, Shaoguo; Mao, Lei; Jiang, Jingfeng; Liu, Chang; Xiong, Shuyu

2018-01-01

Brain tumors can appear anywhere in the brain and have vastly different sizes and morphology. Additionally, these tumors are often diffused and poorly contrasted. Consequently, the segmentation of brain tumor and intratumor subregions using magnetic resonance imaging (MRI) data with minimal human interventions remains a challenging task. In this paper, we present a novel fully automatic segmentation method from MRI data containing in vivo brain gliomas. This approach can not only localize the entire tumor region but can also accurately segment the intratumor structure. The proposed work was based on a cascaded deep learning convolutional neural network consisting of two subnetworks: (1) a tumor localization network (TLN) and (2) an intratumor classification network (ITCN). The TLN, a fully convolutional network (FCN) in conjunction with the transfer learning technology, was used to first process MRI data. The goal of the first subnetwork was to define the tumor region from an MRI slice. Then, the ITCN was used to label the defined tumor region into multiple subregions. Particularly, ITCN exploited a convolutional neural network (CNN) with deeper architecture and smaller kernel. The proposed approach was validated on multimodal brain tumor segmentation (BRATS 2015) datasets, which contain 220 high-grade glioma (HGG) and 54 low-grade glioma (LGG) cases. Dice similarity coefficient (DSC), positive predictive value (PPV), and sensitivity were used as evaluation metrics. Our experimental results indicated that our method could obtain the promising segmentation results and had a faster segmentation speed. More specifically, the proposed method obtained comparable and overall better DSC values (0.89, 0.77, and 0.80) on the combined (HGG + LGG) testing set, as compared to other methods reported in the literature. Additionally, the proposed approach was able to complete a segmentation task at a rate of 1.54 seconds per slice.

Quantitative multiparametric MRI assessment of glioma response to radiotherapy in a rat model.

PubMed

Hong, Xiaohua; Liu, Li; Wang, Meiyun; Ding, Kai; Fan, Ying; Ma, Bo; Lal, Bachchu; Tyler, Betty; Mangraviti, Antonella; Wang, Silun; Wong, John; Laterra, John; Zhou, Jinyuan

2014-06-01

The inability of structural MRI to accurately measure tumor response to therapy complicates care management for patients with gliomas. The purpose of this study was to assess the potential of several noninvasive functional and molecular MRI biomarkers for the assessment of glioma response to radiotherapy. Fourteen U87 tumor-bearing rats were irradiated using a small-animal radiation research platform (40 or 20 Gy), and 6 rats were used as controls. MRI was performed on a 4.7 T animal scanner, preradiation treatment, as well as at 3, 6, 9, and 14 days postradiation. Image features of the tumors, as well as tumor volumes and animal survival, were quantitatively compared. Structural MRI showed that all irradiated tumors still grew in size during the initial days postradiation. The apparent diffusion coefficient (ADC) values of tumors increased significantly postradiation (40 and 20 Gy), except at day 3 postradiation, compared with preradiation. The tumor blood flow decreased significantly postradiation (40 and 20 Gy), but the relative blood flow (tumor vs contralateral) did not show a significant change at most time points postradiation. The amide proton transfer weighted (APTw) signals of the tumor decreased significantly at all time points postradiation (40 Gy), and also at day 9 postradiation (20 Gy). The blood flow and APTw maps demonstrated tumor features that were similar to those seen on gadolinium-enhanced T1-weighted images. Tumor ADC, blood flow, and APTw were all useful imaging biomarkers by which to predict glioma response to radiotherapy. The APTw signal was most promising for early response assessment in this model. © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A vaccine targeting mutant IDH1 induces antitumour immunity.

PubMed

Schumacher, Theresa; Bunse, Lukas; Pusch, Stefan; Sahm, Felix; Wiestler, Benedikt; Quandt, Jasmin; Menn, Oliver; Osswald, Matthias; Oezen, Iris; Ott, Martina; Keil, Melanie; Balß, Jörg; Rauschenbach, Katharina; Grabowska, Agnieszka K; Vogler, Isabel; Diekmann, Jan; Trautwein, Nico; Eichmüller, Stefan B; Okun, Jürgen; Stevanović, Stefan; Riemer, Angelika B; Sahin, Ugur; Friese, Manuel A; Beckhove, Philipp; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

2014-08-21

Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.

Oedema-based model for diffuse low-grade gliomas: application to clinical cases under radiotherapy.

PubMed

Badoual, M; Gerin, C; Deroulers, C; Grammaticos, B; Llitjos, J-F; Oppenheim, C; Varlet, P; Pallud, J

2014-08-01

Diffuse low-grade gliomas are characterized by slow growth. Despite appropriate treatment, they change inexorably into more aggressive forms, jeopardizing the patient's life. Optimizing treatments, for example with the use of mathematical modelling, could help to prevent tumour regrowth and anaplastic transformation. Here, we present a model of the effect of radiotherapy on such tumours. Our objective is to explain observed delay of tumour regrowth following radiotherapy and to predict its duration. We have used a migration-proliferation model complemented by an equation describing appearance and draining of oedema. The model has been applied to clinical data of tumour radius over time, for a population of 28 patients. We were able to show that draining of oedema accounts for regrowth delay after radiotherapy and have been able to fit the clinical data in a robust way. The model predicts strong correlation between high proliferation coefficient and low progression-free gain of lifetime, due to radiotherapy among the patients, in agreement with clinical studies. We argue that, with reasonable assumptions, it is possible to predict (precision ~20%) regrowth delay after radiotherapy and the gain of lifetime due to radiotherapy. Our oedema-based model provides an early estimation of individual duration of tumour response to radiotherapy and thus, opens the door to the possibility of personalized medicine. © 2014 John Wiley & Sons Ltd.

Induction of specific T helper-9 cells to inhibit glioma cell growth

PubMed Central

Zheng, Haiyan; Yang, Baohua; Xu, Dedong; Wang, Wenbo; Tan, Jie; Sun, Liyuan; Li, Qinghua; Sun, Li; Xia, Xuewei

2017-01-01

The effects of Staphylococcal enterotoxin B (SEB) on regulation of immune response have been recognized; whether SEB can enhance the effects of immunotherapy on glioma remains to be investigated. This study tests a hypothesis that administration with SEB enhances the effects of specific immunotherapy on glioma growth in mice. In this study, a glioma-bearing mouse model was developed by adoptive transfer with GL261 cells (a mouse glioma cell line). The mice were treated with the GL261 cell extracts (used as an Ag) with or without administration of SEB. We observed that treating glioma-bearing mice with the glioma Ag and SEB induced glioma-specific Th9 cells in both glioma tissue and the spleen. Treating CD4+ CD25− T cells with SEB increased p300 phosphorylation, histone H3K4 acetylation at the interleukin (IL)-9 promoter locus, and increased the IL-9 transcriptional factor binding to the IL-9 promoter. Treating CD4+ CD25− T cells with both SEB and glioma Ag induced glioma-specific Th9 cells. The glioma-specific Th9 cells induced glioma cell apoptosis in the culture. Treating the glioma-bearing mice with SEB and glioma Ag significantly inhibited the glioma growth. In conclusion, SEB plus glioma Ag immunotherapy inhibits the experimental glioma growth, which may be a novel therapeutic remedy for the treatment of glioma. PMID:28002799

Advanced magnetic resonance imaging methods for planning and monitoring radiation therapy in patients with high-grade glioma.

PubMed

Lupo, Janine M; Nelson, Sarah J

2014-10-01

This review explores how the integration of advanced imaging methods with high-quality anatomical 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 magnetic resonance imaging in conjunction with magnetic resonance 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 effect 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 radiationinduced vascular injury in otherwise normal-appearing brain tissue.

Metronidazole-induced encephalopathy: not always a reversible situation.

PubMed

Hobbs, Kyle; Stern-Nezer, Sara; Buckwalter, Marion S; Fischbein, Nancy; Finley Caulfield, Anna

2015-06-01

Metronidazole is a nitroimidazole antimicrobial drug prescribed to treat infections caused by anaerobic bacteria and protozoa. Uncommonly, it causes central nervous system (CNS) toxicity manifesting as metronidazole-induced encephalopathy (MIE). Case report. A 65-year-old woman with hepatitis B cirrhosis (Child-Pugh class C, MELD 21) developed progressive encephalopathy to GCS 4 during a 3-week course of metronidazole for cholecystitis. Initial MRI was consistent with CNS metronidazole toxicity, with symmetrical T2 hyperintensity and generally restricted diffusion in bilateral dentate nuclei, corpus callosum, midbrain, superior cerebellar peduncles, internal capsules, and cerebral white matter. Laboratory values did not demonstrate significant electrolyte shifts, and continuous EEG was without seizure. High-dose thiamine was empirically administered. Lumbar puncture was not performed due to coagulopathy and thrombocytopenia. Despite discontinuation of metronidazole and keeping ammonia levels near normal, the patient did not improve. MRI was repeated 1 week after discontinuation of metronidazole. Although there was decreased DWI hyperintensity in the dentate nuclei, diffuse T2 hyperintensity persisted and even progressed in the brainstem, basal ganglia, and subcortical white matter. Petechial hemorrhages developed in bilateral corticospinal tracts and subcortical white matter. T1 hypointensity appeared in the corpus callosum. She was transitioned to comfort measures only and died 12 days later. MIE is an uncommon adverse effect of treatment with metronidazole that characteristically affects the dentate nuclei but may also involve the brainstem, corpus callosum, subcortical white matter, and basal ganglia. While the clinical symptoms and neuroimaging changes are usually reversible, persistent encephalopathy with poor outcome may occur.

Surface-to-volume ratio mapping of tumor microstructure using oscillating gradient diffusion weighted imaging

PubMed Central

Reynaud, Olivier; Winters, Kerryanne Veronica; Hoang, Dung Minh; Wadghiri, Youssef Zaim; Novikov, Dmitry S; Kim, Sungheon Gene

2015-01-01

Purpose To disentangle the free diffusivity (D0) and cellular membrane restrictions, via their surface-to-volume ratio (S/V), using the frequency-dependence of the diffusion coefficient D(ω), measured in brain tumors in the short diffusion-time regime using oscillating gradients (OGSE). Methods In vivo and ex vivo OGSE experiments were performed on mice bearing the GL261 murine glioma model (n=10) to identify the relevant time/frequency (t/ω) domain where D(ω) linearly decreases with ω−1/2. Parametric maps (S/V, D0) are compared to conventional DWI metrics. The impact of frequency range and temperature (20°C vs. 37°C) on S/V and D0 is investigated ex vivo. Results The validity of the short diffusion-time regime is demonstrated in vivo and ex vivo. Ex vivo measurements confirm that the purely geometric restrictions embodied in S/V are independent from temperature and frequency range, while the temperature dependence of the free diffusivity D0 is similar to that of pure water. Conclusion Our results suggest that D(ω) in the short diffusion-time regime can be used to uncouple the purely geometric restriction effect, such as S/V, from the intrinsic medium diffusivity properties, and provides a non-empirical and objective way to interpret frequency/time-dependent diffusion changes in tumors in terms of objective biophysical tissue parameters. PMID:26207354

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

DTIC Science & Technology

2014-11-01

LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 39 19b. TELEPHONE...for this mouse cohort was included in Figure 1. Out of 23 GFAP tv- a; p53 floxed mice infected with RCAS-PDGF-B and RCAS-Cre, 18 developed...being used as part of the DIPG preclinical consortium (together with several laboratories that are using human DIPG xenografts ) to help prioritize

Structural and functional connectivity mapping of the vestibular circuitry from human brainstem to cortex.

PubMed

Kirsch, V; Keeser, D; Hergenroeder, T; Erat, O; Ertl-Wagner, B; Brandt, T; Dieterich, M

2016-04-01

Structural and functional interconnections of the bilateral central vestibular network have not yet been completely delineated. This includes both ipsilateral and contralateral pathways and crossing sites on the way from the vestibular nuclei via the thalamic relay stations to multiple "vestibular cortex" areas. This study investigated "vestibular" connectivity in the living human brain in between the vestibular nuclei and the parieto-insular vestibular cortex (PIVC) by combined structural and functional connectivity mapping using diffusion tensor imaging and functional connectivity magnetic resonance imaging in 24 healthy right-handed volunteers. We observed a congruent functional and structural link between the vestibular nuclei and the ipsilateral and contralateral PIVC. Five separate and distinct vestibular pathways were identified: three run ipsilaterally, while the two others cross either in the pons or the midbrain. Two of the ipsilateral projections run through the posterolateral or paramedian thalamic subnuclei, while the third bypasses the thalamus to reach the inferior part of the insular cortex directly. Both contralateral pathways travel through the posterolateral thalamus. At the cortical level, the PIVC regions of both hemispheres with a right hemispherical dominance are interconnected transcallosally through the antero-caudal splenium. The above-described bilateral vestibular circuitry in its entirety takes the form of a structure of a rope ladder extending from the brainstem to the cortex with three crossings in the brainstem (vestibular nuclei, pons, midbrain), none at thalamic level and a fourth cortical crossing through the splenium of the corpus callosum.

Horizontal nystagmus and multiple sclerosis using 3-Tesla magnetic resonance imaging.

PubMed

Iyer, P M; Fagan, A J; Meaney, J F; Colgan, N C; Meredith, S D; Driscoll, D O; Curran, K M; Bradley, D; Redmond, J

2016-11-01

Nystagmus in patients with multiple sclerosis (MS) is generally attributed to brainstem disease. Lesions in other regions may result in nystagmus. The identification of these other sites is enhanced by using 3-Tesla magnetic resonance imaging (3TMRI) due to increased signal-to-noise ratio. We sought to evaluate the distribution of structural lesions and disruption of tracts in patients with horizontal nystagmus secondary to MS using 3TMRI. Twenty-four patients (20 women, 4 men; age range 26-55 years) with horizontal nystagmus secondary to MS underwent 3TMRI brain scans; and 18 patients had diffusion tensor imaging (DTI) for tractography. Nystagmus was bidirectional in 11, right-sided in 6 and left-sided in 7. We identified 194 lesions in 20 regions within the neural integrator circuit in 24 patients; 140 were within the cortex and 54 were within the brainstem. Only two patients had no lesions in the cortex, and 9 had no lesions in the brainstem. There was no relationship between side of lesion and direction of nystagmus. Thirteen of 18 (72 %) had tract disruption with fractional anisotropy (FA) values below 0.2. FA was significantly lower in bidirectional compared to unidirectional nystagmus (p = 0.006). In MS patients with horizontal nystagmus, lesions in all cortical eye fields and their descending connections were evident. Technical improvements in tractography may help identify the specific site(s) resulting in nystagmus in MS.

Loud Music Exposure and Cochlear Synaptopathy in Young Adults: Isolated Auditory Brainstem Response Effects but No Perceptual Consequences.

PubMed

Grose, John H; Buss, Emily; Hall, Joseph W

2017-01-01

The purpose of this study was to test the hypothesis that listeners with frequent exposure to loud music exhibit deficits in suprathreshold auditory performance consistent with cochlear synaptopathy. Young adults with normal audiograms were recruited who either did ( n = 31) or did not ( n = 30) have a history of frequent attendance at loud music venues where the typical sound levels could be expected to result in temporary threshold shifts. A test battery was administered that comprised three sets of procedures: (a) electrophysiological tests including distortion product otoacoustic emissions, auditory brainstem responses, envelope following responses, and the acoustic change complex evoked by an interaural phase inversion; (b) psychoacoustic tests including temporal modulation detection, spectral modulation detection, and sensitivity to interaural phase; and (c) speech tests including filtered phoneme recognition and speech-in-noise recognition. The results demonstrated that a history of loud music exposure can lead to a profile of peripheral auditory function that is consistent with an interpretation of cochlear synaptopathy in humans, namely, modestly abnormal auditory brainstem response Wave I/Wave V ratios in the presence of normal distortion product otoacoustic emissions and normal audiometric thresholds. However, there were no other electrophysiological, psychophysical, or speech perception effects. The absence of any behavioral effects in suprathreshold sound processing indicated that, even if cochlear synaptopathy is a valid pathophysiological condition in humans, its perceptual sequelae are either too diffuse or too inconsequential to permit a simple differential diagnosis of hidden hearing loss.

Retrospective Correction of Physiological Noise in DTI Using an Extended Tensor Model and Peripheral Measurements

PubMed Central

Mohammadi, Siawoosh; Hutton, Chloe; Nagy, Zoltan; Josephs, Oliver; Weiskopf, Nikolaus

2013-01-01

Diffusion tensor imaging is widely used in research and clinical applications, but this modality is highly sensitive to artefacts. We developed an easy-to-implement extension of the original diffusion tensor model to account for physiological noise in diffusion tensor imaging using measures of peripheral physiology (pulse and respiration), the so-called extended tensor model. Within the framework of the extended tensor model two types of regressors, which respectively modeled small (linear) and strong (nonlinear) variations in the diffusion signal, were derived from peripheral measures. We tested the performance of four extended tensor models with different physiological noise regressors on nongated and gated diffusion tensor imaging data, and compared it to an established data-driven robust fitting method. In the brainstem and cerebellum the extended tensor models reduced the noise in the tensor-fit by up to 23% in accordance with previous studies on physiological noise. The extended tensor model addresses both large-amplitude outliers and small-amplitude signal-changes. The framework of the extended tensor model also facilitates further investigation into physiological noise in diffusion tensor imaging. The proposed extended tensor model can be readily combined with other artefact correction methods such as robust fitting and eddy current correction. PMID:22936599

WE-FG-202-08: Assessment of Treatment Response Via Longitudinal Diffusion MRI On A MRI-Guided System: Initial Experience of Quantitative Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi, X; Yang, Y; Yang, L

Purpose: To report our initial experience of systematic monitoring treatment response using longitudinal diffusion MR images on a Co-60 MRI-guided radiotherapy system. Methods: Four patients, including 2 head-and-necks, 1 sarcoma and 1 GBM treated on a 0.35 Tesla MRI-guided treatment system, were analyzed. For each patient, 3D TrueFISP MRIs were acquired during CT simulation and before each treatment for treatment planning and patient setup purposes respectively. Additionally, 2D diffusion-weighted MR images (DWI) were acquired weekly throughout the treatment course. The gross target volume (GTV) and brainstem (as a reference structure) were delineated on weekly 3D TrueFISP MRIs to monitor anatomymore » changes, the contours were then transferred onto the corresponding DWI images after fusing with the weekly TrueFISP images. The patient-specific temporal and spatial variations during the entire treatment course, such as anatomic changes, target apparent diffusion coefficient (ADC) distribution were evaluated in a longitudinal pattern. Results: Routine MRI revealed progressive soft-tissue GTV volume changes (up to 53%) for the H&N cases during the treatment course of 5–7 weeks. Within the GTV, the mean ADC values varied from −44% (ADC decrease) to +26% (ADC increase) in a week. The gradual increase of ADC value was inversely associated with target volume variation for one H&N case. The maximal changes of mean ADC values within the brainstem were 5.3% for the H&N cases. For the large size sarcoma and GBM tumors, spatial heterogeneity and temporal variations were observed through longitudinal ADC analysis. Conclusion: In addition to the superior soft-tissue visualization, the 0.35T MR system on ViewRay showed the potential to quantitatively measure the ADC values for both tumor and normal tissues. For normal tissue that is minimally affected by radiation, its ADC values are reproducible. Tumor ADC values show temporal and spatial fluctuation that can be exploited for personalized adaptive therapy.« less

Exploring the regulatory role of isocitrate dehydrogenase mutant protein on glioma stem cell proliferation.

PubMed

Lu, H-C; Ma, J; Zhuang, Z; Qiu, F; Cheng, H-L; Shi, J-X

2016-08-01

Glioma is the most lethal form of cancer that originates mostly from the brain and less frequently from the spine. Glioma is characterized by abnormal regulation of glial cell differentiation. The severity of the glioma was found to be relaxed in isocitrate dehydrogenase 1 (IDH1) mutant. The present study focused on histological discrimination and regulation of cancer stem cell between IDH1 mutant and in non-IDH1 mutant glioma tissue. Histology, immunohistochemistry and Western blotting techniques are used to analyze the glioma nature and variation in glioma stem cells that differ between IDH1 mutant and in non-IDH1 mutant glioma tissue. The aggressive form of non-IDH1 mutant glioma shows abnormal cellular histological variation with prominent larger nucleus along with abnormal clustering of cells. The longer survival form of IDH1 mutant glioma has a control over glioma stem cell proliferation. Immunohistochemistry with stem cell markers, CD133 and EGFRvIII are used to demonstrate that the IDH1 mutant glioma shows limited dependence on cancer stem cells and it shows marked apoptotic signals in TUNEL assay to regulate abnormal cells. The non-IDH1 mutant glioma failed to regulate misbehaving cells and it promotes cancer stem cell proliferation. Our finding supports that the IDH1 mutant glioma has a regulatory role in glioma stem cells and their survival.

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

PubMed Central

Estlin, E. J.; Lashford, L.; Ablett, S.; Price, L.; Gowing, R.; Gholkar, A.; Kohler, J.; Lewis, I. J.; Morland, B.; Pinkerton, C. R.; Stevens, M. C.; Mott, M.; Stevens, R.; Newell, D. R.; Walker, D.; Dicks-Mireaux, C.; McDowell, H.; Reidenberg, P.; Statkevich, P.; Marco, A.; Batra, V.; Dugan, M.; Pearson, A. D.

1998-01-01

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted. Images Figure 5 p658-b Figure 6 p659-b PMID:9744506

Predicting and monitoring response to chemotherapy by 1,3-bis(2-chloroethyl)-1-nitrosourea in subcutaneously implanted 9L glioma using the apparent diffusion coefficient of water and 23Na MRI.

PubMed

Babsky, Andriy M; Hekmatyar, S K; Zhang, Hong; Solomon, James L; Bansal, Navin

2006-07-01

To examine the effects of the alkylating anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on (23)Na MRI and the water apparent diffusion coefficient (ADC) in subcutaneously- (sc-) implanted 9L glioma in rats. (23)Na MRI and (1)H water ADC measurements were performed on sham-treated control (N = 6) and BCNU-treated (N = 15) Fisher rats one day before BCNU injection and then one, three, and five days after BCNU injection. The BCNU-treated tumors were divided into BCNU-responsive (R(BCNU)) and BCNU-nonresponsive (NR(BCNU)) groups depending on the tumor volume changes that occurred after therapy. The pretreatment (23)Na MRI signal intensity (SI) and water ADC values were higher in R(BCNU) tumors compared to NR(BCNU) tumors. (23)Na MRI SI and water ADC increased with tumor growth in control and NR(BCNU) groups, but these changes were interrupted by BCNU therapy in R(BCNU) group. (23)Na MRI and water ADC measurements may be useful for predicting and monitoring response to chemotherapy in some tumors. However, the changes that occurred in (23)Na MRI SI and water ADC in sc-implanted 9L tumors are in contrast to previously published results for BCNU therapy of orthotopic 9L tumors. This may have important implications for monitoring therapy response in tumors. (c) 2006 Wiley-Liss, Inc.

An autopsy case of chronic active Epstein-Barr virus infection (CAEBV): distribution of central nervous system (CNS) lesions.

PubMed

Kobayashi, Zen; Tsuchiya, Kuniaki; Takahashi, Makoto; Yokota, Osamu; Sasaki, Atsushi; Bhunchet, Ekapot; Arai, Tetsuaki; Akiyama, Haruhiko; Kamoshita, Masaharu; Kotera, Minoru; Mizusawa, Hidehiro

2008-12-15

A 27-year-old Japanese man developed recurrent respiratory and central nervous system (CNS) symptoms, and hemophagocytic syndromes with a clinical course of 6 years. CT demonstrated multiple nodular lesions in the bilateral lungs, and MRI revealed multiple abnormal intensity areas in the brain and spinal cord. Cerebrospinal fluid (CSF) examination disclosed mild pleocytosis and the presence of Epstein-Barr virus (EBV)-DNA detected by polymerase chain reaction (PCR). The patient died of a hemorrhagic shock associated with a hemophagocytic syndrome. A postmortem study revealed massive hemorrhage in the abdominal cavity and iliopsoas muscles, as well as diffuse infiltration of lymphocytes and/or macrophages into the lungs, liver, kidneys, spleen, cardiac muscle, bone marrow, and CNS. The severe involvement was demonstrated in the CNS, especially in the spinal cord and brainstem. The CD3 positive cells of the brainstem were EBV-encoded RNA 1 positive. This is the first autopsy case of chronic active EBV infection (CAEBV) in which severe and extensive CNS involvement was demonstrated.

Acute functional deterioration in a child with cerebral palsy

PubMed Central

Smyth, Elizabeth; Kaliaperumal, Chandrasekaran; Leonard, Jane; Caird, John

2012-01-01

We describe a case of acute functional deterioration in a 13-year-old girl with severe spastic diplegia (GMFCS III) and a new diagnosis of diffuse intrinsic pontine glioma (DIPG). She presented with acute deterioration in mobility and motor function over 1 month, which was associated with dysarthria, dysphagia and behavioural change. Her mother had noticed subtle functional deterioration over the 2 months prior to this. Her physiotherapist who was concerned about her acute functional deterioration referred her for emergency review. Neurological imaging revealed a diffuse pontine lesion consistent with DIPG. She was subsequently referred to oncology. She deteriorated further, clinically, over the next few days and following discussion with the team; her family opted for palliative treatment, given the poor prognosis associated with DIPG. PMID:23257647

Combination of photodynamic therapy and temozolomide on glioma in a rat C6 glioma model.

