Browsing by Subject "Brain Neoplasms"
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Item Approaching gliomas through the translational research lens(2022-03-18) Maher, ElizabethItem Brain metastases: finally a light at the end of this long dark tunnel(2014-06-13) Maher, ElizabethItem Brain tumor(1961-01-19) Eliasson, Sven G.Item Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems(2012-07-16) McEllin, Brian Matthew; Burma, Sandeep; Bachoo, RobertGlioblastoma multiforme (GBM) are deadly brain tumors that are refractory to radiation and chemotherapy. Despite decades of work, little progress has been made in improving patient outcomes. Recent mapping of the GBM genome by the Cancer Genome Atlas Network revealed that these cancers commonly exhibit several signature mutations that promote gliomagenesis (e.g. EGFR amplification/activation, PTEN loss, p53 loss, Ink4a/Arf loss). How these genetic changes may modulate responses to radiation and chemotherapy is not well understood. To elucidate this relationship, genetically defined mouse models have been used for both in vitro and in vivo analysis. Work has uncovered novel links between oncogenic signaling and DNA repair pathways. First, activation of the Akt pathway by EGFRvIII, a constitutively active form of EGFR, promotes DNA double strand break repair by non-homologous end joining in astrocytes and glioma cell lines. This results in faster repair and increased radioresistance, both in vitro and in orthotopic GBM models. While activation of Akt by the loss of PTEN has similar results, data shows that PTEN loss reduces resistance to agents that induce replication-associated DSBs. This phenotype is due to reduced levels of homologous recombination, as astrocytes show increased radial chromosome aberrations and decreased sister chromatid exchanges after PTEN loss. These results have exciting implications, as it has identified two potential new therapeutic strategies for improving treatment in subsets of GBM patients. The cancer stem cell hypothesis postulates that cancers are organized similar to endogenous stem cell compartments, composed of a self-renewing cancer stem cell and other more “differentiated”, non-stem progeny. To determine how key GBM mutations affect the different cell types in GBM, I used the adult neural stem cell compartment as a reductionist model of a tumor. Surprisingly, data demonstrated that quiescent stem cells showed inherent resistance, even in a wild type mouse. In addition, stem cell-specific p53 loss increases radioresistance only in a subset of non-dividing progenitors, while proliferating progenitors remain sensitive to radiation. This model has offered novel insight into the effect of key pathways deregulated in GBM and how they impact different cell types.Item Item Late Effects of Hypothalamic Radiation Exposure in Pediatric Brain Tumor Survivors(2015-03-31) Wu, Susan Y.; Bowers, Daniel C.; Vega, Gloria L.; Gargan, LynnBACKGROUND: Brain tumors are the second most common childhood malignancy and overall survival rates exceed 70%. Pediatric brain tumor survivors treated with hypothalamic radiation are at increased risk for developing components of metabolic syndrome, characterized by central obesity and two of the following: elevated triglycerides, low HDL, elevated blood pressure, or fasting hyperglycemia. These patients may also be at risk for developing decreased bone density, which is associated with pathologic fractures. OBJECTIVE: Our aim is to compare the prevalence of metabolic syndrome or concomitant cardiometabolic risk, bone density, and body composition among pediatric brain tumor survivors treated with and without hypothalamic radiation. METHODS: This study evaluated 146 survivors of childhood brain tumors (70 radiated, 76 non-radiated) between 5-20 years old (mean: 12.3 years, SD: 4.1 years, average survival time: 6 years). Patients underwent fasting lab assays (lipid panel, insulin, glucose, leptin, and adiponectin), anthropometric measurements (height, weight, and waist circumference), and Dual-energy X-ray Absorptiometry (DXA) scan. Insulin resistance was identified using the homeostasis model assessment of insulin resistance (HOMA-IR). Metabolic syndrome was diagnosed according to the International Diabetes Foundation criteria in children 10 years and older; children between 5-10 years of age who met 3 of 5 risk factors were classified as having concomitant cardiometabolic risk. RESULTS: Metabolic syndrome or concomitant cardiometabolic risk was more common in patients who received hypothalamic-pituitary axis (HPA) radiation (7/38, 18.4%) than those who did not (4/76, 5.3%) (p = 0.04). Patients who received HPA radiation were more likely to have elevated triglyceride levels (p = 0.02), low HDL levels (p = 0.04), and lower IGF-1 z-scores (p < 0.001). On DXA scan, patients exposed to HPA radiation had lower Bone Mineral Content (BMC) and Bone Mineral Density (BMD) z-scores (-1.3 vs. -0.3, p = 0.003 and -1.4 vs. -0.2, p < 0.001 respectively) and lower Fat Free Mass Index z-scores (-1.4 vs. -0.1, p = 0.001) despite no significant difference in BMI (21.7 vs. 22.2, p = 0.7) or percent body fat (35.5% vs. 32.8%, p = 0.11). There was no significant difference