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Sample records for brain tumor stem-like

  1. Chemo-Predictive Assay for Targeting Cancer Stem-Like Cells in Patients Affected by Brain Tumors

    PubMed Central

    Nande, Rounak; Neto, Walter; Lawrence, Logan; McCallister, Danielle R.; Denvir, James; Kimmey, Gerrit A.; Mogul, Mark; Oakley, Gerard; Denning, Krista L.; Dougherty, Thomas; Valluri, Jagan V.; Claudio, Pier Paolo

    2014-01-01

    Administration of ineffective anticancer therapy is associated with unnecessary toxicity and development of resistant clones. Cancer stem-like cells (CSLCs) resist chemotherapy, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. We have developed an ex vivo chemotherapy sensitivity assay (ChemoID), which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents. Two patients, a 21-year old male (patient 1) and a 5-month female (patient 2), affected by anaplastic WHO grade-III ependymoma were screened using the ChemoID assay. Patient 1 was found sensitive to the combination of irinotecan and bevacizumab, which resulted in a prolonged disease progression free period of 18 months. Following recurrence, the combination of various chemotherapy drugs was tested again with the ChemoID assay. We found that benzyl isothiocyanate (BITC) greatly increased the chemosensitivity of the ependymoma cells to the combination of irinotecan and bevacizumab. After patient 1 was treated for two months with irinotecan, bevacizumab and supplements of cruciferous vegetable extracts containing BITC, we observed over 50% tumoral regression in comparison with pre-ChemoID scan as evidenced by MRI. Patient 2 was found resistant to all treatments tested and following 6 cycles of vincristine, carboplatin, cyclophosphamide, etoposide, and cisplatin in various combinations, the tumor of this patient rapidly progressed and proton beam therapy was recommended. As expected animal studies conducted with patient derived xenografts treated with ChemoID screened drugs recapitulated the clinical observation. This assay demonstrates that patients with the same histological stage and grade of cancer may vary considerably in their clinical response, suggesting that ChemoID testing which measures the sensitivity of CSLCs as

  2. Molecular Imaging in Tracking Tumor Stem-Like Cells

    PubMed Central

    Xia, Tian; Jiang, Han; Li, Chenrui; Tian, Mei; Zhang, Hong

    2012-01-01

    Cancer remains a major public health problem in many countries. It was found to contain a subset of cancer stem cells (CSCs) that are capable of proliferation and self-renewal, and differentiation into various types of cancer cells. CSCs often display characteristics of chemotherapy resistance and radiotherapy resistance. Numerous putative biomarkers of CSCs are currently identified including CD133, CD44, CD24, ALDH (aldehyde dehydrogenase), and ABCG2. Interestingly, no single marker is exclusively expressed by CSCs. Thus, the various combinations of different biomarkers will be possible to identify CSCs, and considerable work is being done to recognize new ones. In order to demonstrate the mechanisms of resistance and response to therapy and predict the outcome as well as prognosis, the ways to track and identify CSCs will be extremely important. The technologies of molecular imaging will reveal mechanisms of cancer progression and provide visual targets for novel therapeutics. Limited studies were investigated on the detection of various types of CSCs by molecular imaging. Although the tracking of circulating CSCs is still hampered by technological challenges, personalized diagnosis and therapies of cancers are expected to be established based on increased understanding of molecular imaging of cancer stem-like cells biomarkers. PMID:22570529

  3. Growth factors from tumor microenvironment possibly promote the proliferation of glioblastoma-derived stem-like cells in vitro.

    PubMed

    Guo, JingJing; Niu, Rui; Huang, Wenhui; Zhou, Mengliang; Shi, Jixing; Zhang, Luyong; Liao, Hong

    2012-10-01

    Glioblastoma multiform is a lethal brain glial tumor characterized by low survival and high recurrence, partially attributed to the glioblastoma stem cells according to recent researches. Microenvironment or niche in tumor tissue is believed to provide essential support for the aberrant growth of tumor stem cells. In order to explore the effect of growth factors in tumor microenvironment on glioblastoma stem cells behavior, glioblastoma-derived stem-like cells (GDSCs) were isolated from adult human glioblastoma specimen with antibody against surface marker CD133 and were co-cultured with various tumor cells including U87MG cells, unsorted glioblastoma tumor cells, CD133(-) cells and normal rat primary astrocytes. Results suggested that tumor cells could promote GDSCs proliferation while non-tumor cells could not, and several growth factors were exclusively detected in the co-culture system with tumor cells. It was concluded that growth factors derived from tumor microenvironment possibly contributed to the uncontrolled proliferation of GDSCs.

  4. Transcriptional profiling of adult neural stem-like cells from the human brain.

    PubMed

    Sandberg, Cecilie Jonsgar; Vik-Mo, Einar O; Behnan, Jinan; Helseth, Eirik; Langmoen, Iver A

    2014-01-01

    There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33-60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate.

  5. Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells

    PubMed Central

    Mameri, Samir; Dong, Jihu; Salomé, Christophe; Chen, Wanyin; El-Habr, Elias A.; Bousson, Fanny; Sy, Mohamadou; Obszynski, Julie; Boh, Alexandre; Villa, Pascal; Assad Kahn, Suzana; Didier, Bruno; Bagnard, Dominique; Junier, Marie-Pierre; Chneiweiss, Hervé; Haiech, Jacques; Hibert, Marcel; Kilhoffer, Marie-Claude

    2015-01-01

    Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication. PMID:26270679

  6. Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells.

    PubMed

    Zeniou, Maria; Fève, Marie; Mameri, Samir; Dong, Jihu; Salomé, Christophe; Chen, Wanyin; El-Habr, Elias A; Bousson, Fanny; Sy, Mohamadou; Obszynski, Julie; Boh, Alexandre; Villa, Pascal; Assad Kahn, Suzana; Didier, Bruno; Bagnard, Dominique; Junier, Marie-Pierre; Chneiweiss, Hervé; Haiech, Jacques; Hibert, Marcel; Kilhoffer, Marie-Claude

    2015-01-01

    Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication.

  7. Stem-like plasticity and heterogeneity of circulating tumor cells: current status and prospect challenges in liver cancer

    PubMed Central

    Correnti, Margherita; Raggi, Chiara

    2017-01-01

    Poor prognosis and high recurrence remain leading causes of primary liver cancerassociated mortality. The spread of circulating tumor cells (CTCs) in the blood plays a major role in the initiation of metastasis and tumor recurrence after surgery. Nevertheless, only a subset of CTCs can survive, migrate to distant sites and establish secondary tumors. Consistent with cancer stem cell (CSC) hypothesis, stem-like CTCs might represent a potential source for cancer relapse and distant metastasis. Thus, identification of stem-like metastasis-initiating CTC-subset may provide useful clinically prognostic information. This review will emphasize the most relevant findings of CTCs in the context of stem-like biology associated to liver carcinogenesis. In this view, the emerging field of stem-like CTCs may deliver substantial contribution in liver cancer field in order to move to personalized approaches for diagnosis, prognosis and therapy. PMID:27738343

  8. Brain Tumors

    MedlinePlus

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  9. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

    PubMed Central

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O’Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  10. H460 non-small cell lung cancer stem-like holoclones yield tumors with increased vascularity

    PubMed Central

    Manley, Eugene; Waxman, David J.

    2014-01-01

    Cancer stem-like cells were isolated from several human tumor cell lines by limiting dilution assays and holoclone morphology, followed by assessment of self-renewal capacity, tumor growth, vascularity, and blood perfusion. H460 holoclone-derived tumors grew slower than parental H460 tumors, but displayed significantly increased microvessel density and tumor blood perfusion. Microarray analysis identified 177 differentially regulated genes in the holoclone-derived tumors, of which 47 were associated with angiogenesis. The dysregulated genes include several small leucine-rich proteoglycans that may modulate angiogenesis and serve as novel therapeutic targets for inhibiting cancer stem cell-driven angiogenesis. PMID:24334139

  11. H460 non-small cell lung cancer stem-like holoclones yield tumors with increased vascularity.

    PubMed

    Manley, Eugene; Waxman, David J

    2014-04-28

    Cancer stem-like cells were isolated from several human tumor cell lines by limiting dilution assays and holoclone morphology, followed by assessment of self-renewal capacity, tumor growth, vascularity, and blood perfusion. H460 holoclone-derived tumors grew slower than parental H460 tumors, but displayed significantly increased microvessel density and tumor blood perfusion. Microarray analysis identified 177 differentially regulated genes in the holoclone-derived tumors, of which 47 were associated with angiogenesis. The dysregulated genes include several small leucine-rich proteoglycans that may modulate angiogenesis and serve as novel therapeutic targets for inhibiting cancer stem cell-driven angiogenesis.

  12. Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells.

    PubMed

    Rao, Wei; Wang, Hai; Han, Jianfeng; Zhao, Shuting; Dumbleton, Jenna; Agarwal, Pranay; Zhang, Wujie; Zhao, Gang; Yu, Jianhua; Zynger, Debra L; Lu, Xiongbin; He, Xiaoming

    2015-06-23

    Tumor reinitiating cancer stem-like cells are responsible for cancer recurrence associated with conventional chemotherapy. We developed a doxorubicin-encapsulated polymeric nanoparticle surface-decorated with chitosan that can specifically target the CD44 receptors of these cells. This nanoparticle system was engineered to release the doxorubicin in acidic environments, which occurs when the nanoparticles are localized in the acidic tumor microenvironment and when they are internalized and localized in the cellular endosomes/lysosomes. This nanoparticle design strategy increases the cytotoxicity of the doxorubicin by six times in comparison to the use of free doxorubicin for eliminating CD44(+) cancer stem-like cells residing in 3D mammary tumor spheroids (i.e., mammospheres). We further show these nanoparticles reduced the size of tumors in an orthotopic xenograft tumor model with no evident systemic toxicity. The development of nanoparticle system to target cancer stem-like cells with low systemic toxicity provides a new treatment arsenal for improving the survival of cancer patients.

  13. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

    PubMed Central

    Saha, Nayanendu; Eissman, Moritz F.; Xu, Kai; Llerena, Carmen; Kusebauch, Ulrike; Ding, Bi-Sen; Cao, Zhongwei; Rafii, Shahin; Ernst, Matthias; Scott, Andrew M.; Nikolov, Dimitar B.; Lackmann, Martin

    2016-01-01

    The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance. PMID:27503072

  14. Canine mammary tumors contain cancer stem-like cells and form spheroids with an embryonic stem cell signature.

    PubMed

    Ferletta, Maria; Grawé, Jan; Hellmén, Eva

    2011-01-01

    We have investigated the presence of tentative stem-like cells in the canine mammary tumor cell line CMT-U229. This cell line is established from an atypical benign mixed mammary tumor, which has the property of forming duct-like structures in collagen gels. Stem cells in mammary glands are located in the epithelium; therefore we thought that the CMT-U229 cell line would be suitable for detection of tentative cancer stem-like cells. Side population (SP) analyses by flow cytometry were performed with cells that formed spheroids and with cells that did not. Flow cytometric, single sorted cells were expanded and re-cultured as spheroids. The spheroids were paraffin embedded and characterized by immunohistochemistry. SP analyses showed that spheroid forming cells (retenate) as well as single cells (filtrate) contained SP cells. Sca1 positive cells were single cell sorted and thereafter the SP population increased with repeated SP analyses. The SP cells were positively labeled with the cell surface-markers CD44 and CD49f (integrin alpha6); however the expression of CD24 was low or negative. The spheroids expressed the transcription factor and stem cell marker Sox2, as well as Oct4. Interestingly, only peripheral cells of the spheroids and single cells were positive for Oct4 expression. SP cells are suggested to correspond to stem cells and in this study, we have enriched for tentative tumor stem-like cells derived from a canine mammary tumor. All the used markers indicate that the studied CMT-U229 cell line contains SP cells, which in particular have cancer stem-like cell characteristics.

  15. Cancer stem-like cells derived from chemoresistant tumors have a unique capacity to prime tumorigenic myeloid cells.

    PubMed

    Yamashina, Tsunaki; Baghdadi, Muhammad; Yoneda, Akihiro; Kinoshita, Ichiro; Suzu, Shinya; Dosaka-Akita, Hirotoshi; Jinushi, Masahisa

    2014-05-15

    Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells from CD14(+) monocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-R-specific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5(+) CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors. Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumor-associated CSF1 receptor(+) M2 macrophages in patients with non-small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments.

  16. Brain tumor - primary - adults

    MedlinePlus

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  17. Tumor-associated mesenchymal stem-like cells provide extracellular signaling cue for invasiveness of glioblastoma cells

    PubMed Central

    Yoo, Ki-Chun; Lee, Ji-Hyun; Kim, In-Gyu; Kim, Min-Jung; Chang, Jong Hee; Kang, Seok-Gu; Lee, Su-Jae

    2017-01-01

    Hyaluronic acid (HA) is abundant in tumor microenvironment and closely associated with invasiveness of glioblastoma (GBM) cells. However, the cellular mechanism underlying HA-rich microenvironment in GBM remains unexplored. Here, we show that tumor-associated mesenchymal stem-like cells (tMSLCs) contribute to abundance of hyaluronic acid (HA) in tumor microenvironment through HA synthase-2 (HAS2) induction, and thereby enhances invasiveness of GBM cells. In an autocrine manner, C5a secreted by tMSLCs activated ERK MAPK for HAS2 induction in tMSLCs. Importantly, HA acted as a signaling ligand of its cognate receptor RHAMM for intracellular signaling activation underlying invasiveness of GBM cells. Taken together, our study suggests that tMSLCs contribute to HA-rich proinvasive ECM microenvironment in GBM. PMID:27903965

  18. A novel model for evaluating therapies targeting human tumor vasculature and human cancer stem-like cells

    PubMed Central

    Burgos-Ojeda, Daniela; McLean, Karen; Bai, Shoumei; Pulaski, Heather; Gong, Yusong; Silva, Ines; Skorecki, Karl; Tzukerman, Maty; Buckanovich, Ronald J.

    2013-01-01

    Human tumor vessels express tumor vascular markers (TVMs), proteins that are not expressed in normal blood vessels. Antibodies targeting TVMs could act as potent therapeutics. Unfortunately, preclinical in vivo studies testing anti-human TVM therapies have been difficult to perform due to a lack of in vivo models with confirmed expression of human TVMs. We therefore evaluated TVM expression in a human embryonic stem cell derived teratoma (hESCT) tumor model previously shown to have human vessels. We now report that, in the presence of tumor cells, hESCT tumor vessels express human TVMs. The addition of mouse embryonic fibroblasts and human tumor endothelial cells significantly increases the number of human tumor vessels. TVM induction is mostly tumor type specific with ovarian cancer cells inducing primarily ovarian TVMs while breast cancer cells induce breast cancer specific TVMs. We demonstrate the utility of this model to test an anti-human specific TVM immunotherapeutics; anti-human Thy-1 TVM immunotherapy results in central tumor necrosis and a three-fold reduction in human tumor vascular density. Finally, we tested the ability of the hESCT model, with human tumor vascular niche, to enhance the engraftment rate of primary human ovarian cancer stem-like cells (CSC). ALDH+ CSC from patients (n=6) engrafted in hESCT within 4–12 weeks whereas none engrafted in the flank. ALDH- ovarian cancer cells showed no engraftment in the hESCT or flank (n=3). Thus this model represents a useful tool to test anti-human TVM therapy and evaluate in vivo human CSC tumor biology. PMID:23576551

  19. Understanding Brain Tumors

    MedlinePlus

    ... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

  20. Brain tumor - children

    MedlinePlus

    ... children; Neuroglioma - children; Oligodendroglioma - children; Meningioma - children; Cancer - brain tumor (children) ... The cause of primary brain tumors is unknown. Primary brain tumors may ... (spread to nearby areas) Cancerous (malignant) Brain tumors ...

  1. Brain Tumor Diagnosis

    MedlinePlus

    ... Types of Brain Scans X-rays Laboratory Tests DNA Profiling Biopsy Procedure Malignant and Benign Brain Tumors Tumor ... Types of Brain Scans X-rays Laboratory Tests DNA Profiling Biopsy Procedure Malignant and Benign Brain Tumors Tumor ...

  2. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment.

    PubMed

    Würth, Roberto; Bajetto, Adriana; Harrison, Jeffrey K; Barbieri, Federica; Florio, Tullio

    2014-01-01

    Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem-like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4-CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine

  3. Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo.

    PubMed

    Lotti, Roberta; Palazzo, Elisabetta; Petrachi, Tiziana; Dallaglio, Katiuscia; Saltari, Annalisa; Truzzi, Francesca; Quadri, Marika; Puviani, Mario; Maiorana, Antonino; Marconi, Alessandra; Pincelli, Carlo

    2016-01-12

    Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD) and non-RAD (NRAD) cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, β₁-integrin), while it increases the level of differentiation markers (K10, involucrin). Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in Ras(G12V)-IκBα-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1α, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development.

  4. Brain Tumors (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Brain Tumors KidsHealth > For Parents > Brain Tumors Print A ... radiation therapy or chemotherapy, or both. Types of Brain Tumors There are many different types of brain ...

  5. Brain Tumors (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Brain Tumors KidsHealth > For Parents > Brain Tumors A A ... radiation therapy or chemotherapy, or both. Types of Brain Tumors There are many different types of brain ...

  6. Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain.

    PubMed

    Xing, Fei; Kobayashi, Aya; Okuda, Hiroshi; Watabe, Misako; Pai, Sudha K; Pandey, Puspa R; Hirota, Shigeru; Wilber, Andrew; Mo, Yin-Yuan; Moore, Brian E; Liu, Wen; Fukuda, Koji; Iiizumi, Megumi; Sharma, Sambad; Liu, Yin; Wu, Kerui; Peralta, Elizabeth; Watabe, Kounosuke

    2013-03-01

    Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then 'activated' surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.

  7. Ovarian cancer stem-like cells differentiate into endothelial cells and participate in tumor angiogenesis through autocrine CCL5 signaling.

    PubMed

    Tang, Shu; Xiang, Tong; Huang, Shuo; Zhou, Jie; Wang, Zhongyu; Xie, Rongkai; Long, Haixia; Zhu, Bo

    2016-06-28

    Cancer stem cells (CSCs) are well known for their self-regeneration and tumorigenesis potential. In addition, the multi-differentiation potential of CSCs has become a popular issue and continues to attract increased research attention. Recent studies demonstrated that CSCs are able to differentiate into functional endothelial cells and participate in tumor angiogenesis. In this study, we found that ovarian cancer stem-like cells (CSLCs) activate the NF-κB and STAT3 signal pathways through autocrine CCL5 signaling and mediate their own differentiation into endothelial cells (ECs). Our data demonstrate that CSLCs differentiate into ECs morphologically and functionally. Anti-CCL5 antibodies and CCL5-shRNA lead to markedly inhibit EC differentiation and the tube formation of CSLCs, both in vitro and in vivo. Recombinant human-CCL5 significantly promotes ovarian CSLCs that differentiate into ECs and form microtube network. The CCL5-mediated EC differentiation of CSLCs depends on binding to receptors, such as CCR1, CCR3, and CCR5. The results demonstrated that CCL5-CCR1/CCR3/CCR5 activates the NF-κB and STAT3 signal pathways, subsequently mediating the differentiation of CSLCs into ECs. Therefore, this study was conducted based on the theory that CSCs improve tumor angiogenesis and provides a novel strategy for anti-angiogenesis in ovarian cancer.

  8. Pediatric Brain Tumor Foundation

    MedlinePlus

    ... you insights into your child's treatment. LEARN MORE Brain tumors and their treatment can be deadly so ... Pediatric Brain Tumor Foundation Board Read more >> Pediatric Brain Tumor Foundation 302 Ridgefield Court, Asheville, NC 28806 ...

  9. Tumor Types: Understanding Brain Tumors

    MedlinePlus

    ... Resources Tools & Publications Tumor Types: Understanding Brain Tumors World Health Organization (WHO) Updates Official Classification of Tumors ... Central Nervous System On May 9, 2016, the World Health Organization (WHO) published an official reclassification of ...

  10. Autocrine VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

    PubMed Central

    Hamerlik, Petra; Lathia, Justin D.; Rasmussen, Rikke; Wu, Qiulian; Bartkova, Jirina; Lee, MyungHee; Moudry, Pavel; Bartek, Jiri; Fischer, Walter; Lukas, Jiri

    2012-01-01

    Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133+ human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2–Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF–VEGFR2–NRP1, which is associated with VEGFR2–NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF–VEGFR2–NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach. PMID:22393126

  11. Childhood Brain Tumors

    MedlinePlus

    Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

  12. American Brain Tumor Association

    MedlinePlus

    ... Molecule Read More ABTA News April 6, 2017 Chicago-Based American Brain Tumor Association’s Breakthrough for Brain ... Association 8550 W. Bryn Mawr Ave. Ste 550 Chicago, IL 60631 © 2014 American Brain Tumor Association Phone: ...

  13. Epidemiology of Brain Tumors.

    PubMed

    McNeill, Katharine A

    2016-11-01

    Brain tumors are the commonest solid tumor in children, leading to significant cancer-related mortality. Several hereditary syndromes associated with brain tumors are nonfamilial. Ionizing radiation is a well-recognized risk factor for brain tumors. Several industrial exposures have been evaluated for a causal association with brain tumor formation but the results are inconclusive. A casual association between the common mutagens of tobacco, alcohol, or dietary factors has not yet been established. There is no clear evidence that the incidence of brain tumors has changed over time. This article presents the descriptive epidemiology of the commonest brain tumors of children and adults.

  14. ATG4A promotes tumor metastasis by inducing the epithelial-mesenchymal transition and stem-like properties in gastric cells

    PubMed Central

    Yang, Shi-Wei; Ping, Yi-Fang; Jiang, Yu-Xing; Luo, Xiao; Zhang, Xia; Bian, Xiu-Wu; Yu, Pei-Wu

    2016-01-01

    The metastasis of tumor cells to distant organs is an ominous feature of gastric cancer. However, the molecular mechanisms underlying the invasion and metastasis of gastric cancer cells remain elusive. In this study, we found that the expression of ATG4A, an autophagy-regulating molecule, was significantly increased in gastric cancer tissues and was significantlycorrelated with the gastric cancer differentiation degree, tumor invasion and lymph node metastasis. ATG4A over-expression significantly promoted gastric cancer cell migration and invasion in vitro and metastasis in vivo, as well as promoted gastric cancer cell stem-like properties and the epithelial-mesenchymal transition (EMT) phenotype. By contrast, ATG4A knockdown inhibited the migration, invasion and metastasis of cancer cells, as well as the stem-like properties and EMT phenotype. Mechanistically, ATG4A promotes gastric cancer cell stem-like properties and the EMT phenotype through the activation of Notch signaling not via autophagy, and using the Notch signaling inhibitor DAPT attenuated the effects of ATG4A on gastric cancer cells. Taken together, these findings demonstrated that ATG4A promotes the metastasis of gastric cancer cells via the Notch signaling pathway, which is an autophagy-independent mechanism. PMID:27276686

  15. Children's Brain Tumor Foundation

    MedlinePlus

    ... CBTF Justin's Hope Fund Grant Recipients Grants Children’s Brain Tumor Foundation, A non-profit organization, was founded ... and the long term outlook for children with brain and spinal cord tumors through research, support, education, ...

  16. Dissecting tumor metabolic heterogeneity: Telomerase and large cell size metabolically define a sub-population of stem-like, mitochondrial-rich, cancer cells.

    PubMed

    Lamb, Rebecca; Ozsvari, Bela; Bonuccelli, Gloria; Smith, Duncan L; Pestell, Richard G; Martinez-Outschoorn, Ubaldo E; Clarke, Robert B; Sotgia, Federica; Lisanti, Michael P

    2015-09-08

    Tumor cell metabolic heterogeneity is thought to contribute to tumor recurrence, distant metastasis and chemo-resistance in cancer patients, driving poor clinical outcome. To better understand tumor metabolic heterogeneity, here we used the MCF7 breast cancer line as a model system to metabolically fractionate a cancer cell population. First, MCF7 cells were stably transfected with an hTERT-promoter construct driving GFP expression, as a surrogate marker of telomerase transcriptional activity. To enrich for immortal stem-like cancer cells, MCF7 cells expressing the highest levels of GFP (top 5%) were then isolated by FACS analysis. Notably, hTERT-GFP(+) MCF7 cells were significantly more efficient at forming mammospheres (i.e., stem cell activity) and showed increased mitochondrial mass and mitochondrial functional activity, all relative to hTERT-GFP(-) cells. Unbiased proteomics analysis of hTERT-GFP(+) MCF7 cells directly demonstrated the over-expression of 33 key mitochondrial proteins, 17 glycolytic enzymes, 34 ribosome-related proteins and 17 EMT markers, consistent with an anabolic cancer stem-like phenotype. Interestingly, MT-CO2 (cytochrome c oxidase subunit 2; Complex IV) expression was increased by >20-fold. As MT-CO2 is encoded by mt-DNA, this finding is indicative of increased mitochondrial biogenesis in hTERT-GFP(+) MCF7 cells. Importantly, most of these candidate biomarkers were transcriptionally over-expressed in human breast cancer epithelial cells in vivo. Similar results were obtained using cell size (forward/side scatter) to fractionate MCF7 cells. Larger stem-like cells also showed increased hTERT-GFP levels, as well as increased mitochondrial mass and function. Thus, this simple and rapid approach for the enrichment of immortal anabolic stem-like cancer cells will allow us and others to develop new prognostic biomarkers and novel anti-cancer therapies, by specifically and selectively targeting this metabolic sub-population of aggressive cancer

  17. Surgery-induced wound response promotes stem-like and tumor-initiating features of breast cancer cells, via STAT3 signaling

    PubMed Central

    Segatto, Ilenia; Berton, Stefania; Sonego, Maura; Massarut, Samuele; Perin, Tiziana; Piccoli, Erica; Colombatti, Alfonso; Vecchione, Andrea; Baldassarre, Gustavo; Belletti, Barbara

    2014-01-01

    Inflammation is clinically linked to cancer but the mechanisms are not fully understood. Surgery itself elicits a range of inflammatory responses, suggesting that it could represent a perturbing factor in the process of local recurrence and/or metastasis formation. Post-surgery wound fluids (WF), drained from breast cancer patients, are rich in cytokines and growth factors, stimulate the in vitro growth of breast cancer cells and are potent activators of the STAT transcription factors. We wondered whether STAT signaling was functionally involved in the response of breast cancer cells to post-surgical inflammation. We discovered that WF induced the enrichment of breast cancer cells with stem-like phenotypes, via activation of STAT3. In vitro, WF highly stimulated mammosphere formation and self-renewal of breast cancer cells. In vivo, STAT3 signaling was critical for breast cancer cell tumorigenicity and for the formation of local relapse after surgery. Overall, we demonstrate here that surgery-induced inflammation promotes stem-like phenotypes and tumor-initiating abilities of breast cancer cells. Interfering with STAT3 signaling with a peri-surgical treatment is sufficient to strongly suppress this process. The understanding of the crosstalk between breast tumor-initiating cells and their microenvironment may open the way to successful targeting of these cells in their initial stages of growth and be eventually curative. PMID:25026286

  18. Surgery-induced wound response promotes stem-like and tumor-initiating features of breast cancer cells, via STAT3 signaling.

    PubMed

    Segatto, Ilenia; Berton, Stefania; Sonego, Maura; Massarut, Samuele; Perin, Tiziana; Piccoli, Erica; Colombatti, Alfonso; Vecchione, Andrea; Baldassarre, Gustavo; Belletti, Barbara

    2014-08-15

    Inflammation is clinically linked to cancer but the mechanisms are not fully understood. Surgery itself elicits a range of inflammatory responses, suggesting that it could represent a perturbing factor in the process of local recurrence and/or metastasis. Post-surgery wound fluids (WF), drained from breast cancer patients, are rich in cytokines and growth factors, stimulate the in vitro growth of breast cancer cells and are potent activators of the STAT transcription factors. We wondered whether STAT signaling was functionally involved in the response of breast cancer cells to post-surgical inflammation. We discovered that WF induced the enrichment of breast cancer cells with stem-like phenotypes, via activation of STAT3. In vitro, WF highly stimulated mammosphere formation and self-renewal of breast cancer cells. In vivo, STAT3 signaling was critical for breast cancer cell tumorigenicity and for the formation of local relapse after surgery. Overall, we demonstrate here that surgery-induced inflammation promotes stem-like phenotypes and tumor-initiating abilities of breast cancer cells. Interfering with STAT3 signaling with a peri-surgical treatment was sufficient to strongly suppress this process. The understanding of the crosstalk between breast tumor-initiating cells and their microenvironment may open the way to successful targeting of these cells in their initial stages of growth and be eventually curative.

  19. Radioresistance of Brain Tumors

    PubMed Central

    Kelley, Kevin; Knisely, Jonathan; Symons, Marc; Ruggieri, Rosamaria

    2016-01-01

    Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation. PMID:27043632

  20. Co-culture of hepatoma cells with hepatocytic precursor (stem-like) cells inhibits tumor cell growth and invasion by downregulating Akt/NF-κB expression

    PubMed Central

    Sui, Cheng-Jun; Xu, Miao; Li, Wei-Qing; Yang, Jia-Mei; Yan, Hong-Zhu; Liu, Hui-Min; Xia, Chun-Yan; Yu, Hong-Yu

    2016-01-01

    Hepatocytic stem cells (HSCs) have inhibitory effects on hepatocarcinoma cells. The present study investigated the effects of HSC activity in hepatocarcinoma cells in vitro. A Transwell co-culture system of hepatocytic precursor (stem-like) WB-F344 cells and hepatoma CBRH-7919 cells was used to assess HSC activity in metastasized hepatoma cells in vitro. Nude mouse xenografts were used to assess HSC activity in vivo. Co-culture of hepatoma CBRH-7919 cells with WB-F344 cells suppressed the growth and colony formation, tumor cell migration and invasion capacity of CBRH-7919 cells. The nude mouse xenograft assay demonstrated that the xenograft size of CBRH-7919 cells following co-culture with WB-F344 cells was significantly smaller compared with that of control cells. Furthermore, the expression levels of the epithelial markers E-cadherin and β-catenin were downregulated, while the mesenchymal markers α-SMA and vimentin were upregulated. Co-culture of CBRH-7919 cells with WB-F344 cells downregulated NF-κB and phospho-Akt expression. In conclusion, hepatocytic precursor (stem-like) WB-F344 cells inhibited the growth, colony formation and invasion capacity of metastasized hepatoma CBRH-7919 cells in vitro and in vivo by downregulating Akt/NF-κB signaling. PMID:27895771

  1. Immunology of brain tumors.

    PubMed

    Roth, Patrick; Eisele, Günter; Weller, Michael

    2012-01-01

    Brain tumors of different origin, but notably malignant gliomas, are characterized by their immunosuppressive properties which allow them to escape the host's immune surveillance. The activating immune cell ligands that are expressed by tumor cells, together with potentially immunogenic antigens, are overridden by numerous immune inhibitory signals, with TGF-3 as the master immunosuppressive molecule (Figure 4.1).The ongoing investigation of mechanisms of tumor-derived immunosuppression allows for an increasing understanding of brain tumor immunology. Targeting different mechanisms of tumor-derived immunosuppression, such as inhibition of TGF-[, may represent a promising strategy for future immunotherapeutic approaches.

  2. Linking of mPGES-1 and iNOS activates stem-like phenotype in EGFR-driven epithelial tumor cells.

    PubMed

    Terzuoli, Erika; Finetti, Federica; Costanza, Filomena; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2017-03-01

    Inflammatory prostaglandin E-2 (PGE-2) favors cancer progression in epithelial tumors characterized by persistent oncogene input. However, its effects on tumor cell stemness are poorly understood at molecular level. Here we describe two epithelial tumor cells A431 and A459, originating from human lung and skin tumors, in which epithelial growth factor (EGF) induces sequential up-regulation of mPGES-1 and iNOS enzymes, producing an inflammatory intracellular milieu. We demonstrated that concerted action of EGF, mPGES-1 and iNOS causes sharp changes in cell phenotype demonstrated by acquisition of stem-cell features and activation of the epithelial-mesenchymal transition (EMT). When primed with EGF, epithelial tumor cells transfected with mPGES-1 or iNOS to ensure steady enzyme levels display major stem-like and EMT markers, such as reduction in E-cadherin with a concomitant rise in vimentin, ALDH-1, CD133 and ALDH activity. Tumorsphere studies with these cells show increased sphere number and size, enhanced migratory and clonogenic capacity and sharp changes in EMT markers, indicating activation of this process. The concerted action of the enzymes forms a well-orchestrated cascade where expression of iNOS depends on overexpression of mPGES-1. Indeed, we show that through its downstream effectors (PGE-2, PKA, PI3K/Akt), mPGES-1 recruits non-canonical transcription factors, thus facilitating iNOS production. In conclusion, we propose that the initial event leading to tumor stem-cell activation may be a leveraged intrinsic mechanism in which all players are either inherent constituents (EGF) or highly inducible proteins (mPGES-1, iNOS) of tumor cells. We suggest that incipient tumor aggressiveness may be moderated by reducing pivotal input of mPGES-1.

  3. Familiality in brain tumors

    PubMed Central

    Blumenthal, Deborah T.; Cannon-Albright, Lisa A.

    2008-01-01

    Background: Familiality in brain tumors is not definitively substantiated. Methods: We used the Utah Population Data Base (UPDB), a genealogy representing the Utah pioneers and their descendants, record-linked to statewide cancer records, to describe the familial nature of primary brain cancer. We examined the familial clustering of primary brain tumors, including subgroups defined by histologic type and age at diagnosis. The UPDB includes 1,401 primary brain tumor cases defined as astrocytoma or glioblastoma, all with at least three generations of genealogy data. We tested the hypothesis of excess relatedness of brain tumor cases using the Genealogical Index of Familiality method. We estimated relative risks for brain tumors in relatives using rates of brain tumors estimated internally. Results: Significant excess relatedness was observed for astrocytomas and glioblastomas considered as a group (n = 1,401), for astrocytomas considered separately (n = 744), but not for glioblastomas considered separately (n = 658). Significantly increased risks to first- and second-degree relatives for astrocytomas were identified for relatives of astrocytomas considered separately. Significantly increased risks to first-degree relatives, but not second degree, were observed for astrocytoma and glioblastoma cases considered together, and for glioblastoma cases considered separately. Conclusions: This study provides strong evidence for a familial contribution to primary brain cancer risk. There is evidence that this familial aspect includes not only shared environment, but also a heritable component. Extended high-risk brain tumor pedigrees identified in the UPDB may provide the opportunity to identify predisposition genes responsible for familial brain tumors. GLOSSARY GBM = glioblastoma; GIF = Genealogical Index of Familiality; HGG = high-grade gliomas; ICD-O = International Classification of Disease–Oncology; LGG = low-grade gliomas; RR = relative risks; SEER = Surveillance

  4. Metastatic brain tumor

    MedlinePlus

    ... them create an advance directive and power of attorney for health care. Support Groups You can ease ... surgery Brain tumor - children Breast cancer Increased intracranial pressure Lung cancer - small cell Melanoma Renal cell carcinoma ...

  5. Brain Tumor Statistics

    MedlinePlus

    ... About Us Our Founders Board of Directors Staff Leadership Strategic Plan Financials News Press Releases Headlines Newsletter ... About Us Our Founders Board of Directors Staff Leadership Strategic Plan Financials News Careers Brain Tumor Information ...

  6. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway.

    PubMed

    An, Hyunsook; Kim, Ji Young; Lee, Nahyun; Cho, Youngkwan; Oh, Eunhye; Seo, Jae Hong

    2015-10-30

    Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. In the present study, we sought to investigate the mechanisms responsible for salinomycin's selective targeting of BCSCs and its anti-tumor activity. Salinomycin suppressed cell viability, concomitant with the downregulation of cyclin D1 and increased p27(kip1) nuclear accumulation. Mammosphere formation assays revealed that salinomycin suppresses self-renewal of ALDH1-positive BCSCs and downregulates the transcription factors Nanog, Oct4 and Sox2. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of ALDH1 and CD44 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on BCSCs.

  7. Single cell dual adherent-suspension co-culture micro-environment for studying tumor-stromal interactions with functionally selected cancer stem-like cells.

    PubMed

    Chen, Yu-Chih; Zhang, Zhixiong; Fouladdel, Shamileh; Deol, Yadwinder; Ingram, Patrick N; McDermott, Sean P; Azizi, Ebrahim; Wicha, Max S; Yoon, Euisik

    2016-08-07

    Considerable evidence suggests that cancer stem-like cells (CSCs) are critical in tumor pathogenesis, but their rarity and transience has led to much controversy about their exact nature. Although CSCs can be functionally identified using dish-based tumorsphere assays, it is difficult to handle and monitor single cells in dish-based approaches; single cell-based microfluidic approaches offer better control and reliable single cell derived sphere formation. However, like normal stem cells, CSCs are heavily regulated by their microenvironment, requiring tumor-stromal interactions for tumorigenic and proliferative behaviors. To enable single cell derived tumorsphere formation within a stromal microenvironment, we present a dual adherent/suspension co-culture device, which combines a suspension environment for single-cell tumorsphere assays and an adherent environment for co-culturing stromal cells in close proximity by selectively patterning polyHEMA in indented microwells. By minimizing dead volume and improving cell capture efficiency, the presented platform allows for the use of small numbers of cells (<100 cells). As a proof of concept, we co-cultured single T47D (breast cancer) cells and primary cancer associated fibroblasts (CAF) on-chip for 14 days to monitor sphere formation and growth. Compared to mono-culture, co-cultured T47D have higher tumorigenic potential (sphere formation rate) and proliferation rates (larger sphere size). Furthermore, 96-multiplexed single-cell transcriptome analyses were performed to compare the gene expression of co-cultured and mono-cultured T47D cells. Phenotypic changes observed in co-culture correlated with expression changes in genes associated with proliferation, apoptotic suppression, tumorigenicity and even epithelial-to-mesechymal transition. Combining the presented platform with single cell transcriptome analysis, we successfully identified functional CSCs and investigated the phenotypic and transcriptome effects induced

  8. Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells

    PubMed Central

    Okuda, Hiroshi; Kobayashi, Aya; Xia, Bo; Watabe, Misako; Pai, Sudha K; Hirota, Shigeru; Xing, Fei; Liu, Wen; Pandey, Puspa R; Fukuda, Koji; Modur, Vishnu; Ghosh, Arnab; Wilber, Andrew; Watabe, Kounosuke

    2012-01-01

    The molecular mechanisms that operate within the organ microenvironment to support metastatic progression remain unclear. Here we report that upregulation of the hyaluronan synthase HAS2 occurs in highly metastatic breast stem-like cancer cells (CSCs) defined by CD44+/CD24−/ESA+ phenotype, where it plays a critical role in the generation of a pro-metastatic microenvironment in breast cancer. HAS2 was critical for interaction of CSCs with tumor associated macrophages (TAMs), leading to enhanced secretion of PDGF-BB from TAMs which then activated stromal cells and enhanced CSC self-renewal. Loss of HAS2 in CSCs or treatment with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthases which blocks hyaluronan production, drastically reduced the incidence and growth of metastatic lesions in vitro or in vivo, respectively. Taken together, our findings demonstrate a critical role for HAS2 in the development of a pro-metastatic microenvironment and suggest that HAS2 inhibitors can act as anti-metastatic agents that disrupt a paracrine growth factor loop within this microenvironment. PMID:22113945

  9. Pediatric brain tumor cell lines.

    PubMed

    Xu, Jingying; Margol, Ashley; Asgharzadeh, Shahab; Erdreich-Epstein, Anat

    2015-02-01

    Pediatric brain tumors as a group, including medulloblastomas, gliomas, and atypical teratoid rhabdoid tumors (ATRT) are the most common solid tumors in children and the leading cause of death from childhood cancer. Brain tumor-derived cell lines are critical for studying the biology of pediatric brain tumors and can be useful for initial screening of new therapies. Use of appropriate brain tumor cell lines for experiments is important, as results may differ depending on tumor properties, and can thus affect the conclusions and applicability of the model. Despite reports in the literature of over 60 pediatric brain tumor cell lines, the majority of published papers utilize only a small number of these cell lines. Here we list the approximately 60 currently-published pediatric brain tumor cell lines and summarize some of their central features as a resource for scientists seeking pediatric brain tumor cell lines for their research.

  10. Aquaporins and Brain Tumors

    PubMed Central

    Maugeri, Rosario; Schiera, Gabriella; Di Liegro, Carlo Maria; Fricano, Anna; Iacopino, Domenico Gerardo; Di Liegro, Italia

    2016-01-01

    Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood–brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs). PMID:27367682

  11. Drugs Approved for Brain Tumors

    MedlinePlus

    ... Ask about Your Treatment Research Drugs Approved for Brain Tumors This page lists cancer drugs approved by ... that are not listed here. Drugs Approved for Brain Tumors Afinitor (Everolimus) Afinitor Disperz (Everolimus) Avastin (Bevacizumab) ...

  12. Brain tumors in infants

    PubMed Central

    Ghodsi, Seyyed Mohammad; Habibi, Zohreh; Hanaei, Sara; Moradi, Ehsan; Nejat, Farideh

    2015-01-01

    Background: Brain tumors in infants have different clinical presentations, anatomical distribution, histopathological diagnosis, and clinical prognosis compared with older children. Materials and Methods: A retrospective analysis was done in patients <12 months old who were operated on for primary brain tumor in Children's Hospital Medical Center since 2008 to 2014. Results: Thirty-one infants, 20 males and 11 females, with the mean age of 7.13 months (0.5–12) were enrolled. There were 16 supratentorial and 15 infratentorial tumors. The presenting symptoms included increased head circumference (16); bulge fontanel (15); vomiting (15); developmental regression (11); sunset eye (7); seizure (4); loss of consciousness (4); irritability (3); nystagmus (2); visual loss (2); hemiparesis (2); torticollis (2); VI palsy (3); VII, IX, X nerve palsy (each 2); and ptosis (1). Gross total and subtotal resection were performed in 19 and 11 cases, respectively. Fourteen patients needed external ventricular drainage in the perioperative period, from whom four infants required a ventriculoperitoneal shunt. One patient underwent ventriculoperitoneal shunting without tumor resection. The most common histological diagnoses were primitive neuroectodermal tumor (7), followed by anaplastic ependymoma (6) and grade II ependymoma. The rate of 30-day mortality was 19.3%. Eighteen patients are now well-controlled with or without adjuvant therapy (overall survival; 58%), from whom 13 cases are tumor free (disease free survival; 41.9%), 3 cases have residual masses with fixed or decreased size (progression-free survival; 9.6%), and 2 cases are still on chemotherapy. Conclusion: Brain tumors in infants should be treated with surgical resection, followed by chemotherapy when necessary. PMID:26962338

  13. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

    PubMed Central

    Würth, Roberto; Bajetto, Adriana; Harrison, Jeffrey K.; Barbieri, Federica; Florio, Tullio

    2014-01-01

    Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4–CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine

  14. EGFR Amplification and Glioblastoma Stem-Like Cells

    PubMed Central

    Liffers, Katrin; Lamszus, Katrin

    2015-01-01

    Glioblastoma (GBM), the most common malignant brain tumor in adults, contains a subpopulation of cells with a stem-like phenotype (GS-cells). GS-cells can be maintained in vitro using serum-free medium supplemented with epidermal growth factor, basic fibroblast growth factor-2, and heparin. However, this method does not conserve amplification of the Epidermal Growth Factor Receptor (EGFR) gene, which is present in over 50% of all newly diagnosed GBM cases. GS-cells with retained EGFR amplification could overcome the limitations of current in vitro model systems and contribute significantly to preclinical research on EGFR-targeted therapy. This review recapitulates recent methodological approaches to expand stem-like cells from GBM with different EGFR status in order to maintain EGFR-dependent intratumoral heterogeneity in vitro. Further, it will summarize the current knowledge about the impact of EGFR amplification and overexpression on the stem-like phenotype of GBM-derived GS-cells and different approaches to target the EGFR-dependent GS-cell compartment of GBM. PMID:26136784

  15. Adolescent and Pediatric Brain Tumors

    MedlinePlus

    ... a child you love is diagnosed with a brain tumor, it is difficult to think about anything else. There are often more questions than answers. Your life can feel as though it has been turned upside ... Brain Tumor Association for information, insight and support. Our ...

  16. Brain Tumor Epidemiology Consortium (BTEC)

    Cancer.gov

    The Brain Tumor Epidemiology Consortium is an open scientific forum organized to foster the development of multi-center, international and inter-disciplinary collaborations that will lead to a better understanding of the etiology, outcomes, and prevention of brain tumors.

  17. Augmented IFN-γ and TNF-α Induced by Probiotic Bacteria in NK Cells Mediate Differentiation of Stem-Like Tumors Leading to Inhibition of Tumor Growth and Reduction in Inflammatory Cytokine Release; Regulation by IL-10

    PubMed Central

    Bui, Vickie T.; Tseng, Han-Ching; Kozlowska, Anna; Maung, Phyu Ou; Kaur, Kawaljit; Topchyan, Paytsar; Jewett, Anahid

    2015-01-01

    Our previous reports demonstrated that the magnitude of natural killer (NK) cell-mediated cytotoxicity correlate directly with the stage and level of differentiation of tumor cells. In addition, we have shown previously that activated NK cells inhibit growth of cancer cells through induction of differentiation, resulting in the resistance of tumor cells to NK cell-mediated cytotoxicity through secreted cytokines, as well as direct NK-tumor cell contact. In this report, we show that in comparison to IL-2 + anti-CD16mAb-treated NK cells, activation of NK cells by probiotic bacteria (sAJ2) in combination with IL-2 and anti-CD16mAb substantially decreases tumor growth and induces maturation, differentiation, and resistance of oral squamous cancer stem cells, MIA PaCa-2 stem-like/poorly differentiated pancreatic tumors, and healthy stem cells of apical papillae through increased secretion of IFN-γ and TNF-α, as well as direct NK-tumor cell contact. Tumor resistance to NK cell-mediated killing induced by IL-2 + anti-CD16mAb + sAJ2-treated NK cells is induced by combination of IFN-γ and TNF-α since antibodies to both, and not each cytokine alone, were able to restore tumor sensitivity to NK cells. Increased surface expression of CD54, B7H1, and MHC-I on NK-differentiated tumors was mediated by IFN-γ since the addition of anti-IFN-γ abolished their increase and restored the ability of NK cells to trigger cytokine and chemokine release; whereas differentiated tumors inhibited cytokine release by the NK cells. Monocytes synergize with NK cells in the presence of probiotic bacteria to induce regulated differentiation of stem cells through secretion of IL-10 resulting in resistance to NK cell-mediated cytotoxicity and inhibition of cytokine release. Therefore, probiotic bacteria condition activated NK cells to provide augmented differentiation of cancer stem cells resulting in inhibition of tumor growth, and decreased inflammatory cytokine release. PMID

  18. Childhood Brain Tumor Epidemiology: A Brain Tumor Epidemiology Consortium Review

    PubMed Central

    Johnson, Kimberly J.; Cullen, Jennifer; Barnholtz-Sloan, Jill S.; Ostrom, Quinn T.; Langer, Chelsea E.; Turner, Michelle C.; McKean-Cowdin, Roberta; Fisher, James L.; Lupo, Philip J.; Partap, Sonia; Schwartzbaum, Judith A.; Scheurer, Michael E.

    2014-01-01

    Childhood brain tumors are the most common pediatric solid tumor and include several histological subtypes. Although progress has been made in improving survival rates for some subtypes, understanding of risk factors for childhood brain tumors remains limited to a few genetic syndromes and ionizing radiation to the head and neck. In this report, we review descriptive and analytical epidemiology childhood brain tumor studies from the past decade and highlight priority areas for future epidemiology investigations and methodological work that is needed to advance our understanding of childhood brain tumor causes. Specifically, we summarize the results of a review of studies published since 2004 that have analyzed incidence and survival in different international regions and that have examined potential genetic, immune system, developmental and birth characteristics, and environmental risk factors. PMID:25192704

  19. Precision radiotherapy for brain tumors

    PubMed Central

    Yan, Ying; Guo, Zhanwen; Zhang, Haibo; Wang, Ning; Xu, Ying

    2012-01-01

    OBJECTIVE: Precision radiotherapy plays an important role in the management of brain tumors. This study aimed to identify global research trends in precision radiotherapy for brain tumors using a bibliometric analysis of the Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of data retrievals for precision radiotherapy for brain tumors containing the key words cerebral tumor, brain tumor, intensity-modulated radiotherapy, stereotactic body radiation therapy, stereotactic ablative radiotherapy, imaging-guided radiotherapy, dose-guided radiotherapy, stereotactic brachytherapy, and stereotactic radiotherapy using the Web of Science. SELECTION CRITERIA: Inclusion criteria: (a) peer-reviewed articles on precision radiotherapy for brain tumors which were published and indexed in the Web of Science; (b) type of articles: original research articles and reviews; (c) year of publication: 2002-2011. Exclusion criteria: (a) articles that required manual searching or telephone access; (b) Corrected papers or book chapters. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to country; (3) distribution according to institution; (4) top cited publications; (5) distribution according to journals; and (6) comparison of study results on precision radiotherapy for brain tumors. RESULTS: The stereotactic radiotherapy, intensity-modulated radiotherapy, and imaging-guided radiotherapy are three major methods of precision radiotherapy for brain tumors. There were 260 research articles addressing precision radiotherapy for brain tumors found within the Web of Science. The USA published the most papers on precision radiotherapy for brain tumors, followed by Germany and France. European Synchrotron Radiation Facility, German Cancer Research Center and Heidelberg University were the most prolific research institutes for publications on precision radiotherapy for brain tumors. Among the top 13 research institutes publishing in this field, seven

  20. Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells

    PubMed Central

    Isokpehi, Raphael D; Wollenberg Valero, Katharina C; Graham, Barbara E; Pacurari, Maricica; Sims, Jennifer N; Udensi, Udensi K; Ndebele, Kenneth

    2015-01-01

    Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0–AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres. PMID:26279619

  1. Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

    PubMed Central

    Yi, Yang; Hsieh, I-Yun; Huang, Xiaojia; Li, Jie; Zhao, Wei

    2016-01-01

    Glioblastoma multiforme (GBM), grade IV astrocytoma, is the most fatal malignant primary brain tumor. GBM contains functional subsets of cells called glioblastoma stem-like cells (GSCs), which are radioresistant and chemoresistant and eventually lead to tumor recurrence. Recent studies showed that GSCs reside in particular tumor niches that are necessary to support their behavior. To successfully eradicate GBM growth and recurrence, new strategies selectively targeting GSCs and/or their microenvironmental niche should be designed. In this regard, here we focus on elucidating the molecular mechanisms that govern these GSC properties and on understanding the mechanism of the microenvironmental signals within the tumor mass. Moreover, to overcome the blood–brain barrier, which represents a critical limitation of GBM treatments, a new drug delivery system should be developed. Nanoparticles can be easily modified by different methods to facilitate delivery efficiency of chemotherapeutics, to enhance the accumulation within the tumors, and to promote the capacity for targeting the GSCs. Therefore, nanotechnology has become the most promising approach to GSC-targeting therapy. Additionally, we discussed the future of nanotechnology-based targeted therapy and point out the disadvantages that should be overcome. PMID:28003805

  2. Spectroscopic-guided brain tumor resection

    NASA Astrophysics Data System (ADS)

    Lin, Wei-Chiang; Toms, Steven A.; Jansen, E. Duco; Mahadevan-Jansen, Anita

    2000-05-01

    A pilot in vivo study was conducted to investigate the feasibility of using optical spectroscopy for brain tumor margin detection. Fluorescence and diffuse reflectance spectra were acquired using a portable clinical spectroscopic system from normal brain tissues, tumors, and tumor margins in 21 brain tumor patients undergoing craniotomy. Results form this study show the potential of optical spectroscopy in detecting infiltrating tumor margins of primary brain tumors.

  3. Brain Tumor Symptoms

    MedlinePlus

    ... be associated with the type, size, and/or location of the tumor, as well as the treatments used to manage it. Surgery, radiation, chemotherapy, and other treatments all have the potential to ... American ...

  4. T Cells Enhance Stem-Like Properties and Conditional Malignancy in Gliomas

    PubMed Central

    Irvin, Dwain K.; Jouanneau, Emmanuel; Duvall, Gretchen; Zhang, Xiao-xue; Zhai, Yuying; Sarayba, Danielle; Seksenyan, Akop; Panwar, Akanksha; Black, Keith L.; Wheeler, Christopher J.

    2010-01-01

    Background Small populations of highly tumorigenic stem-like cells (cancer stem cells; CSCs) can exist within, and uniquely regenerate cancers including malignant brain tumors (gliomas). Many aspects of glioma CSCs (GSCs), however, have been characterized in non-physiological settings. Methods We found gene expression similarity superiorly defined glioma “stemness”, and revealed that GSC similarity increased with lower tumor grade. Using this method, we examined stemness in human grade IV gliomas (GBM) before and after dendritic cell (DC) vaccine therapy. This was followed by gene expression, phenotypic and functional analysis of murine GL26 tumors recovered from nude, wild-type, or DC-vaccinated host brains. Results GSC similarity was specifically increased in post-vaccine GBMs, and correlated best to vaccine-altered gene expression and endogenous anti-tumor T cell activity. GL26 analysis confirmed immune alterations, specific acquisition of stem cell markers, specifically enhanced sensitivity to anti-stem drug (cyclopamine), and enhanced tumorigenicity in wild-type hosts, in tumors in proportion to anti-tumor T cell activity. Nevertheless, vaccine-exposed GL26 cells were no more tumorigenic than parental GL26 in T cell-deficient hosts, though they otherwise appeared similar to GSCs enriched by chemotherapy. Finally, vaccine-exposed GBM and GL26 exhibited relatively homogeneous expression of genes expressed in progenitor cells and/or differentiation. Conclusions T cell activity represents an inducible physiological process capable of proportionally enriching GSCs in human and mouse gliomas. Stem-like gliomas enriched by strong T cell activity, however, may differ from other GSCs in that their stem-like properties may be disassociated from increased tumor malignancy and heterogeneity under specific host immune conditions. PMID:20539758

  5. Cytogenetics of human brain tumors

    SciTech Connect

    Finkernagel, S.W.; Kletz, T.; Day-Salvatore, D.L.

    1994-09-01

    Chromosome studies of 55 brain tumors, including meningiomas, gliomas, astrocyomas and pituatary adenomas, were performed. Primary and first passage cultures were successfully obtained in 75% of these samples with an average of 18 G-banded metaphases analyzed per tumor. 44% of all the brain tumors showed numerical and or structural abnormalities. 46% of the primary and 38% of the first passage cultures showed similar numerical gains/losses and complex karyotypic changes. The most frequent numerical abnormalities (n {ge} 5) included loss of chromosomes 10, 22, and Y. The structural abnormalities most often seen involved 1p, 2, 5, 7, 17q and 19. This is an ongoing study which will attempt to correlate tumor type with specific karyotypic changes and to see if any of the observed chromosomal abnormalities provide prognostic indicators.

  6. Brain tumors in irradiated monkeys.

    NASA Technical Reports Server (NTRS)

    Haymaker, W.; Miquel, J.; Rubinstein, L. J.

    1972-01-01

    A study was made of 32 monkeys which survived one to seven years after total body exposure to protons or to high-energy X rays. Among these 32 monkeys there were 21 which survived two years or longer after exposure to 200 to 800 rad. Glioblastoma multiforme developed in 3 of the 10 monkeys surviving three to five years after receiving 600 or 800 rad 55-MeV protons. Thus, the incidence of tumor development in the present series was far higher than the incidence of spontaneously developing brain tumors in monkeys cited in the literature. This suggests that the tumors in the present series may have been radiation-induced.

  7. Brain and Spinal Cord Tumors in Adults

    MedlinePlus

    ... Search Search En Español Category Cancer A-Z Brain and Spinal Cord Tumors in Adults If you have a brain or spinal cord tumor or are close to ... cope. Here you can find out all about brain and spinal cord tumors in adults, including risk ...

  8. Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice

    PubMed Central

    Yang, Rui; Tang, Qiusha; Miao, Fengqin; An, Yanli; Li, Mengfei; Han, Yong; Wang, Xihui; Wang, Juan; Liu, Peidang; Chen, Rong

    2015-01-01

    Purpose To explore the thermoresistance and expression of heat-shock protein 90 (HSP90) in magnetic hyperthermia-treated human liver cancer stem-like cells (LCSCs) and the effects of a heat-shock protein HSP90 inhibitor 17-allylamino-17-demethoxgeldanamycin (17-AAG) on hepatocellular carcinoma-burdened nude mice. Methods CD90+ LCSCs were isolated by magnetic-activated cell sorting from BEL-7404. Spheroid formation, proliferation, differentiation, drug resistance, and tumor formation assays were performed to identify stem cell characteristics. CD90-targeted thermosensitive magnetoliposomes (TMs)-encapsulated 17-AAG (CD90@17-AAG/TMs) was prepared by reverse-phase evaporation and its characteristics were studied. Heat tolerance in CD90+ LCSCs and the effect of CD90@17-AAG/TMs-mediated heat sensitivity were examined in vitro and in vivo. Results CD90+ LCSCs showed significant stem cell-like properties. The 17-AAG/TMs were successfully prepared and were spherical in shape with an average size of 128.9±7.7 nm. When exposed to magnetic hyperthermia, HSP90 was up-regulated in CD90+ LCSCs. CD90@17-AAG/TMs inhibited the activity of HSP90 and increased the sensitivity of CD90+ LCSCs to magnetic hyperthermia. Conclusion The inhibition of HSP90 could sensitize CD90+ LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo. PMID:26677324

  9. Target irradiation induced bystander effects between stem-like and non stem-like cancer cells.

    PubMed

    Liu, Yu; Kobayashi, Alisa; Maeda, Takeshi; Fu, Qibin; Oikawa, Masakazu; Yang, Gen; Konishi, Teruaki; Uchihori, Yukio; Hei, Tom K; Wang, Yugang

    2015-03-01

    Tumors are heterogeneous in nature and consist of multiple cell types. Among them, cancer stem-like cells (CSCs) are suggested to be the principal cause of tumor metastasis, resistance and recurrence. Therefore, understanding the behavior of CSCs in direct and indirect irradiations is crucial for clinical radiotherapy. Here, the CSCs and their counterpart non stem-like cancer cells (NSCCs) in human HT1080 fibrosarcoma cell line were sorted and labeled, then the two cell subtypes were mixed together and chosen separately to be irradiated via a proton microbeam. The radiation-induced bystander effect (RIBE) between the CSCs and NSCCs was measured by imaging 53BP1 foci, a widely used indicator for DNA double strand break (DSB). CSCs were found to be less active than NSCCs in both the generation and the response of bystander signals. Moreover, the nitric oxide (NO) scavenger c-PTIO can effectively alleviate the bystander effect in bystander NSCCs but not in bystander CSCs, indicating a difference of the two cell subtypes in NO signal response. To our knowledge, this is the first report shedding light on the RIBE between CSCs and NSCCs, which might contribute to a further understanding of the out-of-field effect in cancer radiotherapy.

  10. Survival Rates for Selected Childhood Brain and Spinal Cord Tumors

    MedlinePlus

    ... Diagnosis, and Staging Survival Rates for Selected Childhood Brain and Spinal Cord Tumors Survival rates are often ... Childhood Brain and Spinal Cord Tumors More In Brain and Spinal Cord Tumors in Children About Brain ...

  11. Stereotaxic interstitial irradiation of malignant brain tumors

    SciTech Connect

    Gutin, P.H.; Leibel, S.A.

    1985-11-01

    The authors discuss the feasibility of treatment of malignant tumors with brachytherapy. The history of brain tumor brachytherapy, its present day use, and future directions are detailed. 24 references.

  12. Brain Tumor-Related Epilepsy

    PubMed Central

    Maschio, Marta

    2012-01-01

    In patients with brain tumor (BT), seizures are the onset symptom in 20-40% of patients, while a further 20-45% of patients will present them during the course of the disease. These patients present a complex therapeutic profile and require a unique and multidisciplinary approach. The choice of antiepileptic drugs is challenging for this particular patient population because brain tumor-related epilepsy (BTRE) is often drug-resistant, has a strong impact on the quality of life and weighs heavily on public health expenditures. In BT patients, the presence of epilepsy is considered the most important risk factor for long-term disability. For this reason, the problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control can significantly improve the patient’s psychological and relational sphere. In these patients, new generation drugs such as gabapentin, lacosamide, levetiracetam, oxcarbazepine, pregabalin, topiramate, zonisamide are preferred because they have fewer drug interactions and cause fewer side effects. Among the recently marketed drugs, lacosamide has demonstrated promising results and should be considered a possible treatment option. Therefore, it is necessary to develop a customized treatment plan for each individual patient with BTRE. This requires a vision of patient management concerned not only with medical therapies (pharmacological, surgical, radiological, etc.) but also with emotional and psychological support for the individual as well as his or her family throughout all stages of the illness. PMID:23204982

  13. Drug delivery systems for brain tumor therapy.

    PubMed

    Rautioa, Jarkko; Chikhale, Prashant J

    2004-01-01

    Brain tumors are one of the most lethal forms of cancer. They are extremely difficult to treat. Although, the rate of brain tumor incidence is relatively low, the field clearly lacks therapeutic strategies capable of overcoming barriers for effective delivery of drugs to brain tumors. Clinical failure of many potentially effective therapeutics for the treatment of brain tumors is usually not due to a lack of drug potency, but rather can be attributed to shortcomings in the methods by which a drug is delivered to the brain and into brain tumors. In response to the lack of efficacy of conventional drug delivery methods, extensive efforts have been made to develop novel strategies to overcome the obstacles for brain tumor drug delivery. The challenge is to design therapeutic strategies that deliver drugs to brain tumors in a safe and effective manner. This review provides some insight into several potential techniques that have been developed to improve drug delivery to brain tumors, and it should be helpful to clinicians and research scientists as well.

  14. Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells.

    PubMed

    Kathagen, Annegret; Schulte, Alexander; Balcke, Gerd; Phillips, Heidi S; Martens, Tobias; Matschke, Jakob; Günther, Hauke S; Soriano, Robert; Modrusan, Zora; Sandmann, Thomas; Kuhl, Carsten; Tissier, Alain; Holz, Mareike; Krawinkel, Lutz A; Glatzel, Markus; Westphal, Manfred; Lamszus, Katrin

    2013-11-01

    Fluctuations in oxygen tension during tissue remodeling impose a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastoma, the most common malignant brain tumor, possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. We identified a reciprocal metabolic switch between the pentose phosphate pathway (PPP) and glycolysis in glioblastoma stem-like (GS) cells. Expression of PPP enzymes is upregulated by acute oxygenation but downregulated by hypoxia, whereas glycolysis enzymes, particularly those of the preparatory phase, are regulated inversely. Glucose flux through the PPP is reduced under hypoxia in favor of flux through glycolysis. PPP enzyme expression is elevated in human glioblastomas compared to normal brain, especially in highly proliferative tumor regions, whereas expression of parallel preparatory phase glycolysis enzymes is reduced in glioblastomas, except for strong upregulation in severely hypoxic regions. Hypoxia stimulates GS cell migration but reduces proliferation, whereas oxygenation has opposite effects, linking the metabolic switch to the "go or grow" potential of the cells. Our findings extend Warburg's observation that tumor cells predominantly utilize glycolysis for energy production, by suggesting that PPP activity is elevated in rapidly proliferating tumor cells but suppressed by acute severe hypoxic stress, favoring glycolysis and migration to protect cells against hypoxic cell damage.

  15. Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells

    SciTech Connect

    Hyun, Kyung-Hwan; Yoon, Chang-Hwan; Kim, Rae-Kwon; Lim, Eun-Jung; An, Sungkwan; Park, Myung-Jin; Hyun, Jin-Won; Suh, Yongjoon; Kim, Min-Jung; Lee, Su-Jae

    2011-07-01

    A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in the malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133{sup +} cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.

