Brain Tumor Malignancy Research Articles

Serum lactate as a potential biomarker of malignancy in primary adult brain tumours

Lactate, a by-product of glycolysis, is an indicator of poor tissue perfusion and is a useful biomarker with prognostic value in risk-stratifying patients in several diseases. Furthermore, elevated lactate production is observed in tumour glycolysis, also known as the Warburg effect, and is essential in promoting tumour cell invasion, metastasis, and immune system evasion, promoting resistance to cell death. However, there are no studies of elevated serum lactate in brain tumour patients as a potential biomarker, to our knowledge. The aim of this study is to determine possible correlations between the malignancy of tumours and pre- and intraoperative serum lactate elevation in patients undergoing craniotomy for tumour resection. We provide initial evidence that a rise in serum lactate can be used as a non-invasive biomarker that correlates with brain tumour grade. The results from this study and future prospective studies may allow for determination of tumour progression and response to therapy using serum lactate as a biomarker.

Fast cell cycle analysis for intraoperative characterization of brain tumor margins and malignancy

Flow cytometry, although indispensable for the characterization of hematologic malignancies, has not been extensively evaluated in solid tumors. To date intraoperative pathology evaluation of frozen sections of tissue obtained during surgery is the gold standard for intraoperative diagnosis. We investigated the value of a modified rapid protocol for cell cycle analysis for the intraoperative characterization of intracranial lesions and their surgical margins. We investigated patients who underwent surgery for an intracranial lesion suspicious for a tumor. DNA analysis and frozen sections were performed on tumor samples that were taken during surgery. Thirty-one patients met the inclusion criteria for the study. There was a significant difference in G0/G1 phase between high-grade and low-grade tumors. Receiver operating characteristic (ROC) analysis provided 75% of G0/G1 fraction as the optimal cutoff value thresholding the discrimination between low and high-grade tumors. There was a significant difference in S-phase and mitoses fraction between high-grade and low-grade tumors. ROC analysis indicated 6% of S-phase and 9.7% of mitoses as the optimal cutoff values thresholding the discrimination between these two groups. In the glioblastoma patients, we also analyzed the perilesional tissue and found significant differences between tumor mass and margins regarding the G0/G1 phase, the S-phase and mitoses fraction. In conclusion rapid cell cycle analysis is a method capable of differentiating low from high-grade tumors and delineating tumor margins in gliomas. Thus, the role of cell cycle analysis in brain tumors warrants further investigation.

In vivo and ex vivo assessment of the blood brain barrier integrity in different glioblastoma animal models.

Blood brain barrier (BBB) disruption is used (pre)clinically as a measure for brain tumor malignancy and grading. During treatment it is one of the parameters followed rigorously to assess therapeutic efficacy. In animal models, both invasive and non-invasive methods are used to determine BBB disruption, among them Evans blue injection prior to sacrifice and T1-weighted magnetic resonance imaging (MRI) post contrast injection. In this study, we have assessed the BBB integrity with the methods mentioned above in two experimental high grade glioma models, namely the GL261 mouse glioblastoma model and the Hs683 human oligodendroglioma model. The GL261 model showed clear BBB integrity loss with both, contrast-enhanced (CE) MRI and Evans blue staining. In contrast, the Hs683 model only displayed BBB disruption with CE-MRI, which was not evident on Evans blue staining, indicating a limited BBB disruption. These results clearly indicate the importance of assessing the BBB integrity status using appropriate methods. Especially when using large therapeutic molecules that have difficulties crossing the BBB, care should be taken with the appropriate BBB disruption assessment studies.

USP11 regulates PML stability to control Notch-induced malignancy in brain tumours

The promyelocytic leukaemia (PML) protein controls multiple tumour suppressive functions and is downregulated in diverse types of human cancers through incompletely characterized post-translational mechanisms. Here we identify USP11 as a PML regulator by RNAi screening. USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20–Cul3 (Cullin 3)–Roc1 complex. We find that USP11 is transcriptionally repressed through a Notch/Hey1-dependent mechanism, leading to PML destabilization. In human glioma, Hey1 upregulation correlates with USP11 and PML downregulation and with high-grade malignancy. The Notch/Hey1-induced downregulation of USP11 and PML not only confers multiple malignant characteristics of aggressive glioma, including proliferation, invasiveness and tumour growth in an orthotopic mouse model, but also potentiates self-renewal, tumour-forming capacity and therapeutic resistance of patient-derived glioma-initiating cells. Our study uncovers a PML degradation mechanism through Notch/Hey1-induced repression of the PML deubiquitinase USP11 and suggests an important role for this pathway in brain tumour pathogenesis.