in leptin/kg fat and adiponectin/kg fat between patients who received HPA radiation and those who did not (p = 0.55 and p = 0.98 respectively). Patients with elevated HOMA-IR had elevated leptin levels (p = 0.001), lower adiponectin levels (p = 0.04), and elevated leptin:adiponectin ratios (p = 0.001). CONCLUSION: These results suggest that exposure to hypothalamic radiation may have significant subclinical consequences that include components of metabolic syndrome, decreased bone density, and altered body composition. These results highlight the need for stringent follow-up surveillance of these patients and suggest that screening for dyslipidemia may be a sensitive way to detect patients at risk for developing metabolic syndrome.Item Magnetic Resonance Spectroscopy Imaging of 2-Hydroxyglutarate in Brain Tumors at 3T and 7T In Vivo(2018-05-30) An, Zhongxu; Sherry, A. Dean; Choi, Changho; Malloy, Craig R.; Pinho, Marco Da Cunha; Ren, JiminThe identification of 2-hydroxyglutarate (2HG) by 1H magnetic resonance spectroscopy (MRS) in patients with isocitrate dehydrogenase mutant gliomas is a significant breakthrough in neuro-oncology imaging. 2HG is the first imaging biomarker that is specific to a genetic mutation in gliomas, making the diagnosis of IDH mutant gliomas possible without biopsy. 2HG also has a significant predictive value with respect to the stage and survival in gliomas because IDH mutation carries a favorable prognosis. Gliomas are highly heterogeneous and infiltrative in malignant transformation and recur beyond the borders of the initial tumor mass. Therefore, a high-resolution 3D imaging platform to measure 2HG rapidly has an outstanding strength for monitoring IDH-mutant tumors. The present work aims to develop new techniques that provide meaningful estimation of 2HG and other metabolites in gliomas in vivo. As the first topic, novel triple refocusing MRS was developed at 3T for improving the 2HG signal sensitivity and specificity compared to prior methods. The optimized triple refocusing sequence conferred excellent discrimination of the 2HG 2.25-ppm signal from the adjacent resonances and consequently improved the precision of 2HG estimation substantially. Another accomplishment was development of fast high-resolution imaging of 2HG in patients at 3T and 7T. A new echo-planar spectroscopic imaging (EPSI) readout was designed incorporating dual-readout alternated gradients (DRAG-EPSI). At 7T, DRAG-EPSI was utilized for increasing the spectral width for fully covering the spectral region of interest, which is not possible with conventional EPSI. DRAG-EPSI was used for 2D imaging of 2HG in 5 patients at 7T. At 3T, at which the spectral width of conventional EPSI is sufficiently large for covering the spectral region of interest, DRAG-EPSI was utilized for reducing the readout gradient strengths, thereby improving the imaging performance and patient compliance. DRAG-EPSI induced frequency drifts smaller by 5.5-fold and acoustic noise lower by 25 dB compared with conventional EPSI. In a 19-min scan, DRAG-EPSI produced, for the first time, 3D imaging of 2HG with precision at a resolution of 10×10×10 mm3 at 3T. Data from 4 patients indicated that DRAG-EPSI may provide reliable 3D high-resolution imaging of 2HG at 3T in vivo.Item The management of metastatic brain tumors(2000-06-01) Levinson, Barry S.Item Mechanistic Analysis of Radiation-Induced Gliomagenesis(2017-07-28) Todorova, Pavlina Krasimirova; Bachoo, Robert; Shay, Jerry W.; Scaglioni, Pier Paolo; Burma, SandeepGlioblastomas (GBM) are devastating brain tumors refractory to any available treatment. Exposure to ionizing radiation (IR) is the only known GBM risk factor. The link between low-linear energy transfer (LET) IR and gliomagenesis has been clearly demonstrated by epidemiological studies of human patients receiving diagnostic or therapeutic radiation. Whether such risk exists with particle radiation exposure, which is more densely ionizing, has not been evaluated. Particle radiation is increasingly used in radiotherapy and is also an occupational hazard for astronauts in space. With no human data available, animal models mimicking the process of radiation carcinogenesis are essential for risk assessment. Through a large scale systematic interrogation of multi-allele transgenic mice with brain-restricted deletions of GBM-relevant tumor suppressor genes we identified two complementary genotypes (NesCreInk4ab-/-ArfF/F and NesCrep53+/F;Pten+/F). We irradiated both models intra-cranially with equal doses of a range of charged particles with different LETs. Interestingly, we found an increase in gliomagenesis with LET until a peak frequency was reached with silicon ions (LET of 79.3 KeV/μm) following which tumor frequencies declined with heavier particles with higher LETs. These radiation-induced mouse tumors phenocopy the histopathological features of human GBM, including infiltrative growth, pseudopalisading necrosis, high mitotic index, and positivity for glial (Gfap, Olig2) and stem/progenitor markers (Sox2). Ex-vivo cultures derived from these tumors showed features of glioma stem-like cells underscoring the undifferentiated nature of the parental tumors. Integrated genomic