Cases Of High-grade Gliomas Research Articles

OUP accepted manuscript

The authors report a case of high-grade glioma with unusual pathology that has not previously been reported in glioma pathology. The 5-year-old patient presented to the emergency department with a 1-day history of a right temporal swelling on a background history of increasing nausea and vomiting for the preceding 5 months. A computed tomography brain was performed, which showed a large right-sided temporoparietal lesion. The patient underwent surgery to remove the mass and pathology confirmed anaplastic astrocytoma (WHO Grade 3). This report focuses on prognostic factors in high-grade glioma, particularly on pathological indicators, namely epidermal growth factor receptor, O6-methylguanine-DNA-methyltransferase expression and BRAF V600D mutation.

Abstract 4623: piRNA and glioma risk: Evidence from a post-GWAS analysis of the GliomaScan Cohort

Abstract Background: Piwi-interacting RNAs (piRNAs) comprise a large but relatively understudied class of small non-coding RNAs that are transcribed from >600,000 loci and act in the silencing of transposable elements in the germline. While a single piRNA sequence may be encoded in thousands of genomic locations, our previous research has demonstrated that piRNAs of moderate copy number (100 or fewer) may also have the capacity to regulate protein-coding genes including oncogenes and/or tumor suppressors in somatic cells. The objective of this study was to explore the association of inherited variants in moderate copy-number piRNA sequences and glioma risk. Methods: Genotype data from 1,840 predominantly high grade glioma cases and 2,401 controls of European ancestry in the GliomaScan Cohort-Based GWAS were downloaded from the dbGaP database. After QC of the Illumina660-QuadV1-generated data, 550,600 SNPs were used to impute the genotypes of 2,361 piRNA SNPs with minor allele frequency ≥ 0.01 identified from a search of all 48,478 moderate copy-number piRNA sequences. Imputation was performed with IMPUTE2 using 1,000 Genomes Phase 3 haplotypes as the reference panel. Odds ratios and 95% confidence intervals for SNP-glioma risk associations were estimated using unconditional logistic regression under an additive model while controlling for gender, age, study design (case/control or cohort), and the first two principal components as estimated by EIGENSTRAT (genomic inflation λ = 1.00). An expression array covering 23,677 piRNAs was used to profile expression in seven grade IV glioma and seven normal brain specimens obtained from the Cooperative Human Tissue Network (CHTN), pooled by tissue type. Results: After exclusion of poorly-imputed SNPs, 1,384 piRNA SNPs were examined for association with glioma risk. Five SNPs were associated with glioma at FDR-adjusted P < 0.10 (rs149336947 in piR-2799, rs62435800 in piR-18913, rs147061479 in piR-598, rs142742690 in piR-11714, and rs35712968 in piR-3266). Rare variant rs149336947 in piR-2799 was most strongly associated with glioma risk, yielding an odds ratio of 2.54 (95% CI: 1.65-3.91, P = 2.34 × 10-5, significant after Bonferroni correction). The potential functional role of this SNP is supported by the finding that piR-2799 was expressed in both grade IV glioma and normal brain specimens (piR-18913, piR-598, and piR-11714 were also expressed; piR-3266 was not included on the array). Intriguingly, rs149336947 is located in a region encoding both piR-2799 and an alternative exon of CASP8 and FADD-like apoptosis regulator (CFLAR), however the functional interrelatedness of these genetic elements in glioma has yet to be elucidated. Conclusions: Together, these results draw a novel link between inherited piRNA variants and the risk of glioma development. Functional analyses are ongoing to specify the biological mechanisms underlying the observed associations. Citation Format: Daniel I. Jacobs, Michael C. Lerro, Alan Fu, Qin Qin, Andrew T. DeWan, Robert Dubrow, Elizabeth B. Claus, Yong Zhu. piRNA and glioma risk: Evidence from a post-GWAS analysis of the GliomaScan Cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4623. doi:10.1158/1538-7445.AM2015-4623

Diagnostic significance of intraoperative ultrasound contrast in evaluating the resection degree of brain glioma by transmission electron microscopic examination.