PubMed

Zhang, Xiaoming; Guo, Mian; Shen, Lei; Hu, Shaoshan

2014-12-01

For glioma, temozolomide (TMZ) is a commonly used chemotherapy drug and photodynamic therapy (PDT) is an important adjuvant therapy. The aim of this study was to evaluate the effect of their combination for the treatment of glioma. A rat C6 glioma model using male Wistar rats (n=180) weighing 280-300 g was established. Glioma-bearing rats (n=100) were treated with mock, hematoporphyrin monomethyl ether (HMME), laser or PDT. The expression of P-glycoprotein (P-gp) in endothelial cells of the blood-tumor-barrier and in glioma tissues was detected using immunohistochemistry and western blot, respectively. Glioma-bearing rats (n=40) were treated with normal saline, TMZ (60 mg/m(2) for five consecutive days), PDT (630 nm for 10 min) or a combination of TMZ and PDT. TMZ concentration in glioma tissues was detected using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and cell death was observed using transmission microscopy. Concurrently, another batch of 40 glioma-bearing rats was subjected to the same treatment, and the survival of these rats was estimated using Kaplan-Meier analysis. PDT significantly decreased the expression of P-gp in endothelial cells comprising the blood-tumor-barrier and in glioma tissues. The combination of TMZ with PDT significantly increased TMZ concentration in glioma tissues, enhanced glioma cell apoptosis and prolonged the median survival of glioma-bearing rats. The combination of PDT with TMZ shows synergistic effect in rat C6 glioma model, indicating its potential clinical use in glioma treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

Brain-stem hemangioblastomas: The seemingly innocuous lesion in a perilous location.

PubMed

Joseph, Jeena; Behari, Sanjay; Gupta, Shruti; Bhaisora, Kamlesh Singh; Gandhi, Anish; Srivastava, Arun; Jaiswal, Awadhesh K

2018-01-01

Hemangioblastomas [75% sporadic, 25% with Von Hippel Lindau (VHL) disease] are highly vascular, benign lesions. The surgical nuances, management, and complication avoidance in brain-stem hemangioblastomas (BHs) have been studied. Over 18 years, 27(mean age: 29 years; range 15-60 years) consecutive cases of BH underwent microsurgical excision. All patients were assessed clinico-radiologically for neurological deficits and screened for VHL disease. Outcome of the patients was based on Karnofsky Performance Status scale (KPS). 12 out of 19 (70.4%) patients with hydrocephalus underwent a cerebrospinal fluid (CSF) diversion procedure. Lower cranial nerve palsy was present in 10 (37%) patients and motor weakness in 13 (48%). The tumours [mean size 3.34 ± 1.06 cm, range: 1.4-5.5 cm; 11 solid, rest solid-cystic; 18 (66.7%) subpial and 9 (33.33%) intramedullary] were divided into four categories based on size: A: <2 cm (n = 5,18.5%); B: 2-3 cm (n = 10,37%); C: 3-4 cm (n = 6,22.2%); D: >4 cm (n = 6,22.2%). Their location was at posterior cervicomedullary junction (n = 12); pontomedullary junction (n = 7); pons (n = 3), medulla (n = 3) and ponto-mesencephalic region (n = 2). Multiple flow voids were seen in >50% patients with tumour >2 cm. 5 patients had syringomyelia; and, 8 had diffuse cervical cord expansion. Two patients with a large vascular tumour underwent preoperative embolization. Six patients had VHL disease; one underwent bilateral adrenalectomy for refractory hypertension; and, the another, nephrectomy for renal cell carcinoma. Twenty-six patients underwent a midline suboccipital craniectomy; and, 1 with a cerebellopontine angle tumour, a retromastoid craniectomy. 15 patients underwent total excision; 10 patients, near-total (<10% remaining) excision, and 2 patients, a subtotal (>10% remaining)) excision. Three patients (2 with VHL disease) expired due to exsanguinating hemorrhage, spreading venous thrombosis and aspiration pneumonitis, respectively. At follow-up visit (median: 25 ± interquartile range 2-56months), 17 patients had improved KPS, 4 remained in same status and 3 (recently operated, on tracheostomy) had worsened KPS. Significant improvement is achievable in neurological status in patients following successful extirpation of a brain-stem hemangioblastoma, despite a turbulent perioperative period. Leaving tumour capsule adherent to the brain-stem often helps in preserving brain-stem function. Postoperatively, the patients should be monitored for their respiratory and lower cranial nerve status to prevent aspiration pneumonitis.

Gamma-glutamylcyclotransferase promotes the growth of human glioma cells by activating Notch-Akt signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao

Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects. GGCT overexpression promotes the expression ofmore » Notch receptors and activates Akt signaling in glioma cells, and Notch-Akt signaling is activated in glioma tissues with high expression of GGCT. Finally, we show that inhibition of Notch-Akt signaling with Notch inhibitor MK-0752 blocks the effects of GGCT on glioma proliferation and colony formation. In conclusion, GGCT plays a critical role in glioma cell proliferation and may be a potential cancer therapeutic target. - Highlights: • GGCT expression is up-regulated in human glioma tissues and cell lines. • GGCT promotes glioma cell growth and colony formation. • GGCT promotes the activation of Notch-Akt signaling in glioma cells and tissues. • Notch inhibition blocks the role of GGCT in human glioma cells.« less

Perspective on translating biomaterials into glioma therapy: Lessons from in vitro models

NASA Astrophysics Data System (ADS)

Cornelison, R. Chase; Munson, Jennifer M.

2018-05-01

Glioblastoma (GBM) is the most common and malignant form of brain cancer. Even with aggressive standard of care, GBM almost always recurs because its diffuse, infiltrative nature makes these tumors difficult to treat. The use of biomaterials is one strategy that has been, and is being, employed to study and overcome recurrence. Biomaterials have been used in GBM in two ways: in vitro as mediums in which to model the tumor microenvironment, and in vivo to sustain release of cytotoxic therapeutics. In vitro systems are a useful platform for studying the effects of drugs and tissue-level effectors on tumor cells in a physiologically relevant context. These systems have aided examination of how glioma cells respond to a variety of natural, synthetic, and semi-synthetic biomaterials with varying substrate properties, biochemical factor presentations, and non-malignant parenchymal cell compositions in both 2D and 3D environments. The current in vivo paradigm is completely different, however. Polymeric implants are simply used to line the post-surgical resection cavities and deliver secondary therapies, offering moderate impacts on survival. Instead, perhaps we can use the data generated from in vitro systems to design novel biomaterial-based treatments for GBM akin to a tissue engineering approach. Here we offer our perspective on the topic, summarizing how biomaterials have been used to identify facets of glioma biology in vitro and discussing the elements that show promise for translating these systems in vivo as new therapies for GBM.

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

PubMed

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

2016-05-19

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

[Functional neuro-navigation and intraoperative magnetic resonance imaging for the resection of gliomas involving eloquent language structures].

PubMed

Chen, Xiao-lei; Xu, Bai-nan; Wang, Fei; Meng, Xiang-hui; Zhang, Jun; Jiang, Jin-li; Yu, Xin-guang; Zhou, Ding-biao

2011-08-01

To explore the clinical value of functional neuro-navigation and high-field-strength intraoperative magnetic resonance imaging (iMRI) for the resection of intracerebral gliomas involving eloquent language structures. From April 2009 to April 2010, 48 patients with intracerebral gliomas involving eloquent language structures, were operated with functional neuro-navigation and iMRI. Blood oxygen level dependent functional MRI (BOLD-fMRI) was used to depict both Broca and Wernicke cortex, while diffusion tensor imaging (DTI) based fiber tracking was used to delineate arcuate fasciculus. The reconstructed language structures were integrated into a navigation system, so that intra-operative microscopic-based functional neuro-navigation could be achieved. iMRI was used to update the images for both language structures and residual tumors. All patients were evaluated for language function pre-operatively and post-operatively upon short-term and long-term follow-up. In all patients, functional neuro-navigation and iMRI were successfully achieved. In 38 cases (79.2%), gross total resection was accomplished, while in the rest 10 cases (20.8%), subtotal resection was achieved. Only 1 case (2.1%) developed long-term (more than 3 months) new language function deficits at post-operative follow-up. No peri-operative mortality was recorded. With functional neuro-navigation and iMRI, the eloquent structures for language can be precisely located, while the resection size can be accurately evaluated intra-operatively. This technique is safe and helpful for preservation of language function.

Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group.

PubMed

Janssens, Geert O; Gandola, Lorenza; Bolle, Stephanie; Mandeville, Henry; Ramos-Albiac, Monica; van Beek, Karen; Benghiat, Helen; Hoeben, Bianca; Morales La Madrid, Andres; Kortmann, Rolf-Dieter; Hargrave, Darren; Menten, Johan; Pecori, Emilia; Biassoni, Veronica; von Bueren, Andre O; van Vuurden, Dannis G; Massimino, Maura; Sturm, Dominik; Peters, Max; Kramm, Christof M

2017-03-01

Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first progression. At first progression, 31 children with DIPG, aged 2-16 years, underwent re-irradiation (dose 19.8-30.0 Gy) alone (n = 16) or combined with systemic therapy (n = 15). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (n = 20) or systemic therapy (n = 19) at progression but no re-irradiation, were eligible for a matched-cohort analysis. Median OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; P = .58), a significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3-6 months: 4.0 versus 2.7; P < .01; 6-12 months: 6.4 versus 3.3; P = .04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4-5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratio = .27-.54; P < .01) and re-irradiation (corrected hazard ratio = .18-.22; P < .01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). The majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability. Copyright © 2017 Elsevier Ltd. All rights reserved.

The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals.

PubMed

Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

2017-01-01

Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood-brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p -aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood-brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p -aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells.

Gap junctions modulate glioma invasion by direct transfer of microRNA.

PubMed

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

2015-06-20

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

Functional analysis of the DEPDC1 oncoantigen in malignant glioma and brain tumor initiating cells.

PubMed

Kikuchi, Ryogo; Sampetrean, Oltea; Saya, Hideyuki; Yoshida, Kazunari; Toda, Masahiro

2017-06-01

DEP domain containing 1 (DEPDC1) is a novel oncoantigen expressed in cancer cells, which presents oncogenic activity and high immunogenicity. Although DEPDC1 has been predicted to be a useful antigen for the development of a cancer vaccine, its pathophysiological roles in glioma have not been investigated. Here, we analyzed the expression and function of DEPDC1 in malignant glioma. DEPDC1 expression in glioma cell lines, glioma tissues, and brain tumor initiating cells (BTICs) was assessed by western blot and quantitative polymerase chain reaction (PCR). The effect of DEPDC1 downregulation on cell growth and nuclear factor kappa B (NFκB) signaling in glioma cells was investigated. Overall survival was assessed in mouse glioma models using human glioma cells and induced mouse brain tumor stem cells (imBTSCs) to determine the effect of DEPDC1 suppression in vivo. DEPDC1 expression was increased in glioma cell lines, tissues, and BTICs. Suppression of endogenous DEPDC1 expression by small interfering RNA (siRNA) inhibited glioma cell viability and induced apoptosis through NFκB signaling. In mouse glioma models using human glioma cells and imBTSCs, downregulation of DEPDC1 expression prolonged overall survival. These results suggest that DEPDC1 represents a target molecule for the treatment of glioma.

The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals

PubMed Central

Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

2017-01-01

Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood–brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p-aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood–brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p-aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells. PMID:28260885

Gap junctions modulate glioma invasion by direct transfer of microRNA

PubMed Central

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

2015-01-01

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

Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma

PubMed Central

Ju, Rui-Jun; Zeng, Fan; Liu, Lei; Mu, Li-Min; Xie, Hong-Jun; Zhao, Yao; Yan, Yan; Wu, Jia-Shuan; Hu, Ying-Jie; Lu, Wan-Liang

2016-01-01

The efficacy of chemotherapy for brain glioma is restricted by the blood–brain barrier (BBB), and surgery or radiotherapy cannot eliminate the glioma cells because of their unique location. Residual brain glioma cells can form vasculogenic mimicry (VM) channels that can cause a recurrence of brain glioma. In the present study, targeting liposomes incorporating epirubicin and celecoxib were prepared and used for the treatment of brain glioma, along with the destruction of their VM channels. Evaluations were performed on the human brain glioma U87MG cells in vitro and on intracranial brain glioma-bearing nude mice. Targeting epirubicin plus celecoxib liposomes in the circulatory blood system were able to be transported across the BBB, and accumulated in the brain glioma region. Then, the liposomes were internalized by brain glioma cells and killed glioma cells by direct cytotoxic injury and the induction of apoptosis. The induction of apoptosis was related to the activation of caspase-8- and -3-signaling pathways, the activation of the proapoptotic protein Bax, and the suppression of the antiapoptotic protein Mcl-1. The destruction of brain glioma VM channels was related to the downregulation of VM channel-forming indictors, which consisted of MMP-2, MMP-9, FAK, VE-Cad, and VEGF. The results demonstrated that the targeting epirubicin plus celecoxib liposomes were able to effectively destroy the glioma VM channels and exhibited significant efficacy in the treatment of intracranial glioma-bearing nude mice. Therefore, targeting epirubicin plus celecoxib liposomes could be a potential nanostructured formulation to treat gliomas and destroy their VM channels. PMID:27042063

Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1

PubMed Central

Zhu, Wen; Carney, Karen E.; Pigott, Victoria M.; Falgoust, Lindsay M.; Clark, Paul A.; Kuo, John S.; Sun, Dandan

2016-01-01

Microglia play important roles in extracellular matrix remodeling, tumor invasion, angiogenesis, and suppression of adaptive immunity in glioma. Na+/H+ exchanger isoform 1 (NHE1) regulates microglial activation and migration. However, little is known about the roles of NHE1 in intratumoral microglial activation and microglia–glioma interactions. Our study revealed up-regulation of NHE1 protein expression in both glioma cells and tumor-associated Iba1+ microglia in glioma xenografts and glioblastoma multiforme microarrays. Moreover, we observed positive correlation of NHE1 expression with Iba1 intensity in microglia/macrophages. Glioma cells, via conditioned medium or non-contact glioma-microglia co-cultures, concurrently upregulated microglial expression of NHE1 protein and other microglial activation markers (iNOS, arginase-1, TGF-β, IL-6, IL-10 and the matrix metalloproteinases MT1-MMP and MMP9). Interestingly, glioma-stimulated microglia reciprocally enhanced glioma proliferation and migration. Most importantly, inhibition of microglial NHE1 activity via small interfering RNA (siRNA) knockdown or the potent NHE1-specific inhibitor HOE642 significantly attenuated microglial activation and abolished microglia-stimulated glioma migration and proliferation. Taken together, our findings provide the first evidence that NHE1 function plays an important role in glioma–microglia interactions, enhancing glioma proliferation and invasion by stimulating microglial release of soluble factors. NHE1 upregulation is a novel marker of the glioma-associated microglial activation phenotype. Inhibition of NHE1 represents a novel glioma therapeutic strategy by targeting tumor-induced microglial activation. PMID:27287871

Automatic Semantic Segmentation of Brain Gliomas from MRI Images Using a Deep Cascaded Neural Network

PubMed Central

Mao, Lei; Liu, Chang; Xiong, Shuyu

2018-01-01

Brain tumors can appear anywhere in the brain and have vastly different sizes and morphology. Additionally, these tumors are often diffused and poorly contrasted. Consequently, the segmentation of brain tumor and intratumor subregions using magnetic resonance imaging (MRI) data with minimal human interventions remains a challenging task. In this paper, we present a novel fully automatic segmentation method from MRI data containing in vivo brain gliomas. This approach can not only localize the entire tumor region but can also accurately segment the intratumor structure. The proposed work was based on a cascaded deep learning convolutional neural network consisting of two subnetworks: (1) a tumor localization network (TLN) and (2) an intratumor classification network (ITCN). The TLN, a fully convolutional network (FCN) in conjunction with the transfer learning technology, was used to first process MRI data. The goal of the first subnetwork was to define the tumor region from an MRI slice. Then, the ITCN was used to label the defined tumor region into multiple subregions. Particularly, ITCN exploited a convolutional neural network (CNN) with deeper architecture and smaller kernel. The proposed approach was validated on multimodal brain tumor segmentation (BRATS 2015) datasets, which contain 220 high-grade glioma (HGG) and 54 low-grade glioma (LGG) cases. Dice similarity coefficient (DSC), positive predictive value (PPV), and sensitivity were used as evaluation metrics. Our experimental results indicated that our method could obtain the promising segmentation results and had a faster segmentation speed. More specifically, the proposed method obtained comparable and overall better DSC values (0.89, 0.77, and 0.80) on the combined (HGG + LGG) testing set, as compared to other methods reported in the literature. Additionally, the proposed approach was able to complete a segmentation task at a rate of 1.54 seconds per slice. PMID:29755716

Assessing the predictability of IDH mutation and MGMT methylation status in glioma patients using relaxation-compensated multi-pool CEST MRI at 7.0 Tesla.

PubMed

Paech, Daniel; Windschuh, Johannes; Oberhollenzer, Johanna; Dreher, Constantin; Sahm, Felix; Meissner, Jan-Eric; Goerke, Steffen; Schuenke, Patrick; Zaiss, Moritz; Regnery, Sebastian; Bickelhaupt, Sebastian; Bäumer, Philipp; Bendszus, Martin; Wick, Wolfgang; Unterberg, Andreas; Bachert, Peter; Ladd, Mark Edward; Schlemmer, Heinz-Peter; Radbruch, Alexander

2018-05-04

Early identification of prognostic superior characteristics in glioma patients such as Isocitrate dehydrogenase(IDH)-mutation and O6-methylguanine-DNA-methyltransferase (MGMT) promotor methylation status is of great clinical importance. The study purpose was to investigate the non-invasive predictability of IDH-mutation status, MGMT promotor methylation, and differentiation of lower versus higher grade glioma (LGG vs. HGG) in newly-diagnosed patients employing relaxation-compensated multi-pool Chemical Exchange Saturation Transfer (CEST) magnetic resonance imaging (MRI) at 7.0 Tesla (7T). Thirty-one newly-diagnosed glioma patients were included in this prospective study. CEST MRI was performed at a 7T whole-body scanner. Nuclear Overhauser Effect (NOE) and isolated amide proton transfer (APT, downfield NOE-suppressed APT=dns-APT) CEST signals (mean value and 90th signal percentile) were quantitatively investigated in the whole tumor area with regard to predictability of IDH-mutation, MGMT promotor methylation status, and differentiation of LGG vs. HGG. Statistics were performed using receiver operating characteristic (ROC) and area under the curve (AUC) analysis. Results were compared to advanced MRI methods (apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) ROC/AUC analysis) obtained at 3T. dns-APT CEST contrasts yielded highest AUCs in IDH-mutation status prediction (dns-APTmean=91.84%, p<0.01; dns-APT90=97.96%, p<0.001). Furthermore, dns-APT metrics enabled significant differentiation of LGG vs. HGG (AUC: dns-APTmean=0.78, p<0.05; dns-APT90=0.83, p<0.05). There was no significant difference regarding MGMT promotor methylation status at any contrast (p>0.05). Relaxation-compensated multi-pool CEST MRI, particularly dns-APT imaging, enabled prediction of IDH-mutation status and differentiation of LGG vs. HGG and should therefore be considered as non-invasive MR biomarker in the diagnostic workup.

Roel Verhaak, Ph.D., Presents the Somatic Genomic Landscape of Glioblastoma - TCGA

Cancer.gov

Diffuse lower grade gliomas (LGGs) are infiltrative neoplasms of the central nervous system that include astrocytoma, oligodendroglioma and oligo-astrocytoma histologies of grades II and III. Roel G.W. Verhaak, Ph.D., presents a comprehensive analysis of 293 LGGs using multiple advanced genomic, transcriptomic and proteomic platforms from The Cancer Genome Atlas to provide a deeper understanding of the molecular features of this group of neoplasms, to classify them in a clinically-relevant manner, and to provide a public resource that identifies potential targets for emerging therapies.

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

An agent-based model identifies MRI regions of probable tumor invasion in a patient with glioblastoma

NASA Astrophysics Data System (ADS)

Chen, L. Leon; Ulmer, Stephan; Deisboeck, Thomas S.

2010-01-01

We present an application of a previously developed agent-based glioma model (Chen et al 2009 Biosystems 95 234-42) for predicting spatio-temporal tumor progression using a patient-specific MRI lattice derived from apparent diffusion coefficient (ADC) data. Agents representing collections of migrating glioma cells are initialized based upon voxels at the outer border of the tumor identified on T1-weighted (Gd+) MRI at an initial time point. These simulated migratory cells exhibit a specific biologically inspired spatial search paradigm, representing a weighting of the differential contribution from haptotactic permission and biomechanical resistance on the migration decision process. ADC data from 9 months after the initial tumor resection were used to select the best search paradigm for the simulation, which was initiated using data from 6 months after the initial operation. Using this search paradigm, 100 simulations were performed to derive a probabilistic map of tumor invasion locations. The simulation was able to successfully predict a recurrence in the dorsal/posterior aspect long before it was depicted on T1-weighted MRI, 18 months after the initial operation.

An agent-based model identifies MRI regions of probable tumor invasion in a patient with glioblastoma.

PubMed

Chen, L Leon; Ulmer, Stephan; Deisboeck, Thomas S

2010-01-21

We present an application of a previously developed agent-based glioma model (Chen et al 2009 Biosystems 95 234-42) for predicting spatio-temporal tumor progression using a patient-specific MRI lattice derived from apparent diffusion coefficient (ADC) data. Agents representing collections of migrating glioma cells are initialized based upon voxels at the outer border of the tumor identified on T1-weighted (Gd+) MRI at an initial time point. These simulated migratory cells exhibit a specific biologically inspired spatial search paradigm, representing a weighting of the differential contribution from haptotactic permission and biomechanical resistance on the migration decision process. ADC data from 9 months after the initial tumor resection were used to select the best search paradigm for the simulation, which was initiated using data from 6 months after the initial operation. Using this search paradigm, 100 simulations were performed to derive a probabilistic map of tumor invasion locations. The simulation was able to successfully predict a recurrence in the dorsal/posterior aspect long before it was depicted on T1-weighted MRI, 18 months after the initial operation.

Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression.

PubMed

Han, Guosheng; Zhao, Wenyuan; Wang, Laixing; Yue, Zhijian; Zhao, Rui; Li, Yanan; Zhou, Xiaoping; Hu, Xiaowu; Liu, Jianmin

2014-01-16

Glioma stem-like cells have been demonstrated to have highly invasive activity, which is the major cause of glioma recurrence after therapy. Leptin plays a role in glioma invasion, however, whether and how leptin contributes to the biological properties of glioma stem-like cells, such as invasion, remains to be explored. In the current study, we aimed to explore the role of leptin during glioma stem-like cells invasion as well as the signaling pathway. We found that glioma stem-like cells exhibited high invasive potential, especially in the presence of leptin, Ob-R coexpressed with CD133 in glioma stem-like cells was showed to be responsible for leptin mediated invasion of glioma stem-like cells. Our results indicated that leptin served as a key intermediary linking the accumulation of excess adipokine to the invasion of glioma stem-like cells, which may be a novel therapeutic target for suppressing tumor invasion and recurrence. © 2013 Published by Elsevier B.V.

Products of cells from gliomas: VIII. Multiple-well immunoperoxidase assay of immunoreactivity of primary hybridoma supernatants with human glioma and brain tissue and cultured glioma cells.

PubMed

McKeever, P E; Wahl, R L; Shakui, P; Jackson, G A; Letica, L H; Liebert, M; Taren, J A; Beierwaltes, W H; Hoff, J T

1990-06-01

To test the feasibility of primary screening of hybridoma supernatants against human glioma tissue, over 5000 combinations of hybridoma supernatants with glioma tissue, cultured glioma cells, and normal central neural tissue were screened with a new multiple-well (M-well) screening system. This is an immunoperoxidase assay system with visual endpoints for screening 20-30 hybridoma supernatants per single microscope slide. There were extensive differences between specificities to tissue and to cultured glioma cells when both were screened with M-wells and when cultured cells were screened with standard semi-automated fluorescence. Primary M-well screening with glioma tissue detected seven hybridoma supernatants that specifically identified parenchymal cells of glioma tissue and that were not detected with cultured cells. Immunoreactivities of individual supernatants for vascular components (nine supernatants), necrosis (five supernatants), and nuclei (three supernatants) were detected. Other supernatants bound multiple sites on glioma tissue and/or subpopulations of neurons and glia of normal tissue. The results show that primary screening with glioma tissue detects a number of different specificities of hybridoma supernatants to gliomas not detected by conventional screening with cultured cells. These are potentially applicable to diagnosis and therapy.

High expression of Bruton's tyrosine kinase (BTK) is required for EGFR-induced NF-κB activation and predicts poor prognosis in human glioma.

PubMed

Yue, Chenglong; Niu, Mingshan; Shan, Qian Qian; Zhou, Ting; Tu, Yiming; Xie, Peng; Hua, Lei; Yu, Rutong; Liu, Xuejiao

2017-09-25

Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted therapeutics for glioma is urgently needed. In this study, we examined the prognostic significance BTK expression in patients with glioma. Furthermore, we investigated the mechanism and therapeutic potential of ibrutinib in the treatment of human glioma in vitro and in vivo. Our data demonstrate that high expression of BTK is a novel prognostic marker for poor survival in patients with glioma. BTK-specific inhibitor ibrutinib effectively inhibits the proliferation, migration and invasion ability of glioma cells. Furthermore, ibrutinib can induce G1 cell-cycle arrest by regulating multiple cell cycle-associated proteins. More importantly, we found that BTK inhibition significantly blocks the degradation of IκBα and prevents the nuclear accumulation of NF-κB p65 subunit induced by EGF in glioma cells. Taken together, our study suggests that BTK is a novel prognostic marker and molecular therapeutic target for glioma. BTK is required for EGFR-induced NF-κB activation in glioma cells. These findings provide the basis for future clinical studies of ibrutinib for the treatment of glioma.