  16. Long Non-Coding RNA HOTAIR Regulates the Proliferation, Self-Renewal Capacity, Tumor Formation and Migration of the Cancer Stem-Like Cell (CSC) Subpopulation Enriched from Breast Cancer Cells

    PubMed Central

    Jiang, Rong; An, Ning; Wang, Xiaoshan; Liu, Bin

    2017-01-01

    Purpose Long non-coding RNAs (lncRNAs) play important roles in the malignant behavior of cancer. HOTAIR, a well-studied lncRNA, contributes to breast cancer development, and overexpression of HOTAIR predicts a poor prognosis. However, the regulatory role of HOTAIR in the cancer stem-like cell (CSC) subpopulation remains largely unknown. Our goal was to determine the regulatory functions of HOTAIR in the processes of self-renewal capacity, tumor formation and proliferation of CSCs derived from breast cancer. Methods We first enriched and incubated the CSC population derived from breast cancer cell line MCF7 (CSC-MCF7) or MDA-MB-231 (MB231, CSC-MB231). Self-renewal capacity and tumor formation were assessed in vitro and in vivo to determine the stemness of CSCs. We assessed the impact on ectopically upregulated or downregulated expression of HOTAIR in CSCs by soft agar, self-renewal capacity and CCK-8 assays. The functional domain of HOTAIR was determined by truncation. RT-qPCR and semiquantitative Western blotting were performed to detect the expression levels of genes of interest. Chromatin IP (ChIP) was employed to detect the transcriptional regulatory activity of p53 on its target gene. Results After the identification of CSC properties, RT-qPCR analysis revealed that HOTAIR, but not other cancer-associated lncRNAs, is highly upregulated in both CSC-MCF7 and CSC-MB231 populations compared with MCF7 and MB231 populations. By modulating the level of HOTAIR expression, we showed that HOTAIR tightly regulates the proliferation, colony formation, migration and self-renewal capacity of CSCs. Moreover, full-length HOTAIR transcriptionally inhibits miR-34a specifically, leading to upregulation of Sox2, which is targeted by miR-34a. Ectopic introduction of miR-34a mimics reverses the effects of HOTAIR on the physiological processes of CSCs, indicating that HOTAIR affects these processes, including self-renewal capacity; these effects are dependent on the regulation of Sox

  17. Harnessing the apoptotic programs in cancer stem-like cells.

    PubMed

    Wang, Ying-Hua; Scadden, David T

    2015-09-01

    Elimination of malignant cells is an unmet challenge for most human cancer types even with therapies targeting specific driver mutations. Therefore, a multi-pronged strategy to alter cancer cell biology on multiple levels is increasingly recognized as essential for cancer cure. One such aspect of cancer cell biology is the relative apoptosis resistance of tumor-initiating cells. Here, we provide an overview of the mechanisms affecting the apoptotic process in tumor cells emphasizing the differences in the tumor-initiating or stem-like cells of cancer. Further, we summarize efforts to exploit these differences to design therapies targeting that important cancer cell population.

  18. Notching on Cancer’s Door: Notch Signaling in Brain Tumors

    PubMed Central

    Teodorczyk, Marcin; Schmidt, Mirko H. H.

    2015-01-01

    Notch receptors play an essential role in the regulation of central cellular processes during embryonic and postnatal development. The mammalian genome encodes for four Notch paralogs (Notch 1–4), which are activated by three Delta-like (Dll1/3/4) and two Serrate-like (Jagged1/2) ligands. Further, non-canonical Notch ligands such as epidermal growth factor like protein 7 (EGFL7) have been identified and serve mostly as antagonists of Notch signaling. The Notch pathway prevents neuronal differentiation in the central nervous system by driving neural stem cell maintenance and commitment of neural progenitor cells into the glial lineage. Notch is therefore often implicated in the development of brain tumors, as tumor cells share various characteristics with neural stem and progenitor cells. Notch receptors are overexpressed in gliomas and their oncogenicity has been confirmed by gain- and loss-of-function studies in vitro and in vivo. To this end, special attention is paid to the impact of Notch signaling on stem-like brain tumor-propagating cells as these cells contribute to growth, survival, invasion, and recurrence of brain tumors. Based on the outcome of ongoing studies in vivo, Notch-directed therapies such as γ-secretase inhibitors and blocking antibodies have entered and completed various clinical trials. This review summarizes the current knowledge on Notch signaling in brain tumor formation and therapy. PMID:25601901

  19. The Microenvironmental Landscape of Brain Tumors.

    PubMed

    Quail, Daniela F; Joyce, Johanna A

    2017-03-13

    The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here, we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases.

  20. CD44v6 regulates growth of brain tumor stem cells partially through the AKT-mediated pathway.

    PubMed

    Jijiwa, Mayumi; Demir, Habibe; Gupta, Snehalata; Leung, Crystal; Joshi, Kaushal; Orozco, Nicholas; Huang, Tiffany; Yildiz, Vedat O; Shibahara, Ichiyo; de Jesus, Jason A; Yong, William H; Mischel, Paul S; Fernandez, Soledad; Kornblum, Harley I; Nakano, Ichiro

    2011-01-01

    Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC) has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6) in BTSC of a subset of glioblastoma multiforme (GBM). Patients with CD44(high) GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44(high) GBM but not from CD44(low) GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN), increased expression of phosphorylated AKT in CD44(high) GBM, but not in CD44(low) GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKT pathway.

  1. Brain tumor immunotherapy: an immunologist's perspective.

    PubMed

    Lampson, Lois A

    2003-01-01

    Key concepts in brain tumor immunotherapy are reviewed. "Immunotherapy" can refer to a fully-developed, tumor-specific immune response, or to its individual cellular or molecular mediators. The immune response is initiated most efficiently in organized lymphoid tissue. After initiation, antigen-specific T lymphocytes (T cells) survey the tissues--including the brain. If the T cells re-encounter their antigen at a tumor site, they can be triggered to carry out their effector functions. T cells can attack tumor in many ways, directly and indirectly, through cell-cell contact, secreted factors, and attraction and activation of other cells, endogenous or blood-borne. Recent work expands the list of candidate tumor antigens: they are not limited to cell surface proteins and need not be absolutely tumor-specific. Once identified, tumor antigens can be targeted immunologically, or in novel ways. The immune response is under complex regulatory control. Most current work aims to enhance initiation of the response (for example, with tumor vaccines), rather than enhancing the effector phase at the tumor site. The effector phase includes a rich, interactive set of cells and mediators; some that are not usually stressed are of particular interest against tumor in the brain. Within the brain, immune regulation varies from site to site, and local neurochemicals (such as substance P or glutamate) can contribute to local control. Given the complexity of a tumor, the brain, and the immune response, animal models are essential, but more emphasis should be given to their limitations and to step-by-step analysis, rather than animal "cures".

  2. Embryonal brain tumors and developmental control genes

    SciTech Connect

    Aguzzi, A.

    1995-12-31

    Cell proliferation in embryogenesis and neoplastic transformation is thought to be controlled by similar sets of regulatory genes. This is certainly true for tumors of embryonic origin, such as Ewing sarcoma, Wilms` tumor and retinoblastoma, in which developmental control genes are either activated as oncogenes to promote proliferation, or are inactivated to eliminate their growth suppressing function. However, to date little is known about the genetic events underlying the pathogenesis of medulloblastoma, the most common brain tumor in children, which still carries an unfavourable prognosis. None of the common genetic alterations identified in other neuroectodermal tumors, such as mutation of the p53 gene or amplification of tyrosine kinase receptor genes, could be uncovered as key events in the formation of medulloblastoma. The identification of regulatory genes which are expressed in this pediatric brain tumor may provide an alternative approach to gain insight into the molecular aspects of tumor formation.

  3. Gefitinib Radiosensitizes Stem-Like Glioma Cells: Inhibition of Epidermal Growth Factor Receptor-Akt-DNA-PK Signaling, Accompanied by Inhibition of DNA Double-Strand Break Repair

    SciTech Connect

    Kang, Khong Bee; Zhu Congju; Wong Yinling; Gao Qiuhan; Ty, Albert; Wong, Meng Cheong

    2012-05-01

    Purpose: We compared radiosensitivity of brain tumor stem cells (BTSCs) with matched nonstem glioma cells, and determined whether gefitinib enhanced BTSC radiosensitivity by inhibiting epidermal growth factor receptor (EGFR)-Akt-DNA-dependent protein kinase (DNA-PK) signaling, followed by enhanced DNA double-stand breaks (DSBs) and inhibition of DSB repair. Methods and Materials: Radiosensitivity of stem-like gliomaspheres and nonstem glioma cells (obtained at patient neurosurgical resection) were evaluated by clonogenic assays, {gamma}-H{sub 2}AX immunostaining and cell cycle distribution. Survival of irradiated and nonirradiated NOD-SCID mice intracranially implanted with stem-like gliomaspheres were monitored. Glioma cells treated with gefitinib, irradiation, or both were assayed for clonogenic survival, {gamma}-H{sub 2}AX immunostaining, DNA-PKcs expression, and phosphorylation of EGFR and Akt. Results: Stem-like gliomaspheres displayed BTSC characteristics of self-renewal; differentiation into lineages of neurons, oligodendrocytes, and astrocytes; and initiation of glioma growth in NOD-SCID mice. Irradiation dose-dependently reduced clonogenic survival, induced G{sub 2}/M arrest and increased {gamma}-H{sub 2}AX immunostaining of nonstem glioma cells, but not stem-like gliomaspheres. There was no difference in survival of irradiated and nonirradiated mice implanted with stem-like gliomaspheres. The addition of gefitinib significantly inhibited clonogenic survival, increased {gamma}-H{sub 2}AX immunostaining, and reduced DNA-PKcs expression of irradiated stem-like gliomaspheres, without affecting irradiated-nonstem glioma cells. Gefitinib alone, and when combined with irradiation, inhibited phosphorylation of EGFR (Y1068 and Y1045) and Akt (S473) in stem-like gliomaspheres. In nonstem glioma cells, gefitinib alone inhibited EGFR Y1068 phosphorylation, with further inhibition by combined gefitinib and irradiation. Conclusions: Stem-like gliomaspheres are

  4. The proteomics of pediatric brain tumors.

    PubMed

    Anagnostopoulos, Athanasios K; Tsangaris, George T

    2014-10-01

    Pediatric tumors of the CNS are the leading cause of cancer-related mortality in children. In pediatric pathology, brain tumors constitute the most frequent solid malignancy. An unparalleled outburst of information in pediatric neuro-oncology research has been witnessed over the last few years, largely due to increased use of high-throughput technologies such as genomics, proteomics and meta-analysis tools. Input from these technologies gives scientists the advantage of early prognosis assessment, more accurate diagnosis and prospective curative intent in the pediatric brain tumor clinical setting. The present review aims to summarize current knowledge on research applying proteomics techniques or proteomics-based approaches performed on pediatric brain tumors. Proteins that can be used as potential disease markers or molecular targets, and their biological significance, are herein listed and discussed. Furthermore, future perspectives that proteomics technologies may offer regarding this devastating disorder are presented.

  5. How Are Brain and Spinal Cord Tumors in Children Diagnosed?

    MedlinePlus

    ... Children Early Detection, Diagnosis, and Staging How Are Brain and Spinal Cord Tumors Diagnosed in Children? Brain ... resonance angiography (MRA) or computerized tomographic angiography (CTA). Brain or spinal cord tumor biopsy Imaging tests such ...

  6. Expression and Prognostic Value of Oct-4 in Astrocytic Brain Tumors

    PubMed Central

    Dahl Sørensen, Mia; Winther Kristensen, Bjarne

    2016-01-01

    Background Glioblastomas are the most frequent type of malignant primary brain tumor with a median overall survival less than 15 months. Therapy resistance of glioblastomas has been attributed to the presence of tumor initiating stem-like cells (TSCs). TSC-related markers have therefore been suggested to have promising potentials as prognostic markers in gliomas. Methodology/Principal Findings The aim of the present study was to investigate the expression and prognostic impact of the TSC-related marker Oct-4 in astrocytic brain tumors of increasing grade. In total 114 grade II, III and IV astrocytic brain tumors were immunohistochemically stained for Oct-4, and the fraction and intensity of Oct-4 positive cells were determined by morphometric analysis of full tumor sections. Oct-4 was expressed in all tumors, and the Oct-4 positive cell fraction increased with tumor grade (p = 0.045). There was no association between survival and Oct-4 positive cell fraction, neither when combining all tumor grades nor in analysis of individual grades. Oct-4 intensity was not associated with grade, but taking IDH1 status into account we found a tendency for high Oct-4 intensity to be associated with poor prognosis in anaplastic astrocytomas. Double immunofluorescence stainings showed co-localization in the perivascular niches of Oct-4 and two other TSC markers CD133 and nestin in glioblastomas. In some areas Oct-4 was expressed independently of CD133 and nestin. Conclusions In conclusion, high Oct-4 fraction was associated with tumor malignancy, but seemed to be without independent prognostic influence in glioblastomas. Identification of a potential prognostic value in anaplastic astrocytomas requires additional studies using larger patient cohorts. PMID:28030635

  7. Metabolic brain imaging correlated with clinical features of brain tumors

    SciTech Connect

    Alavi, J.; Alavi, A.; Dann, R.; Kushner, M.; Chawluk, J.; Powlis, W.; Reivich, M.

    1985-05-01

    Nineteen adults with brain tumors have been studied with positron emission tomography utilizing FDG. Fourteen had biopsy proven cerebral malignant glioma, one each had meningioma, hemangiopericytoma, primitive neuroectodermal tumor (PNET), two had unbiopsied lesions, and one patient had an area of biopsy proven radiation necrosis. Three different patterns of glucose metabolism are observed: marked increase in metabolism at the site of the known tumor in (10 high grade gliomas and the PNET), lower than normal metabolism at the tumor (in 1 grade II glioma, 3 grade III gliomas, 2 unbiopsied low density nonenhancing lesions, and the meningioma), no abnormality (1 enhancing glioma, the hemangiopericytoma and the radiation necrosis.) The metabolic rate of the tumor or the surrounding brain did not appear to be correlated with the history of previous irradiation or chemotherapy. Decreased metabolism was frequently observed in the rest of the affected hemisphere and in the contralateral cerebellum. Tumors of high grade or with enhancing CT characteristics were more likely to show increased metabolism. Among the patients with proven gliomas, survival after PETT scan tended to be longer for those with low metabolic activity tumors than for those with highly active tumors. The authors conclude that PETT may help to predict the malignant potential of tumors, and may add useful clinical information to the CT scan.

  8. Psychiatric aspects of brain tumors: A review

    PubMed Central

    Madhusoodanan, Subramoniam; Ting, Mark Bryan; Farah, Tara; Ugur, Umran

    2015-01-01

    Infrequently, psychiatric symptoms may be the only manifestation of brain tumors. They may present with mood symptoms, psychosis, memory problems, personality changes, anxiety, or anorexia. Symptoms may be misleading, complicating the clinical picture. A comprehensive review of the literature was conducted regarding reports of brain tumors and psychiatric symptoms from 1956-2014. Search engines used include PubMed, Ovid, Psych Info, MEDLINE, and MedScape. Search terms included psychiatric manifestations/symptoms, brain tumors/neoplasms. Our literature search yielded case reports, case studies, and case series. There are no double blind studies except for post-diagnosis/-surgery studies. Early diagnosis is critical for improved quality of life. Symptoms that suggest work-up with neuroimaging include: new-onset psychosis, mood/memory symptoms, occurrence of new or atypical symptoms, personality changes, and anorexia without body dysmorphic symptoms. This article reviews the existing literature regarding the diagnosis and management of this clinically complex condition. PMID:26425442

  9. Psychiatric aspects of brain tumors: A review.

    PubMed

    Madhusoodanan, Subramoniam; Ting, Mark Bryan; Farah, Tara; Ugur, Umran

    2015-09-22

    Infrequently, psychiatric symptoms may be the only manifestation of brain tumors. They may present with mood symptoms, psychosis, memory problems, personality changes, anxiety, or anorexia. Symptoms may be misleading, complicating the clinical picture. A comprehensive review of the literature was conducted regarding reports of brain tumors and psychiatric symptoms from 1956-2014. Search engines used include PubMed, Ovid, Psych Info, MEDLINE, and MedScape. Search terms included psychiatric manifestations/symptoms, brain tumors/neoplasms. Our literature search yielded case reports, case studies, and case series. There are no double blind studies except for post-diagnosis/-surgery studies. Early diagnosis is critical for improved quality of life. Symptoms that suggest work-up with neuroimaging include: new-onset psychosis, mood/memory symptoms, occurrence of new or atypical symptoms, personality changes, and anorexia without body dysmorphic symptoms. This article reviews the existing literature regarding the diagnosis and management of this clinically complex condition.

  10. Confronting pediatric brain tumors: parent stories.

    PubMed

    McMillan, Gigi

    2014-01-01

    This narrative symposium brings to light the extreme difficulties faced by parents of children diagnosed with brain tumors. NIB editorial staff and narrative symposium editors, Gigi McMillan and Christy A. Rentmeester, developed a call for stories that was distributed on several list serves and posted on Narrative Inquiry in Bioethics' website. The call asks parents to share their personal experience of diagnosis, treatment, long-term effects of treatment, social issues and the doctor-patient-parent dynamic that develops during this process. Thirteen stories are found in the print version of the journal and an additional six supplemental stories are published online only through Project MUSE. One change readers may notice is that the story authors are not listed in alphabetical order. The symposium editors had a vision for this issue that included leading readers through the timeline of this topic: diagnosis-treatment-acute recovery-recurrence-treatment (again)-acute recovery (again)-long-term quality of life-(possibly) end of life. Stories are arranged to help lead the reader through this timeline.Gigi McMillan is a patient and research subject advocate, co-founder of We Can, Pediatric Brain Tumor Network, as well as, the mother of a child who suffered from a pediatric brain tumor. She also authored the introduction for this symposium. Christy Rentmeester is an Associate Professor of Health Policy and Ethics in the Creighton University School of Medicine. She served as a commentator for this issue. Other commentators for this issue are Michael Barraza, a clinical psychologist and board member of We Can, Pediatric Brain Tumor Network; Lisa Stern, a pediatrician who has diagnosed six children with brain tumors in her 20 years of practice; and Katie Rose, a pediatric brain tumor patient who shares her special insights about this world.

  11. Neurologic sequelae of brain tumors in children.

    PubMed

    Ullrich, Nicole J

    2009-11-01

    Neurologic signs and symptoms are often the initial presenting features of a primary brain tumor and may also emerge during the course of therapy or as late effects of the tumor and its treatment. Variables that influence the development of such neurologic complications include the type, size, and location of the tumor, the patient's age at diagnosis, and the treatment modalities used. Heightened surveillance and improved neuroimaging modalities have been instrumental in detecting and addressing such complications, which are often not appreciated until many years after completion of therapy. As current brain tumor therapies are continually refined and newer targeted therapies are developed, it will be important for future cooperative group studies to include systematic assessments to determine the incidence of neurologic complications and to provide a framework for the development of novel strategies for prevention and intervention.

  12. Metabolism of steroids by human brain tumors.

    PubMed

    Weidenfeld, J; Schiller, H

    1984-01-01

    Hormonal steroids or their precursors can be metabolized in the CNS to products with altered hormonal activity. The importance of the intracerebral transformation of steroids has been demonstrated, particularly with regard to neuroendocrine regulation and sexual behavior. These studies were carried out on normal brain tissues, but the ability of neoplastic tissues of CNS origin to metabolize steroids is unknown. We investigated the in vitro metabolism of tritiated pregnenolone, testosterone, and estradiol-17 beta by homogenates of four brain tumors defined as astrocytomas. In three tumors of cortical origin, removed from adult patients, the only enzymic activity found was the conversion of estradiol to estrone. In one tumor of cerebellar origin removed from an 11-year-old boy, the following conversions were found: pregnenolone to progesterone, testosterone to either androstenedione or estradiol, and estradiol to estrone. These results demonstrate that human astrocytomas can transform steroids to compounds with modified hormonal activity. These compounds formed by the tumorous tissue can affect brain function, which may be of clinical significance. Furthermore, these results may add important parameters for biochemical characterization of neoplastic brain tissues.

  13. miR-367 promotes proliferation and stem-like traits in medulloblastoma cells

    PubMed Central

    Kaid, Carolini; Silva, Patrícia B G; Cortez, Beatriz A; Rodini, Carolina O; Semedo-Kuriki, Patricia; Okamoto, Oswaldo K

    2015-01-01

    In medulloblastoma, abnormal expression of pluripotency factors such as LIN28 and OCT4 has been correlated with poor patient survival. The miR-302/367 cluster has also been shown to control self-renewal and pluripotency in human embryonic stem cells and induced pluripotent stem cells, but there is limited, mostly correlational, information about these pluripotency-related miRNA in cancer. We evaluated whether aberrant expression of such miRNA could affect tumor cell behavior and stem-like traits, thereby contributing to the aggressiveness of medulloblastoma cells. Basal expression of primary and mature forms of miR-367 were detected in four human medulloblastoma cell lines and expression of the latter was found to be upregulated upon enforced expression of OCT4A. Transient overexpression of miR-367 significantly enhanced tumor features typically correlated with poor prognosis; namely, cell proliferation, 3-D tumor spheroid cell invasion and the ability to generate neurosphere-like structures enriched in CD133 expressing cells. A concurrent downregulation of the miR-367 cancer-related targets RYR3, ITGAV and RAB23, was also detected in miR-367-overexpressing cells. Overall, these findings support the pro-oncogenic activity of miR-367 in medulloblastoma and reveal a possible mechanism contributing to tumor aggressiveness, which could be further explored to improve patient stratification and treatment of this important type of pediatric brain cancer. PMID:26250335

  14. Ion transporters in brain tumors

    PubMed Central

    Cong, Damin; Zhu, Wen; Kuo, John S.; Hu, Shaoshan; Sun, Dandan

    2015-01-01

    Ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions. They have recently emerged as important players in cancer progression. In this review, we discussed two important ion transporter proteins, sodium-potassium-chloride cotransporter isoform 1 (NKCC-1) and sodium-hydrogen exchanger isoform 1 (NHE-1) in Glioblastoma multiforme (GBM) and other malignant tumors. NKCC-1 is a Na+-dependent Cl− transporter that mediates the movement of Na+, K+, and Cl− ions across the plasma membrane and maintains cell volume and intracellular K+ and Cl− homeostasis. NHE-1 is a ubiquitously expressed cell membrane protein which regulates intracellular pH (pHi) and extracellular microdomain pH (pHe) homeostasis and cell volume. Here, we summarized recent pre-clinical experimental studies on NKCC-1 and NHE-1 in GBM and other malignant tumors, such as breast cancer, hepatocellular carcinoma, and lung cancer. These studies illustrated that pharmacological inhibition or down-regulation of these ion transporter proteins reduces proliferation, increases apoptosis, and suppresses migration and invasion of cancer cells. These new findings reveal the potentials of these ion transporters as new targets for cancer diagnosis and/or treatment. PMID:25620102

  15. No role of IFITM3 in brain tumor formation in vivo

    PubMed Central

    Kim, Ella L.; Bros, Matthias; Giese, Alf

    2016-01-01

    Glioblastoma multiforme (GBM) is one of the most lethal solid tumors in adults. Despite aggressive treatment approaches for patients, GBM recurrence is inevitable, in part due to the existence of stem-like brain tumor-propagating cells (BTPCs), which produce factors rendering them resistant to radio- and chemotherapy. Comparative transcriptome analysis of irradiated, patient-derived BTPCs revealed a significant upregulation of the interferon-inducible transmembrane protein 3 (IFITM3), suggesting the protein as a factor mediating radio resistance. Previously, IFITM3 has been described to affect glioma cells; therefore, the role of IFITM3 in the formation and progression of brain tumors has been investigated in vivo. Intracranial implantation studies using radio-selected BTPCs alongside non-irradiated parental BTPCs in immunodeficient mice displayed no influence of irradiation on animal survival. Furthermore, gain and loss of function studies using BTPCs ectopically expressing IFITM3 or having IFITM3 down-modulated by a shRNA approach, did affect neither tumor growth nor animal survival. Additionally, a syngeneic model based on the mouse glioma cell line GL261 was applied in order to consider the possibility that IFITM3 relies on an intact immune system to unfold its tumorigenic potential. GL261 cells ectopically expressing IFITM3 were implanted into the striatum of immunocompetent mice without influencing the survival of glioma-bearing animals. Lastly, the vasculature and the extent of microglia/macrophage invasion into the tumor were studied in BTPC and GL261 tumors but neither parameter was altered by IFITM3. This report presents for the first time that IFITM3 is upregulated in patient-derived BTPCs upon irradiation but does not affect brain tumor formation or progression in vivo. PMID:27835870

  16. Brain tumors: Special characters for research and banking

    PubMed Central

    Kheirollahi, Majid; Dashti, Sepideh; Khalaj, Zahra; Nazemroaia, Fatemeh; Mahzouni, Parvin

    2015-01-01

    A brain tumor is an intracranial neoplasm within the brain or in the central spinal canal. Primary malignant brain tumors affect about 200,000 people worldwide every year. Brain cells have special characters. Due to the specific properties of brain tumors, including epidemiology, growth, and division, investigation of brain tumors and the interpretation of results is not simple. Research to identify the genetic alterations of human tumors improves our knowledge of tumor biology, genetic interactions, progression, and preclinical therapeutic assessment. Obtaining data for prevention, diagnosis, and therapy requires sufficient samples, and brain tumors have a wide range. As a result, establishing the bank of brain tumors is very important and essential. PMID:25625110

  17. Neurocutaneous Syndromes and Brain Tumors.

    PubMed

    Ullrich, Nicole J

    2016-10-01

    The etiology of most childhood cancer remains largely unknown, but is likely attributable to random or induced genetic aberrations in somatic tissue. However, a subset of children develops cancer in the setting of an underlying inheritable condition involving a germline genetic mutation or chromosomal aberration. The term "neurocutaneous syndrome" encompasses a group of multisystem, hereditary disorders that are associated with skin manifestations as well as central and/or peripheral nervous system lesions of variable severity. This review outlines the central nervous system tumors associated with underlying neurocutaneous disorders, including neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis, tuberous sclerosis complex, Von Hippel Lindau, and nevoid basal cell carcinoma syndrome. Recognizing the presence of an underlying syndrome is critically important to both optimizing clinical care and treatment as well as genetic counseling and monitoring of these affected patients and their families.

  18. Brain Tumor Epidemiology: Consensus from the Brain Tumor Epidemiology Consortium (BTEC)

    PubMed Central

    Bondy, Melissa L.; Scheurer, Michael E.; Malmer, Beatrice; Barnholtz-Sloan, Jill S.; Davis, Faith G.; Il’yasova, Dora; Kruchko, Carol; McCarthy, Bridget J.; Rajaraman, Preetha; Schwartzbaum, Judith A.; Sadetzki, Siegal; Schlehofer, Brigitte; Tihan, Tarik; Wiemels, Joseph L.; Wrensch, Margaret; Buffler, Patricia A.

    2010-01-01

    Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings possibly due to small sample sizes in individual studies and differences between studies in subjects, tumor types, and methods of classification. Individual studies have generally lacked sufficient sample size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups such as pediatric brain tumors, the etiology of rare glioma subtypes, such as oligodendroglioma, and meningioma, which not uncommon, has only recently been systematically registered in the US. There is also a pressing need to bring more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. We review the group’s consensus on the current state of scientific findings and present a consensus on research priorities to identify the important areas the science should move to address. PMID:18798534

  19. Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors

    PubMed Central

    Sampson, John H.; Crotty, Laura E.; Lee, Samson; Archer, Gary E.; Ashley, David M.; Wikstrand, Carol J.; Hale, Laura P.; Small, Clayton; Dranoff, Glenn; Friedman, Allan H.; Friedman, Henry S.; Bigner, Darell D.

    2000-01-01

    The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibodydependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fc receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the “immunologically privileged” central nervous system. PMID:10852962

  20. Perspectives on Dual Targeting Delivery Systems for Brain Tumors.

    PubMed

    Gao, Huile

    2017-03-01

    Brain tumor remains one of the most serious threats to human beings. Different from peripheral tumors, drug delivery to brain tumor is largely restricted by the blood brain barrier (BBB). To fully conquer this barrier and specifically deliver drugs to brain tumor, dual targeting delivery systems were explored, which are functionalized with two active targeting ligands: one to the BBB and the other to the brain tumor. The development of dual targeting delivery system is still in its early stage, and attentions need to be paid to issues and concerns that remain unresolved in future studies.

  1. Brain Tumors - Multiple Languages: MedlinePlus

    MedlinePlus

    ... List of All Topics All Brain Tumors - Multiple Languages To use the sharing features on this page, please enable JavaScript. French (français) Japanese (日本語) Korean (한국어) Russian (Русский) Somali (af Soomaali) Spanish (español) Ukrainian (Українська) ...

  2. [Chemotherapy of brain tumors in aduts].

    PubMed

    Roth, P; Weller, M

    2015-04-01

    The treatment of patients with brain tumors has long been the domain of neurosurgery and radiotherapy but chemotherapy is now well established as an additional treatment option for many tumor entities in neuro-oncology. This is particularly true for patients with newly diagnosed and relapsing glioblastoma and anaplastic glioma as well as the treatment of medulloblastoma and primary lymphoma of the central nervous system (CNS). In addition to purely histopathological features, treatment decisions including those for chemotherapy are now based increasingly more on molecular tumor profiling. Within the group of gliomas these markers include the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and the 1p/19q status, which reflects the loss of genetic material on chromosome arms 1p and 19q. The presence of a 1p/19q codeletion is associated with a better prognosis and increased sensitivity to alkylating chemotherapy in patients with anaplastic gliomas.

  3. Subacute brain atrophy after radiation therapy for malignant brain tumor

    SciTech Connect

    Asai, A.; Matsutani, M.; Kohno, T.; Nakamura, O.; Tanaka, H.; Fujimaki, T.; Funada, N.; Matsuda, T.; Nagata, K.; Takakura, K.

    1989-05-15

    Brain atrophy with mental and neurologic deterioration developing a few months after radiation therapy in patients without residual or recurrent brain tumors has been recognized. Two illustrative case reports of this pathologic entity are presented. Six autopsy cases with this entity including the two cases were reviewed neurologically, radiographically, and histopathologically. All patients presented progressive disturbances of mental status and consciousness, akinesia, and tremor-like involuntary movement. Computerized tomography (CT) demonstrated marked enlargement of the ventricles, moderate widening of the cortical sulci, and a moderately attenuated CT number for the white matter in all six patients. Four of the six patients had CSF drainage (ventriculoperitoneal shunt or continuous lumbar drainage), however, none of them improved. Histologic examination demonstrated swelling and loss of the myelin sheath in the white matter in all patients, and reactive astrocytosis in three of the six patients. Neither prominent neuronal loss in the cerebral cortex or basal ganglia, nor axonal loss in the white matter was generally identified. The blood vessels of the cerebral cortex and white matter were normal. Ependymal layer and the surrounding brain tissue were normal in all patients. These findings suggested that this pathologic condition results from demyelination secondary to direct neurotoxic effect of irradiation. The authors' previous report was reviewed and the differential diagnoses, the risk factors for this pathologic entity, and the indication for radiation therapy in aged patients with a malignant brain tumor are discussed.

  4. Brain Tumor Database, a free relational database for collection and analysis of brain tumor patient information.

    PubMed

    Bergamino, Maurizio; Hamilton, David J; Castelletti, Lara; Barletta, Laura; Castellan, Lucio

    2015-03-01

    In this study, we describe the development and utilization of a relational database designed to manage the clinical and radiological data of patients with brain tumors. The Brain Tumor Database was implemented using MySQL v.5.0, while the graphical user interface was created using PHP and HTML, thus making it easily accessible through a web browser. This web-based approach allows for multiple institutions to potentially access the database. The BT Database can record brain tumor patient information (e.g. clinical features, anatomical attributes, and radiological characteristics) and be used for clinical and research purposes. Analytic tools to automatically generate statistics and different plots are provided. The BT Database is a free and powerful user-friendly tool with a wide range of possible clinical and research applications in neurology and neurosurgery. The BT Database graphical user interface source code and manual are freely available at http://tumorsdatabase.altervista.org.

  5. Brain tumor segmentation with Deep Neural Networks.

    PubMed

    Havaei, Mohammad; Davy, Axel; Warde-Farley, David; Biard, Antoine; Courville, Aaron; Bengio, Yoshua; Pal, Chris; Jodoin, Pierre-Marc; Larochelle, Hugo

    2017-01-01

    In this paper, we present a fully automatic brain tumor segmentation method based on Deep Neural Networks (DNNs). The proposed networks are tailored to glioblastomas (both low and high grade) pictured in MR images. By their very nature, these tumors can appear anywhere in the brain and have almost any kind of shape, size, and contrast. These reasons motivate our exploration of a machine learning solution that exploits a flexible, high capacity DNN while being extremely efficient. Here, we give a description of different model choices that we've found to be necessary for obtaining competitive performance. We explore in particular different architectures based on Convolutional Neural Networks (CNN), i.e. DNNs specifically adapted to image data. We present a novel CNN architecture which differs from those traditionally used in computer vision. Our CNN exploits both local features as well as more global contextual features simultaneously. Also, different from most traditional uses of CNNs, our networks use a final layer that is a convolutional implementation of a fully connected layer which allows a 40 fold speed up. We also describe a 2-phase training procedure that allows us to tackle difficulties related to the imbalance of tumor labels. Finally, we explore a cascade architecture in which the output of a basic CNN is treated as an additional source of information for a subsequent CNN. Results reported on the 2013 BRATS test data-set reveal that our architecture improves over the currently published state-of-the-art while being over 30 times faster.

  6. Stereotactic Radiosurgery in Treating Patients With Brain Tumors

    ClinicalTrials.gov

    2012-03-21

    Adult Central Nervous System Germ Cell Tumor; Adult Malignant Meningioma; Adult Medulloblastoma; Adult Noninfiltrating Astrocytoma; Adult Oligodendroglioma; Adult Craniopharyngioma; Adult Meningioma; Brain Metastases; Adult Ependymoma; Adult Pineal Parenchymal Tumor; Adult Brain Stem Glioma; Adult Infiltrating Astrocytoma; Mixed Gliomas; Stage IV Peripheral Primitive Neuroectodermal Tumor

  7. Photodynamic Therapy for Malignant Brain Tumors.

    PubMed

    Akimoto, Jiro

    2016-01-01

    Photodynamic therapy (PDT) using talaporfin sodium together with a semiconductor laser was approved in Japan in October 2003 as a less invasive therapy for early-stage lung cancer. The author believes that the principle of PDT would be applicable for controlling the invading front of malignant brain tumors and verified its efficacy through experiments using glioma cell lines and glioma xenograft models. An investigator-initiated clinical study was jointly conducted with Tokyo Women's Medical University with the support of the Japan Medical Association. Patient enrollment was started in May 2009 and a total of 27 patients were enrolled by March 2012. Of 22 patients included in efficacy analysis, 13 patients with newly diagnosed glioblastoma showed progression-free survival of 12 months, progression-free survival at the site of laser irradiation of 20 months, 1-year survival of 100%, and overall survival of 24.8 months. In addition, the safety analysis of the 27 patients showed that adverse events directly related to PDT were mild. PDT was approved in Japan for health insurance coverage as a new intraoperative therapy with the indication for malignant brain tumors in September 2013. Currently, the post-marketing investigation in the accumulated patients has been conducted, and the preparation of guidelines, holding training courses, and dissemination of information on the safe implementation of PDT using web sites and videos, have been promoted. PDT is expected to be a breakthrough for the treatment of malignant glioma as a tumor cell-selective less invasive therapy for the infiltrated functional brain area.

  8. Positron Scanner for Locating Brain Tumors

    DOE R&D Accomplishments Database

    Rankowitz, S.; Robertson, J. S.; Higinbotham, W. A.; Rosenblum, M. J.

    1962-03-01

    A system is described that makes use of positron emitting isotopes for locating brain tumors. This system inherently provides more information about the distribution of radioactivity in the head in less time than existing scanners which use one or two detectors. A stationary circular array of 32 scintillation detectors scans a horizontal layer of the head from many directions simultaneously. The data, consisting of the number of counts in all possible coincidence pairs, are coded and stored in the memory of a Two-Dimensional Pulse-Height Analyzer. A unique method of displaying and interpreting the data is described that enables rapid approximate analysis of complex source distribution patterns. (auth)

  9. Multifunctional Nanoparticles for Brain Tumor Diagnosis and Therapy

    PubMed Central

    Cheng, Yu; Morshed, Ramin; Auffinger, Brenda; Tobias, Alex L.; Lesniak, Maciej S.

    2013-01-01

    Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells. Furthermore, there is a need for improvements in brain tumor imaging to allow for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional nanoparticles offer the potential to improve upon many of these issues and may lead to breakthroughs in brain tumor management. In this review, we discuss the diagnostic and therapeutic applications of nanoparticles for brain tumors with an emphasis on innovative approaches in tumor targeting, tumor imaging, and therapeutic agent delivery. Clinically feasible nanoparticle administration strategies for brain tumor patients are also examined. Furthermore, we address the barriers towards clinical implementation of multifunctional nanoparticles in the context of brain tumor management. PMID:24060923

  10. Acetate supplementation as a means of inducing glioblastoma stem-like cell growth arrest

    PubMed Central

    Long, Patrick M.; Tighe, Scott W.; Driscoll, Heather E.; Fortner, Karen A.; Viapiano, Mariano S.; Jaworski, Diane M.

    2015-01-01

    Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-L-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth. PMID:25573156

  11. Acetate supplementation as a means of inducing glioblastoma stem-like cell growth arrest.

    PubMed

    Long, Patrick M; Tighe, Scott W; Driscoll, Heather E; Fortner, Karen A; Viapiano, Mariano S; Jaworski, Diane M

    2015-08-01

    Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-l-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth.

  12. Maternal high fat diet promotion of mammary tumor risk in adult progeny is associated with early expansion of mammary cancer stem-like cells and increased maternal oxidative environment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many adult chronic diseases might be programmed during early life by maternal nutritional history. Here, we evaluated effects of maternal high fat diet on mammary gland development and tumor formation in adult progeny. Female Wnt-1 transgenic mice exposed to high fat (HFD, 45% kcal fat) or control C...

  13. Brain tumor imaging: imaging brain metastasis using a brain-metastasizing breast adenocarcinoma.

    PubMed

    Madden, Kelley S; Zettel, Martha L; Majewska, Ania K; Brown, Edward B

    2013-03-01

    Brain metastases from primary or secondary breast tumors are difficult to model in the mouse. When metastatic breast cancer cell lines are injected directly into the arterial circulation, only a small fraction of cells enter the brain to form metastatic foci. To study the molecular and cellular mechanisms of brain metastasis, we have transfected MB-231BR, a brain-homing derivative of a human breast adenocarcinoma line MDA-MB-231, with the yellow fluorescent protein (YFP) variant Venus. MB-231BR selectively enters the brain after intracardiac injection into the arterial circulation, resulting in accumulation of fluorescent foci of cells in the brain that can be viewed by standard fluorescence imaging procedures. We describe how to perform the intracardiac injection and the parameters used to quantify brain metastasis in brain sections by standard one-photon fluorescence imaging. The disadvantage of this model is that the kinetics of growth over time cannot be determined in the same animal. In addition, the injection technique does not permit precise placement of tumor cells within the brain. This model is useful for determining the molecular determinants of brain tumor metastasis.

  14. Two-stage induced differentiation of OCT4+/Nanog+ stem-like cells in lung adenocarcinoma

    PubMed Central

    Ma, Meili; Lou, Yuqing; Zhang, Yanwei; Wu, Lixia; Chang, David W.; Zhao, Picheng; Dong, Qianggang; Wu, Xifeng; Han, Baohui

    2016-01-01

    Stem-like cells in solid tumors are purported to contribute to cancer development and poor treatment outcome. The abilities to self-renew, differentiate, and resist anticancer therapies are hallmarks of these rare cells, and steering them into lineage commitment may be one strategy to curb cancer development or progression. Vitamin D is a prohormone that can alter cell growth and differentiation and may induce the differentiation cancer stem-like cells. In this study, octamer-binding transcription factor 4 (OCT4)-positive/Nanog homeobox (Nanog)- positive lung adenocarcinoma stem-like cells (LACSCs) were enriched from spheroid cultured SPC-A1 cells and differentiated by a two-stage induction (TSI) method, which involved knockdown of hypoxia-inducible factor 1-alpha (HIF1α) expression (first stage) followed by sequential induction with 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3, VD3) and suberoylanilide hydroxamic acid (SAHA) treatment (second stage). The results showed the HIF1α-knockdowned cells displayed diminished cell invasion and clonogenic activities. Moreover, the TSI cells highly expressed tumor suppressor protein p63 (P63) and forkhead box J1 (FOXJ1) and lost stem cell characteristics, including absent expression of OCT4 and Nanog. These cells regained sensitivity to cisplatin in vitro while losing tumorigenic capacity and decreased tumor cell proliferation in vivo. Our results suggest that induced transdifferentiation of LACSCs by vitamin D and SAHA may become novel therapeutic avenue to alter tumor cell phenotypes and improve patient outcome. SIGNIFICANCE STATEMENT The development and progression of lung cancer may involve rare population of stem-like cells that have the ability to grow, differentiate, and resist drug treatment. However, current therapeutic strategies have mostly focused on tumor characteristics and neglected the potential source of cells that may contribute to poor clinical outcome. We generated lung adenocarcinoma stem-like cells from

  15. Brain tumors in man and animals: report of a workshop.

    PubMed Central

    1986-01-01

    This report summarizes the results of a workshop on brain tumors in man and animals. Animals, especially rodents are often used as surrogates for man to detect chemicals that have the potential to induce brain tumors in man. Therefore, the workshop was focused mainly on brain tumors in the F344 rat and B6C3F1 mouse because of the frequent use of these strains in long-term carcinogenesis studies. Over 100 brain tumors in F344 rats and more than 50 brain tumors in B6C3F1 mice were reviewed and compared to tumors found in man and domestic or companion animals. In the F344 rat, spontaneous brain tumors are uncommon, most are of glial origin, and the highly undifferentiated glioblastoma multiforme, a frequent tumor of man was not found. In the B6C3F1 mouse, brain tumors are exceedingly rare. Lipomas of the choroid plexus and meningiomas together account for more than 50% of the tumors found. Both rodent strains examined have low background rates and very little variability between control groups. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. PMID:3536473

  16. Growth patterns of microscopic brain tumors

    NASA Astrophysics Data System (ADS)

    Sander, Leonard M.; Deisboeck, Thomas S.

    2002-11-01

    Highly malignant brain tumors such as glioblastoma multiforme form complex growth patterns in vitro in which invasive cells organize in tenuous branches. Here, we formulate a chemotaxis model for this sort of growth. A key element controlling the pattern is homotype attraction, i.e., the tendency for invasive cells to follow pathways previously explored. We investigate this in two ways: we show that there is an intrinsic instability in the model, which leads to branch formation. We also give a discrete description for the expansion of the invasive zone, and a continuum model for the nutrient supply. The results indicate that both strong heterotype chemotaxis and strong homotype chemoattraction are required for branch formation within the invasive zone. Our model thus can give a way to assess the importance of the various processes, and a way to explore and analyze transitions between different growth regimes.

  17. Fractal analysis of tumoral lesions in brain.

    PubMed

    Martín-Landrove, Miguel; Pereira, Demian; Caldeira, María E; Itriago, Salvador; Juliac, María

    2007-01-01

    In this work, it is proposed a method for supervised characterization and classification of tumoral lesions in brain, based on the analysis of irregularities at the lesion contour on T2-weighted MR images. After the choice of a specific image, a segmentation procedure with a threshold selected from the histogram of intensity levels is applied to isolate the lesion, the contour is detected through the application of a gradient operator followed by a conversion to a "time series" using a chain code procedure. The correlation dimension is calculated and analyzed to discriminate between normal or malignant structures. The results found showed that it is possible to detect a differentiation between benign (cysts) and malignant (gliomas) lesions suggesting the potential of this method as a diagnostic tool.

  18. Neural stem cell-based gene therapy for brain tumors.

    PubMed

    Kim, Seung U

    2011-03-01

    Advances in gene-based medicine since 1990s have ushered in new therapeutic strategy of gene therapy for inborn error genetic diseases and cancer. Malignant brain tumors such as glioblastoma multiforme and medulloblastoma remain virtually untreatable and lethal. Currently available treatment for brain tumors including radical surgical resection followed by radiation and chemotherapy, have substantially improved the survival rate in patients suffering from these brain tumors; however, it remains incurable in large proportion of patients. Therefore, there is substantial need for effective, low-toxicity therapies for patients with malignant brain tumors, and gene therapy targeting brain tumors should fulfill this requirement. Gene therapy for brain tumors includes many therapeutic strategies and these strategies can be grouped in two major categories: molecular and immunologic. The widely used molecular gene therapy approach is suicide gene therapy based on the conversion of non-toxic prodrugs into active anticancer agents via introduction of enzymes and genetic immunotherapy involves the gene transfer of immune-stimulating cytokines including IL-4, IL-12 and TRAIL. For both molecular and immune gene therapy, neural stem cells (NSCs) can be used as delivery vehicle of therapeutic genes. NSCs possess an inherent tumor tropism that supports their use as a reliable delivery vehicle to target therapeutic gene products to primary brain tumors and metastatic cancers throughout the brain. Significance of the NSC-based gene therapy for brain tumor is that it is possible to exploit the tumor-tropic property of NSCs to mediate effective, tumor-selective therapy for primary and metastatic cancers in the brain and outside, for which no tolerated curative treatments are currently available.

  19. Vascular Transdifferentiation in the CNS: A Focus on Neural and Glioblastoma Stem-Like Cells

    PubMed Central

    Bauchet, Luc; Rothhut, Bernard; Hugnot, Jean-Philippe

    2016-01-01

    Glioblastomas are devastating and extensively vascularized brain tumors from which glioblastoma stem-like cells (GSCs) have been isolated by many groups. These cells have a high tumorigenic potential and the capacity to generate heterogeneous phenotypes. There is growing evidence to support the possibility that these cells are derived from the accumulation of mutations in adult neural stem cells (NSCs) as well as in oligodendrocyte progenitors. It was recently reported that GSCs could transdifferentiate into endothelial-like and pericyte-like cells both in vitro and in vivo, notably under the influence of Notch and TGFβ signaling pathways. Vascular cells derived from GBM cells were also observed directly in patient samples. These results could lead to new directions for designing original therapeutic approaches against GBM neovascularization but this specific reprogramming requires further molecular investigations. Transdifferentiation of nontumoral neural stem cells into vascular cells has also been described and conversely vascular cells may generate neural stem cells. In this review, we present and discuss these recent data. As some of them appear controversial, further validation will be needed using new technical approaches such as high throughput profiling and functional analyses to avoid experimental pitfalls and misinterpretations. PMID:27738435

  20. Thermal imaging of brain tumors in a rat glioma model

    NASA Astrophysics Data System (ADS)

    Papaioannou, Thanassis; Thompson, Reid C.; Kateb, Babak; Sorokoumov, Oleg; Grundfest, Warren S.; Black, Keith L.

    2002-05-01

    We have explored the capability of thermal imaging for the detection of brain tumors in a rat glioma mode. Fourteen Wistar rats were injected stereotactically with 100,000 C6 glioma cells. Approximately one and two weeks post implantation, the rats underwent bilateral craniotomy and the exposed brain surface was imaged with a short wave thermal camera. Thermal images were obtained at both low (approximately 28.7 degree(s)C) and high (approximately 38 degree(s)C) core temperatures. Temperature gradients between the tumor site and the contralateral normal brain were calculated. Overall, the tumors appeared cooler than normal brain, for both high and low core temperatures. Average temperature difference between tumor and normal brain were maximal in more advanced tumors (two weeks) and at higher core temperatures. At one week (N equals 6), the average temperature gradient between tumor and normal sites was 0.1 degree(s)C and 0.2 degree(s)C at low and high core temperatures respectively (P(greater than)0.05). At two weeks (N equals 8), the average temperature gradient was 0.3 degree(s)C and 0.7 degree(s)C at low and high core temperatures respectively (P<0.05). We conclude that thermal imaging can detect temperature differences between tumor and normal brain tissue in this model, particularly in more advanced tumors. Thermal imaging may provide a novel means to identify brain tumors intraoperatively.

  1. Parallel optimization of tumor model parameters for fast registration of brain tumor images

    NASA Astrophysics Data System (ADS)

    Zacharaki, Evangelia I.; Hogea, Cosmina S.; Shen, Dinggang; Biros, George; Davatzikos, Christos

    2008-03-01

    The motivation of this work is to register MR brain tumor images with a brain atlas. Such a registration method can make possible the pooling of data from different brain tumor patients into a common stereotaxic space, thereby enabling the construction of statistical brain tumor atlases. Moreover, it allows the mapping of neuroanatomical brain atlases into the patient's space, for segmenting brains and thus facilitating surgical or radiotherapy treatment planning. However, the methods developed for registration of normal brain images are not directly applicable to the registration of a normal atlas with a tumor-bearing image, due to substantial dissimilarity and lack of equivalent image content between the two images, as well as severe deformation or shift of anatomical structures around the tumor. Accordingly, a model that can simulate brain tissue death and deformation induced by the tumor is considered to facilitate the registration. Such tumor growth simulation models are usually initialized by placing a small seed in the normal atlas. The shape, size and location of the initial seed are critical for achieving topological equivalence between the atlas and patient's images. In this study, we focus on the automatic estimation of these parameters, pertaining to tumor simulation. In particular, we propose an objective function reflecting feature-based similarity and elastic stretching energy and optimize it with APPSPACK (Asynchronous Parallel Pattern Search), for achieving significant reduction of the computational cost. The results indicate that the registration accuracy is high in areas around the tumor, as well as in the healthy portion of the brain.

  2. Brain necrosis after radiotherapy for primary intracerebral tumor.

    PubMed

    Hohwieler, M L; Lo, T C; Silverman, M L; Freidberg, S R

    1986-01-01

    Radiotherapy is a standard postoperative treatment for cerebral glioma. We have observed the onset of symptoms related to brain necrosis, as opposed to recurrent tumor, in surviving patients. This has been manifest as dementia with a computed tomographic pattern of low density in the frontal lobe uninvolved with tumor, but within the field of radiotherapy. Two patients presented with mass lesions also unrelated to recurrent tumor. We question the necessity of full brain irradiation and suggest that radiotherapy techniques be altered to target the tumor and not encompass the entire brain.

  3. Yoga Therapy in Treating Patients With Malignant Brain Tumors

    ClinicalTrials.gov

    2017-01-17

    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

  4. Patients With Brain Tumors: Who Receives Postacute Occupational Therapy Services?

    PubMed

    Chan, Vincy; Xiong, Chen; Colantonio, Angela

    2015-01-01

    Data on the utilization of occupational therapy among patients with brain tumors have been limited to those with malignant tumors and small samples of patients outside North America in specialized palliative care settings. We built on this research by examining the characteristics of patients with brain tumors who received postacute occupational therapy services in Ontario, Canada, using health care administrative data. Between fiscal years 2004-2005 and 2008-2009, 3,199 patients with brain tumors received occupational therapy services in the home care setting after hospital discharge; 12.4% had benign brain tumors, 78.2% had malignant brain tumors, and 9.4% had unspecified brain tumors. However, patients with benign brain tumors were older (mean age=63.3 yr), and a higher percentage were female (65.2%). More than 90% of patients received in-home occupational therapy services. Additional research is needed to examine the significance of these differences and to identify factors that influence access to occupational therapy services in the home care setting.

  5. Brain tumors in children with neurofibromatosis: additional neuropsychological morbidity?

    PubMed Central

    De Winter, A. E.; Moore, B. D.; Slopis, J. M.; Ater, J. L.; Copeland, D. R.

    1999-01-01

    Neurofibromatosis type 1 is a common autosomal dominant genetic disorder associated with numerous physical anomalies and an increased incidence of neuropsychological impairment. Tumors of the CNS occur in approximately 15% of children with neurofibromatosis, presenting additional risk for cognitive impairment. This study examines the impact of an additional diagnosis of brain tumor on the cognitive profile of children with neurofibromatosis. A comprehensive battery of neuropsychological tests was administered to 149 children with neurofibromatosis. Thirty-six of these children had a codiagnosis of brain tumor. A subset of 36 children with neurofibromatosis alone was matched with the group of children diagnosed with neurofibromatosis and brain tumor. Although mean scores of the neurofibromatosis plus brain tumor group were, in general, lower than those of the neurofibromatosis alone group, these differences were not statistically significant. Children in the neurofibromatosis plus brain tumor group who received cranial irradiation (n = 9) demonstrated weaker academic abilities than did children with brain tumor who had not received that treatment. These results suggest that neurofibromatosis is associated with impairments in cognitive functioning, but the severity of the problems is not significantly exacerbated by the codiagnosis of a brain tumor unless treatment includes cranial irradiation. PMID:11550319

  6. Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors

    PubMed Central

    Wollmann, Guido; Drokhlyansky, Eugene; Davis, John N.; Cepko, Connie

    2015-01-01

    ABSTRACT High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on in vitro infections of normal and tumor cells, we selected two viruses to test in vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain. IMPORTANCE Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death. We

  7. Pediatric Brain Tumors: Genomics and Epigenomics Pave the Way.

    PubMed

    Fontebasso, Adam M; Jabado, Nada

    2015-01-01

    Primary malignant brain tumors remain a disproportionate cause of morbidity and mortality in humans. A number of studies exploring the cancer genome of brain tumors across ages using integrated genetics and epigenetics and next-generation sequencing technologies have recently emerged. This has led to considerable advances in the understanding of the basic biology and pathogenesis of brain tumors, including the most malignant and common variants in children: gliomas and medulloblastoma. Notably, studies of pediatric brain tumors have identified unexpected oncogenic pathways implicated in tumorigenesis. These range from a single pathway/molecule defect such as abnormalities of the mitogen-activated protein kinase pathway, considered to be a hallmark of pilocytic astrocytomas, to alterations in the epigenome as a critical component altered in many subgroups of high-grade brain tumors. Importantly, the type, timing, and spatial clustering of these molecular alterations provide a better understanding of the pathogenesis of the respective brain tumor they target and critical markers for therapy that will help refine pathological grading. We summarize these novel findings in pediatric brain tumors, which also are put in the context of the evolving notion of molecular pathology, now a mandated tool for proper classification and therapy assignment in the clinical setting.

  8. High Toxoplasma gondii Seropositivity among Brain Tumor Patients in Korea

    PubMed Central

    Jung, Bong-Kwang; Song, Hyemi; Kim, Min-Jae; Cho, Jaeeun; Shin, Eun-Hee; Chai, Jong-Yil

    2016-01-01

    Toxoplasma gondii is an intracellular protozoan that can modulate the environment of the infected host. An unfavorable environment modulated by T. gondii in the brain includes tumor microenvironment. Literature has suggested that T. gondii infection is associated with development of brain tumors. However, in Korea, epidemiological data regarding this correlation have been scarce. In this study, in order to investigate the relationship between T. gondii infection and brain tumor development, we investigated the seroprevalence of T. gondii among 93 confirmed brain tumor patients (various histological types, including meningioma and astrocytoma) in Korea using ELISA. The results revealed that T. gondii seropositivity among brain tumor patients (18.3%) was significantly (P<0.05) higher compared with that of healthy controls (8.6%). The seropositivity of brain tumor patients showed a significant age-tendency, i.e., higher in younger age group, compared with age-matched healthy controls (P<0.05). In conclusion, this study supports the close relationship between T. gondii infection and incidence of brain tumors. PMID:27180580

  9. Novel treatment strategies for brain tumors and metastases

    PubMed Central

    El-Habashy, Salma E.; Nazief, Alaa M.; Adkins, Chris E.; Wen, Ming Ming; El-Kamel, Amal H.; Hamdan, Ahmed M.; Hanafy, Amira S.; Terrell, Tori O.; Mohammad, Afroz S.; Lockman, Paul R.; Nounou, Mohamed Ismail

    2015-01-01

    This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application. PMID:24998288

  10. Brain tumor classification of microscopy images using deep residual learning

    NASA Astrophysics Data System (ADS)

    Ishikawa, Yota; Washiya, Kiyotada; Aoki, Kota; Nagahashi, Hiroshi

    2016-12-01

    The crisis rate of brain tumor is about one point four in ten thousands. In general, cytotechnologists take charge of cytologic diagnosis. However, the number of cytotechnologists who can diagnose brain tumors is not sufficient, because of the necessity of highly specialized skill. Computer-Aided Diagnosis by computational image analysis may dissolve the shortage of experts and support objective pathological examinations. Our purpose is to support a diagnosis from a microscopy image of brain cortex and to identify brain tumor by medical image processing. In this study, we analyze Astrocytes that is a type of glia cell of central nerve system. It is not easy for an expert to discriminate brain tumor correctly since the difference between astrocytes and low grade astrocytoma (tumors formed from Astrocyte) is very slight. In this study, we present a novel method to segment cell regions robustly using BING objectness estimation and to classify brain tumors using deep convolutional neural networks (CNNs) constructed by deep residual learning. BING is a fast object detection method and we use pretrained BING model to detect brain cells. After that, we apply a sequence of post-processing like Voronoi diagram, binarization, watershed transform to obtain fine segmentation. For classification using CNNs, a usual way of data argumentation is applied to brain cells database. Experimental results showed 98.5% accuracy of classification and 98.2% accuracy of segmentation.

  11. Efficacy of cabazitaxel in mouse models of pediatric brain tumors

    PubMed Central

    Girard, Emily; Ditzler, Sally; Lee, Donghoon; Richards, Andrew; Yagle, Kevin; Park, Joshua; Eslamy, Hedieh; Bobilev, Dmitri; Vrignaud, Patricia; Olson, James

    2015-01-01

    Background There is an unmet need in the treatment of pediatric brain tumors for chemotherapy that is efficacious, avoids damage to the developing brain, and crosses the blood-brain barrier. These experiments evaluated the efficacy of cabazitaxel in mouse models of pediatric brain tumors. Methods The antitumor activity of cabazitaxel and docetaxel were compared in flank and orthotopic xenograft models of patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, and central nervous system primitive neuroectodermal tumor (CNS-PNET). Efficacy of cabazitaxel and docetaxel were also assessed in the Smo/Smo spontaneous mouse medulloblastoma tumor model. Results This study observed significant tumor growth inhibition in pediatric patient-derived flank xenograft tumor models of ATRT, medulloblastoma, and CNS-PNET after treatment with either cabazitaxel or docetaxel. Cabazitaxel, but not docetaxel, treatment resulted in sustained tumor growth inhibition in the ATRT and medulloblastoma flank xenograft models. Patient-derived orthotopic xenograft models of ATRT, medulloblastoma, and CNS-PNET showed significantly improved survival with treatment of cabazitaxel. Conclusion These data support further testing of cabazitaxel as a therapy for treating human pediatric brain tumors. PMID:25140037

  12. Cytogenetics and molecular genetics of childhood brain tumors.

    PubMed Central

    Biegel, J. A.

    1999-01-01

    Considerable progress has been made toward improving survival for children with brain tumors, and yet there is still relatively little known regarding the molecular genetic events that contribute to tumor initiation or progression. Nonrandom patterns of chromosomal deletions in several types of childhood brain tumors suggest that the loss or inactivation of tumor suppressor genes are critical events in tumorigenesis. Deletions of chromosomal regions 10q, 11 and 17p, and example, are frequent events in medulloblastoma, whereas loss of a region within 22q11.2, which contains the INI1 gene, is involved in the development of atypical teratoid and rhabdoid tumors. A review of the cytogenetic and molecular genetic changes identified to date in childhood brain tumors will be presented. PMID:11550309

  13. Computational modeling of brain tumors: discrete, continuum or hybrid?

    NASA Astrophysics Data System (ADS)

    Wang, Zhihui; Deisboeck, Thomas S.

    In spite of all efforts, patients diagnosed with highly malignant brain tumors (gliomas), continue to face a grim prognosis. Achieving significant therapeutic advances will also require a more detailed quantitative understanding of the dynamic interactions among tumor cells, and between these cells and their biological microenvironment. Data-driven computational brain tumor models have the potential to provide experimental tumor biologists with such quantitative and cost-efficient tools to generate and test hypotheses on tumor progression, and to infer fundamental operating principles governing bidirectional signal propagation in multicellular cancer systems. This review highlights the modeling objectives of and challenges with developing such in silico brain tumor models by outlining two distinct computational approaches: discrete and continuum, each with representative examples. Future directions of this integrative computational neuro-oncology field, such as hybrid multiscale multiresolution modeling are discussed.

  14. Isolation of stem-like cells from spontaneous feline mammary carcinomas: Phenotypic characterization and tumorigenic potential

    SciTech Connect

    Barbieri, Federica; Wurth, Roberto; Ratto, Alessandra; Campanella, Chiara; Vito, Guendalina; Thellung, Stefano; Daga, Antonio; Cilli, Michele; Ferrari, Angelo; Florio, Tullio

    2012-04-15

    Current carcinogenesis theory states that only a small subset of tumor cells, the cancer stem cells or tumor initiating cells (TICs), are responsible for tumor formation and progression. Human breast cancer-initiating cells have been identified as CD44-expressing cells, which retain tumorigenic activity and display stem cell-like properties. Spontaneous feline mammary carcinoma (FMC) is an aggressive cancer, which shows biological similarities to the human tumor counterpart. We report the isolation and phenotypic characterization of FMC-derived stem/progenitor cells, showing in vitro self-renewal, long-lasting proliferation and in vivo tumorigenicity. Twenty-one FMC samples were collected, histologically classified and characterized for the expression of Ki67, EGFR, ER-{alpha} and CD44, by immunohistochemistry. By culture in stem cell permissive conditions, we isolated, from 13 FMCs, a CD44-positive subpopulation able to survive and proliferate in vitro as mammospheres of different sizes and morphologies. When injected in NOD/SCID mice, FMC stem-like cells initiate tumors, generating cell heterogeneity and recapitulating the original histotype. In serum-containing medium, spheroid cells showed differentiation properties as shown by morphological changes, the loss of CD44 expression and tumorigenic potential. These data show that stem-defined culture of FMC enriches for TICs and validate the use of these cells as a suitable model for comparative oncology studies of mammary biology and testing therapeutic strategies aimed at eradicating TICs. -- Highlights: Black-Right-Pointing-Pointer Feline mammary carcinoma contain a sub-population of stem-like cells expressing CD44 Black-Right-Pointing-Pointer These grow as spheres in serum-free medium and self-renew Black-Right-Pointing-Pointer Isolated stem-like cancer cells initiate tumor in immunodeficient mice Black-Right-Pointing-Pointer Xenografted tumors are phenotypically similar to the original tumor Black

  15. Cilengitide in Treating Children With Refractory Primary Brain Tumors

    ClinicalTrials.gov

    2013-09-27

    Childhood Central Nervous System Germ Cell Tumor; 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 Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  16. Labeled Putrescine as a Probe in Brain Tumors

    NASA Astrophysics Data System (ADS)

    Volkow, Nora; Goldman, Stephen S.; Flamm, Eugene S.; Cravioto, Humberto; Wolf, Alfred P.; Brodie, Jonathan D.

    1983-08-01

    The polyamine metabolism of transplanted N-nitrosomethylurea-derived rat glioma was determined with radiolabeled putrescine used as a marker for malignancy. The uptake of putrescine in vivo was complete within 5 minutes and was specific for tumor tissue. The conversion of putrescine to spermine and other metabolites by the tumor was rapid, in contrast to the case for adjacent normal brain. These results suggest that putrescine labeled with carbon-11 may be used as a positron-emission tomographic tracer for the selective metabolic imaging of brain tumor and may be used in an appropriate model as a marker for tumor growth rate.

  17. Applications of nanotechnology to imaging and therapy of brain tumors.

    PubMed

    Mohs, Aaron M; Provenzale, James M

    2010-08-01

    In the past decade, numerous advances in the understanding of brain tumor physiology, tumor imaging, and tumor therapy have been attained. In some cases, these advances have resulted from refinements of pre-existing technologies (eg, improvements of contrast-enhanced magnetic resonance imaging). In other instances, advances have resulted from development of novel technologies. The development of nanomedicine (ie, applications of nanotechnology to the field of medicine) is an example of the latter. In this review, the authors explain the principles that underlay nanoparticle design and function as well as the means by which nanoparticles can be used for imaging and therapy of brain tumors.

  18. Fractal analysis of microvascular networks in malignant brain tumors.

    PubMed

    Di Ieva, Antonio

    2012-01-01

    Brain tumors are characterized by a microvascular network which differs from normal brain vascularity. Different tumors show individual angiogenic patterns. Microvascular heterogeneity can also be observed within a neoplastic histotype. It has been shown that quantification of neoplastic microvascular patterns could be used in combination with the histological grade for tumor characterization and to refine clinical prognoses, even if no objective parameters have yet been validated. To overcome the limits of the Euclidean approach, we employ fractal geometry to analyze the geometric complexity underlying the microangioarchitectural networks in brain tumors. We have developed a computer-aided fractal-based analysis for the quantification of the microvascular patterns in histological specimens and ultra-high-field (7-Tesla) magnetic resonance images. We demonstrate that the fractal parameters are valid estimators of microvascular geometrical complexity. Furthermore, our analysis allows us to demonstrate the high geometrical variability underlying the angioarchitecture of glioblastoma multiforme and to differentiate low-grade from malignant tumors in histological specimens and radiological images. Based on the results of this study, we speculate the existence of a gradient in the geometrical complexity of microvascular networks from those in the normal brain to those in malignant brain tumors. Here, we summarize a new methodology for the application of fractal analysis to the study of the microangioarchitecture of brain tumors; we further suggest this approach as a tool for quantifying and categorizing different neoplastic microvascular patterns and as a potential morphometric biomarker for use in clinical practice.