Background:Contrast-enhanced ultrasound is a dynamic and continuous modality providing real-time view of vascularization and flow distribution patterns of different organs and tumors. In order to evaluate the diagnostic significance of intraoperative contrast-enhanced ultrasound in assessing the resection degree of brain glioma by transmission electron microscopic (TEM) examination, it is important to have specific knowledge about contrast-enhanced ultrasound.Methods:Ultrasound contrast was applied in operations of 120 cases of brain glioma, to evaluate the degree of tumor resection. Biopsy tissues were obtained the suspicious residual tumors surrounding the tumor cavity. The sensitivity and specificity of the residual tumors were determined by the intraoperative ultrasound contrast according to TEM examination results.Results:There were 44 cases of low-grade gliomas and 76 cases of high-grade gliomas. Three hundred and sixty biopsy tissues were obtained. The sensitivity of intraoperative ultrasound contrast in diagnosing the residual tumor was 62.2%, while the specificity degree of it was 92.8%. The consistency coefficient of the ultrasound contrast diagnosis and TEM examination results was 0.584 (Kappa = 0.584), which was between 0.4 and 0.6, therefore it was of medium consistency.Conclusions:Intraoperative ultrasound contrast was of a high sensitivity and specificity in evaluating the excision degree of tumor. The consistency of the residual tumor rate detected, respectively, by ultrasound contrast and TEM examination was of medium consistency. The application of intraoperative ultrasound contrast can improve the resection rate of brain glioma.

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.

Precise ex vivo histological validation of heightened cellularity and diffusion-restricted necrosis in regions of dark apparent diffusion coefficient in 7 cases of high-grade glioma.

Recent conflicting reports have found both brain tumor hypercellularity and necrosis in regions of restricted diffusion on MRI-derived apparent diffusion coefficient (ADC) images. This study precisely compares ADC and cell density voxel by voxel using postmortem human whole brain samples. Patients with meningioma were evaluated to determine a normative ADC distribution within benign fluid attenuated inversion recovery (FLAIR) T2/hyperintensity surrounding tumor. This distribution was used to calculate a minimum ADC threshold to define regions of ADC-FLAIR mismatch (AFMM), where restricted diffusion presented in conjunction with T2/FLAIR hyperintensity. Contrast-enhancing voxels were excluded from this analysis. AFMM maps were generated using imaging acquired prior to death in 7 patients with high-grade glioma who eventually donated their brains upon death. Histological samples were taken from numerous regions of abnormal FLAIR and AFMM. Each sample was computationally processed to determine cell density. Custom software was then used to downsample coregistered microscopic histology to the more coarse MRI resolution. A voxel-by-voxel evaluation comparing ADC and cellularity was then performed. An ADC threshold of 0.929 × 10(-3) mm(2)/s was calculated from meningioma-induced edema and was used to define AFMM. Regions of AFMM showed significantly greater cell density in 6 of 7 high-grade glioma cases compared with regions of hyperintense FLAIR alone (P < .0001). Two patients had small regions of diffusion-restricted necrosis that had significantly lower ADC than nearby hypercellularity. Regions of AFMM contain hypercellularity except for regions with extremely restricted diffusion, where necrosis is present.

DETECTION OF CIRCULATING TUMOR DNA IN EARLY AND LATE STAGE HUMAN MALIGNANCIES

BACKGROUND: The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. In particular we studied the plasma of 14 medulloblastoma, 13 WHO grade 2-3 glioma and 14 WHO grade IV astrocytoma cases for levels of ctDNA. METHODS: The basis of our approach is to differentiate DNA shed by normal cells from DNA derived from tumor cells. In order to distinguish the two populations of cell-free DNA, we first identify a tumor-specific alteration. We then query for that exact mutation in matching plasma from the same patient to generate a personalized tumor biomarker. Only DNA derived from the tumor will harbor the genetic alteration. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 individuals. DNA was extracted from less than 5 ml of plasma in each case. The majority of plasma samples were queried for levels of ctDNA using a high fidelity next-generation sequencing approach coined Safe-SeqS. RESULTS: We found that at least one tumor-specific mutant molecule could be identified in 75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. Approximately 40% of medulloblastoma and 10% of low or high grade glioma cases had detectable levels of ctDNA. In patients with localized non-CNS tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 colorectal cancer patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: Taken together, these data suggest that ctDNA is a sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer. For individuals with CNS neoplasms, alternate strategies may need to be developed in order to detect cell-free tumor derived DNA at levels that are clinically meaningful. ABSTRACT CATEGORY: Neuropathology & Tumor Biomarkers.

Association of single-nucleotide polymorphisms in ERCC1 and ERCC2 with glioma risk.