and functional analyses revealed the driving oncogenic changes in tumors from the NesCrep53+/F;Pten+/F model. Regardless of radiation quality, all tumors had genomic deletions of the wild-type alleles of both p53 and Pten. Such concomitant loss signifies the crucial roles that p53 and Pten together play as barriers to radiation-induced transformation. Over-expression of the receptor tyrosine kinase Met following a genomic amplification event harbored by 40% of tumors was similarly observed across all radiation qualities. Met overexpression enhanced the stemness phenotype in the context of p53 loss, and additionally conferred radioresistance. These combinatorial effects illustrate the importance of evaluating GBM drivers as integrated nodes in an oncogenic signaling network. In sum, the identification of two mouse models carrying deletions of independent TSGs has allowed us to establish the universal role of radiation as a genotoxic agent capable of inducing high grade gliomas. These models and the identified key molecular changes accompanying radiation-induced gliomagenesis can be used in the design of therapeutic strategies for patients with secondary glioma who are currently limited in their options.Item Multimodality Imaging of Tumor Vasculature and Metabolism(2013-04-08) Zhou, Heling 1985-; Mason, Ralph P.; Zhao, Dawen; Saha, Debabrata; Lu, Hanzhang; Gao, JinmingCancer is the second leading cause of death in America. A number of abnormal features in tumor vasculature and metabolism have been identified as imaging biomarkers to detect tumor boundary, provide physiological information, predict treatment response and guide surgeries. In chapter 2, longitudinal MRI was applied to monitor the initiation and development of intracranial tumors and assess the changes in tumor vascular volume and permeability in a mouse model of breast cancer brain metastases. Using a 9.4T system, high resolution anatomic MRI and dynamic susceptibility contrast (DSC) perfusion MRI were acquired at different time points after an intracardiac injection of brain-tropic breast cancer MDA-MB231-BR-EGFP (231-BR) cells. DSC MRI revealed that relative cerebral blood volume (rCBV) of metastatic tumors was significantly lower than that of contralateral normal brain. Intriguingly, longitudinal measurements showed that rCBV of individual metastases at early stage was similar to, but became significantly lower than that of their healthy counterparts with tumor growth. The rCBV data were in agreement with histological analysis of microvascular density (MVD). In chapter 3, 20 nm super-paramagnetic iron oxide (SPIO) particles were conjugated with a novel monoclonal antibody PGN635 to image the exposed phosphatidylserine (PS) on the tumor vascular endothelial cells and evaluate the enhanced exposure of PS as a result of radiation therapy in mice subcutaneous tumors. Both in vitro and in vivo studies verified the binding of SPIO-PGN635 and showed elevated PS exposure upon irradiation. In the subcutaneous tumor models, the distribution of the contrast appeared to be inhomogeneous across the tumors. Sparse signal loss was observed on the T2 weighted images after the administration of SPIO-PGN635. The signal loss fraction indicated significantly more increase in the irradiated tumor compared to the non-irradiated side. Prussian blue staining confirmed the accumulation of SPIO-PGN635 in the tumors along the blood vessels. Control and blocking studies were conducted to validate antigen specificity. It is recognized that cancer cells exhibit highly elevated glucose metabolism compared to non-tumor cells. In chapter 4, I have applied in vivo optical imaging to study dynamic uptake of a near-infrared dye-labeled glucose analogue, 2-deoxyglucose (2-DG) by orthotopic glioma in a mouse model. Dynamic fluorescent imaging revealed significantly higher signal intensity in the tumor side of the brain than the contralateral normal brain 24 h after injection. Even stronger contrast was achieved by removing the scalp and skull of the mice. In contrast, a control dye, IRDye800CW carboxylate, showed little difference. Ex vivo fluorescence imaging performed on ultrathin cryosections of tumor bearing whole brain revealed distinct tumor margins. Microscopic imaging identified cytoplasmic locations of the 2-DG dye in tumor cells.Item Neural Stem Cells in Brain Tumor Development(2009-09-04) Llaguno, Sheila R. Alcantara; Parada, Luis F.Malignant astrocytomas are highly invasive and incurable brain tumors. Mouse models that genetically resemble the human disease are valuable tools in understanding the pathogenesis of these malignancies. We previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors Nf1, p53 and Pten. Through somatic loss of heterozygosity, these mice develop varying grades of astrocytic malignancy with 100% penetrance. Studies on our tumor suppressor mouse models indicated a central role for neural stem cells and stem cell-like cancer cells in malignant astrocytoma formation. Using stereotactic viral cre-mediated approach, we demonstrate that targeting of tumor suppressor inactivating mutations in the subventricular zone (SVZ) where neural stem and progenitor cells reside is both necessary and