  19. Clinical applications of choline PET/CT in brain tumors.

    PubMed

    Giovannini, Elisabetta; Lazzeri, Patrizia; Milano, Amalia; Gaeta, Maria Chiara; Ciarmiello, Andrea

    2015-01-01

    Malignant gliomas and metastatic tumors are the most common forms of brain tumors. From a clinical perspective, neuroimaging plays a significant role, in diagnosis, treatment planning, and follow-up. To date MRI is considered the current clinical gold standard for imaging, however, despite providing superior structural detail it features poor specificity in identifying viable tumors in brain treated with surgery, radiation, or chemotherapy. In the last years functional neuroimaging has become largely widespread thanks to the use of molecular tracers employed in cellular metabolism which has significantly improved the management of patients with brain tumors, especially in the post-treatment phase. Despite the considerable progress of molecular imaging in oncology its use in the diagnosis of brain tumors is still limited by a few wellknown technical problems. Because 18F-FDG, the most common radiotracer used in oncology, is avidly accumulated by normal cortex, the low tumor/background signal ratio makes it difficult to distinguish the tumor from normal surrounding tissues. By contrast, radiotracers with higher specificity for the tumor are labeled with a short half-life isotopes which restricts their use to those centers equipped with a cyclotron and radiopharmacy facility. 11C-choline has been reported as a suitable tracer for neuroimaging application. The recent availability of choline labeled with a long half-life radioisotope as 18F increases the possibility of studying this tracer's potential role in the staging of brain tumors. The present review focuses on the possible clinical applications of PET/CT with choline tracers in malignant brain tumors and brain metastases, with a special focus on malignant gliomas.

  20. Sex steroids in human brain tumors and breast cancer.

    PubMed

    von Schoultz, E; Bixo, M; Bäckström, T; Silfvenius, H; Wilking, N; Henriksson, R

    1990-02-15

    The concentrations of three sex steroids, estradiol, progesterone and testosterone, were analyzed by radioimmunoassay after celite chromatography in brain tumor and breast cancer tissues. The concentrations in malignant gliomas and breast cancers showed interindividual variations, especially evident with regard to estradiol. High estradiol concentrations were recorded in two patients with malignant astrocytoma. The concentrations of 1.00 pg/mg and 3.32 pg/mg were 10 to 30 times as high as in normal female brain. In five of ten astrocytomas the estradiol concentration was higher than the lowest breast cancer value. The distribution of progesterone seemed more even, and the level was significantly lower in brain tumors and breast cancers as compared with female brain, perhaps indicating an increased metabolism. Testosterone levels were somewhat higher in brain tumors, as compared with breast cancers, but not different from values in brain tissue. There were no significant age or sex correlation or differences in the concentrations of steroids in the brain tumors. The results suggest that manipulation of sex steroid metabolism in malignant brain tumors can be of beneficial therapeutic value as has been shown for breast cancer and prostatic carcinoma.

  1. Comparison of efficacy of Salmonella typhimurium A1-R and chemotherapy on stem-like and non-stem human pancreatic cancer cells.

    PubMed

    Hiroshima, Yukihiko; Zhao, Ming; Zhang, Yong; Maawy, Ali; Hassanein, Mohamed K; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Suetsugu, Atsushi; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2013-09-01

    The XPA1 human pancreatic cancer cell line is dimorphic, with spindle stem-like cells and round non-stem cells. We report here the in vitro IC 50 values of stem-like and non-stem XPA1 human pancreatic cells cells for: (1) 5-fluorouracil (5-FU), (2) cisplatinum (CDDP), (3) gemcitabine (GEM), and (4) tumor-targeting Salmonella typhimurium A1-R (A1-R). IC 50 values of stem-like XPA1 cells were significantly higher than those of non-stem XPA1 cells for 5-FU (P = 0.007) and CDDP (P = 0.012). In contrast, there was no difference between the efficacy of A1-R on stem-like and non-stem XPA1 cells. In vivo, 5-FU and A1-R significantly reduced the tumor weight of non-stem XPA1 cells (5-FU; P = 0.028; A1-R; P = 0.011). In contrast, only A1-R significantly reduced tumor weight of stem-like XPA1 cells (P = 0.012). The combination A1-R with 5-FU improved the antitumor efficacy compared with 5-FU monotherapy on the stem-like cells (P = 0.004). The results of the present report indicate A1-R is a promising therapy for chemo-resistant pancreatic cancer stem-like cells.

  2. Glial brain tumor detection by using symmetry analysis

    NASA Astrophysics Data System (ADS)

    Pedoia, Valentina; Binaghi, Elisabetta; Balbi, Sergio; De Benedictis, Alessandro; Monti, Emanuele; Minotto, Renzo

    2012-02-01

    In this work a fully automatic algorithm to detect brain tumors by using symmetry analysis is proposed. In recent years a great effort of the research in field of medical imaging was focused on brain tumors segmentation. The quantitative analysis of MRI brain tumor allows to obtain useful key indicators of disease progression. The complex problem of segmenting tumor in MRI can be successfully addressed by considering modular and multi-step approaches mimicking the human visual inspection process. The tumor detection is often an essential preliminary phase to solvethe segmentation problem successfully. In visual analysis of the MRI, the first step of the experts cognitive process, is the detection of an anomaly respect the normal tissue, whatever its nature. An healthy brain has a strong sagittal symmetry, that is weakened by the presence of tumor. The comparison between the healthy and ill hemisphere, considering that tumors are generally not symmetrically placed in both hemispheres, was used to detect the anomaly. A clustering method based on energy minimization through Graph-Cut is applied on the volume computed as a difference between the left hemisphere and the right hemisphere mirrored across the symmetry plane. Differential analysis involves the loss the knowledge of the tumor side. Through an histogram analysis the ill hemisphere is recognized. Many experiments are performed to assess the performance of the detection strategy on MRI volumes in presence of tumors varied in terms of shapes positions and intensity levels. The experiments showed good results also in complex situations.

  3. Current state of our knowledge on brain tumor epidemiology.

    PubMed

    Ostrom, Quinn T; Barnholtz-Sloan, Jill S

    2011-06-01

    The overall incidence of brain tumors for benign and malignant tumors combined is 18.71 per 100,000 person-years; 11.52 per 100,000 person-years for benign tumors and 7.19 per 100,000 person-years for malignant tumors. Incidence, response to treatment, and survival after diagnosis vary greatly by age at diagnosis, histologic type of tumor, and degree of neurologic compromise. The only established environmental risk factor for brain tumors is ionizing radiation exposure. Exposure to radiofrequency electromagnetic fields via cell phone use has gained a lot of attention as a potential risk factor for brain tumor development. However, studies have been inconsistent and inconclusive due to systematic differences in study designs and difficulty of accurately measuring cell phone use. Recently studies of genetic risk factors for brain tumors have expanded to genome-wide association studies. In addition, genome-wide studies of somatic genetic changes in tumors show correlation with clinical outcomes.

  4. Chemo Drug May Combat Serious Brain Tumor After All

    MedlinePlus

    ... Chemo Drug May Combat Serious Brain Tumor After All Certain glioblastomas respond to anti-angiogenic compounds, study ... Dec. 22, 2016 HealthDay Copyright (c) 2016 HealthDay . All rights reserved. News stories are written and provided ...

  5. Uranyl phthalocyanines show promise in the treatment of brain tumors

    NASA Technical Reports Server (NTRS)

    Frigerio, N. A.

    1967-01-01

    Processes synthesize sulfonated and nonsulfonated uranyl phthalocyanines for application in neutron therapy of brain tumors. Tests indicate that the compounds are advantageous over the previously used boron and lithium compounds.

  6. Childhood Brain and Spinal Cord Tumors Treatment Overview

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood brain and spinal cord tumors ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...

  7. General Information about Childhood Brain and Spinal Cord Tumors

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood brain and spinal cord tumors ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...

  8. FDTD analysis of a noninvasive hyperthermia system for brain tumors

    PubMed Central

    2012-01-01

    Background Hyperthermia is considered one of the new therapeutic modalities for cancer treatment and is based on the difference in thermal sensitivity between healthy tissues and tumors. During hyperthermia treatment, the temperature of the tumor is raised to 40–45°C for a definite period resulting in the destruction of cancer cells. This paper investigates design, modeling and simulation of a new non-invasive hyperthermia applicator system capable of effectively heating deep seated as well as superficial brain tumors using inexpensive, simple, and easy to fabricate components without harming surrounding healthy brain tissues. Methods The proposed hyperthermia applicator system is composed of an air filled partial half ellipsoidal chamber, a patch antenna, and a head model with an embedded tumor at an arbitrary location. The irradiating antenna is placed at one of the foci of the hyperthermia chamber while the center of the brain tumor is placed at the other focus. The finite difference time domain (FDTD) method is used to compute both the SAR patterns and the temperature distribution in three different head models due to two different patch antennas at a frequency of 915 MHz. Results The obtained results suggest that by using the proposed noninvasive hyperthermia system it is feasible to achieve sufficient and focused energy deposition and temperature rise to therapeutic values in deep seated as well as superficial brain tumors without harming surrounding healthy tissue. Conclusions The proposed noninvasive hyperthermia system proved suitable for raising the temperature in tumors embedded in the brain to therapeutic values by carefully selecting the systems components. The operator of the system only needs to place the center of the brain tumor at a pre-specified location and excite the antenna at a single frequency of 915 MHz. Our study may provide a basis for a clinical applicator prototype capable of heating brain tumors. PMID:22891953

  9. Emerging Insights into Barriers to Effective Brain Tumor Therapeutics

    PubMed Central

    Woodworth, Graeme F.; Dunn, Gavin P.; Nance, Elizabeth A.; Hanes, Justin; Brem, Henry

    2014-01-01

    There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM. PMID:25101239

  10. Challenges for the functional diffusion map in pediatric brain tumors

    PubMed Central

    Grech-Sollars, Matthew; Saunders, Dawn E.; Phipps, Kim P.; Kaur, Ramneek; Paine, Simon M.L.; Jacques, Thomas S.; Clayden, Jonathan D.; Clark, Chris A.

    2014-01-01

    Background The functional diffusion map (fDM) has been suggested as a tool for early detection of tumor treatment efficacy. We aim to study 3 factors that could act as potential confounders in the fDM: areas of necrosis, tumor grade, and change in tumor size. Methods Thirty-four pediatric patients with brain tumors were enrolled in a retrospective study, approved by the local ethics committee, to examine the fDM. Tumors were selected to encompass a range of types and grades. A qualitative analysis was carried out to compare how fDM findings may be affected by each of the 3 confounders by comparing fDM findings to clinical image reports. Results Results show that the fDM in areas of necrosis do not discriminate between treatment response and tumor progression. Furthermore, tumor grade alters the behavior of the fDM: a decrease in apparent diffusion coefficient (ADC) is a sign of tumor progression in high-grade tumors and treatment response in low-grade tumors. Our results also suggest using only tumor area overlap between the 2 time points analyzed for the fDM in tumors of varying size. Conclusions Interpretation of fDM results needs to take into account the underlying biology of both tumor and healthy tissue. Careful interpretation of the results is required with due consideration to areas of necrosis, tumor grade, and change in tumor size. PMID:24305721

  11. Characterization of distinct immunophenotypes across pediatric brain tumor types.

    PubMed

    Griesinger, Andrea M; Birks, Diane K; Donson, Andrew M; Amani, Vladimir; Hoffman, Lindsey M; Waziri, Allen; Wang, Michael; Handler, Michael H; Foreman, Nicholas K

    2013-11-01

    Despite increasing evidence that antitumor immune control exists in the pediatric brain, these findings have yet to be exploited successfully in the clinic. A barrier to development of immunotherapeutic strategies in pediatric brain tumors is that the immunophenotype of these tumors' microenvironment has not been defined. To address this, the current study used multicolor FACS of disaggregated tumor to systematically characterize the frequency and phenotype of infiltrating immune cells in the most common pediatric brain tumor types. The initial study cohort consisted of 7 pilocytic astrocytoma (PA), 19 ependymoma (EPN), 5 glioblastoma (GBM), 6 medulloblastoma (MED), and 5 nontumor brain (NT) control samples obtained from epilepsy surgery. Immune cell types analyzed included both myeloid and T cell lineages and respective markers of activated or suppressed functional phenotypes. Immune parameters that distinguished each of the tumor types were identified. PA and EPN demonstrated significantly higher infiltrating myeloid and lymphoid cells compared with GBM, MED, or NT. Additionally, PA and EPN conveyed a comparatively activated/classically activated myeloid cell-skewed functional phenotype denoted in particular by HLA-DR and CD64 expression. In contrast, GBM and MED contained progressively fewer infiltrating leukocytes and more muted functional phenotypes similar to that of NT. These findings were recapitulated using whole tumor expression of corresponding immune marker genes in a large gene expression microarray cohort of pediatric brain tumors. The results of this cross-tumor comparative analysis demonstrate that different pediatric brain tumor types exhibit distinct immunophenotypes, implying that specific immunotherapeutic approaches may be most effective for each tumor type.

  12. Brain tumor locating in 3D MR volume using symmetry

    NASA Astrophysics Data System (ADS)

    Dvorak, Pavel; Bartusek, Karel

    2014-03-01

    This work deals with the automatic determination of a brain tumor location in 3D magnetic resonance volumes. The aim of this work is not the precise segmentation of the tumor and its parts but only the detection of its location. This work is the first step in the tumor segmentation process, an important topic in neuro-image processing. The algorithm expects 3D magnetic resonance volumes of brain containing a tumor. The detection is based on locating the area that breaks the left-right symmetry of the brain. This is done by multi-resolution comparing of corresponding regions in left and right hemisphere. The output of the computation is the probabilistic map of the tumor location. The created algorithm was tested on 80 volumes from publicly available BRATS databases containing 3D brain volumes afflicted by a brain tumor. These pathological structures had various sizes and shapes and were located in various parts of the brain. The locating performance of the algorithm was 85% for T1-weighted volumes, 91% for T1-weighted contrast enhanced volumes, 96% for FLAIR and T2-wieghted volumes and 95% for their combinations.

  13. Brain tumor imaging of rat fresh tissue using terahertz spectroscopy

    NASA Astrophysics Data System (ADS)

    Yamaguchi, Sayuri; Fukushi, Yasuko; Kubota, Oichi; Itsuji, Takeaki; Ouchi, Toshihiko; Yamamoto, Seiji

    2016-07-01

    Tumor imaging by terahertz spectroscopy of fresh tissue without dye is demonstrated using samples from a rat glioma model. The complex refractive index spectrum obtained by a reflection terahertz time-domain spectroscopy system can discriminate between normal and tumor tissues. Both the refractive index and absorption coefficient of tumor tissues are higher than those of normal tissues and can be attributed to the higher cell density and water content of the tumor region. The results of this study indicate that terahertz technology is useful for detecting brain tumor tissue.

  14. Brain tumor imaging of rat fresh tissue using terahertz spectroscopy

    PubMed Central

    Yamaguchi, Sayuri; Fukushi, Yasuko; Kubota, Oichi; Itsuji, Takeaki; Ouchi, Toshihiko; Yamamoto, Seiji

    2016-01-01

    Tumor imaging by terahertz spectroscopy of fresh tissue without dye is demonstrated using samples from a rat glioma model. The complex refractive index spectrum obtained by a reflection terahertz time-domain spectroscopy system can discriminate between normal and tumor tissues. Both the refractive index and absorption coefficient of tumor tissues are higher than those of normal tissues and can be attributed to the higher cell density and water content of the tumor region. The results of this study indicate that terahertz technology is useful for detecting brain tumor tissue. PMID:27456312

  15. Sports and childhood brain tumors: Can I play?

    PubMed Central

    Perreault, Sébastien; Lober, Robert M.; Davis, Carissa; Stave, Christopher; Partap, Sonia; Fisher, Paul G.

    2014-01-01

    Background It is unknown whether children with brain tumors have a higher risk of complications while participating in sports. We sought to estimate the prevalence of such events by conducting a systematic review of the literature, and we surveyed providers involved with pediatric central nervous system (CNS) tumor patients. Methods A systematic review of the literature in the PubMed, Scopus, and Cochrane databases was conducted for original articles addressing sport-related complications in the brain-tumor population. An online questionnaire was created to survey providers involved with pediatric CNS tumor patients about their current recommendations and experience regarding sports and brain tumors. Results We retrieved 32 subjects, including 19 pediatric cases from the literature. Most lesions associated with sport complications were arachnoid cysts (n = 21), followed by glioma (n = 5). The sports in which symptom onset most commonly occurred were soccer (n = 7), football (n = 5), and running (n = 5). We surveyed 111 pediatric neuro-oncology providers. Sport restriction varied greatly from none to 14 sports. Time to return to play in sports with contact also varied considerably between providers. Rationales for limiting sports activities were partly related to subspecialty. Responders reported 9 sport-related adverse events in patients with brain tumor. Conclusions Sport-related complications are uncommon in children with brain tumors. Patients might not be at a significantly higher risk and should not need to be excluded from most sports activities. PMID:26034627

  16. The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells.

    PubMed

    Boyle, S T; Ingman, W V; Poltavets, V; Faulkner, J W; Whitfield, R J; McColl, S R; Kochetkova, M

    2016-01-07

    The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.

  17. Multiscale modeling for image analysis of brain tumor studies.

    PubMed

    Bauer, Stefan; May, Christian; Dionysiou, Dimitra; Stamatakos, Georgios; Büchler, Philippe; Reyes, Mauricio

    2012-01-01

    Image-based modeling of tumor growth combines methods from cancer simulation and medical imaging. In this context, we present a novel approach to adapt a healthy brain atlas to MR images of tumor patients. In order to establish correspondence between a healthy atlas and a pathologic patient image, tumor growth modeling in combination with registration algorithms is employed. In a first step, the tumor is grown in the atlas based on a new multiscale, multiphysics model including growth simulation from the cellular level up to the biomechanical level, accounting for cell proliferation and tissue deformations. Large-scale deformations are handled with an Eulerian approach for finite element computations, which can operate directly on the image voxel mesh. Subsequently, dense correspondence between the modified atlas and patient image is established using nonrigid registration. The method offers opportunities in atlas-based segmentation of tumor-bearing brain images as well as for improved patient-specific simulation and prognosis of tumor progression.

  18. Current status of gene therapy for brain tumors.

    PubMed

    Murphy, Andrea M; Rabkin, Samuel D

    2013-04-01

    Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replication-competent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.

  19. Current status of gene therapy for brain tumors

    PubMed Central

    MURPHY, ANDREA M.; RABKIN, SAMUEL D.

    2013-01-01

    Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replication-competent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma. PMID:23246627

  20. An epigenetic gateway to brain tumor cell identity.

    PubMed

    Mack, Stephen C; Hubert, Christopher G; Miller, Tyler E; Taylor, Michael D; Rich, Jeremy N

    2016-01-01

    Precise targeting of genetic lesions alone has been insufficient to extend brain tumor patient survival. Brain cancer cells are diverse in their genetic, metabolic and microenvironmental compositions, accounting for their phenotypic heterogeneity and disparate responses to therapy. These factors converge at the level of the epigenome, representing a unified node that can be disrupted by pharmacologic inhibition. Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks and disruption of chromatin structure. In this Review, we describe the convergence of genetic, metabolic and microenvironmental factors on mechanisms of epigenetic deregulation in brain cancer. We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state and neoplastic transformation, as well as addressing the potential to exploit these alterations as new therapeutic strategies for the treatment of brain cancer.

  1. Irinotecan and Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases From Solid Tumors

    ClinicalTrials.gov

    2010-03-15

    Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Long-term Effects Secondary to Cancer Therapy in Adults; Long-term Effects Secondary to Cancer Therapy in Children; Poor Performance Status; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  2. Doublecortin is preferentially expressed in invasive human brain tumors.

    PubMed

    Daou, Marie-Claire; Smith, Thomas W; Litofsky, N Scott; Hsieh, Chung C; Ross, Alonzo H

    2005-11-01

    Doublecortin (DCX) is required for neuroblastic migration during the development of the cerebral cortex. DCX is a microtubule-associated protein that plays a role in cellular motility. These facts led us to hypothesize that DCX is increased in invasive brain tumors. DCX expression was assessed in 69 paraffin-embedded brain tumors of neuroepithelial origin. In addition, mouse brain sections of the subventricular zone and dentate gyrus were used as positive controls for immunostaining, and specificity of antibody staining was demonstrated by peptide neutralization. DCX was highly expressed in both high-grade invasive tumors (glioblastoma, n=11; anaplastic astrocytoma/oligoastrocytoma, n=7; and medulloblastoma/PNET, n=6) and low-grade invasive tumors (oligodendroglioma, n=3; and astrocytoma/oligoastrocytoma, n=5). However, DCX was less intensely expressed in the circumscribed group of tumors (pilocytic astrocytoma, n=6; ependymoma/subependymoma, n=7; dysembryoplastic neuroepithelial tumor, n=4; ganglioglioma, n=2; meningioma, n=9; and schwannoma, n=9). By the Cochran-Mantel-Haenszel statistical test, the circumscribed group was significantly different from both the high-grade invasive group (P<0.0001) and the low-grade invasive group (P<0.0001). We conclude that DCX is preferentially expressed in invasive brain tumors. In addition, DCX immunostaining was stronger at the margin of the tumor than at the center. For a subset of these tumors, we also detected DCX mRNA and protein by Northern and Western blotting. DCX mRNA and protein was detected in glioma cell lines by Northern blotting, immunofluorescence microscopy and Western blotting. Collectively, the immunohistochemistry, Western blots and Northern blots conclusively demonstrate expression of DCX by human brain tumors.

  3. Gene therapeutics: the future of brain tumor therapy?

    PubMed

    Cutter, Jennifer L; Kurozumi, Kazuhiko; Chiocca, E Antonio; Kaur, Balveen

    2006-07-01

    Primary glioblastoma multiforme is an aggressive brain tumor that has no cure. Current treatments include gross resection of the tumor, radiation and chemotherapy. Despite valiant efforts, prognosis remains dismal. A promising new technique involves the use of oncolytic viruses that can specifically replicate and lyse in cancers, without spreading to normal tissues. Currently, these are being tested in relevant preclinical models and clinical trials as a therapeutic modality for many types of cancer. Results from recent clinical trials with oncolytic viruses have revealed the safety of this approach, although evidence for efficacy remains elusive. Oncolytic viral strategies are summarized in this review, with a focus on therapies used in brain tumors.

  4. Medical management of brain tumors and the sequelae of treatment

    PubMed Central

    Schiff, David; Lee, Eudocia Q.; Nayak, Lakshmi; Norden, Andrew D.; Reardon, David A.; Wen, Patrick Y.

    2015-01-01

    Patients with malignant brain tumors are prone to complications that negatively impact their quality of life and sometimes their overall survival as well. Tumors may directly provoke seizures, hypercoagulable states with resultant venous thromboembolism, and mood and cognitive disorders. Antitumor treatments and supportive therapies also produce side effects. In this review, we discuss major aspects of supportive care for patients with malignant brain tumors, with particular attention to management of seizures, venous thromboembolism, corticosteroids and their complications, chemotherapy including bevacizumab, and fatigue, mood, and cognitive dysfunction. PMID:25358508

  5. The roles of viruses in brain tumor initiation and oncomodulation

    PubMed Central

    Kofman, Alexander; Marcinkiewicz, Lucasz; Dupart, Evan; Lyshchev, Anton; Martynov, Boris; Ryndin, Anatolii; Kotelevskaya, Elena; Brown, Jay; Schiff, David

    2012-01-01

    While some avian retroviruses have been shown to induce gliomas in animal models, human herpesviruses, specifically, the most extensively studied cytomegalovirus, and the much less studied roseolovirus HHV-6, and Herpes simplex viruses 1 and 2, currently attract more and more attention as possible contributing or initiating factors in the development of human brain tumors. The aim of this review is to summarize and highlight the most provoking findings indicating a potential causative link between brain tumors, specifically malignant gliomas, and viruses in the context of the concepts of viral oncomodulation and the tumor stem cell origin. PMID:21720806

  6. An evaluative tool for preoperative planning of brain tumor resection

    NASA Astrophysics Data System (ADS)

    Coffey, Aaron M.; Garg, Ishita; Miga, Michael I.; Thompson, Reid C.

    2010-02-01

    A patient specific finite element biphasic brain model has been utilized to codify a surgeon's experience by establishing quantifiable biomechanical measures to score orientations for optimal planning of brain tumor resection. When faced with evaluating several potential approaches to tumor removal during preoperative planning, the goal of this work is to facilitate the surgeon's selection of a patient head orientation such that tumor presentation and resection is assisted via favorable brain shift conditions rather than trying to allay confounding ones. Displacement-based measures consisting of area classification of the brain surface shifting in the craniotomy region and lateral displacement of the tumor center relative to an approach vector defined by the surgeon were calculated over a range of orientations and used to form an objective function. The objective function was used in conjunction with Levenberg-Marquardt optimization to find the ideal patient orientation. For a frontal lobe tumor presentation the model predicts an ideal orientation that indicates the patient should be placed in a lateral decubitus position on the side contralateral to the tumor in order to minimize unfavorable brain shift.

  7. [Surgery of metastatic brain tumors with new surgical instruments].

    PubMed

    Nomura, K; Shibui, S; Matsuoka, K; Watanabe, T; Nakamura, O

    1987-05-01

    The risk of damages of neurological function by the operation of metastatic brain tumors was reduced considerably after introduction of neurosurgical apparatuses, such as ultrasonograph, ultrasonic surgical aspirator and laser scalpel. Of these, ultrasonograph is useful to indicate the exact location of brain tumor at real time during the operation. Ultrasonic surgical aspirator reduced the risk of damage on important brain structures due to the selectivity of fragmentation and the safety of the dissection in the vicinity of important vessels and nerve tissues. Laser scalpel is also useful to extirpate the hemorrhagic tumor with hard consistency. Cases introduced in this paper were: case 1, brain metastasis from lung cancer located just under the left motor area in brain; case 2, metastasis with abundant neovascularization from renal cancer to orbital cavity which showed invasion to orbital roof and frontal bone; case 3, radiation induced sarcoma after the treatment of retinoblastoma; case 4, a large cerebellar metastatic tumor; case 5, neurogenic sarcoma which were successfully removed by using one of or combination of ultrasonograph, ultrasonic aspirator and laser scalpel. Advantage of these new instruments for the surgery on metastatic brain tumor was mentioned here. However, it is necessarily to get a custom before we use these apparatuses at operation efficiently.

  8. 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.

  9. Factors affecting intellectual outcome in pediatric brain tumor patients

    SciTech Connect

    Ellenberg, L.; McComb, J.G.; Siegel, S.E.; Stowe, S.

    1987-11-01

    A prospective study utilizing repeated intellectual testing was undertaken in 73 children with brain tumors consecutively admitted to Childrens Hospital of Los Angeles over a 3-year period to determine the effect of tumor location, extent of surgical resection, hydrocephalus, age of the child, radiation therapy, and chemotherapy on cognitive outcome. Forty-three patients were followed for at least two sequential intellectual assessments and provide the data for this study. Children with hemispheric tumors had the most general cognitive impairment. The degree of tumor resection, adequately treated hydrocephalus, and chemotherapy had no bearing on intellectual outcome. Age of the child affected outcome mainly as it related to radiation. Whole brain radiation therapy was associated with cognitive decline. This was especially true in children below 7 years of age, who experienced a very significant loss of function after whole brain radiation therapy.

  10. Critical Care Management of Cerebral Edema in Brain Tumors.

    PubMed

    Esquenazi, Yoshua; Lo, Victor P; Lee, Kiwon

    2017-01-01

    Cerebral edema associated with brain tumors is extremely common and can occur in both primary and metastatic tumors. The edema surrounding brain tumors results from leakage of plasma across the vessel wall into the parenchyma secondary to disruption of the blood-brain barrier. The clinical signs of brain tumor edema depend on the location of the tumor as well as the extent of the edema, which often exceeds the mass effect induced by the tumor itself. Uncontrolled cerebral edema may result in increased intracranial pressure and acute herniation syndromes that can result in permanent neurological dysfunction and potentially fatal herniation. Treatment strategies for elevated intracranial pressure consist of general measures, medical interventions, and surgery. Alhough the definitive treatment for the edema may ultimately be surgical resection of the tumor, the impact of the critical care management cannot be underestimated and thus patients must be vigilantly monitored in the intensive care unit. In this review, we discuss the pathology, pathophysiology, and clinical features of patients presenting with cerebral edema. Imaging findings and treatment modalities used in the intensive care unit are also discussed.

  11. Neuromorphometry of primary brain tumors by magnetic resonance imaging

    PubMed Central

    Hevia-Montiel, Nidiyare; Rodriguez-Perez, Pedro I.; Lamothe-Molina, Paul J.; Arellano-Reynoso, Alfonso; Bribiesca, Ernesto; Alegria-Loyola, Marco A.

    2015-01-01

    Abstract. Magnetic resonance imaging is a technique for the diagnosis and classification of brain tumors. Discrete compactness is a morphological feature of two-dimensional and three-dimensional objects. This measure determines the compactness of a discretized object depending on the sum of the areas of the connected voxels and has been used for understanding the morphology of nonbrain tumors. We hypothesized that regarding brain tumors, we may improve the malignancy grade classification. We analyzed the values in 20 patients with different subtypes of primary brain tumors: astrocytoma, oligodendroglioma, and glioblastoma multiforme subdivided into the contrast-enhanced and the necrotic tumor regions. The preliminary results show an inverse relationship between the compactness value and the malignancy grade of gliomas. Astrocytomas exhibit a mean of 973±14, whereas oligodendrogliomas exhibit a mean of 942±21. In contrast, the contrast-enhanced region of the glioblastoma presented a mean of 919±43, and the necrotic region presented a mean of 869±66. However, the volume and area of the enclosing surface did not show a relationship with the malignancy grade of the gliomas. Discrete compactness appears to be a stable characteristic between primary brain tumors of different malignancy grades, because similar values were obtained from different patients with the same type of tumor. PMID:26158107

  12. Research of the multimodal brain-tumor segmentation algorithm

    NASA Astrophysics Data System (ADS)

    Lu, Yisu; Chen, Wufan

    2015-12-01

    It is well-known that the number of clusters is one of the most important parameters for automatic segmentation. However, it is difficult to define owing to the high diversity in appearance of tumor tissue among different patients and the ambiguous boundaries of lesions. In this study, a nonparametric mixture of Dirichlet process (MDP) model is applied to segment the tumor images, and the MDP segmentation can be performed without the initialization of the number of clusters. A new nonparametric segmentation algorithm combined with anisotropic diffusion and a Markov random field (MRF) smooth constraint is proposed in this study. Besides the segmentation of single modal brain tumor images, we developed the algorithm to segment multimodal brain tumor images by the magnetic resonance (MR) multimodal features and obtain the active tumor and edema in the same time. The proposed algorithm is evaluated and compared with other approaches. The accuracy and computation time of our algorithm demonstrates very impressive performance.

  13. The therapy of infantile malignant brain tumors: current status?

    PubMed

    Kalifa, Chantal; Grill, Jacques

    2005-12-01

    Malignant brain tumors are not uncommon in infants as their occurrence before the age of three represents 20-25% of all malignant brain tumors in childhood [1]. Genetic predisposition to infantile malignant brain tumors are known in Gorlin syndrome for example who present with desmoplastic medulloblastoma in about 5% of the affected patients. In addition, sequelae from tumor and its treatment are more severe at this age [2]. Thus, malignant brain tumors represent a true therapeutic challenge in neuro-oncology. Before the era of modern imaging and modern neurosurgery these malignant brain tumors were misdiagnosed or could not benefit of the surgical procedures as well as older children because of increased risks in this age group. Since the end of the 80s, noninvasive imaging procedures produce accurate diagnosis of brain tumors and improvement in neurosurgery, neuroanesthesia and perioperative intensive care permit safe tumor resections or at least biopsies. Consequently, the pediatric oncologists are more often confronted with very young children who need a complementary treatment. Before the development of specific approaches for this age group, these children received the same kind of treatment than the older children did, but their survival and quality of life were significantly worse. The reasons of these poor results were probably due in part to the fear of late effects induced by radiation therapy, leading to decrease the necessary doses of irradiation which increased treatment failures without avoiding treatment related complications [3]. At the end of the 80s, pilot studies were performed using postoperative chemotherapy in young medulloblastoma patients. Van Eys treated 12 selected children with medulloblastoma with MOPP regimen and without irradiation; 8 of them were reported to be long term survivors [4]. Subsequently, the pediatric oncology cooperative groups studies have designed therapeutic trials for very young children with malignant brain tumors

  14. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

    PubMed Central

    Stokum, Jesse A.; Schneider, Craig S.; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J.; Kim, Anthony J.; Simard, J. Marc; Winkles, Jeffrey A.; Holland, Eric C.; Woodworth, Graeme F.

    2017-01-01

    -associated microglia- and bone marrow-derived macrophages, and the formation of stem-like cell niches within the tumor. This transgenic rat model may enable detailed interspecies comparisons of fundamental cancer pathways and clinically relevant experimental imaging procedures and interventions that are limited by the smaller size of the mouse brain. PMID:28358926

  15. Blood Brain Barrier: A Challenge for Effectual Therapy of Brain Tumors

    PubMed Central

    Bhowmik, Arijit; Ghosh, Mrinal Kanti

    2015-01-01

    Brain tumors are one of the most formidable diseases of mankind. They have only a fair to poor prognosis and high relapse rate. One of the major causes of extreme difficulty in brain tumor treatment is the presence of blood brain barrier (BBB). BBB comprises different molecular components and transport systems, which in turn create efflux machinery or hindrance for the entry of several drugs in brain. Thus, along with the conventional techniques, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle for treatment of brain tumors. In this review, we have elucidated some critical insights into the composition and function of BBB and along with it we have discussed the effective methods for delivery of drugs to the brain and therapeutic strategies overcoming the barrier. PMID:25866775

  16. Novel anticancer activity of phloroglucinol against breast cancer stem-like cells

    SciTech Connect

    Kim, Rae-Kwon; Uddin, Nizam; Hyun, Jin-Won; Kim, Changil; Suh, Yongjoon; Lee, Su-Jae

    2015-08-01

    Poor prognosis of breast cancer patients is closely associated with metastasis and relapse. There is substantial evidence supporting that cancer stem-like cells (CSCs) are primarily responsible for relapse in breast cancer after anticancer treatment. However, there is a lack of suitable drugs that target breast cancer stem-like cells (BCSCs). Here, we report that phloroglucinol (PG), a natural phlorotannin component of brown algae, suppresses sphere formation, anchorage-independent colony formation and in vivo tumorigenicity. In line with these observations, treatment with PG also decreased CD44{sup +} cancer cell population as well as expression of CSC regulators such as Sox2, CD44, Oct4, Notch2 and β-catenin. Also, treatment with PG sensitized breast cancer cells to anticancer drugs such as cisplatin, etoposide, and taxol as well as to ionizing radiation. Importantly, PG inhibited KRAS and its downstream PI3K/AKT and RAF-1/ERK signaling pathways that regulate the maintenance of CSCs. Taken together, our findings implicate PG as a good candidate to target BCSCs and to prevent the disease relapse. - Highlights: • Phloroglucinol suppresses in vivo tumor formation. • Phloroglucinol sensitizes breast cancer cells to anticancer agents. • Phloroglucinol inhibits breast cancer stem-like cells. • Phloroglucinol inhibits PI3K/AKT and KRAS/RAF/ERK signaling pathways.

  17. Exosomes as Tools to Suppress Primary Brain Tumor.

    PubMed

    Katakowski, Mark; Chopp, Michael

    2016-04-01

    Exosomes are small microvesicles released by cells that efficiently transfer their molecular cargo to other cells, including tumor. Exosomes may pass the blood-brain barrier and have been demonstrated to deliver RNAs contained within to brain. As they are non-viable, the risk profile of exosomes is thought to be less than that of cellular therapies. Exosomes can be manufactured at scale in culture, and exosomes can be engineered to incorporate therapeutic miRNAs, siRNAs, or chemotherapeutic molecules. As natural biological delivery vehicles, interest in the use of exosomes as therapeutic delivery agents is growing. We previously demonstrated a novel treatment whereby mesenchymal stromal cells were employed to package tumor-suppressing miR-146b into exosomes, which were then used to reduce malignant glioma growth in rat. The use of exosomes to raise the immune system against tumor is also drawing interest. Exosomes from dendritic cells which are antigen-presenting, and have been used for treatment of brain tumor may be divided into three categories: (1) exosomes for immunomodulation-based therapy, (2) exosomes as delivery vehicles for anti-tumor nucleotides, and (3) exosomes as drug delivery vehicles. Here, we will provide an overview of these three applications of exosomes to treat brain tumor, and examine their prospects on the long road to clinical use.

  18. Telomerase activity in human brain tumors: astrocytoma and meningioma.

    PubMed

    Kheirollahi, Majid; Mehrazin, Masoud; Kamalian, Naser; Mohammadi-asl, Javad; Mehdipour, Parvin

    2013-05-01

    Somatic cells do not have telomerase activity but immortalized cell lines and more than 85 % of the cancer cells show telomerase activation to prevent the telomere from progressive shortening. The activation of this enzyme has been found in a variety of human tumors and tumor-derived cell lines, but only few studies on telomerase activity in human brain tumors have been reported. Here, we evaluated telomerase activity in different grades of human astrocytoma and meningioma brain tumors. In this study, assay for telomerase activity performed on 50 eligible cases consisted of 26 meningioma, 24 astrocytoma according to the standard protocols. In the brain tissues, telomerase activity was positive in 39 (65 %) of 50 patients. One sample t test showed that the telomerase activity in meningioma and astrocytoma tumors was significantly positive entirely (P < 0.001). Also, grade I of meningioma and low grades of astrocytoma (grades I and II) significantly showed telomerase activity. According to our results, we suggest that activation of telomerase is an event that starts mostly at low grades of brain including meningioma and astrocytoma tumors.

  19. Factors affecting the cerebral network in brain tumor patients.

    PubMed

    Heimans, Jan J; Reijneveld, Jaap C

    2012-06-01

    Brain functions, including cognitive functions, are frequently disturbed in brain tumor patients. These disturbances may result from the tumor itself, but also from the treatment directed against the tumor. Surgery, radiotherapy and chemotherapy all may affect cerebral functioning, both in a positive as well as in a negative way. Apart from the anti-tumor treatment, glioma patients often receive glucocorticoids and anti-epileptic drugs, which both also have influence on brain functioning. The effect of a brain tumor on cerebral functioning is often more global than should be expected on the basis of the local character of the disease, and this is thought to be a consequence of disturbance of the cerebral network as a whole. Any network, whether it be a neural, a social or an electronic network, can be described in parameters assessing the topological characteristics of that particular network. Repeated assessment of neural network characteristics in brain tumor patients during their disease course enables study of the dynamics of neural networks and provides more insight into the plasticity of the diseased brain. Functional MRI, electroencephalography and especially magnetoencephalography are used to measure brain function and the signals that are being registered with these techniques can be analyzed with respect to network characteristics such as "synchronization" and "clustering". Evidence accumulates that loss of optimal neural network architecture negatively impacts complex cerebral functioning and also decreases the threshold to develop epileptic seizures. Future research should be focused on both plasticity of neural networks and the factors that have impact on that plasticity as well as the possible role of assessment of neural network characteristics in the determination of cerebral function during the disease course.

  20. Brain mapping in tumors: intraoperative or extraoperative?

    PubMed

    Duffau, Hugues

    2013-12-01

    In nontumoral epilepsy surgery, the main goal for all preoperative investigation is to first determine the epileptogenic zone, and then to analyze its relation to eloquent cortex, in order to control seizures while avoiding adverse postoperative neurologic outcome. To this end, in addition to neuropsychological assessment, functional neuroimaging and scalp electroencephalography, extraoperative recording, and electrical mapping, especially using subdural strip- or grid-electrodes, has been reported extensively. Nonetheless, in tumoral epilepsy surgery, the rationale is different. Indeed, the first aim is rather to maximize the extent of tumor resection while minimizing postsurgical morbidity, in order to increase the median survival as well as to preserve quality of life. As a consequence, as frequently seen in infiltrating tumors such as gliomas, where these lesions not only grow but also migrate along white matter tracts, the resection should be performed according to functional boundaries both at cortical and subcortical levels. With this in mind, extraoperative mapping by strips/grids is often not sufficient in tumoral surgery, since in essence, it allows study of the cortex but cannot map subcortical pathways. Therefore, intraoperative electrostimulation mapping, especially in awake patients, is more appropriate in tumor surgery, because this technique allows real-time detection of areas crucial for cerebral functions--eloquent cortex and fibers--throughout the resection. In summary, rather than choosing one or the other of different mapping techniques, methodology should be adapted to each pathology, that is, extraoperative mapping in nontumoral epilepsy surgery and intraoperative mapping in tumoral surgery.

  1. Application of SLT contact laser in resection of brain tumors

    NASA Astrophysics Data System (ADS)

    Li, Han-Jie; Li, Zhi-Qiang; Li, Chan-Yuan

    1998-11-01

    28 cases of brain tumors were operated by SLT contact Nd:YAG laser from October 1995 to May 1997 in our hospital. Among these, 14 are menin-giomas, 5 are astrocytomas. Others are tumors such as acoustic neuromas, craniopharyngiomas, etc 21 cases underwent common craniotomy, 3, laser endoscopy operation; and 4, laser therapy under microscopy. Method of tumor resection: firstly, cutting and separating the tumor from brain tissues with GRP by 5-15w; secondly, vaporizing parenchyma of tumor with MTRL and sucking it, again, cutting and separating and so on, lastly removing the tumor entirely. The power of vaporization for glioma or tumors in ventricles is about 20-30w, but for meningiomas, 30-60w. MT was used on power of 15-20w to coagulate and homeostate the left cavity of tumor. According to our experience, laser operation can make bleeding reduced markedly, tumor resection become more thorough, and postoperative response and complications decrease obviously.

  2. Epigallocatechin-3-gallate inhibits stem-like inflammatory breast cancer cells.

    PubMed

    Mineva, Nora D; Paulson, K Eric; Naber, Stephen P; Yee, Amy S; Sonenshein, Gail E

    2013-01-01

    Inflammatory Breast Cancer (IBC) is a highly aggressive form of cancer characterized by high rates of proliferation, lymphangiogenesis and metastasis, and an overall poor survival. As regular green tea consumption has been associated with improved prognosis of breast cancer patients, including decreased risk of recurrence, here the effects of the green tea polyphenol epigallocatechin-3-gallate (EGCG) were tested on two IBC lines: SUM-149 and SUM-190. EGCG decreased expression of genes that promote proliferation, migration, invasion, and survival. Consistently, growth, invasive properties, and survival of IBC cells were reduced by EGCG treatment. EGCG also reduced lymphangiogenesis-promoting genes, in particular VEGF-D. Conditioned media from EGCG-treated IBC cells displayed decreased VEGF-D secretion and reduced ability to promote lymphangiogenesis in vitro as measured by hTERT-HDLEC lymphatic endothelial cell migration and tube formation. Tumorsphere formation by SUM-149 cells was robustly inhibited by EGCG, suggesting effects on self-renewal ability. Stem-like SUM-149 cells with high aldehyde dehydrogenase (ALDH) activity, previously implicated in poor patient prognosis, were isolated. EGCG treatment reduced growth and induced apoptosis of the stem-like SUM-149 cells in culture. In an orthotopic mouse model, EGCG decreased growth of pre-existing tumors derived from ALDH-positive stem-like SUM-149 cells and their expression of VEGF-D, which correlated with a significant decrease in peritumoral lymphatic vessel density. Thus, EGCG inhibits the overall aggressive IBC phenotype. Reduction of the stem-like cell compartment by EGCG may explain the decreased risk of breast cancer recurrence among green tea drinkers. Recent clinical trials demonstrate the efficacy of green tea polyphenol extracts in treatment of prostate cancer and lymphocytic leukemia with low toxicity. Given the poor prognosis of IBC patients, our findings suggest further exploration of EGCG or green

  3. Epigallocatechin-3-Gallate Inhibits Stem-Like Inflammatory Breast Cancer Cells

    PubMed Central

    Mineva, Nora D.; Paulson, K. Eric; Naber, Stephen P.; Yee, Amy S.; Sonenshein, Gail E.

    2013-01-01

    Inflammatory Breast Cancer (IBC) is a highly aggressive form of cancer characterized by high rates of proliferation, lymphangiogenesis and metastasis, and an overall poor survival. As regular green tea consumption has been associated with improved prognosis of breast cancer patients, including decreased risk of recurrence, here the effects of the green tea polyphenol epigallocatechin-3-gallate (EGCG) were tested on two IBC lines: SUM-149 and SUM-190. EGCG decreased expression of genes that promote proliferation, migration, invasion, and survival. Consistently, growth, invasive properties, and survival of IBC cells were reduced by EGCG treatment. EGCG also reduced lymphangiogenesis-promoting genes, in particular VEGF-D. Conditioned media from EGCG-treated IBC cells displayed decreased VEGF-D secretion and reduced ability to promote lymphangiogenesis in vitro as measured by hTERT-HDLEC lymphatic endothelial cell migration and tube formation. Tumorsphere formation by SUM-149 cells was robustly inhibited by EGCG, suggesting effects on self-renewal ability. Stem-like SUM-149 cells with high aldehyde dehydrogenase (ALDH) activity, previously implicated in poor patient prognosis, were isolated. EGCG treatment reduced growth and induced apoptosis of the stem-like SUM-149 cells in culture. In an orthotopic mouse model, EGCG decreased growth of pre-existing tumors derived from ALDH-positive stem-like SUM-149 cells and their expression of VEGF-D, which correlated with a significant decrease in peritumoral lymphatic vessel density. Thus, EGCG inhibits the overall aggressive IBC phenotype. Reduction of the stem-like cell compartment by EGCG may explain the decreased risk of breast cancer recurrence among green tea drinkers. Recent clinical trials demonstrate the efficacy of green tea polyphenol extracts in treatment of prostate cancer and lymphocytic leukemia with low toxicity. Given the poor prognosis of IBC patients, our findings suggest further exploration of EGCG or green

  4. Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate.

    PubMed

    Ram, Z; Samid, D; Walbridge, S; Oshiro, E M; Viola, J J; Tao-Cheng, J H; Shack, S; Thibault, A; Myers, C E; Oldfield, E H

    1994-06-01

    Phenylacetate is a naturally occurring plasma component that suppresses the growth of tumor cells and induces differentiation in vitro. To evaluate the in vivo potential and preventive and therapeutic antitumor efficacy of sodium phenylacetate against malignant brain tumors, Fischer 344 rats (n = 50) bearing cerebral 9L gliosarcomas received phenylacetate by continuous s.c. release starting on the day of tumor inoculation (n = 10) using s.c. osmotic minipumps (550 mg/kg/day for 28 days). Rats with established brain tumors (n = 12) received continuous s.c. phenylacetate supplemented with additional daily i.p. dose (300 mg/kg). Control rats (n = 25) were treated in a similar way with saline. Rats were sacrificed during treatment for electron microscopic studies of their tumors, in vivo proliferation assays, and measurement of phenylacetate levels in the serum and cerebrospinal fluid. Treatment with phenylacetate extended survival when started on the day of tumor inoculation (P < 0.01) or 7 days after inoculation (P < 0.03) without any associated adverse effects. In the latter group, phenylacetate levels in pooled serum and cerebrospinal fluid samples after 7 days of treatment were in the therapeutic range as determined in vitro (2.45 mM in serum and 3.1 mM in cerebrospinal fluid). Electron microscopy of treated tumors demonstrated marked hypertrophy and organization of the rough endoplasmic reticulum, indicating cell differentiation, in contrast to the scant and randomly distributed endoplasmic reticulum in tumors from untreated animals. In addition, in vitro studies demonstrated dose-dependent inhibition of the rate of tumor proliferation and restoration of anchorage dependency, a marker of phenotypic reversion. Phenylacetate, used at clinically achievable concentrations, prolongs survival of rats with malignant brain tumors through induction of tumor differentiation. Its role in the treatment of brain tumors and other cancers should be explored further.

  5. Culture and Isolation of Brain Tumor Initiating Cells.

    PubMed

    Vora, Parvez; Venugopal, Chitra; McFarlane, Nicole; Singh, Sheila K

    2015-08-03

    Brain tumors are typically composed of heterogeneous cells that exhibit distinct phenotypic characteristics and proliferative potentials. Only a relatively small fraction of cells in the tumor with stem cell properties, termed brain tumor initiating cells (BTICs), possess an ability to differentiate along multiple lineages, self-renew, and initiate tumors in vivo. This unit describes protocols for the culture and isolation BTICs. We applied culture conditions and assays originally used for normal neural stem cells (NSCs) in vitro to a variety of brain tumors. Using fluorescence-activated cell sorting for the neural precursor cell surface marker CD133/CD15, BTICs can be isolated and studied prospectively. Isolation of BTICs from GBM bulk tumor will enable examination of dissimilar morphologies, self-renewal capacities, tumorigenicity, and therapeutic sensitivities. As cancer is also considered a disease of unregulated self-renewal and differentiation, an understanding of BTICs is fundamental to understanding tumor growth. Ultimately, it will lead to novel drug discovery approaches that strategically target the functionally relevant BTIC population.

  6. Comparative expression study of the endo-G protein coupled receptor (GPCR) repertoire in human glioblastoma cancer stem-like cells, U87-MG cells and non malignant cells of neural origin unveils new potential therapeutic targets.

    PubMed

    Fève, Marie; Saliou, Jean-Michel; Zeniou, Maria; Lennon, Sarah; Carapito, Christine; Dong, Jihu; Van Dorsselaer, Alain; Junier, Marie-Pierre; Chneiweiss, Hervé; Cianférani, Sarah; Haiech, Jacques; Kilhoffer, Marie-Claude

    2014-01-01

    Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets.

  7. Circulating biomarker panels for targeted therapy in brain tumors.

    PubMed

    Tanase, Cristiana; Albulescu, Radu; Codrici, Elena; Popescu, Ionela Daniela; Mihai, Simona; Enciu, Ana Maria; Cruceru, Maria Linda; Popa, Adrian Claudiu; Neagu, Ana Iulia; Necula, Laura Georgiana; Mambet, Cristina; Neagu, Monica

    2015-01-01

    An important goal of oncology is the development of cancer risk-identifier biomarkers that aid early detection and target therapy. High-throughput profiling represents a major concern for cancer research, including brain tumors. A promising approach for efficacious monitoring of disease progression and therapy could be circulating biomarker panels using molecular proteomic patterns. Tailoring treatment by targeting specific protein-protein interactions and signaling networks, microRNA and cancer stem cell signaling in accordance with tumor phenotype or patient clustering based on biomarker panels represents the future of personalized medicine for brain tumors. Gathering current data regarding biomarker candidates, we address the major challenges surrounding the biomarker field of this devastating tumor type, exploring potential perspectives for the development of more effective predictive biomarker panels.

  8. Delayed Contrast Extravasation MRI for Depicting Tumor and Non-Tumoral Tissues in Primary and Metastatic Brain Tumors

    PubMed Central

    Zach, Leor; Guez, David; Last, David; Daniels, Dianne; Grober, Yuval; Nissim, Ouzi; Hoffmann, Chen; Nass, Dvora; Talianski, Alisa; Spiegelmann, Roberto; Cohen, Zvi R.; Mardor, Yael

    2012-01-01

    The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution

  9. The heterogeneity of cancer stem-like cells at the invasive front.

    PubMed

    Yoshida, Go J

    2017-01-01

    Cancer stem-like cells exhibit the multi-functional roles to survive and persist for a long period in the minimal residual disease after the conventional anti-cancer treatments. Cancer stem-like cells of solid malignant tumors which highly express CD44v8-10, the variant isoform of CD44 generated by alternative splicing, has a resistance to redox stress by the robust production of glutathione mediated by ESRP1-CD44v-xCT (cystine/glutamate antiporter) axis. It has been reported that CD44v and c-Myc tend to show the inversed expression pattern at the invasive front of the aggressive tumors. Given that the accumulation of reactive oxygen species triggers the activation of Wnt/β-catenin signal pathway, it is hypothesized that CD44v causes the negative feedback machinery in the regulation of c-Myc expression via the attenuated ROS-induced Wnt signal pathway. To address the fundamental question whether and how both proliferative and quiescent cancer stem-like cells heterogeneously exist at the invasive/metastatic edge, researchers need to investigate into the E3-ubiquitin ligase activity essential for c-Myc degradation. CSCs heterogeneity at the invasive/metastatic front is expected to demonstrate the dynamic tumor evolution with the selective pressure of anti-cancer treatments. Furthermore, the novel molecular targeting therapeutic strategies would be established to disrupt the finely-regulated c-Myc expression in the heterogeneous CSC population in combination with the typical drug-repositioning with xCT inhibitor.

  10. Drug screening identifies niclosamide as an inhibitor of breast cancer stem-like cells.

    PubMed

    Wang, Yu-Chi; Chao, Tai-Kuang; Chang, Cheng-Chang; Yo, Yi-Te; Yu, Mu-Hsien; Lai, Hung-Cheng

    2013-01-01

    The primary cause of death from breast cancer is the progressive growth of tumors and resistance to conventional therapies. It is currently believed that recurrent cancer is repopulated according to a recently proposed cancer stem cell hypothesis. New therapeutic strategies that specifically target cancer stem-like cells may represent a new avenue of cancer therapy. We aimed to discover novel compounds that target breast cancer stem-like cells. We used a dye-exclusion method to isolate side population (SP) cancer cells and, subsequently, subjected these SP cells to a sphere formation assay to generate SP spheres (SPS) from breast cancer cell lines. Surface markers, stemness genes, and tumorigenicity were used to test stem properties. We performed a high-throughput drug screening using these SPS. The effects of candidate compounds were assessed in vitro and in vivo. We successfully generated breast cancer SPS with stem-like properties. These SPS were enriched for CD44(high) (2.8-fold) and CD24(low) (4-fold) cells. OCT4 and ABCG2 were overexpressed in SPS. Moreover, SPS grew tumors at a density of 10(3), whereas an equivalent number of parental cells did not initiate tumor formation. A clinically approved drug, niclosamide, was identified from the LOPAC chemical library of 1,258 compounds. Niclosamide downregulated stem pathways, inhibited the formation of spheroids, and induced apoptosis in breast cancer SPS. Animal studies also confirmed this therapeutic effect. The results of this proof-of-principle study may facilitate the development of new breast cancer therapies in the near future. The extension of niclosamide clinical trials is warranted.

  11. Remote Postoperative Epidural Hematoma after Brain Tumor Surgery

    PubMed Central

    Chung, Ho-Jung; Park, Jae-Sung; Jeun, Sin-Soo

    2015-01-01

    A postoperative epidural hematoma (EDH) is a serious and embarrassing complication, which usually occurs at the site of operation after intracranial surgery. However, remote EDH is relatively rare. We report three cases of remote EDH after brain tumor surgery. All three cases seemed to have different causes of remote postoperative EDH; however, all patients were managed promptly and showed excellent outcomes. Although the exact mechanism of remote postoperative EDH is unknown, surgeons should be cautious of the speed of lowering intracranial pressure and implement basic procedures to prevent this hazardous complication of brain tumor surgery. PMID:26605271

  12. Interpreting WAIS-III performance after primary brain tumor surgery.

    PubMed

    Gonçalves, Marta de A; Simões, Mário R; Castro-Caldas, Alexandre

    2017-01-01

    The literature lacks information on the performance of patients with brain tumors on the Wechsler Intelligence Scales. This study aimed to explore the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) performance profile of 23 consecutive patients with brain tumors and 23 matched controls selected from the Portuguese WAIS-III standardization sample, using the technical manual steps recommended for score interpretation. The control group was demographically matched to the tumor group regarding gender, age, education, profession, and geographic region. The technical manual steps recommended for score interpretation were applied. Patients with brain tumors had significantly lower performances on the Performance IQ, Full-Scale IQ, Perceptual Organization Index, Working Memory Index, Processing Speed Index, Arithmetic, Object Assembly, and Picture Arrangement, though all scaled scores were within the normal range according to the manual tables. Only Vocabulary and Comprehension scatter scores were statistically different between groups. No strengths or weaknesses were found for either group. The mean discrepancy scores do not appear to have clinical value for this population. In conclusion, the study results did not reveal a specific profile for patients with brain tumors on the WAIS-III.

  13. Training stem cells for treatment of malignant brain tumors.

    PubMed

    Li, Shengwen Calvin; Kabeer, Mustafa H; Vu, Long T; Keschrumrus, Vic; Yin, Hong Zhen; Dethlefs, Brent A; Zhong, Jiang F; Weiss, John H; Loudon, William G

    2014-09-26

    The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for patients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution (i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system.

  14. Diffusion in the extracellular space in brain and tumors

    NASA Astrophysics Data System (ADS)

    Verkman, A. S.

    2013-08-01

    Diffusion of solutes and macromolecules in the extracellular space (ECS) in brain is important for non-synaptic intercellular communication, extracellular ionic buffering, and delivery of drugs and metabolites. Diffusion in tumor ECS is important for delivery of anti-tumor drugs. The ECS in brain comprises ˜20% of brain parenchymal volume and contains cell-cell gaps down to ˜50 nm. We have developed fluorescence methods to quantify solute diffusion in the ECS, allowing measurements deep in solid tissues using microfiberoptics with micron tip size. Diffusion through the tortuous ECS in brain is generally slowed by ˜3-5-fold compared with that in water, with approximately half of the slowing due to tortuous ECS geometry and half due to the mildly viscous extracellular matrix (ECM). Mathematical modeling of slowed diffusion in an ECS with reasonable anatomical accuracy is in good agreement with experiment. In tumor tissue, diffusion of small macromolecules is only mildly slowed (<3-fold slower than in water) in superficial tumor, but is greatly slowed (>10-fold) at a depth of few millimeters as the tumor tissue becomes more compact. Slowing by ECM components such as collagen contribute to the slowed diffusion. Therefore, as found within cells, cellular crowding and highly tortuous transport can produce only minor slowing of diffusion in the ECS.

  15. Progress on the diagnosis and evaluation of brain tumors

    PubMed Central

    Gao, Huile

    2013-01-01

    Abstract Brain tumors are one of the most challenging disorders encountered, and early and accurate diagnosis is essential for the management and treatment of these tumors. In this article, diagnostic modalities including single-photon emission computed tomography, positron emission tomography, magnetic resonance imaging, and optical imaging are reviewed. We mainly focus on the newly emerging, specific imaging probes, and their potential use in animal models and clinical settings. PMID:24334439

  16. Agnosias: recognition disorders in patients with brain tumors.

    PubMed

    Gainotti, Guido

    2012-06-01

    Two main varieties of recognition disorders are distinguished in neuropsychology: agnosias and semantic disorders. The term agnosias is generally used to denote recognition defects limited to a single perceptual modality (which is itself apparently intact), whereas the term semantic disorders is used to denote recognition defects involving all the sensory modalities in a roughly similar manner. Brain tumors can be one of the aetiologies underlying agnosias and semantic disorders. However, due to the heterogeneity and the rarity of recognition disorders, their investigation can be useful only to suggest or exclude the oncological nature of a brain lesion, but not to systematically monitor the clinical outcome in tumor patients. Furthermore, the relevance of recognition disorders as a hint toward a diagnosis of brain tumor varies according to the type of agnosia and of semantic disorder and the localization of the underlying brain pathology. The hypothesis that a variety of agnosia (or of semantic disorder) may be due to a neoplastic lesion can, therefore, be advanced if it is consistent with our knowledge about the usual localization and the growing patterns of different types of brain tumors.

  17. Enhanced Performance of Brain Tumor Classification via Tumor Region Augmentation and Partition.

    PubMed

    Cheng, Jun; Huang, Wei; Cao, Shuangliang; Yang, Ru; Yang, Wei; Yun, Zhaoqiang; Wang, Zhijian; Feng, Qianjin

    2015-01-01

    Automatic classification of tissue types of region of interest (ROI) plays an important role in computer-aided diagnosis. In the current study, we focus on the classification of three types of brain tumors (i.e., meningioma, glioma, and pituitary tumor) in T1-weighted contrast-enhanced MRI (CE-MRI) images. Spatial pyramid matching (SPM), which splits the image into increasingly fine rectangular subregions and computes histograms of local features from each subregion, exhibits excellent results for natural scene classification. However, this approach is not applicable for brain tumors, because of the great variations in tumor shape and size. In this paper, we propose a method to enhance the classification performance. First, the augmented tumor region via image dilation is used as the ROI instead of the original tumor region because tumor surrounding tissues can also offer important clues for tumor types. Second, the augmented tumor region is split into increasingly fine ring-form subregions. We evaluate the efficacy of the proposed method on a large dataset with three feature extraction methods, namely, intensity histogram, gray level co-occurrence matrix (GLCM), and bag-of-words (BoW) model. Compared with using tumor region as ROI, using augmented tumor region as ROI improves the accuracies to 82.31% from 71.39%, 84.75% from 78.18%, and 88.19% from 83.54% for intensity histogram, GLCM, and BoW model, respectively. In addition to region augmentation, ring-form partition can further improve the accuracies up to 87.54%, 89.72%, and 91.28%. These experimental results demonstrate that the proposed method is feasible and effective for the classification of brain tumors in T1-weighted CE-MRI.

  18. Enhanced Performance of Brain Tumor Classification via Tumor Region Augmentation and Partition

    PubMed Central

    Cheng, Jun; Huang, Wei; Cao, Shuangliang; Yang, Ru; Yang, Wei; Yun, Zhaoqiang; Wang, Zhijian; Feng, Qianjin

    2015-01-01

    Automatic classification of tissue types of region of interest (ROI) plays an important role in computer-aided diagnosis. In the current study, we focus on the classification of three types of brain tumors (i.e., meningioma, glioma, and pituitary tumor) in T1-weighted contrast-enhanced MRI (CE-MRI) images. Spatial pyramid matching (SPM), which splits the image into increasingly fine rectangular subregions and computes histograms of local features from each subregion, exhibits excellent results for natural scene classification. However, this approach is not applicable for brain tumors, because of the great variations in tumor shape and size. In this paper, we propose a method to enhance the classification performance. First, the augmented tumor region via image dilation is used as the ROI instead of the original tumor region because tumor surrounding tissues can also offer important clues for tumor types. Second, the augmented tumor region is split into increasingly fine ring-form subregions. We evaluate the efficacy of the proposed method on a large dataset with three feature extraction methods, namely, intensity histogram, gray level co-occurrence matrix (GLCM), and bag-of-words (BoW) model. Compared with using tumor region as ROI, using augmented tumor region as ROI improves the accuracies to 82.31% from 71.39%, 84.75% from 78.18%, and 88.19% from 83.54% for intensity histogram, GLCM, and BoW model, respectively. In addition to region augmentation, ring-form partition can further improve the accuracies up to 87.54%, 89.72%, and 91.28%. These experimental results demonstrate that the proposed method is feasible and effective for the classification of brain tumors in T1-weighted CE-MRI. PMID:26447861

  19. A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies.

    PubMed

    Chadwick, Emily J; Yang, David P; Filbin, Mariella G; Mazzola, Emanuele; Sun, Yu; Behar, Oded; Pazyra-Murphy, Maria F; Goumnerova, Liliana; Ligon, Keith L; Stiles, Charles D; Segal, Rosalind A

    2015-11-07

    Brain tumors are a major cause of cancer-related morbidity and mortality. Developing new therapeutics for these cancers is difficult, as many of these tumors are not easily grown in standard culture conditions. Neurosphere cultures under serum-free conditions and orthotopic xenografts have expanded the range of tumors that can be maintained. However, many types of brain tumors remain difficult to propagate or study. This is particularly true for pediatric brain tumors such as pilocytic astrocytomas and medulloblastomas. This protocol describes a system that allows primary human brain tumors to be grown in culture. This quantitative assay can be used to investigate the effect of microenvironment on tumor growth, and to test new drug therapies. This protocol describes a system where fluorescently labeled brain tumor cells are grown on an organotypic brain slice from a juvenile mouse. The response of tumor cells to drug treatments can be studied in this assay, by analyzing changes in the number of cells on the slice over time. In addition, this system can address the nature of the microenvironment that normally fosters growth of brain tumors. This brain tumor organotypic slice co-culture assay provides a propitious system for testing new drugs on human tumor cells within a brain microenvironment.

  20. A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies

    PubMed Central

    Chadwick, Emily J.; Yang, David P.; Filbin, Mariella G.; Mazzola, Emanuele; Sun, Yu; Behar, Oded; Pazyra-Murphy, Maria F.; Goumnerova, Liliana; Ligon, Keith L.; Stiles, Charles D.; Segal, Rosalind A.