EDL-360: A Potential Novel Antiglioma Agent

Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for more than 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains dismal. The main focus of our research is to identify potent novel antiglioma small molecules. We previously showed that EDL-360, a tetrahydroisoquinoline (THIQ) analog, as being highly cytotoxic to human glioma cell cultures. Here we show that EDL-360 significantly induced apoptosis in human glioma cell lines (U87 and LN18). However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis. In an attempt to enhance EDL-360 induced cell death, we tested simultaneous treatment with EDL-360 and embelin (an inhibitor of the anti-apoptotic protein, XIAP). We found that, glioma cells had significant lower viability when EDL-360 and embelin were used in combination when compared to EDL-360 alone. We also used combination treatment of EDL-360 with decylubiquinone (dUb), a caspase-9 inhibitor, and found that the combination treatment induced a significant cell death when compared to treatment with EDL-360 alone. This is the first report that suggests that dUb has anticancer activity, and perhaps acts as a XIAP inhibitor. Finally, our in vivo data showed that EDL-360 treatment induced a partial regression in glioma tumorigenesis and induced cell death in the treated tumors as shown by H&E staining. Taken together these data suggests that EDL-360 has a potential therapeutic application for treating glioma, especially when combined with XIAP inhibitors.

Cardiovascular morbidity in long‐term survivors of early‐onset cancer: A population‐based study

Improvements in cancer therapy have resulted in an expanding population of early-onset cancer survivors. In contrast to childhood and adolescent cancer survivors, there is still a lack of data concerning late morbidities among young adult (YA) cancer survivors. Thus, our aim was to investigate cardiac and vascular morbidity among early-onset cancer survivors with a special interest in YA cancer survivors. In a population-based setting, we explored the risk of cardiovascular disease in early-onset cancer survivors compared to healthy siblings. Patients diagnosed with cancer below 35 years of age since 1975 were identified from the Finnish Cancer Registry, and 5-year survivors were included in our study (N = 13,860). Information on cardiovascular morbidity was collected from the national hospital discharge registry. Compared to siblings, cancer survivors aged 0-19 and 20-34 at diagnosis had significantly elevated hazard ratios (HRs) for the studied outcomes: HR 13.5 (95% CI 8.9-20.4) and 3.6 (95% CI 2.8-4.6) for cardiomyopathy/cardiac insufficiency; HR 3.4 (95% CI 2.3-5.1) and 1.7 (95% CI 1.4-2.0) for atherosclerosis/brain vascular thrombosis; HR 3.3 (95% CI 1.7-6.5) and 1.8 (95% CI 1.5-2.1) for myocardial infarction/cardiac ischemia and HR 1.7 (95% CI 1.2-2.6) and 1.4 (95% CI 1.2-1.7) for cardiac arrhythmia. In both groups, depending on the outcome, the HR for adverse events was highest among lymphoma, brain tumor, leukemia and testicular malignancy survivors. Our results regarding late effects of childhood cancer survivors confirmed previous findings. Additionally, our study provides novel information concerning the YA cancer survivor population. Hence, our data may help in planning the risk-based long-term follow-up of early-onset cancer survivors.

Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study

Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours. For the discovery cohort, we used samples obtained from patients with paediatric brain tumours and individuals with normal brain tissues stored at the German Cancer Research Center (Heidelberg, Germany). We used methylation arrays for genome-wide assessment of DNA. For the validation cohort, we used samples obtained from several tissues for which full clinical and follow-up data were available from two hospitals in Toronto (ON, Canada). We did methylation analysis using quantitative Sequenom and pyrosequencing of an identified region of the TERT promoter. We assessed TERT expression by real-time PCR. To establish whether the biomarker could be used to assess and predict progression, we analysed methylation in paired samples of tumours that transformed from low to high grade and from localised to metastatic, and in choroid plexus tumours of different grades. Finally, we investigated overall survival in patients with posterior fossa ependymomas in which the identified region was hypermethylated or not. All individuals responsible for assays were masked to the outcome of the patients. Analysis of 280 samples in the discovery cohort identified one CpG site (cg11625005) in which 78 (99%) of 79 samples from normal brain tissues and low-grade tumours were not hypermethylated, but 145 (72%) of 201 samples from malignant tumours were hypermethylated (>15% methylated; p<0.0001). Analysis of 68 samples in the validation cohort identified a subset of five CpG sites (henceforth, upstream of the transcription start site [UTSS]) that was hypermethylated in all malignant paediatric brain tumours that expressed TERT but not in normal tissues that did not express TERT (p<0.0001). UTSS had a positive predictive value of 1.00 (95% CI 0.95-1.00) and a negative predictive value of 0.95 (0.87-0.99). In two paired samples of paediatric gliomas, UTSS methylation increased during transformation from low to high grade; it also increased in two paired samples that progressed from localised to metastatic disease. Two of eight atypical papillomas that had high UTSS methylation progressed to carcinomas, while the other six assessed did not progress or require additional treatment. 5-year overall survival was 51% (95% CI 31-71) for 25 patients with hypermethylated UTSS posterior fossa ependymomas and 95% (86-100) for 20 with non-hypermethylated tumours (p=0.0008). 5-year progression-free survival was 86% (68-100) for the 25 patients with non-hypermethylated UTSS tumours and 30% (10-50) for those with hypermethylated tumours (p=0.0008). Hypermethylation of the UTSS region in the TERT promoter is associated with TERT expression in cancers. In paediatric brain tumours, UTSS hypermethylation is associated with tumour progression and poor prognosis. This region is easy to amplify, and the assay to establish hypermethylation can be done on most tissues in most clinical laboratories. Therefore the UTSS region is a potentially accessible biomarker for various cancers. The Canadian Institute of Health Research and the Terry Fox Foundation.

Hepatocyte Growth Factor Sensitizes Brain Tumors to c-MET Kinase Inhibition

The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors. We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examined factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGF receptor small-molecule kinase inhibitor. These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors.

Rho GTPases in primary brain tumor malignancy and invasion

Gliomas are the most common type of malignant primary brain tumor in humans, accounting for 80% of malignant cases. Expression and activity of Rho GTPases, which coordinate several cellular processes including cell-cycle progression and cell migration, are commonly altered in many types of primary brain tumor. Here we review the suggested effects of deregulated Rho GTPase signaling on brain tumor malignancy, highlighting the controversy in the field. For instance, whereas expression of RhoA and RhoB has been found to be significantly reduced in astrocytic tumors, other studies have reported Rho-dependent LPA-induced migration in glioma cells. Moreover, whereas the Rac1 expression level has been found to be reduced in astrocytic tumor, it was overexpressed and induced invasion in medulloblastoma tumors. In addition to the Rho GTPases themselves, several of their downstream effectors (including ROCK, mDia, and N-WASP) and upstream regulators (including GEFs, GAPs, PI3K, and PTEN) have also been implicated in primary brain tumors.

Abstract 1821: Hepatocyte growth factor sensitizes brain tumor cells and xenografts to c-Met kinase inhibition