We conducted a case-control study to assess the role of three single-nucleotide polymorphisms (SNPs) in excision repair cross-complementation group 1 (ERCC1) and two SNPs in excision repair cross-complementation group 2 (ERCC2) on the glioma risk in a Chinese population, and investigate the gene-environmental interaction for the cancer risk. A 1:2 matched case-control study was conducted. Logistic regression analysis revealed that individuals carrying ERCC1 rs2298881 CC genotype were associated with risk of glioma when compared with AA genotype carriers. The significant associations of ERCC1 rs2298881 polymorphism with glioma susceptibility were observed in both the dominant and the recessive models. In a stratification analysis, we found that ERCC1 rs2298881 variants showed an increased association with the risk of glioma in males, ever smokers, and high-grade glioma cases. In conclusion, our study suggests that ERCC1 rs2298881 polymorphism is associated with risk of glioma in codominant, dominant, and recessive models, especially in males, smokers, and high-grade glioma cases. This finding could be useful in revealing the genetic characteristics of glioma and suggests more effective strategies for prevention and treatment.

Stroke and Stroke Mimics: A case of High-grade glioma

The clinical diagnosis of acute stroke is inaccurate approximately 10%-30% of the time, which can lead to unnecessary administration of thrombolytic therapy or delays in appropriate therapy. Rapid and accurate neuroimaging triage is essential to guide therapy and exclude mimics. Although many conditions that mimic stroke clinically have imaging appearances that can overlap acute stroke, these conditions can be differentiated in most cases by using a careful pattern-based approach. We describe a case of 67 yo male patient who had a clinic of wakeup stroke and at the first magnetic resonance image (MRI) it was found that was an acute stroke of middle cerebral artery.The patient did not improve and a second MRI revelead a two times growth of the lesion, and the MRI findings were compatible with tumor. At the surgery they found a infiltrative lesion and the anatomopathological exam showed that it was a high grade glioma.The diagnosis of ischemic stroke is often straight forward; however, the clinical diagnosis of acute stroke is inaccurate in many cases. Furthermore, many of these conditions, such as encephalitis, mass lesions, seizures, hypoglycemia, transient global amnesia (TGA),demyelinating disease, drug toxicity, and metabolic disturbances, have imaging appearances that can mimic acute or subacute infarction; however, an accurate diagnosis can often be made by using a pattern-based approach.

Number of glioma polyploid giant cancer cells (PGCCs) associated with vasculogenic mimicry formation and tumor grade in human glioma

BackgroundPolyploid giant cancer cells (PGCCs) contribute to solid tumor heterogeneity. This study investigated the relationships among PGCCs numbers, vasculogenic mimicry (VM) formation, and tumor grades in glioma.MethodsA total of 76 paraffin-embedded glioma tissue samples, including 28 cases of low grade and 48 cases of high grade gliomas, were performed with H&E and immunohistochemical staining for Ki-67 and hemoglobin. The size of PGCCs nuclei was measured by a micrometer using H&E section and defined as at least three times larger than the nuclei of regular diploid cancer cells. The number of PGCCs and different blood supply patterns were compared in different grade gliomas. Microcirculation patterns in tumors were assessed using CD31 immunohistochemical and PAS histochemical double staining. Human glioma cancer cell line C6 was injected into the chicken embryonating eggs to form xenografts, which was used to observe the PGCCs and microcirculation patterns.ResultsIn human glioma, the number of PGCCs increased with the grade of tumors (χ2 = 4.781, P = 0.015). There were three kinds of microcirculation pattern in human glioma including VM, mosaic vessel (MV) and endothelium dependent vessel. PGCCs were able to generate erythrocytes via budding to form VM. The walls of VM were positive (or negative) for PAS staining and negative for CD31 staining. There were more VM and MVs in high grade gliomas than those in low grade gliomas. The differences have statistical significances for VM (t = 3.745, P = 0.000) and MVs (t = 4.789, P = 0.000). PGCCs, VM and MVs can also be observed in C6 chicken embryonating eggs xenografts.ConclusionsThe data demonstrated presence of PGCCs, VM and MVs in glioma and PGCCs generating erythrocytes contribute the formation of VM and MVs.