    2015-01-01

    Brain tumors are a major cause of cancer-related morbidity and mortality. Developing new therapeutics for these cancers is difficult, as many of these tumors are not easily grown in standard culture conditions. Neurosphere cultures under serum-free conditions and orthotopic xenografts have expanded the range of tumors that can be maintained. However, many types of brain tumors remain difficult to propagate or study. This is particularly true for pediatric brain tumors such as pilocytic astrocytomas and medulloblastomas. This protocol describes a system that allows primary human brain tumors to be grown in culture. This quantitative assay can be used to investigate the effect of microenvironment on tumor growth, and to test new drug therapies. This protocol describes a system where fluorescently labeled brain tumor cells are grown on an organotypic brain slice from a juvenile mouse. The response of tumor cells to drug treatments can be studied in this assay, by analyzing changes in the number of cells on the slice over time. In addition, this system can address the nature of the microenvironment that normally fosters growth of brain tumors. This brain tumor organotypic slice co-culture assay provides a propitious system for testing new drugs on human tumor cells within a brain microenvironment. PMID:26575352

  1. Intracranial foreign body granuloma simulating brain tumor: a case report

    PubMed Central

    Saeidiborojeni, Hamid Reza; Fakheri, Taravat; Iizadi, Babak

    2011-01-01

    Intracranial foreign body granulomas are rarely reported. Clinical symptoms caused by foreign body granulomas can be noticed from months to many years after surgical procedure. The most common reported etiology is suture material. A 45-year-old woman was presented with grand mal epilepsy. She was operated for brain tumor 19 years ago. In CT scan, a round radio-dense mass resembling a tumor at anterior fossa was seen. She underwent craniotomy and resected a granuloma with cotton fibers surrounded by yellow capsule without residual or recurrent tumor. Granuloma can mimic intracranial meningioma and special attention should be paid not to leave cotton pledgets during operations. PMID:22091258

  2. Hallmarks in colorectal cancer: angiogenesis and cancer stem-like cells.

    PubMed

    Mathonnet, Muriel; Perraud, Aurelie; Christou, Niki; Akil, Hussein; Melin, Carole; Battu, Serge; Jauberteau, Marie-Odile; Denizot, Yves

    2014-04-21

    Carcinogenesis is a multistep process that requires the accumulation of various genetic and epigenetic aberrations to drive the progressive malignant transformation of normal human cells. Two major hallmarks of carcinogenesis that have been described are angiogenesis and the stem cell characteristic of limitless replicative potential. These properties have been targeted over the past decade in the development of therapeutic treatments for colorectal cancer (CRC), one of the most commonly diagnosed and lethal cancers worldwide. The treatment of solid tumor cancers such as CRC has been challenging due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells. Furthermore, the same microenvironment that maintains the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia also provides the necessary conditions for proliferative growth of cancer stem-like cells. These cancer stem-like cells are responsible for the resistance to therapy and cancer recurrence, though they represent less than 2.5% of the tumor mass. The stromal environment surrounding the tumor cells, referred to as the tumor niche, also supports angiogenesis, which supplies the oxygen and nutrients needed for tumor development. Anti-angiogenic therapy, such as with bevacizumab, a monoclonal antibody against vascular-endothelial growth factor, significantly prolongs the survival of metastatic CRC patients. However, such treatments are not completely curative, and a large proportion of patient tumors retain chemoresistance or show recurrence. This article reviews the current knowledge regarding the molecular phenotype of CRC cancer cells, as well as discusses the mechanisms contributing to their maintenance. Future personalized therapeutic approaches that are based on the interaction of the carcinogenic hallmarks, namely angiogenic and proliferative attributes, could improve survival and decrease adverse effects induced by

  3. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling.

    PubMed

    Schroeder, Anne; Herrmann, Andreas; Cherryholmes, Gregory; Kowolik, Claudia; Buettner, Ralf; Pal, Sumanta; Yu, Hua; Müller-Newen, Gerhard; Jove, Richard

    2014-02-15

    Androgen receptor (AR) signaling is important for prostate cancer progression. However, androgen-deprivation and/or AR targeting-based therapies often lead to resistance. Here, we demonstrate that loss of AR expression results in STAT3 activation in prostate cancer cells. AR downregulation further leads to development of prostate cancer stem-like cells (CSC), which requires STAT3. In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased interleukin (IL)-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs. Together, these findings indicate an opposing role of AR and STAT3 in prostate CSC development.

  4. Development of multifunctional nanoparticles for brain tumor diagnosis and therapy

    NASA Astrophysics Data System (ADS)

    Veiseh, Omid

    Magnetic nanoparticles (MNPs) represent a class of non-invasive imaging agents developed for magnetic resonance (MR) imaging and drug delivery. MNPs have traditionally been developed for disease imaging via passive targeting, but recent advances in nanotechnology have enabled cellular-specific targeting, drug delivery and multi-modal imaging using these nanoparticles. Opportunities now exist to engineer MNP with designated features (e.g., size, coatings, and molecular functionalizations) for specific biomedical applications. The goal of this interdisciplinary research project is to develop targeting multifunctional nanoparticles, serving as both contrast agents and drug carriers that can effectively pass biological barriers, for diagnosis, staging and treatment of brain tumors. The developed nanoparticle system consists of a superparamagnetic iron oxide nanoparticle core (NP) and a shell comprised of biodegradable polymers such as polyethylene glycol (PEG) and chitosan. Additionally, near-infrared fluorescing (NIRF) molecules were integrated onto the NP shell to enable optical detection. Tumor targeting was achieved by the addition of chlorotoxin, a peptide with that has high affinity to 74 out of the 79 classifications of primary brain tumors and ability to illicit a therapeutic effect. This novel NP system was tested both in vitro and in vivo and was shown to specifically target gliomas in tissue culture and medulloblastomas in transgenic mice with an intact blood brain barriers (BBB), and delineate tumor boundaries in both MR and optical imaging. Additionally, the therapeutic potential of this NP system was explored in vitro, which revealed a unique nanoparticle-enabled pathway that enhances the therapeutic potential of bound peptides by promoting the internalization of membrane bound cell surface receptors. This NP system was further modified with siRNA and evaluated as a carrier for brain tumor targeted gene therapy. Most significantly, the evaluation of

  5. American brain tumor patients treated with BNCT in Japan

    SciTech Connect

    Laramore, G.E.; Griffin, B.R.; Spence, A.

    1995-11-01

    The purpose of this work is to establish and maintain a database for patients from the United States who have received BNCT in Japan for malignant gliomas of the brain. This database will serve as a resource for the DOE to aid in decisions relating to BNCT research in the United States, as well as assisting the design and implementation of clinical trials of BNCT for brain cancer patients in this country. The database will also serve as an information resource for patients with brain tumors and their families who are considering this form of therapy.

  6. Dexamethasone alleviates tumor-associated brain damage and angiogenesis.

    PubMed

    Fan, Zheng; Sehm, Tina; Rauh, Manfred; Buchfelder, Michael; Eyupoglu, Ilker Y; Savaskan, Nicolai E

    2014-01-01

    Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc-; SLC7a11) and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G) resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage.

  7. Dexamethasone Alleviates Tumor-Associated Brain Damage and Angiogenesis

    PubMed Central

    Fan, Zheng; Sehm, Tina; Rauh, Manfred; Buchfelder, Michael

    2014-01-01

    Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc−; SLC7a11) and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G) resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage. PMID:24714627

  8. MRI virtual biopsy and treatment of brain metastatic tumors with targeted nanobioconjugates: nanoclinic in the brain.

    PubMed

    Patil, Rameshwar; Ljubimov, Alexander V; Gangalum, Pallavi R; Ding, Hui; Portilla-Arias, Jose; Wagner, Shawn; Inoue, Satoshi; Konda, Bindu; Rekechenetskiy, Arthur; Chesnokova, Alexandra; Markman, Janet L; Ljubimov, Vladimir A; Li, Debiao; Prasad, Ravi S; Black, Keith L; Holler, Eggehard; Ljubimova, Julia Y

    2015-05-26

    Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections, or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise noninvasive MRI diagnostic method, we have engineered a new class of poly(β-l-malic acid) polymeric nanoimaging agents (NIAs). The NIAs carrying attached MRI tracer are able to pass through the blood-brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative "MRI virtual biopsy" method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in a significant increase in animal survival and markedly reduced immunostaining for several cancer stem cell markers. Novel NIAs could be useful for brain diagnostic MRI in the clinic without currently performed brain biopsies. This technology shows promise for differential MRI diagnosis and treatment of brain metastases and other pathologies when biopsies are difficult to perform.

  9. The effect of salinomycin on ovarian cancer stem-like cells

    PubMed Central

    Chung, Hyewon; Kim, Yu-Hwan; Kwon, Myoung; Shin, So-Jin; Kwon, Sang-Hoon; Cha, Soon-Do

    2016-01-01

    Objective The identification of cancer stem-like cells is a recent development in ovarian cancer. Compared to other cancer cells, cancer stem-like cells present more chemo-resistance and more aggressive characteristics. They play an important role in the recurrence and drug resistance of cancer. Therefore, the target therapy of cancer stem-like cell may become a promising and effective approach for ovarian cancer treatment. It may also help to provide novel diagnostic and therapeutic strategies. Methods The OVCAR3 cell line was cultured under serum-free conditions to produce floating spheres. The CD44+CD117+ cell line was isolated from the human ovarian cancer cell line OVCAR3 by using immune magnetic-activated cell sorting system. The expression of stemness genes such as OCT3/4, NANOG and SOX2 mRNA were determined by reverse transcription polymerase chain reaction. OVCAR3 parental and OVCAR3 CD44+CD117+ cells were grown in different doses of paclitaxel and salinomycin to evaluate the effect of salinomycin. And growth inhibition of OVCAR3 CD44+CD117+ cells by paclitaxel combined with salinomycin was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results Tumor spheroids generated from the OVCAR3 cell line are shown to have highly enriched CD44 and CD117 expression. Treatment with a combination of paclitaxel and salinomycin demonstrated growth inhibition of OVCAR3 CD44+CD117+ cells. Conclusion The present study is a detailed investigation on the expression of CD44 and CD117 in cancer stem cells and evaluates their specific tumorigenic characteristics in ovarian cancer. This study also demonstrates significant growth inhibition of cancer stem-like cells by paclitaxel combined with salinomycin. Identification of these cancer stem-like cell markers and growth inhibition effect of salinomycin may be the next step to the development of novel target therapy in ovarian cancer. PMID:27462592

  10. Drug Delivery Using Nanoparticles for Cancer Stem-Like Cell Targeting

    PubMed Central

    Lu, Bing; Huang, Xiaojia; Mo, Jingxin; Zhao, Wei

    2016-01-01

    The theory of cancer stem-like cell (or cancer stem cell, CSC) has been established to explain how tumor heterogeneity arises and contributes to tumor progression in diverse cancer types. CSCs are believed to drive tumor growth and elicit resistance to conventional therapeutics. Therefore, CSCs are becoming novel target in both medical researches and clinical studies. Emerging evidences showed that nanoparticles effectively inhibit many types of CSCs by targeting various specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) and signaling pathways (Notch, Hedgehog, and TGF-β), which are critically involved in CSC function and maintenance. In this review, we briefly summarize the current status of CSC research and review a number of state-of-the-art nanomedicine approaches targeting CSC. In addition, we discuss emerging therapeutic strategies using epigenetic drugs to eliminate CSCs and inhibit cancer cell reprogramming. PMID:27148051

  11. Drug Delivery Using Nanoparticles for Cancer Stem-Like Cell Targeting.

    PubMed

    Lu, Bing; Huang, Xiaojia; Mo, Jingxin; Zhao, Wei

    2016-01-01

    The theory of cancer stem-like cell (or cancer stem cell, CSC) has been established to explain how tumor heterogeneity arises and contributes to tumor progression in diverse cancer types. CSCs are believed to drive tumor growth and elicit resistance to conventional therapeutics. Therefore, CSCs are becoming novel target in both medical researches and clinical studies. Emerging evidences showed that nanoparticles effectively inhibit many types of CSCs by targeting various specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) and signaling pathways (Notch, Hedgehog, and TGF-β), which are critically involved in CSC function and maintenance. In this review, we briefly summarize the current status of CSC research and review a number of state-of-the-art nanomedicine approaches targeting CSC. In addition, we discuss emerging therapeutic strategies using epigenetic drugs to eliminate CSCs and inhibit cancer cell reprogramming.

  12. Biology and immunology of cancer stem(-like) cells in head and neck cancer.

    PubMed

    Qian, Xu; Ma, Chenming; Nie, Xiaobo; Lu, Jianxin; Lenarz, Minoo; Kaufmann, Andreas M; Albers, Andreas E

    2015-09-01

    Immunological approaches against tumors including head and neck squamous cell carcinoma (HNSCC) have been investigated for about 50 years. Such immunotherapeutic treatments are still not sufficiently effective for therapy of HNSCC. Despite the existence of immunosurveillance tumor cells may escape from the host immune system by a variety of mechanisms. Recent findings have indicated that cancer stem(-like) cells (CSCs) in HNSCC have the ability to reconstitute the heterogeneity of the bulk tumor and contribute to immunosuppression and resistance to current therapies. With regard to the CSC model, future immunotherapy possibly in combination with other modes of treatment should target this subpopulation specifically to reduce local recurrence and metastasis. In this review, we will summarize recent research findings on immunological features of CSCs and the potential of immune targeting of CSCs.

  13. Learning Profiles of Survivors of Pediatric Brain Tumors

    ERIC Educational Resources Information Center

    Barkon, Beverly

    2009-01-01

    By 2010 it is predicted that one in 900 adults will be survivors of some form of pediatric cancer. The numbers are somewhat lower for survivors of brain tumors, though their numbers are increasing. Schools mistakenly believe that these children easily fit pre-existing categories of disability. Though these students share some of the…

  14. Life Satisfaction in Adult Survivors of Childhood Brain Tumors

    PubMed Central

    Crom, Deborah B.; Li, Zhenghong; Brinkman, Tara M.; Hudson, Melissa M.; Armstrong, Gregory T.; Neglia, Joseph; Ness, Kirsten K.

    2014-01-01

    Adult survivors of childhood brain tumors experience multiple, significant, life-long deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors’ physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggests some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population–based matched controls. Chi-square tests, t-tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors’ general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population. PMID:25027187

  15. Life satisfaction in adult survivors of childhood brain tumors.

    PubMed

    Crom, Deborah B; Li, Zhenghong; Brinkman, Tara M; Hudson, Melissa M; Armstrong, Gregory T; Neglia, Joseph; Ness, Kirsten K

    2014-01-01

    Adult survivors of childhood brain tumors experience multiple, significant, lifelong deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors' physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggest some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population-based matched controls. Chi-square tests, t tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated that life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors' general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population.

  16. Genetic abnormality predicts benefit for a rare brain tumor

    Cancer.gov

    A clinical trial has shown that addition of chemotherapy to radiation therapy leads to a near doubling of median survival time in patients with a form of brain tumor (oligodendroglioma) that carries a chromosomal abnormality called the 1p19q co-deletion.

  17. ER-mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem-like cells.

    PubMed

    Bassoy, Esen Yonca; Kasahara, Atsuko; Chiusolo, Valentina; Jacquemin, Guillaume; Boydell, Emma; Zamorano, Sebastian; Riccadonna, Cristina; Pellegatta, Serena; Hulo, Nicolas; Dutoit, Valérie; Derouazi, Madiha; Dietrich, Pierre Yves; Walker, Paul R; Martinvalet, Denis

    2017-03-10

    Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells (GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER-mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER-mitochondria contacts compared to GDCs. Forced ER-mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER-mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma.

  18. Targeting atypical protein kinase C iota reduces viability in glioblastoma stem-like cells via a notch signaling mechanism.

    PubMed

    Phillips, Emma; Lang, Verena; Bohlen, Jonathan; Bethke, Frederic; Puccio, Laura; Tichy, Diana; Herold-Mende, Christel; Hielscher, Thomas; Lichter, Peter; Goidts, Violaine

    2016-10-15

    In a previous study, Protein Kinase C iota (PRKCI) emerged as an important candidate gene for glioblastoma (GBM) stem-like cell (GSC) survival. Here, we show that PKCι is overexpressed and activated in patient derived GSCs compared with normal neural stem cells and normal brain lysate, and that silencing of PRKCI in GSCs causes apoptosis, along with loss of clonogenicity and reduced proliferation. Notably, PRKCI silencing reduces tumor growth in vivo in a xenograft mouse model. PKCι has been intensively studied as a therapeutic target in non-small cell lung cancer, resulting in the identification of an inhibitor, aurothiomalate (ATM), which disrupts the PKCι/ERK signaling axis. However, we show that, although sensitive to pharmacological inhibition via a pseudosubstrate peptide inhibitor, GSCs are much less sensitive to ATM, suggesting that PKCι acts along a different signaling axis in GSCs. Gene expression profiling of PRKCI-silenced GSCs revealed a novel role of the Notch signaling pathway in PKCι mediated GSC survival. A proximity ligation assay showed that Notch1 and PKCι are in close proximity in GSCs. Targeting PKCι in the context of Notch signaling could be an effective way of attacking the GSC population in GBM.

  19. Gene therapy for brain tumors: basic developments and clinical implementation.

    PubMed

    Assi, Hikmat; Candolfi, Marianela; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro R; Castro, Maria G

    2012-10-11

    Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM.

  20. Gene Therapy for Brain Tumors: Basic Developments and Clinical Implementation

    PubMed Central

    Assi, Hikmat; Candolfi, Marianela; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro R; Castro, Maria G

    2012-01-01

    Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM. PMID:22906921

  1. Antiangiogenic (metronomic) chemotherapy for brain tumors: current and future perspectives.

    PubMed

    Samuel, David P; Wen, Patrick Y; Kieran, Mark W

    2009-07-01

    Significant advances in the diagnosis and treatment of brain tumors have been made through better imaging, surgical techniques and advances in radiation therapy. However, the cure rate for most adult and pediatric brain tumor patients has not mirrored this success. Angiogenesis, the development of neovascularization, provides the required nutrients and oxygen to an expanding tumor and is controlled by a complex balance of proangiogenic cytokines and antiangiogenic factors. A series of new inhibitors of angiogenesis are now in clinical trials. Most of these rely on inhibiting tumor cell-mediated cytokines or blocking the activation of their cognate receptors. Cytotoxic chemotherapy, by contrast, targets dividing cells but can be modulated to attack dividing endothelial cells. This review will focus on the use of low-dose antiangiogenic (also called metronomic) chemotherapy to inhibit endothelial cell function and resultant neovascularization in the treatment of adult and pediatric brain tumors. By examining the biology and preclinical findings that led to the development of antiangiogenic/metronomic chemotherapy, clinical studies have been undertaken that support the role of this approach in the clinic, and have led to the introduction of a number of markers being used to better predict active combinations and appropriate patient populations.

  2. Cerenkov and radioluminescence imaging of brain tumor specimens during neurosurgery

    NASA Astrophysics Data System (ADS)

    Spinelli, Antonello Enrico; Schiariti, Marco P.; Grana, Chiara M.; Ferrari, Mahila; Cremonesi, Marta; Boschi, Federico

    2016-05-01

    We presented the first example of Cerenkov luminescence imaging (CLI) and radioluminescence imaging (RLI) of human tumor specimens. A patient with a brain meningioma localized in the left parietal region was injected with 166 MBq of Y90-DOTATOC the day before neurosurgery. The specimens of the tumor removed during surgery were imaged using both CLI and RLI using an optical imager prototype developed in our laboratory. The system is based on a cooled electron multiplied charge coupled device coupled with an f/0.95 17-mm C-mount lens. We showed for the first time the possibility of obtaining CLI and RLI images of fresh human brain tumor specimens removed during neurosurgery.

  3. Unsupervised measurement of brain tumor volume on MR images.

    PubMed

    Velthuizen, R P; Clarke, L P; Phuphanich, S; Hall, L O; Bensaid, A M; Arrington, J A; Greenberg, H M; Silbiger, M L

    1995-01-01

    We examined unsupervised methods of segmentation of MR images of the brain for measuring tumor volume in response to treatment. Two clustering methods were used: fuzzy c-means and a nonfuzzy clustering algorithm. Results were compared with volume segmentations by two supervised methods, k-nearest neighbors and region growing, and all results were compared with manual labelings. Results of individual segmentations are presented as well as comparisons on the application of the different methods with 10 data sets of patients with brain tumors. Unsupervised segmentation is preferred for measuring tumor volumes in response to treatment, as it eliminates operator dependency and may be adequate for delineation of the target volume in radiation therapy. Some obstacles need to be overcome, in particular regarding the detection of anatomically relevant tissue classes. This study shows that these improvements are possible.

  4. Alterations of telomere length in human brain tumors.

    PubMed

    Kheirollahi, Majid; Mehrazin, Masoud; Kamalian, Naser; Mehdipour, Parvin

    2011-09-01

    Telomeres at the ends of human chromosomes consist of tandem hexametric (TTAGGG)n repeats, which protect them from degradation. At each cycle of cell division, most normal somatic cells lose approximately 50-100 bp of the terminal telomeric repeat DNA. Precise prediction of growth and estimation of the malignant potential of brain tumors require additional markers. DNA extraction was performed from the 51 frozen tissues, and a non-radioactive chemiluminescent assay was used for Southern blotting. One sample t-test shows highly significant difference in telomere length in meningioma and astrocytoma with normal range. According to our results, higher grades of meningioma and astrocytoma tumors show more heterogeneity in telomere length, and also it seems shortening process of telomeres is an early event in brain tumors.

  5. Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

    PubMed Central

    Klinger, Neil V.

    2016-01-01

    Brain malignancies currently carry a poor prognosis despite the current multimodal standard of care that includes surgical resection and adjuvant chemotherapy and radiation. As new therapies are desperately needed, naturally occurring chemical compounds have been studied for their potential chemotherapeutic benefits and low toxicity profile. Curcumin, found in the rhizome of turmeric, has extensive therapeutic promise via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown it to be an effective treatment for brain tumors including glioblastoma multiforme. These effects are potentiated by curcumin's ability to induce G2/M cell cycle arrest, activation of apoptotic pathways, induction of autophagy, disruption of molecular signaling, inhibition of invasion, and metastasis and by increasing the efficacy of existing chemotherapeutics. Further, clinical data suggest that it has low toxicity in humans even at large doses. Curcumin is a promising nutraceutical compound that should be evaluated in clinical trials for the treatment of human brain tumors. PMID:27807473

  6. Simulation of brain tumor resection in image-guided neurosurgery

    NASA Astrophysics Data System (ADS)

    Fan, Xiaoyao; Ji, Songbai; Fontaine, Kathryn; Hartov, Alex; Roberts, David; Paulsen, Keith

    2011-03-01

    Preoperative magnetic resonance images are typically used for neuronavigation in image-guided neurosurgery. However, intraoperative brain deformation (e.g., as a result of gravitation, loss of cerebrospinal fluid, retraction, resection, etc.) significantly degrades the accuracy in image guidance, and must be compensated for in order to maintain sufficient accuracy for navigation. Biomechanical finite element models are effective techniques that assimilate intraoperative data and compute whole-brain deformation from which to generate model-updated MR images (uMR) to improve accuracy in intraoperative guidance. To date, most studies have focused on early surgical stages (i.e., after craniotomy and durotomy), whereas simulation of more complex events at later surgical stages has remained to be a challenge using biomechanical models. We have developed a method to simulate partial or complete tumor resection that incorporates intraoperative volumetric ultrasound (US) and stereovision (SV), and the resulting whole-brain deformation was used to generate uMR. The 3D ultrasound and stereovision systems are complimentary to each other because they capture features deeper in the brain beneath the craniotomy and at the exposed cortical surface, respectively. In this paper, we illustrate the application of the proposed method to simulate brain tumor resection at three temporally distinct surgical stages throughout a clinical surgery case using sparse displacement data obtained from both the US and SV systems. We demonstrate that our technique is feasible to produce uMR that agrees well with intraoperative US and SV images after dural opening, after partial tumor resection, and after complete tumor resection. Currently, the computational cost to simulate tumor resection can be up to 30 min because of the need for re-meshing and the trial-and-error approach to refine the amount of tissue resection. However, this approach introduces minimal interruption to the surgical workflow

  7. Banking Brain Tumor Specimens Using a University Core Facility.

    PubMed

    Bregy, Amade; Papadimitriou, Kyriakos; Faber, David A; Shah, Ashish H; Gomez, Carmen R; Komotar, Ricardo J; Egea, Sophie C

    2015-08-01

    Within the past three decades, the significance of banking human cancer tissue for the advancement of cancer research has grown exponentially. The purpose of this article is to detail our experience in collecting brain tumor specimens in collaboration with the University of Miami/Sylvester Tissue Bank Core Facility (UM-TBCF), to ensure the availability of high-quality samples of central nervous system tumor tissue for research. Successful tissue collection begins with obtaining informed consent from patients following institutional IRB and federal HIPAA guidelines, and it needs a well-trained professional staff and continued maintenance of high ethical standards and record keeping. Since starting in 2011, we have successfully banked 225 brain tumor specimens for research. Thus far, the most common tumor histology identified among those specimens has been glioblastoma (22.1%), followed by meningioma (18.1%). The majority of patients were White, non-Hispanics accounting for 45.1% of the patient population; Hispanic/Latinos accounted for 23%, and Black/African Americans accounted for 14%, which represent the particular population of the State of Florida according to the 2010 census data. The most common tumors found in each subgroup were as follows: Black/African American, glioblastoma and meningioma; Hispanic, metastasis and glioblastoma; White, glioblastoma and meningioma. The UM-TBCF is a valuable repository, offering high-quality tumor samples from a unique patient population.

  8. What Are the Risk Factors for Brain and Spinal Cord Tumors in Children?

    MedlinePlus

    ... and Prevention What Are the Risk Factors for Brain and Spinal Cord Tumors in Children? A risk ... Factors with uncertain, controversial, or unproven effects on brain tumor risk Cell phone use Cell phones give ...

  9. Advanced MRI for Pediatric Brain Tumors with Emphasis on Clinical Benefits

    PubMed Central

    Ra, Young-Shin

    2017-01-01

    Conventional anatomic brain MRI is often limited in evaluating pediatric brain tumors, the most common solid tumors and a leading cause of death in children. Advanced brain MRI techniques have great potential to improve diagnostic performance in children with brain tumors and overcome diagnostic pitfalls resulting from diverse tumor pathologies as well as nonspecific or overlapped imaging findings. Advanced MRI techniques used for evaluating pediatric brain tumors include diffusion-weighted imaging, diffusion tensor imaging, functional MRI, perfusion imaging, spectroscopy, susceptibility-weighted imaging, and chemical exchange saturation transfer imaging. Because pediatric brain tumors differ from adult counterparts in various aspects, MRI protocols should be designed to achieve maximal clinical benefits in pediatric brain tumors. In this study, we review advanced MRI techniques and interpretation algorithms for pediatric brain tumors. PMID:28096729

  10. Imaging of brain tumor proliferative activity with iodine-131-iododeoxyuridine

    SciTech Connect

    Tjuvajev, J.G.; Macapinlac, H.A.; Daghighian, F.

    1994-09-01

    Iodine-131-iododeoxyuridine (IUdR) uptake and retention was imaged with SPECT at 2 and 24 hr after administering a 10-mCi dose to six patients with primary brain tumors. The SPECT images were directly compared to gadolinium contrast-enhanced MR images as well as to ({sup 18}F) fluorodeoxyglucose (FDG) PET scans and {sup 201}Tl SPECT scans. Localized uptake and retention of IUdR-derived radioactivity was observed in five of six patients. The plasma half-life of ({sup 131}I) IUdR was short (1.5 min) in comparison to the half-life of total plasma radioactivity (6.4 hr). The pattern of ({sup 131}I)IUdR-derived radioactivity was markedly different in the 2-hr compared to 24-hr images. Radioactivity was localized along the periphery of the tumor and extended beyond the margin of tumor identified by contrast enhancement on MRI. The estimated levels of tumor radioactivity at 24 hr, based on semiquantitative phantom studies, ranged between <0.1 and 0.2 {mu}Ci/cc (<0.001% and 0.002% dose/cc); brain levels were not measurable. Iodine-131-IUdR SPECT imaging of brain tumor proliferation has low (marginal) sensitivity due to low count rates and can detect only the most active regions of tumor growth. Imaging at 24 hr represents a washout strategy to reduce {sup 131}I-labeled metabolites contributing to background activity in the tumors, and is more likely to show the pattern of ({sup 131}I)IUdR-DNA incorporation and thereby increase image specificity. Iodine-123-IUdR SPECT imaging at 12 hr and the use of ({sup 124}I)IUdR and PET will improve count acquisitions and image quality. 74 refs., 6 figs., 2 tabs.

  11. Radiation treatment of brain tumors: Concepts and strategies

    SciTech Connect

    Marks, J.E. )

    1989-01-01

    Ionizing radiation has demonstrated clinical value for a multitude of CNS tumors. Application of the different physical modalities available has made it possible for the radiotherapist to concentrate the radiation in the region of the tumor with relative sparing of the surrounding normal tissues. Correlation of radiation dose with effect on cranial soft tissues, normal brain, and tumor has shown increasing effect with increasing dose. By using different physical modalities to alter the distribution of radiation dose, it is possible to increase the dose to the tumor and reduce the dose to the normal tissues. Alteration of the volume irradiated and the dose delivered to cranial soft tissues, normal brain, and tumor are strategies that have been effective in improving survival and decreasing complications. The quest for therapeutic gain using hyperbaric oxygen, neutrons, radiation sensitizers, chemotherapeutic agents, and BNCT has met with limited success. Both neoplastic and normal cells are affected simultaneously by all modalities of treatment, including ionizing radiation. Consequently, one is unable to totally depopulate a tumor without irreversibly damaging the normal tissues. In the case of radiation, it is the brain that limits delivery of curative doses, and in the case of chemical additives, it is other organ systems, such as bone marrow, liver, lung, kidneys, and peripheral nerves. Thus, the major obstacle in the treatment of malignant gliomas is our inability to preferentially affect the tumor with the modalities available. Until it is possible to directly target the neoplastic cell without affecting so many of the adjacent normal cells, the quest for therapeutic gain will go unrealized.72 references.

  12. The long non-coding RNA – HIF1A-AS2 facilitates the maintenance of mesenchymal glioblastoma stem-like cells in hypoxic niches

    PubMed Central

    Mineo, Marco; Ricklefs, Franz; Rooj, Arun K.; Lyons, Shawn M.; Ivanov, Pavel; Ansari, Khairul I.; Nakano, Ichiro; Chiocca, E. Antonio; Godlewski, Jakub; Bronisz, Agnieszka

    2016-01-01

    Long-non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia inducible lncRNA, up-regulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal and hypoxia-dependent molecular reprogramming. Amongst the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Down-regulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome/targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context. PMID:27264189

  13. 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits

    PubMed Central

    Calvani, Maura; Taddei, Maria Letizia; Giannoni, Elisa; Kopetz, Scott; Kazmi, Syed Mohammad Ali; Pia, Morelli Maria; Pettazzoni, Piergiorgio; Sacco, Elena; Caselli, Anna; Vanoni, Marco; Landriscina, Matteo; Cirri, Paolo; Chiarugi, Paola

    2015-01-01

    Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer. PMID:26527315

  14. 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.

    PubMed

    Denise, Corti; Paoli, Paolo; Calvani, Maura; Taddei, Maria Letizia; Giannoni, Elisa; Kopetz, Scott; Kazmi, Syed Mohammad Ali; Pia, Morelli Maria; Pettazzoni, Piergiorgio; Sacco, Elena; Caselli, Anna; Vanoni, Marco; Landriscina, Matteo; Cirri, Paolo; Chiarugi, Paola

    2015-12-08

    Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer.

  15. Emerging techniques and technologies in brain tumor imaging

    PubMed Central

    Ellingson, Benjamin M.; Bendszus, Martin; Sorensen, A. Gregory; Pope, Whitney B.

    2014-01-01

    The purpose of this report is to describe the state of imaging techniques and technologies for detecting response of brain tumors to treatment in the setting of multicenter clinical trials. Within currently used technologies, implementation of standardized image acquisition and the use of volumetric estimates and subtraction maps are likely to help to improve tumor visualization, delineation, and quantification. Upon further development, refinement, and standardization, imaging technologies such as diffusion and perfusion MRI and amino acid PET may contribute to the detection of tumor response to treatment, particularly in specific treatment settings. Over the next few years, new technologies such as 23Na MRI and CEST imaging technologies will be explored for their use in expanding the ability to quantitatively image tumor response to therapies in a clinical trial setting. PMID:25313234

  16. Postictal Magnetic Resonance Imaging Changes Masquerading as Brain Tumor Progression: A Case Series

    PubMed Central

    Dunn-Pirio, Anastasie M.; Billakota, Santoshi; Peters, Katherine B.

    2016-01-01

    Seizures are common among patients with brain tumors. Transient, postictal magnetic resonance imaging abnormalities are a long recognized phenomenon. However, these radiographic changes are not as well studied in the brain tumor population. Moreover, reversible neuroimaging abnormalities following seizure activity may be misinterpreted for tumor progression and could consequently result in unnecessary tumor-directed treatment. Here, we describe two cases of patients with brain tumors who developed peri-ictal pseudoprogression and review the relevant literature. PMID:27462237

  17. History and evolution of brain tumor imaging: insights through radiology.

    PubMed

    Castillo, Mauricio

    2014-11-01

    This review recounts the history of brain tumor diagnosis from antiquity to the present and, indirectly, the history of neuroradiology. Imaging of the brain has from the beginning held an enormous interest because of the inherent difficulty of this endeavor due to the presence of the skull. Because of this, most techniques when newly developed have always been used in neuroradiology and, although some have proved to be inappropriate for this purpose, many were easily incorporated into the specialty. The first major advance in modern neuroimaging was contrast agent-enhanced computed tomography, which permitted accurate anatomic localization of brain tumors and, by virtue of contrast enhancement, malignant ones. The most important advances in neuroimaging occurred with the development of magnetic resonance imaging and diffusion-weighted sequences that allowed an indirect estimation of tumor cellularity; this was further refined by the development of perfusion and permeability mapping. From its beginnings with indirect and purely anatomic imaging techniques, neuroradiology now uses a combination of anatomic and physiologic techniques that will play a critical role in biologic tumor imaging and radiologic genomics.

  18. Brain Tumor Segmentation Using Convolutional Neural Networks in MRI Images.

    PubMed

    Pereira, Sergio; Pinto, Adriano; Alves, Victor; Silva, Carlos A

    2016-05-01

    Among brain tumors, gliomas are the most common and aggressive, leading to a very short life expectancy in their highest grade. Thus, treatment planning is a key stage to improve the quality of life of oncological patients. Magnetic resonance imaging (MRI) is a widely used imaging technique to assess these tumors, but the large amount of data produced by MRI prevents manual segmentation in a reasonable time, limiting the use of precise quantitative measurements in the clinical practice. So, automatic and reliable segmentation methods are required; however, the large spatial and structural variability among brain tumors make automatic segmentation a challenging problem. In this paper, we propose an automatic segmentation method based on Convolutional Neural Networks (CNN), exploring small 3 ×3 kernels. The use of small kernels allows designing a deeper architecture, besides having a positive effect against overfitting, given the fewer number of weights in the network. We also investigated the use of intensity normalization as a pre-processing step, which though not common in CNN-based segmentation methods, proved together with data augmentation to be very effective for brain tumor segmentation in MRI images. Our proposal was validated in the Brain Tumor Segmentation Challenge 2013 database (BRATS 2013), obtaining simultaneously the first position for the complete, core, and enhancing regions in Dice Similarity Coefficient metric (0.88, 0.83, 0.77) for the Challenge data set. Also, it obtained the overall first position by the online evaluation platform. We also participated in the on-site BRATS 2015 Challenge using the same model, obtaining the second place, with Dice Similarity Coefficient metric of 0.78, 0.65, and 0.75 for the complete, core, and enhancing regions, respectively.

  19. Brain Tumor Segmentation using Convolutional Neural Networks in MRI Images.

    PubMed

    Pereira, Sergio; Pinto, Adriano; Alves, Victor; Silva, Carlos A

    2016-03-04

    Among brain tumors, gliomas are the most common and aggressive, leading to a very short life expectancy in their highest grade. Thus, treatment planning is a key stage to improve the quality of life of oncological patients. Magnetic Resonance Imaging (MRI) is a widely used imaging technique to assess these tumors, but the large amount of data produced by MRI prevents manual segmentation in a reasonable time, limiting the use of precise quantitative measurements in the clinical practice. So, automatic and reliable segmentation methods are required; however, the large spatial and structural variability among brain tumors make automatic segmentation a challenging problem. In this paper, we propose an automatic segmentation method based on Convolutional Neural Networks (CNN), exploring small 33 kernels. The use of small kernels allows designing a deeper architecture, besides having a positive effect against overfitting, given the fewer number of weights in the network. We also investigated the use of intensity normalization as a pre-processing step, which though not common in CNN-based segmentation methods, proved together with data augmentation to be very effective for brain tumor segmentation in MRI images. Our proposal was validated in the Brain Tumor Segmentation Challenge 2013 database (BRATS 2013), obtaining simultaneously the first position for the complete, core, and enhancing regions in Dice Similarity Coefficient metric (0:88, 0:83, 0:77) for the Challenge data set. Also, it obtained the overall first position by the online evaluation platform. We also participated in the on-site BRATS 2015 Challenge using the same model, obtaining the second place, with Dice Similarity Coefficient metric of 0:78, 0:65, and 0:75 for the complete, core, and enhancing regions, respectively.

  20. Electroretinography and Visual Evoked Potentials in Childhood Brain Tumor Survivors.

    PubMed

    Pietilä, Sari; Lenko, Hanna L; Oja, Sakari; Koivisto, Anna-Maija; Pietilä, Timo; Mäkipernaa, Anne

    2016-07-01

    This population-based cross-sectional study evaluates the clinical value of electroretinography and visual evoked potentials in childhood brain tumor survivors. A flash electroretinography and a checkerboard reversal pattern visual evoked potential (or alternatively a flash visual evoked potential) were done for 51 survivors (age 3.8-28.7 years) after a mean follow-up time of 7.6 (1.5-15.1) years. Abnormal electroretinography was obtained in 1 case, bilaterally delayed abnormal visual evoked potentials in 22/51 (43%) cases. Nine of 25 patients with infratentorial tumor location, and altogether 12 out of 31 (39%) patients who did not have tumors involving the visual pathways, had abnormal visual evoked potentials. Abnormal electroretinographies are rarely observed, but abnormal visual evoked potentials are common even without evident anatomic lesions in the visual pathway. Bilateral changes suggest a general and possibly multifactorial toxic/adverse effect on the visual pathway. Electroretinography and visual evoked potential may have clinical and scientific value while evaluating long-term effects of childhood brain tumors and tumor treatment.

  1. Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight

    PubMed Central

    Savaskan, Nicolai E.; Fan, Zheng; Broggini, Thomas; Buchfelder, Michael; Eyüpoglu, Ilker Y.

    2015-01-01

    Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets. PMID:26411769

  2. Numerical simulations of MREIT conductivity imaging for brain tumor detection.

    PubMed

    Meng, Zi Jun; Sajib, Saurav Z K; Chauhan, Munish; Sadleir, Rosalind J; Kim, Hyung Joong; Kwon, Oh In; Woo, Eung Je

    2013-01-01

    Magnetic resonance electrical impedance tomography (MREIT) is a new modality capable of imaging the electrical properties of human body using MRI phase information in conjunction with external current injection. Recent in vivo animal and human MREIT studies have revealed unique conductivity contrasts related to different physiological and pathological conditions of tissues or organs. When performing in vivo brain imaging, small imaging currents must be injected so as not to stimulate peripheral nerves in the skin, while delivery of imaging currents to the brain is relatively small due to the skull's low conductivity. As a result, injected imaging currents may induce small phase signals and the overall low phase SNR in brain tissues. In this study, we present numerical simulation results of the use of head MREIT for brain tumor detection. We used a realistic three-dimensional head model to compute signal levels produced as a consequence of a predicted doubling of conductivity occurring within simulated tumorous brain tissues. We determined the feasibility of measuring these changes in a time acceptable to human subjects by adding realistic noise levels measured from a candidate 3 T system. We also reconstructed conductivity contrast images, showing that such conductivity differences can be both detected and imaged.

  3. Advanced MR Imaging in Pediatric Brain Tumors, Clinical Applications.

    PubMed

    Lequin, Maarten; Hendrikse, Jeroen

    2017-02-01

    Advanced MR imaging techniques, such as spectroscopy, perfusion, diffusion, and functional imaging, have improved the diagnosis of brain tumors in children and also play an important role in defining surgical as well as therapeutic responses in these patients. In addition to the anatomic or structural information gained with conventional MR imaging sequences, advanced MR imaging techniques also provide physiologic information about tumor morphology, metabolism, and hemodynamics. This article reviews the physiology, techniques, and clinical applications of diffusion-weighted and diffusion tensor imaging, MR spectroscopy, perfusion MR imaging, susceptibility-weighted imaging, and functional MR imaging in the setting of neuro-oncology.

  4. Collecting and Storing Blood and Brain Tumor Tissue Samples From Children With Brain Tumors

    ClinicalTrials.gov

    2016-11-21

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Newly Diagnosed Childhood Ependymoma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma

  5. Cellular phones and risk of brain tumors.

    PubMed

    Frumkin, H; Jacobson, A; Gansler, T; Thun, M J

    2001-01-01

    As cellular telephones are a relatively new technology, we do not yet have long-term follow-up on their possible biological effects. However, the lack of ionizing radiation and the low energy level emitted from cell phones and absorbed by human tissues make it unlikely that these devices cause cancer. Moreover, several well-designed epidemiologic studies find no consistent association between cell phone use and brain cancer. It is impossible to prove that any product or exposure is absolutely safe, especially in the absence of very long-term follow-up. Accordingly, the following summary from the Food and Drug Administration Center for Devices and Radiological Health offers advice to people concerned about their risk: If there is a risk from these products--and at this point we do not know that there is--it is probably very small. But if people are concerned about avoiding even potential risks, there are simple steps they can take to do so. People who must conduct extended conversations in their cars every day could switch to a type of mobile phone that places more distance between their bodies and the source of the RF, since the exposure level drops off dramatically with distance. For example, they could switch to: a mobile phone in which the antenna is located outside the vehicle, a hand-held phone with a built-in antenna connected to a different antenna mounted on the outside of the car or built into a separate package, or a headset with a remote antenna to a mobile phone carried at the waist. Again the scientific data do not demonstrate that mobile phones are harmful. But if people are concerned about the radiofrequency energy from these products, taking the simple precautions outlined above can reduce any possible risk. In addition, people who are concerned might choose digital rather than analog telephones, since the former use lower RF levels.

  6. Efficient multilevel brain tumor segmentation with integrated bayesian model classification.

    PubMed

    Corso, J J; Sharon, E; Dube, S; El-Saden, S; Sinha, U; Yuille, A

    2008-05-01

    We present a new method for automatic segmentation of heterogeneous image data that takes a step toward bridging the gap between bottom-up affinity-based segmentation methods and top-down generative model based approaches. The main contribution of the paper is a Bayesian formulation for incorporating soft model assignments into the calculation of affinities, which are conventionally model free. We integrate the resulting model-aware affinities into the multilevel segmentation by weighted aggregation algorithm, and apply the technique to the task of detecting and segmenting brain tumor and edema in multichannel magnetic resonance (MR) volumes. The computationally efficient method runs orders of magnitude faster than current state-of-the-art techniques giving comparable or improved results. Our quantitative results indicate the benefit of incorporating model-aware affinities into the segmentation process for the difficult case of glioblastoma multiforme brain tumor.

  7. Late sequelae in children treated for brain tumors and leukemia.

    PubMed

    Jereb, B; Korenjak, R; Krzisnik, C; Petric-Grabnar, G; Zadravec-Zaletel, L; Anzic, J; Stare, J

    1994-01-01

    Forty-two survivors treated at an age of 2-16 years for brain tumors or leukemia were, 4-21 years after treatment, subjected to an extensive follow-up investigation, including physical examination and interview; 35 of them also had endocrinological and 33 psychological evaluation. Hormonal deficiencies were found in about two-thirds of patients and were most common in those treated for brain tumors. The great majority had verbal intelligence quotient (VIQ) within normal range. Also, the performance intelligence quotients (PIQ) were normal in most patients. However, the results suggested that the primary intellectual capacity in children treated for cancer was not being fully utilized, their PIQ being on the average higher than their VIQ; this tendency was especially pronounced in the leukemia patients.

  8. Management of children with brain tumors in Paraguay

    PubMed Central

    Baskin, Jacquelyn L.; Lezcano, Eva; Kim, Bo Sung; Figueredo, Diego; Lassaletta, Alvaro; Perez-Martinez, Antonio; Madero, Luis; Caniza, Miguela A.; Howard, Scott C.; Samudio, Angelica; Finlay, Jonathan L.

    2013-01-01

    Background Cure rates among children with brain tumors differ between low-income and high-income countries. To evaluate causes of these differences, we analyzed aspects of care provided to pediatric neuro-oncology patients in a low middle-income South American country. Methods Three methods were used to evaluate treatment of children with brain tumors in Paraguay: (1) a quantitative needs assessment questionnaire for local treating physicians, (2) site visits to assess 3 tertiary care centers in Asunción and a satellite clinic in an underdeveloped area, and (3) interviews with health care workers from relevant disciplines to determine their perceptions of available resources. Treatment failure was defined as abandonment of therapy, relapse, or death. Results All 3 tertiary care facilities have access to chemotherapy and pediatric oncologists but lack training and tools for neuropathology and optimal neurosurgery. The 2 public hospitals also lack access to appropriate radiological tests and timely radiotherapy. These results demonstrate disparities in Paraguay, with rates of treatment failure ranging from 37% to 83% among the 3 facilities. Conclusions National and center-specific deficiencies in resources to manage pediatric brain tumors contribute to poor outcomes in Paraguay and suggest that both national and center-specific interventions are warranted to improve care. Disparities in Paraguay reflect different levels of governmental and philanthropic support, program development, and socio-economic status of patients and families, which must be considered when developing targeted strategies to improve management. Effective targeted interventions can serve as a model to develop pediatric brain tumor programs in other low- and middle-income countries. PMID:23197688

  9. Automatic brain tumor detection in MRI: methodology and statistical validation

    NASA Astrophysics Data System (ADS)

    Iftekharuddin, Khan M.; Islam, Mohammad A.; Shaik, Jahangheer; Parra, Carlos; Ogg, Robert

    2005-04-01

    Automated brain tumor segmentation and detection are immensely important in medical diagnostics because it provides information associated to anatomical structures as well as potential abnormal tissue necessary to delineate appropriate surgical planning. In this work, we propose a novel automated brain tumor segmentation technique based on multiresolution texture information that combines fractal Brownian motion (fBm) and wavelet multiresolution analysis. Our wavelet-fractal technique combines the excellent multiresolution localization property of wavelets to texture extraction of fractal. We prove the efficacy of our technique by successfully segmenting pediatric brain MR images (MRIs) from St. Jude Children"s Research Hospital. We use self-organizing map (SOM) as our clustering tool wherein we exploit both pixel intensity and multiresolution texture features to obtain segmented tumor. Our test results show that our technique successfully segments abnormal brain tissues in a set of T1 images. In the next step, we design a classifier using Feed-Forward (FF) neural network to statistically validate the presence of tumor in MRI using both the multiresolution texture and the pixel intensity features. We estimate the corresponding receiver operating curve (ROC) based on the findings of true positive fractions and false positive fractions estimated from our classifier at different threshold values. An ROC, which can be considered as a gold standard to prove the competence of a classifier, is obtained to ascertain the sensitivity and specificity of our classifier. We observe that at threshold 0.4 we achieve true positive value of 1.0 (100%) sacrificing only 0.16 (16%) false positive value for the set of 50 T1 MRI analyzed in this experiment.

  10. Handling of solid brain tumor tissue for protein analysis.

    PubMed

    Ericsson, Christer; Nistér, Monica

    2011-01-01

    Optimal protein analysis requires unfixed tissue samples. We suggest handling the brain tumor tissue sterilely and coldly (on ice) for as short time as possible prior to processing, but for no more than 8 h. This simple protocol results in apparently intact morphology, immunoreactivity, protein integrity, and protein phosphorylation with the criteria we apply. Sample handling for Pathological Anatomical Diagnosis (PAD) and for protein analysis can be one and the same.

  11. Liposomally formulated phospholipid-conjugated indocyanine green for intra-operative brain tumor detection and resection.

    PubMed

    Suganami, Akiko; Iwadate, Yasuo; Shibata, Sayaka; Yamashita, Masamichi; Tanaka, Tsutomu; Shinozaki, Natsuki; Aoki, Ichio; Saeki, Naokatsu; Shirasawa, Hiroshi; Okamoto, Yoshiharu; Tamura, Yutaka

    2015-12-30

    Some tumor-specific near-infrared (NIR) fluorescent dyes such as indocyanine green (ICG), IDRye800CW, and 5-aminolevulinic acid have been used clinically for detecting tumor margins or micro-cancer lesions. In this study, we evaluated the physicochemical properties of liposomally formulated phospholipid-conjugated ICG, denoted by LP-iDOPE, as a clinically translatable NIR imaging nanoparticle for brain tumors. We also confirmed its brain-tumor-specific biodistribution and its characteristics as the intra-operative NIR imaging nanoparticles for brain tumor surgery. These properties of LP-iDOPE may enable neurosurgeons to achieve more accurate identification and more complete resection of brain tumor.

  12. Sigma and opioid receptors in human brain tumors

    SciTech Connect

    Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J. )

    1990-01-01

    Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using ({sup 3}H) 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: {mu}, (D-ala{sup 2}, mePhe{sup 4}, gly-ol{sup 5}) enkephalin (DAMGE); {kappa}, ethylketocyclazocine (EKC) or U69,593; {delta}, (D-pen{sup 2}, D-pen{sup 5}) enkephalin (DPDPE) or (D-ala{sup 2}, D-leu{sup 5}) enkephalin (DADLE) with {mu} suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. {kappa} opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed.

  13. Heavy Metals and Epigenetic Alterations in Brain Tumors

    PubMed Central

    Caffo, Maria; Caruso, Gerardo; Fata, Giuseppe La; Barresi, Valeria; Visalli, Maria; Venza, Mario; Venza, Isabella

    2014-01-01

    Heavy metals and their derivatives can cause various diseases. Numerous studies have evaluated the possible link between exposure to heavy metals and various cancers. Recent data show a correlation between heavy metals and aberration of genetic and epigenetic patterns. From a literature search we noticed few experimental and epidemiological studies that evaluate a possible correlation between heavy metals and brain tumors. Gliomas arise due to genetic and epigenetic alterations of glial cells. Changes in gene expression result in the alteration of the cellular division process. Epigenetic alterations in brain tumors include the hypermethylation of CpG group, hypomethylation of specific genes, aberrant activation of genes, and changes in the position of various histones. Heavy metals are capable of generating reactive oxygen assumes that key functions in various pathological mechanisms. Alteration of homeostasis of metals could cause the overproduction of reactive oxygen species and induce DNA damage, lipid peroxidation, and alteration of proteins. In this study we summarize the possible correlation between heavy metals, epigenetic alterations and brain tumors. We report, moreover, the review of relevant literature. PMID:25646073

  14. Gene markers in brain tumors: what the epileptologist should know.

    PubMed

    Ostrom, Quinn; Cohen, Mark L; Ondracek, Annie; Sloan, Andrew; Barnholtz-Sloan, Jill

    2013-12-01

    Gene markers or biomarkers can be used for diagnostic or prognostic purposes for all different types of complex disease, including brain tumors. Prognostic markers can be useful to explain differences not only in overall survival but also in response to treatment and for development of targeted therapies. Multiple genes with specific types of alterations have now been identified that are associated with improved response to chemotherapy and radiotherapy, such as O(6)-methylguanine methyltranferase (MGMT) or loss of chromosomes 1p and/or 19q. Other alterations have been identified that are associated with improved overall survival, such as mutations in isocitrate dehydrogenase 1 (IDH1) and/or isocitrate dehydrogenase 2 (IDH2) or having the glioma CpG island DNA methylator phenotype (G-CIMP). There are many biomarkers that may have relevance in brain tumor-associated epilepsy that do not respond to treatment. Given the rapidly changing landscape of high throughput "omics" technologies, there is significant potential for gaining further knowledge via integration of multiple different types of high genome-wide data. This knowledge can be translated into improved therapies and clinical outcomes for patients with brain tumors.

  15. Childhood brain tumors and paternal occupation in the aerospace industry.

    PubMed

    Olshan, A F; Breslow, N E; Daling, J R; Weiss, N S; Leviton, A

    1986-07-01

    Data from a case-control study of childhood brain tumors were analyzed to examine the possibility that paternal occupation in the aerospace industry is related to the development of a brain tumor in offspring. Parents of 51 children with brain tumors diagnosed in western Washington State during 1978-81 were interviewed, and their responses were compared to those of parents of 142 children selected at random from this population. Among all children, proportions of case and control fathers who had ever been employed in the aerospace industry were nearly identical [relative risk (RR) = 0.94; 95% confidence interval (CI) = 0.40-2.19]. Employment in the aerospace industry during the period from 1 year prior to birth to the time of diagnosis and any employment in the manufacturing part of the industry were not associated with increased risk. However, stratification by age at diagnosis revealed an increased risk associated with father's ever-employment in the industry (RR = 2.10; 95% CI = 0.79-5.60) for children under 10 years old. A corresponding decreased risk (RR = 0.12; 95% CI = 0.01-1.08) was found for children over 10 years old. Because of the relatively small number of cases with a positive paternal occupational history, interpretations of the difference in the direction of the association according to age at diagnosis must remain tentative ones.

  16. A new 2-pyrone derivative, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one, suppresses stemness in glioma stem-like cells.

    PubMed

    Kim, Rae-Kwon; Kim, Min-Jung; Yoon, Chang-Hwan; Lim, Eun-Jung; Yoo, Ki-Chun; Lee, Ga-Haeng; Kim, Young-Heon; Kim, Hyeonmi; Jin, Yeung Bae; Lee, Yoon-Jin; Cho, Cheon-Gyu; Oh, Yeong Seok; Gye, Myung Chan; Suh, Yongjoon; Lee, Su-Jae

    2012-09-01

    Glioma cells with stem cell properties, termed glioma stem-like cells (GSCs), have been linked to tumor formation, maintenance, and progression and are responsible for the failure of chemotherapy and radiotherapy. Because conventional glioma treatments often fail to eliminate GSCs completely, residual surviving GSCs are able to repopulate the tumor. Compounds that target GSCs might be helpful in overcoming resistance to anticancer treatments in human brain tumors. In this study, we showed that 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, suppressed the maintenance of the GSC population in both a glioma cell line and patient-derived glioma cells. Treatment of GSCs with BHP effectively inhibited sphere formation and suppressed the CD133(+) cell population. Treatment with BHP also suppressed expression of the stemness-regulating transcription factors Sox2, Notch2, and β-catenin in sphere-cultured glioma cells. Treatment of GSCs with BHP significantly suppressed two fundamental characteristics of cancer stem cells: self-renewal and tumorigenicity. BHP treatment dramatically inhibited clone-forming ability at the single-cell level and suppressed in vivo tumor formation. BHP markedly inhibited both phosphoinositide 3-kinase/Akt and Ras/Raf-1/extracellular signal-regulated kinase signaling, which suggests that one or both of these pathways are involved in BHP-induced suppression of GSCs. In addition, treatment with BHP effectively sensitized GSCs to chemotherapy and radiotherapy. Taken together, these results indicate that BHP targets GSCs and enhances their sensitivity to anticancer treatments and suggest that BHP treatment may be useful for treating brain tumors by eliminating GSCs.

  17. The p53 gene and protein in human brain tumors

    SciTech Connect

    Louis, D.N. )

    1994-01-01

    Because p53 gene alterations are commonplace in human tumors and because p53 protein is involved in a number of important cellular pathways, p53 has become a topic of intensive investigation, both by basic scientists and clinicians. p53 was initially identified by two independent laboratories in 1979 as a 53 kilodalton (kD) protein that complexes with the large T antigen of SV40 virus. Shortly thereafter, it was shown that the E1B oncoprotein of adenovirus also binds p53. The binding of two different oncogenic viral tumor proteins to the same cellular protein suggested that p53 might be integral to tumorigenesis. The human p53 cDNA and gene were subsequently cloned in the mid-1980s, and analysis of p53 gene alterations in human tumors followed a few year later. During these 10 years, researchers grappling with the vagaries of p53 first characterized the gene as an oncogene, then as a tumor suppressor gene, and most recently as both a tumor suppressor gene and a so-called [open quotes]dominant negative[close quotes] oncogene. The last few years have seen an explosion in work on this single gene and its protein product. A review of a computerized medical database revealed approximately 650 articles on p53 in 1992 alone. p53 has assumed importance in neuro-oncology because p53 mutations and protein alterations are frequent in the common diffuse, fibrillary astrocytic tumors of adults. p53 mutations in astrocytomas were first described in 1989 and were followed by more extensive analyses of gene mutations and protein alterations in adult astrocytomas. The gene has also been studied in less common brain tumors. Elucidating the role of p53 in brain tumorigenesis will not only enhance understanding of brain tumor biology but may also contribute to improved diagnosis and therapy. This discussion reviews key aspects of the p53 gene and protein, and describe their emerging roles in central nervous system neoplasia. 102 refs., 6 figs., 1 tab.

  18. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.

    PubMed

    Zhu, Thant S; Costello, Mark A; Talsma, Caroline E; Flack, Callie G; Crowley, Jessica G; Hamm, Lisa L; He, Xiaobing; Hervey-Jumper, Shawn L; Heth, Jason A; Muraszko, Karin M; DiMeco, Francesco; Vescovi, Angelo L; Fan, Xing

    2011-09-15

    One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.

  19. Monitoring brain tumor response to therapy using MRI segmentation.

    PubMed

    Vaidyanathan, M; Clarke, L P; Hall, L O; Heidtman, C; Velthuizen, R; Gosche, K; Phuphanich, S; Wagner, H; Greenberg, H; Silbiger, M L

    1997-01-01

    The performance evaluation of a semi-supervised fuzzy c-means (SFCM) clustering method for monitoring brain tumor volume changes during the course of routine clinical radiation-therapeutic and chemo-therapeutic regimens is presented. The tumor volume determined using the SFCM method was compared with the volume estimates obtained using three other methods: (a) a k nearest neighbor (kNN) classifier, b) a grey level thresholding and seed growing (ISG-SG) method and c) a manual pixel labeling (GT) method for ground truth estimation. The SFCM and kNN methods are applied to the multispectral, contrast enhanced T1, proton density, and T2 weighted, magnetic resonance images (MRI) whereas the ISG-SG and GT methods are applied only to the contrast enhanced T1 weighted image. Estimations of tumor volume were made on eight patient cases with follow-up MRI scans performed over a 32 week interval during treatment. The tumor cases studied include one meningioma, two brain metastases and five gliomas. Comparisons with manually labeled ground truth estimations showed that there is a limited agreement between the segmentation methods for absolute tumor volume measurements when using images of patients after treatment. The average intraobserver reproducibility for the SFCM, kNN and ISG-SG methods was found to be 5.8%, 6.6% and 8.9%, respectively. The average of the interobserver reproducibility of these methods was found to be 5.5%, 6.5% and 11.4%, respectively. For the measurement of relative change of tumor volume as required for the response assessment, the multi-spectral methods kNN and SFCM are therefore preferred over the seedgrowing method.

  20. Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

    PubMed Central

    Woolf, Eric C.; Syed, Nelofer; Scheck, Adrienne C.

    2016-01-01

    Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma. PMID:27899882

  1. Disulfiram inhibits TGF-β-induced epithelial-mesenchymal transition and stem-like features in breast cancer via ERK/NF-κB/Snail pathway

    PubMed Central

    Chang, Chan; Zhu, Fang; Xiao, Yin; Li, Qiuhui; Zhang, Tao; Zhang, Liling

    2015-01-01

    Disulfiram (DSF), an anti-alcoholism drug, has been reported as an inhibitor of NF-κB. NF-κB is involved in epithelial-mesenchymal transition (EMT) and self-renewal of breast cancer stem cells (CSCs). In this study, we treated MCF-7 and MDA-MB-231 breast cancer cells with TGF-β to induce EMT and cancer stem-like features and studied whether DSF can reverse this process. We found that DSF inhibited TGF-β induced EMT in breast cancer cells in a dose-dependent manner. Also, DSF inhibited EMT-associated stem-like features, migration and invasion of tumor cells as well as tumor growth in xenograft model. The activation of NF-κB was linked with EMT and stem-like cells. We conclude that DSF can suppress NF-κB activity and downregulate ERK/NF-κB/Snail pathway, leading to reverse EMT and stem-like features. Our data suggest that DSF inhibits EMT and stem-like properties in breast cancer cells associated with inhibition of the ERK/NF-κB/Snail pathway. PMID:26517513

  2. Boswellic acid activity against glioblastoma stem-like cells

    PubMed Central

    SCHNEIDER, HANNAH; WELLER, MICHAEL

    2016-01-01

    Boswellic acids (BAs) have long been considered as useful adjunct pharmacological agents for the treatment of patients with malignant brain tumors, notably glioblastoma. Two principal modes of action associated with BAs have been postulated: i) Anti-inflammatory properties, which are useful for containing edema formation, and ii) intrinsic antitumor cell properties, with a hitherto ill-defined mode of action. The present study assessed the effects of various BA derivatives on the viability and clonogenicity of a panel of nine long-term glioma cell lines and five glioma-initiating cell lines, studied cell cycle progression and the mode of cell death induction, and explored potential synergy with temozolomide (TMZ) or irradiation. BA induced the concentration-dependent loss of viability and clonogenicity that was independent of tumor protein 53 status and O6-methylguanine DNA methyltransferase expression. The treatment of glioma cells with BA resulted in cell death induction, prior to or upon S phase entry, and exhibited features of apoptotic cell death. Synergy with irradiation or TMZ was detected at certain concentrations; however, the inhibitory effects were mostly additive, and never antagonistic. While the intrinsic cytotoxic properties of BA at low micromolecular concentrations were confirmed and the potential synergy with irradiation and TMZ was identified, the proximate pharmacodynamic target of BA remains to be identified. PMID:27313764

  3. Radiomics in Brain Tumors: An Emerging Technique for Characterization of Tumor Environment.

    PubMed

    Kotrotsou, Aikaterini; Zinn, Pascal O; Colen, Rivka R

    2016-11-01

    The role of radiomics in the diagnosis, monitoring, and therapy planning of brain tumors is becoming increasingly clear. Incorporation of quantitative approaches in radiology, in combination with increased computer power, offers unique insights into macroscopic tumor characteristics and their direct association with the underlying pathophysiology. This article presents the most recent findings in radiomics and radiogenomics with respect to identifying potential imaging biomarkers with prognostic value that can lead to individualized therapy. In addition, a brief introduction to the concept of big data and its significance in medicine is presented.

  4. A rational approach for cancer stem-like cell isolation and characterization using CD44 and prominin-1(CD133) as selection markers

    PubMed Central

    Lee, Yi-Jen; Wu, Chang-Cheng; Li, Jhy-Wei; Ou, Chien-Chih; Hsu, Shih-Chung; Tseng, Hsiu-Hsueh; Kao, Ming-Ching; Liu, Jah-Yao

    2016-01-01

    The availability of adequate cancer stem cells or cancer stem-like cell (CSC) is important in cancer study. From ovarian cancer cell lines, SKOV3 and OVCAR3, we induced peritoneal ascites tumors in immunodeficient mice. Among the cells (SKOV3.PX1 and OVCAR3.PX1) from those tumors, we sorted both CD44 and CD133 positive cells (SKOV3.PX1_133+44+, OVCAR3.PX1_133+44+), which manifest the characteristics of self-renewal, multi-lineage differentiation, chemoresistance and tumorigenicity, those of cancer stem-like cells (CSLC). Intraperitoneal transplantation of these CD44 and CD133 positive cells resulted in poorer survival in the engrafted animals. Clinically, increased CD133 expression was found in moderately and poorly differentiated (grade II and III) ovarian serous cystadenocarcinomas. The ascites tumor cells from human ovarian cancers demonstrated more CD133 and CD44 expressions than those from primary ovarian or metastatic tumors and confer tumorigenicity in immunodeficient mice. Compared to their parental cells, the SKOV3.PX1_133+44+ and OVCAR3.PX1_133+44+ cells uniquely expressed 5 CD markers (CD97, CD104, CD107a, CD121a, and CD125). Among these markers, CD97, CD104, CD107a, and CD121a are significantly more expressed in the CD133+ and CD44+ double positive cells of human ovarian ascites tumor cells (Ascites_133+44+) than those from primary ovarian or metastatic tumors. The cancer stem-like cells were enriched from 3% to more than 70% after this manipulation. This intraperitoneal enrichment of cancer stem-like cells, from ovarian cancer cell lines or primary ovarian tumor, potentially provides an adequate amount of ovarian cancer stem-like cells for the ovarian cancer study and possibly benefits cancer therapy. PMID:27655682

  5. Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice.