Abstract The receptor tyrosine kinase c-Met and its ligand hepatocyte growth factor (HGF) are frequently deregulated in many cancers, including brain tumors. c-Met activation induces brain tumor malignancy and is associated with poor clinical outcome. Consequently, c-Met inhibitors have been developed by pharmaceutical companies. However, the factors that determine sensitivity to c-Met inhibitors have not been determined to date. In the present study, we systematically investigated the factor(s) that determine sensitivity of brain tumors to c-Met kinase inhibitors and thereby also uncovered a new strategy for enhancing sensitivity to the inhibitors. We investigated the effects of a clinically applicable c-Met kinase inhibitor, PF-2341066, on fifteen different medulloblastoma and glioma cells and stem cells that possess different molecular characteristics. We investigated potential correlations between the effects of PF-2341066 on cell proliferation and death and the levels of total c-Met, p-Met, HGF, PTEN and EGFR co-expression. PF-2341066 completely inhibited basal and HGF-induced c-Met activation in all cells. However, the effects of PF-2341066 on cell proliferation and cell death varied tremendously between the different cell lines. The anti-proliferative and anti-survival effects of PF-2341066 did not correlate with c-Met, phospho-Met or PTEN or EGFR expressions in the cells. However, there was a statistically significant correlation between HGF expression levels and PF-2341066-induced inhibition of cell proliferation and cell survival (p&amp;lt;0.01). Similarly, orthotopic xenografts derived from cell line with high HGF expression level were significantly stronger inhibited by oral administration of PF-2341066 to than xenografts derived from low-expressing HGF cells. Therefore, HGF co-expression is the best predictor of response to c-Met kinase inhibitors. Surprisingly, we also found that when glioma cells and stem cells are pretreated with HGF, PF-2341066 is able to induce significantly greater (34-79%) cell death than in non-pretreated cells (p&amp;lt;0.01). The optimal time of pre-activation that achieved strongest sensitization to c-Met inhibitor-induced cell death was 2-4 hours. In vivo experiments showed that short-term bolus HGF pre-treatment of glioma stem cell-derived xenografts significantly sensitized the tumors to c-Met inhibition by PF-2341066. We therefore hypothesize that short-term exogenous activation of c-Met by HGF is able to trigger fast oncogene addition and therefore sensitize brain tumors to c-Met inhibitors. Overall, our data identify for the first time HGF co-expression as the determining factor in tumor sensitivity to c-Met kinase inhibitors and uncover HGF pre-treatment as a new strategy for enhancing the effects of the inhibitors. These findings have important practical implications for the efficient use of recently developed c-Met kinase inhibitors in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1821. doi:1538-7445.AM2012-1821

Advances in optical biopsy – correlation of malignancy and cell density of primary brain tumors using Raman microspectroscopic imaging

Raman spectroscopy is a promising tool towards biopsy under vision as it provides label-free image contrast based on intrinsic vibrational spectroscopic fingerprints of the specimen. The current study applied the spectral unmixing algorithm vertex component analysis (VCA) to probe cell density and cell nuclei in Raman images of primary brain tumor tissue sections. Six Raman images were collected at 785 nm excitation that consisted of 61 by 61 spectra at a step size of 2 micrometers. After data acquisition the samples were stained with hematoxylin and eosin for comparison. VCA abundance plots coincided well with histopathological findings. Raman spectra of high grade tumor cells were found to contain more intense spectral contributions of nucleic acids than those of low grade tumor cells. Similarly, VCA endmember signatures of Raman images from high grade gliomas showed increased nucleic acid bands. Further abundance plots and endmember spectra were assigned to tissue containing proteins and lipids, and cholesterol microcrystals. Since no sample preparation is required, an important advantage of the Raman imaging methodology is that all tissue components can be observed - even those that may be lost in sample staining steps. The results demonstrate how morphology and chemical composition obtained by Raman imaging correlate with histopathology and provide complementary, diagnostically relevant information at the cellular level.

Can Dietary Antioxidants Reduce the Incidence of Brain Tumors?

The incidence of brain tumor and other types of cancer are markedly increased during the last few decades. There are many etiological and environmental factors involved in the initiation of different types of cancers including brain tumors. Mutations in tumor suppressor gene p53 and its expression are associated with shorter survival and higher mortality rate of patients with brain tumors. Another factor, N-nitrosamines have received much attention as a potential risk factor for brain tumor. These compounds are potent carcinogens and occur widely in the environment, and also can be formed endogenously in the stomach from the interaction of ingested nitrate or nitrite with secondary amines. Free radicals are another etiological factor of brain tumor and are removed by cellular antioxidants in the human body. Brain tissue is vulnerable to the damaging effects of free radicals as a result of low antioxidant levels. Interestingly, there is an inverse correlation between the total antioxidant levels and oxidative DNA damage in transitional meningioma compared with normal brain tissues. Also, an inverse relationship between antioxidant levels and grades of malignancy has been found after histopathological examination of brain tumors. Moreover, high intake of vitamin E is correlated with greater survival for all patients diagnosed as Grade III malignant glioma. Dietary supplementation with antioxidants [e.g. vitamins C & E] was found to reduce the incidence of brain tumors in children whose mothers took these vitamins throughout pregnancy. On the other hand, decreases in antioxidant levels were correlated with the severity of malignancy of brain tumors, and also with accumulation of considerable amounts of oxidative stress products including free radicals which damage this tissue. The mechanisms of protection of these antioxidants against brain tumors might be due to inhibition of the nitrosation process, decreasing of tumor necrotic factor, scavenging of free radicals, inhibition of telomerase activity which facilitates telomere attrition. It is concluded that administration of antioxidants could reduce the incidence of brain tumors and probably other types of cancer.