Imaging Biomarker Dynamics in an Intracranial Murine Glioma Study of Radiation and Antiangiogenic Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chung, Caroline, E-mail: caroline.chung@rmp.uhn.on.ca; Jalali, Shahrzad; Foltz, Warren

2013-03-01

Purpose: There is a growing need for noninvasive biomarkers to guide individualized spatiotemporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI). Methods and Materials: Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhancedmore » T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K{sub trans}, K{sub ep}). Results: Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K{sub trans} reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K{sub ep} reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of −0.878 (P=.002) and −0.80 (P=.01), respectively. Conclusions: Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future.« less

Centrosomal Protein of 55 Regulates Glucose Metabolism, Proliferation and Apoptosis of Glioma Cells via the Akt/mTOR Signaling Pathway

PubMed Central

Wang, Guangzhi; Liu, Mingna; Wang, Hongjun; Yu, Shan; Jiang, Zhenfeng; Sun, Jiahang; Han, Ke; Shen, Jia; Zhu, Minwei; Lin, Zhiguo; Jiang, Chuanlu; Guo, Mian

2016-01-01

Introduction: Glioma is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and the progression of glioma are elusive and controversial. Centrosomal protein of 55 (CEP55) was initially described as a highly coiled-coil protein that plays critical roles in cell division, but was recently identified as being overexpressed in many human cancers. The function of CEP55 has not previously been characterized in glioma. We aim to discover the effect and mechanism of CEP55 in glioma development. Method: qRT-PCR and immunohistochemistry were used to analyze CEP55 expression. Glucose uptake, western blot, MTS, CCK-8, Caspase-3 activity and TUNEL staining assays were performed to investigate the role and mechanism of CEP55 on glioma cell process. Results: We found that the levels of CEP55 expression were upregulated in glioma. In addition, CEP55 appeared to regulate glucose metabolism of glioma cells. Furthermore, knockdown of CEP55 inhibited cell proliferation and induced cell apoptosis in glioma. Finally, we provided preliminary evidence that knockdown of CEP55 inhibited glioma development via suppressing the activity of Akt/mTOR signaling. Conclusions: Our results demonstrated that CEP55 regulates glucose metabolism, proliferation and apoptosis of glioma cells via the Akt/mTOR signaling pathway, and its promotive effect on glioma tumorigenesis can be a potential target for glioma therapy in the future. PMID:27471559

Subacute Sclerosing Panencephalitis of the Brainstem as a Clinical Entity.

PubMed

Upadhyayula, Pavan S; Yang, Jason; Yue, John K; Ciacci, Joseph D

2017-11-07

Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurological disorder of early adolescence caused by persistent infection of the measles virus, which remains prevalent worldwide despite an effective vaccine. SSPE is a devastating disease with a characteristic clinical course in subcortical white matter; however, atypical presentations of brainstem involvement may be seen in rare cases. This review summarizes reports to date on brainstem involvement in SSPE, including the clinical course of disease, neuroimaging presentations, and guidelines for treatment. A comprehensive literature search was performed for English-language publications with keywords "subacute sclerosing panencephalitis" and "brainstem" using the National Library of Medicine PubMed database (March 1981-September 2017). Eleven articles focusing on SSPE of the brainstem were included. Predominant brainstem involvement remains uncharacteristic of SSPE, which may lead to misdiagnosis and poor outcome. A number of case reports have demonstrated brainstem involvement associated with other intracranial lesions commonly presenting in later SSPE stages (III and IV). However, brainstem lesions can appear in all stages, independent of higher cortical structures. The varied clinical presentations complicate diagnosis from a neuroimaging perspective. SSPE of the brainstem is a rare but important clinical entity. It may present like canonical SSPE or with unique clinical features such as absence seizures and pronounced ataxia. While SSPE generally progresses to the brainstem, it can also begin with a primary focus of infection in the brainstem. Awareness of varied SSPE presentations can aid in early diagnosis as well as guide management and treatment.

Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas.

PubMed

Park, Y W; Han, K; Ahn, S S; Choi, Y S; Chang, J H; Kim, S H; Kang, S-G; Kim, E H; Lee, S-K

2018-04-01

Prediction of the isocitrate dehydrogenase 1 (IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1 -mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. Ninety-three patients with World Health Organization grade II gliomas with known IDH1- mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1- mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1 -mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1 -mutant subgroups were evaluated using the least absolute shrinkage and selection operator. Various histogram and texture parameters differed significantly according to IDH1 -mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1 -mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1 -mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. © 2018 by American Journal of Neuroradiology.

Chronic spatial working memory deficit associated with the superior longitudinal fasciculus: a study using voxel-based lesion-symptom mapping and intraoperative direct stimulation in right prefrontal glioma surgery.

PubMed

Kinoshita, Masashi; Nakajima, Riho; Shinohara, Harumichi; Miyashita, Katsuyoshi; Tanaka, Shingo; Okita, Hirokazu; Nakada, Mitsutoshi; Hayashi, Yutaka

2016-10-01

OBJECTIVE Although the right prefrontal region is regarded as a silent area, chronic deficits of the executive function, including working memory (WM), could occur after resection of a right prefrontal glioma. This may be overlooked by postoperative standard examinations, and the disabilities could affect the patient's professional life. The right prefrontal region is a part of the frontoparietal network and is subserved by the superior longitudinal fasciculus (SLF); however, the role of the SLF in spatial WM is unclear. This study investigated a persistent spatial WM deficit in patients who underwent right prefrontal glioma resection, and evaluated the relationship between the spatial WM deficit and the SLF. METHODS Spatial WM was examined in 24 patients who underwent prefrontal glioma resection (right, n = 14; left, n = 10) and in 14 healthy volunteers using a spatial 2-back task during the long-term postoperative period. The neural correlates of spatial WM were evaluated using lesion mapping and voxel-based lesion-symptom mapping. In addition, the spatial 2-back task was performed during surgery under direct subcortical electrical stimulation in 2 patients with right prefrontal gliomas. RESULTS Patients with a right prefrontal lesion had a significant chronic spatial WM deficit. Voxel-based lesion-symptom mapping analysis revealed a significant correlation between spatial WM deficit and the region that overlapped the first and second segments of the SLF (SLF I and SLF II). Two patients underwent awake surgery and had difficulties providing the correct responses in the spatial 2-back task with direct subcortical electrical stimulation on the SLF I, which was preserved and confirmed by postoperative diffusion tensor imaging tractography. These patients exhibited no spatial WM deficits during the postoperative immediate and long-term periods. CONCLUSIONS Spatial WM deficits may persist in patients who undergo resection of the tumor located in the right prefrontal brain parenchyma. Injury to the dorsal frontoparietal subcortical white matter pathway, i.e., the SLF I or SLF I and II, could play a causal role in this chronic deficit. A persistent spatial WM deficit, without motor and language deficits, could affect the professional life of the patient. In such cases, awake surgery would be useful to detect the spatial WM network with appropriate task during tumor exploration.

[Expression and mechanism of Twist2 in glioma].

PubMed

Wang, L Z; Wang, W J; Xiong, Y F; Xu, S; Wang, S S; Tu, Y; Wang, Z Y; Yan, X L; Mei, J H; Wang, C L

2017-12-08

Objective: To investigate the significance of Twist2 in glioma and whether it is involved in the malignant transformation of glioma by epithelial-mesenchymal transition (EMT). Methods: Using immunohistochemical method detected the expression level of Twist2 in 60 cases of gliomas (including WHO grades Ⅱ, Ⅲ and Ⅳ, each for 20 cases) and 20 cases of non-tumor brain tissues. Real-time fluorescence quantitative PCR and Western blot were used to detect the expression level of Twist2 mRNA and protein in 61 cases of fresh glioma tissue (WHO grade Ⅱ 16 cases, Ⅲ 21 cases, Ⅳ 24 cases) and 12 cases of adjacent tissues, and the expression levels of E-cadherin, N-cadherin and vimentin were also investigated in fresh glioma tissue. Results: Immunohistochemistry results showed that the percentages of Twist2 expression in glioma was 90%(54/60) compared with 30%(6/20) in non-tumor brain tissues( P <0.01). The percentages of Twist2 expression were 75% (15/20), 95% (19/20), and 100% (20/20) in the WHO gradesⅡ, Ⅲ and Ⅳ gliomas, respectively. WHO grades Ⅳ and Ⅲ were significantly higher than that of WHO grade Ⅱ ( P <0.01). There was no significant difference between WHO grade Ⅳand WHO Ⅲ glioma ( P >0.05). Real-time fluorescence quantitative PCR and Western blot showed that the expression level of Twist 2 in gliomas was significantly higher than that in para-cancerous tissues ( P <0.01), and those in WHO grades Ⅳ and Ⅲ gliomas were significantly higher than that in WHO grade Ⅱ glioma ( P <0.01). There was no significant difference between WHO grade Ⅳand grade Ⅲ glioma ( P >0.05). Detection of key protein expression in EMT by Western blot displayed that the expression of E-cadherin was negatively associated with Twist2 in glioma ( r =-0.972, P <0.01). The expression of N-cadherin and vimentin was positively associated with Twist2 in glioma( r =0.971, P <0.01; r =0.968, P <0.01). Conclusions: The expression of Twist2 in human glioma is positively correlated with the malignant grade of glioma, which may be involved in the malignant progression of glioma by EMT.

Investigation of adhesion and mechanical properties of human glioma cells by single cell force spectroscopy and atomic force microscopy.

PubMed

Andolfi, Laura; Bourkoula, Eugenia; Migliorini, Elisa; Palma, Anita; Pucer, Anja; Skrap, Miran; Scoles, Giacinto; Beltrami, Antonio Paolo; Cesselli, Daniela; Lazzarino, Marco

2014-01-01

Active cell migration and invasion is a peculiar feature of glioma that makes this tumor able to rapidly infiltrate into the surrounding brain tissue. In our recent work, we identified a novel class of glioma-associated-stem cells (defined as GASC for high-grade glioma--HG--and Gasc for low-grade glioma--LG) that, although not tumorigenic, act supporting the biological aggressiveness of glioma-initiating stem cells (defined as GSC for HG and Gsc for LG) favoring also their motility. Migrating cancer cells undergo considerable molecular and cellular changes by remodeling their cytoskeleton and cell interactions with surrounding environment. To get a better understanding about the role of the glioma-associated-stem cells in tumor progression, cell deformability and interactions between glioma-initiating stem cells and glioma-associated-stem cells were investigated. Adhesion of HG/LG-cancer cells on HG/LG-glioma-associated stem cells was studied by time-lapse microscopy, while cell deformability and cell-cell adhesion strengths were quantified by indentation measurements by atomic force microscopy and single cell force spectroscopy. Our results demonstrate that for both HG and LG glioma, cancer-initiating-stem cells are softer than glioma-associated-stem cells, in agreement with their neoplastic features. The adhesion strength of GSC on GASC appears to be significantly lower than that observed for Gsc on Gasc. Whereas, GSC spread and firmly adhere on Gasc with an adhesion strength increased as compared to that obtained on GASC. These findings highlight that the grade of glioma-associated-stem cells plays an important role in modulating cancer cell adhesion, which could affect glioma cell migration, invasion and thus cancer aggressiveness. Moreover this work provides evidence about the importance of investigating cell adhesion and elasticity for new developments in disease diagnostics and therapeutics.

Upregulation of B23 promotes tumor cell proliferation and predicts poor prognosis in glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Jianguo; Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province; Sun, Jie

B23 (also known as Nucleophosmin, NPM, numatrin or NO38) is a ubiquitously expressed phosphoprotein belonging to the nucleoplasmin family of chaperones. In this study we intended to investigate the clinical significance of B23 expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that B23 was overexpressed in glioma tissues and glioma cell lines. In addition, the expression level of B23 was positively correlated with glioma pathological grade and Ki-67 expression. Kaplan–Meier analysis revealed that a higher B23 expression in patients with glioma was associated with a poorer prognosis. In vitro, after the releasemore » of glioma cell lines from serum starvation, the expression of B23 was upregulated, as well as PCNA (Proliferating Cell Nuclear Antigen) and cyclin A. In addition, knockdown of B23 by small interfering RNA transfection diminished the expression of PCNA, cyclin D1 and arrested cell growth at G1 phase. Taken together, our results implied that B23 could be a candidate prognostic biomarker as well as a potential therapeutical target of glioma. - Highlights: • B23 expression increased as the malignant degree of glioma increased, which was consistent with Ki-67 expression. • High expression of B23 could be a strong determinant of poor prognosis in glioma. • B23 may be involved in the proliferation of glioma in a cell-cycle-dependent pathway. • Knockdown of B23 expression by siRNA could affect the progression of glioma. • B23 may be a potential prognosis biomarker and a possible therapeutic target for glioma.« less

Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis

PubMed Central

Chen, Dongfeng; Persson, Annette; Sun, Yingyu; Salford, Leif G.; Nord, David Gisselsson; Englund, Elisabet; Jiang, Tao; Fan, Xiaolong

2013-01-01

Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis. PMID:23630597

Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study.

PubMed

Melin, Beatrice; Dahlin, Anna M; Andersson, Ulrika; Wang, Zhaoming; Henriksson, Roger; Hallmans, Göran; Bondy, Melissa L; Johansen, Christoffer; Feychting, Maria; Ahlbom, Anders; Kitahara, Cari M; Wang, Sophia S; Ruder, Avima M; Carreón, Tania; Butler, Mary Ann; Inskip, Peter D; Purdue, Mark; Hsing, Ann W; Mechanic, Leah; Gillanders, Elizabeth; Yeager, Meredith; Linet, Martha; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

2013-05-15

Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours. Copyright © 2012 UICC.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Bin; Hu, Zhiqiang, E-mail: zhiqhutg@126.com; Huang, Hui

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

Gpx 4 is involved in the proliferation, migration and apoptosis of glioma cells.

PubMed

Zhao, Hongyu; Ji, Bin; Chen, Jianguo; Huang, Qingfeng; Lu, Xueguan

2017-06-01

Glioma is one of the most common and aggressive types of human brain tumor, it is important to explore novel glioma-associated genes. In this report, we defined Gpx4 as a therapeutic target for glioma. Western blot and immunohistochemistry(IHC) analysis revealed that the protein level of Gpx4 was higher in glioma tissues and cell lines. In addition, IHC stain revealed that there was statistical significance between the expression of Gpx4 and the WHO grade (P=0.004) and Ki-67(P=0.000) expression. Kaplan-Meier curve showed that high expression of Gpx4 was associated with poor prognosis of glioma patients (P<0.01). To determine whether Gpx4 could regulate the proliferation and migration of glioma cells, we transfected glioma cells with Gpx4-siRNA and then investigated cell proliferation with cell counting kit (CCK) -8, flow cytometry assay and colony formation analyses, and we used wound-healing and transwell assays to investigate cell migration. Our results indicated that knockdown of Gpx4 would inhibit the proliferation and migration of glioma cells. Besides, silencing of Gpx4 could induce the apoptosis of glioma cells. This research indicated that Gpx4 might be thought of as a new prognostic factor in glioma and be closely correlated with glioma cell proliferation, migration and apoptosis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Knockdown of DIXDC1 Inhibits the Proliferation and Migration of Human Glioma Cells.

PubMed

Chen, Jianguo; Shen, Chaoyan; Shi, Jinlong; Shen, Jianhong; Chen, Wenjuan; Sun, Jie; Fan, Shaocheng; Bei, Yuanqi; Xu, Peng; Chang, Hao; Jiang, Rui; Hua, Lu; Ji, Bin; Huang, Qingfeng

2017-08-01

DIX domain containing 1 (DIXDC1), the human homolog of coiled-coil-DIX1 (Ccd1), is a positive regulator of Wnt signaling pathway. Recently, it was found to act as a candidate oncogene in colon cancer, non-small-cell lung cancer, and gastric cancer. In this study, we aimed to investigate the clinical significance of DIXDC1 expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that DIXDC1 was overexpressed in glioma tissues and glioma cell lines. The expression level of DIXDC1 was evidently linked to glioma pathological grade and Ki-67 expression. Kaplan-Meier curve showed that high expression of DIXDC1 may lead to poor outcome of glioma patients. Serum starvation and refeeding assay indicated that the expression of DIXDC1 was associated with cell cycle. To determine whether DIXDC1 could regulate the proliferation and migration of glioma cells, we transfected glioma cells with interfering RNA-targeting DIXDC1; investigated cell proliferation with Cell Counting Kit (CCK)-8, flow cytometry assays, and colony formation analyses; and investigated cell migration with wound healing assays and transwell assays. According to our data, knockdown of DIXDC1 significantly inhibited proliferation and migration of glioma cells. These data implied that DIXDC1 might participate in the development of glioma, suggesting that DIXDC1 can become a potential therapeutic strategy for glioma.

The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells

PubMed Central

Ying, Xue; Wang, Yahua; Xu, Haolun; Li, Xia; Yan, Helu; Tang, Hui; Wen, Chen; Li, Yingchun

2017-01-01

Brain gliomas, one of the most fatal tumors to human, severely threat the health and life of human. They are capable of extremely strong invasion ability. And invasive glioma cells could rapidly penetrate into normal brain tissues and break them. We prepared a kind of functional liposomes, which could be transported acrossing the blood-brain barrier (BBB) and afterwards induce the apoptosis of glioma stem cells. In this research, we chose ursolic acids (UA) as an anti-cancer drug to inhibit the growth of C6 glioma cells, while epigallocatechin 3-gallate(EGCG) as the agent that could induce the apoptosis of C6 glioma stem cells. With the targeting ability of MAN, the liposomes could be delivered through the BBB and finally were concentrated on the brain gliomas. Cell experiments in vitro demonstrated that the functional liposomes were able to significantly enhance the anti-cancer effects of the drugs due to promoting the apoptosis and endocytosis effects of C6 glioma cells and C6 glioma stem cells at the same time. Furthermore, the evaluations through animal models showed that the drugs could obviously prolong the survival period of brain glioma-bearing mice and inhibit the tumor growth. Consequently, multifunctional targeting ursolic acids liposomes could potentially improve the therapeutic effects on C6 glioma cells and C6 glioma stem cells. PMID:28969057

Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer

PubMed Central

Andersson, Ulrika; Wibom, Carl; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Armstrong, Georgina N.; Shete, Sanjay; Lau, Ching C.; Bainbridge, Matthew N.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Lai, Rose; Il'yasova, Dora; Houlston, Richard S.; Schildkraut, Joellen; Bernstein, Jonine L.; Olson, Sara H.; Jenkins, Robert B.; Lachance, Daniel H.; Wrensch, Margaret; Davis, Faith G.; Merrell, Ryan; Johansen, Christoffer; Sadetzki, Siegal; Bondy, Melissa L.; Melin, Beatrice S.; Adatto, Phyllis; Morice, Fabian; Payen, Sam; McQuinn, Lacey; McGaha, Rebecca; Guerra, Sandra; Paith, Leslie; Roth, Katherine; Zeng, Dong; Zhang, Hui; Yung, Alfred; Aldape, Kenneth; Gilbert, Mark; Weinberger, Jeffrey; Colman, Howard; Conrad, Charles; de Groot, John; Forman, Arthur; Groves, Morris; Levin, Victor; Loghin, Monica; Puduvalli, Vinay; Sawaya, Raymond; Heimberger, Amy; Lang, Frederick; Levine, Nicholas; Tolentino, Lori; Saunders, Kate; Thach, Thu-Trang; Iacono, Donna Dello; Sloan, Andrew; Gerson, Stanton; Selman, Warren; Bambakidis, Nicholas; Hart, David; Miller, Jonathan; Hoffer, Alan; Cohen, Mark; Rogers, Lisa; Nock, Charles J; Wolinsky, Yingli; Devine, Karen; Fulop, Jordonna; Barrett, Wendi; Shimmel, Kristen; Ostrom, Quinn; Barnett, Gene; Rosenfeld, Steven; Vogelbaum, Michael; Weil, Robert; Ahluwalia, Manmeet; Peereboom, David; Staugaitis, Susan; Schilero, Cathy; Brewer, Cathy; Smolenski, Kathy; McGraw, Mary; Naska, Theresa; Rosenfeld, Steven; Ram, Zvi; Blumenthal, Deborah T.; Bokstein, Felix; Umansky, Felix; Zaaroor, Menashe; Cohen, Avi; Tzuk-Shina, Tzeela; Voldby, Bo; Laursen, René; Andersen, Claus; Brennum, Jannick; Henriksen, Matilde Bille; Marzouk, Maya; Davis, Mary Elizabeth; Boland, Eamon; Smith, Marcel; Eze, Ogechukwu; Way, Mahalia; Lada, Pat; Miedzianowski, Nancy; Frechette, Michelle; Paleologos, Nina; Byström, Gudrun; Svedberg, Eva; Huggert, Sara; Kimdal, Mikael; Sandström, Monica; Brännström, Nikolina; Hayat, Amina; Tihan, Tarik; Zheng, Shichun; Berger, Mitchel; Butowski, Nicholas; Chang, Susan; Clarke, Jennifer; Prados, Michael; Rice, Terri; Sison, Jeannette; Kivett, Valerie; Duo, Xiaoqin; Hansen, Helen; Hsuang, George; Lamela, Rosito; Ramos, Christian; Patoka, Joe; Wagenman, Katherine; Zhou, Mi; Klein, Adam; McGee, Nora; Pfefferle, Jon; Wilson, Callie; Morris, Pagan; Hughes, Mary; Britt-Williams, Marlin; Foft, Jessica; Madsen, Julia; Polony, Csaba; McCarthy, Bridget; Zahora, Candice; Villano, John; Engelhard, Herbert; Borg, Ake; Chanock, Stephen K; Collins, Peter; Elston, Robert; Kleihues, Paul; Kruchko, Carol; Petersen, Gloria; Plon, Sharon; Thompson, Patricia; Johansen, C.; Sadetzki, S.; Melin, B.; Bondy, Melissa L.; Lau, Ching C.; Scheurer, Michael E.; Armstrong, Georgina N.; Liu, Yanhong; Shete, Sanjay; Yu, Robert K.; Aldape, Kenneth D.; Gilbert, Mark R.; Weinberg, Jeffrey; Houlston, Richard S.; Hosking, Fay J.; Robertson, Lindsay; Papaemmanuil, Elli; Claus, Elizabeth B.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Sloan, Andrew E.; Barnett, Gene; Devine, Karen; Wolinsky, Yingli; Lai, Rose; McKean-Cowdin, Roberta; Il'yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Yechezkel, Galit Hirsh; Bruchim, Revital Bar-Sade; Aslanov, Lili; Sadetzki, Siegal; Johansen, Christoffer; Kosteljanetz, Michael; Broholm, Helle; Bernstein, Jonine L.; Olson, Sara H.; Schubert, Erica; DeAngelis, Lisa; Jenkins, Robert B.; Yang, Ping; Rynearson, Amanda; Andersson, Ulrika; Wibom, Carl; Henriksson, Roger; Melin, Beatrice S.; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Merrell, Ryan; Lada, Patricia; Wrensch, Margaret; Wiencke, John; Wiemels, Joe; McCoy, Lucie; McCarthy, Bridget J.; Davis, Faith G.

2014-01-01

Background Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes. PMID:24723567

End-of-life care of children with diffuse intrinsic pontine glioma.

PubMed

Hasan, Fyeza; Weingarten, Kevin; Rapoport, Adam; Bouffet, Eric; Bartels, Ute

2018-05-01

The end-of-life management of children with diffuse intrinsic pontine glioma (DIPG) is challenging. Families cope with debilitating symptoms and make complex decisions regarding their child's care. However, there is little evidence guiding palliative care provision for these children. Our objective was to describe the dying trajectory of children with DIPG, their symptoms, the care they require and the end-of-life decisions made for them. This retrospective cohort study analyzed the end-of-life care of 41 consecutive patients with DIPG who died between January 2001 and June 2010. All patients died of disease progression, experiencing a significant symptom burden prior to death. Despite this, the majority of patient days at the end of life were spent at home. However, 60% of patients were hospitalized at least once in their final 3 months, often close to the time of death. A wide range of healthcare professionals were involved, providing a range of medicinal/non-medicinal interventions. Chemotherapy was given to 30% of patients in their final month. Thirty of 33 families approached (91%) agreed to a "Do not resuscitate" order. A small subset of families opted for intensive treatment towards the end of life including cardiopulmonary resuscitation, intensive care admission and mechanical ventilation. Children with DIPG have complex needs and require intensive multidisciplinary support. This paper describes the end-of-life choices made for these children and discusses how these choices influence our institutional model for palliative care. We believe this approach will be useful to clinicians caring for similar patients.

A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume.

PubMed

Singh, Ranjodh; Zhou, Zhiping; Tisnado, Jamie; Haque, Sofia; Peck, Kyung K; Young, Robert J; Tsiouris, Apostolos John; Thakur, Sunitha B; Souweidane, Mark M

2016-11-01

OBJECTIVE Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important. The aims of the current study were to 1) measure DIPG volumes using methods that require different degrees of subjective judgment; and 2) evaluate interobserver agreement of measurements made using these methods. METHODS Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post-radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin's concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement. CONCLUSIONS The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods highlighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interobserver agreement and produced tumor volumes with delineated borders.

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

PubMed

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

2016-07-01

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

DNA methylation analysis of paediatric low-grade astrocytomas identifies a tumour-specific hypomethylation signature in pilocytic astrocytomas.

PubMed

Jeyapalan, Jennie N; Doctor, Gabriel T; Jones, Tania A; Alberman, Samuel N; Tep, Alexander; Haria, Chirag M; Schwalbe, Edward C; Morley, Isabel C F; Hill, Alfred A; LeCain, Magdalena; Ottaviani, Diego; Clifford, Steven C; Qaddoumi, Ibrahim; Tatevossian, Ruth G; Ellison, David W; Sheer, Denise

2016-05-27

Low-grade gliomas (LGGs) account for about a third of all brain tumours in children. We conducted a detailed study of DNA methylation and gene expression to improve our understanding of the biology of pilocytic and diffuse astrocytomas. Pilocytic astrocytomas were found to have a distinctive signature at 315 CpG sites, of which 312 were hypomethylated and 3 were hypermethylated. Genomic analysis revealed that 182 of these sites are within annotated enhancers. The signature was not present in diffuse astrocytomas, or in published profiles of other brain tumours and normal brain tissue. The AP-1 transcription factor was predicted to bind within 200 bp of a subset of the 315 differentially methylated CpG sites; the AP-1 factors, FOS and FOSL1 were found to be up-regulated in pilocytic astrocytomas. We also analysed splice variants of the AP-1 target gene, CCND1, which encodes cell cycle regulator cyclin D1. CCND1a was found to be highly expressed in both pilocytic and diffuse astrocytomas, but diffuse astrocytomas have far higher expression of the oncogenic variant, CCND1b. These findings highlight novel genetic and epigenetic differences between pilocytic and diffuse astrocytoma, in addition to well-described alterations involving BRAF, MYB and FGFR1.