    PubMed

    Kozlowska, Anna K; Kaur, Kawaljit; Topchyan, Paytsar; Jewett, Anahid

    2016-07-01

    Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, and melanoma CSCs were capable of forming large tumors in humanized bone marrow, liver, thymus (hu-BLT) mice with fully reconstituted human immune system. In addition, major human immune subsets including NK cells, T cells, B cells, and monocytes were present in the spleen, bone marrow, peripheral blood, and tumor microenvironment. Similar to our previously published in vitro data, CSCs differentiated with split anergized NK cells prior to implantation in mice formed smaller tumors. Intravenous injection of functionally potent osteoclast-expanded NK cells inhibited tumor growth through differentiation of CSCs in humanized mice. In this review, we present current approaches, advances, and existing limitations in studying interactions of the immune system with the tumor, in particular NK cells with CSCs, using in vivo preclinical hu-BLT mouse model. In addition, we discuss the use of osteoclast-expanded NK cells in targeting cancer stem-like tumors in humanized mice-a strategy that provides a much-needed platform to develop effective cancer immunotherapies.

  6. Generation of cancer stem-like cells through the formation of polyploid giant cancer cells.

    PubMed

    Zhang, S; Mercado-Uribe, I; Xing, Z; Sun, B; Kuang, J; Liu, J

    2014-01-02

    Polyploid giant cancer cells (PGCCs) have been observed by pathologists for over a century. PGCCs contribute to solid tumor heterogeneity, but their functions are largely undefined. Little attention has been given to these cells, largely because PGCCs have been generally thought to originate from repeated failure of mitosis/cytokinesis and have no capacity for long-term survival or proliferation. Here we report our successful purification and culture of PGCCs from human ovarian cancer cell lines and primary ovarian cancer. These cells are highly resistant to oxygen deprivation and could form through endoreduplication or cell fusion, generating regular-sized cancer cells quickly through budding or bursting similar to simple organisms like fungi. They express normal and cancer stem cell markers, they divide asymmetrically and they cycle slowly. They can differentiate into adipose, cartilage and bone. A single PGCC formed cancer spheroids in vitro and generated tumors in immunodeficient mice. These PGCC-derived tumors gained a mesenchymal phenotype with increased expression of cancer stem cell markers CD44 and CD133 and become more resistant to treatment with cisplatin. Taken together, our results reveal that PGCCs represent a resistant form of human cancer using an ancient, evolutionarily conserved mechanism in response to hypoxia stress; they can contribute to the generation of cancer stem-like cells, and also play a fundamental role in regulating tumor heterogeneity, tumor growth and chemoresistance in human cancer.

  7. Multi-parametric analysis and registration of brain tumors: constructing statistical atlases and diagnostic tools of predictive value.

    PubMed

    Davatzikos, Christos; Zacharaki, Evangelia I; Gooya, Ali; Clark, Vanessa

    2011-01-01

    We discuss computer-based image analysis algorithms of multi-parametric MRI of brain tumors, aiming to assist in early diagnosis of infiltrating brain tumors, and to construct statistical atlases summarizing population-based characteristics of brain tumors. These methods combine machine learning, deformable registration, multi-parametric segmentation, and biophysical modeling of brain tumors.

  8. Image updating for brain deformation compensation in tumor resection

    NASA Astrophysics Data System (ADS)

    Fan, Xiaoyao; Ji, Songbai; Olson, Jonathan D.; Roberts, David W.; Hartov, Alex; Paulsen, Keith D.

    2016-03-01

    Preoperative magnetic resonance images (pMR) are typically used for intraoperative guidance in image-guided neurosurgery, the accuracy of which can be significantly compromised by brain deformation. Biomechanical finite element models (FEM) have been developed to estimate whole-brain deformation and produce model-updated MR (uMR) that compensates for brain deformation at different surgical stages. Early stages of surgery, such as after craniotomy and after dural opening, have been well studied, whereas later stages after tumor resection begins remain challenging. In this paper, we present a method to simulate tumor resection by incorporating data from intraoperative stereovision (iSV). The amount of tissue resection was estimated from iSV using a "trial-and-error" approach, and the cortical shift was measured from iSV through a surface registration method using projected images and an optical flow (OF) motion tracking algorithm. The measured displacements were employed to drive the biomechanical brain deformation model, and the estimated whole-brain deformation was subsequently used to deform pMR and produce uMR. We illustrate the method using one patient example. The results show that the uMR aligned well with iSV and the overall misfit between model estimates and measured displacements was 1.46 mm. The overall computational time was ~5 min, including iSV image acquisition after resection, surface registration, modeling, and image warping, with minimal interruption to the surgical flow. Furthermore, we compare uMR against intraoperative MR (iMR) that was acquired following iSV acquisition.

  9. Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy.

    PubMed

    Wankhede, Mamta; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G

    2012-03-01

    Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood-brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.

  10. The biology of radiosurgery and its clinical applications for brain tumors

    PubMed Central

    Kondziolka, Douglas; Shin, Samuel M.; Brunswick, Andrew; Kim, Irene; Silverman, Joshua S.

    2015-01-01

    Stereotactic radiosurgery (SRS) was developed decades ago but only began to impact brain tumor care when it was coupled with high-resolution brain imaging techniques such as computed tomography and magnetic resonance imaging. The technique has played a key role in the management of virtually all forms of brain tumor. We reviewed the radiobiological principles of SRS on tissue and how they pertain to different brain tumor disorders. We reviewed the clinical outcomes on the most common indications. This review found that outcomes are well documented for safety and efficacy and show increasing long-term outcomes for benign tumors. Brain metastases SRS is common, and its clinical utility remains in evolution. The role of SRS in brain tumor care is established. Together with surgical resection, conventional radiotherapy, and medical therapies, patients have an expanding list of options for their care. Clinicians should be familiar with radiosurgical principles and expected outcomes that may pertain to different brain tumor scenarios. PMID:25267803

  11. Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy

    PubMed Central

    Wankhede, Mamta; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G

    2012-01-01

    Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood–brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors. PMID:22390560

  12. Boron Neutron Capture Therapy for Malignant Brain Tumors

    PubMed Central

    MIYATAKE, Shin-Ichi; KAWABATA, Shinji; HIRAMATSU, Ryo; KUROIWA, Toshihiko; SUZUKI, Minoru; KONDO, Natsuko; ONO, Koji

    2016-01-01

    Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting. PMID:27250576

  13. Boron Neutron Capture Therapy for Malignant Brain Tumors.

    PubMed

    Miyatake, Shin-Ichi; Kawabata, Shinji; Hiramatsu, Ryo; Kuroiwa, Toshihiko; Suzuki, Minoru; Kondo, Natsuko; Ono, Koji

    2016-07-15

    Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting.

  14. Radiopotentiation of human brain tumor cells by sodium phenylacetate.

    PubMed

    Ozawa, T; Lu, R M; Hu, L J; Lamborn, K R; Prados, M D; Deen, D F

    1999-08-03

    Phenylacetate (PA) inhibits the growth of tumor cells in vitro and in vivo and shows promise as a relatively nontoxic agent for cancer treatment. A recent report shows that prolonged exposure of cells to low concentrations of PA can enhance the radiation response of brain tumor cells in vitro, opening up the possibility of using this drug to improve the radiation therapy of brain tumor patients. We investigated the cytotoxicity produced by sodium phenylacetate (NaPA) alone and in combination with X-rays in SF-767 human glioblastoma cells and in two medulloblastoma cell lines, Masden and Daoy. Exposure of all three cell lines to relatively low concentrations of NaPA for up to 5 days did not enhance the subsequent cell killing produced by X-irradiation. However, enhanced cell killing was achieved by exposing either oxic or hypoxic cells to relatively high drug concentrations ( > 50-70 mM) for 1 h immediately before X-irradiation. Because central nervous system toxicity can occur in humans at serum concentrations of approximately 6 mM PA, translation of these results into clinical trials will likely require local drug-delivery strategies to achieve drug concentrations that can enhance the radiation response. The safety of such an approach with this drug has not been demonstrated.

  15. Adaptive Intuitionistic Fuzzy Enhancement of Brain Tumor MR Images

    NASA Astrophysics Data System (ADS)

    Deng, He; Deng, Wankai; Sun, Xianping; Ye, Chaohui; Zhou, Xin

    2016-10-01

    Image enhancement techniques are able to improve the contrast and visual quality of magnetic resonance (MR) images. However, conventional methods cannot make up some deficiencies encountered by respective brain tumor MR imaging modes. In this paper, we propose an adaptive intuitionistic fuzzy sets-based scheme, called as AIFE, which takes information provided from different MR acquisitions and tries to enhance the normal and abnormal structural regions of the brain while displaying the enhanced results as a single image. The AIFE scheme firstly separates an input image into several sub images, then divides each sub image into object and background areas. After that, different novel fuzzification, hyperbolization and defuzzification operations are implemented on each object/background area, and finally an enhanced result is achieved via nonlinear fusion operators. The fuzzy implementations can be processed in parallel. Real data experiments demonstrate that the AIFE scheme is not only effectively useful to have information from images acquired with different MR sequences fused in a single image, but also has better enhancement performance when compared to conventional baseline algorithms. This indicates that the proposed AIFE scheme has potential for improving the detection and diagnosis of brain tumors.

  16. Adaptive Intuitionistic Fuzzy Enhancement of Brain Tumor MR Images

    PubMed Central

    Deng, He; Deng, Wankai; Sun, Xianping; Ye, Chaohui; Zhou, Xin

    2016-01-01

    Image enhancement techniques are able to improve the contrast and visual quality of magnetic resonance (MR) images. However, conventional methods cannot make up some deficiencies encountered by respective brain tumor MR imaging modes. In this paper, we propose an adaptive intuitionistic fuzzy sets-based scheme, called as AIFE, which takes information provided from different MR acquisitions and tries to enhance the normal and abnormal structural regions of the brain while displaying the enhanced results as a single image. The AIFE scheme firstly separates an input image into several sub images, then divides each sub image into object and background areas. After that, different novel fuzzification, hyperbolization and defuzzification operations are implemented on each object/background area, and finally an enhanced result is achieved via nonlinear fusion operators. The fuzzy implementations can be processed in parallel. Real data experiments demonstrate that the AIFE scheme is not only effectively useful to have information from images acquired with different MR sequences fused in a single image, but also has better enhancement performance when compared to conventional baseline algorithms. This indicates that the proposed AIFE scheme has potential for improving the detection and diagnosis of brain tumors. PMID:27786240

  17. Round Randomized Learning Vector Quantization for Brain Tumor Imaging

    PubMed Central

    2016-01-01

    Brain magnetic resonance imaging (MRI) classification into normal and abnormal is a critical and challenging task. Owing to that, several medical imaging classification techniques have been devised in which Learning Vector Quantization (LVQ) is amongst the potential. The main goal of this paper is to enhance the performance of LVQ technique in order to gain higher accuracy detection for brain tumor in MRIs. The classical way of selecting the winner code vector in LVQ is to measure the distance between the input vector and the codebook vectors using Euclidean distance function. In order to improve the winner selection technique, round off function is employed along with the Euclidean distance function. Moreover, in competitive learning classifiers, the fitting model is highly dependent on the class distribution. Therefore this paper proposed a multiresampling technique for which better class distribution can be achieved. This multiresampling is executed by using random selection via preclassification. The test data sample used are the brain tumor magnetic resonance images collected from Universiti Kebangsaan Malaysia Medical Center and UCI benchmark data sets. Comparative studies showed that the proposed methods with promising results are LVQ1, Multipass LVQ, Hierarchical LVQ, Multilayer Perceptron, and Radial Basis Function. PMID:27516807

  18. MR Vascular Fingerprinting in Stroke and Brain Tumors Models

    NASA Astrophysics Data System (ADS)

    Lemasson, B.; Pannetier, N.; Coquery, N.; Boisserand, Ligia S. B.; Collomb, Nora; Schuff, N.; Moseley, M.; Zaharchuk, G.; Barbier, E. L.; Christen, T.

    2016-11-01

    In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases.

  19. MR Vascular Fingerprinting in Stroke and Brain Tumors Models

    PubMed Central

    Lemasson, B.; Pannetier, N.; Coquery, N.; Boisserand, Ligia S. B.; Collomb, Nora; Schuff, N.; Moseley, M.; Zaharchuk, G.; Barbier, E. L.; Christen, T.

    2016-01-01

    In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases. PMID:27883015

  20. MR Vascular Fingerprinting in Stroke and Brain Tumors Models.

    PubMed

    Lemasson, B; Pannetier, N; Coquery, N; Boisserand, Ligia S B; Collomb, Nora; Schuff, N; Moseley, M; Zaharchuk, G; Barbier, E L; Christen, T

    2016-11-24

    In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases.

  1. Adaptive Intuitionistic Fuzzy Enhancement of Brain Tumor MR Images.

    PubMed

    Deng, He; Deng, Wankai; Sun, Xianping; Ye, Chaohui; Zhou, Xin

    2016-10-27

    Image enhancement techniques are able to improve the contrast and visual quality of magnetic resonance (MR) images. However, conventional methods cannot make up some deficiencies encountered by respective brain tumor MR imaging modes. In this paper, we propose an adaptive intuitionistic fuzzy sets-based scheme, called as AIFE, which takes information provided from different MR acquisitions and tries to enhance the normal and abnormal structural regions of the brain while displaying the enhanced results as a single image. The AIFE scheme firstly separates an input image into several sub images, then divides each sub image into object and background areas. After that, different novel fuzzification, hyperbolization and defuzzification operations are implemented on each object/background area, and finally an enhanced result is achieved via nonlinear fusion operators. The fuzzy implementations can be processed in parallel. Real data experiments demonstrate that the AIFE scheme is not only effectively useful to have information from images acquired with different MR sequences fused in a single image, but also has better enhancement performance when compared to conventional baseline algorithms. This indicates that the proposed AIFE scheme has potential for improving the detection and diagnosis of brain tumors.

  2. Disulfiram modulates stemness and metabolism of brain tumor initiating cells in atypical teratoid/rhabdoid tumors

    PubMed Central

    Choi, Seung Ah; Choi, Jung Won; Wang, Kyu-Chang; Phi, Ji Hoon; Lee, Ji Yeoun; Park, Kyung Duk; Eum, Dayoung; Park, Sung-Hye; Kim, Il Han; Kim, Seung-Ki

    2015-01-01

    Background Atypical teratoid/rhabdoid tumors (AT/RT) are among the most malignant pediatric brain tumors. Cells from brain tumors with high aldehyde dehydrogenase (ALDH) activity have a number of characteristics that are similar to brain tumor initiating cells (BTICs). This study aimed to evaluate the therapeutic potential of ALDH inhibition using disulfiram (DSF) against BTICs from AT/RT. Methods Primary cultured BTICs from AT/RT were stained with Aldefluor and isolated by fluorescence activated cell sorting. The therapeutic effect of DSF against BTICs from AT/RT was confirmed in vitro and in vivo. Results AT/RT cells displayed a high expression of ALDH. DSF demonstrated a more potent cytotoxic effect on ALDH+ AT/RT cells compared with standard anticancer agents. Notably, treatment with DSF did not have a considerable effect on normal neural stem cells or fibroblasts. DSF significantly inhibited the ALDH enzyme activity of AT/RT cells. DSF decreased self-renewal ability, cell viability, and proliferation potential and induced apoptosis and cell cycle arrest in ALDH+ AT/RT cells. Importantly, DSF reduced the metabolism of ALDH+ AT/RT cells by increasing the nicotinamide adenine dinucleotide ratio of NAD+/NADH and regulating Silent mating type Information Regulator 2 homolog 1 (SIRT1), nuclear factor-kappaB, Lin28A/B, and miRNA let-7g. Animals in the DSF-treated group demonstrated a reduction of tumor volume (P < .05) and a significant survival benefit (P = .02). Conclusion Our study demonstrated the therapeutic potential of DSF against BTICs from AT/RT and suggested the possibility of ALDH inhibition for clinical application. PMID:25378634

  3. Cancer stem-like cell: a novel target for nasopharyngeal carcinoma therapy

    PubMed Central

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx, and is extremely common in southern regions of China. Although the standard combination of radiotherapy and chemotherapy has improved the efficiency in patients with NPC, relapse and early metastasis are still the common causes of mortality. Cancer stem-like cells (CSCs) or tumor initial cells are hypothesized to be involved in cancer metastasis and recurrence. Over the past decade, increasing numbers of studies have been carried out to identify CSCs from human NPC cells and tissues. The present paper will summarize the investigations on nasopharyngeal CSCs, including isolation, characteristics, and therapeutic approaches. Although there are still numerous challenges to translate basic research into clinical applications, understanding the molecular details of CSCs is essential for developing effective strategies to prevent the recurrence and metastasis of NPC. PMID:25158069

  4. Cell-surface Vimentin: A mislocalized protein for isolating csVimentin(+) CD133(-) novel stem-like hepatocellular carcinoma cells expressing EMT markers.

    PubMed

    Mitra, Abhisek; Satelli, Arun; Xia, Xueqing; Cutrera, Jeffrey; Mishra, Lopa; Li, Shulin

    2015-07-15

    Recent advances in cancer stem cell biology have shown that cancer stem-like cells with epithelial-mesenchymal transition (EMT) phenotypes are more aggressive and cause relapse; however, absence of a specific marker to isolate these EMT stem-like cells hampers research in this direction. Cell surface markers have been identified for isolating cancer stem-like cells, but none has been identified for isolating cancer stem-like cells with EMT phenotype. Recently, we discovered that Vimentin, an intracellular EMT tumor cell marker, is present on the surface of colon metastatic tumor nodules in the liver. In our study, we examined the potential of targeting cell surface Vimentin (CSV) to isolate stem-like cancer cells with EMT phenotype, by using a specific CSV-binding antibody, 84-1. Using this antibody, we purified the CSV-positive, CD133-negative (csVim(+) CD133(-) ) cell population from primary liver tumor cell suspensions and characterized for stem cell properties. The results of sphere assays and staining for the stem cell markers Sox2 and Oct4A demonstrated that csVim(+) CD133(-) cells have stem-like properties similar to csVim(-) CD133(+) population. Our investigation further revealed that the csVim(+) CD133(-) cells had EMT phenotypes, as evidenced by the presence of Twist and Slug in the nucleus, the absence of EpCAM on the cell surface and basal level of expression of epithelial marker E-cadherin. The csVimentin-negative CD133-positive stem cells do not have any EMT phenotypes. csVim(+) CD133(-) cells exhibited more aggressively metastatic in livers than csVim(-) CD133(+) cells. Our findings indicate that csVim(+) CD133(-) cells are promising targets for treatment and prevention of metastatic hepatocellular carcinoma.

  5. A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.

    PubMed

    Blumcke, Ingmar; Aronica, Eleonora; Urbach, Horst; Alexopoulos, Andreas; Gonzalez-Martinez, Jorge A

    2014-07-01

    Every fourth patient submitted to epilepsy surgery suffers from a brain tumor. Microscopically, these neoplasms present with a wide-ranging spectrum of glial or glio-neuronal tumor subtypes. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNTs) are the most frequently recognized entities accounting for 65 % of 1,551 tumors collected at the European Epilepsy Brain Bank (n = 5,842 epilepsy surgery samples). These tumors often present with early seizure onset at a mean age of 16.5 years, with 77 % of neoplasms affecting the temporal lobe. Relapse and malignant progression are rare events in this particular group of brain tumors. Surgical resection should be regarded, therefore, also as important treatment strategy to prevent epilepsy progression as well as seizure- and medication-related comorbidities. The characteristic clinical presentation and broad histopathological spectrum of these highly epileptogenic brain tumors will herein be classified as "long-term epilepsy associated tumors-LEATs". LEATs differ from most other brain tumors by early onset of spontaneous seizures, and conceptually are regarded as developmental tumors to explain their pleomorphic microscopic appearance and frequent association with Focal Cortical Dysplasia Type IIIb. However, the broad neuropathologic spectrum and lack of reliable histopathological signatures make these tumors difficult to classify using the WHO system of brain tumors. As another consequence from poor agreement in published LEAT series, molecular diagnostic data remain ambiguous. Availability of surgical tissue specimens from patients which have been well characterized during their presurgical evaluation should open the possibility to systematically address the origin and epileptogenicity of LEATs, and will be further discussed herein. As a conclusion, the authors propose a novel A-B-C terminology of epileptogenic brain tumors ("epileptomas") which hopefully promote the discussion between neuropathologists

  6. Tumor treating fields: a novel treatment modality and its use in brain tumors

    PubMed Central

    Pacheco, Patricia

    2016-01-01

    Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly. This novel treatment modality has shown promise in a variety of tumor types. It has been evaluated in randomized phase 3 trials in glioblastoma (GBM) and demonstrated to prolong progression-free survival (PFS) and overall survival (OS) when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM. TTFields are continuously delivered by 4 transducer arrays consisting each of 9 insulated electrodes that are placed on the patient’s shaved scalp and connected to a portable device. Here we summarize the preclinical data and mechanism of action, the available clinical data, and further outlook of this treatment modality in brain tumors and other cancer indications. PMID:27664860

  7. Regional brain glucose metabolism in patients with brain tumors before and after radiotherapy

    SciTech Connect

    Wang, G.J.; Volkow, N.D.; Lau, Y.H.

    1994-05-01

    This study was performed to measure regional glucose metabolism in nonaffected brain regions of patients with primary or metastatic brain tumors. Seven female and four male patients (mean age 51.5{plus_minus}14.0 years old) were compared with eleven age and sex matched normal subjects. None of the patients had hydrocephalus and/or increased intracranial pressure. Brain glucose metabolism was measured using FDG-PET scan. Five of the patients were reevaluated one week after receiving radiation treatment (RT) to the brain. Patients were on Decadron and/or Dilantin at the time of both scan. PET images were analyzed with a template of 115 nonoverlapping regions of interest and then grouped into eight gray matter regions on each hemisphere. Brain regions with tumors and edema shown in MR imaging were excluded. Z scores were used to compare individual patients` regional values with those of normal subjects. The number of regional values with Z scores of less than - 3.0 were considered abnormal and were quantified. The mean global glucose metabolic rate (mean of all regions) in nonaffected brain regions of patients was significantly lower than that of normal controls (32.1{plus_minus}9.0 versus 44.8{plus_minus}6.3 {mu}mol/100g/min, p<0.001). Analyses of individual subjects revealed that none of the controls and 8 of the 11 patients had at least one abnormal region. In these 8 patients the regions which were abnormal were most frequently localized in right (n=5) and left occipital (n=6) and right orbital frontal cortex (n=7) whereas the basal ganglia was not affected. Five of the patients who had repeated scans following RT showed decrements in tumor metabolism (41{plus_minus}20.5%) and a significant increase in whole brain metabolism (8.6{plus_minus}5.3%, p<0.001). The improvement in whole brain metabolism after RT suggests that the brain metabolic decrements in the patients were related to the presence of tumoral tissue and not just a medication effect.

  8. Statistical feature selection for enhanced detection of brain tumor

    NASA Astrophysics Data System (ADS)

    Chaddad, Ahmad; Colen, Rivka R.

    2014-09-01

    Feature-based methods are widely used in the brain tumor recognition system. Robust of early cancer detection is one of the most powerful image processing tools. Specifically, statistical features, such as geometric mean, harmonic mean, mean excluding outliers, median, percentiles, skewness and kurtosis, have been extracted from brain tumor glioma to aid in discriminating two levels namely, Level I and Level II using fluid attenuated inversion recovery (FLAIR) sequence in the diagnosis of brain tumor. Statistical feature describes the major characteristics of each level from glioma which is an important step to evaluate heterogeneity of cancer area pixels. In this paper, we address the task of feature selection to identify the relevant subset of features in the statistical domain, while discarding those that are either redundant or confusing, thereby improving the performance of feature-based scheme to distinguish between Level I and Level II. We apply a Decision Structure algorithm to find the optimal combination of nonhomogeneity based statistical features for the problem at hand. We employ a Naïve Bayes classifier to evaluate the performance of the optimal statistical feature based scheme in terms of its glioma Level I and Level II discrimination capability and use real-data collected from 17 patients have a glioblastoma multiforme (GBM). Dataset provided from 3 Tesla MR imaging system by MD Anderson Cancer Center. For the specific data analyzed, it is shown that the identified dominant features yield higher classification accuracy, with lower number of false alarms and missed detections, compared to the full statistical based feature set. This work has been proposed and analyzed specific GBM types which Level I and Level II and the dominant features were considered as feature aid to prognostic indicators. These features were selected automatically to be better able to determine prognosis from classical imaging studies.

  9. Spatial organization and correlations of cell nuclei in brain tumors.

    PubMed

    Jiao, Yang; Berman, Hal; Kiehl, Tim-Rasmus; Torquato, Salvatore

    2011-01-01

    Accepting the hypothesis that cancers are self-organizing, opportunistic systems, it is crucial to understand the collective behavior of cancer cells in their tumorous heterogeneous environment. In the present paper, we ask the following basic question: Is this self-organization of tumor evolution reflected in the manner in which malignant cells are spatially distributed in their heterogeneous environment? We employ a variety of nontrivial statistical microstructural descriptors that arise in the theory of heterogeneous media to characterize the spatial distributions of the nuclei of both benign brain white matter cells and brain glioma cells as obtained from histological images. These descriptors, which include the pair correlation function, structure factor and various nearest neighbor functions, quantify how pairs of cell nuclei are correlated in space in various ways. We map the centroids of the cell nuclei into point distributions to show that while commonly used local spatial statistics (e.g., cell areas and number of neighboring cells) cannot clearly distinguish spatial correlations in distributions of normal and abnormal cell nuclei, their salient structural features are captured very well by the aforementioned microstructural descriptors. We show that the tumorous cells pack more densely than normal cells and exhibit stronger effective repulsions between any pair of cells. Moreover, we demonstrate that brain gliomas are organized in a collective way rather than randomly on intermediate and large length scales. The existence of nontrivial spatial correlations between the abnormal cells strongly supports the view that cancer is not an unorganized collection of malignant cells but rather a complex emergent integrated system.

  10. Confidence-based ensemble for GBM brain tumor segmentation

    NASA Astrophysics Data System (ADS)

    Huo, Jing; van Rikxoort, Eva M.; Okada, Kazunori; Kim, Hyun J.; Pope, Whitney; Goldin, Jonathan; Brown, Matthew

    2011-03-01

    It is a challenging task to automatically segment glioblastoma multiforme (GBM) brain tumors on T1w post-contrast isotropic MR images. A semi-automated system using fuzzy connectedness has recently been developed for computing the tumor volume that reduces the cost of manual annotation. In this study, we propose a an ensemble method that combines multiple segmentation results into a final ensemble one. The method is evaluated on a dataset of 20 cases from a multi-center pharmaceutical drug trial and compared to the fuzzy connectedness method. Three individual methods were used in the framework: fuzzy connectedness, GrowCut, and voxel classification. The combination method is a confidence map averaging (CMA) method. The CMA method shows an improved ROC curve compared to the fuzzy connectedness method (p < 0.001). The CMA ensemble result is more robust compared to the three individual methods.

  11. The Multimodal Brain Tumor Image Segmentation Benchmark (BRATS)

    PubMed Central

    Jakab, Andras; Bauer, Stefan; Kalpathy-Cramer, Jayashree; Farahani, Keyvan; Kirby, Justin; Burren, Yuliya; Porz, Nicole; Slotboom, Johannes; Wiest, Roland; Lanczi, Levente; Gerstner, Elizabeth; Weber, Marc-André; Arbel, Tal; Avants, Brian B.; Ayache, Nicholas; Buendia, Patricia; Collins, D. Louis; Cordier, Nicolas; Corso, Jason J.; Criminisi, Antonio; Das, Tilak; Delingette, Hervé; Demiralp, Çağatay; Durst, Christopher R.; Dojat, Michel; Doyle, Senan; Festa, Joana; Forbes, Florence; Geremia, Ezequiel; Glocker, Ben; Golland, Polina; Guo, Xiaotao; Hamamci, Andac; Iftekharuddin, Khan M.; Jena, Raj; John, Nigel M.; Konukoglu, Ender; Lashkari, Danial; Mariz, José António; Meier, Raphael; Pereira, Sérgio; Precup, Doina; Price, Stephen J.; Raviv, Tammy Riklin; Reza, Syed M. S.; Ryan, Michael; Sarikaya, Duygu; Schwartz, Lawrence; Shin, Hoo-Chang; Shotton, Jamie; Silva, Carlos A.; Sousa, Nuno; Subbanna, Nagesh K.; Szekely, Gabor; Taylor, Thomas J.; Thomas, Owen M.; Tustison, Nicholas J.; Unal, Gozde; Vasseur, Flor; Wintermark, Max; Ye, Dong Hye; Zhao, Liang; Zhao, Binsheng; Zikic, Darko; Prastawa, Marcel; Reyes, Mauricio; Van Leemput, Koen

    2016-01-01

    In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low- and high-grade glioma patients—manually annotated by up to four raters—and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%–85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub-regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource. PMID:25494501

  12. The Multimodal Brain Tumor Image Segmentation Benchmark (BRATS).

    PubMed

    Menze, Bjoern H; Jakab, Andras; Bauer, Stefan; Kalpathy-Cramer, Jayashree; Farahani, Keyvan; Kirby, Justin; Burren, Yuliya; Porz, Nicole; Slotboom, Johannes; Wiest, Roland; Lanczi, Levente; Gerstner, Elizabeth; Weber, Marc-André; Arbel, Tal; Avants, Brian B; Ayache, Nicholas; Buendia, Patricia; Collins, D Louis; Cordier, Nicolas; Corso, Jason J; Criminisi, Antonio; Das, Tilak; Delingette, Hervé; Demiralp, Çağatay; Durst, Christopher R; Dojat, Michel; Doyle, Senan; Festa, Joana; Forbes, Florence; Geremia, Ezequiel; Glocker, Ben; Golland, Polina; Guo, Xiaotao; Hamamci, Andac; Iftekharuddin, Khan M; Jena, Raj; John, Nigel M; Konukoglu, Ender; Lashkari, Danial; Mariz, José Antonió; Meier, Raphael; Pereira, Sérgio; Precup, Doina; Price, Stephen J; Raviv, Tammy Riklin; Reza, Syed M S; Ryan, Michael; Sarikaya, Duygu; Schwartz, Lawrence; Shin, Hoo-Chang; Shotton, Jamie; Silva, Carlos A; Sousa, Nuno; Subbanna, Nagesh K; Szekely, Gabor; Taylor, Thomas J; Thomas, Owen M; Tustison, Nicholas J; Unal, Gozde; Vasseur, Flor; Wintermark, Max; Ye, Dong Hye; Zhao, Liang; Zhao, Binsheng; Zikic, Darko; Prastawa, Marcel; Reyes, Mauricio; Van Leemput, Koen

    2015-10-01

    In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low- and high-grade glioma patients-manually annotated by up to four raters-and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%-85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub-regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource.

  13. Absence of human cytomegalovirus infection in childhood brain tumors

    PubMed Central

    Sardi, Iacopo; Lucchesi, Maurizio; Becciani, Sabrina; Facchini, Ludovica; Guidi, Milena; Buccoliero, Anna Maria; Moriondo, Maria; Baroni, Gianna; Stival, Alessia; Farina, Silvia; Genitori, Lorenzo; de Martino, Maurizio

    2015-01-01

    Human cytomegalovirus (HCMV) is a common human pathogen which induces different clinical manifestations related to the age and the immune conditions of the host. HCMV infection seems to be involved in the pathogenesis of adult glioblastomas. The aim of our study was to detect the presence of HCMV in high grade gliomas and other pediatric brain tumors. This hypothesis might have important therapeutic implications, offering a new target for adjuvant therapies. Among 106 pediatric patients affected by CNS tumors we selected 27 patients with a positive HCMV serology. The serological analysis revealed 7 patients with positive HCMV IGG (≥14 U/mL), whom had also a high HCMV IgG avidity, suggesting a more than 6 months-dated infection. Furthermore, HCMV IGM were positive (≥22 U/mL) in 20 patients. Molecular and immunohistochemical analyses were performed in all the 27 samples. Despite a positive HCMV serology, confirmed by ELISA, no viral DNA was shown at the PCR analysis in the patients’ neoplastic cells. At immunohistochemistry, no expression of HCMV antigens was observed in tumoral cells. Our results are in agreement with recent results in adults which did not evidence the presence of HCMV genome in glioblastoma lesions. We did not find any correlation between HCMV infection and pediatric CNS tumors. PMID:26396923

  14. Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling.

    PubMed

    Yu, Ling; Fan, Zhengfu; Fang, Shuo; Yang, Jian; Gao, Tian; Simões, Bruno M; Eyre, Rachel; Guo, Weichun; Clarke, Robert B

    2016-05-31

    Notch signaling regulates normal stem cells and is also thought to regulate cancer stem cells (CSCs). Recent data indicate that Notch signaling plays a role in the development and progression of osteosarcoma, however the regulation of Notch in chemo-resistant stem-like cells has not yet been fully elucidated. In this study we generated cisplatin-resistant osteosarcoma cells by treating them with sub-lethal dose of cisplatin, sufficient to induce DNA damage responses. Cisplatin-resistant osteosarcoma cells exhibited lower proliferation, enhanced spheroid formation and more mesenchymal characteristics than cisplatin-sensitive cells, were enriched for Stro-1+/CD117+ cells and showed increased expression of stem cell-related genes. A similar effect was observed in vivo, and in addition in vivo tumorigenicity was enhanced during serial transplantation. Using several publicly available datasets, we identified that Notch expression was closely associated with osteosarcoma stem cells and chemotherapy resistance. We confirmed that cisplatin-induced enrichment of osteosarcoma stem cells was mediated through Notch signaling in vitro, and immunohistochemistry showed that cleaved Notch1 (NICD1) positive cells were significantly increased in a relapsed xenograft which had received cisplatin treatment. Furthermore, pretreatment with a γ-secretase inhibitor (GSI) to prevent Notch signalling inhibited cisplatin-enriched osteosarcoma stem cell activity in vitro, including Stro-1+/CD117+ double positive cells and spheroid formation capacity. The Notch inhibitor DAPT also prevented tumor recurrence in resistant xenograft tumors. Overall, our results show that cisplatin induces the enrichment of osteosarcoma stem-like cells through Notch signaling, and targeted inactivation of Notch may be useful for the elimination of CSCs and overcoming drug resistance.

  15. Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model

    PubMed Central

    Wanjiku, Teresia; Rudek, Michelle A; Joshi, Avadhut; Gallia, Gary L.; Riggins, Gregory J.

    2015-01-01

    Purpose Mebendazole (MBZ), first used as an antiparasitic drug, shows preclinical efficacy in models of glioblastoma and medulloblastoma. Three different MBZ polymorphs (A, B and C) exist and a detailed assessment of the brain penetration, pharmacokinetics and anti-tumor properties of each individual MBZ polymorph is necessary to improve mebendazole-based brain cancer therapy. Experimental Design and Results In this study, various marketed and custom-formulated MBZ tablets were analyzed for their polymorph content by IR spectroscopy and subsequently tested in orthotopic GL261 mouse glioma model for efficacy and tolerability. The pharmacokinetics and brain concentration of MBZ polymorphs and two main metabolites were analyzed by LC-MS. We found that polymorph B and C both increased survival in a GL261 glioma model, as B exhibited greater toxicity. Polymorph A showed no benefit. Both, polymorph B and C, reached concentrations in the brain that exceeded the IC50 in GL261 cells 29-fold. In addition, polymorph C demonstrated an AUC0-24h brain-to-plasma (B/P) ratio of 0.82, whereas B showed higher plasma AUC and lower B/P ratio. In contrast, polymorph A presented markedly lower levels in the plasma and brain. Furthermore, the combination with elacridar was able to significantly improve the efficacy of polymorph C in GL261 glioma and D425 medulloblastoma models in mice. Conclusion Among MBZ polymorphs, C reaches therapeutically effective concentrations in the brain tissue and tumor with less side effects and is the better choice for brain cancer therapy. Its efficacy can be further enhanced by combination with elacridar. PMID:25862759

  16. Phenylalanine-coupled solid lipid nanoparticles for brain tumor targeting

    NASA Astrophysics Data System (ADS)

    Kharya, Parul; Jain, Ashish; Gulbake, Arvind; Shilpi, Satish; Jain, Ankit; Hurkat, Pooja; Majumdar, Subrata; Jain, Sanjay K.

    2013-11-01

    The purpose of this study is to investigate the targeting potential of amino acid (phenylalanine)-coupled solid lipid nanoparticles (SLN) loaded with ionically complexed doxorubicin HCl (Dox). Ionic complexation was used to enhance the loading efficiency and release characteristics of water soluble form of Dox. l-Type amino acid transporters (LAT1) are highly expressed on blood brain barrier as well as on many brain cancer cells, thus targeting LAT1 using phenylalanine improved anticancer activity of prepared nanocarrier. The phenylalanine-coupled SLN were characterized by fourier transform infrared spectroscopy, scanning electron microscope, transmission electron microscopy, particle size, zeta potential, entrapment efficiency and in vitro release. The particle size of the resulting SLN was found to be in the range of 163.3 ± 5.2 to 113.0 ± 2.6 nm, with a slightly negative surface charge. In ex vivo study on C6 glioma cell lines, the cellular cytotoxicity of the SLN was highly increased when coupled with phenylalanine. In addition, stealthing sheath of PEG present on the surface of the SLN enhanced the cellular uptake of the SLN on C6 glioma cell line. Results of biodistribution and fluorescence studies clearly revealed that phenylalanine-coupled SLN could deliver high amount of drug into the brain tumor cells and showed the brain-targeting potential.

  17. Three-Staged Stereotactic Radiotherapy Without Whole Brain Irradiation for Large Metastatic Brain Tumors

    SciTech Connect

    Higuchi, Yoshinori Serizawa, Toru; Nagano, Osamu; Matsuda, Shinji; Ono, Junichi; Sato, Makoto; Iwadate, Yasuo; Saeki, Naokatsu

    2009-08-01

    Purpose: To evaluate the efficacy and toxicity of staged stereotactic radiotherapy with a 2-week interfraction interval for unresectable brain metastases more than 10 cm{sup 3} in volume. Patients and Methods: Subjects included 43 patients (24 men and 19 women), ranging in age from 41 to 84 years, who had large brain metastases (> 10 cc in volume). Primary tumors were in the colon in 14 patients, lung in 12, breast in 11, and other in 6. The peripheral dose was 10 Gy in three fractions. The interval between fractions was 2 weeks. The mean tumor volume before treatment was 17.6 {+-} 6.3 cm{sup 3} (mean {+-} SD). Mean follow-up interval was 7.8 months. The local tumor control rate, as well as overall, neurological, and qualitative survivals, were calculated using the Kaplan-Meier method. Results: At the time of the second and third fractions, mean tumor volumes were 14.3 {+-} 6.5 (18.8% reduction) and 10.6 {+-} 6.1 cm{sup 3} (39.8% reduction), respectively, showing significant reductions. The median overall survival period was 8.8 months. Neurological and qualitative survivals at 12 months were 81.8% and 76.2%, respectively. Local tumor control rates were 89.8% and 75.9% at 6 and 12 months, respectively. Tumor recurrence-free and symptomatic edema-free rates at 12 months were 80.7% and 84.4%, respectively. Conclusions: The 2-week interval allowed significant reduction of the treatment volume. Our results suggest staged stereotactic radiotherapy using our protocol to be a possible alternative for treating large brain metastases.

  18. Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells.

    PubMed

    Hira, Vashendriya V V; Verbovšek, Urška; Breznik, Barbara; Srdič, Matic; Novinec, Marko; Kakar, Hala; Wormer, Jill; der Swaan, Britt Van; Lenarčič, Brigita; Juliano, Luiz; Mehta, Shwetal; Van Noorden, Cornelis J F; Lah, Tamara T

    2017-03-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1α cleavage by CatK inactivates SDF-1α and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1α after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1α at 3 sites in the N-terminus, which is the region of SDF-1α that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1α and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1α had chemotactic activity whereas CatK cleavage products of SDF-1α did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1α. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation.

  19. ET-11RESVERATROL REGULATES GLIOBLASTOMA AND GLIOBLASTOMA STEM-LIKE CELLS VIA ANTI-TUMORIGENIC AKT DEPHOSPHORYLATION AND p53 ACTIVATION

    PubMed Central

    Clark, Paul; Bhattacharya, Saswati; van Ginkel, Paul; Darjatmoko, Soesiawati; Elmayam, Ardem; Polans, Arthur; Kuo, John

    2014-01-01

    Resveratrol (RES), a natural non-toxic plant product, exerts broad anti-cancer effects. RES was investigated for efficacy against glioblastoma (GBM) and therapeutically resistant GBM stem-like cells (GSC) hypothesized to drive tumor recurrence. Patient-derived GSC lines (12.1, 22, 33, 44) isolated via marker-neutral sphere cultures in stem cell medium, and U87 glioma were treated with RES. Low RES (25 µM) achieved significant inhibition of U87 cell proliferation after 4 days compared to control vehicle (DMSO) treatment. RES also inhibited GSC sphere-forming ability, with 50% inhibitory concentrations (IC50) from 5-25 µM. Interestingly, both 12.1 and 22 GSC lines highly express stem cell markers and initiate focal orthotopic GBM xenografts in brains of immunodeficient mice, and were most sensitive to RES compared to 33 and 44 GSC lines that cause highly infiltrative xenografts. This suggests differential RES response by various GBM/GSC subtypes. In a Matrigel transwell assay, 50 µM RES significantly inhibited invasion (>50%) of both U87 and 44 GSCs. RES also altered GSC progenitor marker expression, with 50 µM RES inducing increased expression of neural differentiation markers GFAP (astrocyte) and βIII-tubulin (neuron) after 3 days on western immunoblotting. We observed the broad anti-tumorigenic RES effects against GBM/GSC by dephosphorylating oncogenic AKT and activating tumor suppressor p53. Quantitative PCR revealed RES activates a large p53 tumor suppressive gene network (PIGG8, CD95, TP53, and NOXA). In U87 flank xenografts, oral RES (50 mg/kg daily) significantly inhibited xenograft growth, and single intra-tumoral 1mg injections reduced tumor volume by >60% compared to injection of vehicle control. In conclusion, RES causes broad anti-GBM and anti-GSC effects via AKT dephosphorylation and p53 activation, and warrants further study as a non-toxic adjuvant GBM therapy.

  20. Tumor growth model for atlas based registration of pathological brain MR images

    NASA Astrophysics Data System (ADS)

    Moualhi, Wafa; Ezzeddine, Zagrouba

    2015-02-01

    The motivation of this work is to register a tumor brain magnetic resonance (MR) image with a normal brain atlas. A normal brain atlas is deformed in order to take account of the presence of a large space occupying tumor. The method use a priori model of tumor growth assuming that the tumor grows in a radial way from a starting point. First, an affine transformation is used in order to bring the patient image and the brain atlas in a global correspondence. Second, the seeding of a synthetic tumor into the brain atlas provides a template for the lesion. Finally, the seeded atlas is deformed combining a method derived from optical flow principles and a model for tumor growth (MTG). Results show that an automatic segmentation method of brain structures in the presence of large deformation can be provided.

  1. Detection of human brain tumor infiltration with quantitative stimulated Raman scattering microscopy.

    PubMed

    Ji, Minbiao; Lewis, Spencer; Camelo-Piragua, Sandra; Ramkissoon, Shakti H; Snuderl, Matija; Venneti, Sriram; Fisher-Hubbard, Amanda; Garrard, Mia; Fu, Dan; Wang, Anthony C; Heth, Jason A; Maher, Cormac O; Sanai, Nader; Johnson, Timothy D; Freudiger, Christian W; Sagher, Oren; Xie, Xiaoliang Sunney; Orringer, Daniel A

    2015-10-14

    Differentiating tumor from normal brain is a major barrier to achieving optimal outcome in brain tumor surgery. New imaging techniques for visualizing tumor margins during surgery are needed to improve surgical results. We recently demonstrated the ability of stimulated Raman scattering (SRS) microscopy, a nondestructive, label-free optical method, to reveal glioma infiltration in animal models. We show that SRS reveals human brain tumor infiltration in fresh, unprocessed surgical specimens from 22 neurosurgical patients. SRS detects tumor infiltration in near-perfect agreement with standard hematoxylin and eosin light microscopy (κ = 0.86). The unique chemical contrast specific to SRS microscopy enables tumor detection by revealing quantifiable alterations in tissue cellularity, axonal density, and protein/lipid ratio in tumor-infiltrated tissues. To ensure that SRS microscopic data can be easily used in brain tumor surgery, without the need for expert interpretation, we created a classifier based on cellularity, axonal density, and protein/lipid ratio in SRS images capable of detecting tumor infiltration with 97.5% sensitivity and 98.5% specificity. Quantitative SRS microscopy detects the spread of tumor cells, even in brain tissue surrounding a tumor that appears grossly normal. By accurately revealing tumor infiltration, quantitative SRS microscopy holds potential for improving the accuracy of brain tumor surgery.

  2. Detection of human brain tumor infiltration with quantitative stimulated Raman scattering microscopy

    PubMed Central

    Ji, Minbiao; Lewis, Spencer; Camelo-Piragua, Sandra; Ramkissoon, Shakti H.; Snuderl, Matija; Venneti, Sriram; Fisher-Hubbard, Amanda; Garrard, Mia; Fu, Dan; Wang, Anthony C.; Heth, Jason A.; Maher, Cormac O.; Sanai, Nader; Johnson, Timothy D.; Freudiger, Christian W.; Sagher, Oren; Xie, Xiaoliang Sunney; Orringer, Daniel A.

    2016-01-01

    Differentiating tumor from normal brain is a major barrier to achieving optimal outcome in brain tumor surgery. New imaging techniques for visualizing tumor margins during surgery are needed to improve surgical results. We recently demonstrated the ability of stimulated Raman scattering (SRS) microscopy, a non-destructive, label-free optical method, to reveal glioma infiltration in animal models. Here we show that SRS reveals human brain tumor infiltration in fresh, unprocessed surgical specimens from 22 neurosurgical patients. SRS detects tumor infiltration in near-perfect agreement with standard hematoxylin and eosin light microscopy (κ=0.86). The unique chemical contrast specific to SRS microscopy enables tumor detection by revealing quantifiable alterations in tissue cellularity, axonal density and protein:lipid ratio in tumor-infiltrated tissues. To ensure that SRS microscopic data can be easily used in brain tumor surgery, without the need for expert interpretation, we created a classifier based on cellularity, axonal density and protein:lipid ratio in SRS images capable of detecting tumor infiltration with 97.5% sensitivity and 98.5% specificity. Importantly, quantitative SRS microscopy detects the spread of tumor cells, even in brain tissue surrounding a tumor that appears grossly normal. By accurately revealing tumor infiltration, quantitative SRS microscopy holds potential for improving the accuracy of brain tumor surgery. PMID:26468325

  3. Targeting BRAF V600E and Autophagy in Pediatric Brain Tumors

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0414 TITLE: Targeting BRAF V600E and Autophagy in Pediatric Brain Tumors PRINCIPAL INVESTIGATOR: Jean Mulcahy...29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-14-1-0414 Targeting BRAF V600E and Autophagy in Pediatric Brain Tumors 5b. GRANT...ABSTRACT 200 words most significant findings 15. SUBJECT TERMS autophagy, BRAF, brain tumor. pediatric 16. SECURITY CLASSIFICATION OF: 17

  4. Consensus Conference on Brain Tumor Definition for registration. November 10, 2000.

    PubMed Central

    McCarthy, Bridget J.; Surawicz, Tanya; Bruner, Janet M.; Kruchko, Carol; Davis, Faith

    2002-01-01

    The Consensus Conference on Brain Tumor Definition was facilitated by the Central Brain Tumor Registry of the United States and held on November 10, 2000, in Chicago, Illinois, to reach multidisciplinary agreement on a standard definition of brain tumors for collecting and comparing data in the U.S. The Brain Tumor Working Group, convened in 1998 to determine the status of brain tumor collection in the U.S., outlined 4 recommendations of which the first 2 guided the discussion for the Consensus Conference: (1) standardization of a definition of primary brain tumors that is based on site alone, rather than on site and behavior, and that can be used by surveillance organizations in collecting these tumors; and (2) development of a reporting scheme that can be used for comparing estimates of primary brain tumors across registries. Consensus was reached on the collection of all primary brain tumor histologies found and reported in the brain or CNS ICD-O site codes (C70.0-C72.9 and C75.1-C75.3), including those coded benign and uncertain as well as those coded malignant. In addition, a comprehensive listing of histologies occurring in the brain and CNS, based on the CBTRUS grouping scheme, was formulated to provide a template for reporting in accordance with the second recommendation of the Brain Tumor Working Group. With consensus achieved on the first 2 recommendations, the stage is set to move forward in estimating additional resources necessary for the collection of these tumors, including funding, training for cancer registrars, identifying quality control measures, and developing computerized edit checks, as outlined in the last 2 recommendations of the Brain Tumor Working Group. PMID:11916506

  5. Validation of IR-spectroscopic brain tumor classification

    NASA Astrophysics Data System (ADS)

    Beleites, C.; Steiner, G.; Sobottka, S.; Schackert, G.; Salzer, R.

    2006-02-01

    As a molecular probe of tissue composition, infrared spectroscopic imaging serves as an adjunct to histopathology in detecting and diagnosing disease. In the past it was demonstrated that the IR spectra of brain tumors can be discriminated from one another according to their grade of malignancy. Although classification success rates up to 93% were observed one problem consists in the variation of the models depending on the number of samples used for the development of the classification model. In order to open the path for clinical trials the classification has to be validated. A series of classification models were built using a k-fold cross validation scheme and the classification predictions from the various models were combined to provide an aggregated prediction. The validation highlights instabilities in the models, error rates, sensitivity as well as specificity of the classification and allows the determination of confidence intervals. Better classification models could be achieved by an aggregated prediction. The validation shows that brain tumors can be classified by infrared spectroscopy and the grade of malignancy corresponds reasonably to the histopathological assignment.

  6. "Armed" oncolytic herpes simplex viruses for brain tumor therapy.

    PubMed

    Todo, Tomoki

    2008-01-01

    Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for brain tumors and other solid cancers. They can replicate in situ, spread and exhibit oncolytic activity via a direct cytocidal effect. One of the advantages of HSV-1 is the capacity to incorporate large and/or multiple transgenes within the viral genome. Oncolytic HSV-1 can therefore be "armed" to add certain functions. Recently, the field of armed oncolytic HSV-1 has drastically advanced, due to development of recombinant HSV-1 generation systems that utilize bacterial artificial chromosome and multiple DNA recombinases. Because antitumor immunity is induced in the course of oncolytic activities of HSV-1, transgenes encoding immunomodulatory molecules have been most frequently used for arming. Other armed oncolytic HSV-1 include those that express antiangiogenic factors, fusogenic membrane glycoproteins, suicide gene products, and proapoptotic proteins. Provided that the transgene product does not interfere with viral replication, such arming of oncolytic HSV-1 results in augmentation of antitumor efficacy. Immediate-early viral promoters are often used to control the arming transgenes, but strict-late viral promoters have been shown useful to restrict the expression in the late stage of viral replication when desirable. Some armed oncolytic HSV-1 have been created for the purpose of noninvasive in vivo imaging of viral infection and replication. Development of a wide variety of armed oncolytic HSV-1 will lead to an establishment of a new genre of therapy for brain tumors as well as other cancers.

  7. Cognitive Remediation Therapy for Brain Tumor Survivors with Cognitive Deficits

    PubMed Central

    Sacks-Zimmerman, Amanda; Liberta, Taylor

    2015-01-01

    Cognitive deficits have been widely observed in patients with primary brain tumors consequent to diagnosis and treatment. Given the early onset and the relatively long survival rate of patients, it seems pertinent to study and refine the techniques used to treat these deficits. The purpose of this article is to discuss cognitive deficits that follow neurosurgical treatment for low-grade gliomas as well as to outline a neuropsychological intervention to treat these deficits, specifically working memory and attention. Cognitive remediation therapy is a neuropsychological intervention that aims to enhance attention, working memory, and executive functioning, thereby diminishing the impact of these deficits on daily functioning. Computerized cognitive remediation training programs facilitate access to treatment through providing online participation. The authors include preliminary results of three participants who have completed the computerized training program as part of an ongoing study that is investigating the efficacy of this program in patients who have undergone treatment for low-grade gliomas. The results so far suggest some improvement in working memory and attention from baseline scores. It is the hope of the present authors to highlight the importance of this treatment in the continuity of care of brain tumor survivors. PMID:26623205

  8. What's New in Research and Treatment for Brain Tumors in Children?

    MedlinePlus

    ... Brain and Spinal Cord Tumors in Children What’s New in Research and Treatment for Brain and Spinal ... an investigational method, and studies are continuing. Other new treatment strategies Researchers are also testing some newer ...

  9. Comparative Expression Study of the Endo–G Protein Coupled Receptor (GPCR) Repertoire in Human Glioblastoma Cancer Stem-like Cells, U87-MG Cells and Non Malignant Cells of Neural Origin Unveils New Potential Therapeutic Targets

    PubMed Central

    Lennon, Sarah; Carapito, Christine; Dong, Jihu; Van Dorsselaer, Alain; Junier, Marie-Pierre; Chneiweiss, Hervé; Cianférani, Sarah; Haiech, Jacques; Kilhoffer, Marie-Claude

    2014-01-01

    Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets. PMID:24662753

  10. Analysis of plasma free amino acid profiles in canine brain tumors

    PubMed Central

    Utsugi, Shinichi; Azuma, Kazuo; Osaki, Tomohiro; Murahata, Yusuke; Tsuka, Takeshi; Ito, Norihiko; Imagawa, Tomohiro; Okamoto, Yoshiharu

    2017-01-01

    Canine brain tumors are best diagnosed using magnetic resonance imaging (MRI). However, opportunities of MRI examination are restricted due to its limited availability in veterinary facilities; thus, numerous canine brain tumors are diagnosed at an advanced stage. Therefore, development of a noninvasive diagnostic biomarker is required for the early detection of brain tumors. In the present study, plasma free amino acid (PFAA) profiles between dogs with and without brain tumors were compared. A total of 12 dogs with brain tumors, diagnosed based on clinical signs, and on the results of intracranial MRI and/or pathological examination were evaluated. In addition, eight dogs diagnosed with idiopathic epilepsy and 16 healthy dogs were also included. A liquid chromatography system with automated pre-column derivatization functionality was used to measure the levels of 20 amino acids. As a result, the levels of three amino acids (alanine, proline and isoleucine) were increased significantly (1.6-, 1.5- and 1.6-fold, respectively) in the plasma of dogs with brain tumors as compared with the levels in control dogs (all P<0.05). Thus, the PFAA levels of dogs with brain tumors differed from those of healthy dogs. The present study demonstrated that analysis of PFAA levels of dogs with brain tumors may serve as a useful biomarker for the early detection of canine brain tumors. PMID:28357072

  11. Automatic metastatic brain tumor segmentation for stereotactic radiosurgery applications

    NASA Astrophysics Data System (ADS)

    Liu, Yan; Stojadinovic, Strahinja; Hrycushko, Brian; Wardak, Zabi; Lu, Weiguo; Yan, Yulong; Jiang, Steve B.; Timmerman, Robert; Abdulrahman, Ramzi; Nedzi, Lucien; Gu, Xuejun

    2016-12-01

    The objective of this study is to develop an automatic segmentation strategy for efficient and accurate metastatic brain tumor delineation on contrast-enhanced T1-weighted (T1c) magnetic resonance images (MRI) for stereotactic radiosurgery (SRS) applications. The proposed four-step automatic brain metastases segmentation strategy is comprised of pre-processing, initial contouring, contour evolution, and contour triage. First, T1c brain images are preprocessed to remove the skull. Second, an initial tumor contour is created using a multi-scaled adaptive threshold-based bounding box and a super-voxel clustering technique. Third, the initial contours are evolved to the tumor boundary using a regional active contour technique. Fourth, all detected false-positive contours are removed with geometric characterization. The segmentation process was validated on a realistic virtual phantom containing Gaussian or Rician noise. For each type of noise distribution, five different noise levels were tested. Twenty-one cases from the multimodal brain tumor image segmentation (BRATS) challenge dataset and fifteen clinical metastases cases were also included in validation. Segmentation performance was quantified by the Dice coefficient (DC), normalized mutual information (NMI), structural similarity (SSIM), Hausdorff distance (HD), mean value of surface-to-surface distance (MSSD) and standard deviation of surface-to-surface distance (SDSSD). In the numerical phantom study, the evaluation yielded a DC of 0.98  ±  0.01, an NMI of 0.97  ±  0.01, an SSIM of 0.999  ±  0.001, an HD of 2.2  ±  0.8 mm, an MSSD of 0.1  ±  0.1 mm, and an SDSSD of 0.3  ±  0.1 mm. The validation on the BRATS data resulted in a DC of 0.89  ±  0.08, which outperform the BRATS challenge algorithms. Evaluation on clinical datasets gave a DC of 0.86  ±  0.09, an NMI of 0.80  ±  0.11, an SSIM of 0.999  ±  0.001, an HD of 8

  12. Automatic metastatic brain tumor segmentation for stereotactic radiosurgery applications.

    PubMed

    Liu, Yan; Stojadinovic, Strahinja; Hrycushko, Brian; Wardak, Zabi; Lu, Weiguo; Yan, Yulong; Jiang, Steve B; Timmerman, Robert; Abdulrahman, Ramzi; Nedzi, Lucien; Gu, Xuejun

    2016-12-21

    The objective of this study is to develop an automatic segmentation strategy for efficient and accurate metastatic brain tumor delineation on contrast-enhanced T1-weighted (T1c) magnetic resonance images (MRI) for stereotactic radiosurgery (SRS) applications. The proposed four-step automatic brain metastases segmentation strategy is comprised of pre-processing, initial contouring, contour evolution, and contour triage. First, T1c brain images are preprocessed to remove the skull. Second, an initial tumor contour is created using a multi-scaled adaptive threshold-based bounding box and a super-voxel clustering technique. Third, the initial contours are evolved to the tumor boundary using a regional active contour technique. Fourth, all detected false-positive contours are removed with geometric characterization. The segmentation process was validated on a realistic virtual phantom containing Gaussian or Rician noise. For each type of noise distribution, five different noise levels were tested. Twenty-one cases from the multimodal brain tumor image segmentation (BRATS) challenge dataset and fifteen clinical metastases cases were also included in validation. Segmentation performance was quantified by the Dice coefficient (DC), normalized mutual information (NMI), structural similarity (SSIM), Hausdorff distance (HD), mean value of surface-to-surface distance (MSSD) and standard deviation of surface-to-surface distance (SDSSD). In the numerical phantom study, the evaluation yielded a DC of 0.98  ±  0.01, an NMI of 0.97  ±  0.01, an SSIM of 0.999  ±  0.001, an HD of 2.2  ±  0.8 mm, an MSSD of 0.1  ±  0.1 mm, and an SDSSD of 0.3  ±  0.1 mm. The validation on the BRATS data resulted in a DC of 0.89  ±  0.08, which outperform the BRATS challenge algorithms. Evaluation on clinical datasets gave a DC of 0.86  ±  0.09, an NMI of 0.80  ±  0.11, an SSIM of 0.999  ±  0.001, an HD of 8

  13. Establishment and Analysis of Cancer Stem-Like and Non-Cancer Stem-Like Clone Cells from the Human Colon Cancer Cell Line SW480.

    PubMed

    Takaya, Akari; Hirohashi, Yoshihiko; Murai, Aiko; Morita, Rena; Saijo, Hiroshi; Yamamoto, Eri; Kubo, Terufumi; Nakatsugawa, Munehide; Kanaseki, Takayuki; Tsukahara, Tomohide; Tamura, Yasuaki; Takemasa, Ichiro; Kondo, Toru; Sato, Noriyuki; Torigoe, Toshihiko

    2016-01-01

    Human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be isolated as side population (SP) cells, aldehyde dehydrogenase high (ALDHhigh) cells or cell surface marker-positive cells including CD44+ cells and CD133+ cells. CSCs/CICs and non-CSCs/CICs are unstable in in vitro culture, and CSCs/CICs can differentiate into non-CSCs/CICs and some non-CSCs/CICs can dedifferentiate into CSCs/CICs. Therefore, experiments using a large amount of CSCs/CICs are technically very difficult. In this study, we isolated single cell clones from SP cells and main population (MP) cells derived from the human colon cancer cell line SW480. SP analysis revealed that SP clone cells had relatively high percentages of SP cells, whereas MP clone cells showed very few SP cells, and the phenotypes were sustainable for more than 2 months of in vitro culture. Xenograft transplantation revealed that SP clone cells have higher tumor-initiating ability than that of MP clone cells and SP clone cell showed higher chemo-resistance compared with MP clone cells. These results indicate that SP clone cells derived from SW480 cells are enriched with CSCs/CICs, whereas MP clone cells are pure non-CSCs/CICs. SP clone cells and MP clone cells are a very stable in vitro CSC/CIC-enriched and non-CSC/CIC model for further analysis.

  14. Long-term mobile phone use and brain tumor risk.

    PubMed

    Lönn, Stefan; Ahlbom, Anders; Hall, Per; Feychting, Maria

    2005-03-15

    Handheld mobile phones were introduced in Sweden during the late 1980s. The purpose of this population-based, case-control study was to test the hypothesis that long-term mobile phone use increases the risk of brain tumors. The authors identified all cases aged 20-69 years who were diagnosed with glioma or meningioma during 2000-2002 in certain parts of Sweden. Randomly selected controls were stratified on age, gender, and residential area. Detailed information about mobile phone use was collected from 371 (74%) glioma and 273 (85%) meningioma cases and 674 (71%) controls. For regular mobile phone use, the odds ratio was 0.8 (95% confidence interval: 0.6, 1.0) for glioma and 0.7 (95% confidence interval: 0.5, 0.9) for meningioma. Similar results were found for more than 10 years' duration of mobile phone use. No risk increase was found for ipsilateral phone use for tumors located in the temporal and parietal lobes. Furthermore, the odds ratio did not increase, regardless of tumor histology, type of phone, and amount of use. This study includes a large number of long-term mobile phone users, and the authors conclude that the data do not support the hypothesis that mobile phone use is related to an increased risk of glioma or meningioma.

  15. [Factors significant for cerebral circulacion in patients with supratentorial brain tumors].

    PubMed

    Sboev, A Yu; Dolgih, V T; Larkin, V I

    2013-01-01

    Using the Doppler ultrasonography method the condition of brain blood circulation of 90 patients with supratentorial brain tumors (gliomas--43, meningiomas--34, metastasis--9) during pre-surgical period was studied. The factors changing brain blood circulation at patients with with supratentorial brain tumors were brain displacement, increase of intracranial pressure, histologic structure and the first symptoms duration of illness. Localization (for an exception of an occipital lobe) and the size of a tumor directly didn't render influence on blood circulation parameters.