SP100 reduces malignancy of human glioma cells

The nuclear autoantigen SP100 (speckled protein 100) is reported to control cellular gene expression, cell growth and differentiation. To investigate its relevance in brain tumors, we investigated SP100 expression and function in human glioblastomas and meningiomas. SP100 was expressed in both tumors at the mRNA and protein levels in situ and in vitro, however, expression in meningioma samples and meningioma cells exceeded that in glioblastoma samples and cultivated cells significantly. Moreover, whereas nearly all meningioma cells were SP100-immunopositive, only part of the glioblastoma cells were SP100 stainable. In vitro, SP100 was upregulated by interferon-α and -γ in both malignant cell types. To study its functional role, SP100 was overexpressed in glioblastoma cells. This SP100 overexpression reduced considerably the glioblastoma cell proliferation and migration to fetal calf serum. We conclude that SP100 expression reduces malignancy of brain tumors. Since meningiomas show a generally higher SP100 expression, this may be one of the factors explaining their lower malignancy compared to glioblastomas.

Magnetic resonance imaging in the analysis of pediatric orbital tumors: Utility of diffusion-weighted imaging

To identify common radiographic features of pediatric orbital tumors by the use of magnetic resonance imaging (MRI) techniques, diffusion-weighted imaging (DWI), fat saturated T2, and pre- and postgadolinium T1. DWI is hypothesized to help identify and predict the malignancy of specific brain tumors. To our knowledge, a similar analysis in which the authors have used this combination of MRI techniques has not been performed with orbital tumors. We performed a retrospective chart review of all patients younger than 18 years of age, each diagnosed with an orbital mass lesion, imaged by MRI from 2005 to 2008. The MR images were analyzed by use of the aforementioned techniques. Mass lesions identified in the chart review included rhabdomyosarcoma (n = 4), myofibroma (n = 2), hemangioma (n = 4), lymphangioma (n = 2), neurofibroma (n = 4), Langerhans histiocytosis (n = 2), and one of each of the following: giant cell tumor, meningioma, lymphoid hyperplasia of the lacrimal gland (chronic sclerosing sialadenitis), optic nerve glioma, lipodermoid, and dermoid. DWI was used to differentiate tumors into those with increased diffusion, restricted diffusion, and a mixed diffusion pattern. Capillary hemangiomas and rhabdomyosarcomas 2 tumors with potentially overlapping appearances with traditional MRI techniques had contrasting appearances with DNI. DWI can help to distinguish among certain pediatric orbital tumors when combined with traditional MRI techniques. This technique may thus be considered an additional tool to help, refine the differential diagnosis of orbital tumors in children.

Abstract 3625: Exogenous short-term activation of c-Met and EGFR sensitizes them to kinase inhibitors