Congenital brainstem disconnection associated with a syrinx of the brainstem.

PubMed

Barth, P G; de Vries, L S; Nikkels, P G J; Troost, D

2008-02-01

We report a case of congenital brainstem disconnection including the second detailed autopsy. A full-term newborn presented with irreversible apnoea and died on the fifth day. MRI revealed disconnection of the brainstem. The autopsy included a series of transverse sections of the mesencephalon, medulla oblongata and bridging tissue fragments. A fragile tube walled by mature brainstem tissue could be reconstructed. It enveloped a cylinder of fluid within the ventral pons extending to the mesencephalon and the lower brainstem. The aqueduct was patent and outside the lesion. The basilar artery was represented by a tiny median vessel. The ventral and lateral parts of the posterior brainstem were surrounded by heterotopic glial tissue. The olivary nucleus was absent and the cerebellar dentate nucleus was dysplastic. Considering the maturity of the remaining parts of the pons, the onset of structural decline is likely to be close to the time of birth. Probable causes are progressively insufficient perfusion through an hypoplastic basilar artery, and obstructed venous drainage through an abnormal glial barrier surrounding the posterior brainstem. The morphological findings can be characterized as a syrinx, known from disorders in which brainstem or spinal cord are damaged by a combination of mechanical and circulatory factors.

Pediatric Glioma at the Optic Pathway and Thalamus

PubMed Central

Park, Eun Suk; Park, Jun Bum; Ra, Young-Shin

2018-01-01

Gliomas are the most common pediatric tumors of the central nervous system. In this review, we discuss the clinical features, treatment paradigms, and evolving concepts related to two types of pediatric gliomas affecting two main locations: the optic pathway and thalamus. In particular, we discuss recently revised pathologic classification, which adopting molecular parameter. We believe that our review contribute to the readers’ better understanding of pediatric glioma because pediatric glioma differs in many ways from adult glioma according to the newest advances in molecular characterization of this tumor. A better understanding of current and evolving issues in pediatric glioma is needed to ensure effective management decision. PMID:29742884

Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study.

PubMed

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

2016-02-01

Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58-0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. ©2016 American Association for Cancer Research.

Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study

PubMed Central

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

2015-01-01

Background Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. Methods The GICC contains detailed information on history of atopic conditions for 4533 cases and 4171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis odds ratios, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Results Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared to not having respiratory allergies (mOR: 0.72, 95% CI: 0.58–0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. Conclusions A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. Impact As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biological mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. PMID:26908595

Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study.

PubMed

Berntsson, Shala G; Merrell, Ryan T; Amirian, E Susan; Armstrong, Georgina N; Lachance, Daniel; Smits, Anja; Zhou, Renke; Jacobs, Daniel I; Wrensch, Margaret R; Olson, Sara H; Il'yasova, Dora; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Schildkraut, Joellen; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S; Jenkins, Robert B; Bernstein, Jonine L; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Bondy, Melissa L; Melin, Beatrice S

2018-04-23

The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma.

Vestibular evoked myogenic potentials and MRI in early multiple sclerosis: Validation of the VEMP score.

PubMed

Crnošija, Luka; Krbot Skorić, Magdalena; Gabelić, Tereza; Adamec, Ivan; Habek, Mario

2017-01-15

To validate the VEMP score as a measure of brainstem dysfunction in patients with the first symptom of multiple sclerosis (MS) (clinically isolated syndrome (CIS)) and to investigate the correlation between VEMP and brainstem MRI results. 121 consecutive CIS patients were enrolled and brainstem functional system score (BSFS) was determined. Ocular VEMP (oVEMP) and cervical VEMP (cVEMP) were analyzed for latencies, conduction block and amplitude asymmetry ratio and the VEMP score was calculated. MRI was analyzed for the presence of brainstem lesions as a whole and separately for the presence of pontine, midbrain and medulla oblongata lesions. Patients with signs of brainstem involvement during the neurological examination (with BSFS ≥1) had a higher oVEMP score compared to patients with no signs of brainstem involvement. A binary logistic regression model showed that patients with brainstem lesion on the MRI are 6.780 times more likely to have BSFS ≥1 (p=0.001); and also, a higher VEMP score is associated with BSFS ≥1 (p=0.042). Furthermore, significant correlations were found between clinical brainstem involvement and brainstem and pontine MRI lesions, and prolonged latencies and/or absent VEMP responses. The VEMP score is a valuable tool in evaluation of brainstem involvement in patients with early MS. Copyright © 2016 Elsevier B.V. All rights reserved.

C-type natriuretic peptide-modified lipid vesicles: fabrication and use for the treatment of brain glioma.

PubMed

Wu, Jia-Shuan; Mu, Li-Min; Bu, Ying-Zi; Liu, Lei; Yan, Yan; Hu, Ying-Jie; Bai, Jing; Zhang, Jing-Ying; Lu, Weiyue; Lu, Wan-Liang

2017-06-20

Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo. The results showed that the CNP-modified vinorelbine lipid vesicles could transport vinorelbine across the BBB, kill the brain glioma, and destroy neovasculatures effectively. The above mechanisms could be associated with the following aspects, namely, long circulation in the blood; drug transport across the BBB via natriuretic peptide receptor B (NPRB)-mediated transcytosis; elimination of brain glioma cells and disruption of neovasculatures by targeting uptake and cytotoxic injury. Besides, CNP-modified vinorelbine lipid vesicles could induce apoptosis of the glioma cells. The mechanisms could be related to the activations of caspase 8, caspase 3, p53, and reactive oxygen species (ROS), and inhibition of survivin. Hence, CNP-modified lipid vesicles could be used as a carrier material for treating brain glioma and disabling glioma neovasculatures.

Overexpressed homeobox B9 regulates oncogenic activities by transforming growth factor-β1 in gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Liping; Xu, Yinghui; Zou, Lijuan, E-mail: zoulijuantg@126.com

2014-03-28

Highlights: • HOXB9 is overexpressed in gliomas. • HOXB9 over expression had shorter survival time than down expression in gliomas. • HOXB9 stimulated the proliferation, migration and sphere formation of glioma cells. • Activation of TGF-β1 contributed to HOXB9-induced oncogenic activities. - Abstract: Glioma is the leading cause of deaths related to tumors in the central nervous system. The mechanisms of gliomagenesis remain elusive to date. Homeobox B9 (HOXB9) has a crucial function in the regulation of gene expression and cell survival, but its functions in glioma formation and development have yet to be elucidated. This study showed that HOXB9more » expression in glioma tissues was significantly higher than that in nontumor tissues. Higher HOXB9 expression was also significantly associated with advanced clinical stage in glioma patients. HOXB9 overexpression stimulated the proliferation, migration, and sphere formation of glioma cells, whereas HOXB9 knockdown elicited an opposite effect. HOXB9 overexpression also increased the tumorigenicity of glioma cells in vivo. Moreover, the activation of transforming growth factor-β1 contributed to HOXB9-induced oncogenic activities. HOXB9 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in glioma for diagnosis or prognosis.« less

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma.

PubMed

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood-brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma.

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma

PubMed Central

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood–brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma. PMID:28579776

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

2017-11-07

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

Auditory Brainstem Responses in Autism: Brainstem Dysfunction or Peripheral Hearing Loss?

ERIC Educational Resources Information Center

Klin, Ami

1993-01-01

A review of 11 studies of auditory brainstem response (ABR) in individuals with autism concludes that the ABR data are only suggestive (rather than supportive) of brainstem involvement in autism. The presence of peripheral hearing impairment was observed in some of the autistic individuals. (Author/DB)

The molecular profile of microglia under the influence of glioma

PubMed Central

Li, Wei; Graeber, Manuel B.

2012-01-01

Microglia, which contribute substantially to the tumor mass of glioblastoma, have been shown to play an important role in glioma growth and invasion. While a large number of experimental studies on functional attributes of microglia in glioma provide evidence for their tumor-supporting roles, there also exist hints in support of their anti-tumor properties. Microglial activities during glioma progression seem multifaceted. They have been attributed to the receptors expressed on the microglia surface, to glioma-derived molecules that have an effect on microglia, and to the molecules released by microglia in response to their environment under glioma control, which can have autocrine effects. In this paper, the microglia and glioma literature is reviewed. We provide a synopsis of the molecular profile of microglia under the influence of glioma in order to help establish a rational basis for their potential therapeutic use. The ability of microglia precursors to cross the blood–brain barrier makes them an attractive target for the development of novel cell-based treatments of malignant glioma. PMID:22573310

MiR-200c Inhibits the Tumor Progression of Glioma via Targeting Moesin

PubMed Central

Qin, Yuanyuan; Chen, Weilong; Liu, Bingjie; Zhou, Lei; Deng, Lu; Niu, Wanxiang; Bao, Dejun; Cheng, Chuandong; Li, Dongxue; Liu, Suling; Niu, Chaoshi

2017-01-01

We attempt to demonstrate the regulatory role of miR-200c in glioma progression and its mechanisms behind. Here, we show that miR-200c expression was significantly reduced in the glioma tissues compared to paratumor tissues, especially in malignant glioma. Exogenous overexpression of miR-200c inhibited the proliferation and invasion of glioma cells. In addition, the in vivo mouse xenograft model showed that miR-200c inhibited glioma growth and liver metastasis, which is mainly regulated by targeting moesin (MSN). We demonstrated that the expression of MSN in glioma specimens were negatively correlated with miR-200c expression, and MSN overexpression rescued the phenotype about cell proliferation and invasion induced by miR-200c. Moreover, knockdown of MSN was able to mimic the effects induced by miR-200c in glioma cells. These results indicate that miR-200c plays an important role in the regulation of glioma through targeting MSN. PMID:28529643

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma.

PubMed

Qin, Elizabeth Y; Cooper, Dominique D; Abbott, Keene L; Lennon, James; Nagaraja, Surya; Mackay, Alan; Jones, Chris; Vogel, Hannes; Jackson, Peter K; Monje, Michelle

2017-08-24

The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.

Motion Artifact Reduction in Pediatric Diffusion Tensor Imaging Using Fast Prospective Correction

PubMed Central

Alhamud, A.; Taylor, Paul A.; Laughton, Barbara; van der Kouwe, André J.W.; Meintjes, Ernesta M.

2014-01-01

Purpose To evaluate the patterns of head motion in scans of young children and to examine the influence of corrective techniques, both qualitatively and quantitatively. We investigate changes that both retrospective (with and without diffusion table reorientation) and prospective (implemented with a short navigator sequence) motion correction induce in the resulting diffusion tensor measures. Materials and Methods Eighteen pediatric subjects (aged 5–6 years) were scanned using 1) a twice-refocused, 2D diffusion pulse sequence, 2) a prospectively motion-corrected, navigated diffusion sequence with reacquisition of a maximum of five corrupted diffusion volumes, and 3) a T1-weighted structural image. Mean fractional anisotropy (FA) values in white and gray matter regions, as well as tractography in the brainstem and projection fibers, were evaluated to assess differences arising from retrospective (via FLIRT in FSL) and prospective motion correction. In addition to human scans, a stationary phantom was also used for further evaluation. Results In several white and gray matter regions retrospective correction led to significantly (P < 0.05) reduced FA means and altered distributions compared to the navigated sequence. Spurious tractographic changes in the retrospectively corrected data were also observed in subject data, as well as in phantom and simulated data. Conclusion Due to the heterogeneity of brain structures and the comparatively low resolution (~2 mm) of diffusion data using 2D single shot sequencing, retrospective motion correction is susceptible to distortion from partial voluming. These changes often negatively bias diffusion tensor imaging parameters. Prospective motion correction was shown to produce smaller changes. PMID:24935904

Motion artifact reduction in pediatric diffusion tensor imaging using fast prospective correction.

PubMed

Alhamud, A; Taylor, Paul A; Laughton, Barbara; van der Kouwe, André J W; Meintjes, Ernesta M

2015-05-01

To evaluate the patterns of head motion in scans of young children and to examine the influence of corrective techniques, both qualitatively and quantitatively. We investigate changes that both retrospective (with and without diffusion table reorientation) and prospective (implemented with a short navigator sequence) motion correction induce in the resulting diffusion tensor measures. Eighteen pediatric subjects (aged 5-6 years) were scanned using 1) a twice-refocused, 2D diffusion pulse sequence, 2) a prospectively motion-corrected, navigated diffusion sequence with reacquisition of a maximum of five corrupted diffusion volumes, and 3) a T1 -weighted structural image. Mean fractional anisotropy (FA) values in white and gray matter regions, as well as tractography in the brainstem and projection fibers, were evaluated to assess differences arising from retrospective (via FLIRT in FSL) and prospective motion correction. In addition to human scans, a stationary phantom was also used for further evaluation. In several white and gray matter regions retrospective correction led to significantly (P < 0.05) reduced FA means and altered distributions compared to the navigated sequence. Spurious tractographic changes in the retrospectively corrected data were also observed in subject data, as well as in phantom and simulated data. Due to the heterogeneity of brain structures and the comparatively low resolution (∼2 mm) of diffusion data using 2D single shot sequencing, retrospective motion correction is susceptible to distortion from partial voluming. These changes often negatively bias diffusion tensor imaging parameters. Prospective motion correction was shown to produce smaller changes. © 2014 Wiley Periodicals, Inc.

Frequent Nek1 overexpression in human gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Jun; Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Cai, Yu, E-mail: aihaozuqiu22@163.com

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

Tunicamycin inhibits progression of glioma cells through downregulation of the MEG-3-regulated wnt/β-catenin signaling pathway.

PubMed

Li, Xin; Xue, Lei; Peng, Qin

2018-06-01

Glioma is derived from the oncogenic transformation of brain and spinal cord glial cells, and is one of the most common primary brain tumors. Tunicamycin (TUN) can significantly inhibit glioma growth and aggressiveness by promoting apoptosis in glioma cells. The purpose of the present study was to investigate the effects of TUN on growth of glioma cells and examine the TUN-mediated signaling pathway. The inhibitory effects of TUN on apoptosis, growth, aggressiveness and cell cycle arrest of glioma tumor cells were determined by western blotting, reverse transcription-quantitative polymerase chain reaction, apoptotic assays and immunofluorescence. The results demonstrated that treatment with TUN suppressed growth, migration and invasion of glioma carcinoma cells. In addition, TUN treatment induced apoptosis of glioma cells through downregulation of Bcl-2 and P53 expression levels. Findings also indicated that TUN suppressed proliferation and arrested the glioma cells in the S phase of the cell cycle. Further analysis of the mechanisms of TUN demonstrated that TUN treatment upregulated the expression levels of maternally expressed gene (MEG)-3, wnt and β-catenin in glioma cells. Furthermore, knockdown of MEG-3 expression reversed the TUN-decreased wnt/β-catenin signaling pathway, which subsequently also reversed the TUN-inhibited growth and aggressiveness of glioma cells. In conclusion, the findings in the present study indicated that TUN treatment inhibited growth and aggressiveness through MEG-3-mediated wnt/β-catenin signaling, suggesting that TUN may be an efficient anticancer agent for the treatment of glioma.

Diffusion-weighted imaging in patients with acute brain ischemia at 3 T: current possibilities and future perspectives comparing conventional echoplanar diffusion-weighted imaging and fast spin echo diffusion-weighted imaging sequences using BLADE (PROPELLER).

PubMed

Fries, Peter; Runge, Val M; Kirchin, Miles A; Stemmer, Alto; Naul, L Gill; Wiliams, Kenneth D; Reith, Wolfgang; Bücker, Arno; Schneider, Günther

2009-06-01

To compare diffusion-weighted imaging (DWI) based on a fast spin echo (FSE) sequence using BLADE (PROPELLER) with conventional DWI-echoplanar imaging (EPI) techniques at 3 T and to demonstrate the influence of hardware developments on signal-to-noise ratio (SNR) with these techniques using 12- and 32-channel head coils. Fourteen patients with brain ischemia were evaluated with DWI using EPI and FSE BLADE sequences, with a 12-channel head coil, in the axial plane and 1 additional plane (either sagittal or coronal). SNR and CNR were calculated from region-of-interest measurements. Scans were evaluated in a blinded fashion by 2 experienced neuroradiologists. SNR of both DWI techniques was evaluated in 12 healthy volunteers using different parallel imaging (PI) factors (for the EPI sequence) and both the 12- and 32-channel coils. DWI-BLADE sequences acquired with the 12-channel coil revealed a significant reduction in SNR (mean +/- SD) of ischemic lesions (SNR(lesion) [5.0 +/- 2.5]), normal brain (SNR(brain) [3.0 +/- 1.9]), and subsequently in CNR (3.0 +/- 1.8) as compared with the DWI-EPI sequence (SNR(lesion) [9.3 +/- 5.2], SNR(brain) [7.7 +/- 3.5], CNR [6.1 +/- 2.8], P < 0.001). Despite this reduction in SNR and CNR, the blinded read revealed a marked preference for the DWI-BLADE sequence, or equality between the sequences, in the majority of patients because lesion detection was degraded by susceptibility artifacts on axial DWI-EPI scans in 14% to 43% of cases (but in no instance with the DWI-BLADE sequence). In particular, preference for the DWI-BLADE sequence or equality between the 2 techniques for lesion detection in the brainstem and cerebellum was observed. On some DWI-BLADE scans, in the additional plane, radial-like artifacts degraded lesion detection.In volunteers, SNR was significantly improved using the 32-channel coil, irrespective of scan technique. Comparing DWI-EPI acquired with the 12-channel coil (iPAT = 2) to DWI-BLADE acquired with the 32-channel coil, comparable SNR values were obtained. The 32-channel coil also makes feasible, with DWI-EPI, an increase in the PI factor to 4, which allows for a further reduction of bulk susceptibility artifacts. However, still DWI-BLADE sequences performed better because of absence of bulk susceptibility artifacts at comparable SNR values. Despite lower SNR at comparable PI factors, DWI-BLADE sequences acquired using the 12-channel coil are preferable in most instances, as compared with DWI-EPI sequences, because of the absence of susceptibility artifacts and subsequently improved depiction of ischemic lesions in the brainstem and cerebellum. With the 32-channel coil, recently FDA approved, DWI-BLADE acquired with an iPAT = 2 provides comparable SNR without bulk susceptibility artifacts as compared with the DWI-EPI sequences acquired for clinical routine to date and has the potential to replace the standard DWI technique for special indications like DWI of the cerebellum and the brainstem or in presence of metallic implants or hemorrhage.

Brain stem evoked response audiometry of former drug users.

PubMed

Weich, Tainara Milbradt; Tochetto, Tania Maria; Seligman, Lilian

2012-10-01

Illicit drugs are known for their deleterious effects upon the central nervous system and more specifically for how they adversely affect hearing. This study aims to analyze and compare the hearing complaints and the results of brainstem evoked response audiometry (BERA) of former drug user support group goers. This is a cross-sectional non-experimental descriptive quantitative study. The sample consisted of 17 subjects divided by their preferred drug of use. Ten individuals were placed in the marijuana group (G1) and seven in the crack/cocaine group (G2). The subjects were further divided based on how long they had been using drugs: 1 to 5 years, 6 to 10 years, and over 15 years. They were interviewed, and assessed by pure tone audiometry, acoustic impedance tests, and BERA. No statistically significant differences were found between G1 and G2 or time of drug use in absolute latencies and interpeak intervals. However, only five of the 17 individuals had BERA results with adequate results for their ages. Marijuana and crack/cocaine may cause diffuse disorders in the brainstem and compromise the transmission of auditory stimuli regardless of how long these substances are used for.

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma.

PubMed

Wang, Yun; Huang, Nanxin; Li, Hongli; Liu, Shubao; Chen, Xianjun; Yu, Shichang; Wu, Nan; Bian, Xiu-Wu; Shen, Hai-Ying; Li, Chengren; Xiao, Lan

2017-06-06

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma

PubMed Central

Li, Hongli; Liu, Shubao; Chen, Xianjun; Yu, Shichang; Wu, Nan; Bian, Xiu-Wu; Li, Chengren

2017-01-01

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma. PMID:28415586

miR-423-5p knockdown enhances the sensitivity of glioma stem cells to apigenin through the mitochondrial pathway.

PubMed

Wan, Yi; Fei, Xifeng; Wang, Zhimin; Jiang, Dongyi; Chen, Hanchun; Wang, Mian; Zhou, Shijun

2017-04-01

This study aimed to investigate the effect of miR-423-5p on the sensitivity of glioma stem cells to apigenin and to explore the potential mechanism. Previous research indicated that apigenin can effectively inhibit the proliferation of many cancer cells, including glioma cells, though our data unexpectedly showed that apigenin had no effect on glioma stem cell apoptosis. As many studies have reported that malignant transformation and progression of glioma are due to glioma stem cells, an anti-glioma stem cell approach has become an important direction for glioma treatment. In this study, we found miR-423-5p to be overexpressed in glioma tissues and corresponding glioma stem cells. Downregulation of miR-423-5p repressed glioma stem cell growth but did not cause apoptosis. Based on the concept of "Pharmaco-miR," this study further demonstrated that the combination of miR-423-5p knockdown and apigenin had a notable additive effect on inhibiting proliferation and promoting apoptosis in glioma stem cells. Hoechst staining showed higher apoptosis rates and typical apoptotic morphological changes of the cell nucleus, and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazolylcarbocya-nine iodide) staining revealed reduced mitochondrial membrane potential. Further research demonstrated that the mechanism is associated with a shift in the Bax/Bcl-2 ratio, an increased cytochrome c level, Apaf-1 induction, and caspase-3 activation. In conclusion, this study indicates that downregulation of miR-423-5p enhances the sensitivity of glioma stem cells to apigenin through the mitochondrial pathway.

The histone deacetylase SIRT6 suppresses the expression of the RNA-binding protein PCBP2 in glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Xin; Hao, Bin; Liu, Ying

Highlights: • PCBP2 expression is over-expressed in human glioma tissues and cell lines. • SIRT6 is decreased in glioma and correlated with PCBP2. • SIRT6 inhibits PCBP2 expression by deacetylating H3K9. • SIRT6 inhibits glioma growth in vitro and in vivo. - Abstract: More than 80% of tumors that occur in the brain are malignant gliomas. The prognosis of glioma patients is still poor, which makes glioma an urgent subject of cancer research. Previous evidence and our present data show that PCBP2 is over-expressed in human glioma tissues and predicts poor outcome. However, the mechanism by which PCBP2 is regulatedmore » in glioma remains elusive. We find that SIRT6, one of the NAD{sup +}-dependent class III deacetylase SIRTUINs, is down-regulated in human glioma tissues and that the level of SIRT6 is negatively correlated with PCBP2 level while H3K9ac enrichment on the promoter of PCBP2 is positively correlated with PCBP2 expression. Furthermore, we identify PCBP2 as a target of SIRT6. We demonstrate that PCBP2 expression is inhibited by SIRT6, which depends upon deacetylating H3K9ac. Finally, our results reveal that SIRT6 inhibits glioma cell proliferation and colony formation in vitro and glioma cell growth in vivo in a PCBP2 dependent manner. In summary, our findings implicate that SIRT6 inhibits PCBP2 expression through deacetylating H3K9ac and SIRT6 acts as a tumor suppressor in human glioma.« less

Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway

PubMed Central

Rolón-Reyes, Kimberleve; Kucheryavykh, Yuriy V.; Cubano, Luis A.; Inyushin, Mikhail; Skatchkov, Serguei N.; Eaton, Misty J.; Harrison, Jeffrey K.; Kucheryavykh, Lilia Y.

2015-01-01

Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells. PMID:26098895

Antitumor Activity of Rat Mesenchymal Stem Cells during Direct or Indirect Co-Culturing with C6 Glioma Cells.

PubMed

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

2016-02-01

The tumor-suppressive effect of rat mesenchymal stem cells against low-differentiated rat C6 glioma cells during their direct and indirect co-culturing and during culturing of C6 glioma cells in the medium conditioned by mesenchymal stem cells was studied in an in vitro experiment. The most pronounced antitumor activity of mesenchymal stem cells was observed during direct co-culturing with C6 glioma cells. The number of live C6 glioma cells during indirect co-culturing and during culturing in conditioned medium was slightly higher than during direct co-culturing, but significantly differed from the control (C6 glioma cells cultured in medium conditioned by C6 glioma cells). The cytotoxic effect of medium conditioned by mesenchymal stem cells was not related to medium depletion by glioma cells during their growth. The medium conditioned by other "non-stem" cells (rat astrocytes and fibroblasts) produced no tumor-suppressive effect. Rat mesenchymal stem cells, similar to rat C6 glioma cells express connexin 43, the main astroglial gap junction protein. During co-culturing, mesenchymal stem cells and glioma C6 cells formed functionally active gap junctions. Gap junction blockade with connexon inhibitor carbenoxolone attenuated the antitumor effect observed during direct co-culturing of C6 glioma cells and mesenchymal stem cells to the level produced by conditioned medium. Cell-cell signaling mediated by gap junctions can be a mechanism of the tumor-suppressive effect of mesenchymal stem cells against C6 glioma cells. This phenomenon can be used for the development of new methods of cell therapy for high-grade malignant gliomas.

Myristic Acid-Modified DA7R Peptide for Whole-Process Glioma-Targeted Drug Delivery.