  16. Breast cancer stem-like cells: clinical implications and therapeutic strategies

    PubMed Central

    TUDORAN, OANA MIHAELA; BALACESCU, OVIDIU; BERINDAN-NEAGOE, IOANA

    2016-01-01

    Breast cancer is the most frequently diagnosed cancer in women, being also the leading cause of cancer death among female population, including in Romania. Resistance to therapy represents a major problem for cancer treatment. Current cancer treatments are both expensive and induce serious side effects; therefore ineffective therapies are both traumatic and pricy. Characterizing predictive markers that can identify high-risk patients could contribute to dedicated/personalized therapy to improve the life quality and expectancy of cancer patients. Moreover, there are some markers that govern specific tumor molecular features that can be targeted with specific therapies for those patients who are most likely to benefit. The identification of stem cells in both normal and malignant breast tissue have lead to the hypothesis that breast tumors arise from breast cancer stem-like cells (CSCs), and that these cells influence tumor’s response to therapy. CSCs have similar self-renewal properties to normal stem cells, however the balance between the signaling pathways is altered towards tumor formation In this review, we discuss the molecular aspects of breast CSCs and the controversies regarding their use in the diagnosis and treatment decision of breast cancer patients. PMID:27152067

  17. CCL21/CCR7 Axis Contributed to CD133+ Pancreatic Cancer Stem-Like Cell Metastasis via EMT and Erk/NF-κB Pathway

    PubMed Central

    Zhang, Lirong; Wang, Dongqing; Li, Yumei; Liu, Yanfang; Xie, Xiaodong; Wu, Yingying; Zhou, Yuepeng; Ren, Jing; Zhang, Jianxin; Zhu, Haitao; Su, Zhaoliang

    2016-01-01

    Background Tumor metastasis is driven by malignant cells and stromal cell components of the tumor microenvironment. Cancer stem cells (CSCs) are thought to be responsible for metastasis by altering the tumor microenvironment. Epithelial-mesenchymal transition (EMT) processes contribute to specific stages of the metastatic cascade, promoted by cytokines and chemokines secreted by stromal cell components in the tumor microenvironment. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine ligand 21(CCL21), to mediate metastasis in some cancer cells lines. This study investigated the role of CCL21/CCR7 in promoting EMT and metastasis of cluster of differentiation 133+ (CD133+) pancreatic cancer stem-like cells. Methods Panc-1, AsPC-1, and MIA PaCa-2 pancreatic cancer cells were selected because of their aggressive invasive potentials. CCR7 expression levels were examined in total, CD133+ and CD133− cell fractions by Immunofluorescence analysis and real time-quantitative polymerase chain reaction (RT-qPCR). The role of CCL21/CCR7 in mediating metastasis and survival of CD133+ pancreatic cancer stem-like cells was detected by Transwell assays and flow cytometry, respectively. EMT and lymph node metastasis related markers (E-cadherin, N- cadherin, LYVE-1) were analyzed by western blot. CCR7 expression levels were analyzed by immunohistochemical staining and RT-qPCR in resected tumor tissues, metastatic lymph nodes, normal lymph nodes and adjacent normal tissues from patients with pancreatic carcinoma. Results CCR7 expression was significantly increased in CD133+ pancreatic cancer stem-like cells, resected pancreatic cancer tissues, and metastatic lymph nodes, compared with CD133− cancer cells, adjacent normal tissues and normal lymph nodes, respectively. CCL21/CCR7 promoted metastasis and survival of CD133+ pancreatic cancer stem-like cells and regulated CD133+ pancreatic cancer stem-like cells metastasis by modulating EMT and Erk/NF-κB pathway

  18. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake.

    PubMed

    Flavahan, William A; Wu, Qiulian; Hitomi, Masahiro; Rahim, Nasiha; Kim, Youngmi; Sloan, Andrew E; Weil, Robert J; Nakano, Ichiro; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Li, Meizhang; Lathia, Justin D; Rich, Jeremy N; Hjelmeland, Anita B

    2013-10-01

    Like all cancers, brain tumors require a continuous source of energy and molecular resources for new cell production. In normal brain, glucose is an essential neuronal fuel, but the blood-brain barrier limits its delivery. We now report that nutrient restriction contributes to tumor progression by enriching for brain tumor initiating cells (BTICs) owing to preferential BTIC survival and to adaptation of non-BTICs through acquisition of BTIC features. BTICs outcompete for glucose uptake by co-opting the high affinity neuronal glucose transporter, type 3 (Glut3, SLC2A3). BTICs preferentially express Glut3, and targeting Glut3 inhibits BTIC growth and tumorigenic potential. Glut3, but not Glut1, correlates with poor survival in brain tumors and other cancers; thus, tumor initiating cells may extract nutrients with high affinity. As altered metabolism represents a cancer hallmark, metabolic reprogramming may maintain the tumor hierarchy and portend poor prognosis.

  19. Using Ferumoxytol-Enhanced MRI to Measure Inflammation in Patients With Brain Tumors or Other Conditions of the CNS

    ClinicalTrials.gov

    2017-02-21

    Brain Injury; Central Nervous System Degenerative Disorder; Central Nervous System Infectious Disorder; Central Nervous System Vascular Malformation; Hemorrhagic Cerebrovascular Accident; Ischemic Cerebrovascular Accident; Primary Brain Neoplasm; Brain Cancer; Brain Tumors

  20. Notch4+ cancer stem-like cells promote the metastatic and invasive ability of melanoma.

    PubMed

    Lin, Xian; Sun, Baocun; Zhu, Dongwang; Zhao, Xiulan; Sun, Ran; Zhang, Yanhui; Zhang, Danfang; Dong, Xueyi; Gu, Qiang; Li, Yanlei; Liu, Fang

    2016-08-01

    Sphere formation in conditioned serum-free culture medium supplemented with epidermal growth factor and basic fibroblast growth factor (tumorospheres) is considered useful for the enrichment of cancer stem-like cells, also known as tumor-initiating cells. We used a gene expression microarray to investigate the gene expression profile of melanoma cancer stem-like cells (MCSLCs). The results showed that MCSLCs highly expressed the following Notch signaling pathway molecules: Notch3 (NM_008716), Notch4 (NM_010929), Dtx4 (NM_172442), and JAG2 (NM_010588). Immunofluorescence staining showed tumorosphere cells highly expressed Notch4. Notch4(high) B16F10 cells were isolated by FACS, and Western blotting showed that high Notch4 expression is related to the expression of epithelial-mesenchymal transition (EMT)-associated proteins. Reduced invasive and migratory properties concomitant with the downregulation of the EMT markers Twist1, vimentin, and VE-cadherin and the overexpression of E-cadherin was observed in human melanoma A375 and MUM-2B cells. In these cells, Notch4 was also downregulated, both by Notch4 gene knockdown and by application of the γ-secretase inhibitor, DAPT. Mechanistically, the re-overexpression of Twist1 by the transfection of cells with a Twist1 expression plasmid led to an increase in VE-cadherin expression and a decrease in E-cadherin expression. Immunohistochemical analysis of 120 human melanoma tissues revealed a significant correlation between the high expression of Notch4 and the metastasis of melanoma. Taken together, our findings indicate that Notch4+ MCSLCs trigger EMT and promote the metastasis of melanoma cells.

  1. miR128-1 inhibits the growth of glioblastoma multiforme and glioma stem-like cells via targeting BMI1 and E2F3

    PubMed Central

    Shan, Zheng-nan; Tian, Rui; Zhang, Min; Gui, Zhao-hua; Wu, Jing; Ding, Min; Zhou, Xin-Fu; He, Jie

    2016-01-01

    MicroRNA128-1 (miR128-1), as a brain-specific miRNA, is downregulated in glioblastoma multiforme (GBM) and closely associated with the progression of GBM. However, the underlying molecular mechanism of the downregulation and its role in the regulation of tumorigenesis and anticancer drug resistance in GBM remains largely unknown. In the current study,we found that miR128-1 was downregulated in GBM and glioma stem-like cells (GSCs). Intriguingly, treatment with the DNA methylation inhibitors 5-Aza-CdR (Aza) and 4-phenylbutyric acid (PBA) resulted in miR128-1 upregulation in both GBM cells and GSCs. Either forced expression of miR128-1 or Aza/PBA treatment inhibited tumor cell proliferation, migration and invasion in vitro. Moreover, overexpression of miR128-1 inhibited the growth of transplant tumor in vivo. BMI1 and E2F3 were found to be direct targets of miR128-1 and downregulated by miR128-1 in vitro and in vivo. Our results revealed a mechanism of methylation that controls miR128-1 expression in GBM cells and GSCs and indicate miR128-1 could function as a tumor suppressor in GBM by negatively regulating tumor cell proliferation, invasion and self-renewal through direct targeting BMI1 and E2F3. Our findings suggest that DNA methylation inhibitors are potential agents for GBM treatment by upregulating miR-128-1. PMID:27705931

  2. Identification of T cell target antigens in glioblastoma stem-like cells using an integrated proteomics-based approach in patient specimens.

    PubMed

    Rapp, Carmen; Warta, Rolf; Stamova, Slava; Nowrouzi, Ali; Geisenberger, Christoph; Gal, Zoltan; Roesch, Saskia; Dettling, Steffen; Juenger, Simone; Bucur, Mariana; Jungk, Christine; DaoTrong, Philip; Ahmadi, Rezvan; Sahm, Felix; Reuss, David; Fermi, Valentina; Herpel, Esther; Eckstein, Volker; Grabe, Niels; Schramm, Christoph; Weigand, Markus A; Debus, Juergen; von Deimling, Andreas; Unterberg, Andreas; Abdollahi, Amir; Beckhove, Philipp; Herold-Mende, Christel

    2017-03-22

    Glioblastoma (GBM) is a highly aggressive brain tumor and still remains incurable. Among others, an immature subpopulation of self-renewing and therapy-resistant tumor cells-often referred to as glioblastoma stem-like cells (GSCs)-has been shown to contribute to disease recurrence. To target these cells personalized immunotherapy has gained a lot of interest, e.g. by reactivating pre-existing anti-tumor immune responses against GSC antigens. To identify T cell targets commonly presented by GSCs and their differentiated counterpart, we used a proteomics-based separation of GSC proteins in combination with a T cell activation assay. Altogether, 713 proteins were identified by LC-ESI-MS/MS mass spectrometry. After a thorough filtering process, 32 proteins were chosen for further analyses. Immunogenicity of corresponding peptides was tested ex vivo. A considerable number of these antigens induced T cell responses in GBM patients but not in healthy donors. Moreover, most of them were overexpressed in primary GBM and also highly expressed in recurrent GBM tissues. Interestingly, expression of the most frequent T cell target antigens could also be confirmed in quiescent, slow-cycling GSCs isolated in high purity by the DEPArray technology. Finally, for a subset of these T cell target antigens, an association between expression levels and higher T cell infiltration as well as an increased expression of positive immune modulators was observed. In summary, we identified novel immunogenic proteins, which frequently induce tumor-specific T cell responses in GBM patients and were also detected in vitro in therapy-resistant quiescent, slow-cycling GSCs. Stable expression of these T cell targets in primary and recurrent GBM support their suitability for future clinical use.

  3. Raloxifene and antiestrogenic gonadorelin inhibits intestinal tumorigenesis by modulating immune cells and decreasing stem-like cells.

    PubMed

    Janakiram, Naveena B; Mohammed, Altaf; Brewer, Misty; Bryant, Taylor; Biddick, Laura; Lightfoot, Stan; Pathuri, Gopal; Gali, Hariprasad; Rao, Chinthalapally V

    2014-03-01

    Studies suggest that estrogen plays a contributing role in colorectal cancer. This project examined the preventive effects of raloxifene, a selective estrogen receptor modulator (SERM), and gonadorelin, an antiestrogenic drug, in female Apc(Min/+) mouse intestinal tumorigenesis. Six-week-old Apc(Min/+)mice were fed diet containing 1 ppm raloxifene or control diet. Gonadorelin (150 ng/mouse) was injected subcutaneously into one treatment group. Intestinal tumors were evaluated for tumor multiplicity and size. Mice treated with raloxifene and gonadorelin showed colon tumor inhibition of 80% and 75%, respectively. Both drugs significantly inhibited small intestinal tumor multiplicity and size (75%-65%, P < 0.0001). Raloxifene and gonadorelin showed significant tumor inhibition with 98% and 94% inhibition of polyps >2 mm in size. In mice fed with raloxifene or injected with gonadorelin, tumors showed significantly reduced proliferating cell nuclear antigen expression (58%-65%, P < 0.0001). Raloxifene treatment decreased β-catenin, cyclin D1, laminin 1β, Ccl6, and stem-like cells (Lgr 5, EpCAM, CD44/CD24), as well as suppressed inflammatory genes (COX-2, mPGES-1, 5-LOX,). Gonadorelin showed significant decrease in COX-2, mPGES-1, iNOS, and stem-like cells or increased NK cells and chemokines required for NK cells. Both drugs were effective in suppressing tumor growth albeit with different mechanisms. These observations show that either suppression of estrogen levels or modulation of estrogen receptor dramatically suppresses small intestinal and colonic tumor formation in female Apc(Min/+) mice. These results support the concept of chemoprevention by these agents in reducing endogenous levels of estrogen or modulating ER signaling.

  4. Brain Magnetic Resonance Imaging After High-Dose Chemotherapy and Radiotherapy for Childhood Brain Tumors

    SciTech Connect

    Spreafico, Filippo Gandola, Lorenza; Marchiano, Alfonso; Simonetti, Fabio; Poggi, Geraldina; Adduci, Anna; Clerici, Carlo Alfredo; Luksch, Roberto; Biassoni, Veronica; Meazza, Cristina; Catania, Serena; Terenziani, Monica; Musumeci, Renato; Fossati-Bellani, Franca; Massimino, Maura

    2008-03-15

    Purpose: Brain necrosis or other subacute iatrogenic reactions has been recognized as a potential complication of radiotherapy (RT), although the possible synergistic effects of high-dose chemotherapy and RT might have been underestimated. Methods and Materials: We reviewed the clinical and radiologic data of 49 consecutive children with malignant brain tumors treated with high-dose thiotepa and autologous hematopoietic stem cell rescue, preceded or followed by RT. The patients were assessed for neurocognitive tests to identify any correlation with magnetic resonance imaging (MRI) anomalies. Results: Of the 49 children, 18 (6 of 25 with high-grade gliomas and 12 of 24 with primitive neuroectodermal tumors) had abnormal brain MRI findings occurring a median of 8 months (range, 2-39 months) after RT and beginning to regress a median of 13 months (range, 2-26 months) after onset. The most common lesion pattern involved multiple pseudonodular, millimeter-size, T{sub 1}-weighted unevenly enhancing, and T{sub 2}-weighted hyperintense foci. Four patients with primitive neuroectodermal tumors also had subdural fluid leaks, with meningeal enhancement over the effusion. One-half of the patients had symptoms relating to the new radiographic findings. The MRI lesion-free survival rate was 74% {+-} 6% at 1 year and 57% {+-} 8% at 2 years. The number of marrow ablative courses correlated significantly to the incidence of radiographic anomalies. No significant difference was found in intelligent quotient scores between children with and without radiographic changes. Conclusion: Multiple enhancing cerebral lesions were frequently seen on MRI scans soon after high-dose chemotherapy and RT. Such findings pose a major diagnostic challenge in terms of their differential diagnosis vis-a-vis recurrent tumor. Their correlation with neurocognitive results deserves further investigation.

  5. Isolated angiitis in the hypothalamus mimicking brain tumor.

    PubMed

    Tsutsumi, Satoshi; Ito, Masanori; Yasumoto, Yukimasa; Kaneda, Kazuhiko

    2008-01-01

    A 64-year-old female presented with exaggerating somnolence without contributory medical and lifestyle histories. She was not aware of any preceding infection or headache. Cerebral magnetic resonance imaging demonstrated an isolated enhanced mass in the hypothalamus without meningeal enhancement. Blood and cerebrospinal fluid examinations showed no significant findings except for hypernatremia and hyperprolactinemia. She underwent an open biopsy via the interhemispheric route. Histological examination revealed marked perivascular lymphocytic aggregation with polyclonal immunostaining both for B and T lymphocytes. No findings suggestive of underlying malignancy were recognized. Extensive work-up aiming at systemic vasculitis and lymphoma revealed no signs of extracranial lesion, so the most probable diagnosis was isolated angiitis in the hypothalamus. Angiitis may originate from the hypothalamus and should be considered in the differential diagnosis of hypothalamic lesion mimicking brain tumor on neuroimaging.

  6. Brain Tumor Epidemiology - A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014.

    PubMed

    Woehrer, Adelheid; Lau, Ching C; Prayer, Daniela; Bauchet, Luc; Rosenfeld, Myrna; Capper, David; Fisher, Paul G; Kool, Marcel; Müller, Martin; Kros, Johan M; Kruchko, Carol; Wiemels, Joseph; Wrensch, Margaret; Danysh, Heather E; Zouaoui, Sonia; Heck, Julia E; Johnson, Kimberly J; Qi, Xiaoyang; O'Neill, Brian P; Afzal, Samina; Scheurer, Michael E; Bainbridge, Matthew N; Nousome, Darryl; Bahassi, El Mustapha; Hainfellner, Johannes A; Barnholtz-Sloan, Jill S

    2015-01-01

    The Brain Tumor Epidemiology Consortium (BTEC) is an open scientific forum, which fosters the development of multi-center, international and inter-disciplinary collaborations. BTEC aims to develop a better understanding of the etiology, outcomes, and prevention of brain tumors (http://epi.grants.cancer.gov/btec/). The 15th annual Brain Tumor Epidemiology Consortium Meeting, hosted by the Austrian Societies of Neuropathology and Neuro-oncology, was held on September 9 - 11, 2014 in Vienna, Austria. The meeting focused on the central role of brain tumor epidemiology within multidisciplinary neuro-oncology. Knowledge of disease incidence, outcomes, as well as risk factors is fundamental to all fields involved in research and treatment of patients with brain tumors; thus, epidemiology constitutes an important link between disciplines, indeed the very hub. This was reflected by the scientific program, which included various sessions linking brain tumor epidemiology with clinical neuro-oncology, tissue-based research, and cancer registration. Renowned experts from Europe and the United States contributed their personal perspectives stimulating further group discussions. Several concrete action plans evolved for the group to move forward until next year's meeting, which will be held at the Mayo Clinic at Rochester, MN, USA.

  7. Significant predictors of patients' uncertainty in primary brain tumors.

    PubMed

    Lin, Lin; Chien, Lung-Chang; Acquaye, Alvina A; Vera-Bolanos, Elizabeth; Gilbert, Mark R; Armstrong, Terri S

    2015-05-01

    Patients with primary brain tumors (PBT) face uncertainty related to prognosis, symptoms and treatment response and toxicity. Uncertainty is correlated to negative mood states and symptom severity and interference. This study identified predictors of uncertainty during different treatment stages (newly-diagnosed, on treatment, followed-up without active treatment). One hundred eighty six patients with PBT were accrued at various points in the illness trajectory. Data collection tools included: a clinical checklist/a demographic data sheet/the Mishel Uncertainty in Illness Scale-Brain Tumor Form. The structured additive regression model was used to identify significant demographic and clinical predictors of illness-related uncertainty. Participants were primarily white (80 %) males (53 %). They ranged in age from 19-80 (mean = 44.2 ± 12.6). Thirty-two of the 186 patients were newly-diagnosed, 64 were on treatment at the time of clinical visit with MRI evaluation, 21 were without MRI, and 69 were not on active treatment. Three subscales (ambiguity/inconsistency; unpredictability-disease prognoses; unpredictability-symptoms and other triggers) were different amongst the treatment groups (P < .01). However, patients' uncertainty during active treatment was as high as in newly-diagnosed period. Other than treatment stages, change of employment status due to the illness was the most significant predictor of illness-related uncertainty. The illness trajectory of PBT remains ambiguous, complex, and unpredictable, leading to a high incidence of uncertainty. There was variation in the subscales of uncertainty depending on treatment status. Although patients who are newly diagnosed reported the highest scores on most of the subscales, patients on treatment felt more uncertain about unpredictability of symptoms than other groups. Due to the complexity and impact of the disease, associated symptoms, and interference with functional status, comprehensive assessment of patients

  8. Household pesticides and risk of pediatric brain tumors.

    PubMed Central

    Pogoda, J M; Preston-Martin, S

    1997-01-01

    A follow-up to a population-based case-control study of pediatric brain tumors in Los Angeles County, California, involving mothers of 224 cases and 218 controls, investigated the risk of household pesticide use from pregnancy to diagnosis. Risk was significantly elevated for prenatal exposure to flea/tick pesticides -odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.1-2.6-, particularly among subjects less than 5 years old at diagnosis (OR = 2.5; CI, 1. 2-5.5). Prenatal risk was highest for mothers who prepared, applied, or cleaned up flea/tick products themselves (OR = 2.2; CI, 1.1-4.2; for subjects <5 years of age, OR = 5.4; CI, 1.3-22.3). A significant trend of increased risk with increased exposure was observed for number of pets treated (p = 0.04). Multivariate analysis of types of flea/tick products indicated that sprays/foggers were the only products significantly related to risk (OR =10.8; CI, 1.3-89.1). Elevated risks were not observed for termite or lice treatments, pesticides for nuisance pests, or yard and garden insecticides, herbicides, fungicides, or snail killer. Certain precautions,if ignored, were associated with significant increased risk: evacuating the house after spraying or dusting for pests (OR = 1.6; CI, 1.0-2.6), delaying the harvest of food after pesticide treatment (OR = 3.6; CI, 1.0-13.7), and following instructions on pesticide labels (OR = 3. 7;CI, 1.5-9.6). These findings indicate that chemicals used in flea/tick products may increase risk of pediatric brain tumors and suggest that further research be done to pinpoint specific chemicals involved. PMID:9370522

  9. Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy.

    PubMed

    Stricker, Thomas; Arteaga, Carlos L

    2015-11-01

    Two recent studies report deep molecular profiling of matched brain metastases and primary tumors. In both studies, somatic alterations in the brain metastases were frequently discordant with those in the primary tumor, suggesting divergent evolution at metastatic sites and raising questions about the use of biomarkers in patients in clinical trials with targeted therapies.

  10. The exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    PubMed Central

    Agrahari, Vivek

    2017-01-01

    Delivering therapeutics to the central nervous system (CNS) and brain-tumor has been a major challenge. The current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in providing significant benefits to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB). The BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nanotherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer significant advantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are briefly discussed. The drug transport mechanisms at the BBB are outlined. The approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic approaches for their enhanced clinical application in brain-tumor therapy are discussed.

  11. DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors.

    PubMed

    Sin-Chan, Patrick; Huang, Annie

    2014-10-01

    Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural-specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors.

  12. Triterpenoid saponins from Albizia lebbeck (L.) Benth and their inhibitory effect on the survival of high grade human brain tumor cells.

    PubMed

    Noté, Olivier Placide; Jihu, Dong; Antheaume, Cyril; Zeniou, Maria; Pegnyemb, Dieudonné Emmanuel; Guillaume, Dominique; Chneiwess, Hervé; Kilhoffer, Marie Claude; Lobstein, Annelise

    2015-03-02

    As part of our search of new bioactive triterpenoid saponins from Cameroonian Mimosaceae plants, phytochemical investigation of the roots of Albizia lebbeck led to the isolation of two new oleanane-type saponins, named lebbeckosides A-B (1-2). Their structures were established on the basis of extensive 1D and 2D NMR ((1)H, (13)C NMR, DEPT, COSY, TOCSY, ROESY, HSQC, and HMBC) and HRESIMS studies, and by chemical evidence. Compounds 1-2 were evaluated for their inhibitory effect on the metabolism of high grade human brain tumor cells, the human glioblastoma U-87 MG cell lines and the glioblastoma stem-like TG1 cells isolated from a patient tumor, and known to be particularly resistant to standard therapies. The isolated saponins showed significant cytotoxic activity against U-87 MG and TG1 cancer cells with IC50 values of 3.46 μM and 1.36 μM for 1, and 2.10 μM and 2.24 μM for 2, respectively.

  13. The incidence of second brain tumors related to cranial irradiation.

    PubMed

    Marta, Gustavo Nader; Murphy, Erin; Chao, Samuel; Yu, Jennifer S; Suh, John H

    2015-03-01

    Secondary brain tumor (SBT) is a devastating complication of cranial irradiation (CI). We reviewed the literature to determine the incidence of SBT as related to specific radiation therapy (RT) treatment modalities. The relative risk of radiation-associated SBT after conventional and conformal RT is well established and ranges from 5.65 to 10.9; latent time to develop second tumor ranges from 5.8 to 22.4 years, depending on radiation dose and primary disease. Theories and dosimetric models suggest that intensity-modulated radiation therapy may result in an increased risk of SBT, but clinical evidence is limited. The incidence of stereotactic radiosurgery-related SBT is low. Initial data suggest that no increased risk from proton therapy and dosimetric models predict a lower incidence of SBT compared with photons. In conclusion, the incidence of SBT related to CI is low. Longer follow-up is needed to clarify the impact of intensity-modulated radiation therapy, proton therapy and other developing technologies.

  14. Aptamer for imaging and therapeutic targeting of brain tumor glioblastoma.

    PubMed

    Delač, Mateja; Motaln, Helena; Ulrich, Henning; Lah, Tamara T

    2015-09-01

    Aptamers are short single-stranded nucleic acids (RNA or ssDNA), identified by an in vitro selection process, denominated SELEX, from a partially random oligonucleotide library. They bind to a molecular target, a protein or other complex macromolecular structures of interest with high affinity and specificity, comparable to those of antibodies. Recently, aptamer selection protocols were developed for targeting living cells, including tumors. Chemical modifications of the aptamers and modalities of their detection and delivery systems are already available with high selectivity and targeting ability for the desired cancer cell type, making them promising for diagnosis and therapy. Glioblastoma multiformae represents the most malignant and fatal stage of glioma, and is also the most frequent brain tumor. Glioblastoma-specific aptamers were developed by either targeting the whole cell surface or known glioma biomarkers. These aptamers may gain importance for imaging, tumor cell isolation from biopsies and drug delivery. In biomedical imaging techniques, aptamers coupled with radionuclide or fluorescent labels, bioconjugates and nanoparticles offer an advanced, noninvasive manner for defining the glioblastoma tissue border. Though single modality aptamer imaging probes have some limitations, these are overcome by the use of multimodal probes. Due to selectivity and chemical characteristics, aptamers can be coupled to functionalized nanoparticles and loaded with a drug, appeared promising for in vivo targeting of glioblastoma. Finally, aptamers are effective mediators for gene silencing when coupled to small interfering RNA and a viral vector, thus providing a novel tool with enhanced targeting capability in drug delivery, designed for tailored treatment of glioblastoma patients.

  15. A Mathematical Model to Elucidate Brain Tumor Abrogation by Immunotherapy with T11 Target Structure

    PubMed Central

    Chaudhuri, Swapna

    2015-01-01

    T11 Target structure (T11TS), a membrane glycoprotein isolated from sheep erythrocytes, reverses the immune suppressed state of brain tumor induced animals by boosting the functional status of the immune cells. This study aims at aiding in the design of more efficacious brain tumor therapies with T11 target structure. We propose a mathematical model for brain tumor (glioma) and the immune system interactions, which aims in designing efficacious brain tumor therapy. The model encompasses considerations of the interactive dynamics of glioma cells, macrophages, cytotoxic T-lymphocytes (CD8+ T-cells), TGF-β, IFN-γ and the T11TS. The system undergoes sensitivity analysis, that determines which state variables are sensitive to the given parameters and the parameters are estimated from the published data. Computer simulations were used for model verification and validation, which highlight the importance of T11 target structure in brain tumor therapy. PMID:25955428

  16. Occupational exposure to electromagnetic fields and the occurrence of brain tumors. An analysis of possible associations

    SciTech Connect

    Lin, R.S.; Dischinger, P.C.; Conde, J.; Farrell, K.P.

    1985-06-01

    To explore the association between occupation and the occurrence of brain tumor, an epidemiologic study was conducted using data from the death certificates of 951 adult white male Maryland residents who died of brain tumor during the period 1969 through 1982. Compared with the controls, men employed in electricity-related occupations, such as electrician, electric or electronic engineer, and utility company serviceman, were found to experience a significantly higher proportion of primary brain tumors. An increase in the odds ratio for brain tumor was found to be positively related to electromagnetic (EM) field exposure levels. Furthermore, the mean age at death was found to be significantly younger among cases in the presumed high EM-exposure group. These findings suggest that EM exposure may be associated with the pathogenesis of brain tumors, particularly in the promoting stage.

  17. Donepezil in Treating Young Patients With Primary Brain Tumors Previously Treated With Radiation Therapy to the Brain

    ClinicalTrials.gov

    2016-07-26

    Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Long-term Effects Secondary to Cancer Therapy in Children; Neurotoxicity; Psychosocial Effects of Cancer and Its Treatment; Radiation Toxicity

  18. Fotemustine in the treatment of brain primary tumors and metastases.

    PubMed

    Khayat, D; Giroux, B; Berille, J; Cour, V; Gerard, B; Sarkany, M; Bertrand, P; Bizzari, J P

    1994-01-01

    Fotemustine is a new chloroethylnitrosourea characterized by the grafting of a phosphonoalanine group onto a nitrosourea radical. Clinical studies using fotemustine have been conducted in malignant glioma, brain metastasis of non-small cell lung cancer, and disseminated malignant melanoma. In recurrent malignant glioma, fotemustine has been used as a single agent: assessed by computed tomography scan, after 8 weeks, the objective response rate was 26.3% among 38 evaluable patients. Median duration of response was 33 weeks. The main toxicity was hematological (thrombocytopenia and leucopenia). A trial with high-dose fotemustine and autologous bone marrow rescue in newly diagnosed glioma was conducted in 26 patients, and 6 showed a partial response. The median overall survival was approximately 11 months. Myelosuppression was noted in all patients except 1, and other toxicity reported was central nervous system toxicity and epigastric pain. Combined with radiotherapy in 55 patients, a 29% response rate was observed, and this combination was well tolerated and easily manageable on an outpatient basis. Finally, fotemustine has been used intraarterially, with 10 objective responses observed among 26 evaluable patients. In brain metastases of non-small cell lung cancer, fotemustine proved to be active with a response rate of 16.7%. Combined with cisplatinum, fotemustine is still under study, but preliminary results are promising. In cerebral metastases of disseminated malignant melanoma, fotemustine has been evaluated in a total of 140 patients in the various studies: median response rate is 24.3%, ranging from 8.3% to 60.0%. Fotemustine appears to be a good candidate in the treatment of primary brain tumors and metastases.

  19. Generation of Novel Thyroid Cancer Stem-Like Cell Clones: Effects of Resveratrol and Valproic Acid.

    PubMed

    Hardin, Heather; Yu, Xiao-Min; Harrison, April D; Larrain, Carolina; Zhang, Ranran; Chen, Jidong; Chen, Herbert; Lloyd, Ricardo V

    2016-06-01

    Anaplastic thyroid cancer is an aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Cancer stem-like cells (CSCs) represent a small fraction of cells in the cancer that are resistant to chemotherapy and radiation therapy and are responsible for tumor reoccurrence and metastasis. We characterized CSCs in thyroid carcinomas and generated clones of CSC lines. Our study showed that anaplastic thyroid cancers had significantly more CSCs than well-differentiated thyroid cancers. We also showed that Aldefluor-positive cells revealed significantly higher expression of stem cell markers, self-renewal properties, thyrosphere formation, and enhanced tumorigenicity. In vivo passaging of Aldefluor-positive cells resulted in the growth of larger, more aggressive tumors. We isolated and generated two clonal spheroid CSC lines derived from anaplastic thyroid cancer that were even more enriched with stem cell markers and more tumorigenic than the freshly isolated Aldefluor-positive cells. Resveratrol and valproic acid treatment of one of the CSC lines resulted in a significant decrease in stem cell markers, Aldefluor expression, proliferation, and invasiveness, with an increase in apoptosis and thyroid differentiation markers, suggesting that these cell lines may be useful for discovering new adjuvant therapies for aggressive thyroid cancers. For the first time, we have two thyroid CSC lines that will be useful tools for the study of thyroid CSC targeted therapies.

  20. Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis

    PubMed Central

    Zheng, Xiangrong; Pang, Bo; Gu, Guangyan; Gao, Taihong; Zhang, Rui; Pang, Qi; Liu, Qian

    2017-01-01

    Glioblastoma stem-like cells (GSCs) play essential roles in glioma growth, radio- and chemo-resistance, and recurrence. Elimination of GSCs has therefore become a key strategy and challenge in glioblastoma therapy. Here, we show that melatonin, an indolamine derived from I-tryptophan, significantly inhibited viability and self-renewal ability of GSCs accompanied by a decrease of stem cell markers. We have identified EZH2-NOTCH1 signaling as the key signal pathway that regulated the effects of melatonin in the GSCs. Instead of transcriptionally silencing gene expression by generating a methylated epigenetic mark at histone 3 at lysine 27 (H3K27), EZH2 regulates NOTCH1 expression by directly binding to the NOTCH1 promoter. Moreover, correlation between the expressions of EZH2 and NOTCH intracellular domain 1 (NICD1) was observed in the clinical tumor samples, evidently supporting the existence of EZH2-NOTCH1 interaction in the gliomas and GSCs. Collectively, we demonstrated that melatonin, a potential tumor inhibitor, performs its function partly by suppressing GSC properties through EZH2-NOTCH1 signaling axis. PMID:28255276

  1. Radiotherapy diagnostic biomarkers in radioresistant human H460 lung cancer stem-like cells.

    PubMed

    Yun, Hong Shik; Baek, Jeong-Hwa; Yim, Ji-Hye; Um, Hong-Duck; Park, Jong Kuk; Song, Jie-Young; Park, In-Chul; Kim, Jae-Sung; Lee, Su-Jae; Lee, Chang-Woo; Hwang, Sang-Gu

    2016-01-01

    Tumor cell radioresistance is a major contributor to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. In this work, we established a radioresistant H460 (RR-H460) cell line from parental radiosensitive H460 lung cancer cells by exposure to fractionated radiation. The radiation-resistant, anti-apoptotic phenotype of RR-H460 cell lines was confirmed by their enhanced clonogenic survival and increased expression of the radioresistance genes Hsp90 and Her-3. RR-H460 cells displayed characteristics of cancer stem-like cells (CSCs), including induction of the surface marker CD44 and stem cell markers Nanog, Oct4, and Sox2. RR-H460 cells also exhibited sphere formation and malignant behavior, further supporting a CSC phenotype. Using proteomic analyses, we identified 8 proteins that were up-regulated in RR-H460 CSC lines and therefore potentially involved in radioresistance and CSC-related biological processes. Notably, 4 of these-PAI-2, NOMO2, KLC4, and PLOD3-have not been previously linked to radioresistance. Depletion of these individual genes sensitized RR-H460 cells to radiotoxicity and additively enhancing radiation-induced apoptosis. Our findings suggest the possibility of integrating molecular targeted therapy with radiotherapy as a strategy for resolving the radioresistance of lung tumors.

  2. Laser interstitial thermal therapy in treatment of brain tumors--the NeuroBlate System.

    PubMed

    Mohammadi, Alireza M; Schroeder, Jason L

    2014-03-01

    Treatment of brain tumors remains challenging. Cytoreductive surgery is used as the first line treatment for most brain tumors. However complete, curative, resection is not achievable in many tumors leading to the need for adjuvant chemotherapy and radiation therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive cytoreductive treatment. A low voltage laser is used to induce hyperthermia and to kill tumor cells. The extent of thermal damage is controlled through use of real-time MR-thermography guidance. Initial results have shown the feasibility of LITT for a variety of brain pathologies. LITT can be considered as an alternative type of surgery for difficult to access brain tumors and also for tumors in patients who are deemed high risk for more traditional surgery. Randomized trials are currently planned to continue assessing the efficacy of LITT and long-term follow-up data are awaited.

  3. Apoptosis imaging for monitoring DR5 antibody accumulation and pharmacodynamics in brain tumors non-invasively

    PubMed Central

    Weber, Thomas G.; Osl, Franz; Renner, Anja; Pöschinger, Thomas; Galbán, Stefanie; Rehemtulla, Alnawaz; Scheuer, Werner

    2014-01-01

    High grade gliomas often possess an impaired blood-brain barrier (BBB) which allows delivery of large molecules to brain tumors. However, achieving optimal drug concentrations in brain tumors remains a significant hurdle for treating patients successfully. Thus, detailed investigations of drug activities in gliomas are needed. To investigate BBB penetration, pharmacodynamics and tumor retention kinetics, we studied an agonistic DR5 antibody in a brain tumor xenograft model to investigate a non-invasive imaging method for longitudinal monitoring of apoptosis induction by this antibody. Brain tumors were induced by intracranial (i.c.) implantation of a luciferase-expressing tumor cell line as a reporter. To quantify accumulation of anti-DR5 in brain tumors, we generated a dose response curve for apoptosis induction after i.c. delivery of fluorescence-labeled anti-DR5 at different dosages. Assuming 100% drug delivery after i.c. application, the amount of accumulated antibody after i.v. application was calculated relative to its apoptosis induction. We found that up to 0.20–0.97% of antibody delivered i.v. reached the brain tumor, but that apoptosis induction declined quickly within 24 hours. These results were confirmed by 3D fluorescence microscopy of antibody accumulation in explanted brains. Nonetheless, significant antitumor efficacy was documented after anti-DR5 delivery. We further demonstrated that antibody crossing the BBB was facilitated its impairment in brain tumors. These imaging methods enable the quantification of antibody accumulation and pharmacodynamics in brain tumors, offering a holistic approach for assessment of CNS targeting drugs. PMID:24509903

  4. EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells

    PubMed Central

    Krusche, Benjamin; Ottone, Cristina; Clements, Melanie P; Johnstone, Ewan R; Goetsch, Katrin; Lieven, Huang; Mota, Silvia G; Singh, Poonam; Khadayate, Sanjay; Ashraf, Azhaar; Davies, Timothy; Pollard, Steven M; De Paola, Vincenzo; Roncaroli, Federico; Martinez-Torrecuadrada, Jorge; Bertone, Paul; Parrinello, Simona

    2016-01-01

    Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM. DOI: http://dx.doi.org/10.7554/eLife.14845.001 PMID:27350048

  5. Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells.

    PubMed

    Giraud, Julie; Failla, Laura M; Pascussi, Jean-Marc; Lagerqvist, Ebba L; Ollier, Jérémy; Finetti, Pascal; Bertucci, François; Ya, Chu; Gasmi, Imène; Bourgaux, Jean-François; Prudhomme, Michel; Mazard, Thibault; Ait-Arsa, Imade; Houhou, Leila; Birnbaum, Daniel; Pélegrin, André; Vincent, Charles; Ryall, James G; Joubert, Dominique; Pannequin, Julie; Hollande, Frédéric

    2016-06-15

    Subpopulations of cancer stem-like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference-mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDH(high) cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDH(high) CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618-28. ©2016 AACR.

  6. Halofuginone inhibits angiogenesis and growth in implanted metastatic rat brain tumor model--an MRI study.

    PubMed

    Abramovitch, Rinat; Itzik, Anna; Harel, Hila; Nagler, Arnon; Vlodavsky, Israel; Siegal, Tali

    2004-01-01

    Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF) is a potent inhibitor of collagen type alpha1(I). In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI), we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001). Treatment with HF significantly prolonged survival of treated animals (142%; P = .001). In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05). Additionally, HF treatment inhibited vessel maturation (P = .03). Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

  7. Stem-like cancer cells are inducible by increasing genomic instability in cancer cells.

    PubMed

    Liang, Yi; Zhong, Zhendong; Huang, Yijun; Deng, Wen; Cao, Junxia; Tsao, George; Liu, Quentin; Pei, Duanqing; Kang, Tiebang; Zeng, Yi-Xin

    2010-02-12

    The existence of cancer stem cells (CSCs) or stem-like cancer cells (SLCCs) is regarded as the cause of tumor formation and recurrence. However, the origin of such cells remains controversial with two competing hypotheses: CSCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Compelling evidence has determined the chromosomal aneuploidy to be one of the hallmarks of cancer cells, indicating genome instability plays an important role in tumorigenesis, for which CSCs are believed to be the initiator. To gain direct evidence that genomic instability is involved in the induction of SLCCs, we utilized multiple approaches to enhance genomic instability and monitored the percentage of SLCC in cultured cancer cells. Using side population (SP) cells as a marker for SLCC in human nasopharyngeal carcinoma (NPC) and CD133 for human neuroblastoma cells, we found that DNA damage inducers, UV and mitomycin C were capable of increasing SP cells in NPC CNE-2 and neuroblastoma SKN-SH cells. Likewise, either overexpression of a key regulator of cell cycle, Mad2, or knock down of Aurora B, an important kinase in mitosis, or Cdh1, a key E3 ligase in cell cycle, resulted in a significant increase of SP cells in CNE-2. More interestingly, enrichment of SP cells was observed in recurrent tumor tissues as compared with the primary tumor in the same NPC patients. Our study thus suggested that, beside transformation of tissue stem cells leading to CSC generation, genomic instability could be another potential mechanism resulting in SLCC formation, especially at tumor recurrence stage.

  8. Biphasic modeling of brain tumor biomechanics and response to radiation treatment.

    PubMed

    Angeli, Stelios; Stylianopoulos, Triantafyllos

    2016-06-14

    Biomechanical forces are central in tumor progression and response to treatment. This becomes more important in brain cancers where tumors are surrounded by tissues with different mechanical properties. Existing mathematical models ignore direct mechanical interactions of the tumor with the normal brain. Here, we developed a clinically relevant model, which predicts tumor growth accounting directly for mechanical interactions. A three-dimensional model of the gray and white matter and the cerebrospinal fluid was constructed from magnetic resonance images of a normal brain. Subsequently, a biphasic tissue growth theory for an initial tumor seed was employed, incorporating the effects of radiotherapy. Additionally, three different sets of brain tissue properties taken from the literature were used to investigate their effect on tumor growth. Results show the evolution of solid stress and interstitial fluid pressure within the tumor and the normal brain. Heterogeneous distribution of the solid stress exerted on the tumor resulted in a 35% spatial variation in cancer cell proliferation. Interestingly, the model predicted that distant from the tumor, normal tissues still undergo significant deformations while it was found that intratumoral fluid pressure is elevated. Our predictions relate to clinical symptoms of brain cancers and present useful tools for therapy planning.

  9. Vorinostat and Temozolomide in Treating Young Patients With Relapsed or Refractory Primary Brain Tumors or Spinal Cord Tumors

    ClinicalTrials.gov

    2013-05-01

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Embryonal 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 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 Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Extra-adrenal Paraganglioma; 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 Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  10. [Interdisciplinary neuro-oncology: part 2: systemic therapy of primary brain tumors].

    PubMed

    Tabatabai, G; Hattingen, E; Schlegel, J; Stummer, W; Schlegel, U

    2014-08-01

    By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High-end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function has become dramatically more extensive. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors.

  11. [Interdisciplinary neuro-oncology: part 1: diagnostics and operative therapy of primary brain tumors].

    PubMed

    Tabatabai, G; Hattingen, E; Schlegel, J; Stummer, W; Schlegel, U

    2014-08-01

    By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High-end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function is increasingly feasible. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors.

  12. Invited review--neuroimaging response assessment criteria for brain tumors in veterinary patients.

    PubMed

    Rossmeisl, John H; Garcia, Paulo A; Daniel, Gregory B; Bourland, John Daniel; Debinski, Waldemar; Dervisis, Nikolaos; Klahn, Shawna

    2014-01-01

    The evaluation of therapeutic response using cross-sectional imaging techniques, particularly gadolinium-enhanced MRI, is an integral part of the clinical management of brain tumors in veterinary patients. Spontaneous canine brain tumors are increasingly recognized and utilized as a translational model for the study of human brain tumors. However, no standardized neuroimaging response assessment criteria have been formulated for use in veterinary clinical trials. Previous studies have found that the pathophysiologic features inherent to brain tumors and the surrounding brain complicate the use of the response evaluation criteria in solid tumors (RECIST) assessment system. Objectives of this review are to describe strengths and limitations of published imaging-based brain tumor response criteria and propose a system for use in veterinary patients. The widely used human Macdonald and response assessment in neuro-oncology (RANO) criteria are reviewed and described as to how they can be applied to veterinary brain tumors. Discussion points will include current challenges associated with the interpretation of brain tumor therapeutic responses such as imaging pseudophenomena and treatment-induced necrosis, and how advancements in perfusion imaging, positron emission tomography, and magnetic resonance spectroscopy have shown promise in differentiating tumor progression from therapy-induced changes. Finally, although objective endpoints such as MR imaging and survival estimates will likely continue to comprise the foundations for outcome measures in veterinary brain tumor clinical trials, we propose that in order to provide a more relevant therapeutic response metric for veterinary patients, composite response systems should be formulated and validated that combine imaging and clinical assessment criteria.

  13. INVITED REVIEW – NEUROIMAGING RESPONSE ASSESSMENT CRITERIA FOR BRAIN TUMORS IN VETERINARY PATIENTS

    PubMed Central

    Rossmeisl, John H.; Garcia, Paulo A.; Daniel, Gregory B.; Bourland, John Daniel; Debinski, Waldemar; Dervisis, Nikolaos; Klahn, Shawna

    2013-01-01

    The evaluation of therapeutic response using cross-sectional imaging techniques, particularly gadolinium-enhanced MRI, is an integral part of the clinical management of brain tumors in veterinary patients. Spontaneous canine brain tumors are increasingly recognized and utilized as a translational model for the study of human brain tumors. However, no standardized neuroimaging response assessment criteria have been formulated for use in veterinary clinical trials. Previous studies have found that the pathophysiologic features inherent to brain tumors and the surrounding brain complicate the use of the Response Evaluation Criteria in Solid Tumors (RECIST) assessment system. Objectives of this review are to describe strengths and limitations of published imaging-based brain tumor response criteria and propose a system for use in veterinary patients. The widely used human Macdonald and Response Assessment in Neuro-oncology (RANO) criteria are reviewed and described as to how they can be applied to veterinary brain tumors. Discussion points will include current challenges associated with the interpretation of brain tumor therapeutic responses such as imaging pseudophenomena and treatment-induced necrosis, and how advancements in perfusion imaging, positron emission tomography, and magnetic resonance spectroscopy have shown promise in differentiating tumor progression from therapy-induced changes. Finally, although objective endpoints such as MR-imaging and survival estimates will likely continue to comprise the foundations for outcome measures in veterinary brain tumor clinical trials, we propose that in order to provide a more relevant therapeutic response metric for veterinary patients, composite response systems should be formulated and validated that combine imaging and clinical assessment criteria. PMID:24219161

  14. What Are Brain and Spinal Cord Tumors in Children?

    MedlinePlus

    ... brain stem. Each area has a special function. Cerebrum: The cerebrum is the large, outer part of the brain. ... other senses Cerebellum: The cerebellum lies under the cerebrum at the back part of the brain. It ...

  15. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors.

    PubMed

    Rubin, Joshua B; Kung, Andrew L; Klein, Robyn S; Chan, Jennifer A; Sun, YanPing; Schmidt, Karl; Kieran, Mark W; Luster, Andrew D; Segal, Rosalind A

    2003-11-11

    The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.

  16. Quantitative assessment of Cerenkov luminescence for radioguided brain tumor resection surgery.

    PubMed

    Klein, Justin S; Mitchell, Gregory; Cherry, Simon

    2017-03-13

    Cerenkov luminescence imaging (CLI) is a developing imaging modality that detects radiolabeled molecules via visible light emitted during the radioactive decay process. We used a Monte Carlo based computer simulation to quantitatively investigate CLI compared to direct detection of the ionizing radiation itself as an intraoperative imaging tool for assessment of brain tumor margins. Our brain tumor model consisted of a 1 mm spherical tumor remnant embedded up to 5 mm in depth below the surface of normal brain tissue. Tumor to background contrast ranging from 2:1 to 10:1 were considered. We quantified all decay signals (e+/-, gamma photon, Cerenkov photons) reaching the brain volume surface. CLI proved to be the most sensitive method for detecting the tumor volume in both imaging and non-imaging strategies as assessed by contrast-to-noise ratio and by receiver operating characteristic output of a channelized Hotelling observer.

  17. Metastasis Infiltration: An Investigation of the Postoperative Brain-Tumor Interface

    SciTech Connect

    Raore, Bethwel; Schniederjan, Matthew; Prabhu, Roshan; Brat, Daniel J.; Shu, Hui-Kuo; Olson, Jeffrey J.

    2011-11-15

    Purpose: This study aims to evaluate brain infiltration of metastatic tumor cells past the main tumor resection margin to assess the biological basis for the use of stereotactic radiosurgery treatment of the tumor resection cavity and visualized resection edge or clinical target volume. Methods and Materials: Resection margin tissue was obtained after gross total resection of a small group of metastatic lesions from a variety of primary sources. The tissue at the border of the tumor and brain tissue was carefully oriented and processed to evaluate the presence of tumor cells within brain tissue and their distance from the resection margin. Results: Microscopic assessment of the radially oriented tissue samples showed no tumor cells infiltrating the surrounding brain tissue. Among the positive findings were reactive astrocytosis observed on the brain tissue immediately adjacent to the tumor resection bed margin. Conclusions: The lack of evidence of metastatic tumor cell infiltration into surrounding brain suggests the need to target only a narrow depth of the resection cavity margin to minimize normal tissue injury and prevent treatment size-dependent stereotactic radiosurgery complications.

  18. Prognostic Significance of Hyperglycemia in Patients with Brain Tumors: a Meta-Analysis.

    PubMed

    Liu, Hongwei; Liu, Zhixiong; Jiang, Bing; Ding, Xiping; Huo, Lei; Wan, Xin; Liu, Jinfang; Xia, Zhenyun

    2016-04-01

    Hyperglycemia has been associated with poor outcomes of patients with various diseases. There were several studies published to assess the association between hyperglycemia and prognosis of patients with brain tumors, but no consistent conclusion was available. We therefore performed a meta-analysis of available studies to evaluate the prognostic role of hyperglycemia in brain tumors. Several common databases were searched for eligible studies on the association between hyperglycemia and survival of patients with brain tumors. Two investigators used a set of predefined inclusion criteria to assess eligible studies independently. The pooled hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the prognostic role of hyperglycemia. Finally, seven studies with a total of 2168 patients with brain tumors were included into the meta-analysis. Meta-analysis of total seven studies showed that hyperglycemia was significantly associated with shorter overall survival of brain tumors (HR = 2.04, 95% CI 1.51-2.76, P < 0.001). Meta-analysis of studies focusing on hyperglycemia showed that hyperglycemia was still significantly associated with shorter overall survival of brain tumors (HR = 1.82, 95% CI 1.29-2.59, P = 0.001). Meta-analysis of three studies on diabetes showed that diabetes was significantly associated with shorter overall survival of brain tumors (HR = 2.09, 95% CI 1.22-3.57, P = 0.007). Meta-regression analysis showed that there was no obvious difference in the roles of between hyperglycemia caused by glucocorticoids and hyperglycemia from diabetes (P = 0.25). Thus, hyperglycemia has an obvious prognostic significance in patients with brain tumors, and hyperglycemia is significantly associated with shorter overall survival of brain tumors.

  19. Removal of a malignant cystic brain tumor utilizing pyoktanin blue and fibrin glue: Technical note

    PubMed Central

    Hayashi, Nobuhide; Sasaki, Takahiro; Tomura, Nagatsuki; Okada, Hideo; Kuwata, Toshikazu

    2017-01-01

    Background: The leakage of cystic fluid during metastatic cystic brain tumor resection may cause tumor dissemination. When the cyst wall is thin, excision without removing the wall is often difficult. Methods: We were able to perform an en bloc resection of a cystic malignant brain tumor after aspirating the cystic fluid, injecting pyoktanin blue into the cyst to stain the cyst walls, and solidifying the empty cyst cavity by filling it with fibrin glue. Results: Pyoktanin blue readily stained the thin cystic walls and enabled visualization of mural damage. Solidification of the tumor made it easier to grasp and facilitated the dissection of tumor margins. Conclusions: This method has the potential to become a useful technique for the resection of malignant cystic brain tumors. PMID:28303204

  20. S100B Mediates Stemness of Ovarian Cancer Stem-Like Cells Through Inhibiting p53.

    PubMed

    Yang, Tao; Cheng, Jianan; Yang, Yang; Qi, Wei; Zhao, Yuetao; Long, Haixia; Xie, Rongkai; Zhu, Bo

    2017-02-01

    S100B is one of the members of the S100 protein family and is involved in the progression of a variety of cancers. Ovarian cancer is driven by cancer stem-like cells (CSLCs) that are involved in tumorigenesis, metastasis, chemo-resistance and relapse. We then hypothesized that S100B might exert pro-tumor effects by regulating ovarian CSLCs stemness, a key characteristic of CSLCs. First, we observed the high expression of S100B in ovarian cancer specimens when compared to that in normal ovary. The S100B upregulation associated with more advanced tumor stages, poorer differentiation and poorer survival. In addition, elevated S100B expression correlated with increased expression of stem cell markers including CD133, Nanog and Oct4. Then, we found that S100B was preferentially expressed in CD133(+) ovarian CSLCs derived from both ovarian cancer cell lines and primary tumors of patients. More importantly, we revealed that S100B knockdown suppressed the in vitro self-renewal and in vivo tumorigenicity of ovarian CSLCs and decreased their expression of stem cell markers. S100B ectopic expression endowed non-CSLCs with stemness, which has been demonstrated with both in vitro and in vivo experiments. Mechanically, we demonstrated that the underlying mechanism of S100B-mediated effects on CSLCs stemness was not dependent on its binding with a receptor for advanced glycation end products (RAGE), but might be through intracellular regulation, through the inhibition of p53 expression and phosphorylation. In conclusion, our results elucidate the importance of S100B in maintenance of ovarian CSLCs stemness, which might provide a promising therapeutic target for ovarian cancer. Stem Cells 2017;35:325-336.

  1. The diagnostic accuracy of multiparametric MRI to determine pediatric brain tumor grades and types.

    PubMed

    Koob, Mériam; Girard, Nadine; Ghattas, Badih; Fellah, Slim; Confort-Gouny, Sylviane; Figarella-Branger, Dominique; Scavarda, Didier

    2016-04-01

    Childhood brain tumors show great histological variability. The goal of this retrospective study was to assess the diagnostic accuracy of multimodal MR imaging (diffusion, perfusion, MR spectroscopy) in the distinction of pediatric brain tumor grades and types. Seventy-six patients (range 1 month to 18 years) with brain tumors underwent multimodal MR imaging. Tumors were categorized by grade (I-IV) and by histological type (A-H). Multivariate statistical analysis was performed to evaluate the diagnostic accuracy of single and combined MR modalities, and of single imaging parameters to distinguish the different groups. The highest diagnostic accuracy for tumor grading was obtained with diffusion-perfusion (73.24%) and for tumor typing with diffusion-perfusion-MR spectroscopy (55.76%). The best diagnostic accuracy was obtained for tumor grading in I and IV and for tumor typing in embryonal tumor and pilocytic astrocytoma. Poor accuracy was seen in other grades and types. ADC and rADC were the best parameters for tumor grading and typing followed by choline level with an intermediate echo time, CBV for grading and Tmax for typing. Multiparametric MR imaging can be accurate in determining tumor grades (primarily grades I and IV) and types (mainly pilocytic astrocytomas and embryonal tumors) in children.

  2. Determination of intra-axial brain tumors cellularity through the analysis of T2 Relaxation time of brain tumors before surgery using MATLAB software

    PubMed Central

    Abdolmohammadi, Jamil; Shafiee, Mohsen; Faeghi, Fariborz; Arefan, Douman; Zali, Alireza; Motiei-Langroudi, Rouzbeh; Farshidfar, Zahra; Nazarlou, Ali Kiani; Tavakkoli, Ali; Yarham, Mohammad

    2016-01-01

    Introduction Timely diagnosis of brain tumors could considerably affect the process of patient treatment. To do so, para-clinical methods, particularly MRI, cannot be ignored. MRI has so far answered significant questions regarding tumor characteristics, as well as helping neurosurgeons. In order to detect the tumor cellularity, neuro-surgeons currently have to sample specimens by biopsy and then send them to the pathology unit. The aim of this study is to determine the tumor cellularity in the brain. Methods In this cross-sectional study, 32 patients (18 males and 14 females from 18–77 y/o) were admitted to the neurosurgery department of Shohada-E Tajrish Hospital in Tehran, Iran from April 2012 to February 2014. In addition to routine pulse sequences, T2W Multi echo pulse sequences were taken and the images were analyzed using the MATLAB software to determine the brain tumor cellularity, compared with the biopsy Results These findings illustrate the need for more T2 relaxation time decreases, the higher classes of tumors will stand out in the designed table. In this study, the results show T2 relaxation time with a 85% diagnostic weight, compared with the biopsy, to determine the brain tumor cellularity (p<0.05). Conclusion Our results indicate that the T2 relaxation time feature is the best method to distinguish and present the degree of intra-axial brain tumors cellularity (85% accuracy compared to biopsy). The use of more data is recommended in order to increase the percent accuracy of this techniques. PMID:27757181

  3. Radiation Dose to the Brain and Subsequent Risk of Developing Brain Tumors in Pediatric Patients Undergoing Interventional Neuroradiology Procedures

    PubMed Central

    Thierry-Chef; Simon, S. L.; Land, C. E.; Miller, D. L.

    2014-01-01

    Radiation dose to the brain and subsequent lifetime risk of diagnosis of radiation-related brain tumors were estimated for pediatric patients undergoing intracranial embolization. Average dose to the whole brain was calculated using dosimetric data from the Radiation Doses in Interventional Radiology Study for 49 pediatric patients who underwent neuroradiological procedures, and lifetime risk of developing radiation-related brain tumors was estimated using published algorithms based on A-bomb survivor data. The distribution of absorbed dose within the brain can vary significantly depending on field size and movement during procedures. Depending on the exposure conditions and age of the patient, organ-averaged brain dose was estimated to vary from 6 to 1600 mGy. The lifetime risk of brain tumor diagnosis was estimated to be increased over the normal background rates (57 cases per 10,000) by 3 to 40% depending on the dose received, age at exposure, and gender. While significant uncertainties are associated with these estimates, we have quantified the range of possible dose and propagated the uncertainty to derive a credible range of estimated lifetime risk for each subject. Collimation and limiting fluoroscopy time and dose rate are the most effective means to minimize dose and risk of future induction of radiation-related tumors. PMID:18959462

  4. Systematic Review of Brain Tumor Treatment in Dogs.

    PubMed

    Hu, H; Barker, A; Harcourt-Brown, T; Jeffery, N

    2015-01-01

    Intracranial neoplasia is commonly diagnosed in dogs and can be treated by a variety of methods, but formal comparisons of treatment efficacy are currently unavailable. This review was undertaken to summarize the current state of knowledge regarding outcome after the treatment of intracranial masses in dogs, with the aim of defining optimal recommendations for owners. This review summarizes data from 794 cases in 22 previously published reports and follows PRISMA guidelines for systematic review. A Pubmed search was used to identify suitable articles. These then were analyzed for quality and interstudy variability of inclusion and exclusion criteria and the outcome data extracted for summary in graphs and tables. There was a high degree of heterogeneity among studies with respect to inclusion and exclusion criteria, definition of survival periods, and cases lost to follow-up making comparisons among modalities troublesome. There is a need for standardized design and reporting of outcomes of treatment for brain tumors in dogs. The available data do not support lomustine as an effective treatment, but also do not show a clear difference in outcome between radiotherapy and surgery for those cases in which the choice is available.

  5. Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells.

    PubMed

    Huang, Yu-Ja; Hoffmann, Gwendolyn; Wheeler, Benjamin; Schiapparelli, Paula; Quinones-Hinojosa, Alfredo; Searson, Peter

    2016-02-22

    Galvanotaxis is a complex process that represents the collective outcome of various contributing mechanisms, including asymmetric ion influxes, preferential activation of voltage-gated channels, and electrophoretic redistribution of membrane components. While a large number of studies have focused on various up- and downstream signaling pathways, little is known about how the surrounding microenvironment may interact and contribute to the directional response. Using a customized galvanotaxis chip capable of carrying out experiments in both two- and three-dimensional microenvironments, we show that cell-extracellular matrix (ECM) interactions modulate the galvanotaxis of brain tumor initiating cells (BTICs). Five different BTICs across three different glioblastoma subtypes were examined and shown to all migrate toward the anode in the presence of a direct-current electric field (dcEF) when cultured on a poly-L-ornithine/laminin coated surface, while the fetal-derived neural progenitor cells (fNPCs) migrated toward the cathode. Interestingly, when embedded in a 3D ECM composed of hyaluronic acid and collagen, BTICs exhibited opposite directional response and migrated toward the cathode. Pharmacological inhibition against a panel of key molecules involved in galvanotaxis further revealed the mechanistic differences between 2- and 3D galvanotaxis in BTICs. Both myosin II and phosphoinositide 3-kinase (PI3K) were found to hold strikingly different roles in different microenvironments.

  6. Ex vivo brain tumor analysis using spectroscopic optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Lenz, Marcel; Krug, Robin; Welp, Hubert; Schmieder, Kirsten; Hofmann, Martin R.

    2016-03-01

    A big challenge during neurosurgeries is to distinguish between healthy tissue and cancerous tissue, but currently a suitable non-invasive real time imaging modality is not available. Optical Coherence Tomography (OCT) is a potential technique for such a modality. OCT has a penetration depth of 1-2 mm and a resolution of 1-15 μm which is sufficient to illustrate structural differences between healthy tissue and brain tumor. Therefore, we investigated gray and white matter of healthy central nervous system and meningioma samples with a Spectral Domain OCT System (Thorlabs Callisto). Additional OCT images were generated after paraffin embedding and after the samples were cut into 10 μm thin slices for histological investigation with a bright field microscope. All samples were stained with Hematoxylin and Eosin. In all cases B-scans and 3D images were made. Furthermore, a camera image of the investigated area was made by the built-in video camera of our OCT system. For orientation, the backsides of all samples were marked with blue ink. The structural differences between healthy tissue and meningioma samples were most pronounced directly after removal. After paraffin embedding these differences diminished. A correlation between OCT en face images and microscopy images can be seen. In order to increase contrast, post processing algorithms were applied. Hence we employed Spectroscopic OCT, pattern recognition algorithms and machine learning algorithms such as k-means Clustering and Principal Component Analysis.

  7. Perceived social competency in children with brain tumors: comparison between children on and off therapy.

    PubMed

    Hardy, Kristina K; Willard, Victoria W; Watral, Melody Ann; Bonner, Melanie J

    2010-01-01

    Children with brain tumors are at risk for a number of cognitive, academic, and social difficulties as a consequence of their illness and its treatment. Of these, the least is known about social functioning, particularly over the course of the illness. Thirty children with brain tumors were evaluated using neurocognitive and psychological measures, including a measure of perceived competency. Results indicated that off-therapy brain tumor patients reported more concerns about their social competence than both a normative sample and children on treatment. Findings highlight the need for more research aimed at helping survivors cope with long-term stressors associated with their illness.

  8. Targeting Prostate Cancer Stem-Like Cells Through Cell Surface-Expressed GRP78

    DTIC Science & Technology

    2013-10-01

    hypothesis that cell surface GRP78 drives cancer stem-like behavior by activating an Akt/GSK-3/ Snail -1 signaling axis in prostate cancer stem-like...investigate the hypothesis that cell surface GRP78 drives cancer stem-like behavior by activating an Akt/GSK-3/ Snail -1 signaling axis in prostate cancer stem...investigate these signaling pathways in year 2. Task 4: Investigate the relative expression of Snail -1, a GSK-3 target, in adherent prostate cancer cells

  9. mir-300 promotes self-renewal and inhibits the differentiation of glioma stem-like cells.

    PubMed

    Zhang, Daming; Yang, Guang; Chen, Xin; Li, Chunmei; Wang, Lu; Liu, Yaohua; Han, Dayong; Liu, Huailei; Hou, Xu; Zhang, Weiguang; Li, Chenguang; Han, Zhanqiang; Gao, Xin; Zhao, Shiguang

    2014-08-01

    MicroRNAs (miRNAs) are small noncoding RNAs that have been critically implicated in several human cancers. miRNAs are thought to participate in various biological processes, including proliferation, cell cycle, apoptosis, and even the regulation of the stemness properties of cancer stem cells. In this study, we explore the potential role of miR-300 in glioma stem-like cells (GSLCs). We isolated GSLCs from glioma biopsy specimens and identified the stemness properties of the cells through neurosphere formation assays, multilineage differentiation ability analysis, and immunofluorescence analysis of glioma stem cell markers. We found that miR-300 is commonly upregulated in glioma tissues, and the expression of miR-300 was higher in GSLCs. The results of functional experiments demonstrated that miR-300 can enhance the self-renewal of GSLCs and reduce differentiation toward both astrocyte and neural fates. In addition, LZTS2 is a direct target of miR-300. In conclusion, our results demonstrate the critical role of miR-300 in GSLCs and its functions in LZTS2 inhibition and describe a new approach for the molecular regulation of tumor stem cells.

  10. Interferon-α/β enhances temozolomide activity against MGMT-positive glioma stem-like cells.

    PubMed

    Shen, Dong; Guo, Cheng-Cheng; Wang, Jing; Qiu, Zhi-Kun; Sai, Ke; Yang, Qun-Ying; Chen, Yin-Sheng; Chen, Fu-Rong; Wang, Jie; Panasci, Lawrence; Chen, Zhong-Ping

    2015-11-01

    Glioma is one of the most common primary tumors of the central nervous system in adults. Glioblastoma (GBM) is the most lethal type of glioma, whose 5-year survival is 9.8% at best. Glioma stem-like cells (GSCs) play an important role in recurrence and treatment resistance. MGMT is a DNA repair protein that removes DNA adducts and therefore attenuates treatment efficiency. It has been reported that interferon-α/β (IFN-α/β) downregulates the level of MGMT and sensitizes glioma cells to temozolomide. In the present study, we assessed whether IFN-α/β is able to sensitize GSCs to temozolomide by modulating MGMT expression. Upon the treatment of IFN-α/β, the efficacy of temozolomide against MGMT‑positive GSCs was markedly enhanced by combination treatment with IFN-α/β when compared with the temozolomide single agent group, and MGMT expression was markedly decreased at the same time. Further mechanistic study showed that IFN-α/β suppressed the NF-κB activity, which further mediated the sensitization of MGMT‑positive GSCs to temozolomide. Our data therefore demonstrated that the application of IFN-α/β is a promising agent with which to enhance temozolomide efficiency and reduce drug resistance, and our findings shed light on improving clinical outcomes and prolonging the survival of patients with malignant gliomas.

