Browsing by Subject "Glioma"
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Item Approaching gliomas through the translational research lens(2022-03-18) Maher, ElizabethItem 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 Malignant Gliomas Originate From Neural Stem/Progenitor Cells and Are Maintained By Cancer Stem Cells(2011-12-12) Chen, Jian; Parada, Luis F.Malignant glioma is one of the most aggressive cancers. To study the biology of glioma, our lab previously developed a series of mouse models that phenocopy both tumor initiation and progression through stochastic tumor suppressor loss-of-heterozygosity (LOH). To determine whether the mouse models recapitulate human glioma at the molecular level, we have performed gene set enrichment analysis (GSEA) comparing the molecular signature of tumors that develop in our mouse glioma models to the gene expression profiles of a number of human tumors. Our mouse glioma models share high similarity with human GBM and showed a generally proneural marker gene expression profile. We also found that tumors from the same initial genetic mutations can be further divided into several subtypes. Previous studies suggested a neural stem/progenitor cell (NSC) origin for gliomas, however strict exprimental evidence was still lacking. To examine the role of NSCs in glioma, we developed an NSC-specific tamoxifen-inducible nestin-cre driver mouse. When crossed to the NF/p53/Pten flox mice and induced with tamoxifen at E13.5, the Nes-Cre;Nf/p53/Pten mutant mice exhibited tumor initiation and progression similar to our previous mouse model using hGFAP-cre, with complete penetrance. All analyzed mice that were induced at 4 weeks such that only adult neural stem cells were targeted, developed malignant astrocytoma 7 - 12 months after induction. These findings indicate that despite their rarity, neural stem/progenitor cells are sufficient targets for the accumulation of mutations that initiate malignant astrocytomas. Our highly physiological relevant mouse model also allowed us to address the question of how glioma is maintained in vivo: whether tumors are maintained by a subpopulation of cells with self-renewal capacity that supplies tumor bulk, or whether the majority of tumor cells have the capacity to maintain the tumor. In our spontaneous somatic mouse model of glioma, a Nestin-¦¤TK-IRES-GFP transgene labels the primary tumor cells that are required for tumorigenicity in allograft assays. Ablating endogenous Nes-¦¤TK-positive cells significantly extended the survival of tumor-bearing mice by decreasing tumor proliferation and infiltration. We show that the glioma drug, temozolomide, selectively targets endogenous CSC-derived proliferating cells. Furthermore, a combination therapy targeting both dividing cells and the CSCs arrests tumor progression.Item Unraveling the fundamentals of brain tumor cell migration(2015-08-14) Bachoo, Robert M.