PubMed

Ying, Man; Wang, Songli; Zhang, Mingfei; Wang, Ruifeng; Zhu, Hangchang; Ruan, Huitong; Ran, Danni; Chai, Zhilan; Wang, Xiaoyi; Lu, Weiyue

2018-06-13

The clinical treatment of aggressive glioma has been a great challenge, mainly because of the complexity of the glioma microenvironment and the existence of the blood-brain tumor barrier (BBTB)/blood-brain barrier (BBB), which severely hampers the effective accumulation of most therapeutic agents in the glioma region. Additionally, vasculogenic mimicry (VM), angiogenesis, and glioma stem cells (GSC) in malignant glioma also lead to the failure of clinical therapy. To address the aforementioned issues, a whole-process glioma-targeted drug delivery strategy was proposed. The D A7R peptide has effective BBTB-penetrating and notable glioma-, angiogenesis-, and VM-targeting abilities. Herein, we designed a myristic acid modified D A7R ligand (MC- D A7R), which combines tumor-homing D A7R with BBB-penetrable MC. MC- D A7R was then immobilized to PEGylated liposomes (MC- D A7R-LS) to form a whole-process glioma-targeting system. MC- D A7R-LS exhibited exceptional internalization in glioma, tumor neovascular, and brain capillary endothelial cells. Enhanced BBTB- and BBB-traversing efficiencies were also observed on MC- D A7R-LS. Ex vivo imaging on brain tumors also demonstrated the feasibility of MC- D A7R-LS in intracranial glioma-homing, whereas the immunofluorescence studies demonstrated its GSC and angiogenesis homing. Furthermore, doxorubicin-loaded MC- D A7R-LS accomplished a remarkable therapeutic outcome, as a result of a synergistic improvement on the glioma microenvironment. Our study highlights the potential of the MC-modified D A7R peptide as a great candidate for the whole-process glioma-targeted drug delivery.

The effects of gene polymorphisms on glioma prognosis.

PubMed

Cui, Ying; Li, Guolin; Yan, Mengdan; Li, Jing; Jin, Tianbo; Li, Shanqu; Mu, Shijie

2017-11-01

Malignant gliomas are the most common primary brain tumors. Various genetic factors play important roles in the development and prognosis of glioma. The present study focuses on the impact of MPHOSPH6, TNIP1 and several other genes (ACYP2, NAF1, TERC, TERT, OBFC1, ZNF208 and RTEL1) on telomere length and how this affects the prognosis of glioma. Forty-three polymorphisms in nine genes from 605 glioma patients were selected. The association between genotype and survival outcome was analyzed using the Kaplan-Meier method, Cox regression analysis and the log-rank test. The 1-year overall survival (OS) rates of patients younger than 40 years of age was higher compared to those in patients older than 40 years of age. The 1-year OS rate of patients who underwent total resection was higher than that of patients whose gliomas were not completely resected. The 1-year OS rates of patients undergoing chemotherapy and of patients who did not undergo chemotherapy were 39.90% and 26.80%, respectively. Univariate analyses showed that ACYP2 rs12615793 and TERT rs2853676 loci affected progression-free survival in glioma patients; both ZNF208 rs8105767 and ACYP2 rs843720 affected the OS of patients with low-grade gliomas. Multivariate analyses suggested that MPHOSPH6 rs1056629 and rs1056654, and TERT rs2853676 loci were associated with good prognoses of patients with glioma or high-grade gliomas, whereas ZNF208 rs8105767 was associated with good prognosis of patients with low-grade glioma. Age, surgical resection and chemotherapy influenced the survival rates of glioma patients. TERT, MPHOSPH6, ACYP2 and ZNF208 genes were found to affect glioma prognosis. Copyright © 2017 John Wiley & Sons, Ltd.

Functional analysis of a novel glioma antigen, EFTUD1

PubMed Central

Saito, Katsuya; Iizuka, Yukihiko; Ohta, Shigeki; Takahashi, Satoshi; Nakamura, Kenta; Saya, Hideyuki; Yoshida, Kazunari; Kawakami, Yutaka; Toda, Masahiro

2014-01-01

Background A cDNA library made from 2 glioma cell lines, U87MG and T98G, was screened by serological identification of antigens by recombinant cDNA expression (SEREX) using serum from a glioblastoma patient. Elongation factor Tu GTP binding domain containing protein 1 (EFTUD1), which is required for ribosome biogenesis, was identified. A cancer microarray database showed overexpression of EFTUD1 in gliomas, suggesting that EFTUD1 is a candidate molecular target for gliomas. Methods EFTUD1 expression in glioma cell lines and glioma tissue was assessed by Western blot, quantitative PCR, and immunohistochemistry. The effect on ribosome biogenesis, cell growth, cell cycle, and induction of apoptosis and autophagy in glioma cells during the downregulation of EFTUD1 was investigated. To reveal the role of autophagy, the autophagy-blocker, chloroquine (CQ), was used in glioma cells downregulating EFTUD1. The effect of combining CQ with EFTUD1 inhibition in glioma cells was analyzed. Results EFTUD1 expression in glioma cell lines and tissue was higher than in normal brain tissue. Downregulating EFTUD1 induced G1 cell-cycle arrest and apoptosis, leading to reduced glioma cell proliferation. The mechanism underlying this antitumor effect was impaired ribosome biogenesis via EFTUD1 inhibition. Additionally, protective autophagy was induced by glioma cells as an adaptive response to EFTUD1 inhibition. The antitumor effect induced by the combined treatment was significantly higher than that of either EFTUD1 inhibition or CQ alone. Conclusion These results suggest that EFTUD1 represents a novel therapeutic target and that the combination of EFTUD1 inhibition with autophagy blockade may be effective in the treatment of gliomas. PMID:25015090

USP22 acts as an oncoprotein to maintain glioma malignancy through deubiquitinating BMI1 for stabilization.

PubMed

Qiu, Guan-Zhong; Mao, Xiao-Yuan; Ma, Yue; Gao, Xing-Chun; Wang, Zhen; Jin, Ming-Zhu; Sun, Wei; Zou, Yong-Xiang; Lin, Jing; Fu, Hua-Lin; Jin, Wei-Lin

2018-05-22

USP22 is a member of "death-from-cancer" signature, which plays a key role in cancer progression. Although previous evidence has shown that USP22 is overexpressed and correlated with poor prognosis in glioma. The effect and mechanism of USP22 in glioma malignancy especially cancer stemness remain elusive. Here, we find USP22 is more enriched in stem-like tumorspheres than differentiated glioma cells. USP22 knockdown inhibits cancer stemness in glioma cell lines. With a cell-penetrating TAT-tag protein, BMI1, a robust glioma stem-cell marker, is found to mediate the effect of USP22 on glioma stemness. By immunofluorescence, USP22 and BMI1 are found to share similar intranuclear expression in glioma cells. By analysis with immunohistochemistry and bioinformatics, USP22 is found to positively correlated with BMI1 only in the post-translational level rather than transcriptional level. By immunoprecipitation and in vivo deubiquitination assay, USP22 is found to interact with and deubiquitinate BMI1 for protein stabilization. Microarray analysis reveals that USP22 and BMI1 mutually regulate a series of genes involved in glioma stemness such as POSTN, HEY2, PDGFRA and ATF3. In vivo study with nude mice confirms the role of USP22 in promoting glioma tumorigenesis by regulating BMI1. All these findings indicate USP22 as a novel deubiquitinase of BMI1 in glioma. We propose a working model of USP22-BMI1 axis, which promotes glioma stemness and tumorigenesis through oncogenic activation. Thus, targeting USP22 might be an effective strategy to treat glioma especially those with elevated BMI1 expression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature.

PubMed

Ardissone, Anna; Tonduti, Davide; Legati, Andrea; Lamantea, Eleonora; Barone, Rita; Dorboz, Imen; Boespflug-Tanguy, Odile; Nebbia, Gabriella; Maggioni, Marco; Garavaglia, Barbara; Moroni, Isabella; Farina, Laura; Pichiecchio, Anna; Orcesi, Simona; Chiapparini, Luisa; Ghezzi, Daniele

2018-04-04

KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.

The magnetic resonance imaging spectrum of Pelizaeus-Merzbacher disease: A multicenter study of 19 patients.

PubMed

Sumida, Kaoru; Inoue, Ken; Takanashi, Jun-Ichi; Sasaki, Masayuki; Watanabe, Kenji; Suzuki, Motomasa; Kurahashi, Hirokazu; Omata, Taku; Tanaka, Manabu; Yokochi, Kenji; Iio, Jun; Iyoda, Kuniaki; Kurokawa, Toru; Matsuo, Muneaki; Sato, Tamotu; Iwaki, Akiko; Osaka, Hitoshi; Kurosawa, Kenji; Yamamoto, Toshiyuki; Matsumoto, Naomichi; Maikusa, Norihide; Matsuda, Hiroshi; Sato, Noriko

2016-06-01

We retrospectively evaluated the imaging spectrum of Pelizaeus-Merzbacher disease (PMD) in correlation with the clinical course and genetic abnormality. We collected the magnetic resonance imaging (MRI) findings of 19 genetically proven PMD patients (all males, aged 0-29years old) using our integrated web-based MRI data collection system from 14 hospitals. The patterns of hypomyelination were determined mainly by the signals of the cerebrum, corticospinal tract, and brainstem on T2-weighted images (T2WI). We assessed the degree of myelination age on T1-weighted images (T1WI) and T2WI independently, and we evaluated cerebellar and callosal atrophy. The clinical severity and genetic abnormalities (causal mutations of the proteolipid protein gene PLP1) were analyzed together with the imaging findings. The clinical stage tended to be more severe when the whole brainstem, or corticospinal tract in the internal capsule showed abnormally high intensity on T2WI. Diffuse T2-high signal of brainstem was observed only in the patients with PLP1 point mutation. Myelination age "before birth" on T1WI is a second manifestation correlated with the clinically severe phenotypes. On the other hand, eight patients whose myelination ages were > 4months on T1WI were associated with mild clinical phenotypes. Four of them showed almost complete myelination on T1WI with a discrepancy in myelination age between T1WI and T2WI. A random and patchy pattern of myelination on T2WI was noted in one patient with PLP1 point mutation. Advanced myelination was observed in three of the seven followed-up patients. Four patients had atrophy of the cerebellum, and 17 patients had atrophy of the corpus callosum. Our multicenter study has demonstrated a wide variety of imaging findings of PMD. Signal intensity of brainstem and corticospinal tract of internal capsule would be the points to presume clinical severity in PMD patients. The spectrum of MRI findings should be kept in mind to diagnose PMD and to differentiate from other demyelinating leukodystrophies. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Magnetic resonance imaging differential diagnosis of brainstem lesions in children

PubMed Central

Quattrocchi, Carlo Cosimo; Errante, Yuri; Rossi Espagnet, Maria Camilla; Galassi, Stefania; Della Sala, Sabino Walter; Bernardi, Bruno; Fariello, Giuseppe; Longo, Daniela

2016-01-01

Differential diagnosis of brainstem lesions, either isolated or in association with cerebellar and supra-tentorial lesions, can be challenging. Knowledge of the structural organization is crucial for the differential diagnosis and establishment of prognosis of pathologies with involvement of the brainstem. Familiarity with the location of the lesions in the brainstem is essential, especially in the pediatric population. Magnetic resonance imaging (MRI) is the most sensitive and specific imaging technique for diagnosing disorders of the posterior fossa and, particularly, the brainstem. High magnetic static field MRI allows detailed visualization of the morphology, signal intensity and metabolic content of the brainstem nuclei, together with visualization of the normal development and myelination. In this pictorial essay we review the brainstem pathology in pediatric patients and consider the MR imaging patterns that may help the radiologist to differentiate among vascular, toxico-metabolic, infective-inflammatory, degenerative and neoplastic processes. Helpful MR tips can guide the differential diagnosis: These include the location and morphology of lesions, the brainstem vascularization territories, gray and white matter distribution and tissue selective vulnerability. PMID:26834941

Noise-induced tinnitus: auditory evoked potential in symptomatic and asymptomatic patients.

PubMed

Santos-Filha, Valdete Alves Valentins dos; Samelli, Alessandra Giannella; Matas, Carla Gentile

2014-07-01

We evaluated the central auditory pathways in workers with noise-induced tinnitus with normal hearing thresholds, compared the auditory brainstem response results in groups with and without tinnitus and correlated the tinnitus location to the auditory brainstem response findings in individuals with a history of occupational noise exposure. Sixty individuals participated in the study and the following procedures were performed: anamnesis, immittance measures, pure-tone air conduction thresholds at all frequencies between 0.25-8 kHz and auditory brainstem response. The mean auditory brainstem response latencies were lower in the Control group than in the Tinnitus group, but no significant differences between the groups were observed. Qualitative analysis showed more alterations in the lower brainstem in the Tinnitus group. The strongest relationship between tinnitus location and auditory brainstem response alterations was detected in individuals with bilateral tinnitus and bilateral auditory brainstem response alterations compared with patients with unilateral alterations. Our findings suggest the occurrence of a possible dysfunction in the central auditory nervous system (brainstem) in individuals with noise-induced tinnitus and a normal hearing threshold.

Subacute Sclerosing Panencephalitis of the Brainstem as a Clinical Entity

PubMed Central

Yang, Jason; Ciacci, Joseph D.

2017-01-01

Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurological disorder of early adolescence caused by persistent infection of the measles virus, which remains prevalent worldwide despite an effective vaccine. SSPE is a devastating disease with a characteristic clinical course in subcortical white matter; however, atypical presentations of brainstem involvement may be seen in rare cases. This review summarizes reports to date on brainstem involvement in SSPE, including the clinical course of disease, neuroimaging presentations, and guidelines for treatment. A comprehensive literature search was performed for English-language publications with keywords “subacute sclerosing panencephalitis” and “brainstem” using the National Library of Medicine PubMed database (March 1981–September 2017). Eleven articles focusing on SSPE of the brainstem were included. Predominant brainstem involvement remains uncharacteristic of SSPE, which may lead to misdiagnosis and poor outcome. A number of case reports have demonstrated brainstem involvement associated with other intracranial lesions commonly presenting in later SSPE stages (III and IV). However, brainstem lesions can appear in all stages, independent of higher cortical structures. The varied clinical presentations complicate diagnosis from a neuroimaging perspective. SSPE of the brainstem is a rare but important clinical entity. It may present like canonical SSPE or with unique clinical features such as absence seizures and pronounced ataxia. While SSPE generally progresses to the brainstem, it can also begin with a primary focus of infection in the brainstem. Awareness of varied SSPE presentations can aid in early diagnosis as well as guide management and treatment. PMID:29112137

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giantsoudi, D; Adams, J; MacDonald, S

Purpose: In proton radiation therapy of posterior fossa tumors, to spare other sensitive structures, the preferred beam geometry results in placing the treatment field distal edge within or just beyond the brainstem, including in at least partially in the treatment volume. Concerns for brainstem toxicity are increased and a controversy exists as to weather the beam’s distal edge should be placed within the brainstem or beyond it, to avoid elevated linear energy transfer (LET) and relative biological effectiveness (RBE) within the brainstem. The dosimetric efficacy of these techniques was examined, accounting for LET- and dose-dependent variable RBE distributions. Methods: Threemore » treatment planning techniques were applied in six ependymoma cases: (a) three-field dose-sparing, with beams’ distal edge within the brainstem; (b) three-field LET-sparing, using same beam directions as (a) but extended field ranges beyond the brainstem; (c) two-posterior-oblique LET-sparing, with extended ranges as (b). Monte Carlo calculated dose, LET and RBE-weighted dose distributions were compared. Results: Lower LET values in the brainstem were accompanied by higher median dose: 53.7 Gy[RBE] and 54.3 Gy[RBE] for techniques (b) and (c) versus 52.1 Gy[RBE] for (a). Accounting for variable RBE, a 15% increase of the brainstem volume receiving at least 60 Gy[RBE] was observed for technique (c) versus (a). Maximum variable-RBE-weighted brainstem dose was comparable for all techniques. Conclusion: Extending the treatment beam range beyond the brainstem, significantly increased its volume receiving high dose radiation, even when accounting for the decreased LET values. The dosimetric benefits of techniques limiting the brainstem dose may outweigh the impact of LET reduction achieved through this technique, especially since clinical consequences of increased LET at the end of range have not been proven yet.« less

Coptis Chinensis affects the function of glioma cells through the down-regulation of phosphorylation of STAT3 by reducing HDAC3.

PubMed

Li, Jiangan; Ni, Lulu; Li, Bing; Wang, Mingdeng; Ding, Zhemin; Xiong, Chunrong; Lu, Xiaojie

2017-12-06

Glioma remains the most common cause of brain cancer-related mortality. Glioma accounts for 50-60% of brain cancer. Due to their low toxicity and infrequent side effects, traditional herbs have been increasingly popular. Coptis Chinensis is commonly used in cancer treatment in combination with other Chinese Medicine herbs. However, little is known about its biological functions and mechanisms in glioma cells. In this study, the anti-glioma cell effect of Coptis Chinensis was determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method, plate clone test, scratch tests, flow cytometry, western blotting and a glioma xenograft tumor model. The results showed that Coptis Chinensis significantly suppressed glioma cell proliferation, tumor formation, migration and tumor growth, and prolonged the survival time of glioma cell-bearing mice. The flow cytometry result showed that Coptis Chinensis induced cell cycle arrest and apoptosis in glioma cells. Western blotting showed that Coptis Chinensis down-regulated the Signal transducer and activator of transcription 3 (STAT3) phosphorylation levels and reduced the expression of Histone deacetylase 3 (HDAC3) and caspase 3. Coptis Chinensis can inhibit various aspects of glioma cell functions. This study provides favorable scientific evidence for the potential use of natural products such as Coptis Chinensis in the clinical treatment of patients with glioma.

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2016-05-01

Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Recent Advances in Targeted Therapy for Glioma.

PubMed

Lin, Lin; Cai, Jinquan; Jiang, Chuanlu

2017-01-01

Gliomas are the most common primary malignant brain tumors, which have a universally fatal outcome. Current standard treatment for glioma patients is surgical removal followed by radiotherapy and adjuvant chemotherapy. Due to therapeutic resistance and tumor recurrence, efforts are ongoing to identify the molecules that are fundamental to regulate the tumor progression and provide additional methods for individual treatment of glioma patients. By studying the initiation and maintenance of glioma, studies focused on the targets of tyrosine kinase receptors including EGFR, PDGFR and other crucial signal pathways such as PI3K/AKT and RAS/RAF/MAPK pathway. Furthermore, recent advances in targeting immunotherapy and stem cell therapy also brought numerous strategies to glioma treatment. This article reviewed the researches focused on the advanced strategies of various target therapies for improving the glioma treatment efficacy, and discussed the challenges and future directions for glioma therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

AKT Axis, miR-21, and RECK Play Pivotal Roles in Dihydroartemisinin Killing Malignant Glioma Cells

PubMed Central

Shao, Ying-Ying; Zhang, Tao-Lan; Wu, Lan-Xiang; Zou, He-Cun; Li, Shuang; Huang, Jin; Zhou, Hong-Hao

2017-01-01

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, is known to play important roles in inhibiting proliferation rate, inducing apoptosis, as well as hindering the metastasis and invasion of glioma cells, but the underlying mechanisms are still unclear so far. In this study, methyl thiazolyl tetrazolium (MTT), colony-forming, wound healing, invasion, and apoptosis assays were performed to investigate the effect of DHA on malignant glioma cells. Results showed that DHA induced apoptosis of malignant glioma cells through Protein Kinase B (AKT) axis, induced death of malignant glioma cells by downregulating miR-21, and inhibited the invasion of malignant glioma cells corresponding with up-regulation of the reversion-inducing-cysteine-rich protein with kazal motifs (RECK). These results revealed that AKT axis, miR-21, and RECK play pivotal roles in DHA killing malignant glioma cells, suggesting that DHA is a potential agent for treating glioma. PMID:28208619

Dissociation of spontaneous seizures and brainstem seizure thresholds in mice exposed to eight flurothyl-induced generalized seizures.

PubMed

Kadiyala, Sridhar B; Ferland, Russell J

2017-03-01

C57BL/6J mice exposed to eight flurothyl-induced generalized clonic seizures exhibit a change in seizure phenotype following a 28-day incubation period and subsequent flurothyl rechallenge. Mice now develop a complex seizure semiology originating in the forebrain and propagating into the brainstem seizure network (a forebrain→brainstem seizure). In contrast, this phenotype change does not occur in seizure-sensitive DBA/2J mice. The underlying mechanism(s) was the focus of these studies. DBA2/J mice were exposed to eight flurothyl-induced seizures (1/day) followed by 24-hour video-electroencephalographic recordings for 28-days. Forebrain and brainstem seizure thresholds were determined in C57BL/6J and DBA/2J mice following one or eight flurothyl-induced seizures, or after eight flurothyl-induced seizures, a 28-day incubation period, and final flurothyl rechallenge. Similar to C57BL/6J mice, DBA2/J mice expressed spontaneous seizures. However, unlike C57BL/6J mice, DBA2/J mice continued to have spontaneous seizures without remission. Because DBA2/J mice do not express forebrain→brainstem seizures following flurothyl rechallenge after a 28-day incubation period, this indicated that spontaneous seizures were not sufficient for the evolution of forebrain→brainstem seizures. Therefore, we determined whether brainstem seizure thresholds were changing during this repeated-flurothyl model and whether this could account for the expression of forebrain→brainstem seizures. Brainstem seizure thresholds were not different between C57BL/6J and DBA/2J mice on day one or on the last induction seizure trial (day eight). However, brainstem seizure thresholds did differ significantly on flurothyl rechallenge (day 28) with DBA/2J mice showing no lowering of their brainstem seizure thresholds. These results demonstrated that DBA/2J mice exposed to the repeated-flurothyl model develop spontaneous seizures without evidence of seizure remission and provide a new model of epileptogenesis. Moreover, these findings indicated that the transition of forebrain ictal discharge into the brainstem seizure network occurs due to changes in brainstem seizure thresholds that are independent of spontaneous seizure expression.

Neural connectivity of the posterior body of the fornix in the human brain: diffusion tensor imaging study.

PubMed

Jang, Sung Ho; Kwon, Hyeok Gyu

2013-08-09

Little is known about the neural connectivity of the fornix in the human brain. In the current study, using diffusion tensor imaging, we attempted to investigate the neural connectivity of the posterior body of the fornix in the normal human brain. A total of 43 healthy subjects were recruited for this study. DTIs were acquired using a sensitivity-encoding head coil at 1.5T. For connectivity of the posterior body of the fornix, a seed region of interest was used on the posterior body of the fornix. Connectivity was defined as the incidence of connection between the posterior body of the fornix and any neural structure of the brain at the threshold of 5, 25, and 50 streamline. At the threshold of 5, 25, and 50, the posterior body of the fornix showed connectivity to the precentral gyrus (37%, 19%, and 15%), the postcentral gyrus (25%, 11.5%, and 7%), the posterior parietal cortex (16.5%, 5%, and 5%), the brainstem (12%, 4.5%, and 3.5%), the crus of the fornix (34%, 10.5%, and 7%), the contralateral splenium of the corpus callosum (12.5%, 5%, and 0%), and the ipsilateral splenium of the CC (69.8%%, 33.7%, and 23.3%), respectively. Findings of this study showed that the posterior body of the fornix had connectivity with the cerebral cortex, the brainstem, the fornical crus, and the contralateral splenium through the splenium of the corpus callosum in normal subjects. We believe that the results of this study would be helpful in investigation of the neural network related to memory and recovery mechanisms following fornical injury in the human brain. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Recovery of Patients with Pure Diffuse Axonal Injury Who Remained in a Coma for 6 Hours or More.

PubMed

Almeida Vieira, Rita de Cássia; Paiva, Wellingson Silva; de Oliveira, Daniel Vieira; de Paula Guirado, Vinícius Monteiro; Caetano Lança, Ellen de Fátima; de Sousa, Regina Márcia Cardoso

2018-01-01

Diffuse axonal injury (DAI) is a traumatic brain injury and one of the most common causes of unfavorable outcome and death. The aim of this study was to investigate the recovery of patients with pure DAI who remained in a coma for 6 hours or longer after brain injury. This was a follow-up study of 75 patients diagnosed with pure DAI, aged 18-60 years, with a Glasgow Coma Scale score ≤8 at hospital admission. Patient data were collected at hospital admission, hospital discharge, and 3 and 6 months after DAI. Recovery was assessed by score changes in the Katz Index of Independence in Activities of Daily Living and Extended Glasgow Outcome Scale. The percentage of patients in a coma for 6-24 hours, >24 hours without brainstem signs, and >24 hours with brainstem signs was 42.7%, 20%, and 37.3%, respectively. The 6-month mortality rate was 32.0%, and the mean Extended Glasgow Outcome Scale score among survivors decreased from 3.8 at discharge (SD = 1.2) to 2.1 at 3 months (SD = 1.6) and 1.2 at 6 months (SD = 1.6). The mean Katz Index of Independence in Activities of Daily Living scores were 8.5 (SD = 5.5), 3.5 (SD = 5.8), and 1.8 (SD = 4.5) at discharge and 3 and 6 months after trauma, respectively. Statistically significant differences were observed among the 3 evaluation periods. Mortality was high among patients with DAI, but almost all survivors had favorable outcomes at 6 months. Functional improvement was more pronounced in the first 3 months. Copyright © 2017. Published by Elsevier Inc.

Ferritin heavy chain as a molecular imaging reporter gene in glioma xenografts.

PubMed

Cheng, Sen; Mi, Ruifang; Xu, Yu; Jin, Guishan; Zhang, Junwen; Zhou, Yiqiang; Chen, Zhengguang; Liu, Fusheng

2017-06-01

The development of glioma therapy in clinical practice (e.g., gene therapy) calls for efficiently visualizing and tracking glioma cells in vivo. Human ferritin heavy chain is a novel gene reporter in magnetic resonance imaging. This study proposes hFTH as a reporter gene for MR molecular imaging in glioma xenografts. Rat C6 glioma cells were infected by packaged lentivirus carrying hFTH and EGFP genes and obtained by fluorescence-activated cell sorting. The iron-loaded ability was analyzed by the total iron reagent kit. Glioma nude mouse models were established subcutaneously and intracranially. Then, in vivo tumor bioluminescence was performed via the IVIS spectrum imaging system. The MR imaging analysis was analyzed on a 7T animal MRI scanner. Finally, the expression of hFTH was analyzed by western blotting and histological analysis. Stable glioma cells carrying hFTH and EGFP reporter genes were successfully obtained. The intracellular iron concentration was increased without impairing the cell proliferation rate. Glioma cells overexpressing hFTH showed significantly decreased signal intensity on T 2 -weighted MRI both in vitro and in vivo. EGFP fluorescent imaging could also be detected in the subcutaneous and intracranial glioma xenografts. Moreover, the expression of the transferritin receptor was significantly increased in glioma cells carrying the hFTH reporter gene. Our study illustrated that hFTH generated cellular MR imaging contrast efficiently in glioma via regulating the expression of transferritin receptor. This might be a useful reporter gene in cell tracking and MR molecular imaging for glioma diagnosis, gene therapy and tumor metastasis.

Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations

ClinicalTrials.gov

2018-06-13

Advanced Malignant Solid Neoplasm; Glioblastoma; IDH1 Gene Mutation; IDH2 Gene Mutation; Recurrent Cholangiocarcinoma; Recurrent Glioma; Recurrent Malignant Solid Neoplasm; WHO Grade II Glioma; WHO Grade III Glioma

MiR-661 inhibits glioma cell proliferation, migration and invasion by targeting hTERT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Zhen, E-mail: lizhen7111@163.com; Liu, Yun-hui; Diao, Hong-yu

In this study, we analyzed the functional role of miR-661 in glioma cell proliferation, migration and invasion. We found that overexpression of miR-661 obviously suppressed the proliferation, migration and invasion of glioma cells. MiRNA target prediction algorithms implied that hTERT is a candidate target gene for miR-661. A fluorescent reporter assay confirmed that miR-661 could lead to hTERT gene silencing by recognizing and specifically binding to the predicted site of the hTERT mRNA 3′ untranslated region (3′UTR) specifically. Furthermore, hTERT knockdown significantly decreased the growth and viability of glioma cells. These results indicate that miR-661 can inhibit glioma cell proliferation,more » migration and invasion by targeting hTERT. - Highlights: • MiR-661 was downregulated in glioma tissues and functional as a tumor suppressor. • MiR-661 modulates cell proliferation, invasion and migration of glioma cells. • MiR-661 directly target hTERT in glioma cells. • MiR-661 inhibits glioma cell tumorgenesis by targeting hTERT.« less

Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma.

PubMed

Song, Ye; Zheng, Shihao; Wang, Jizhou; Long, Hao; Fang, Luxiong; Wang, Gang; Li, Zhiyong; Que, Tianshi; Liu, Yi; Li, Yilei; Zhang, Xi'an; Fang, Weiyi; Qi, Songtao

2017-06-27

Gliomas are the most common form of malignant primary brain tumors with poor 5-year survival rate. Dysregulation of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was observed in gliomas, but the specific role and molecular mechanism of PLOD2 in glioma have not been reported yet. In this study, PLOD2 was found to be frequently up-regulated in glioma and could serve as an independent prognostic marker to identify patients with poor clinical outcome. Knockdown of PLOD2 inhibited proliferation, migration and invasion of glioma cells in vitro and in vivo. Mechanistically, inhibition of PLOD2 inactivated PI3K/AKT signaling pathway and thus regulated the expression of its downstream epithelial-mesenchymal transition (EMT)-associated regulators, including E-cadherin, vimentin, N-cadherin, β-catenin, snail and slug in glioma cells. Moreover, PLOD2 could be induced by hypoxia-inducible factor-1α (HIF-1α) via hypoxia, thereby promoting hypoxia-induced EMT in glioma cells. Our data suggests that PLOD2 may be a potential therapeutic target for patients with glioma.

Photodynamic therapy on the ultrastructure of glioma cell

NASA Astrophysics Data System (ADS)

Hu, Shaoshan; Zhang, Ruyou; Zheng, Yongri

2005-07-01

OBJECTIVE ：the main purpose of this experiment was to study the change of C6 glioma cells' ultrastructure treated by photodynamic therapy(PDT), observe the change of morphology METHOD ：Make the model of rat glioma by transplanted C6 glioma cells into caudate nucleus，treated the glioma rat by PDT after two weeks. Observed the difference of subcellular structure before and after PDT by electron microscope. RESULT ： Apoptosis and necrosis can be seen after treated by PDT in the C6 glioma, basal membrance damaged ，number of cellular organ of endothelial cell of blood capillary declined，tight junction of endothelial cell lengthen and the gap enlarge. The PDT has slightly effect on the nomorl rat"s subcellular structue. CONCLUSION: PDT can induce the apoptosis and necrosis of C6 glioma cell. The damage of the ultramicrostructure of mitochondria and endoplasmic reticulum was the foundmentol of the change. PDT initiate the damage of BBB of the C6 glioma cell and weeken the function、and makes it a useful way of treating the glioma combained with chemotherapy.

A syngeneic glioma model to assess the impact of neural progenitor target cell age on tumor malignancy

PubMed Central

Mikheev, Andrei M; Stoll, Elizabeth A; Mikheeva, Svetlana A; Maxwell, John-Patrick; Jankowski, Pawel P; Ray, Sutapa; Uo, Takuma; Morrison, Richard S; Horner, Philip J; Rostomily, Robert C

2010-01-01

Summary Human glioma incidence, malignancy and treatment resistance are directly proportional to patient age. Cell intrinsic factors are reported to contribute to human age-dependent glioma malignancy but suitable animal models to examine the role of aging are lacking. Here we developed an orthotopic syngeneic glioma model to test the hypothesis that the age of neural progenitor cells (NPCs), presumed cells of glioma origin, influences glioma malignancy. Gliomas generated from transformed donor 3-, 12-, and 18-month-old NPCs in same-aged adult hosts all formed highly invasive glial tumors that phenocopied the human disease. Survival analysis indicated increased malignancy of gliomas generated from older 12- and 18-month-old transformed NPCs compared with their 3-month counterparts (median survival of 38.5 and 42.5 vs. 77 days, respectively). This study showed for the first time that age of target cells at the time of transformation can affect malignancy and demonstrated the feasibility of a syngeneic model using transformed NPCs for future examination of the relative impacts of age-related cell intrinsic and cell-extrinsic factors in glioma malignancy. PMID:19489742

Development of a novel combined fluorescence and reflectance spectroscopy system for guiding high-grade glioma resections: confirmation of capability in lab experiments

NASA Astrophysics Data System (ADS)

Mousavi, Monirehalsadat; Xie, Haiyan; Xie, Zhiyuan; Brydegaard, Mikkel; Axelsson, Johan; Andersson-Engels, Stefan

2013-11-01

Total resection of glioblastoma multiform (GBM), the most common and aggressive malignant brain tumor, is challenging among other things due to difficulty in intraoperative discrimination between normal and residual tumor cells. This project demonstrates the potential of a system based on a combination of autofluorescence and diffuse reflectance spectroscopy to be useful as an intraoperative guiding tool. In this context, a system based on 5 LEDs coupled to optical fibers was employed to deliver UV/visible light to the sample sequentially. Remitted light from the tissue; including diffuse reflected and fluorescence of endogenous and exogenous fluorophores, as well as its photobleaching product, is transmitted to one photodiode and four avalanche photodiodes. This instrument has been evaluated with very promising results by performing various tissue-equivalent phantom laboratory and clinical studies on skin lesions.

Class A1 scavenger receptor modulates glioma progression by regulating M2-like tumor-associated macrophage polarization

PubMed Central

Zhang, Hanwen; Zhang, Wenbin; Sun, Xuan; Dang, Ruoyu; Zhou, Rongmei; Bai, Hui; Ben, Jingjing; Zhu, Xudong; Zhang, Yan; Yang, Qing; Xu, Yong; Chen, Qi

2016-01-01

Macrophages enhance glioma development and progression by shaping the tumor microenvironment. Class A1 scavenger receptor (SR-A1), a pattern recognition receptor primarily expressed in macrophages, is up-regulated in many human solid tumors. We found that SR-A1 expression in 136 human gliomas was positively correlated with tumor grade (P<0.01), but not prognosis or tumor recurrence. SR-A1-expressing macrophages originated primarily from circulating monocytes attracted to tumor tissue, and were almost twice as numerous as resident microglia in glioma tissues (P<0.001). The effects of SR-A1 on glioma proliferation and invasion were assessed in vivo using an SR-A1-deficient murine orthotopic glioma model. SR-A1 deletion promoted M2-like tumor-associated macrophage (TAM) polarization in mice by activating STAT3 and STAT6, which resulted in robust orthotopic glioma proliferation and angiogenesis. Finally, we found that HSP70 might be an endogenous ligand that activates SR-A1-dependent anti-tumorigenic pathways in gliomas, although its expression does not appear informative for diagnostic purposes. Our findings demonstrate a relationship between TAMs, SR-A1 expression and glioma growth and provide new insights into the pathogenic role of TAMs in glioma. PMID:27367025

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro.

PubMed

Sun, Ting; Zhang, Zizhu; Li, Bin; Chen, Guilin; Xie, Xueshun; Wei, Yongxin; Wu, Jie; Zhou, Youxin; Du, Ziwei

2013-08-06

Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.

Significance of perivascular tumour cells defined by CD109 expression in progression of glioma.

PubMed

Shiraki, Yukihiro; Mii, Shinji; Enomoto, Atsushi; Momota, Hiroyuki; Han, Yi-Peng; Kato, Takuya; Ushida, Kaori; Kato, Akira; Asai, Naoya; Murakumo, Yoshiki; Aoki, Kosuke; Suzuki, Hiromichi; Ohka, Fumiharu; Wakabayashi, Toshihiko; Todo, Tomoki; Ogawa, Seishi; Natsume, Atsushi; Takahashi, Masahide

2017-12-01

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

PubMed

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

2016-04-01

Gliomas are the most common and the most malignant brain tumors, accouting for 45-55% of all intracranial tumors. The incidence of glioma worldwide is about 6-12 per 100,000. Recently, several studies showed that the activation of the oncogenes and the inactivation and/or loss of the tumor suppressor genes, especially for miRNA-21, let-7 and so on, are the most primary molecule event in gliomas. MicroRNAs (miRNAs) are a class of endogenously expressed small noncoding RNAs which are usually 21-23 nucleotides long. miRNAs regulate gene expression and play important roles in a variety of physiological and pathological processes, such as cell proliferation, differentiation and apoptosis. To date, Growing evidence has shown that mi RNAs are frequently dysregulated in human cancers and can act as both tumor suppressors and oncogenes. Along with the discovery of micro RNA, more and more research focusing on its relationship with glioma was carried out to investigate the biological features of glioma and to provide experimental evidence for glioma mechanism. In the present study, we aimed to verify the miRNA-126 down-regulation which showed in the results of glioma tissue miRNAs chip and discuss the miRNA-126 methylation in patients with glioma. A total of 50 samples from patients with glioma and 20 control samples from patients with cerebral trauma were included in this study. The expression levels of the miR-126 gene were detected using quantitative polymerase chain reaction (PCR), and the methylation status of miR-126 was examined using methylation-specific PCR-denaturing high-performance liquid chromatography (MSP-DHPLC). The expression level of miRNA-126 was found to be significantly higher in the control group (0.6134 ± 0.1214) than in the glioma group (0.2771 ± 0.1529; P < 0.05). The expression was also significantly elevated in low-grade gliomas (0.3117 ± 0.1474) compared with high-grade gliomas (0.1582 ± 0.1345; P < 0.05). In addition, increased methylation of miR-126 was found in 40% of glioma patients in our study (20/50 cases), resulting in significantly decreased miR-126 expression (0.1715 ± 0.1376; P < 0.05). Our results indicate that we verified successfully the miRNA-126 down-regulation phenomenon in patients with glioma which showed in the results of glioma tissue miRNAs chip and the miRNA-126 down-regulation through methylation in patients with glioma. So we could say that epigenetic modification is a crucial mechanism for controlling the expression of miR-126 in glioma.

MicroRNA-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1.

PubMed

Quan, Junjie; Qu, Jianqiang; Zhou, Le

2017-09-01

Dysregulation of microRNAs (miRNAs) has been suggested to contribute to malignant progression of glioma. Previous studies have demonstrated that miR-539 is dysregulated in malignant progression of cancers. However, the potential role and mechanism of miR-539 in the progression of glioma remains unclear. In this study, we aimed to investigate the expression status and functional significance of miR-539 in glioma. We found that miR-539 expression was significantly decreased in glioma cell lines and tissues. Overexpression of miR-539 markedly inhibited glioma cell proliferation and invasion, while miR-539 suppression exhibited the opposite effect. Bioinformatics analysis and dual-luciferase reporter assays showed that miR-539 directly targeted the 3'-untranslated region of Disheveled-axin domain containing 1 (DIXDC1). DIXDC1 expression was negatively regualted by miR-539 overexpression. An inverse correlation between DIXDC1 mRNA expression and miR-539 expression was found in glioma specimens. Furthermore, knockdown of DIXC1 significantly inhibited proliferation, invasion and Wnt signaling in glioma cells. Overexpression of DIXDC1 partially reversed the inhibitory effect of miR-539 on glioma cell proliferation and invasion. Overall, these findings demonstrate that miR-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1. Our study suggests that the miR-539 may serve as a potential target for the clinical diagnosis and treatment of glioma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma.

PubMed

Kim, Julius W; Kane, J Robert; Young, Jacob S; Chang, Alan L; Kanojia, Deepak; Morshed, Ramin A; Miska, Jason; Ahmed, Atique U; Balyasnikova, Irina V; Han, Yu; Zhang, Lingjiao; Curiel, David T; Lesniak, Maciej S

2015-09-01

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as "GliomaFF." We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.

A two-year longitudinal pilot MRI study of the brainstem in autism.

PubMed

Jou, Roger J; Frazier, Thomas W; Keshavan, Matcheri S; Minshew, Nancy J; Hardan, Antonio Y

2013-08-15

Research has demonstrated the potential role of the brainstem in the pathobiology of autism. Previous studies have suggested reductions in brainstem volume and a relationship between this structure and sensory abnormalities. However, little is known regarding the developmental aspects of the brainstem across childhood and adolescence. The goal of this pilot study was to examine brainstem development via MRI volumetry using a longitudinal research design. Participants included 23 boys with autism and 23 matched controls (age range=8-17 years), all without intellectual disability. Participants underwent structural MRI scans once at baseline and again at two-year follow-up. Brainstem volumetric measurements were performed using the BRAINS2 software package. There were no significant group differences in age, gender, handedness, and total brain volume; however, full-scale IQ was higher in controls. Autism and control groups showed different patterns of growth in brainstem volume. While whole brainstem volume remained stable in controls over the two-year period, the autism group showed increases with age reaching volumes comparable to controls by age 15 years. This increase of whole brainstem volume was primarily driven by bilateral increases in gray matter volume. Findings from this preliminary study are suggestive of developmental brainstem abnormalities in autism primarily involving gray matter structures. These findings are consistent with autism being conceptualized as a neurodevelopmental disorder with alterations in brain-growth trajectories. More longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral data to confirm and elucidate the clinical significance of these atypical growth patterns. Copyright © 2013 Elsevier B.V. All rights reserved.

Brainstem timing: implications for cortical processing and literacy.

PubMed

Banai, Karen; Nicol, Trent; Zecker, Steven G; Kraus, Nina

2005-10-26

The search for a unique biological marker of language-based learning disabilities has so far yielded inconclusive findings. Previous studies have shown a plethora of auditory processing deficits in learning disabilities at both the perceptual and physiological levels. In this study, we investigated the association among brainstem timing, cortical processing of stimulus differences, and literacy skills. To that end, brainstem timing and cortical sensitivity to acoustic change [mismatch negativity (MMN)] were measured in a group of children with learning disabilities and normal-learning children. The learning-disabled (LD) group was further divided into two subgroups with normal and abnormal brainstem timing. MMNs, literacy, and cognitive abilities were compared among the three groups. LD individuals with abnormal brainstem timing were more likely to show reduced processing of acoustic change at the cortical level compared with both normal-learning individuals and LD individuals with normal brainstem timing. This group was also characterized by a more severe form of learning disability manifested by poorer reading, listening comprehension, and general cognitive ability. We conclude that abnormal brainstem timing in learning disabilities is related to higher incidence of reduced cortical sensitivity to acoustic change and to deficient literacy skills. These findings suggest that abnormal brainstem timing may serve as a reliable marker of a subgroup of individuals with learning disabilities. They also suggest that faulty mechanisms of neural timing at the brainstem may be the biological basis of malfunction in this group.

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

PubMed

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

2017-03-01

Current classification of gliomas is based on histological criteria according to the World Health Organization (WHO) classification of tumors of the central nervous system. Over the past years, characteristic genetic profiles have been identified in various glioma types. These can refine tumor diagnostics and provide important prognostic and predictive information. We report on the establishment and validation of gene panel next generation sequencing (NGS) for the molecular diagnostics of gliomas. We designed a glioma-tailored gene panel covering 660 amplicons derived from 20 genes frequently aberrant in different glioma types. Sensitivity and specificity of glioma gene panel NGS for detection of DNA sequence variants and copy number changes were validated by single gene analyses. NGS-based mutation detection was optimized for application on formalin-fixed paraffin-embedded tissue specimens including small stereotactic biopsy samples. NGS data obtained in a retrospective analysis of 121 gliomas allowed for their molecular classification into distinct biological groups, including (i) isocitrate dehydrogenase gene (IDH) 1 or 2 mutant astrocytic gliomas with frequent α-thalassemia/mental retardation syndrome X-linked (ATRX) and tumor protein p53 (TP53) gene mutations, (ii) IDH mutant oligodendroglial tumors with 1p/19q codeletion, telomerase reverse transcriptase (TERT) promoter mutation and frequent Drosophila homolog of capicua (CIC) gene mutation, as well as (iii) IDH wildtype glioblastomas with frequent TERT promoter mutation, phosphatase and tensin homolog (PTEN) mutation and/or epidermal growth factor receptor (EGFR) amplification. Oligoastrocytic gliomas were genetically assigned to either of these groups. Our findings implicate gene panel NGS as a promising diagnostic technique that may facilitate integrated histological and molecular glioma classification. © 2016 International Society of Neuropathology.

S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages

PubMed Central

Wang, Huaqing; Zhang, Leying; Zhang, Ian Y.; Chen, Xuebo; Da Fonseca, Anna; Wu, Shihua; Ren, Hui; Badie, Sam; Sadeghi, Sam; Ouyang, Mao; Warden, Charles D.; Badie, Behnam

2013-01-01

Purpose S100B is member of a multigenic family of Ca2+-binding proteins that is overexpressed by gliomas. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAMs). Experimental Design We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100Bhigh) or underexpressed (S100Blow) S100B and compared their growth characteristics to intracranial wild-type (S100Bwt) tumors. Results Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100Blow tumors, S100Bwt and S100Bhigh intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, RAGE (receptor for advanced glycation end products), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that CCL2 was upregulated in S100Bhigh tumors. Furthermore, analysis of TCGA’s glioma data bank demonstrated a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. Conclusions These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy. PMID:23719262

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry.

PubMed

Hou, Huagang; Krishnamurthy Nemani, Venkata; Du, Gaixin; Montano, Ryan; Song, Rui; Gimi, Barjor; Swartz, Harold M; Eastman, Alan; Khan, Nadeem

2015-04-01

Hypoxia is a critical hallmark of glioma, and significantly compromises treatment efficacy. Unfortunately, techniques for monitoring glioma pO2 to facilitate translational research are lacking. Furthermore, poor prognosis of patients with malignant glioma, in particular glioblastoma multiforme, warrant effective strategies that can inhibit hypoxia and improve treatment outcome. EPR oximetry using implantable resonators was implemented for monitoring pO2 in normal cerebral tissue and U251 glioma in mice. Breathing carbogen (95% O2 + 5% CO2 ) was tested for hyperoxia in the normal brain and glioma xenografts. A new strategy to inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor, was also investigated. The mean pO2 of left and right hemisphere were ∼56-69 mmHg in the normal cerebral tissue of mice. The mean baseline pO2 of U251 glioma on the first and fifth day of measurement was 21.9 ± 3.7 and 14.1 ± 2.4 mmHg, respectively. The mean brain pO2 including glioma increased by at least 100% on carbogen inhalation, although the response varied between the animals over days. Treatment with gemcitabine + MK-8776 significantly increased pO2 and inhibited glioma growth assessed by MRI. In conclusion, EPR oximetry with implantable resonators can be used to monitor the efficacy of carbogen inhalation and chemotherapy on orthotopic glioma in mice. The increase in glioma pO2 of mice breathing carbogen can be used to improve treatment outcome. The treatment with gemcitabine + MK-8776 is a promising strategy that warrants further investigation. © 2014 UICC.

Ectopic High Expression of E2-EPF Ubiquitin Carrier Protein Indicates a More Unfavorable Prognosis in Brain Glioma.

PubMed

Zhang, Xiaohui; Zhao, Fangbo; Zhang, Shujun; Song, Yichun

2017-04-01

Ubiquitination of proteins meant for elimination is a primary method of eukaryotic cellular protein degradation. The ubiquitin carrier protein E2-EPF is a key degradation enzyme that is highly expressed in many tumors. However, its expression and prognostic significance in brain glioma are still unclear. The aim of this study was to reveal how the level of E2-EPF relates to prognosis in brain glioma. Thirty low-grade and 30 high-grade brain glioma samples were divided into two tissue microarrays each. Levels of E2-EPF protein were examined by immunohistochemistry and immunofluorescence. Quantitative real-time polymerase chain reaction was used to analyze the level of E2-EPF in 60 glioma and 3 normal brain tissue samples. The relationship between E2-EPF levels and prognosis was analyzed by Kaplan-Meier survival curves. E2-EPF levels were low in normal brain tissue samples but high in glioma nuclei. E2-EPF levels gradually increased as glioma grade increased (p < 0.05). Ectopic E2-EPF levels in high-grade glioma were significantly higher than in low-grade glioma (p < 0.01). The 5-year survival rate of glioma patients with high E2-EPF levels was shorter than in patients with low expression (p < 0.05). Furthermore, the 5-year survival rate of patients with ectopic E2-EPF was significantly shorter than patients with only nuclear E2-EPF (p < 0.01). These results suggest that higher E2-EPF levels, especially ectopic, are associated with higher grade glioma and shorter survival. E2-EPF levels may play a key role in predicting the prognosis for patients with brain glioma.

Increased rate of positive penicillin skin tests among patients with glioma: insights into the association between allergies and glioma risk.

PubMed

Han, Sheng; Huang, Yanming; Wang, Zixun; Li, Zhonghua; Qin, Xiaofei; Wu, Anhua

2014-11-01

Allergy and immunoglobulin E levels are inversely associated with glioma risk. Previous studies have focused on respiratory and food allergies, and little information is available regarding drug allergies. This study evaluated the rate of positive penicillin skin tests (PenSTs) and blood eosinophil counts in a large population of patients with glioma compared with nontumor controls to provide evidence for the relationship between drug allergies and glioma risk. A retrospective case-control study was conducted in patients diagnosed with glioma (n = 913) between January 2004 and June 2013. The study patients were matched with nontumor controls (n = 1091) for age, sex, and date of admission to the hospital. Preoperative results of the PenST and eosinophil counts were obtained, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression models, while a Kaplan-Meier analysis was used to assess overall survival. The percentage of positive PenSTs was higher among patients with glioma than in control subjects. The age-, sex-, and admission date-adjusted OR for positive versus negative PenSTs was 2.392 (95% CI 1.891-3.026). Eosinophil counts were also higher in glioma cases than in controls: the OR for eosinophil > 0.06 × 10(9)/L versus ≤ 0.06 × 10(9)/L was 1.923 (95% CI 1.608-2.301). There was no association between positive PenST/eosinophil counts and glioma grade or patient survival (n = 105). In contrast to previously reported relationships between allergy and glioma, in the present study a significantly higher rate of positive PenSTs and higher eosinophil counts were found in patients with glioma than in nontumor controls. These results suggest a complex relationship between allergies and glioma development.

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

PubMed

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

2013-04-01

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

Human umbilical cord blood stem cells show PDGF-D–dependent glioma cell tropism in vitro and in vivo

PubMed Central

Gondi, Christopher S.; Veeravalli, Krishna Kumar; Gorantla, Bharathi; Dinh, Dzung H.; Fassett, Dan; Klopfenstein, Jeffrey D.; Gujrati, Meena; Rao, Jasti S.

2010-01-01

Despite advances in clinical therapies and technologies, the prognosis for patients with malignant glioma is poor. Neural stem cells (NSCs) have a chemotactic tropism toward glioma cells. The use of NSCs as carriers of therapeutic agents for gliomas is currently being explored. Here, we demonstrate that cells isolated from the umbilical cord blood show mesenchymal characteristics and can differentiate to adipocytes, osteocytes, and neural cells and show tropism toward cancer cells. We also show that these stem cells derived from the human umbilical cord blood (hUCB) induce apoptosis-like cell death in the glioma cell line SNB19 via Fas-mediated caspase-8 activation. From our glioma tropism studies, we have observed that hUCB cells show tropism toward glioma cells in vitro, in vivo, and ex vivo. We determined that this migration is partially dependent on the expression levels of platelet-derived growth factor (PDGF)-D from glioma cells and have observed that local concentration gradient of PDGF-D is sufficient to cause migration of hUCB cells toward the gradient as seen from our brain slice cultures. In our animal experiment studies, we observed that intracranially implanted SNB19 green fluorescent protein cells induced tropism of the hUCB cells toward themselves. In addition, the ability of these hUCBs to inhibit established intracranial tumors was also observed. We also determined that the migration of stem cells toward glioma cells was partially dependent on PDGF secreted by glioma cells and that the presence of PDGF-receptor (PDGFR) on hUCB is required for migration. Our results demonstrate that hUCB are capable of inducing apoptosis in human glioma cells and also show that glioma tropism and hUCB tropism toward glioma cells are partially dependent on the PDGF/PGGFR system. PMID:20406896

Expression of REST4 in human gliomas in vivo and influence of pioglitazone on REST in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Huan; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; Gao, Zhangfeng

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have a role of antineoplastic in various tumor cells, which includingmore » glioma cells. Moreover, study indicated that PPARγ agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down-regulating REST mRNA level but not by inducing alternative splicing of REST pre-mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma. - Highlights: • A specific isoform REST4 is expressed in glioma specimens in vivo. • REST4 will influence the mRNA level of REST in vivo. • Pioglitazone can inhibit proliferation and induce apoptosis of glioma cells. • The role of pioglitazone in anti-glioma may be mediated by down-regulating REST.« less

Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P{sub 2} on cell migration and invasiveness

DOE Office of Scientific and Technical Information (OSTI.GOV)

Young, Nicholas; Van Brocklyn, James R.