  11. Accumulation efficiency of cancer stem-like cells post γ-ray and proton irradiation

    NASA Astrophysics Data System (ADS)

    Quan, Yi; Wang, Weikang; Fu, Qibin; Mei, Tao; Wu, Jingwen; Li, Jia; Yang, Gen; Wang, Yugang

    2012-09-01

    Ionizing radiation (IR) has been proven to be a powerful medical treatment in cancer therapy. Rational and effective use of its killing power depends on understanding IR-mediated responses at the molecular, cellular and tissue levels. Increasing evidence supports that cancer stem-like cells (CSCs) play an important role in tumor regrowth and spread post radiotherapy, for they are resistant to various therapy methods including radiation. Presently, SW620 colon carcinoma monolayer culture cells were irradiated with γ-rays and protons of 2 Gy. Then apoptosis, clonogenic survival and the expression of CD133+ protein were examined. The results showed that there was no significantly difference either on long-term clonogenic survival or on short-term apoptosis ratio. However, compared with γ-rays, irradiation with protons was less efficient to accumulate CSCs at the same dose, although both protons and γ-rays can significantly accumulate the CD133+ CSCs subpopulation. In addition, the results of sphere formation assay also confirmed that proton irradiation is less efficient in CSCs accumulation, suggesting proton irradiation might have higher efficiency in CSCs elimination for cancer radiotherapy.

  12. Etoposide-Bevacizumab a new strategy against human melanoma cells expressing stem-like traits

    PubMed Central

    Calvani, Maura; Bianchini, Francesca; Taddei, Maria Letizia; Becatti, Matteo; Giannoni, Elisa; Chiarugi, Paola; Calorini, Lido

    2016-01-01

    Tumors contain a sub-population of self-renewing and expanding cells known as cancer stem cells (CSCs). Putative CSCs were isolated from human melanoma cells of a different aggressiveness, Hs294T and A375 cell lines, grown under hypoxia using “sphere-forming assay”, CD133 surface expression and migration ability. We found that a cell sub-population enriched for P1 sphere-initiating ability and CD133 expression also express larger amount of VEGF-R2. Etoposide does not influence phenotype of this sub-population of melanoma cells, while a combined treatment with Etoposide and Bevacizumab significantly abolished P1 sphere-forming ability, an effect associated with apoptosis of this subset of cells. Hypoxic melanoma cells sorted for VEGF-R2/CD133 positivity also undergo apoptosis when exposed to Etoposide and Bevacizumab. When Etoposide and Bevacizumab-treated hypoxic cells were injected intravenously into immunodeficient mice revealed a reduced capacity to induce lung colonies, which also appear with a longer latency period. Hence, our study indicates that a combined exposure to Etoposide and Bevacizumab targets melanoma cells endowed with stem-like properties and might be considered a novel approach to treat cancer-initiating cells. PMID:27303923

  13. Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

    PubMed Central

    MacDiarmid, Jennifer A.; Langova, Veronika; Bailey, Dale; Pattison, Scott T.; Pattison, Stacey L.; Christensen, Neil; Armstrong, Luke R.; Brahmbhatt, Vatsala N.; Smolarczyk, Katarzyna; Harrison, Matthew T.; Costa, Marylia; Mugridge, Nancy B.; Sedliarou, Ilya; Grimes, Nicholas A.; Kiss, Debra L.; Stillman, Bruce; Hann, Christine L.; Gallia, Gary L.; Graham, Robert M.; Brahmbhatt, Himanshu

    2016-01-01

    Background Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. Methodology/Principle Findings EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Conclusions/Significance Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On

  14. [Cognitive functions and personality traits in patients with brain tumors: the role of lesion localization].

    PubMed

    Razumnikova, O M; Perfil'ev, A M; Stupak, V V

    2014-01-01

    Personality traits and cognitive functions were studied depending on a tumor localization in the brain in 21 neurosurgical patients and the results were compared with a control group. In patients with brain damage, mostly affected were personality traits associated with emotion regulation and social interaction (neuroticism, psychoticism and social conformity). Increases in psychoticism and decreases in neuroticism were more expressed in patients with a left-hemisphere localization of tumors. The tumor-induced decrease in cognitive abilities was more presented in performing figurative tasks and less in verbal ones. Verbal functions were more decreased in the group with frontal localization of tumor compared to that with parietal localization.

  15. Third harmonic generation imaging for fast, label-free pathology of human brain tumors

    PubMed Central

    Kuzmin, N. V.; Wesseling, P.; Hamer, P. C. de Witt; Noske, D. P.; Galgano, G. D.; Mansvelder, H. D.; Baayen, J. C.; Groot, M. L.

    2016-01-01

    In brain tumor surgery, recognition of tumor boundaries is key. However, intraoperative assessment of tumor boundaries by the neurosurgeon is difficult. Therefore, there is an urgent need for tools that provide the neurosurgeon with pathological information during the operation. We show that third harmonic generation (THG) microscopy provides label-free, real-time images of histopathological quality; increased cellularity, nuclear pleomorphism, and rarefaction of neuropil in fresh, unstained human brain tissue could be clearly recognized. We further demonstrate THG images taken with a GRIN objective, as a step toward in situ THG microendoscopy of tumor boundaries. THG imaging is thus a promising tool for optical biopsies. PMID:27231629

  16. Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels.

    PubMed

    Wrobel, Jagoda K; Wolff, Gretchen; Xiao, Rijin; Power, Ronan F; Toborek, Michal

    2016-08-01

    Various dietary agents can modulate tumor invasiveness. The current study explored whether selenoglycoproteins (SeGPs) extracted from selenium-enriched yeast affect tumor cell homing and growth in the brain. Mice were fed diets enriched with specific SeGPs (SeGP40 or SeGP65, 1 mg/kg Se each), glycoproteins (GP40 or GP65, 0.2-0.3 mg/kg Se each) or a control diet (0.2-0.3 mg/kg Se) for 12 weeks. Then, murine Lewis lung carcinoma cells were infused into the brain circulation. Analyses were performed at early (48 h) and late stages (3 weeks) post tumor cell infusion. Imaging of tumor progression in the brain revealed that mice fed SeGP65-enriched diet displayed diminished metastatic tumor growth, fewer extravasating tumor cells and smaller metastatic lesions. While administration of tumor cells resulted in a significant upregulation of adhesion molecules in the early stage of tumor progression, overexpression of VCAM-1 (vascular call adhesion molecule-1) and ALCAM (activated leukocyte cell adhesion molecule) messenger RNA (mRNA) was diminished in SeGP65 supplemented mice. Additionally, mice fed SeGP65 showed decreased expression of acetylated NF-κB p65, 48 h post tumor cell infusion. The results indicate that tumor progression in the brain can be modulated by specific SeGPs. Selenium-containing compounds were more effective than their glycoprotein controls, implicating selenium as a potential negative regulator of metastatic process.

  17. Monitoring of /sup 57/Co-bleomycin delivery to brain metastases and their tumors of origin

    SciTech Connect

    Front, D.; Even-Sapir, E.; Iosilevsky, G.; Israel, O.; Frenkel, A.; Kolodny, G.M.; Feinsud, M.

    1987-10-01

    The concentration of cobalt-57 (/sup 57/Co)-labeled bleomycin delivered to three brain metastases and to their tumors of origin in the lungs was measured using a single-photon emission computerized tomography technique. In two brain metastases the /sup 57/Co-bleomycin concentration measured at different times after the intravenous injection was significantly lower than that in the originating lung tumors (p less than 0.01 and p less than 0.001). In these two patients, the tumor cumulative concentration (TCC) of drug in the brain neoplasm compared to the lung carcinoma was 12.92 versus 15.12 and 10.30 versus 19.74 micrograms/cc/min. In the third patient there was no significant difference in drug concentration between the tumor in the brain and in the lung (TCC 16.02 vs. 15.09 micrograms/cc/min). There was a significant difference in the drug TCC between the three brain metastases: the difference between the lowest and highest concentrations was more than 50% (10.3 vs. 16.02 micrograms/cc/min). When the concentration in the tumor over time (CT(t)) of the /sup 57/Co-bleomycin was compared in the brain and lung tumors, a good correlation was found in each of the three cases (r = 0.93, 0.99, and 0.97). This suggests that the difference in drug uptake between brain metastases and their originating lung tumor is a quantitative rather than a qualitative phenomenon. The results show that the amount of drug to which brain metastases are exposed varies and may be very low in some tumors; therefore, effectiveness of drug delivery may play a role in the nonresponsiveness of brain metastases to treatment.

  18. Anosmin-1 contributes to brain tumor malignancy through integrin signal pathways

    PubMed Central

    Choy, Catherine T; Kim, Haseong; Lee, Ji-Young; Williams, David M; Palethorpe, David; Fellows, Greg; Wright, Alan J; Laing, Ken; Bridges, Leslie R; Howe, Franklyn A; Kim, Soo-Hyun

    2014-01-01

    Anosmin-1, encoded by the KAL1 gene, is an extracellular matrix (ECM)-associated protein which plays essential roles in the establishment of olfactory and GNRH neurons during early brain development. Loss-of-function mutations of KAL1 results in Kallmann syndrome with delayed puberty and anosmia. There is, however, little comprehension of its role in the developed brain. As reactivation of developmental signal pathways often takes part in tumorigenesis, we investigated if anosmin-1-mediated cellular mechanisms associated with brain tumors. Our meta-analysis of gene expression profiles of patients' samples and public microarray datasets indicated that KAL1 mRNA was significantly upregulated in high-grade primary brain tumors compared with the normal brain and low-grade tumors. The tumor-promoting capacity of anosmin-1 was demonstrated in the glioblastoma cell lines, where anosmin-1 enhanced cell motility and proliferation. Notably, anosmin-1 formed a part of active β1 integrin complex, inducing downstream signaling pathways. ShRNA-mediated knockdown of anosmin-1 attenuated motility and growth of tumor cells and induced apoptosis. Anosmin-1 may also enhance the invasion of tumor cells within the ECM by modulating cell adhesion and activating extracellular proteases. In a mouse xenograft model, anosmin-1-expressing tumors grew faster, indicating the role of anosmin-1 in tumor microenvironment in vivo. Combined, these data suggest that anosmin-1 can facilitate tumor cell proliferation, migration, invasion, and survival. Therefore, although the normal function of anosmin-1 is required in the proper development of GNRH neurons, overexpression of anosmin-1 in the developed brain may be an underlying mechanism for some brain tumors. PMID:24189182

  19. A survey of MRI-based medical image analysis for brain tumor studies.

    PubMed

    Bauer, Stefan; Wiest, Roland; Nolte, Lutz-P; Reyes, Mauricio

    2013-07-07

    MRI-based medical image analysis for brain tumor studies is gaining attention in recent times due to an increased need for efficient and objective evaluation of large amounts of data. While the pioneering approaches applying automated methods for the analysis of brain tumor images date back almost two decades, the current methods are becoming more mature and coming closer to routine clinical application. This review aims to provide a comprehensive overview by giving a brief introduction to brain tumors and imaging of brain tumors first. Then, we review the state of the art in segmentation, registration and modeling related to tumor-bearing brain images with a focus on gliomas. The objective in the segmentation is outlining the tumor including its sub-compartments and surrounding tissues, while the main challenge in registration and modeling is the handling of morphological changes caused by the tumor. The qualities of different approaches are discussed with a focus on methods that can be applied on standard clinical imaging protocols. Finally, a critical assessment of the current state is performed and future developments and trends are addressed, giving special attention to recent developments in radiological tumor assessment guidelines.

  20. A survey of MRI-based medical image analysis for brain tumor studies

    NASA Astrophysics Data System (ADS)

    Bauer, Stefan; Wiest, Roland; Nolte, Lutz-P.; Reyes, Mauricio

    2013-07-01

    MRI-based medical image analysis for brain tumor studies is gaining attention in recent times due to an increased need for efficient and objective evaluation of large amounts of data. While the pioneering approaches applying automated methods for the analysis of brain tumor images date back almost two decades, the current methods are becoming more mature and coming closer to routine clinical application. This review aims to provide a comprehensive overview by giving a brief introduction to brain tumors and imaging of brain tumors first. Then, we review the state of the art in segmentation, registration and modeling related to tumor-bearing brain images with a focus on gliomas. The objective in the segmentation is outlining the tumor including its sub-compartments and surrounding tissues, while the main challenge in registration and modeling is the handling of morphological changes caused by the tumor. The qualities of different approaches are discussed with a focus on methods that can be applied on standard clinical imaging protocols. Finally, a critical assessment of the current state is performed and future developments and trends are addressed, giving special attention to recent developments in radiological tumor assessment guidelines.

  1. Molecular genetics of pediatric brain stem gliomas. Application of PCR techniques to small and archival brain tumor specimens

    SciTech Connect

    Louis, D.N.; Rubio, M.P.; Correa, K.M.; Gusella, J.F.; Deimling, A. von )

    1993-09-01

    Brain stem gliomas are pediatric astrocytomas that histologically resemble adult supratentorial astrocytomas such as gliobastomas multiforme (GBM). The molecular genetic studies have suggested that adult GBM can be divided into two genetic subsets: Tumors with p53 tumor suppressor gene mutations and chromosome 17p loss that occur more commonly in younger patients; and tumors with epidermal growth factor receptor (EGFR) gene amplification that occur more commonly in older patients. Brain stem gliomas have not been studied since biopsies of these tumors are rare and extremely small. The authors investigated the molecular genetic composition of seven brain stem glioblastomas (two small biopsies, five autopsies) using polymerase chain reaction (PCR) assays for chromosomal loss, gene mutation and gene amplification. Four cases lost portions of chromosome 17p that included the 53p gene. These four cases and one additional case had mutations in the p53 gene. None of the cases showed amplification of the EGFR gene. Allelic losses of the long arm of chromosome 10 were noted in four cases. These results suggest similarities between pediatric brain stem glioblastomas and those GBM that occur in younger adult patients, and confirm the utility of PCR-based means of studying small and archival brain tumor specimens. 47 refs., 7 figs., 2 tabs.

  2. Celecoxib Suppresses the Phosphorylation of STAT3 Protein and Can Enhance the Radiosensitivity of Medulloblastoma-Derived Cancer Stem-Like Cells

    PubMed Central

    Yang, Meng-Yin; Lee, Hsu-Tung; Chen, Chien-Min; Shen, Chiung-Chyi; Ma, Hsin-I

    2014-01-01

    Medulloblastoma (MB) is a malignant primary brain tumor with poor prognosis. MB-derived CD133/Nestin double-positive cells (MB-DPs) exhibit cancer stem-like cell (CSC)-like properties that may contribute to chemoradioresistance, tumorigenesis and recurrence. In various tumors, signal transducer and activator of transcription 3 (STAT3) upregulation including MB which can regulate the expression of Nestin. Celecoxib, a selective COX-2 inhibitor, has been shown to potentially reduce STAT3 phosphorylation. The aim of the present study was to investigate the role of celecoxib in enhancing the effects of ionizing radiotherapy (IR) on MB-DP. MB-DPs and MB-derived CD133/Nestin double-negative cells (MB-DNs) were isolated from medulloblastoma cell line Daoy. Then, both of them were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, sphere formation, radiosensitivity, colony formation, apoptotic activity and mouse xenografting experiments in MB-DPs and MB-DNs treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated. We isolated MB-DPs from MB cell line Daoy, which exhibited typical CSC-like characteristics. Microarray analysis and Western blotting both indicated the upregulation of Janus kinase (JAK)-STAT cascade and STAT3 phosphorylation. Incubation with celecoxib dose-dependently suppressed the CSC-like properties and enhanced the IR effect on the induction of apoptosis, as detected by TUNEL assay and staining for Caspase 3 and Annexin V. Finally, celecoxib also enhanced the IR effect to suppress tumorigenesis and synergistically improve the recipient survival in orthotopic MB-derived CD133/Nestin double-positive cells (MB-DP cells) bearing mice. PMID:24945311

  3. Is primary prevention with antiepileptic drugs effective in brain tumors or brain metastases?

    PubMed

    Lobos-Urbina, Diego; Kittsteiner-Manubens, Lucas; Peña, José

    2017-03-21

    Patients with brain tumors –primary or metastatic- have an increased risk of presenting seizures during the course of their disease. So, prophylactic antiepileptic drugs have been proposed. However, the effects of this intervention are not yet clear. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple databases. We identified 12 systematic reviews including 80 studies overall. Twelve corresponded to randomized trials, but only two answered the question of interest. We extracted data, conducted a meta-analysis and generated a summary of findings table using the GRADE method. We concluded primary prevention with antiepileptic drugs might not reduce the risk of seizures, and it is associated to frequent adverse effects.

  4. Pien Tze Huang suppresses the stem-like side population in colorectal cancer cells.

    PubMed

    Wei, Lihui; Chen, Pangyu; Chen, Youqin; Shen, Aling; Chen, Hongwei; Lin, Wei; Hong, Zhenfeng; Sferra, Thomas J; Peng, Jun

    2014-01-01

    Accumulating evidence suggests that a small population of cells termed cancer stem cells (CSCs) are crucial in tumor development and drug resistance, leading to cancer relapse and metastasis and eventually the failure of clinical cancer treatment. Therefore, targeting CSCs is a promising approach for anticancer therapies. Due to the drug resistance and adverse effects of currently used chemotherapies, traditional Chinese medicines (TCM) have recently received attention due to the relatively few side-effects. Thus, they have been used as important alternative remedies for various diseases, including cancer. Pien Tze Huang (PZH), a well-known TCM formula that was first prescribed more than 450 years ago in the Ming Dynasty, has been used in China and Southeast Asia for centuries as a folk remedy for various types of cancer. Previously, it was reported that PZH inhibits colon cancer growth via the promotion of cancer cell apoptosis and inhibition of cell proliferation and tumor angiogenesis, which is probably mediated by its regulatory effect on multiple intracellular signaling pathways. To elucidate the mechanism of the tumoricidal activity of PZH, the aim of the present study was to investigate the effect of PZH on CSCs that were isolated as the side population (SP) from the HT-29 colorectal cancer cell line. The results demonstrated that PZH significantly and dose-dependently reduced the percentage of the colorectal cancer stem-like SP cells, decreased the viability and sphere-forming capacity of HT-29 SP cells, indicating that PZH is potent in suppressing the growth of colorectal cancer stem cells. Moreover, PZH treatment in HT-29 SP cells markedly inhibited the mRNA levels of ABCB1 and ABCG2, which are members of the ABC transporter superfamily, thereby contributing to the SP phenotype and multi-drug resistance. Findings of the present study suggest that inhibiting the growth of CSCs is a potential mechanism by which PZH can be used in cancer treatment.

  5. Coffee and green tea consumption in relation to brain tumor risk in a Japanese population.

    PubMed

    Ogawa, Takahiro; Sawada, Norie; Iwasaki, Motoki; Budhathoki, Sanjeev; Hidaka, Akihisa; Yamaji, Taiki; Shimazu, Taichi; Sasazuki, Shizuka; Narita, Yoshitaka; Tsugane, Shoichiro

    2016-12-15

    Few prospective studies have investigated the etiology of brain tumor, especially among Asian populations. Both coffee and green tea are popular beverages, but their relation with brain tumor risk, particularly with glioma, has been inconsistent in epidemiological studies. In this study, we evaluated the association between coffee and greed tea intake and brain tumor risk in a Japanese population. We evaluated a cohort of 106,324 subjects (50,438 men and 55,886 women) in the Japan Public Health Center-Based Prospective Study (JPHC Study). Subjects were followed from 1990 for Cohort I and 1993 for Cohort II until December 31, 2012. One hundred and fifty-seven (70 men and 87 women) newly diagnosed cases of brain tumor were identified during the study period. Hazard ratio (HR) and 95% confidence intervals (95%CIs) for the association between coffee or green tea consumption and brain tumor risk were assessed using a Cox proportional hazards regression model. We found a significant inverse association between coffee consumption and brain tumor risk in both total subjects (≥3 cups/day; HR = 0.47, 95%CI = 0.22-0.98) and in women (≥3 cups/day; HR = 0.24, 95%CI = 0.06-0.99), although the number of cases in the highest category was small. Furthermore, glioma risk tended to decrease with higher coffee consumption (≥3 cups/day; HR = 0.54, 95%CI = 0.16-1.80). No association was seen between green tea and brain tumor risk. In conclusion, our study suggested that coffee consumption might reduce the risk of brain tumor, including that of glioma, in the Japanese population.

  6. Magnetic resonance microscopy at 14 Tesla and correlative histopathology of human brain tumor tissue.

    PubMed

    Gonzalez-Segura, Ana; Morales, Jose Manuel; Gonzalez-Darder, Jose Manuel; Cardona-Marsal, Ramon; Lopez-Gines, Concepcion; Cerda-Nicolas, Miguel; Monleon, Daniel

    2011-01-01

    Magnetic Resonance Microscopy (MRM) can provide high microstructural detail in excised human lesions. Previous MRM images on some experimental models and a few human samples suggest the large potential of the technique. The aim of this study was the characterization of specific morphological features of human brain tumor samples by MRM and correlative histopathology. We performed MRM imaging and correlative histopathology in 19 meningioma and 11 glioma human brain tumor samples obtained at surgery. To our knowledge, this is the first MRM direct structural characterization of human brain tumor samples. MRM of brain tumor tissue provided images with 35 to 40 µm spatial resolution. The use of MRM to study human brain tumor samples provides new microstructural information on brain tumors for better classification and characterization. The correlation between MRM and histopathology images allowed the determination of image parameters for critical microstructures of the tumor, like collagen patterns, necrotic foci, calcifications and/or psammoma bodies, vascular distribution and hemorrhage among others. Therefore, MRM may help in interpreting the Clinical Magnetic Resonance images in terms of cell biology processes and tissue patterns. Finally, and most importantly for clinical diagnosis purposes, it provides three-dimensional information in intact samples which may help in selecting a preferential orientation for the histopathology slicing which contains most of the informative elements of the biopsy. Overall, the findings reported here provide a new and unique microstructural view of intact human brain tumor tissue. At this point, our approach and results allow the identification of specific tissue types and pathological features in unprocessed tumor samples.

  7. Magnetic Resonance Microscopy at 14 Tesla and Correlative Histopathology of Human Brain Tumor Tissue

    PubMed Central

    Gonzalez-Segura, Ana; Morales, Jose Manuel; Gonzalez-Darder, Jose Manuel; Cardona-Marsal, Ramon; Lopez-Gines, Concepcion; Cerda-Nicolas, Miguel; Monleon, Daniel

    2011-01-01

    Magnetic Resonance Microscopy (MRM) can provide high microstructural detail in excised human lesions. Previous MRM images on some experimental models and a few human samples suggest the large potential of the technique. The aim of this study was the characterization of specific morphological features of human brain tumor samples by MRM and correlative histopathology. We performed MRM imaging and correlative histopathology in 19 meningioma and 11 glioma human brain tumor samples obtained at surgery. To our knowledge, this is the first MRM direct structural characterization of human brain tumor samples. MRM of brain tumor tissue provided images with 35 to 40 µm spatial resolution. The use of MRM to study human brain tumor samples provides new microstructural information on brain tumors for better classification and characterization. The correlation between MRM and histopathology images allowed the determination of image parameters for critical microstructures of the tumor, like collagen patterns, necrotic foci, calcifications and/or psammoma bodies, vascular distribution and hemorrhage among others. Therefore, MRM may help in interpreting the Clinical Magnetic Resonance images in terms of cell biology processes and tissue patterns. Finally, and most importantly for clinical diagnosis purposes, it provides three-dimensional information in intact samples which may help in selecting a preferential orientation for the histopathology slicing which contains most of the informative elements of the biopsy. Overall, the findings reported here provide a new and unique microstructural view of intact human brain tumor tissue. At this point, our approach and results allow the identification of specific tissue types and pathological features in unprocessed tumor samples. PMID:22110653

  8. Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.

    PubMed

    Morfouace, Marie; Nimmervoll, Birgit; Boulos, Nidal; Patel, Yogesh T; Shelat, Anang; Freeman, Burgess B; Robinson, Giles W; Wright, Karen; Gajjar, Amar; Stewart, Clinton F; Gilbertson, Richard J; Roussel, Martine F

    2016-01-01

    Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials.

  9. [Effects of different culture system of isolating and passage of sheep embryonic stem-like cells].

    PubMed

    Bai, Changming; Liu, Chousheng; Wang, Zhigang; Wang, Xinzhuang

    2008-07-01

    In this research, we use mouse embryonic fibroblasts as feeder layers. To eliminate the influence of serum and mouse embryonic stem cells (ESCs) conditioned medium (ESCCM) on self-renewal of sheep embryonic stem-like cells, knockout serum replacement (KSR) was used to replace serum, then supplanted with ESCCM for the isolation and cloning of sheep embryonic stem-like cells. We found when inner cell masses (ICMs) cultured in the control group with medium supplanted with fetal bovine serum (FBS), sheep ES-like cells could not survive for more than 3 passages. However, sheep embryonic stem-like cells could remain undifferentiated for 5 passages when cultured in the medium that FBS was substituted by KSR. The result indicates that KSR culture system was more suitable for the isolation and cloning of sheep embryonic stem-like cells compared to FBS culture system. Finally we applied medium with 15% KSR as basic medium supplanted with 40% ESCCM as a new culture system to isolate sheep embryonic stem-like cells, we found one embryonic stem-like cell line still maintained undifferentiating for 8 passages, which characterized with a normal and stable karyotype and high expression of alkaline phosphatase. These results suggest that it is suitable to culture sheep ICM in the new culture system with 15% KSR as basic medium and supplanted with 40% ESCCM, which indicated that mouse ES cells might secrete factors playing important roles in promoting sheep ES-like cells' self-renewal.

  10. In-vivo optical detection of brain tumor and tumor margin: a combined auto-fluorescence and diffuse reflectance spectroscopic study

    NASA Astrophysics Data System (ADS)

    Majumder, Shovan K.; Gebhart, Steven; Thompson, Reid; Weaver, Kyle D.; Johnson, Mahlon D.; Lin, Wei-Chiang; Mahadevan-Jansen, Anita

    2007-02-01

    Recently, optical spectroscopy has shown considerable promise to be used as a potential clinical tool for human brain tumor detection and therapeutic guidance. Our group showed for the first time the possibility of using combined autofluorescence and diffuse reflectance spectroscopy and established its applicability for human brain tumor demarcation in previous in vitro and in vivo studies. We report in this paper the results of a clinical study designed to further evaluate the efficacy of the approach for demarcation of brain tumors and tumor margins from normal brain tissues in intra-operative clinical setting. Using a portable system, optical spectra were collected from the brain of 110 patients undergoing craniotomy at the Vanderbilt University Medical Center. Spectral measurements were taken from multiple sites of tumor core, tumor margin and normal areas of brain tissues and the resulting spectra were correlated with the corresponding histopathologic diagnosis. Using histology as the gold standard, a probabilistic multi-class diagnostic algorithm was developed to simultaneously distinguish tumor core and tumor margin from normal brain tissue sites using independent training and validation sets of data. An unbiased estimate of the accuracy of the model indicates that combined autofluorescence and diffuse reflectance spectroscopy was able to distinguish tumor core and tumor margin from normal brain tissues with an average predictive accuracy of ~88%.

  11. The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment

    PubMed Central

    Albino, Domenico; Civenni, Gianluca; Rossi, Simona; Mitra, Abhishek; Catapano, Carlo V.; Carbone, Giuseppina M.

    2016-01-01

    Metastatic prostate cancer represents a yet unsolved clinical problem due to the high frequency of relapse and treatment resistance. Understanding the pathways that lead to prostate cancer progression is an important task to prevent this deadly disease. The ETS transcription factor ESE3/EHF has an important role in differentiation of human prostate epithelial cells. Loss of ESE3/EHF in prostate epithelial cells determines transformation, epithelial-to-mesenchymal transition (EMT) and acquisition of stem-like properties. In this study we identify IL-6 as a direct target of ESE3/EHF that is activated in prostate epithelial cells upon loss of ESE3/EHF. ESE3/EHF and IL-6 were significantly inversely correlated in prostate tumors. Chromatin immunoprecipitation confirmed binding of ESE3/EHF to a novel ETS binding site in the IL-6 gene promoter. Inhibition of IL-6 reverted transformation and stem-like phenotype in tumorigenic ESE3/EHF knockdown prostate epithelial cell models. Conversely, IL-6 stimulation induced malignant phenotypes, stem-like behavior and STAT3 activation. Increased level of IL-6 was observed in prostatospheres compared with adherent bulk cancer cells and this was associated with stronger activation of STAT3. Human prostate tumors with IL-6 elevation and loss of ESE3/EHF were associated with STAT3 activation and displayed upregulation of genes related to cell adhesion, cancer stem-like and metastatic spread. Pharmacological inhibition of IL-6/STAT3 activation by a JAK inhibitor restrained cancer stem cell growth in vitro and inhibited self-renewal in vivo. This study identifies a novel connection between the transcription factor ESE3/EHF and the IL-6/JAK/STAT3 pathway and suggests that targeting this axis might be preferentially beneficial in tumors with loss of ESE3/EHF. PMID:27732936

  12. Substrate-mediated reprogramming of human fibroblasts into neural crest stem-like cells and their applications in neural repair.

    PubMed

    Tseng, Ting-Chen; Hsieh, Fu-Yu; Dai, Niann-Tzyy; Hsu, Shan-Hui

    2016-09-01

    Cell- and gene-based therapies have emerged as promising strategies for treating neurological diseases. The sources of neural stem cells are limited while the induced pluripotent stem (iPS) cells have risk of tumor formation. Here, we proposed the generation of self-renewable, multipotent, and neural lineage-related neural crest stem-like cells by chitosan substrate-mediated gene transfer of a single factor forkhead box D3 (FOXD3) for the use in neural repair. A simple, non-toxic, substrate-mediated method was applied to deliver the naked FOXD3 plasmid into human fibroblasts. The transfection of FOXD3 increased cell proliferation and up-regulated the neural crest marker genes (FOXD3, SOX2, and CD271), stemness marker genes (OCT4, NANOG, and SOX2), and neural lineage-related genes (Nestin, β-tubulin and GFAP). The expression levels of stemness marker genes and neural crest maker genes in the FOXD3-transfected fibroblasts were maintained until the fifth passage. The FOXD3 reprogrammed fibroblasts based on the new method significantly rescued the neural function of the impaired zebrafish. The chitosan substrate-mediated delivery of naked plasmid showed feasibility in reprogramming somatic cells. Particularly, the FOXD3 reprogrammed fibroblasts hold promise as an easily accessible cellular source with neural crest stem-like behavior for treating neural diseases in the future.

  13. Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells

    PubMed Central

    Min, Soonki; Park, Ki Cheong; Park, Sunho; Hwang, Tae Hyun; Ryu, Do Hyun; Hwang, Geum-Sook; Cheong, Jae-Ho

    2016-01-01

    Abnormal tumor cell metabolism is a consequence of alterations in signaling pathways that provide critical selective advantage to cancer cells. However, a systematic characterization of the metabolic and signaling pathways altered in cancer stem-like cells (CSCs) is currently lacking. Using nuclear magnetic resonance and mass spectrometry, we profiled the whole-cell metabolites of a pair of parental (P-231) and stem-like cancer cells (S-231), and then integrated with whole transcriptome profiles. We identified elevated NAAD+ in S-231 along with a coordinated increased expression of genes in Wnt/calcium signaling pathway, reflecting the correlation between metabolic reprogramming and altered signaling pathways. The expression of CD38 and ALP, upstream NAAD+ regulatory enzymes, was oppositely regulated between P- and S-231; high CD38 strongly correlated with NAADP in P-231 while high ALP with NAAD+ levels in S-231. Antagonizing Wnt activity by dnTCF4 transfection reversed the levels of NAAD+ and ALP expression in S-231. Of note, elevated NAAD+ caused a decrease of cytosolic Ca2+ levels preventing calcium-induced apoptosis in nutrient-deprived conditions. Reprograming of NAD+ metabolic pathway instigated by Wnt signaling prevented cytosolic Ca2+ overload thereby inhibiting calcium-induced apoptosis in S-231. These results suggest that “oncometabolites” resulting from cross talk between the deranged core cancer signaling pathway and metabolic network provide a selective advantage to CSCs. PMID:27391070

  14. RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells.

    PubMed

    Di Cecilia, Serena; Zhang, Fan; Sancho, Ana; Li, SiDe; Aguiló, Francesca; Sun, Yifei; Rengasamy, Madhumitha; Zhang, Weijia; Del Vecchio, Luigi; Salvatore, Francesco; Walsh, Martin J

    2016-10-01

    Cancer-initiating cells (CIC) undergo asymmetric growth patterns that increase phenotypic diversity and drive selection for chemotherapeutic resistance and tumor relapse. WNT signaling is a hallmark of colon CIC, often caused by APC mutations, which enable activation of β-catenin and MYC Accumulating evidence indicates that long noncoding RNAs (lncRNA) contribute to the stem-like character of colon cancer cells. In this study, we report enrichment of the lncRNA RBM5-AS1/LUST during sphere formation of colon CIC. Its silencing impaired WNT signaling, whereas its overexpression enforced WNT signaling, cell growth, and survival in serum-free media. RBM5-AS1 has been little characterized previously, and we determined it to be a nuclear-retained transcript that selectively interacted with β-catenin. Mechanistic investigations showed that silencing or overexpression of RBM5-AS1 caused a respective loss or retention of β-catenin from TCF4 complexes bound to the WNT target genes SGK1, YAP1, and MYC Our work suggests that RBM5-AS1 activity is critical for the functional enablement of colon cancer stem-like cells. Furthermore, it defines the mechanism of action of RBM5-AS1 in the WNT pathway via physical interactions with β-catenin, helping organize transcriptional complexes that sustain colon CIC function. Cancer Res; 76(19); 5615-27. ©2016 AACR.

  15. Automatic Brain Tumor Detection in T2-weighted Magnetic Resonance Images

    NASA Astrophysics Data System (ADS)

    Dvořák, P.; Kropatsch, W. G.; Bartušek, K.

    2013-10-01

    This work focuses on fully automatic detection of brain tumors. The first aim is to determine, whether the image contains a brain with a tumor, and if it does, localize it. The goal of this work is not the exact segmentation of tumors, but the localization of their approximate position. The test database contains 203 T2-weighted images of which 131 are images of healthy brain and the remaining 72 images contain brain with pathological area. The estimation, whether the image shows an afflicted brain and where a pathological area is, is done by multi resolution symmetry analysis. The first goal was tested by five-fold cross-validation technique with 100 repetitions to avoid the result dependency on sample order. This part of the proposed method reaches the true positive rate of 87.52% and the true negative rate of 93.14% for an afflicted brain detection. The evaluation of the second part of the algorithm was carried out by comparing the estimated location to the true tumor location. The detection of the tumor location reaches the rate of 95.83% of correct anomaly detection and the rate 87.5% of correct tumor location.

  16. Detection of brain tumors using fluorescence diffuse optical tomography and nanoparticles as contrast agents

    NASA Astrophysics Data System (ADS)

    Fortin, Pierre-Yves; Genevois, Coralie; Koenig, Anne; Heinrich, Emilie; Texier, Isabelle; Couillaud, Franck

    2012-12-01

    Near-infrared fluorescence-enhanced diffuse optical tomography (fDOT) is used to localize tumors in mice using fluorescent nanoparticles as a blood pool contrast agent. The infrared dye DiR is loaded in the lipid core of nontargeted nanoparticles (DiR-lipidots) and injected systemically via the tail vein in mice bearing U87 tumors. Distribution and time-course of DiR-lipidots are followed using in vivo fluorescence reflectance imaging and reveal enhanced fluorescent signal within the subcutaneous tumors up to seven days due to the enhanced permeability and retention effect. Tumor growth into the brain is followed using bioluminescent imaging, and tumor localization is further determined by magnetic resonance imaging. The fDOT provides three-dimensional fluorescent maps that allow for consistent localization for both subcutaneous and brain tumors.

  17. Structural Brain Alterations in Children an Average of 5 Years after Surgery and Chemotherapy for Brain Tumors

    PubMed Central

    Nelson, Mary Baron; Macey, Paul M.; Harper, Ronald M.; Jacob, Eufemia; Patel, Sunita K.; Finlay, Jonathan L.; Nelson, Marvin D.; Compton, Peggy

    2014-01-01

    Background Young children with brain tumors are often treated with high-dose chemotherapy after surgery to avoid brain tissue injury associated with irradiation. The effects of systemic chemotherapy on healthy brain tissue in this population, however, are unclear. Our objective was to compare gray and white matter integrity using MRI procedures in children with brain tumors (n=7, mean age 8.3 years), treated with surgery and high-dose chemotherapy followed by autologous hematopoietic cell rescue (AuHCR) an average of 5.4 years earlier, to age- and gender-matched healthy controls (n=9, mean age 9.3 years). Methods Diffusion tensor imaging data were collected to evaluate tissue integrity throughout the brain, as measured by mean diffusivity (MD), a marker of glial, neuronal, and axonal status, and fractional anisotropy (FA), an index of axonal health. Individual MD and FA maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance, with age and sex as covariates. Results Higher mean diffusivity values, indicative of injury, emerged in patients compared with controls (p<0.05, corrected for multiple comparisons), and were especially apparent in the central thalamus, external capsule, putamen, globus pallidus and pons. Reduced FA values in some regions did not reach significance after correction for multiple comparisons. Conclusions Children treated with surgery and high-dose chemotherapy with AuHCR for brain tumors an average of 5.4 years earlier show alterations in white and gray matter in multiple brain areas distant from the tumor site, raising the possibility for long-term consequences of the tumor or treatment. PMID:24830985

  18. Non-invasive monitoring of hemodynamic changes in orthotropic brain tumor

    NASA Astrophysics Data System (ADS)

    Kashyap, Dheerendra; Sharma, Vikrant; Liu, Hanli

    2007-02-01

    Radio surgical interventions such as Gamma Knife and Cyberknife have become attractive as therapeutic interventions. However, one of the drawbacks of cyberknife is radionecrosis, which is caused by excessive radiation to surrounding normal tissues. Radionecrosis occurs in about 10-15% of cases and could have adverse effects leading to death. Currently available imaging techniques have failed to reliably distinguish radionecrosis from tumor growth. Development of imaging techniques that could provide distinction between tumor growth and radionecrosis would give us ability to monitor effects of radiation therapy non-invasively. This paper investigates the use of near infrared spectroscopy (NIRS) as a new technique to monitor the growth of brain tumors. Brain tumors (9L glioma cell line) were implanted in right caudate nucleus of rats (250-300 gms, Male Fisher C) through a guide screw. A new algorithm was developed, which used broadband steady-state reflectance measurements made using a single source-detector pair, to quantify absolute concentrations of hemoglobin derivatives and reduced scattering coefficients. Preliminary results from the brain tumors indicated decreases in oxygen saturation, oxygenated hemoglobin concentrations and increases in deoxygenated hemoglobin concentrations with tumor growth. The study demonstrates that NIRS technology could provide an efficient, noninvasive means of monitoring vascular oxygenation dynamics of brain tumors and further facilitate investigations of efficacy of tumor treatments.

  19. Plasmonics-enhanced and optically modulated delivery of gold nanostars into brain tumor.

    PubMed

    Yuan, Hsiangkuo; Wilson, Christy M; Xia, Jun; Doyle, Sarah L; Li, Shuqin; Fales, Andrew M; Liu, Yang; Ozaki, Ema; Mulfaul, Kelly; Hanna, Gabi; Palmer, Gregory M; Wang, Lihong V; Grant, Gerald A; Vo-Dinh, Tuan

    2014-04-21

    Plasmonics-active gold nanostars exhibiting strong imaging contrast and efficient photothermal transduction were synthesized for a novel pulsed laser-modulated plasmonics-enhanced brain tumor microvascular permeabilization. We demonstrate a selective, optically modulated delivery of nanoprobes into the tumor parenchyma with minimal off-target distribution.

  20. Plasmonics-enhanced and optically modulated delivery of gold nanostars into brain tumor

    PubMed Central

    Yuan, Hsiangkuo; Wilson, Christy M.; Xia, Jun; Doyle, Sarah L.; Li, Shuqin; Fales, Andrew M; Liu, Yang; Ozaki, Ema; Mulfaul, Kelly; Hanna, Gabi; Palmer, Gregory M.; Wang, Lihong V.; Grant, Gerald A.

    2014-01-01

    Plasmonics-active gold nanostars exhibiting strong imaging contrast and efficient photothermal transduction were synthesized for a novel pulsed laser-modulated plasmonics-enhanced brain tumor microvascular permeabilization. We demonstrate a selective, optically modulated delivery of nanoprobes into the tumor parenchyma with minimal off-target distribution. PMID:24619405

  1. Direct cortical stimulation but not transcranial electrical stimulation motor evoked potentials detect brain ischemia during brain tumor resection.

    PubMed

    Li, Fenghua; Deshaies, Eric M; Allott, Geoffrey; Canute, Gregory; Gorji, Reza

    2011-09-01

    Motor evoked potentials (MEPs) elicited by both direct cortical stimulation (DCS) and transcranial electrical stimulation are used during brain tumor resection. Parallel use of direct cortical stimulation motor evoked potentials (DCS-MEPs) and transcranial electrical stimulation motor evoked potentials (TCeMEPs) has been practiced during brain tumor resection. We report that DCS-MEPs elicited by direct subdural grid stimulation, but not TCeMEPs, detected brain ischemia during brain tumor resection. Following resection of a brainstem high-grade glioma in a 21-year-old, the threshold of cortical motor-evoked-potentials (cMEPs) increased from 13 mA to 20 mA while amplitudes decreased. No changes were noted in transcranial motor evoked potentials (TCMEPs), somatosensory evoked potentials (SSEPs), auditory evoked potentials (AEPs), anesthetics, or hemodynamic parameters. Our case showed the loss of cMEPs and SSEPs, but not TCeMEPs. Permanent loss of DCS-MEPs and SSEPs was correlated with permanent left hemiplegia in our patient even when appropriate action was taken. Parallel use of DCS- and TCeMEPs with SSEPs improves sensitivity of intraoperative detection of motor impairment. DCS may be superior to TCeMEPs during brain tumor resection.

  2. Genome-Wide Microarray Expression and Genomic Alterations by Array-CGH Analysis in Neuroblastoma Stem-Like Cells

    PubMed Central

    Martínez-Soto, Soledad; Legarra, Sheila; Pata-Merci, Noémie; Guegan, Justine; Danglot, Giselle; Bernheim, Alain; Meléndez, Bárbara; Rey, Juan A.; Castresana, Javier S.

    2014-01-01

    Neuroblastoma has a very diverse clinical behaviour: from spontaneous regression to a very aggressive malignant progression and resistance to chemotherapy. This heterogeneous clinical behaviour might be due to the existence of Cancer Stem Cells (CSC), a subpopulation within the tumor with stem-like cell properties: a significant proliferation capacity, a unique self-renewal capacity, and therefore, a higher ability to form new tumors. We enriched the CSC-like cell population content of two commercial neuroblastoma cell lines by the use of conditioned cell culture media for neurospheres, and compared genomic gains and losses and genome expression by array-CGH and microarray analysis, respectively (in CSC-like versus standard tumor cells culture). Despite the array-CGH did not show significant differences between standard and CSC-like in both analyzed cell lines, the microarray expression analysis highlighted some of the most relevant biological processes and molecular functions that might be responsible for the CSC-like phenotype. Some signalling pathways detected seem to be involved in self-renewal of normal tissues (Wnt, Notch, Hh and TGF-β) and contribute to CSC phenotype. We focused on the aberrant activation of TGF-β and Hh signalling pathways, confirming the inhibition of repressors of TGF-β pathway, as SMAD6 and SMAD7 by RT-qPCR. The analysis of the Sonic Hedgehog pathway showed overexpression of PTCH1, GLI1 and SMO. We found overexpression of CD133 and CD15 in SIMA neurospheres, confirming that this cell line was particularly enriched in stem-like cells. This work shows a cross-talk among different pathways in neuroblastoma and its importance in CSC-like cells. PMID:25392930

  3. Anticancer effects of cinnamic acid in lung adenocarcinoma cell line h1299-derived stem-like cells.

    PubMed

    Huang, Yanyan; Zeng, Fang; Xu, Liyun; Zhou, Jihang; Liu, Xiaoguang; Le, Hanbo

    2013-01-01

    Lung cancer is a lethal solid tumor with poor prognosis because of its high metastasis and resistance to current therapies. Recently, cancer stem cells (CSCs) were suggested to be major contributors to tumorigenicity and cancer relapse. However, therapeutic targets for lung cancer-related CSCs remain undetermined. The objective of the current study was to investigate whether cinnamic acid (CINN) exerts an antitumor activity against sphere-derived lung CSCs. In this study, CSCs were isolated from the non-small cell lung cancer cell line H1299 as tumor spheres under CSC-selective conditions, and found to have increased tumorigenicity, chemoresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared with parental cells. These observations are consistent with the notion that CSCs are tumorigenic, display the ability to self-renew, and generate differentiated progeny that constitute the majority of cells in tumors. Treatment of sphere-derived stem cells with CINN could diminish their CSC-like abilities by decreasing their proliferation and invasive abilities and facilitating their differentiation into CD133-negative cells. Furthermore, CINN treatment increased the sensitivity of CSCs to chemotherapeutic drugs through apoptosis. Of note, xenotransplantation experiments revealed that CINN combined with cisplatin had a synergistic effect in inhibiting the tumorigenicity of CSCs. In summary, our study clearly revealed the presence of a population of sphere-forming cells with stem-like properties among H1299 cells and CINN can attenuate CSC properties of this stem-like cell population. The potential of CINN should be verified further in future studies of anti-CSC therapy.

  4. The Influence of Neuronal Activity on Breast Tumor Metastasis to the Brain

    DTIC Science & Technology

    2009-09-01

    drugs to alter brain activity: caffeine, methylphenidate and modafinil . While the smallest effect may be expected from caffeine which is not as potent...caffeine, we have initiated experiments to test the effects of modafinil on breast tumor metastasis to the brain in our model. Unfortunately, we have had

  5. Targeted delivery of nano-PTX to the brain tumor-associated macrophages

    PubMed Central

    Zou, Lei; Tao, Youhua; Payne, Gregory; Do, Linh; Thomas, Tima; Rodriguez, Juan; Dou, Huanyu

    2017-01-01

    Nanoparticles containing mixed lipid monolayer shell, biodegradable polymer core and rabies virus glycoprotein (RVG) peptide as brain targeting ligand, were developed for brain targeted delivery of paclitaxel (PTX) to treat malignant glioma. RVG conjugated PTX loaded NPs (RVG-PTX-NPs) had the desirable size (~140 nm), narrow size distribution and spherical shape. RVG-PTX-NPs showed poor uptake by neurons and selective targeting to the brain tumor associated macrophages (TAMs) with controlled release and tumor specific toxicity. In vivo studies revealed that RVG-PTX-NPs were significant to cross the blood-brain barrier (BBB) and had specific targeting to the brain. Most importantly, RVG-PTX-NPs showed effectiveness for anti-glioma therapy on human glioma of mice model. We concluded that RVG-PTX-NPs provided an effective approach for brain-TAMs targeted delivery for the treatment of glioma. PMID:28036254

  6. Recognition of Transmembrane Protein 39A as a Tumor-Specific Marker in Brain Tumor

    PubMed Central

    Park, Jisoo; Lee, Hyunji; Tran, Quangdon; Mun, Kisun; Kim, Dohoon; Hong, Youngeun; Kwon, So Hee; Brazil, Derek; Park, Jongsun; Kim, Seon-Hwan

    2017-01-01

    Transmembrane protein 39A (TMEM39A) belongs to the TMEM39 family. TMEM39A gene is a susceptibility locus for multiple sclerosis. In addition, TMEM39A seems to be implicated in systemic lupus erythematosus. However, any possible involvement of TMEM39A in cancer remains largely unknown. In the present report, we provide evidence that TMEM39A may play a role in brain tumors. Western blotting using an anti-TMEM39A antibody indicated that TMEM39A was overexpressed in glioblastoma cell lines, including U87-MG and U251-MG. Deep-sequencing transcriptomic profiling of U87-MG and U251-MG cells revealed that TMEM39A transcripts were upregulated in such cells compared with those of the cerebral cortex. Confocal microscopic analysis of U251-MG cells stained with anti-TMEM39A antibody showed that TMEM39A was located in dot-like structures lying close to the nucleus. TMEM39A probably located to mitochondria or to endosomes. Immunohistochemical analysis of glioma tissue specimens indicated that TMEM39A was markedly upregulated in such samples. Bioinformatic analysis of the Rembrandt knowledge base also supported upregulation of TMEM39A mRNA levels in glioma patients. Together, the results afford strong evidence that TMEM39A is upregulated in glioma cell lines and glioma tissue specimens. Therefore, TMEM39A may serve as a novel diagnostic marker of, and a therapeutic target for, gliomas and other cancers. PMID:28133515

  7. The Relationship between Parkinson Disease and Brain Tumor: A Meta-Analysis

    PubMed Central

    Ye, Rong; Shen, Ting; Jiang, Yasi; Xu, Lingjia; Si, Xiaoli; Zhang, Baorong

    2016-01-01

    Objective Epidemiological studies have investigated the association between Parkinson disease (PD) occurrence and the risk of brain tumors, while the results remain controversial. We performed a meta-analysis to clarify the exact relationship between PD and brain tumors. Methods A systematic literature search was conducted using PubMed, Embase, ScienceDirect and CBM (China Biology Medicine Disc) before February 2016. Eligible studies were those that reported risk estimates of brain tumors among patients with PD or vice versa. A random-effects model was used to calculate the pooled odds ratio (OR) of the outcomes. Subgroup analyses and sensitivity analysis were conducted to explore the potential sources of heterogeneity. Results In total, eight studies involving 329,276 participants met our inclusion criteria. The pooled OR was 1.51 (95%CI 1.21–1.89), indicating that PD carried a higher risk of brain tumor. Analyses by temporal relationship found that the occurrence of brain tumor was significantly higher after the diagnosis of PD (OR 1.55, 95% CI 1.18–2.05), but not statistically significant before PD diagnosis (OR 1.21, 95%CI 0.93–1.58). Subgroup analysis showed that gender differences, ethnicity differences and the characteristic of the tumor (benign or malignant) did not make much change in the association between brain tumor and PD. Conclusions Our meta-analysis collecting epidemiological studies suggested a positive association of PD with brain tumors, while the influence of anti-parkinson drugs and ascertainment bias could not be excluded. Further studies with larger sample size and more strict inclusion criteria should be conducted in the future. PMID:27764145

  8. Estimating the risk of brain tumors from cellphone use: Published case-control studies.

    PubMed

    Morgan, L Lloyd

    2009-08-01

    This paper reviews the results of early cellphone studies, where exposure duration was too short to expect tumorigenesis, as well as two sets of more recent studies with longer exposure duration: the Interphone studies and the Swedish studies led by Dr. Lennart Hardell. The recent studies reach very different conclusions. With four exceptions the industry-funded Interphone studies found no increased risk of brain tumors from cellphone use, while the Swedish studies, independent of industry funding, reported numerous findings of significant increased brain tumor risk from cellphone and cordless phone use. An analysis of the data from the Interphone studies suggests that either the use of a cellphone protects the user from a brain tumor, or the studies had serious design flaws. Eleven flaws are identified: (1) selection bias, (2) insufficient latency time, (3) definition of 'regular' cellphone user, (4) exclusion of young adults and children, (5) brain tumor risk from cellphones radiating higher power levels in rural areas were not investigated, (6) exposure to other transmitting sources are excluded, (7) exclusion of brain tumor types, (8) tumors outside the cellphone radiation plume are treated as exposed, (9) exclusion of brain tumor cases because of death or illness, (10) recall accuracy of cellphone use, and (11) funding bias. The Interphone studies have all 11 flaws, and the Swedish studies have 3 flaws (8, 9 and 10). The data from the Swedish studies are consistent with what would be expected if cellphone use were a risk for brain tumors, while the Interphone studies data are incredulous. If a risk does exist, the public health cost will be large. These are the circumstances where application of the Precautionary Principle is indicated, especially if low-cost options could reduce the absorbed cellphone radiation by several orders of magnitude.

  9. Quality of life and symptoms in pediatric brain tumor survivors: a systematic review.

    PubMed

    Macartney, Gail; Harrison, Margaret B; VanDenKerkhof, Elizabeth; Stacey, Dawn; McCarthy, Patricia

    2014-01-01

    Little is known about the quality of life of children and youth under the age of 20 who have completed treatment for a pediatric brain tumor. This systematic review was conducted to (a) describe the health-related quality of life (HRQL) outcomes in pediatric brain tumor survivors, (b) identify instruments used to measure HRQL, and (c) determine the relationship between symptoms and HRQL. Using a systematic search and review methodology, databases searched included CINAHL, Medline, Embase, and PsycInfo. No date restrictions were used. Search results elicited 485 articles, of which16 met the inclusion criteria. Compared with their healthy peers, pediatric brain tumor survivors did worse on most measures of physical, psychosocial, social, and cognitive domains of HRQL. Compared with other cancer patients, survivors scored themselves significantly lower on the Pediatric Quality of Life Inventory (PedsQL) social functioning scale, and parents of brain tumor survivors reported lower PedsQL social and total functioning scores for their children. Other variables that were associated with decreased HRQL were degree of hypothalamic tumor involvement, osteopenia, need for special education, older age at diagnosis, greater than 1 year since treatment, and radiation treatment. In these studies, pediatric brain tumor survivors fared worse compared with other cancer survivors or healthy peers on several HRQL domains. Only 3 studies explored the relationship between symptoms, including pain or fatigue, and HRQL in pediatric brain tumor survivors. The relationship between symptoms and HRQL was not well elucidated. More research is needed to explore the multidimensional symptom experience and HRQL outcomes in pediatric brain tumor survivors.

  10. EARLY POSTOPERATIVE MAGNETIC RESONANCE IMAGING FINDINGS IN FIVE DOGS WITH CONFIRMED AND SUSPECTED BRAIN TUMORS.

    PubMed

    Chow, Kathleen Ella; Tyrrell, Dayle; Long, Sam Nicholas

    2015-01-01

    Early postoperative neuroimaging has been performed in people for over 20 years to detect residual brain tumor tissue and surgical complications. The purpose of this retrospective study was to describe characteristics observed using early postoperative magnetic resonance imaging in a group of dogs undergoing craniotomy for brain tumor removal. Two independent observers came to a consensus opinion for presence/absence of the following MRI characteristics: residual tumor tissue; hemorrhage and ischemic lesions; abnormal enhancement (including the margins of the resection cavity, choroid plexus, meninges) and signal intensity changes on diffusion-weighted imaging. Five dogs were included in the study, having had preoperative and early postoperative MRI acquired within four days after surgery. The most commonly observed characteristics were abnormal meningeal enhancement, linear enhancement at margins of the resection cavity, hemorrhage, and a thin rim of hyperintensity surrounding the resection cavity on diffusion-weighted imaging. Residual tumor tissue was detected in one case of an enhancing tumor and in one case of a tumor containing areas of hemorrhage preoperatively. Residual tumor tissue was suspected but could not be confirmed when tumors were nonenhancing. Findings supported the use of early postoperative MRI as a method for detecting residual brain tumor tissue in dogs.

  11. Management of childhood brain tumors: consensus report by the Pediatric Hematology Oncology (PHO) Chapter of Indian Academy of Pediatrics (IAP).

    PubMed

    Bhat, Sunil; Yadav, Satya Prakash; Suri, Vaishali; Patir, Rana; Kurkure, Purna; Kellie, Stewart; Sachdeva, Anupam

    2011-12-01

    Brain tumors are the second most common childhood tumors and remain the leading cause of cancer related deaths in children. Appropriate diagnosis and management of these tumors are essential to improve survival. There are no clinical practical guidelines available for the management of brain tumors in India. This document is a consensus report prepared after a National Consultation on Pediatric Brain Tumors held in Delhi on 06 Nov 2008. The meeting was attended by eminent experts from all over the country, in the fields of Neurosurgery, Radiation Oncology, Pediatric Oncology, Neuropathology, Diagnostic Imaging, Pediatric Endocrinology and Allied Health Professionals. This article highlights that physicians looking after children with brain tumors should work as part of a multidisciplinary team to improve the survival, quality of life, neuro-cognitive outcomes and standards of care for children with brain tumors. Recommendations for when to suspect, diagnostic workup, initial management, long-term follow up and specific management of individual tumors are outlined.

  12. Improving the accuracy of brain tumor surgery via Raman-based technology.

    PubMed

    Hollon, Todd; Lewis, Spencer; Freudiger, Christian W; Sunney Xie, X; Orringer, Daniel A

    2016-03-01

    Despite advances in the surgical management of brain tumors, achieving optimal surgical results and identification of tumor remains a challenge. Raman spectroscopy, a laser-based technique that can be used to nondestructively differentiate molecules based on the inelastic scattering of light, is being applied toward improving the accuracy of brain tumor surgery. Here, the authors systematically review the application of Raman spectroscopy for guidance during brain tumor surgery. Raman spectroscopy can differentiate normal brain from necrotic and vital glioma tissue in human specimens based on chemical differences, and has recently been shown to differentiate tumor-infiltrated tissues from noninfiltrated tissues during surgery. Raman spectroscopy also forms the basis for coherent Raman scattering (CRS) microscopy, a technique that amplifies spontaneous Raman signals by 10,000-fold, enabling real-time histological imaging without the need for tissue processing, sectioning, or staining. The authors review the relevant basic and translational studies on CRS microscopy as a means of providing real-time intraoperative guidance. Recent studies have demonstrated how CRS can be used to differentiate tumor-infiltrated tissues from noninfiltrated tissues and that it has excellent agreement with traditional histology. Under simulated operative conditions, CRS has been shown to identify tumor margins that would be undetectable using standard bright-field microscopy. In addition, CRS microscopy has been shown to detect tumor in human surgical specimens with near-perfect agreement to standard H & E microscopy. The authors suggest that as the intraoperative application and instrumentation for Raman spectroscopy and imaging matures, it will become an essential component in the neurosurgical armamentarium for identifying residual tumor and improving the surgical management of brain tumors.

  13. Expression of the HOX genes and HOTAIR in atypical teratoid rhabdoid tumors and other pediatric brain tumors.

    PubMed

    Chakravadhanula, Madhavi; Ozols, Victor V; Hampton, Chris N; Zhou, Li; Catchpoole, Daniel; Bhardwaj, Ratan D

    2014-09-01

    Pediatric brain tumors such as atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive and predominantly occur in young children. A characteristic feature of ATRT is aberrations of the SMARCB1 (hSNF5/INI1) gene. Developmental gene defects may play an important role in the biology of pediatric brain tumors. HOX genes are transcription factors that play a pivotal role in anterior-posterior body axis patterning and are misexpressed in tumors such as lung carcinoma, neuroblastoma, and glioma. HOX genes are also known to be associated with long noncoding RNAs (lncRNAs) such as HOTAIR, which induces transcriptional silencing of the HOXD locus by recruiting polycomb repressive complex 2 to the HOXD locus. In this study, transcriptome analysis using the nanoString platform was performed, and expression of the HOX and HOTAIR genes was studied in pediatric tumors: 20 ATRTs, 10 ependymomas, 10 medulloblastomas, six glioblastoma multiforme, and nine juvenile pilocytic astrocytomas (JPAs). Results indicate that in ATRTs, medulloblastomas, and JPAs, the HOTAIR and HOXC genes are highly expressed; however, HOXD8-10 genes are not silenced. In ependymomas, there is low expression of the HOXC, HOTAIR, and HOXD8-10 genes. These interesting results need to be elucidated further so that the functions of these genes in pediatric tumors is understood.

  14. Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord

    PubMed Central

    Wang, Yuxuan; Springer, Simeon; Zhang, Ming; McMahon, K. Wyatt; Kinde, Isaac; Dobbyn, Lisa; Ptak, Janine; Brem, Henry; Chaichana, Kaisorn; Gallia, Gary L.; Gokaslan, Ziya L.; Groves, Mari L.; Jallo, George I.; Lim, Michael; Olivi, Alessandro; Quinones-Hinojosa, Alfredo; Rigamonti, Daniele; Riggins, Greg J.; Sciubba, Daniel M.; Weingart, Jon D.; Wolinsky, Jean-Paul; Ye, Xiaobu; Oba-Shinjo, Sueli Mieko; Marie, Suely K. N.; Holdhoff, Matthias; Agrawal, Nishant; Diaz, Luis A.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Bettegowda, Chetan

    2015-01-01

    Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57–88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88–100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher’s exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord. PMID:26195750

  15. A Distinct Slow-Cycling Cancer Stem-like Subpopulation of Pancreatic Adenocarcinoma Cells is maintained in Vivo

    PubMed Central

    Dembinski, Jennifer L.; Krauss, Stefan

    2010-01-01

    Pancreatic adenocarcinoma has the worst prognosis of any major malignancy, with <5% of patients surviving five years. This can be contributed to the often late diagnosis, lack of sufficient treatment and metastatic spread. Heterogeneity within tumors is increasingly becoming a focus in cancer research, as novel therapies are required to target the most aggressive subpopulations of cells that are frequently termed cancer stem cells (CSCs). In the current study, we describe the identification of a slow-cycling cancer stem-like population of cells in vivo in BxPC-3 and Panc03.27 xenografts. A distinct slow-cycling label-retaining population of cells (DiI+/SCC) was found both at the edge of tumors, and in small circumscribed areas within the tumors. DiI+/SCC in these areas display an epithelial-to-mesenchymal transition (EMT) fingerprint, including an upregulation of the mesenchymal markers vimentin and N-cadherin and a loss of the epithelial marker E-cadherin. DiI+/SCC also displayed a critical re-localization of beta-catenin from the membrane to the nucleus. Additionally, the DiI+/SCC population was found to express the developmental signaling molecule sonic hedgehog. This study represents a novel step in defining the biological activities of a tumorigenic subpopulation within the heterogeneous tumor microenvironment in vivo. Understanding the interactions and functions of a CSC population within the context of the tumor microenvironment is critical to design targeted therapeutics. PMID:24281215

  16. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes

    PubMed Central

    Nielsen, Susan Searles; McKean-Cowdin, Roberta; Farin, Federico M.; Holly, Elizabeth A.; Preston-Martin, Susan; Mueller, Beth A.