Optic Radiation Fiber Tractography in Glioma Patients Based on High Angular Resolution Diffusion Imaging with Compressed Sensing Compared with Diffusion Tensor Imaging - Initial Experience

ObjectiveUp to now, fiber tractography in the clinical routine is mostly based on diffusion tensor imaging (DTI). However, there are known drawbacks in the resolution of crossing or kissing fibers and in the vicinity of a tumor or edema. These restrictions can be overcome by tractography based on High Angular Resolution Diffusion Imaging (HARDI) which in turn requires larger numbers of gradients resulting in longer acquisition times. Using compressed sensing (CS) techniques, HARDI signals can be obtained by using less non-collinear diffusion gradients, thus enabling the use of HARDI-based fiber tractography in the clinical routine.MethodsEight patients with gliomas in the temporal lobe, in proximity to the optic radiation (OR), underwent 3T MRI including a diffusion-weighted dataset with 30 gradient directions. Fiber tractography of the OR using a deterministic streamline algorithm based on DTI was compared to tractography based on reconstructed diffusion signals using HARDI+CS.ResultsHARDI+CS based tractography displayed the OR more conclusively compared to the DTI-based results in all eight cases. In particular, the potential of HARDI+CS-based tractography was observed for cases of high grade gliomas with significant peritumoral edema, larger tumor size or closer proximity of tumor and reconstructed fiber tract.ConclusionsOvercoming the problem of long acquisition times, HARDI+CS seems to be a promising basis for fiber tractography of the OR in regions of disturbed diffusion, areas of high interest in glioma surgery.

Expression of histone deacetylase 1 in astrocytomas

Objective To investigate protein levels of histone deacetylase 1 ( HDAC1 ) in low grade and high grade of astrocytomas and its correlation with clinical prognosis of astrocytomas.Methods Samples from 283 primary gliomas of WHO Ⅱ -Ⅳ and 52 recurrent lesions were evaluated.The histopathologic diagnoses were as follows:59 cases of low-grade gliomas ( grade Ⅱ) and 276 cases of high-grade gliomas (26 grade Ⅲ and 250 glioblastomas).The expression of HDAC1 was immunohistochemically analyzed and its correlation with tumor differentiation,tumor proliferation and survival was analyzed.Results Totally 59.6％ of the tumors showed HDAC1 nuclear expression,and about 19.1％ of them showed more than 50％ nuclear expression. In 6 individuals who underwent tumor relapse with increasing in WHO grade,the immunoreactivity was decreased with tumor progression in 2 cases,remained stable immunoreactivity in 3 cases,and increased in 1 case.In 20 cases who underwent tumor relapse without increasing in WHO grade,HDAC1 immunoreactivity was decreased in 4 cases,remained stable in 4 cases and increased in the rest 12 cases.HDAC1 expression showed no correlations with WHO grade,Ki-67 expression or Nestin expression,and there was no significant association between HDAC1 expression and patients' survival (P ＞ 0.05,respectively).Conclusion Our findings suggest that HDAC1 is strongly expressed in astrocytic tumors and HDAC1 expression is increased during tumor recurrence. Key words: Histone deacetylase 1; Astrocytic tumor

Prognostic Implication of Histological Oligodendroglial Tumor Component: Clinicopathological Analysis of 111 Cases of Malignant Gliomas

The favorable prognosis of high-grade oligodendroglial tumor such as glioblastoma (GBM) with oligodendroglioma component (GBMO) has been suggested; however, the studies which examine the prognostic significance of oligodendroglial tumor were limited. In this study, we performed a histopathology-based reevaluation of 111 cases of high grade gliomas according to the latest World Health Organization (WHO), and compared the clinical outcomes between oligodendroglial tumors and pure astrocytic tumors. The survival analysis revealed that the patients with high grade oligodendroglial tumor including GBMO significantly indicated better prognosis compared to the patients with high grade pure astrocytic tumors (GBM and AA, anaplastic astrocytoma) as expected, and the obtained survival curves were almost identical to those from the patients with conventional Grade III or Grade IV tumors, respectively. Moreover, if the cases of oligodendroglial tumor were histopathologically excluded, the patients with AA exhibited extremely poor prognosis which was similar to that of GBM, suggesting that the histological identification of oligodendroglial tumor component, even partially, prescribe the prognosis of high grade glioma patients. This is the prominent report of retrospective clinicopathological analysis for high-grade gliomas throughout Grade III and IV, especially referring to the prognostic value of histological oligodendroglial tumor component; in addition, our results might offer an alternative aspect for the grading of high-grade astrocytic/oligodendroglial tumors.