2007-05-01

Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of five G-protein-coupled receptors, termed S1P{sub 1-5}. S1P stimulates growth and invasiveness of glioma cells, and high expression levels of the enzyme that forms S1P, sphingosine kinase-1, correlate with short survival of glioma patients. In this study we examined the mechanism of S1P stimulation of glioma cell proliferation and invasion by either overexpressing or knocking down, by RNA interference, S1P receptor expression in glioma cell lines. S1P{sub 1}, S1P{sub 2} and S1P{sub 3} all contribute positively to S1P-stimulated glioma cell proliferation, with S1P{sub 1} being the major contributor. Stimulationmore » of glioma cell proliferation by these receptors correlated with activation of ERK MAP kinase. S1P{sub 5} blocks glioma cell proliferation, and inhibits ERK activation. S1P{sub 1} and S1P{sub 3} enhance glioma cell migration and invasion. S1P{sub 2} inhibits migration through Rho activation, Rho kinase signaling and stress fiber formation, but unexpectedly, enhances glioma cell invasiveness by stimulating cell adhesion. S1P{sub 2} also potently enhances expression of the matricellular protein CCN1/Cyr61, which has been implicated in tumor cell adhesion, and invasion as well as tumor angiogenesis. A neutralizing antibody to CCN1 blocked S1P{sub 2}-stimulated glioma invasion. Thus, while S1P{sub 2} decreases glioma cell motility, it may enhance invasion through induction of proteins that modulate glioma cell interaction with the extracellular matrix.« less

Spontaneous complete regression of a brain stem glioma pathologically diagnosed as a high-grade glioma.

PubMed

Ishihara, Masahiro; Yamamoto, Kazumi; Miwa, Hideaki; Nishi, Masaya

2017-12-01

Spontaneous regressions of brain stem gliomas are extremely rare. Only six cases have been reported in the literature. We describe the case of a patient who was diagnosed with a pontomedullary dorsal brain stem glioma at the age of 15 years. An open biopsy showed the presence of an anaplastic glioma. Because the patient and her parents refused conventional therapies, including radiation and chemotherapy, we followed up the patient by performing magnetic resonance imaging scans on her every 3 months. At 3 months after biopsy, we observed the radiological disappearance of her tumor. One year after biopsy, the tumor retained the spontaneous complete regression observed earlier. In this case report, we present the first report of the spontaneous complete regression of a brain stem glioma that was histologically proven to be a high-grade glioma and we believe that this regression was the natural progression of this case, as may be the scenario in a few other cases of brain stem gliomas.

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation.

PubMed

Xing, Yang; Ge, Yuqing; Liu, Chanjuan; Zhang, Xiaobiao; Jiang, Jianhai; Wei, Yuanyan

2016-06-14

Glioma-initiating cells possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Therefore, their elimination is an essential factor for the development of efficient therapy. Here, we report that endoplasmic reticulum (ER) stress inducer tunicamycin inhibits glioma-initiating cell self-renewal as determined by neurosphere formation assay. Moreover, tunicamycin decreases the efficiency of glioma-initiating cell to initiate tumor formation. Although tunicamycin induces glioma-initiating cell apoptosis, apoptosis inhibitor z-VAD-fmk only partly abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Indeed, tunicamycin reduces the expression of self-renewal regulator Sox2 at translation level. Overexpression of Sox2 obviously abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Taken together, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma-initiating cell partly through reducing Sox2 translation. This finding provides a cue to potential effective treatment of glioblastoma through controlling stem cells.

Downregulation of miR-130a promotes cell growth and epithelial to mesenchymal transition by activating HMGB2 in glioma.

PubMed

Tang, Chunhai; Yang, Zhenxiu; Chen, Dongliang; Xie, Qinghai; Peng, Tao; Wu, Jingzhan; Qi, Songtao

2017-12-01

Aberrant expression of miR-130a is usually found in cancer studies; however, the role of miR-130a has seldom been reported in glioma. We explored miR-130a's function and the underlying mechanism in glioma. It was found that miR-130a expression was significantly down-regulated in glioma tissues and cell lines. Overexpression of miR-130a decreased glioma cell growth and invasion both in vitro and in vivo. We identified the oncogene HMGB2 as a downstream target of miR-130a by using luciferase and western blot assays. Knockdown of HMGB2 mimicked the effect of miR-130a in glioma cells. Taken together, our study demonstrate that miR-130a may function as a tumor suppressor in glioma and suggest that miR-130a is a potential therapeutic target for glioma patients. Copyright © 2017. Published by Elsevier Ltd.

Modulation of glioma risk and progression by dietary nutrients and anti-inflammatory agents

PubMed Central

Kyritsis, Athanassios P.; Bondy, Melissa L.; Levin, Victor A.

2011-01-01

Gliomas are tumors of glial origin formed in the central nervous system and exhibit profound morphological and genetic heterogeneity. The etiology of this heterogeneity involves an interaction between genetic alterations and environmental risk factors. Scientific evidence suggests that certain natural dietary components, such as phytoestrogens, flavonoids, polyunsaturated fatty acids and vitamins may exert a protective effect against gliomas by changing the nature of the interaction between genetics and environment. Similarly, certain anti-inflammatory drugs and dietary modifications, such as methionine restriction and the adoption of low-calorie or ketogenic diets, may take advantage of glioma and normal glial cells’ differential requirements for glucose, methionine, and ketone bodies and may therefore be effective as part of preventive or treatment strategies for gliomas. Treatment trials of glioma patients and chemoprevention trials of individuals with a known genetic predisposition to glioma using the most promising of these agents, such as the anti-inflammatory drugs curcumin and gamma-linolenic acid, are needed to validate or refute these agents’ putative role in gliomas. PMID:21302177

CREB1 regulates glucose transport of glioma cell line U87 by targeting GLUT1.

PubMed

Chen, Jiaying; Zhang, Can; Mi, Yang; Chen, Fuxue; Du, Dongshu

2017-12-01

Glioma is stemmed from the glial cells in the brain, which is accounted for about 45% of all intracranial tumors. The characteristic of glioma is invasive growth, as well as there is no obvious boundary between normal brain tissue and glioma tissue, so it is difficult to resect completely with worst prognosis. The metabolism of glioma is following the Warburg effect. Previous researches have shown that GLUT1, as a glucose transporter carrier, affected the Warburg effect, but the molecular mechanism is not very clear. CREB1 (cAMP responsive element-binding protein1) is involved in various biological processes, and relevant studies confirmed that CREB1 protein regulated the expression of GLUT1, thus mediating glucose transport in cells. Our experiments mainly reveal that the CREB1 could affect glucose transport in glioma cells by regulating the expression of GLUT1, which controlled the metabolism of glioma and affected the progression of glioma.

Integrated analysis of dynamic FET PET/CT parameters, histology, and methylation profiling of 44 gliomas.

PubMed

Röhrich, Manuel; Huang, Kristin; Schrimpf, Daniel; Albert, Nathalie L; Hielscher, Thomas; von Deimling, Andreas; Schüller, Ulrich; Dimitrakopoulou-Strauss, Antonia; Haberkorn, Uwe

2018-05-07

Dynamic 18 F-FET PET/CT is a powerful tool for the diagnosis of gliomas. 18 F-FET PET time-activity curves (TAC) allow differentiation between histological low-grade gliomas (LGG) and high-grade gliomas (HGG). Molecular methods such as epigenetic profiling are of rising importance for glioma grading and subclassification. Here, we analysed dynamic 18 F-FET PET data, and the histological and epigenetic features of 44 gliomas. Dynamic 18 F-FET PET was performed in 44 patients with newly diagnosed, untreated glioma: 10 WHO grade II glioma, 13 WHO grade III glioma and 21 glioblastoma (GBM). All patients underwent stereotactic biopsy or tumour resection after 18 F-FET PET imaging. As well as histological analysis of tissue samples, DNA was subjected to epigenetic analysis using the Illumina 850 K methylation array. TACs, standardized uptake values corrected for background uptake in healthy tissue (SUVmax/BG), time to peak (TTP) and kinetic modelling parameters were correlated with histological diagnoses and with epigenetic signatures. Multivariate analyses were performed to evaluate the diagnostic accuracy of 18 F-FET PET in relation to the tumour groups identified by histological and methylation-based analysis. Epigenetic profiling led to substantial tumour reclassification, with six grade II/III gliomas reclassified as GBM. Overlap of HGG-typical TACs and LGG-typical TACs was dramatically reduced when tumours were clustered on the basis of their methylation profile. SUVmax/BG values of GBM were higher than those of LGGs following both histological diagnosis and methylation-based diagnosis. The differences in TTP between GBMs and grade II/III gliomas were greater following methylation-based diagnosis than following histological diagnosis. Kinetic modeling showed that relative K1 and fractal dimension (FD) values significantly differed in histology- and methylation-based GBM and grade II/III glioma between those diagnosed histologically and those diagnosed by methylation analysis. Multivariate analysis revealed slightly greater diagnostic accuracy with methylation-based diagnosis. IDH-mutant gliomas and GBM subgroups tended to differ in their 18 F-FET PET kinetics. The status of dynamic 18 F-FET PET as a biologically and clinically relevant imaging modality is confirmed in the context of molecular glioma diagnosis.

Compound 331 selectively induces glioma cell death by upregulating miR-494 and downregulating CDC20

PubMed Central

Zhang, Lei; Niu, Tianhui; Huang, Yafei; Zhu, Haichuan; Zhong, Wu; Lin, Jian; Zhang, Yan

2015-01-01

Malignant gliomas are the most common malignant tumors in the central nervous system (CNS). Up to date, the prognosis of glioma is still very poor, effective therapy with less side-effect is very necessary. Herein, we identify a compound named as “331” selectively induced cell death in glioma cells but not in astrocytes. Compound 331 upregulated miR-494 and downregulated CDC20 in glioma cells but not in astrocytes. These results suggest that compound 331 could be a potential drug selectively targeting glioma cells through upregulating miR-494 and downregulating CDC20. PMID:26153143

The epidemiology of glioma in adults: a “state of the science” review

PubMed Central

Ostrom, Quinn T.; Bauchet, Luc; Davis, Faith G.; Deltour, Isabelle; Fisher, James L.; Langer, Chelsea Eastman; Pekmezci, Melike; Schwartzbaum, Judith A.; Turner, Michelle C.; Walsh, Kyle M.; Wrensch, Margaret R.; Barnholtz-Sloan, Jill S.

2014-01-01

Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O6-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine–phosphate–guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults. PMID:24842956

CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells.

PubMed

Johansson, Elinn; Grassi, Elisa S; Pantazopoulou, Vasiliki; Tong, Bei; Lindgren, David; Berg, Tracy J; Pietras, Elin J; Axelson, Håkan; Pietras, Alexander

2017-08-15

Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2α through interaction with CD44, independently of oxygen. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A role for ion channels in perivascular glioma invasion

PubMed Central

Thompson, Emily G.

2017-01-01

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

5-Aminolevulinic Acid-Induced Fluorescence in Cerebellar Primary Central Nervous System Lymphoma: A Case Report and Literature Review.

PubMed

Yamamoto, Junkoh; Kitagawa, Takehiro; Akiba, Daisuke; Nishizawa, Shigeru

2015-01-01

5-Aminolevulinic acid (5-ALA)-induced fluorescence-guided resection is a widely used procedure for patients with malignant gliomas. However, the clinical application of 5-ALA for surgery in primary central nervous system lymphoma (PCNSL) is uncommon. Here, we present a case of PCNSL treated using 5-ALA-induced fluorescence-guided resective surgery. A 70-year-old woman presented with cerebellar ataxia, and magnetic resonance imaging revealed an irregularly shaped and homogenously enhanced mass with surrounding brain edema in the vermis that extended to the right hemisphere of the cerebellum. Under the preoperative diagnosis of a malignant glioma in the cerebellum, the patient underwent 5-ALA-induced fluorescence-guided surgery. Under blue light illumination, the tumor revealed strong 5-ALA-induced fluorescence. The tumor was identified as a diffuse large B-cell lymphoma. After partial resection, the patient received adjuvant chemotherapy and radiotherapy. Importantly, the neurological deficit of the patient improved, and recurrence of the tumor was not observed 21 months post-surgery. Together with previous reports, this case study emphasizes the efficacy of the surgical application of 5-ALA for PCNSL.

Malignant Brain Tumours in Children : Present and Future Perspectives.

PubMed

Rutka, James T

2018-05-01

In contrast to many of the malignant tumors that occur in the central nervous system in adults, the management, responses to therapy, and future perspectives of children with malignant lesions of the brain hold considerable promise. Within the past 5 years, remarkable progress has been made with our understanding of the basic biology of the molecular genetics of several pediatric malignant brain tumors including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumour, and high grade glioma/diffuse intrinsic pontine glioma. The recent literature in pediatric neuro-oncology was reviewed, and a summary of the major findings are presented. Meaningful sub-classifications of these tumors have arisen, placing children into discrete categories of disease with requirements for targeted therapy. While the mainstay of therapy these past 30 years has been a combination of central nervous system irradiation and conventional chemotherapy, now with the advent of high resolution genetic mapping, targeted therapies have emerged, and less emphasis is being placed on craniospinal irradiation. In this article, the present and future perspective of pediatric brain malignancy are reviewed in detail. The progress that has been made offers significant hope for the future for patients with these tumours.

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

PubMed Central

2013-01-01

Background Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. Methods The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. Results The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Conclusions Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma. PMID:23915425

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

PubMed Central

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

2016-01-01

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

Toenail selenium, genetic variation in selenoenzymes and risk and outcome in glioma.

PubMed

Peeri, Noah C; Creed, Jordan H; Anic, Gabriella M; Thompson, Reid C; Olson, Jeffrey J; LaRocca, Renato V; Chowdhary, Sajeel A; Brockman, John D; Gerke, Travis A; Nabors, L Burton; Egan, Kathleen M

2018-05-16

Selenium is an essential trace element obtained through diet that plays a critical role in DNA synthesis and protection from oxidative damage. Selenium intake and polymorphisms in selenoproteins have been linked to the risk of certain cancers though data for glioma are sparse. In a case-control study of glioma, we examined the associations of selenium in toenails and genetic variants in the selenoenzyme pathway with the risk of glioma and patient survival. A total of 423 genetic variants in 29 candidate genes in the selenoenzyme pathway were studied in 1547 glioma cases and 1014 healthy controls. Genetic associations were also examined in the UK Biobank cohort comprised of 313,868 persons with 322 incident glioma cases. Toenail selenium was measured in a subcohort of 300 glioma cases and 300 age-matched controls from the case-control study. None of the 423 variants studied were consistently associated with glioma risk in the case-control and cohort studies. Moreover, toenail selenium in the case-control study had no significant association with glioma risk (p trend = 0.70) or patient survival among 254 patients with high grade tumors (p trend = 0.70). The present study offers no support for the hypothesis that selenium plays a role in the onset of glioma or patient outcome. Copyright © 2018 Elsevier Ltd. All rights reserved.

MiR-188 Inhibits Glioma Cell Proliferation and Cell Cycle Progression through Targeting ß-catenin.

PubMed

Li, Nan; Shi, Hangyu; Zhang, Lu; Li, Xu; Gao, Lu; Zhang, Gang; Shi, Yongqiang; Guo, Shiwen

2017-12-21

MicroRNAs (miRNAs) play important roles in several human cancers. Although miR188 has been suggested to function as a tumor repressor in cancers, its precise role in glioma and the molecular mechanism remain unknown. In the present study, we investigated the effect of miR-188 on glioma and explored its relevant mechanisms. We found that the expression of miR-188 is dramatically downregulated in glioma tissues and cell lines. Subsequent investigation revealed that miR-188 expression was inversely correlated with ß-catenin expression in glioma tissue samples. Using a luciferase reporter assay, ß-catenin was determined to be a direct target of miR-188. Overexpression of miR-188 reduced ß-catenin expression at both the mRNA and protein levels, and inhibition of miR-188 increased ß-catenin expression. Moreover, we found that overexpression of miR-188 suppressed glioma cell proliferation and cell cycle G1-S transition, whereas inhibition of miR-188 promoted glioma cell proliferation. Importantly, silencing ß-catenin recapitulated the cellular and molecular effects seen upon miR-188 overexpression, which included inhibiting glioma cell proliferation and G1-S transition. Taken together, our results demonstrated that miR188 inhibits glioma cell proliferation by targeting ß-catenin, representing an effective therapeutic strategy for glioma.

MicroRNA-584-3p, a novel tumor suppressor and prognostic marker, reduces the migration and invasion of human glioma cells by targeting hypoxia-induced ROCK1

PubMed Central

Xue, Hao; Guo, Xing; Han, Xiao; Yan, Shaofeng; Zhang, Jinsen; Xu, Shugang; Li, Tong; Guo, Xiaofan; Zhang, Ping; Gao, Xiao; Liu, Qinglin; Li, Gang

2016-01-01

Here, we report that microRNA-584-3p (miR-584-3p) is up-regulated in hypoxic glioma cells and in high-grade human glioma tumors (WHO grades III–IV) relative to normoxic cells and to low-grade tumors (WHO grades I–II), respectively. The postoperative survival time was significantly prolonged in the high-grade glioma patients with high miR-584-3p expression compared with those with low miR-584-3p expression. miR-584-3p may function as a potent tumor suppressor and as a prognostic biomarker for malignant glioma. However, the molecular mechanisms underlying these properties remain poorly understood. Our mechanistic studies revealed that miR-584-3p suppressed the migration and invasion of glioma cells by disrupting hypoxia-induced stress fiber formation. Specifically, we have found that ROCK1 is a direct and functionally relevant target of miR-584-3p in glioma cells. Our results have demonstrated a tumor suppressive function of miR-584-3p in glioma, in which it inhibits the migration and invasion of tumor cells by antagonizing hypoxia-induced, ROCK1-dependent stress fiber formation. Our findings have potential implications for glioma gene therapy and suggest that miR-584-3p could represent a prognostic indicator for glioma. PMID:26715733

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

PubMed

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

2015-12-08

Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization. Copyright © 2015, American Association for the Advancement of Science.

Neuroanatomy and Physiology of Brain Dysfunction in Sepsis.

PubMed

Mazeraud, Aurelien; Pascal, Quentin; Verdonk, Franck; Heming, Nicholas; Chrétien, Fabrice; Sharshar, Tarek

2016-06-01

Sepsis-associated encephalopathy (SAE), a complication of sepsis, is often complicated by acute and long-term brain dysfunction. SAE is associated with electroencephalogram pattern changes and abnormal neuroimaging findings. The major processes involved are neuroinflammation, circulatory dysfunction, and excitotoxicity. Neuroinflammation and microcirculatory alterations are diffuse, whereas excitotoxicity might occur in more specific structures involved in the response to stress and the control of vital functions. A dysfunction of the brainstem, amygdala, and hippocampus might account for the increased mortality, psychological disorders, and cognitive impairment. This review summarizes clinical and paraclinical features of SAE and describes its mechanisms at cellular and structural levels. Copyright © 2016 Elsevier Inc. All rights reserved.

Receptor-Mediated Drug Delivery Systems Targeting to Glioma

PubMed Central

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

2015-01-01

Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications. PMID:28344260

Glioma Stem Cells and Immunotherapy for the Treatment of Malignant Gliomas

PubMed Central

Toda, Masahiro

2013-01-01

Stem cell research has led to the discovery of glioma stem cells (GSCs), and because these cells are resistant to chemotherapy and radiotherapy, analysis of their properties has been rapidly pursued for targeted treatment of malignant glioma. Recent studies have also revealed complex crosstalk between GSCs and their specialized environment (niche). Therefore, targeting not only GSCs but also their niche may be a principle for novel therapies of malignant glioma. One possible novel strategy for targeting GSCs and their niches is immunotherapy with different antitumor mechanism(s) from those of conventional therapy. Recent clinical studies of immunotherapy using peptide vaccines and antibodies have shown promising results. This review describes the recent findings related to GSCs and their niches, as well as immunotherapies for glioma, followed by discussion of immunotherapies that target GSCs for the treatment of malignant glioma. PMID:23762610

Glioma stem cells and immunotherapy for the treatment of malignant gliomas.

PubMed

Toda, Masahiro

2013-01-01

Stem cell research has led to the discovery of glioma stem cells (GSCs), and because these cells are resistant to chemotherapy and radiotherapy, analysis of their properties has been rapidly pursued for targeted treatment of malignant glioma. Recent studies have also revealed complex crosstalk between GSCs and their specialized environment (niche). Therefore, targeting not only GSCs but also their niche may be a principle for novel therapies of malignant glioma. One possible novel strategy for targeting GSCs and their niches is immunotherapy with different antitumor mechanism(s) from those of conventional therapy. Recent clinical studies of immunotherapy using peptide vaccines and antibodies have shown promising results. This review describes the recent findings related to GSCs and their niches, as well as immunotherapies for glioma, followed by discussion of immunotherapies that target GSCs for the treatment of malignant glioma.

Brainstem response patterns in deeply-sedated critically-ill patients predict 28-day mortality.

PubMed

Rohaut, Benjamin; Porcher, Raphael; Hissem, Tarik; Heming, Nicholas; Chillet, Patrick; Djedaini, Kamel; Moneger, Guy; Kandelman, Stanislas; Allary, Jeremy; Cariou, Alain; Sonneville, Romain; Polito, Andréa; Antona, Marion; Azabou, Eric; Annane, Djillali; Siami, Shidasp; Chrétien, Fabrice; Mantz, Jean; Sharshar, Tarek

2017-01-01

Deep sedation is associated with acute brain dysfunction and increased mortality. We had previously shown that early-assessed brainstem reflexes may predict outcome in deeply sedated patients. The primary objective was to determine whether patterns of brainstem reflexes might predict mortality in deeply sedated patients. The secondary objective was to generate a score predicting mortality in these patients. Observational prospective multicenter cohort study of 148 non-brain injured deeply sedated patients, defined by a Richmond Assessment sedation Scale (RASS) <-3. Brainstem reflexes and Glasgow Coma Scale were assessed within 24 hours of sedation and categorized using latent class analysis. The Full Outline Of Unresponsiveness score (FOUR) was also assessed. Primary outcome measure was 28-day mortality. A "Brainstem Responses Assessment Sedation Score" (BRASS) was generated. Two distinct sub-phenotypes referred as homogeneous and heterogeneous brainstem reactivity were identified (accounting for respectively 54.6% and 45.4% of patients). Homogeneous brainstem reactivity was characterized by preserved reactivity to nociceptive stimuli and a partial and topographically homogenous depression of brainstem reflexes. Heterogeneous brainstem reactivity was characterized by a loss of reactivity to nociceptive stimuli associated with heterogeneous brainstem reflexes depression. Heterogeneous sub-phenotype was a predictor of increased risk of 28-day mortality after adjustment to Simplified Acute Physiology Score-II (SAPS-II) and RASS (Odds Ratio [95% confidence interval] = 6.44 [2.63-15.8]; p<0.0001) or Sequential Organ Failure Assessment (SOFA) and RASS (OR [95%CI] = 5.02 [2.01-12.5]; p = 0.0005). The BRASS (and marginally the FOUR) predicted 28-day mortality (c-index [95%CI] = 0.69 [0.54-0.84] and 0.65 [0.49-0.80] respectively). In this prospective cohort study, around half of all deeply sedated critically ill patients displayed an early particular neurological sub-phenotype predicting 28-day mortality, which may reflect a dysfunction of the brainstem.

Correlation of Acute and Late Brainstem Toxicities With Dose-Volume Data for Pediatric Patients With Posterior Fossa Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nanda, Ronica H., E-mail: rhazari@emory.edu; Ganju, Rohit G.; Schreibmann, Edward

Purpose: Radiation-induced brainstem toxicity after treatment of pediatric posterior fossa malignancies is incompletely understood, especially in the era of intensity modulated radiation therapy (IMRT). The rates of, and predictive factors for, brainstem toxicity after photon RT for posterior fossa tumors were examined. Methods and Materials: After institutional review board approval, 60 pediatric patients treated at our institution for nonmetastatic infratentorial ependymoma and medulloblastoma with IMRT were included in the present analysis. Dosimetric variables, including the mean and maximum dose to the brainstem, the dose to 10% to 90% of the brainstem (in 10% increments), and the volume of the brainstemmore » receiving 40, 45, 50, and 55 Gy were recorded for each patient. Acute (onset within 3 months) and late (>3 months of RT completion) RT-induced brainstem toxicities with clinical and radiographic correlates were scored using Common Terminology Criteria for Adverse Events, version 4.0. Results: Patients aged 1.4 to 21.8 years underwent IMRT or volumetric arc therapy postoperatively to the posterior fossa or tumor bed. At a median clinical follow-up period of 2.8 years, 14 patients had developed symptomatic brainstem toxicity (crude incidence 23.3%). No correlation was found between the dosimetric variables examined and brainstem toxicity. Vascular injury or ischemia showed a strong trend toward predicting brainstem toxicity (P=.054). Patients with grade 3 to 5 brainstem toxicity had undergone treatment to significant volumes of the posterior fossa. Conclusion: The results of the present series demonstrate a low, but not negligible, risk of brainstem radiation necrosis for pediatric patients with posterior fossa malignancies treated with IMRT. No specific dose-volume correlations were identified; however, modern treatment volumes might help limit the incidence of severe toxicity. Additional work investigating inherent biologic sensitivity might also provide further insight into this clinical problem.« less

The link between diffusion MRI and tumor heterogeneity: Mapping cell eccentricity and density by diffusional variance decomposition (DIVIDE).