Abstract Activation of the c-Met and EGFR receptor tyrosine kinases induces brain tumor malignancy and is associated with poor clinical outcome of brain tumor patients. Consequently, c-Met and EGFR are promising targets for the therapy of brain tumors and clinically applicable inhibitors of these receptors have been developed by biotechnology and pharmaceutical companies. We tested the effects of a specific and potent c-Met kinase inhibitor (PF-2341066) on glioma cells and glioma stem cells. Surprisingly, we found that the inhibitor induced significantly greater cell death when c-Met was shortly pre-activated with its ligand hepatocyte growth factor (HGF). Glioblastoma cells (U87, U373), primary glioblastoma cells (GBM10) and glioblastoma stem cells (1228, 0308) were pre-treated with 20 ng/ml HGF for 2h, 4h, 6h, 8h, 16h or 24h prior to treatment with PF-2341066 (100 nM for established and primary cells and 300 nM for cancer stem cells) for 24 hr. The cells were subsequently assessed for apoptosis using annexin-V flow cytometry. The results showed that the inhibitor induced significantly greater (34-79%) absolute cell death in pre-activated cells than in non-activated cells. The optimal time of pre-activation that achieved greatest sensitization of the receptor to kinase inhibitor-induced cell death was 2-4 hours. Using a similar experimental approach, we also tested the effects of EGFR pre-activation on EGFR inhibitor erlotinib-induced cell death in glioma cells. Glioma cells were pre-treated with EGF (100ng/ml) for 3h, 6h, 16h or 24h prior to treatment with erlotinib (2.5 µM) for 24 hrs and assessment of cell death by annexin V flow cytometry. EGFR pre-activation led to significantly greater (138 %) erlotinib-induced cell death than without pre-activation. Based on the above findings, we hypothesize that short-term exogenous activation of c-Met, EGFR and possibly also other receptor tyrosine kinases can trigger fast oncogene addiction that sensitizes tumor cells to death induced by receptor tyrosine kinase inhibitors. We are currently testing this hypothesis using in vivo glioblastoma animal models. Verification of this new hypothesis would imply that quick short-term activation of tyrosine kinase receptors by bolus delivery of receptor tyrosine kinase ligands would sensitize tumors to kinase inhibitors and therefore improve the efficacy of these inhibitors in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3625.

Correlation of MIB-1 staining index and 201Tl-SPECT retention index in preoperative evaluation of malignancy of brain tumors

MIB-1 staining provides a useful index of the malignancy of brain tumors. However, because of the difficulty of evaluating malignancy based on the preoperative imaging findings, we investigated the correlation between the (201)Tl-SPECT retention index (RI) and MIB-1 staining index (MIB-1 SI) to determine the usefulness of RI for preoperative evaluation of the malignancy of brain tumors. The subjects of this study were 47 patients who underwent tumor removal surgery at our hospital in 2006 and 2007. The tumors consisted of 16 intraaxial tumors (all gliomas: 9 glioblastomas, 2 anaplastic astrocytomas, 2 anaplastic oligoastrocytomas, 1 oligodendroglioma, and 2 ependymomas), 8 other malignant brain tumors, and 23 extraaxial tumors (10 meningiomas, 7 pituitary adenomas, and 6 schwannomas). The mean RI and mean MIB-1 SI of the intraaxial tumors were 0.628% and 32.0%, respectively, and after MIB-1 SI was converted to the natural logarithm (log MIB-1 SI), Pearson's coefficient for the correlation between them was significant (r = 0.752, P < 0.001). The mean RI and mean MIB-1 SI of the extraaxial tumors were 0.377% and 3.01%, respectively, and after MIB-1 SI was converted to log MIB-1 SI, Pearson's coefficient for the correlation between them was significant (r = 0.803, P < 0.001). Thus, the MIB-1 SI values of highly malignant intraaxial tumors was strongly correlated with their RI values, and the (201)Tl-SPECT RI values were useful as an index of malignancy. RI values may also be useful for evaluating apparently benign extraaxial tumors for possible malignancy.

The experience of body image of children and adolescents with cancer: A meta-synthesis.

The experience of body image of children and adolescents with cancer: A meta-synthesis.