Coplanar versus noncoplanar intensity‐modulated radiation therapy (IMRT) and volumetric‐modulated arc therapy (VMAT) treatment planning for fronto‐temporal high‐grade glioma

The purpose of this study was to compare dosimetric and radiobiological parameters of treatment plans using coplanar and noncoplanar beam arrangements in patients with fronto‐temporal high‐grade glioma (HGG) generated for intensity‐modulated radiotherapy (IMRT) or volumetric‐modulated arc therapy (VMAT). Ten cases of HGG overlapping the optic apparatus were selected. Four separate plans were created for each case: coplanar IMRT, noncoplanar IMRT (ncIMRT), VMAT, and noncoplanar VMAT (ncVMAT). The prescription dose was 60 Gy in 30 fractions. Dose‐volume histograms and equivalent uniform doses (EUD) for planning target volumes (PTVs) and organs at risk (OARs) were generated. The four techniques resulted in comparable mean, minimum, maximum PTV doses, and PTV EUDs (p≥0.33). The mean PTV dose and EUD averaged for all techniques were 59.98 Gy (Standard Deviation (SD)±0.15) and 59.86 Gy (SD±0.27). Noncoplanar IMRT significantly reduced contralateral anterior globe EUDs (6.7 Gy versus 8.2 Gy, p=0.05), while both ncIMRT and ncVMAT reduced contralateral retina EUDs (16 Gy versus 18.8 Gy, p=0.03). Noncoplanar techniques resulted in lower contralateral temporal lobe dose (22.2 Gy versus 24.7 Gy). Compared to IMRT, VMAT techniques required fewer monitor units (755 vs. 478, p≤0.001) but longer optimization times. Treatment delivery times were 6.1 and 10.5 minutes for coplanar and ncIMRT versus 2.9 and 5.0 minutes for coplanar and ncVMAT. In this study, all techniques achieved comparable target coverage. Superior sparing of contralateral optic structures was seen with ncIMRT. The VMAT techniques reduced treatment delivery duration but prolonged plan optimization times, compared to IMRT techniques. Technique selection should be individualized, based on patient‐specific clinical and dosimetric parameters.PACS number: 87

YB-1 Bridges Neural Stem Cells and Brain Tumor–Initiating Cells via Its Roles in Differentiation and Cell Growth

The Y-box binding protein 1 (YB-1) is upregulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here, we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knockout mice had reduced Sox-2, nestin, and musashi-1 expression in the SVZ. Although primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Glial tumors often express NSC markers and tend to loose the cellular control that governs differentiation; therefore, we addressed whether YB-1 served a similar role in cancer cells. YB-1, Sox-2, musashi-1, Bmi-1, and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary brain tumor-initiating cells (BTIC). Silencing YB-1 with siRNA attenuated the expression of these NSC markers, reduced neurosphere growth, and triggered differentiation via coordinate loss of GSK3-β. Furthermore, differentiation of BTIC with 1% serum or bone morphogenetic protein-4 suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 expression increased with tumor grade (n = 49 cases). YB-1 was also coexpressed with Bmi-1 (Spearmans 0.80, P > 0.001) and Sox-2 (Spearmans 0.66, P > 0.001) based on the analysis of 282 cases of high-grade gliomas. These proteins were highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 correlatively expresses with NSC markers where it functions to promote cell growth and inhibit differentiation.

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

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

Value of susceptibilityweighted imaging in glioma classification

：Objective To study thecharacteristics of susceptibility weighted imaging (SWI) and it's role in gliomaclassfication. Methods 45 glioma patients with pathologically confirmion, underwentpreopera-tive plain MRI, enhanced MRI and SWI examination. By using double blind method,the score of T1 WI, T2WI, enhanced T1 WI, SWI and enhanced SWI were acquired to displayenhancing tumor, peritumoral edema, tumor hemorrhage and tumor vein. The tumor volume oflow signal areas was measured by using measurement software to acquire the bleeding oftumor. Results In 26 cases of high grade gliomas,18 patients with intratu-moral, multiplepatchy low signal cords in varying degrees, which were proved by pathology as tumorhemorrhage and tumor blood vessels; in 19 case of low grade gliomas, 10 cases occured afew spots, linear low signal in tumor, which were proved by pathology as tumor hemorrhage;the bleeding of high grade gliomas was higher than that of the low level group ( P <0.05 ). SWI was superior to T, WI, T2 WI on displaying tumor hemorrhage and tumorvein(P<0. 05). Conclusion Different grades of glioma show obvious different display onSWI, and SWI probably be helpful for evaluation of glioma grading preoperatively.