sufficient to induce astrocytoma formation. We also show evidence of spontaneous differentiation and infiltration of these cancer-initiating cells in situ during tumor development. These studies have so far shown that neural stem cells or its progeny can give rise to astrocytomas. Neural stem cells, which have unlimited self-renewal potential, produce transit amplifying cells, or progenitor cells, which undergo limited mitoses before differentiating into more mature cell types. By genetically targeting transit amplifying cells using the Ascl1-creERT2 transgenic mouse, we show that tumor suppressor inactivation in the progenitor compartment alone induces malignant astrocytoma formation. Defects in proliferation, differentiation, and migration are likewise found several months prior to advanced disease. This establishes both neural stem and progenitor cells as cells of origin of malignant astrocytomas in our tumor suppressor mouse models. In another study, we isolated and characterized a population of stem cell-like cancer cells from murine astrocytomas that are enriched for tumor cells compared to primary tumor tissue, exhibit aberrant stem cell properties, and are tumorigenic in vivo. We demonstrate resistance to a known chemotherapeutic agent and the migratory capacity of these cells. We also investigated the mechanisms involved in astrocytoma progression and maintenance by gene expression analysis. Genomic profiling of tumor-derived neurosphere-forming cells from conditional astrocytoma mouse models show prominent dysregulation of genes involved in neurodevelopmental processes and transcriptional regulation, particularly the hox transcription factors, in high-grade astrocytomas. Taken together, we have demonstrated that neural stem and progenitor cells are the origins of malignant astrocytoma in tumor suppressor mouse models. We have established a system by which molecular mechanisms of tumor development can be further investigated and performed genomic profiling of tumor-derived neurosphere-forming cells, suggesting a possible role for homeobox transcription factors in malignant astrocytoma formation. These mouse models thus represent powerful tools in understanding various aspects of cancer development that otherwise cannot be explored in humans. Further studies will provide a better understanding of the biology of these tumors and will hopefully pave the way for more effective therapeutic approaches for these devastating diseases.Item [News](1981-01-05) Rutherford, SusanItem Pre-Surgical fMRI Mapping of Language: Accuracy of Mapping Language Regions in Patients with Mass Lesions(2017-01-17) Thrikutam, Nikhitha; O'Neill, Thomas; Yetkin, Zerrin; Patel, ToralOBJECTIVES: (1) To introduce a novel methodology for co-registration of pre- and post-surgical clinical imaging. (2) To document prognostic imaging correlates of functional imaging/tractography to post-surgical outcome. BACKGROUND: The accuracy, reproducibility, and clinical applicability of pre-surgical imaging evaluation of language in patients with mass lesions near language areas has been previously demonstrated by this group. The accuracy and clinical applicability of pre-surgical mapping can be confirmed by correlating pre-surgical imaging to post-surgical imaging and then to any related language deficits. It is hypothesized that if the surgical resection cavity includes areas of language activation language deficits will result. Correlation of outcomes with language mapping and post-surgical imaging has not been documented in the literature. MATERIALS AND METHODS: Pre-surgical functional maps and diffusion tensor tracts were created utilizing AFNI and DynaSuite software following fMRI/DTI tractography protocol to evaluate language regions. Post-surgical follow-up of speech deficits was obtained from the medical charts. A computerized method was used to co-register pre- and post-surgical images. Multiple variables including structural, functional, and clinical findings were documented and analyzed for correlation to outcome. RESULTS: 13 patients with left-sided mass lesions with complete pre- and post-surgical clinical imaging and clinical evaluation were included in this retrospective study. Of the 13 patients only 1 patient was noted to have a severe post-operative language deficit and 4 patients were noted to have moderate post-operative laguage deficits. Accurate co-registration was achieved in all cases. Prognostic indicators of language deficits included proximity of activation to the resection cavity, the level of resection, and involvement of the adjacent trajectory of arcuate fasciculus. CONCLUSIONS: (1) Pre-surgical fMRI was accurately co-registered with post-surgical images. (2) Structural, functional, and DTI images were shown to have prognostic value for post-surgical language deficits.Item [Southwestern News](2001-11-05) Harrell, AnnItem [Southwestern News](2002-05-22) Baxter, MindyItem [Southwestern News](1994-01-27) Donovan, JenniferItem [Southwestern News](1995-05-16) Martinez, EmilyItem [Southwestern News](2000-12-06) Donihoo, RachelItem [Southwestern News](1995-07-05) Lyons, MorganItem Unraveling the fundamentals of brain tumor cell migration(2015-08-14) Bachoo, Robert M.