Non-invasive detection of glycine as a biomarker of malignancy in childhood brain tumours using in-vivo 1 H MRS at 1.5 Tesla confirmed by ex-vivo high-resolution magic-angle spinning NMR

Management of brain tumours in children would benefit from improved non-invasive diagnosis, characterisation and prognostic biomarkers. Metabolite profiles derived from in-vivo MRS have been shown to provide such information. Studies indicate that using optimum a priori information on metabolite contents in the construction of linear combination (LC) models of MR spectra leads to improved metabolite profile estimation. Glycine (Gly) is usually neglected in such models due to strong overlap with myo-inositol (mI) and a low concentration in normal brain. However, biological studies indicate that Gly is abundant in high-grade brain tumours. This study aimed to investigate the quantitation of Gly in paediatric brain tumours using MRS analysed by LCModel, and its potential as a non-invasive biomarker of malignancy. Single-voxel MRS was performed using PRESS (TR 1500 ms, TE 30 ms/135 ms) on a 1.5 T scanner. Forty-seven cases (18 high grade (HG), 17 low grade (LG), 12 ungraded) were retrospectively selected if both short-TE and long-TE MRS (n = 33) or short-TE MRS and high-resolution magic-angle spinning (HRMAS) of matched surgical samples (n = 15) were available. The inclusion of Gly in LCModel analyses led to significantly reduced fit residues for both short-TE and long-TE MRS (p < 0.05). The Gly concentrations estimated from short-TE MRS were significantly correlated with the long-TE values (R = 0.91, p < 0.001). The Gly concentration estimated by LCModel was significantly higher in HG versus LG tumours for both short-TE (p < 1e-6) and long-TE (p = 0.003) MRS. This was consistent with the HRMAS results, which showed a significantly higher normalised Gly concentration in HG tumours (p < 0.05) and a significant correlation with the normalised Gly concentration measured from short-TE in-vivo MRS (p < 0.05). This study suggests that glycine can be reliably detected in paediatric brain tumours using in-vivo MRS on standard clinical scanners and that it is a promising biomarker of tumour aggressiveness.

Expression of Zonulin, c-kit, and Glial Fibrillary Acidic Protein in Human Gliomas

The hallmarks of human malignant gliomas are their marked invasiveness and vascularity. Because angiogenesis and tumor invasion have been associated with extracellular matrix degradation and intercellular tight junctions, the involvement of zonulin in glioma biology is in the focus. We selected for histological examination five cases of glioblastoma WHO IV (nomenclature of the World Health Organization) and one case each from astrocytoma WHO III, meningioma WHO III, and meningioma WHO I as control samples. The meningioma WHO I is regarded as benign, whereas the meningioma WHO III is recognized as the transition form of malignant tumors in humans. The visualization of a newly designed antibody against human zonulin was studied in triple-labeling studies using fluorescence immunocytochemistry and compared with the expression of c-kit and glial fibrillary acidic protein in differently developed human gliomas. We found that increasing the expression of c-kit is accompanied by an increase of zonulin expression. Both are correlated to the degree of malignancy of human brain tumors. The expression of zonulin is correlated to the degradation of the blood-brain barrier as revealed by Griffonia simplicifolia lectin. In differently graded tumors, we found differently graded involvement of blood vessels in the tumor development, explaining patients' survival.

Evaluation of radiotherapy effect in resveratrol-treated medulloblastoma cancer stem-like cells

Resveratrol (RV), a natural polyphenol derived from red wine, recently showed the potential of anticancer and radiosensitizing effects. A recent study has suggested that the cancer stem cells (CSCs) may reflect the clinical refractory malignancy of brain tumors, including medulloblastoma (MB). The aim of the present study is to investigate the possible role of RV in radiosensitivity of MB cells and MB-associated CSCs. MB-associated CSCs were isolated and cultured by serum-free medium with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). The parental MB cells and MB-CSCs were treated with RV in different concentrations and assessed for cell viability. The treatment includes RV alone, radiation alone, or radiation combined with RV. MB-CSCs selected by serum-free medium with bFGF and EGF can form 3D spheroid formation and display enhanced self-renewal and highly co-expressed "stem cell" genes (Oct-4, Nanog, Nestin, and Musashi-1) as well as antiapoptotic genes (Bcl-2 and Bcl-xL). These MB-CSCs showed significant resistance to radiotherapy as compared to the parental MB cells. Importantly, 100 muM RV could effectively inhibit the proliferation of MB-CSCs and significantly enhance the radiosensitivity in RV-treated MB-CSCs. Our data suggest that RV can effectively inhibit the proliferation and tumorigenicity of MB-CSCs and significantly synergistically enhance radiosensitivity in RV-treated MB-CSCs.