Follow‐up evaluation of radiation‐induced DNA damage in CSF disseminated high‐grade glioma using phospho‐histone H2AX antibody

Cytological examination of cerebrospinal fluid (CSF) is used not only for the diagnosis of spinal disease, but also to assess the postoperative effect of treatment. We experienced a case of high-grade glioma in disseminated CSF, and retrospectively examined the clinical, pathological and cytological features. We further investigated radiation-induced DNA damage in glioma cells using phospho-Histone H2AX antibody. A five-year-old boy received a clinical diagnosis of optic nerve glioma, and was followed-up for three months after chemotherapy. Magnetic resonance imaging was repeated, revealing abnormalities in other brain areas. The pathological diagnosis was anaplastic astrocytoma. CSF dissemination was detected, and increases in the number and mitosis of tumor cells were observed in CSF cytology. After radiotherapy the tumor cells in CSF decreased markedly. On cytomorphologic and immunocytochemical evaluation post-irradiation, tumor cells showed vacuolation of both the nucleus and cytoplasm, degeneration of nuclear chromatin, and alteration of the phospho-Histone H2AX expression, compared with tumor cells before the irradiation. CSF cytology is an effective means of evaluating DNA damage in tumor cells after irradiation, and may be useful in assessing the therapeutic response.

Abstract LB-101: Y-box binding protein-1 (YB-1) inhibition triggers differentiation of normal and cancer stem cells from the brain

Abstract The Y-box-binding protein-1 (YB-1) is up-regulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knock-out mice had reduced Sox-2, nestin and musashi expression in the SVZ. While primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Likewise, YB-1, Sox-2, mushashi, Bmi-1 and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary CSCs. Silencing YB-1 with small interfering RNA attenuated the expression of these NSC markers, reduced neurosphere growth and triggered differentiation via coordinate loss of GSK3-β. Further, differentiation of CSCs with 1% serum or bone morphogenetic protein-4 (BMP-4) suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 was preferentially expressed in highly undifferentiated primary gliomas based on the analysis of WHO grade 1-IV tumors (n=49 cases). YB-1 was also co-expressed with Bmi-1 (Spearmans 0.80, p&amp;gt;0.001) and Sox-2 (Spearmans 0.66, p&amp;gt;0.001) based on the analysis of 282 cases of high-grade gliomas. These CSC markers were also highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 is a key feature of stem cells where it functions to suppress differentiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-101. doi:10.1158/1538-7445.AM2011-LB-101

Pseudoprogression and Pseudoresponse: Imaging Challenges in the Assessment of Posttreatment Glioma

The current standard of care for newly diagnosed cases of high-grade glioma is surgical resection followed by RT with concurrent chemotherapy. The most widely used criteria for assessing treatment response are based on a 2D measurement of the enhancing area on MR imaging known as the Macdonald Criteria. Recently, nontumoral increases (pseudoprogression) and decreases (pseudoresponse) in enhancement have been found, and these can confuse outcome evaluation. Here we review pseudoprogression and pseudoresponse and describe how better understanding of these phenomena can aid interpretation.

Dosimetric comparison of three dimensional conformal radiotherapy and intensity modulated radiotherapy in high grade gliomas

Dosimetric comparison of three dimensional conformal radiotherapy and intensity modulated radiotherapy in high grade gliomas Treatment of high-grade gliomas continues to be frustrating for the clinician as the medial survival stands at a dismal 14.5 months for glioblastoma multiforme (GBM) with the current standard of care. Given the high dose and generous margins required to be irradiated, three dimensional conformal radiotherapy (3DCRT) has become standard practice. Radiation dose escalation beyond 60 Gy, by means of stereotactic or intensity modulated radiotherapy (IMRT) boost, has not yielded clinically significant benefits in terms of local control or survival. At the same time, the potential of IMRT to spare normal tissues such as the brain stem and the optic apparatus makes it an attractive tool for modern radiation oncologists in seeking to improve post-radiotherapy quality of life. At our centre, we have been treating a large number of cases of high grade glioma with 3DCRT and IMRT for the last several years. The present study has been an effort to understand any potential benefits that IMRT, even without dose escalation, can offer.