PubMed

Szczepankiewicz, Filip; van Westen, Danielle; Englund, Elisabet; Westin, Carl-Fredrik; Ståhlberg, Freddy; Lätt, Jimmy; Sundgren, Pia C; Nilsson, Markus

2016-11-15

The structural heterogeneity of tumor tissue can be probed by diffusion MRI (dMRI) in terms of the variance of apparent diffusivities within a voxel. However, the link between the diffusional variance and the tissue heterogeneity is not well-established. To investigate this link we test the hypothesis that diffusional variance, caused by microscopic anisotropy and isotropic heterogeneity, is associated with variable cell eccentricity and cell density in brain tumors. We performed dMRI using a novel encoding scheme for diffusional variance decomposition (DIVIDE) in 7 meningiomas and 8 gliomas prior to surgery. The diffusional variance was quantified from dMRI in terms of the total mean kurtosis (MK T ), and DIVIDE was used to decompose MK T into components caused by microscopic anisotropy (MK A ) and isotropic heterogeneity (MK I ). Diffusion anisotropy was evaluated in terms of the fractional anisotropy (FA) and microscopic fractional anisotropy (μFA). Quantitative microscopy was performed on the excised tumor tissue, where structural anisotropy and cell density were quantified by structure tensor analysis and cell nuclei segmentation, respectively. In order to validate the DIVIDE parameters they were correlated to the corresponding parameters derived from microscopy. We found an excellent agreement between the DIVIDE parameters and corresponding microscopy parameters; MK A correlated with cell eccentricity (r=0.95, p<10 -7 ) and MK I with the cell density variance (r=0.83, p<10 -3 ). The diffusion anisotropy correlated with structure tensor anisotropy on the voxel-scale (FA, r=0.80, p<10 -3 ) and microscopic scale (μFA, r=0.93, p<10 -6 ). A multiple regression analysis showed that the conventional MK T parameter reflects both variable cell eccentricity and cell density, and therefore lacks specificity in terms of microstructure characteristics. However, specificity was obtained by decomposing the two contributions; MK A was associated only to cell eccentricity, and MK I only to cell density variance. The variance in meningiomas was caused primarily by microscopic anisotropy (mean±s.d.) MK A =1.11±0.33 vs MK I =0.44±0.20 (p<10 -3 ), whereas in the gliomas, it was mostly caused by isotropic heterogeneity MK I =0.57±0.30 vs MK A =0.26±0.11 (p<0.05). In conclusion, DIVIDE allows non-invasive mapping of parameters that reflect variable cell eccentricity and density. These results constitute convincing evidence that a link exists between specific aspects of tissue heterogeneity and parameters from dMRI. Decomposing effects of microscopic anisotropy and isotropic heterogeneity facilitates an improved interpretation of tumor heterogeneity as well as diffusion anisotropy on both the microscopic and macroscopic scale. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

TGF-β promotes glioma cell growth via activating Nodal expression through Smad and ERK1/2 pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Jing; Liu, Su-zhi; Lin, Yan

Highlights: •TGF-β promoted Nodal expression in glioma cells. •TGF-β promoted Nodal expression via activating Smad and ERK1/2 pathways. •TGF-β promotes glioma cell growth via activating Nodal expression. -- Abstract: While there were certain studies focusing on the mechanism of TGF-β promoting the growth of glioma cells, the present work revealed another novel mechanism that TGF-β may promote glioma cell growth via enhancing Nodal expression. Our results showed that Nodal expression was significantly upregulated in glioma cells when TGF-β was added, whereas the TGF-β-induced Nodal expression was evidently inhibited by transfection Smad2 or Smad3 siRNAs, and the suppression was especially significantmore » when the Smad3 was downregulated. Another, the attenuation of TGF-β-induced Nodal expression was observed with blockade of the ERK1/2 pathway also. Further detection of the proliferation, apoptosis, and invasion of glioma cells indicated that Nodal overexpression promoted the proliferation and invasion of tumor cells and inhibited their apoptosis, resembling the effect of TGF-β addition. Downregulation of Nodal expression via transfection Nodal-specific siRNA in the presence of TGF-β weakened the promoting effect of the latter on glioma cells growth, and transfecting Nodal siRNA alone in the absence of exogenous TGF-β more profoundly inhibited the growth of glioma cells. These results demonstrated that while both TGF-β and Nodal promoted glioma cells growth, the former might exert such effect by enhancing Nodal expression, which may form a new target for glioma therapy.« less

Analysis of expression and prognostic significance of vimentin and the response to temozolomide in glioma patients.

PubMed

Lin, Lin; Wang, Guangzhi; Ming, Jianguang; Meng, Xiangqi; Han, Bo; Sun, Bo; Cai, Jinquan; Jiang, Chuanlu

2016-11-01

Gliomas are the most common primary intracranial malignant tumors in adults. Surgical resection followed by optional radiotherapy and chemotherapy is the current standard therapy for glioma patients. Vimentin, a protein of intermediate filament family, could maintain the cellular integrity and participate in several cell signal pathways to modulate the motility and invasion of cancer cells. The purpose of the present research was to identify the relationship between vimentin expression and clinical characteristics and detect the prognostic and predictive ability of vimentin in patients with glioma. To determine the expression of vimentin in glioma tissues, paraffin-embedded blocks from glioma patients by surgical resection were obtained and evaluated by immunohistochemistry. To further investigate the association of vimentin expression with survival, we employed mRNA expression of vimentin genes from the Chinese Glioma Genome Atlas (CGGA) and the GSE 16011 dataset. Kaplan-Meier analysis and Cox regression model were used to statistical analysis. We detected positive vimentin straining in 84 % of high-grade compared to 47 % in low-grade glioma patients. Additionally, vimentin mRNA expression was correlated with glioma grade in both CGGA and GSE16011 dataset. Patients with low vimentin expression have longer survival than high expression. In multivariate analysis, vimentin was an independent significant prognostic factor for high-grade glioma patients. We also identified that glioblastoma patients with low vimentin expression had a better response to temozolomide therapy. Vimentin expression has a significant association with tumor grade and overall survival of high-grade glioma patients. Low vimentin expression may benefit from temozolomide therapy.

Magnetoliposomes Loaded with Poly-Unsaturated Fatty Acids as Novel Theranostic Anti-Inflammatory Formulations

PubMed Central

Calle, Daniel; Negri, Viviana; Ballesteros, Paloma; Cerdán, Sebastián

2015-01-01

We describe the preparation, physico-chemical characterization and anti-inflammatory properties of liposomes containing the superparamagnetic nanoparticle Nanotex, the fluorescent dye Rhodamine-100 and omega-3 polyunsaturated fatty acid ethyl ester (ω-3 PUFA-EE), as theranostic anti-inflammatory agents. Liposomes were prepared after drying chloroform suspensions of egg phosphatidylcholine, hydration of the lipid film with aqueous phases containing or not Nanotex, Rhodamine-100 dye or ω-3 PUFA-EE, and eleven extrusion steps through nanometric membrane filters. This resulted in uniform preparations of liposomes of approximately 200 nm diameter. Extraliposomal contents were removed from the preparation by gel filtration chromatography. High Resolution Magic Angle Spinning 1H NMR Spectroscopy of the liposomal preparations containing ω-3 PUFA-EE revealed well resolved 1H resonances from highly mobile ω-3 PUFA-EE, suggesting the formation of very small (ca. 10 nm) ω-3 PUFA-EE nanogoticules, tumbling fast in the NMR timescale. Chloroform extraction of the liposomal preparations revealed additionally the incorporation of ω-3 PUFA-EE within the membrane domain. Water diffusion weighted spectra, indicated that the goticules of ω-3 PUFA-EE or its insertion in the membrane did not affect the average translational diffusion coefficient of water, suggesting an intraliposomal localization, that was confirmed by ultrafiltration. The therapeutic efficacy of these preparations was tested in two different models of inflammatory disease as inflammatory colitis or the inflammatory component associated to glioma development. Results indicate that the magnetoliposomes loaded with ω-3 PUFA-EE allowed MRI visualization in vivo and improved the outcome of inflammatory disease in both animal models, decreasing significantly colonic inflammation and delaying, or even reversing, glioma development. Together, our results indicate that magnetoliposomes loaded with ω-3 PUFA-EE may become useful anti-inflammatory agents for image guided drug delivery. PMID:25767616

Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma

PubMed Central

Philippe, Cathy; Paulsson, Janna; Andreiuolo, Felipe; Guerrini-Rousseau, Léa; Cornilleau, Gaétan; Le Dret, Ludivine; Richon, Catherine; Lacroix, Ludovic; Puget, Stéphanie; Geoerger, Birgit; Vassal, Gilles; Östman, Arne; Grill, Jacques

2015-01-01

Abstract Background Platelet-derived growth factor receptor A is altered by amplification and/or mutation in diffuse intrinsic pontine glioma (DIPG). We explored in vitro on new DIPG models the efficacy of dasatinib, a multi-tyrosine kinase inhibitor targeting this receptor. Methods Gene expression profiles were generated from 41 DIPGs biopsied at diagnosis and compared with the signature associated with sensitivity/resistance to dasatinib. A panel of 12 new DIPG cell lines were established from biopsy at diagnosis, serially passaged, and characterized by gene expression analyses. Effects of dasatinib (1–10 μM) on proliferation, invasion, and cytotoxicity were determined on 4 of these cell lines using live-cell imaging and flow cytometry assays. Downstream signaling and receptor tyrosine kinases (RTKs) were assessed by western blot and phospho-RTK array. The effect of the combination with the c-Met inhibitor cabozantinib was studied on cellular growth and invasion analyzed by the Chou–Talaly method. Results DIPG primary tumors and cell lines exhibited the gene expression signature of sensitivity to dasatinib. Dasatinib reduced proliferation (half-maximal inhibitory concentration = 10–100 nM) and invasion (30%–60% reduction) at 100 nM in 4/4 cultures and induced apoptosis in 1 of 4 DIPG cell lines. Activity of downstream effectors of dasatinib targets including activin receptor 1 was strongly reduced. Since multiple RTKs were activated simultaneously in DIPG cell lines, including c-Met, which can be also amplified in DIPG, the benefit of the combination of dasatinib with cabozantinib was explored for its synergistic effects on proliferation and migration/invasion in these cell lines. Conclusion Dasatinib exhibits antitumor effects in vitro that could be increased by the combination with another RTK inhibitor targeting c-Met. PMID:25534822

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janssens, Geert O., E-mail: g.janssens@rther.umcn.nl; Jansen, Marc H.; Lauwers, Selmer J.

2013-02-01

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

A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume

PubMed Central

Singh, Ranjodh; Zhou, Zhiping; Tisnado, Jamie; Haque, Sofia; Peck, Kyung K.; Young, Robert J.; Tsiouris, Apostolos John; Thakur, Sunitha B.; Souweidane, Mark M.

2017-01-01

OBJECTIVE Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important. The aims of the current study were to 1) measure DIPG volumes using methods that require different degrees of subjective judgment; and 2) evaluate interobserver agreement of measurements made using these methods. METHODS Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post–radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin’s concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement. CONCLUSIONS The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods high-lighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interob-server agreement and produced tumor volumes with delineated borders. PMID:27391980

A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.

PubMed

Macy, Margaret E; Kieran, Mark W; Chi, Susan N; Cohen, Kenneth J; MacDonald, Tobey J; Smith, Amy A; Etzl, Michael M; Kuei, Michele C; Donson, Andrew M; Gore, Lia; DiRenzo, Jennifer; Trippett, Tanya M; Ostrovnaya, Irina; Narendran, Aru; Foreman, Nicholas K; Dunkel, Ira J

2017-11-01

Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population. © 2017 Wiley Periodicals, Inc.

Dynamic imaging response following radiation therapy predicts long-term outcomes for diffuse low-grade gliomas.

PubMed

Pallud, Johan; Llitjos, Jean-François; Dhermain, Frédéric; Varlet, Pascale; Dezamis, Edouard; Devaux, Bertrand; Souillard-Scémama, Raphaëlle; Sanai, Nader; Koziak, Maria; Page, Philippe; Schlienger, Michel; Daumas-Duport, Catherine; Meder, Jean-François; Oppenheim, Catherine; Roux, François-Xavier

2012-04-01

Quantitative imaging assessment of radiation therapy (RT) for diffuse low-grade gliomas (DLGG) by measuring the velocity of diametric expansion (VDE) over time has never been studied. We assessed the VDE changes following RT and determined whether this parameter can serve as a prognostic factor. We reviewed a consecutive series of 33 adults with supratentorial DLGG treated with first-line RT with available imaging follow-up (median follow-up, 103 months). Before RT, all patients presented with a spontaneous tumor volume increase (positive VDE, mean 5.9 mm/year). After RT, all patients demonstrated a tumor volume decrease (negative VDE, mean, -16.7 mm/year) during a mean 49-month duration. In univariate analysis, initial tumor volume (>100 cm(3)), lack of IDH1 expression, p53 expression, high proliferation index, and fast post-RT tumor volume decrease (VDE at -10 mm/year or faster, fast responders) were associated with a significantly shorter overall survival (OS). The median OS was significantly longer (120.8 months) for slow responders (post-RT VDE slower than -10.0 mm/year) than for fast responders (47.9 months). In multivariate analysis, fast responders, larger initial tumor volume, lack of IDH1 expression, and p53 expression were independent poor prognostic factors for OS. A high proliferation index was significantly more frequent in the fast responder subgroup than in the slow responder subgroup. We conclude that the pattern of post-RT VDE changes is an independent prognostic factor for DLGG and offers a quantitative parameter to predict long-term outcomes. We propose to monitor individually the post-RT VDE changes using MRI follow-up, with particular attention to fast responders.

Dynamic imaging response following radiation therapy predicts long-term outcomes for diffuse low-grade gliomas

PubMed Central

Pallud, Johan; Llitjos, Jean-François; Dhermain, Frédéric; Varlet, Pascale; Dezamis, Edouard; Devaux, Bertrand; Souillard-Scémama, Raphaëlle; Sanai, Nader; Koziak, Maria; Page, Philippe; Schlienger, Michel; Daumas-Duport, Catherine; Meder, Jean-François; Oppenheim, Catherine; Roux, François-Xavier

2012-01-01

Quantitative imaging assessment of radiation therapy (RT) for diffuse low-grade gliomas (DLGG) by measuring the velocity of diametric expansion (VDE) over time has never been studied. We assessed the VDE changes following RT and determined whether this parameter can serve as a prognostic factor. We reviewed a consecutive series of 33 adults with supratentorial DLGG treated with first-line RT with available imaging follow-up (median follow-up, 103 months). Before RT, all patients presented with a spontaneous tumor volume increase (positive VDE, mean 5.9 mm/year). After RT, all patients demonstrated a tumor volume decrease (negative VDE, mean, −16.7 mm/year) during a mean 49-month duration. In univariate analysis, initial tumor volume (>100 cm3), lack of IDH1 expression, p53 expression, high proliferation index, and fast post-RT tumor volume decrease (VDE at −10 mm/year or faster, fast responders) were associated with a significantly shorter overall survival (OS). The median OS was significantly longer (120.8 months) for slow responders (post-RT VDE slower than −10.0 mm/year) than for fast responders (47.9 months). In multivariate analysis, fast responders, larger initial tumor volume, lack of IDH1 expression, and p53 expression were independent poor prognostic factors for OS. A high proliferation index was significantly more frequent in the fast responder subgroup than in the slow responder subgroup. We conclude that the pattern of post-RT VDE changes is an independent prognostic factor for DLGG and offers a quantitative parameter to predict long-term outcomes. We propose to monitor individually the post-RT VDE changes using MRI follow-up, with particular attention to fast responders. PMID:22416109

External validation of the diffuse intrinsic pontine glioma survival prediction model: a collaborative report from the International DIPG Registry and the SIOPE DIPG Registry.

PubMed

Veldhuijzen van Zanten, Sophie E M; Lane, Adam; Heymans, Martijn W; Baugh, Joshua; Chaney, Brooklyn; Hoffman, Lindsey M; Doughman, Renee; Jansen, Marc H A; Sanchez, Esther; Vandertop, William P; Kaspers, Gertjan J L; van Vuurden, Dannis G; Fouladi, Maryam; Jones, Blaise V; Leach, James

2017-08-01

We aimed to perform external validation of the recently developed survival prediction model for diffuse intrinsic pontine glioma (DIPG), and discuss its utility. The DIPG survival prediction model was developed in a cohort of patients from the Netherlands, United Kingdom and Germany, registered in the SIOPE DIPG Registry, and includes age <3 years, longer symptom duration and receipt of chemotherapy as favorable predictors, and presence of ring-enhancement on MRI as unfavorable predictor. Model performance was evaluated by analyzing the discrimination and calibration abilities. External validation was performed using an unselected cohort from the International DIPG Registry, including patients from United States, Canada, Australia and New Zealand. Basic comparison with the results of the original study was performed using descriptive statistics, and univariate- and multivariable regression analyses in the validation cohort. External validation was assessed following a variety of analyses described previously. Baseline patient characteristics and results from the regression analyses were largely comparable. Kaplan-Meier curves of the validation cohort reproduced separated groups of standard (n = 39), intermediate (n = 125), and high-risk (n = 78) patients. This discriminative ability was confirmed by similar values for the hazard ratios across these risk groups. The calibration curve in the validation cohort showed a symmetric underestimation of the predicted survival probabilities. In this external validation study, we demonstrate that the DIPG survival prediction model has acceptable cross-cohort calibration and is able to discriminate patients with short, average, and increased survival. We discuss how this clinico-radiological model may serve a useful role in current clinical practice.

PD-1 (PDCD1) Promoter Methylation Is a Prognostic Factor in Patients With Diffuse Lower-Grade Gliomas Harboring Isocitrate Dehydrogenase (IDH) Mutations.

PubMed

Röver, Lea Kristin; Gevensleben, Heidrun; Dietrich, Jörn; Bootz, Friedrich; Landsberg, Jennifer; Goltz, Diane; Dietrich, Dimo

2018-02-01

Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas. PD-L1, PD-L2, and CTLA-4 mRNA expression levels showed a significant inverse correlation with promoter methylation (PD-L1: p=0.005; PD-L2: p<0.001; CTLA-4: p<0.001). Furthermore, immune checkpoint methylation was significantly associated with age (PD-L2: p=0.003; PD-1: p=0.015), molecular alterations, i.e. MGMT methylation (PD-L1: p<0.001; PD-L2: p<0.001), ATRX mutations (PD-L2: p<0.001, PD-1: p=0.001), and TERT mutations (PD-L1: p=0.035, PD-L2: p<0.001, PD-1: p<0.001, CTLA4: p<0.001) as well as methylation subgroups and immune cell infiltrates. In multivariate Cox proportional hazard analysis, PD-1 methylation qualified as strong prognostic factor (HR=0.51 [0.34-0.76], p=0.001). Our findings suggest an epigenetic regulation of immune checkpoint genes via DNA methylation in LGG. PD-1 methylation may assist the identification of patients that might benefit from an alternative treatment, particularly in the context of emerging immunotherapies. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

ED-11DEMOGRAPHIC, CLINICAL AND SURVIVAL FEATURES OF CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS IN ISTANBUL UNIVERSITY, ONCOLOGY INSTITUTE DURING 22 YEARS (1990-2012)

PubMed Central

Kebudi, Rejin; Darendeliler, Emin; Gorgun, Omer; Agaoglu, Fulya Yaman; Uludag, Dilek; Ayan, Inci

2014-01-01

OBJECTIVES: The aim of this study is to identify demographic, clinical and survival features of childhood central nervous system (CNS) tumors admitted to Istanbul University, Oncology Institute, Pediatric Hematology-Oncology in 22 years. METHODS: Charts of patients <19 years admitted were evaluated retrospectively. (Istanbul University Cerrahpasa Medical Faculty Clinical Trials, Ethics Committee no. 83045809-3507). RESULTS: CNS tumors (n = 494) comprised 20,5 % of the 2413 children with cancer, diagnosed between 1990-2012. Male/female:1,25. Median age was 6,5 years (0.13-18yrs). 51 patients had NF1, 4 had tuberosclerosis. Distrubution according to histopathology/diagnosis was as follows: 35 % (n = 173) Medulloblastoma and other embryonal tumors, 17% (n = 84) astrocytoma other than optic gliomas, 16,5% (n = 82) ependymoma and choroid plexus tumors, 14% (n = 69) optic glioma, and 12,8% (n = 63) diffuse pontine gliomas. 5-yrs and 10-yrs overall survival (OS) in the whole group were 61% and 55,4% respectively. 29,6 % of the patients had metastasis in the CSF and/or the spinal axis and/or gross residual tumor, these had 5-yrs and 10-yrs OS of 36,5% and 27,2 %, whereas the rest had 5-yrs and 10-yrs OS are 73% and 68,9% (p < 0,001). Medulloblastoma and other embryonal tumors had 5-yrs and 10-yrs OS 58,4% and 57,5% . Ependymoma and choroid plexus carcinomas had 5-yrs and 10-yrs OS of 48,4% and 31,4%. Low grade and high grade astrocytomas had 10-yrs OS of 95 % and 40% respectively (p < 0,001). Second tumors were diagnosed in two medulloblastoma patients, one malignant nerve sheath tumor at 9 years, a case with concurrent high glade glioma and mediastinal lymphoblastic lymphoma at 3,5 years. CONCLUSIONS: The most common solid tumor in our cohort, similar to developed countries, was CNS tumors. Embryonal tumors comprised the majority of the CNS tumors treated in our institution. 5 year survival was 61 %. These children should be followed up for late effects including second tumors.

[An evaluation of clinical characteristics and prognosis of brain-stem infarction in diabetics].

PubMed

Lu, Zheng-qi; Li, Hai-yan; Hu, Xue-qiang; Zhang, Bing-jun

2011-01-01

To analyze the relationship between diabetics and the onset, clinical outcomes and prognosis of brainstem infarction, and to evaluate the impact of diabetes on brainstem infarction. Compare 172 cases of acute brainstem infarction in patients with or without diabetes. Analyze the associated risk factors of patients with brain-stem infarction in diabetics by multi-variate logistic regression analysis. Compare the National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin scale (mRS) Score, pathogenetic condition and the outcome of the two groups in different times. The systolic blood pressure (SBP), TG, LDL-C, apolipoprotein B (Apo B), glutamyl transpeptidase (γ-GT), fibrinogen (Fb), fasting blood glucose (FPG) and glycosylated hemoglobin(HbA1c)in diabetic group were higher than those in non-diabetic group, which was statistically significant (P < 0.05). From multi-variate logistic regression analysis, γ-GT, Apo B and FPG were the risk predictors of diabetes with brainstem infarction(OR = 1.017, 4.667 and 3.173, respectively), while HDL-C was protective (OR = 0.288). HbA1c was a risk predictor of severity for acute brainstem infarction (OR = 1.299), while Apo A was beneficial (OR = 0.212). Compared with brain-stem infarction in non-diabetic group, NIHSS score and intensive care therapy of diabetic groups on the admission had no statistically significance, while the NIHSS score on discharge and the outcome at 6 months' of follow-up were statistically significant. Diabetes is closely associated with brainstem infarction. Brainstem infarction with diabetes cause more rapid progression, poorer prognosis, higher rates of mortality as well as disability and higher recurrence rate of cerebral infarction.

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

Brainstem Auditory Evoked Potential in HIV-Positive Adults.

PubMed

Matas, Carla Gentile; Samelli, Alessandra Giannella; Angrisani, Rosanna Giaffredo; Magliaro, Fernanda Cristina Leite; Segurado, Aluísio C

2015-10-20

To characterize the findings of brainstem auditory evoked potential in HIV-positive individuals exposed and not exposed to antiretroviral treatment. This research was a cross-sectional, observational, and descriptive study. Forty-five HIV-positive individuals (18 not exposed and 27 exposed to the antiretroviral treatment - research groups I and II, respectively - and 30 control group individuals) were assessed through brainstem auditory evoked potential. There were no significant between-group differences regarding wave latencies. A higher percentage of altered brainstem auditory evoked potential was observed in the HIV-positive groups when compared to the control group. The most common alteration was in the low brainstem. HIV-positive individuals have a higher percentage of altered brainstem auditory evoked potential that suggests central auditory pathway impairment when compared to HIV-negative individuals. There was no significant difference between individuals exposed and not exposed to antiretroviral treatment.

Earlier Detection of Tumor Treatment Response Using Magnetic Resonance Diffusion Imaging with Oscillating Gradients

PubMed Central

Colvin, Daniel C.; Loveless, Mary E.; Does, Mark D.; Yue, Zou; Yankeelov, Thomas E.; Gore, John C.

2011-01-01

An improved method for detecting early changes in tumors in response to treatment, based on a modification of diffusion-weighted magnetic resonance imaging, has been demonstrated in an animal model. Early detection of therapeutic response in tumors is important both clinically and in pre-clinical assessments of novel treatments. Non-invasive imaging methods that can detect and assess tumor response early in the course of treatment, and before frank changes in tumor morphology are evident, are of considerable interest as potential biomarkers of treatment efficacy. Diffusion-weighted magnetic resonance imaging is sensitive to changes in water diffusion rates in tissues that result from structural variations in the local cellular environment, but conventional methods mainly reflect changes in tissue cellularity and do not convey information specific to micro-structural variations at sub-cellular scales. We implemented a modified imaging technique using oscillating gradients of the magnetic field for evaluating water diffusion rates over very short spatial scales that are more specific for detecting changes in intracellular structure that may precede changes in cellularity. Results from a study of orthotopic 9L gliomas in rat brains indicate that this method can detect changes as early as 24 hours following treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), when conventional approaches do not find significant effects. These studies suggest that diffusion imaging using oscillating gradients may be used to obtain an earlier indication of treatment efficacy than previous magnetic resonance imaging methods. PMID:21190804