    2010-01-01

    Background Insecticides that target the nervous system may play a role in the development of childhood brain tumors (CBTs). Constitutive genetic variation affects metabolism of these chemicals. Methods We analyzed population-based case–control data to examine whether CBT is associated with the functional genetic polymorphisms PON1C–108T, PON1Q192R, PON1L55M, BCHEA539T, FMO1C–9536A, FMO3E158K, ALDH3A1S134A, and GSTT1 (null). DNA was obtained from newborn screening archives for 201 cases and 285 controls, ≤ 10 years of age, and born in California or Washington State between 1978 and 1990. Conception-to-diagnosis home insecticide treatment history was ascertained by interview. Results We observed no biologically plausible main effects for any of the metabolic polymorphisms with CBT risk. However, we observed strong interactions between genotype and insecticide exposure during childhood. Among exposed children, CBT risk increased per PON1–108T allele [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.1–3.0] and FMO1–9536A (*6) allele (OR = 2.7; 95% CI, 1.2–5.9), whereas among children never exposed, CBT risk was not increased (PON1: OR = 0.7; 95% CI, 0.5–1.0, interaction p = 0.005; FMO1: OR = 1.0; 95% CI, 0.6–1.6, interaction p = 0.009). We observed a similar but statistically nonsignificant interaction between childhood exposure and BCHEA539T (interaction p = 0.08). These interactions were present among both Hispanic and non-Hispanic white children. Conclusion Based on known effects of these variants, these results suggest that exposure in childhood to organophosphorus and perhaps to carbamate insecticides in combination with a reduced ability to detoxify them may be associated with CBT. Confirmation in other studies is required. PMID:20056567

  17. Bufalin suppresses cancer stem-like cells in gemcitabine-resistant pancreatic cancer cells via Hedgehog signaling

    PubMed Central

    Wang, Haiyong; Ning, Zhouyu; Li, Yingyi; Zhu, Xiaoyan; Meng, Zhiqiang

    2016-01-01

    Cancer stem cells (CSCs) are important in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Agents with the ability to suppress CSCs are likely to provide novel opportunities for combating tumor proliferation and metastasis. The present study aimed to evaluate the effects of bufalin on pancreatic CSCs in vivo and in vitro. Using a serum-free suspension culture, tumor spheres were enriched in a gemcitabine-resistant human pancreatic cancer cell line, which had a higher percentage of CSCs, and western blotting, flow cytometry, and colony and tumor formation assays were used to demonstrate that these sphere cells exhibited CSC characteristics. Using these cancer stem-like cells as a model, the present study examined the effect of bufalin on pancreatic CSCs. It was demonstrated that bufalin inhibited the number of tumor spheres, and western blotting and immunohistochemical assays showed that the expression levels of CD24 and epithelial specific antigen (ESA) were downregulated by bufalin. Furthermore, in a subcutaneous xenograft model of implanted gemcitabine-resistant MiaPaCa2 cells, bufalin inhibited tumor growth and prolonged the duration of tumor formation. Additionally, the expression levels of CD24 and ESA were inhibited in the bufalin-treated mice. Notably, in another cancer model injected with tumor cells via the tail vein, fewer metastatic lesions were detected in the group in which tumor cells were pretreated with bufalin in vitro, compared with those without pretreatment. Of note, the Hedgehog (Hh) signaling pathway was found to be inhibited in the bufalin-treated cells. Taken together, these results suggested that bufalin suppressed pancreatic CSCs in gemcitabine-resistant MiaPaCa2 cells, and the Hh signaling pathway may be involved in this process. PMID:27432228

  18. Blood flow in an experimental rat brain tumor by tissue equilibration and indicator fractionation.

    PubMed

    Graham, M M; Spence, A M; Abbott, G L; O'Gorman, L; Muzi, M

    1987-01-01

    The tissue equilibration technique (Kety) was compared with the indicator fractionation technique for the measurement of blood flow to normal brain and an experimental brain tumor in the rat. The tumor was a cloned astrocytic glioma implanted in the cerebral hemisphere of F-344 rats. I-125 Iodoantipyrine, using a rising infusion for one minute, was used for the tissue equilibration technique. C-14 butanol, injected as a bolus 8 seconds before sacrifice, was used for the indicator fractionation technique. Samples were assayed using liquid scintillation counting and the iodoantipyrine results were regressed against the butanol results. For normal tissue R = 0.832, SEE = 0.115 ml/g/min, and Slope = 0.626. For tumor R = 0.796, SEE = 0.070 ml/g/min, and Slope = 0.441. The iodoantipyrine tissue/blood partition coefficient for normal hemisphere (gray and white matter) was 0.861 +/-0.037 (SD) and for tumor was 0.876 +/-0.042. The indicator fractionation technique with C-14 butanol underestimated blood flow in a consistent manner, probably because of incomplete extraction, early washout of activity from tissue and from evaporation of butanol during processing. Our experiments revealed no differences between tumor and normal brain tissue that might invalidate the comparison of iodoantipyrine blood flow results in brain tumors and surrounding normal brain.

  19. Support after Brain Tumor Means Different Things: Family Caregivers’ Experiences of Support and Relationship Changes

    PubMed Central

    Ownsworth, Tamara; Goadby, Elizabeth; Chambers, Suzanne Kathleen

    2015-01-01

    Shorter hospital stays and greater emphasis on outpatient care means that family members have the primary responsibility for supporting a person with brain tumor to manage the physical, cognitive, behavioral, and emotional effects of the illness and its treatment. Given the integral role of family caregivers, it is essential to understand their experience of the impact of brain tumor and their own support needs. Accordingly, this qualitative study aimed to investigate family caregivers’ experiences of support and relationship changes in the context of brain tumor. In-depth interviews were conducted with 11 family caregivers (8 spouse/partner, 3 parents) of people with malignant or benign tumor. A thematic analysis of interview transcripts identified two major themes, namely, “Meanings of Support” and “Relationship Impacts.” The Meanings of Support theme was characterized by intertwined and distinct support needs, varied expectations of support and factors influencing support expectations. The Relationship Impacts theme depicted mixed experiences of strengthened, maintained, and strained relations with the person with brain tumor. Overall, the findings highlight that there is considerable variability in caregivers’ experiences and expectations of support and the impact of brain tumor on relationships. The implications of these findings for the provision of caregiver support are discussed. PMID:25729740

  20. Biodistribution of ultra small gadolinium-based nanoparticles as theranostic agent: application to brain tumors.

    PubMed

    Miladi, Imen; Duc, Géraldine Le; Kryza, David; Berniard, Aurélie; Mowat, Pierre; Roux, Stéphane; Taleb, Jacqueline; Bonazza, Pauline; Perriat, Pascal; Lux, François; Tillement, Olivier; Billotey, Claire; Janier, Marc

    2013-09-01

    Gadolinium-based nanoparticles are novel objects with interesting physical properties, allowing their use for diagnostic and therapeutic applications. Gadolinium-based nanoparticles were imaged following intravenous injection in healthy rats and rats grafted with 9L gliosarcoma tumors using magnetic resonance imaging and scintigraphic imaging. Quantitative biodistribution using gamma-counting of each sampled organ confirmed that these nanoparticles were rapidly cleared essentially by renal excretion. Accumulation of these nanoparticles in 9L gliosarcoma tumors implanted in the rat brain was quantitated. This passive and long-duration accumulation of gadolinium-based nanoparticles in tumor, which is related to disruption of the blood-brain barrier, is in good agreement with the use of these nanoparticles as radiosensitizers for brain tumors.

  1. Postoperative Stereotactic Radiosurgery Without Whole-Brain Radiation Therapy for Brain Metastases: Potential Role of Preoperative Tumor Size

    SciTech Connect

    Hartford, Alan C.; Paravati, Anthony J.; Spire, William J.; Li, Zhongze; Jarvis, Lesley A.; Fadul, Camilo E.; Erkmen, Kadir; Friedman, Jonathan; Gladstone, David J.; Hug, Eugen B.; Roberts, David W.; Simmons, Nathan E.

    2013-03-01

    Purpose: Radiation therapy following resection of a brain metastasis increases the probability of disease control at the surgical site. We analyzed our experience with postoperative stereotactic radiosurgery (SRS) as an alternative to whole-brain radiotherapy (WBRT), with an emphasis on identifying factors that might predict intracranial disease control and overall survival (OS). Methods and Materials: We retrospectively reviewed all patients through December 2008, who, after surgical resection, underwent SRS to the tumor bed, deferring WBRT. Multiple factors were analyzed for time to intracranial recurrence (ICR), whether local recurrence (LR) at the surgical bed or “distant” recurrence (DR) in the brain, for time to WBRT, and for OS. Results: A total of 49 lesions in 47 patients were treated with postoperative SRS. With median follow-up of 9.3 months (range, 1.1-61.4 months), local control rates at the resection cavity were 85.5% at 1 year and 66.9% at 2 years. OS rates at 1 and 2 years were 52.5% and 31.7%, respectively. On univariate analysis (preoperative) tumors larger than 3.0 cm exhibited a significantly shorter time to LR. At a cutoff of 2.0 cm, larger tumors resulted in significantly shorter times not only for LR but also for DR, ICR, and salvage WBRT. While multivariate Cox regressions showed preoperative size to be significant for times to DR, ICR, and WBRT, in similar multivariate analysis for OS, only the graded prognostic assessment proved to be significant. However, the number of intracranial metastases at presentation was not significantly associated with OS nor with other outcome variables. Conclusions: Larger tumor size was associated with shorter time to recurrence and with shorter time to salvage WBRT; however, larger tumors were not associated with decrements in OS, suggesting successful salvage. SRS to the tumor bed without WBRT is an effective treatment for resected brain metastases, achieving local control particularly for tumors up to

  2. Distribution of anionic sites on the capillary endothelium in an experimental brain tumor model.

    PubMed

    Vincent, S; DePace, D; Finkelstein, S

    1988-02-01

    The distribution of anionic domains on the capillary endothelium of experimental brain tumors was determined using cationic ferritin (CF) in order to ascertain whether the pattern of these domains is different from that on normal cerebral capillaries. Tumors were induced by stereotaxic injection of cultured neoplastic glial cells, A15A5, into the caudate nucleus of Sprague-Dawley rats. Following a 14-21 day growth period tumors appeared as vascularized, sharply circumscribed masses which caused compression of the surrounding brain tissue. Anionic domains were distributed in a patchy and irregular pattern on the luminal plasma membrane of the endothelia of blood vessels in the tumors. Some variability in this pattern was observed infrequently in limited regions of the tumor where there was either a continuous layer of CF or an absence of CF binding. Plasmalemmal vesicles, coated vesicles, coated pits, multivesicular bodies, and some junctional complexes showed varying degrees of labeling with the probe. Capillaries in the tumor periphery and normal cerebral vessels showed a uniform distribution of anionic groups. These results indicate that there is an altered surface charge on the endothelial luminal plasma membrane of blood vessels in brain tumors. A correlation may exist between the altered surface charge and the degree to which the blood-brain barrier is impaired in these vessels.

  3. Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

    PubMed Central

    Mulcahy Levy, Jean M; Zahedi, Shadi; Griesinger, Andrea M; Morin, Andrew; Davies, Kurtis D; Aisner, Dara L; Kleinschmidt-DeMasters, BK; Fitzwalter, Brent E; Goodall, Megan L; Thorburn, Jacqueline; Amani, Vladimir; Donson, Andrew M; Birks, Diane K; Mirsky, David M; Hankinson, Todd C; Handler, Michael H; Green, Adam L; Vibhakar, Rajeev; Foreman, Nicholas K; Thorburn, Andrew

    2017-01-01

    Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors. DOI: http://dx.doi.org/10.7554/eLife.19671.001 PMID:28094001

  4. Differentiating histologic malignancy of primary brain tumors: Pentavalent Technetium-99m-DMSA

    SciTech Connect

    Hirano, Tsuneo; Otake, Hidenori; Shibasaki, Takashi

    1997-01-01

    This study assessed pentavalent {sup 99m}Tc-DMSA uptake in primary brain tumors and evaluated the relationship between retention and histologic malignancy. SPECT images of the brain were obtained at 30 min and 3 hr after intravenous administration of approximately 555 MBq {sup 99m}Tc(V)-DMSA in patients with brain tumors. Sixty studies were performed in 57 patients and 63 lesions were demonstrated: 11 glioblastomas, 13 anaplastic astrocytomas (Grade 3), 11 astrocytomas (Grade 2), 18 meningiomas and 10 schwannomas. Uptake ratios, retention ratio and retention index were calculated and compared with tumor histology and malignancy grade. Approximately 95% of both benign and malignant primary brain tumors were demonstrated by {sup 99m}Tc(V)-DMSA SPECT images. False negative was noted in three cases. The early uptake ratios were closely related to the tumor vascularity but had no statistically significant difference in the tumor vascularity but had no statistically significant difference in the tumor histology or histologic malignancy. 16 refs., 6 figs., 2 tabs.

  5. Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth.

    PubMed

    Orr, Brent A; Bai, Haibo; Odia, Yazmin; Jain, Deepali; Anders, Robert A; Eberhart, Charles G

    2011-07-01

    The hippo pathway and its downstream mediator yes-associated protein 1 (YAP1) regulate mammalian organ size in part through modulating progenitor cell numbers. YAP1 has also been implicated as an oncogene in multiple human cancers. Currently, little is known about the expression of YAP1 either in normal human brain tissue or in central nervous system neoplasms. We used immunohistochemistry to evaluate nuclear YAP1 expression in the fetal and normal adult human brains and in 264 brain tumors. YAP1 was expressed in fetal and adult brain regions known to harbor neural progenitor cells, but there was little YAP1 immunoreactivity in the adult cerebral cortex. YAP1 protein was also readily detected in the nuclei of human brain tumors. In medulloblastoma, the expression varied between histologic subtypes and was most prominent in nodular/desmoplastic tumors. In gliomas, it was frequently expressed in infiltrating astrocytomas and oligodendrogliomas but rarely in pilocytic astrocytomas. Using a loss-of-function approach, we show that YAP1 promoted growth of glioblastoma cell lines in vitro. High levels of YAP1 messenger RNA expression were associated with aggressive molecular subsets of glioblastoma and with a nonsignificant trend toward reduced mean survival in human astrocytoma patients. These findings suggest that YAP1 may play an important role in normal human brain development and that it could represent a new target in human brain tumors.

  6. Neovascularization and tumor growth in the rabbit brain. A model for experimental studies of angiogenesis and the blood-brain barrier.

    PubMed Central

    Zagzag, D.; Brem, S.; Robert, F.

    1988-01-01

    A model for the study of tumor angiogenesis within the rabbit brain is presented. Implantation of the VX2 carcinoma provides a reproducible tumor accompanied by angiogenesis. The authors report the sequential growth, histology, tumor neovascularization, and vascular permeability of this tumor following its intracerebral implantation. Tumor angiogenesis correlates with the rapid and logarithmic intracerebral tumor growth. The proliferation of blood vessels in the tumor and the organization of tumor cells around tumor vessels are described. Breakdown of the blood-brain barrier (detected by Evans blue leakage) starts in the early stages of tumor development and becomes prominent as the tumor vasculature and size increase. This model is useful for experimental studies of angiogenesis. Images Figure 2 Figure 3 Figure 6 Figure 4 Figure 5 Figure 7 Figure 8 Figure 10 Figure 12 Figure 13 Figure 15 PMID:2451889

  7. A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

    PubMed Central

    Xu, Hui; Li, Zhongyu; Yu, Yue; Sizdahkhani, Saman; Ho, Winson S.; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Zhuang, Zhengping; Qin, Jianhua

    2016-01-01

    The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes–permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research. PMID:27830712

  8. A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

    NASA Astrophysics Data System (ADS)

    Xu, Hui; Li, Zhongyu; Yu, Yue; Sizdahkhani, Saman; Ho, Winson S.; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Zhuang, Zhengping; Qin, Jianhua

    2016-11-01

    The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes–permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

  9. Effect of barrier opening on brain edema in human brain tumors.

    PubMed

    Sato, S; Suga, S; Yunoki, K; Mihara, B

    1994-01-01

    Blood-brain barrier (BBB) opening was carried out in 10 patients with cerebral lesions, and the MRI findings were evaluated following the barrier opening. An intra-arterial injection of 10% glycerol (4 ml/kg, 1 approximately 2 ml/s) was given as a hyperosmotic solution. T2-weighted MRI was undertaken using a TOSHIBA 22A at 30 minutes after BBB opening. Barrier-opening MRI was performed 10 times in 10 patients, including 5 cases of glioblastoma multiforme, 2 cases of astrocytoma, 1 case of malignant lymphoma, 1 case of cerebral contusion and 1 case of neurinoma. The high-intensity area (HIA) was compared with that in MRI without barrier opening. Three types of changes of HIA in MRI were observed after BBB opening as follows. Type 1: Expansion of the HIA was noted in 4 of 5 cases of glioblastoma multiforme, the 1 case of malignant lymphoma and the 1 case of cerebral contusion. Type 2: Almost no change was observed in the 1 case of neuronoma. Type 3: A decrease in HIA was noted in the 2 cases of astrocytoma and in 1 case of glioblastoma multiforme. The MRI following BBB opening evidently showed 3 types of changes according to the degree of BBB disruption. Glioblastoma multiforme or contusion with a severely disrupted BBB revealed an increase in HIA following barrier opening. Benign posterior fossa neurinoma showed no change in HIA after barrier opening. Moderate malignant tumors exhibited a decrease in HIA on barrier-opening MRI. It was concluded that malignant tumors have a severely damaged BBB, which is readily disrupted by osmotic barrier opening.

  10. Dimethyl sulfoxide (DMSO) as a potential contrast agent for brain tumors.

    PubMed

    Delgado-Goñi, T; Martín-Sitjar, J; Simões, R V; Acosta, M; Lope-Piedrafita, S; Arús, C

    2013-02-01

    Dimethyl sulfoxide (DMSO) is commonly used in preclinical studies of animal models of high-grade glioma as a solvent for chemotherapeutic agents. A strong DMSO signal was detected by single-voxel MRS in the brain of three C57BL/6 control mice during a pilot study of DMSO tolerance after intragastric administration. This led us to investigate the accumulation and wash-out kinetics of DMSO in both normal brain parenchyma (n=3 control mice) by single-voxel MRS, and in 12 GL261 glioblastomas (GBMs) by single-voxel MRS (n=3) and MRSI (n=9). DMSO accumulated differently in each tissue type, reaching its highest concentration in tumors: 6.18 ± 0.85 µmol/g water, 1.5-fold higher than in control mouse brain (p<0.05). A faster wash-out was detected in normal brain parenchyma with respect to GBM tissue: half-lives of 2.06 ± 0.58 and 4.57 ± 1.15 h, respectively. MRSI maps of time-course DMSO changes revealed clear hotspots of differential spatial accumulation in GL261 tumors. Additional MRSI studies with four mice bearing oligodendrogliomas (ODs) revealed similar results as in GBM tumors. The lack of T(1) contrast enhancement post-gadolinium (gadopentetate dimeglumine, Gd-DTPA) in control mouse brain and mice with ODs suggested that DMSO was fully able to cross the intact blood-brain barrier in both normal brain parenchyma and in low-grade tumors. Our results indicate a potential role for DMSO as a contrast agent for brain tumor detection, even in those tumors 'invisible' to standard gadolinium-enhanced MRI, and possibly for monitoring heterogeneities associated with progression or with therapeutic response.

  11. Absorption edge subtraction imaging for volumetric measurement in an animal model of malignant brain tumor

    NASA Astrophysics Data System (ADS)

    Rigley, S.; Rigon, L.; Ataelmannan, K.; Chapman, D.; Doucette, R.; Griebel, R.; Juurlink, B.; Arfelli, F.; Menk, R.-H.; Tromba, G.; Barroso, R. C.; Beveridge, T.; Lewis, R.; Pavlov, K.; Siu, K.; Hall, C.; Schültke, E.

    2005-08-01

    The goal of this project is to determine the feasibility of utilizing colloidal gold as a marker for C6 glioblastoma cells implanted into rat brain as an appropriate model for volumetric measurements of tumors using absorption edge subtraction (AES). Phase sensitive X-ray imaging is combined with KES to give good soft tissue contrast. Current methods for volumetric measurements of implanted C6 glioblastoma tumors in rat brains using MRI technology are inadequate due to the small size of the tumor (2.5-4 mm in diameter) and the thickness of the MRI slice (1-1.5 mm). Previously, our group has shown that AES detection of colloidal gold labeled C6 glioblastoma cells implanted into a rat brains may be feasible. The long-term goal for this project is to establish a method, which would allow the researcher to monitor the development of a tumor over time. Most importantly, this technique should allow researchers to accurately determine the potency of a treatment on the size and growth rate for a C6 implanted tumors. In addition, we plan to challenge the hypothesis that tumors of the glioma type do not metastasize outside of the brain. A sensitive technique for the detection of C6 cells, such as that using colloidal gold and AES/DEI, should enable researchers to detect C6 cells, which have metastasized and migrated to different areas of the body. The ability to detect implanted C6 cells followed by the development of the tumor, the possible migration of the cells and the ability to accurately measure the effects of treatments on the volume of the tumor would be of the utmost importance to brain tumor research.

  12. Autocrine interleukin-23 promotes self-renewal of CD133+ ovarian cancer stem-like cells

    PubMed Central

    Lin, Kailong; Yin, Pin; Jiang, Lupin; Liang, Zhiqing; Zhu, Bo

    2016-01-01

    Cancer stem cells (CSCs) are a group of cells which possess the ability of self-renewing and unlimited proliferation. And these CSCs are thought to be the cause of metastasis, recurrence and resistance. Recent study has found that pro-inflammatory cytokine and chemotactic factor mediate the self-renewing and differentiation of most of CSCs. Thus we speculate that ovarian cancer stem cells (OCSCs) can also maintain the ability of self-renewing and differentiation by releasing inflammatory factor. This report we discuss the biological characteristics and the specific molecular mechanism mediated by interleukin-23 (IL-23) and its receptor on the self-renewing of OCSCs. We found that OCSCs had high expression of IL-23 and IL-23R. IL-23 could promote the self-renewal ability of OCSCs and played a very important role to maintain the stable expression of stem cell markers in vitro. Moreover, we verified that IL-23 could maintain the potential tumorigenic of OCSCs in vivo and mediate the self-renewal ability and the formation of tumor in OCSCs by activating the signal pathways of STAT3 and NF-κB. In addition, human low differentiation tissues showed overexpression of IL-23. And IL-23 positively correlated to the expression level of CD133, Nanog and Oct4. In conclusion, Our discoveries demonstrate that autocrine IL-23 contribute to ovarian cancer malignancy through promoting the self-renewal of CD133+ ovarian cancer stem-like cells, and this suggests that IL-23 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer. PMID:27738346

  13. Calreticulin is highly expressed in pancreatic cancer stem-like cells.

    PubMed

    Matsukuma, Satoshi; Yoshimura, Kiyoshi; Ueno, Tomio; Oga, Atsunori; Inoue, Moeko; Watanabe, Yusaku; Kuramasu, Atsuo; Fuse, Masanori; Tsunedomi, Ryouichi; Nagaoka, Satoshi; Eguchi, Hidetoshi; Matsui, Hiroto; Shindo, Yoshitaro; Maeda, Noriko; Tokuhisa, Yoshihiro; Kawano, Reo; Furuya-Kondo, Tomoko; Itoh, Hiroshi; Yoshino, Shigefumi; Hazama, Shoichi; Oka, Masaaki; Nagano, Hiroaki

    2016-11-01

    Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). A P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by 2-D electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis indicated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in the CRT(high) /CD44v9(low) population was much higher than that in the CRT(low) /CD44v9(high) population. Calreticulin expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and postoperative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.

  14. DC120, a novel AKT inhibitor, preferentially suppresses nasopharyngeal carcinoma cancer stem-like cells by downregulating Sox2

    PubMed Central

    Tang, Jun; Yang, Fen; Feng, Gong-Kan; Chen, Wen-Dan; Wu, Xiao-Qi; Qian, Xiao-Jun; Ding, Ke; Zhu, Xiao-Feng

    2015-01-01

    Side population (SP) contains cancer stem-like cells (CSLCs). In this study, we characterized SP cells from nasopharyngeal carcinoma (NPC) cell lines and found that SP cells had a higher self-renewal ability in vitro and greater tumorigenicity in vivo. The AKT pathway was activated in NPC SP cells. DC120, a 2-pyrimidyl-5-amidothiazole inhibitor of the ATP binding site of AKT, inhibited phosphorylation of FKHRL1 and GSK-3β. DC120 inhibited SP fraction, the sphere-forming ability in vitro and growth of primary xenografts as well as secondary xenografts’ tumor recurrence. This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a. A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo. Clinical evaluation of DC120 is warranted. PMID:25749514

  15. Noninvasive method of immortalized neural stem-like cell transplantation in an experimental model of Huntington's disease.

    PubMed

    Lee, Soon-Tae; Park, Jung-Eun; Lee, Kyungmi; Kang, Lami; Chu, Kon; Kim, Seung U; Kim, Manho; Roh, Jae-Kyu

    2006-04-15

    A loss of neostriatal neurons is a characteristic of Huntington's disease (HD), and neural tissue transplantation has been performed directly into the striatum. Since the neural stem cells have ability to migrate into the lesion site, we administered immortalized neural stem-like cells (NSC) into the ventricle or via a tail vein following unilateral intrastriatal quinolinic acid lesioning in Sprague-Dawley rats. To identify transplanted NSC, cells were encoded with lac Z and beta-galactosidase histochemistry was performed. lac Z+ cells were detected in the lesioned striatum but tissue damage or tumor formation was not observed. This study shows that NSC migrate into the striatum, either from ventricle or from the systemic circulation, providing less invasive routes for stem cell application in HD.

  16. Inflammatory infiltrates and natural killer cell presence in human brain tumors.

    PubMed

    Stevens, A; Klöter, I; Roggendorf, W

    1988-02-15

    Immunohistochemical analysis of subpopulations of inflammatory cells in 81 primary and secondary human brain tumors was done. Natural killer (NK) cells, representing non-major histocompatibility complex-restricted, spontaneous cytotoxicity and monocytic cells are virtually absent in infiltrates of gliomas and account only for a minor percentage of inflammatory cells in brain metastases of carcinoma and in craniopharyngeomas. Infiltrates in gliomas consist almost exclusively of T-cells of the suppressor/cytotoxic type whereas infiltrates in carcinoma metastases and craniopharyngeomas contain considerable numbers of T-helper/inducer cells and B-cells. From this the authors conclude (1) that NK cells do not play a major role in tumor rejection, and (2) that the kind of inflammatory reaction does not depend upon the tumor site but more likely on the tumor type. No correlation between tumor differentiation and infiltrate composition is evident.

  17. Novel polyomavirus associated with brain tumors in free-ranging raccoons, western United States.

    PubMed

    Dela Cruz, Florante N; Giannitti, Federico; Li, Linlin; Woods, Leslie W; Del Valle, Luis; Delwart, Eric; Pesavento, Patricia A

    2013-01-01

    Tumors of any type are exceedingly rare in raccoons. High-grade brain tumors, consistently located in the frontal lobes and olfactory tracts, were detected in 10 raccoons during March 2010-May 2012 in California and Oregon, suggesting an emerging, infectious origin. We have identified a candidate etiologic agent, dubbed raccoon polyomavirus, that was present in the tumor tissue of all affected animals but not in tissues from 20 unaffected animals. Southern blot hybridization and rolling circle amplification showed the episomal viral genome in the tumors. The multifunctional nuclear protein large T-antigen was detectable by immunohistochemical analyses in a subset of neoplastic cells. Raccoon polyomavirus may contribute to the development of malignant brain tumors of raccoons.

  18. Notch1 and notch2 have opposite effects on embryonal brain tumor growth.

    PubMed

    Fan, Xing; Mikolaenko, Irina; Elhassan, Ihab; Ni, Xingzhi; Wang, Yunyue; Ball, Douglas; Brat, Daniel J; Perry, Arie; Eberhart, Charles G

    2004-11-01

    The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P = 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.

  19. Imaging diagnosis and fundamental knowledge of common brain tumors in adults.

    PubMed

    Tanaka, Akio

    2006-07-01

    The most common primary brain tumors in Japanese adults are meningiomas, gliomas, pituitary adenomas, and schwannomas, which together account for 84.0% of all primary brain tumors. The typical imaging findings of these tumors are well known by radiologists; therefore, the clinical and pathological issues, including terminology, genetics, and relation to hormones are discussed in this article. Other diseases important for the differential diagnoses are also mentioned. The molecular genetic analysis of brain tumors has recently become important. For instance, genetic analysis is important for differentiating oligodendroglial tumors from astrocytic tumors, and the gene mutation predicts response to chemotherapy for anaplastic oligodendrogliomas. Background factors such as hormones, history of cranial irradiation, and medications influence oncogenesis, tumor growth, and tumor appearances as seen by imaging modalities. A differential diagnosis with knowledge of the above may have some advantages over diagnoses based on imaging findings alone. Nonneoplastic diseases such as abscesses and demyelinating diseases may mimic gliomas. Pituitary adenomas may be confused with nonneoplastic conditions such as physiological hypertrophy and Rathke's cleft cyst. Such misdiagnoses would result in a treatment protocol very different from what would be suitable. Such conditions should be carefully distinguished from neoplasms.

  20. Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites?

    PubMed Central

    Dutoit, Valérie; Migliorini, Denis; Dietrich, Pierre-Yves; Walker, Paul R.

    2016-01-01

    Immunotherapy is now advancing at remarkable pace for tumors located in various tissues, including the brain. Strategies launched decades ago, such as tumor antigen-specific therapeutic vaccines and adoptive transfer of tumor-infiltrating lymphocytes are being complemented by molecular engineering approaches allowing the development of tumor-specific TCR transgenic and chimeric antigen receptor T cells. In addition, the spectacular results obtained in the last years with immune checkpoint inhibitors are transfiguring immunotherapy, these agents being used both as single molecules, but also in combination with other immunotherapeutic modalities. Implementation of these various strategies is ongoing for more and more malignancies, including tumors located in the brain, raising the question of the immunological particularities of this site. This may necessitate cautious selection of tumor antigens, minimizing the immunosuppressive environment and promoting efficient T cell trafficking to the tumor. Once these aspects are taken into account, we might efficiently design immunotherapy for patients suffering from tumors located in the brain, with beneficial clinical outcome. PMID:28003994

  1. Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide

    PubMed Central

    Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

    2014-01-01

    Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

  2. Characterization of sphere-forming cells with stem-like properties from the small cell lung cancer cell line H446.

    PubMed

    Qiu, Xiaofei; Wang, Zhengyan; Li, Yanlei; Miao, Yajing; Ren, Yu; Luan, Yajing

    2012-10-28

    A relatively novel paradigm in tumor biology hypothesizes that cancer growth is driven by tumor cells with stem-like properties. However, direct proof of a population of stem cells in small cell lung cancer (SCLC) remains elusive. In this study, we enriched for stem-like cells from the SCLC cell line H446 by growing them as spheres in a defined serum-free medium. Sphere-derived cells have increased in vitro clonogenic and in vivo tumorigenic potentials as well as drug-resistant properties. After enrichment for stem-like cells, we used multiple candidate stem cell markers to examine the expression profile and found that the sphere-derived cells contained a higher proportion of cells expressing the stem cell surface markers uPAR and CD133 when compared with parental cells. To identify a selectable marker for the sphere-forming cells, we evaluated the sphere-forming abilities of uPAR(+) and uPAR(-) cells as well as the sphere-forming abilities of CD133(+) and CD133(-) cells. Both CD133(+) and CD133(-) cell fractions were capable of forming spheres, and no statistically significant difference was observed in the sphere-forming efficiency between these two populations. In contrast, cells derived from the uPAR(+) fraction were capable of forming spheres, whereas cells derived from the uPAR(-) fraction remained as single cells. Moreover, uPAR(+) cells efficiently formed transplantable tumors, whereas uPAR(-) cells were unable to initiate tumors when transplanted at equivalent cell numbers. In addition, uPAR(+) cells could differentiate into CD56(+)cells, CK(+) cells, and uPAR(-) cells. These data support the existence of a population of tumor sphere-forming cells with stem cell properties in the H446 SCLC cell line. Furthermore, the stem cell population may be enriched in cells expressing the uPAR cell surface marker.

  3. Beauty product-related exposures and childhood brain tumors in seven countries: results from the SEARCH International Brain Tumor Study.

    PubMed

    Efird, J T; Holly, E A; Cordier, S; Mueller, B A; Lubin, F; Filippini, G; Peris-Bonet, R; McCredie, M; Arslan, A; Bracci, P; Preston-Martin, S

    2005-04-01

    Data from 1218 cases of childhood brain tumors (CBT) diagnosed between 1976 and 1994 and 2223 matched controls from the general population were included in an analysis of maternal beauty product exposure and beauty-related employment in 9 centers in 7 countries. A 50% increased odds ratio (OR) [95% confidence interval (CI) = 1.0-2.1] for CBT was observed among children of mothers who were exposed via personal use of and/or possible ambient contact with beauty products during the 5 years preceding the index child's birth compared with children of mothers never exposed to beauty products during this time period. Overall maternal personal use of hair-coloring agents in the month before or during the pregnancy of the index child's birth was not associated with CBT (OR = 1.0, CI = 0.83-1.3) or with astroglial (OR = 1.1, CI = 0.85-1.4), PNET (OR = 1.0, CI = 0.71-1.5) and other glial subtypes (OR = 1.0, CI = 0.62-1.0). Similarly, no statistically increased ORs or discernable pattern of risk estimates were observed for period of use or for number of applications per year for maternal personal use of hair-coloring agents overall or by histologic type. Among children born on or after 1980, increased ORs for CBT were associated with maternal non-work-related exposure to any beauty products (OR = 2.6, CI = 1.2-5.9), hair-dyes (OR = 11, CI = 1.2-90), and hair sprays (OR = 3.4, CI = 1.0-11). No overall increased OR for CBT was observed among children of mothers employed in beauty-related jobs during the 5 years preceding the index child's birth compared with those who reported no beauty-related employment. In general, other specific beauty product-related exposures were not associated with increased ORs for CBT. Data from our study provide little evidence of an increased risk for CBT with mothers' exposures to beauty products.

  4. High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant.

    PubMed

    Farnie, Gillian; Sotgia, Federica; Lisanti, Michael P

    2015-10-13

    Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic breast cancer patient samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as aldehyde dehydrogenase (ALDH) activity, and they were ESA+/CD24-/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2-fold increase in mitochondrial mass in large cells (>12-μm), relative to the smaller cell population (4-8-μm). Moreover, the mito-high cell population showed a 2.4-fold enrichment in tumor-initiating cell activity, based on limiting dilution assays in murine xenografts. Importantly, primary human breast CSCs isolated from patients with metastatic breast cancer or a patient derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to paclitaxel, resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub-population of breast cancer cells confers a stem-like phenotype and chemo-resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population.

  5. In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells

    PubMed Central

    McKenzie, Brienne A.; Zemp, Franz J.; Pisklakova, Alexandra; Narendran, Aru; McFadden, Grant; Lun, Xueqing; Kenchappa, Rajappa S.; Kurz, Ebba U.; Forsyth, Peter A.

    2015-01-01

    Background Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy. Methods A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed. Results Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro. Conclusions This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model. PMID:25605818

  6. Anti-Cancer Stem-like Cell Compounds in Clinical Development – An Overview and Critical Appraisal

    PubMed Central

    Marcucci, Fabrizio; Rumio, Cristiano; Lefoulon, François

    2016-01-01

    Cancer stem-like cells (CSC) represent a subpopulation of tumor cells with elevated tumor-initiating potential. Upon differentiation, they replenish the bulk of the tumor cell population. Enhanced tumor-forming capacity, resistance to antitumor drugs, and metastasis-forming potential are the hallmark traits of CSCs. Given these properties, it is not surprising that CSCs have become a therapeutic target of prime interest in drug discovery. In fact, over the last few years, an enormous number of articles describing compounds endowed with anti-CSC activities have been published. In the meanwhile, several of these compounds and also approaches that are not based on the use of pharmacologically active compounds (e.g., vaccination, radiotherapy) have progressed into clinical studies. This article gives an overview of these compounds, proposes a tentative classification, and describes their biological properties and their developmental stage. Eventually, we discuss the optimal clinical setting for these compounds, the need for biomarkers allowing patient selection, the redundancy of CSC signaling pathways and the utility of employing combinations of anti-CSC compounds and the therapeutic limitations posed by the plasticity of CSCs. PMID:27242955

  7. Failed First Craniotomy and Tumor Removal of Parasagittal Meningioma with Severe Peritumoral Brain Edema

    PubMed Central

    Shim, Youngbo

    2016-01-01

    Parasagittal meningioma often presents as peritumoral brain edema (PTBE). The risk of edema increases when the tumor occludes the superior sagittal sinus (SSS). Although PTBE may be expected based on the patient’s symptoms or radiologic findings, extensive brain swelling and extracranial herniation during elective surgery are rare. Herniation during surgery could lead to irreversible neurological damage and even brain rupture. We report a case of a failed routine craniotomy for a parasagittal meningioma with complete occlusion of the posterior third of the SSS in a 30-year-old male patient. The patient developed extensive brain swelling and extracranial herniation during surgery. PMID:27867923

  8. Epidemiology of primary brain tumors: current concepts and review of the literature.

    PubMed Central

    Wrensch, Margaret; Minn, Yuriko; Chew, Terri; Bondy, Melissa; Berger, Mitchel S.

    2002-01-01

    The purpose of this review is to provide a sufficiently detailed perspective on epidemiologic studies of primary brain tumors to encourage multidisciplinary etiologic and prognostic studies among surgeons, neuro-oncologists, epidemiologists, and molecular scientists. Molecular tumor markers that predict survival and treatment response are being identified with hope of even greater gains in this area from emerging array technologies. Regarding risk factors, studies of inherited susceptibility and constitutive polymorphisms in genes pertinent to carcinogenesis (for example, DNA repair and detoxification genes and mutagen sensitivity) have revealed provocative findings. Inverse associations of the history of allergies with glioma risk observed in 3 large studies and reports of inverse associations of glioma with common infections suggest a possible role of immune factors in glioma genesis or progression. Studies continue to suggest that brain tumors might result from workplace, dietary, and other personal and residential exposures, but studies of cell phone use and power frequency electromagnetic fields have found little to support a causal connection with brain tumors; caveats remain. The only proven causes of brain tumors (that is, rare hereditary syndromes, therapeutic radiation, and immune suppression giving rise to brain lymphomas) account for a small proportion of cases. Progress in understanding primary brain tumors might result from studies of well-defined histologic and molecular tumor types incorporating assessment of potentially relevant information on subject susceptibility and environmental and noninherited endogenous factors (viruses, radiation, and carcinogenic or protective chemical exposures through diet, workplace, oxidative metabolism, or other sources). Such studies will require the cooperation of researchers from many disciplines. PMID:12356358

  9. Intraoperative Spectroscopy with Ultrahigh Sensitivity for Image-Guided Surgery of Malignant Brain Tumors.

    PubMed

    Kairdolf, Brad A; Bouras, Alexandros; Kaluzova, Milota; Sharma, Abhinav K; Wang, May Dongmei; Hadjipanayis, Constantinos G; Nie, Shuming

    2016-01-05

    Intraoperative cancer imaging and fluorescence-guided surgery have attracted considerable interest because fluorescence signals can provide real-time guidance to assist a surgeon in differentiating cancerous and normal tissues. Recent advances have led to the clinical use of a natural fluorophore called protoporphyrin IX (PpIX) for image-guided surgical resection of high-grade brain tumors (glioblastomas). However, traditional fluorescence imaging methods have only limited detection sensitivity and identification accuracy and are unable to detect low-grade or diffuse infiltrating gliomas (DIGs). Here we report a low-cost hand-held spectroscopic device that is capable of ultrasensitive detection of protoporphyrin IX fluorescence in vivo, together with intraoperative spectroscopic data obtained from both animal xenografts and human brain tumor specimens. The results indicate that intraoperative spectroscopy is at least 3 orders of magnitude more sensitive than the current surgical microscopes, allowing ultrasensitive detection of as few as 1000 tumor cells. For detection specificity, intraoperative spectroscopy allows the differentiation of brain tumor cells from normal brain cells with a contrast signal ratio over 100. In vivo animal studies reveal that protoporphyrin IX fluorescence is strongly correlated with both MRI and histological staining, confirming that the fluorescence signals are highly specific to tumor cells. Furthermore, ex vivo spectroscopic studies of excised brain tissues demonstrate that the hand-held spectroscopic device is capable of detecting diffuse tumor margins with low fluorescence contrast that are not detectable with current systems in the operating room. These results open new opportunities for intraoperative detection and fluorescence-guided resection of microscopic and low-grade glioma brain tumors with invasive or diffusive margins.

  10. Enhanced transfection of brain tumor suppressor genes by photochemical internalization

    NASA Astrophysics Data System (ADS)

    Chou, Chih H.; Sun, Chung-Ho; Zhou, Yi-Hong; Madsen, Steen J.; Hirschberg, Henry

    2011-03-01

    One of many limitations for cancer gene therapy is the inability of the therapeutic gene to transfect a sufficient number of tumor cells. Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. The utility of PCI for the delivery of a tumor suppressor gene (PAX-6) was investigated in monolayers and spheroids consisting of F98 rat glioma cells.

  11. 3D variational brain tumor segmentation on a clustered feature set

    NASA Astrophysics Data System (ADS)

    Popuri, Karteek; Cobzas, Dana; Jagersand, Martin; Shah, Sirish L.; Murtha, Albert

    2009-02-01

    Tumor segmentation from MRI data is a particularly challenging and time consuming task. Tumors have a large diversity in shape and appearance with intensities overlapping the normal brain tissues. In addition, an expanding tumor can also deflect and deform nearby tissue. Our work addresses these last two difficult problems. We use the available MRI modalities (T1, T1c, T2) and their texture characteristics to construct a multi-dimensional feature set. Further, we extract clusters which provide a compact representation of the essential information in these features. The main idea in this paper is to incorporate these clustered features into the 3D variational segmentation framework. In contrast to the previous variational approaches, we propose a segmentation method that evolves the contour in a supervised fashion. The segmentation boundary is driven by the learned inside and outside region voxel probabilities in the cluster space. We incorporate prior knowledge about the normal brain tissue appearance, during the estimation of these region statistics. In particular, we use a Dirichlet prior that discourages the clusters in the ventricles to be in the tumor and hence better disambiguate the tumor from brain tissue. We show the performance of our method on real MRI scans. The experimental dataset includes MRI scans, from patients with difficult instances, with tumors that are inhomogeneous in appearance, small in size and in proximity to the major structures in the brain. Our method shows good results on these test cases.

  12. Radiation necrosis in the brain: imaging features and differentiation from tumor recurrence.

    PubMed

    Shah, Ritu; Vattoth, Surjith; Jacob, Rojymon; Manzil, Fathima Fijula Palot; O'Malley, Janis P; Borghei, Peyman; Patel, Bhavik N; Curé, Joel K

    2012-01-01

    Radiation necrosis in the brain commonly occurs in three distinct clinical scenarios, namely, radiation therapy for head and neck malignancy or intracranial extraaxial tumor, stereotactic radiation therapy (including radiosurgery) for brain metastasis, and radiation therapy for primary brain tumors. Knowledge of the radiation treatment plan, amount of brain tissue included in the radiation port, type of radiation, location of the primary malignancy, and amount of time elapsed since radiation therapy is extremely important in determining whether the imaging abnormality represents radiation necrosis or recurrent tumor. Conventional magnetic resonance (MR) imaging findings of these two entities overlap considerably, and even at histopathologic analysis, tumor mixed with radiation necrosis is a common finding. Advanced imaging modalities such as diffusion tensor imaging and perfusion MR imaging (with calculation of certain specific parameters such as apparent diffusion coefficient ratios, relative peak height, and percentage of signal recovery), MR spectroscopy, and positron emission tomography can be useful in differentiating between recurrent tumor and radiation necrosis. In everyday practice, the visual assessment of diffusion-weighted and perfusion images may also be helpful by favoring one diagnosis over the other, with restricted diffusion and an elevated relative cerebral blood volume being seen much more frequently in recurrent tumor than in radiation necrosis.

  13. Numerical modelling and in vivo analysis of fluorescent and laser light backscattered from glial brain tumors

    NASA Astrophysics Data System (ADS)

    Savelieva, Tatiana A.; Kalyagina, Nina A.; Kholodtsova, Maria N.; Loschenov, Victor B.; Goryainov, Sergey A.; Potapov, Aleksander A.

    2012-03-01

    Brain glial tumors have peculiar features of the perifocal region extension, characterized by its indistinct area, which complicates determination of the borders for tissue resection. In the present study filter-reduced back-scattered laser light signals, compared to the data from mathematical modeling, were used for description of the brain white matter. The simulations of the scattered light distributions were performed in a Monte Carlo program using scattering and absorption parameters of the different grades of the brain glial tumors. The parameters were obtained by the Mie calculations for three main types of scatterers: myelinated axon fibers, cell nuclei and mitochondria. It was revealed that diffuse-reflected light, measured at the perifocal areas of the glial brain tumors, shows a significant difference relative to the signal, measured at the normal tissue, which signifies the possibility to provide diagnostically useful information on the tissue state, and to determine the borders of the tumor, thus to reduce the recurrence appearance. Differences in the values of ratios of diffuse reflectance from active growth parts of tumors and normal white matter can be useful for determination of the degree of tumor progress during the spectroscopic analysis.

  14. Metabolism of [U-13C]glucose in Human Brain Tumors In Vivo

    PubMed Central

    Maher, Elizabeth A.; Marin-Valencia, Isaac; Bachoo, Robert M.; Mashimo, Tomoyuki; Raisanen, Jack; Hatanpaa, Kimmo J.; Jindal, Ashish; Jeffrey, F. Mark; Choi, Changho; Madden, Christopher; Mathews, Dana; Pascual, Juan M.; Mickey, Bruce E.; Malloy, Craig R.; DeBerardinis, Ralph J.

    2012-01-01

    Glioblastomas (GBMs) and brain metastases demonstrate avid uptake of 18fluoro-2-deoxyglucose (FDG) by positron emission tomography (PET) and display perturbations of intracellular metabolite pools by 1H magnetic resonance spectroscopy (MRS). These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. FDG-positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation compared to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain malignancies to oxidize glucose in the tricarboxylic acid cycle is unknown. Here we studied the metabolism of human brain tumors in situ. [U-13C]glucose was infused during surgical resection, and tumor samples were subsequently subjected to 13C NMR spectroscopy. Analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the TCA cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl-CoA pool was derived from blood-borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of 13C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse malignancies growing in their native microenvironment. PMID:22419606

  15. Pre- and postoperative neurocognitive deficits in brain tumor patients assessed by a computer based screening test.

    PubMed

    Hoffermann, Markus; Bruckmann, Lukas; Mahdy Ali, Kariem; Zaar, Karla; Avian, Alexander; von Campe, Gord

    2017-02-01

    Neurocognitive assessment becomes increasingly important in neuro-oncology. The presence and degree of neurocognitive deficits in patients with brain tumors appear to be important not only as outcome measures but also in treatment planning and as possible prognostic markers for tumor-progression. Common screening methods for neurocognitive deficits are often insufficient in uncovering subtle changes or harbor the risk of being observer-dependent and time-consuming. We present data of brain tumor patients screened by a computer-based neurocognitive assessment tool before and after surgery. 196 patients with tumor resections were tested at our institution using the NeuroCog Fx® software 2days before and 3-4months after surgery. Additionally to the test results, patient-related information, such as age, sex, handedness, level of education, pre- and postoperative neurological status, KPS, location and histopathological diagnosis were recorded. These prospectively collected results were correlated in the here presented retrospective study. The majority of patients with malignant gliomas, metastases and meningiomas showed significant deficits in various neurocognitive domains, most of them improved or did not decline in their postoperative neurocognitive performances. Interestingly, there was no significant correlation of neurocognitive deficits and brain tumor location. In future, standardized neuropsychological assessment should become an essential part of the management and care of patients with brain tumors to provide a more personalized and tailored treatment. Further studies will improve the understanding of the influence of various treatment modalities on neuro-cognition.

  16. Improving Care in Pediatric Neuro-oncology Patients:An Overview of the Unique Needs of Children with Brain Tumors

    PubMed Central

    Fischer, Cheryl; Petriccione, Mary; Donzelli, Maria; Pottenger, Elaine

    2016-01-01

    Brain tumors represent the most common solid tumors in childhood, accounting for almost 25% of all childhood cancer, second only to leukemia. Childhood CNS tumors encompass a wide variety of diagnoses, from benign to malignant. Any brain tumor can be associated with significant morbidity, even when low grade, and mortality from childhood CNS tumors is disproportionately high compared to other childhood malignancies. Management of children with CNS tumors requires knowledge of the unique aspects of care associated with this particular patient population, beyond general oncology care. Pediatric brain tumor patients have unique needs during treatment, as cancer survivors, and at end of life. A multidisciplinary team approach, including advanced practice nurses with a specialty in neuro-oncology, allows for better supportive care. Knowledge of the unique aspects of care for children with brain tumors, and the appropriate interventions required, allows for improved quality of life. PMID:26245798

  17. Improving Care in Pediatric Neuro-oncology Patients: An Overview of the Unique Needs of Children With Brain Tumors.

    PubMed

    Fischer, Cheryl; Petriccione, Mary; Donzelli, Maria; Pottenger, Elaine

    2016-03-01

    Brain tumors represent the most common solid tumors in childhood, accounting for almost 25% of all childhood cancer, second only to leukemia. Pediatric central nervous system tumors encompass a wide variety of diagnoses, from benign to malignant. Any brain tumor can be associated with significant morbidity, even when low grade, and mortality from pediatric central nervous system tumors is disproportionately high compared to other childhood malignancies. Management of children with central nervous system tumors requires knowledge of the unique aspects of care associated with this particular patient population, beyond general oncology care. Pediatric brain tumor patients have unique needs during treatment, as cancer survivors, and at end of life. A multidisciplinary team approach, including advanced practice nurses with a specialty in neuro-oncology, allows for better supportive care. Knowledge of the unique aspects of care for children with brain tumors, and the appropriate interventions required, allows for improved quality of life.

  18. Nanoparticle-assisted photothermal ablation of brain tumor in an orthotopic canine model

    NASA Astrophysics Data System (ADS)

    Schwartz, Jon A.; Shetty, Anil M.; Price, Roger E.; Stafford, R. Jason; Wang, James C.; Uthamanthil, Rajesh K.; Pham, Kevin; McNichols, Roger J.; Coleman, Chris L.; Payne, J. Donald

    2009-02-01

    We report on a pilot study demonstrating a proof of concept for the passive delivery of nanoshells to an orthotopic tumor where they induce a local, confined therapeutic response distinct from that of normal brain resulting in the photo-thermal ablation of canine Transmissible Venereal Tumor (cTVT) in a canine brain model. cTVT fragments grown in SCID mice were successfully inoculated in the parietal lobe of immuno-suppressed, mixed-breed hound dogs. A single dose of near-infrared absorbing, 150 nm nanoshells was infused intravenously and allowed time to passively accumulate in the intracranial tumors which served as a proxy for an orthotopic brain metastasis. The nanoshells accumulated within the intracranial cTVT suggesting that its neo-vasculature represented an interruption of the normal blood-brain barrier. Tumors were thermally ablated by percutaneous, optical fiber-delivered, near-infrared radiation using a 3.5 W average, 3-minute laser dose at 808 nm that selectively elevated the temperature of tumor tissue to 65.8+/-4.1ºC. Identical laser doses applied to normal white and gray matter on the contralateral side of the brain yielded sub-lethal temperatures of 48.6+/-1.1ºC. The laser dose was designed to minimize thermal damage to normal brain tissue in the absence of nanoshells and compensate for variability in the accumulation of nanoshells in tumor. Post-mortem histopathology of treated brain sections demonstrated the effectiveness and selectivity of the nanoshell-assisted thermal ablation.

  19. Angiogenesis-targeting microbubbles combined with ultrasound-mediated gene therapy in brain tumors.

    PubMed

    Chang, En-Ling; Ting, Chien-Yu; Hsu, Po-Hong; Lin, Yu-Chun; Liao, En-Chi; Huang, Chiung-Yin; Chang, Yuan-Chih; Chan, Hong-Lin; Chiang, Chi-Shiun; Liu, Hao-Li; Wei, Kuo-Chen; Fan, Ching-Hsiang; Yeh, Chih-Kuang

    2017-04-10

    The major challenges in gene therapy for brain cancer are poor transgene expression due to the blood-brain barrier (BBB) and neurologic damage caused by conventional intracerebral injection. Non-viral gene delivery using ultrasound-targeted microbubble (MB) oscillation via the systematic transvascular route is attractive, but there is currently no high-yielding and targeted gene expression method. In this study, we developed a non-viral and angiogenesis-targeting gene delivery approach for efficient brain tumor gene therapy without brain damage. We developed a VEGFR2-targeted and cationic microbubble (VCMB) gene vector for use with transcranial focused ultrasound (FUS) exposure to allow transient gene delivery. The system was tested in a brain tumor model using the firefly luciferase gene and herpes simplex virus type 1 thymidine kinase/ganciclovir (pHSV-TK/GCV) with VCMBs under FUS exposure for transgene expression and anti-tumor effect. In vitro data showed that VCMBs have a high DNA-loading efficiency and high affinity for cancer cells. In vivo data confirmed that this technique enhanced gene delivery into tumor tissues without affecting normal brain tissues. The VCMB group resulted in higher luciferase expression (3.8 fold) relative to the CMB group (1.9 fold), and the direct injection group. The tumor volume on day 25 was significantly smaller in rats treated with the pHSV-TK/GCV system using VCMBs under FUS (9.7±5.2mm(3)) than in the direct injection group (40.1±4.3mm(3)). We demonstrated the successful use of DNA-loaded VCMBs and FUS for non-viral, non-invasive and targeted gene delivery to brain tumors.

  20. Brain tumor vessel response to synchrotron microbeam radiation therapy: a short-term in vivo study

    NASA Astrophysics Data System (ADS)

    Serduc, Raphaël; Christen, Thomas; Laissue, Jean; Farion, Régine; Bouchet, Audrey; van der Sanden, Boudewijn; Segebarth, Christoph; Bräuer-Krisch, Elke; LeDuc, Géraldine; Bravin, Alberto; Rémy, Chantal; Barbier, Emmanuel L.

    2008-07-01

    The aim of this work focuses on the description of the short-term response of a 9L brain tumor model and its vasculature to microbeam radiation therapy (MRT) using magnetic resonance imaging (MRI). Rat 9L gliosarcomas implanted in nude mice brains were irradiated by MRT 13 days after tumor inoculation using two orthogonal arrays of equally spaced 28 planar microbeams (25 µm width, 211 µm spacing and dose 500 Gy). At 1, 7 and 14 days after MRT, apparent diffusion coefficient, blood volume and vessel size index were mapped by MRI. Mean survival time after tumor inoculation increased significantly between MRT-treated and untreated groups (23 and 28 days respectively, log-rank test, p < 0.0001). A significant increase of apparent diffusion coefficient was observed 24 h after MRT in irradiated tumors versus non-irradiated ones. In the untreated group, both tumor size and vessel size index increased significantly (from 7.6 ± 2.2 to 19.2 ± 4.0 mm2 and +23%, respectively) between the 14th and the 21st day after tumor cell inoculation. During the same period, in the MRT-treated group, no difference in tumor size was observed. The vessel size index measured in the MRT-treated group increased significantly (+26%) between 14 and 28 days of tumor growth. We did not observe the significant difference in blood volume between the MRT-treated and untreated groups. MRT slows 9L tumor growth in a mouse brain but MRI results suggest that the increase in survival time after our MRT approach may be rather due to a cytoreduction than to early direct effects of ionizing radiation on tumor vessels. These results suggest that MRT parameters need to be optimized to further damage tumor vessels.

  1. Resting functional connectivity in patients with brain tumors in eloquent areas

    PubMed Central

    Martino, Juan; Honma, Susanne M.; Findlay, Anne M.; Guggisberg, Adrian G.; Kirsch, Heidi E.; Berger, Mitchel S.; Nagarajan, Srikantan S.

    2014-01-01

    Objective Resection of brain tumors adjacent to eloquent areas represents a challenge in neurosurgery. If maximal resection is desired without inducing postoperative neurological deficits, a detailed knowledge of the functional topography in and around the tumor is crucial. The aim of the present work is to evaluate the value of preoperative magnetoencephalography (MEG) imaging of functional connectivity to predict the results of intraoperative electrical stimulation (IES) mapping, the clinical gold standard for neurosurgical localization of functional areas. Methods Resting-state whole-cortex MEG recordings were obtained from 57 consecutive subjects with focal brain tumors near or within motor, sensory or language areas. Neural activity was estimated using adaptive spatial filtering algorithms, and the mean imaginary coherence between the rest of the brain and voxels in and around brain tumors were compared to the mean imaginary coherence between the rest of the brain and contralesional voxels as an index of functional connectivity. IES mapping was performed in all subjects. The cortical connectivity pattern near the tumor was compared to IES results. Results Maps with decreased resting-state functional connectivity in the entire tumor area had a negative predictive value of 100% for absence of eloquent cortex during IES. Maps showing increased resting-state functional connectivity within the tumor area had a positive predictive value of 64% for finding language, motor or sensory cortical sites during IES mapping. Interpretation Preoperative resting state MEG connectivity analysis is a useful noninvasive tool to evaluate the functionality of the tissue surrounding tumors within eloquent areas, and could potentially contribute to surgical planning and patient counseling. PMID:21400562

  2. A Correlative Optical Microscopy and Scanning Electron Microscopy Approach to Locating Nanoparticles in Brain Tumors

    PubMed Central

    Kempen, Paul J.; Kircher, Moritz F.; de la Zerda, Adam; Zavaleta, Cristina L; Jokerst, Jesse V.; Mellinghoff, Ingo K.; Gambhir, Sanjiv S; Sinclair, Robert

    2014-01-01

    The growing use of nanoparticles in biomedical applications, including cancer diagnosis and treatment, demands the capability to exactly locate them within complex biological systems. In this work a correlative optical and scanning electron microscopy technique was developed to locate and observe multi-modal gold core nanoparticle accumulation in brain tumor models. Entire brain sections from mice containing orthotopic brain tumors injected intravenously with nanoparticles were imaged using both optical microscopy to identify the brain tumor, and scanning electron microscopy to identify the individual nanoparticles. Gold-based nanoparticles were readily identified in the scanning electron microscope using backscattered electron imaging as bright spots against a darker background. This information was then correlated to determine the exact location of the nanoparticles within the brain tissue. The nanoparticles were located only in areas that contained tumor cells, and not in the surrounding healthy brain tissue. This correlative technique provides a powerful method to relate the macro- and micro-scale features visible in light microscopy with the nanoscale features resolvable in scanning electron microscopy. PMID:25464144

  3. A correlative optical microscopy and scanning electron microscopy approach to locating nanoparticles in brain tumors.

    PubMed

    Kempen, Paul J; Kircher, Moritz F; de la Zerda, Adam; Zavaleta, Cristina L; Jokerst, Jesse V; Mellinghoff, Ingo K; Gambhir, Sanjiv S; Sinclair, Robert

    2015-01-01

    The growing use of nanoparticles in biomedical applications, including cancer diagnosis and treatment, demands the capability to exactly locate them within complex biological systems. In this work a correlative optical and scanning electron microscopy technique was developed to locate and observe multi-modal gold core nanoparticle accumulation in brain tumor models. Entire brain sections from mice containing orthotopic brain tumors injected intravenously with nanoparticles were imaged using both optical microscopy to identify the brain tumor, and scanning electron microscopy to identify the individual nanoparticles. Gold-based nanoparticles were readily identified in the scanning electron microscope using backscattered electron imaging as bright spots against a darker background. This information was then correlated to determine the exact location of the nanoparticles within the brain tissue. The nanoparticles were located only in areas that contained tumor cells, and not in the surrounding healthy brain tissue. This correlative technique provides a powerful method to relate the macro- and micro-scale features visible in light microscopy with the nanoscale features resolvable in scanning electron microscopy.

  4. Brain tumor modeling using the CRISPR/Cas9 system: state of the art and view to the future

    PubMed Central

    Mao, Xiao-Yuan; Dai, Jin-Xiang; Zhou, Hong-Hao; Liu, Zhao-Qian; Jin, Wei-Lin

    2016-01-01

    Although brain tumors have been known tremendously over the past decade, there are still many problems to be solved. The etiology of brain tumors is not well understood and the treatment remains modest. There is in great need to develop a suitable brain tumor models that faithfully mirror the etiology of human brain neoplasm and subsequently get more efficient therapeutic approaches for these disorders. In this review, we described the current status of animal models of brain tumors and analyzed their advantages and disadvantages. Additionally, prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), a versatile genome editing technology for investigating the functions of target genes, and its application were also introduced in our present work. We firstly proposed that brain tumor modeling could be well established via CRISPR/Cas9 techniques. And CRISPR/Cas9-mediated brain tumor modeling was likely to be more suitable for figuring out the pathogenesis of brain tumors, as CRISPR/Cas9 platform was a simple and more efficient biological toolbox for implementing mutagenesis of oncogenes or tumor suppressors that were closely linked with brain tumors. PMID:26993776

  5. Brain tumor modeling using the CRISPR/Cas9 system: state of the art and view to the future.

    PubMed

    Mao, Xiao-Yuan; Dai, Jin-Xiang; Zhou, Hong-Hao; Liu, Zhao-Qian; Jin, Wei-Lin

    2016-05-31

    Although brain tumors have been known tremendously over the past decade, there are still many problems to be solved. The etiology of brain tumors is not well understood and the treatment remains modest. There is in great need to develop a suitable brain tumor models that faithfully mirror the etiology of human brain neoplasm and subsequently get more efficient therapeutic approaches for these disorders. In this review, we described the current status of animal models of brain tumors and analyzed their advantages and disadvantages. Additionally, prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), a versatile genome editing technology for investigating the functions of target genes, and its application were also introduced in our present work. We firstly proposed that brain tumor modeling could be well established via CRISPR/Cas9 techniques. And CRISPR/Cas9-mediated brain tumor modeling was likely to be more suitable for figuring out the pathogenesis of brain tumors, as CRISPR/Cas9 platform was a simple and more efficient biological toolbox for implementing mutagenesis of oncogenes or tumor suppressors that were closely linked with brain tumors.

  6. Pharmacologic perturbation as a potential tool to increase the sensitivity of FDG-PET in the evaluation of brain tumors

    SciTech Connect

    Wong, F.C.L.; Kim, E.E.; Yung, W.K.A.

    1994-05-01

    The usefulness of F-18 FDG PET in the study of brain tumors is limited by the high baseline cortical uptake which decreases the contrast of the tumor. Two alternatives to increase the tumor/background contrast have been reported: barbiturate-induced coma and postprandial state. This project evaluates the effects of sedation with diazepam or of oral glucose intake on the brain tumor/background contrast during F-18 FDG PET studies.

  7. Automatic brain tumor extraction from T1-weighted coronal MRI using fast bounding box and dynamic snake.

    PubMed

    Xu, Tao; Mandal, Mrinal

    2012-01-01

    Brain tumor segmentation from MRI data is an important but challenging task. This paper presents an efficient and fully automatic brain tumor segmentation technique. The proposed technique includes a fuzzy C-means (FCM) based preprocessing to enhance the quality of T1-weighted coronal MR images, a fast bounding box (FBB) detection algorithm to locate a rectangle around tumor, and a new dynamic snake using modified Hausdorff distance (MHD) for the final tumor extraction.

  8. Comparison of CT and MRI brain tumor imaging using a canine glioma model.

    PubMed

    Whelan, H T; Clanton, J A; Wilson, R E; Tulipan, N B

    1988-01-01

    A canine gliosarcoma model was used to study the effectiveness of magnetic resonance imaging (MRI) with gadolinium contrast enhancement in defining the histologic margins of brain tumors. The effectiveness of this technique was compared to conventional computed tomography (CT) using iodinated contrast enhancement. Cultured canine gliosarcoma cells were injected into the left hemisphere of adult mongrel dogs. The dogs developed brain tumors and progressive clinical signs. Serial MRI with and without gadolinium diethylene triamine penta-acetic acid was compared to serial CT with and without sodium iothalamate obtained on the same days. After the final scans, animals were sacrificed; the brains were removed and processed for routine histopathologic study. All tumors were visualized with contrast-enhanced MRI which proved most sensitive. Gadolinium di-ethylene triamine penta-acetic acid caused bright enhancement of tumors in a distribution that consistently corresponded to areas of pathologically proved tumor infiltration. Gross and microscopic autopsy findings correlated better with MRI than with CT which tended to produce poorer resolution and underrepresent the size of viable tumor. Gadolinium-enhanced MRI is more accurate than unenhanced MRI, unenhanced CT, or enhanced CT in defining the histologic margins of tumors.

  9. Radiotherapy and death from cerebrovascular disease in patients with primary brain tumors.

    PubMed

    Aizer, Ayal A; Du, Rose; Wen, Patrick Y; Arvold, Nils D

    2015-09-01

    Radiotherapy is often used in the management of primary brain tumors, but late cerebrovascular risks remain incompletely characterized. We examined the relationship between radiotherapy and the risk of death from cerebrovascular disease (CVD) in this population. We used the Surveillance, Epidemiology, and End Results Program to identify 19,565 patients of any age diagnosed with a primary brain tumor between 1983-2002. Multivariable competing risks analysis and an interaction model were used to determine whether receipt of radiotherapy was associated with an increased risk of CVD-specific death, adjusting for tumor proximity to central arterial circulations of the brain. The median follow up in surviving patients was 12.75 years. Baseline characteristics were similar in patients who did and did not receive radiotherapy. Ten-year CVD-specific mortality in patients with tumors near central arterial circulations who did and did not receive radiotherapy were 0.64 % (95 % CI 0.42-0.93 %) versus 0.16 % (95 % CI 0.055-0.40 %), p = 0.01. After adjustment for demographic, tumor-related, and treatment-related covariates, patients with tumors near central arterial circulations were significantly more likely to experience CVD-specific mortality after radiotherapy (HR 2.81; 95 % CI 1.25-6.31; p = 0.01); no association was observed among patients with more distant tumors (HR 0.77; 95 % CI 0.50-1.16; p = 0.21). The interaction model showed that tumor location was a key predictor of the risk of radiotherapy-associated, CVD-specific mortality (p-interaction = 0.004). Patients receiving radiotherapy for tumors near but not distant from the central vasculature of the brain are at increased risk for death secondary to CVD, which should be considered when counseling patients.