Differentiation of brain tumor-related edema based on 3D T1rho imaging.
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ABSTRACT:
SUBMITTER: Villanueva-Meyer JE
PROVIDER: S-EPMC5563444 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:BackgroundThree-dimensional visualization of the brain vasculature and its interactions with surrounding cells may shed light on diseases where aberrant microvascular organization is involved, including glioblastoma (GBM). Intravital confocal imaging allows 3D visualization of microvascular structures and migration of cells in the brain of mice, however, with limited imaging depth. To enable comprehensive analysis of GBM and the brain microenvironment, in-depth 3D imaging methods are needed. Here, we employed methods for optical tissue clearing prior to 3D microscopy to visualize the brain microvasculature and routes of invasion of GBM cells.MethodsWe present a workflow for ex vivo imaging of optically cleared brain tumor tissues and subsequent computational modeling. This workflow was used for quantification of the microvasculature in relation to nuclear or cellular density in healthy mouse brain tissues and in human orthotopic, infiltrative GBM8 and E98 glioblastoma models.ResultsEx vivo cleared mouse brain tissues had a >10-fold imaging depth as compared to intravital imaging of mouse brain in vivo. Imaging of optically cleared brain tissue allowed quantification of the 3D microvascular characteristics in healthy mouse brains and in tissues with diffuse, infiltrative growing GBM8 brain tumors. Detailed 3D visualization revealed the organization of tumor cells relative to the vasculature, in both gray matter and white matter regions, and patterns of multicellular GBM networks collectively invading the brain parenchyma.ConclusionsOptical tissue clearing opens new avenues for combined quantitative and 3D microscopic analysis of the topographical relationship between GBM cells and their microenvironment.
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Project description:PurposeInflammation occurs routinely when managing gliomas and is not easily distinguishable from tumor regrowth by current MRI methods. The lack of noninvasive technologies that monitor inflammation prevents us to understand whether it is beneficial or detrimental for the patient, and current therapies do not take this host response in consideration. We aim to establish whether a gadolinium (Gd)-based agent targeting the inflammatory enzyme myeloperoxidase (MPO) can selectively detect intra- and peritumoral inflammation as well as glioma response to treatment by MRI.MethodsWe carried out serial Gd-bis-5-HT-DTPA (MPO-Gd) MRI before and after treating rodent gliomas with different doses of oncolytic virus (OV) and analyzed animal survival. The imaging results were compared with histopathologic and molecular analyses of the tumors for macrophage/microglia infiltration, virus persistence, and MPO levels.ResultsElevated MPO activity was observed by MRI inside the tumor and in the peritumoral cerebrum at day 1 post-OV injection, which corresponded with activation/infiltration of myeloid cells inhibiting OV intratumoral persistence. MPO activity decreased, whereas tumor size increased, as the virus and the immune cells were cleared (days 1-7 post-OV injection). A 10-fold increase in viral dose temporally decreased tumor size, but augmented MPO activity, thus preventing extension of viral intratumoral persistence.ConclusionsMPO-Gd MRI can distinguish enhancement patterns that reflect treatment-induced spatiotemporal changes of intratumoral and intracerebral inflammation from those indicating tumor and peritumoral edema. This technology improves the posttreatment diagnosis of gliomas and will increase our understanding of the role of inflammation in cancer therapy.
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Project description:Background and objective: Phase difference enhanced imaging (PADRE), a new phase-related MRI technique, can enhance both paramagnetic and diamagnetic substances, and select which phases to be enhanced. Utilizing these characteristics, we developed color map of PADRE (Color PADRE), which enables simultaneous visualization of myelin-rich structures and veins. Our aim was to determine whether Color PADRE is sufficient to delineate the characteristics of non-gadolinium-enhancing T2-hyperintense regions related with metastatic tumors (MTs), diffuse astrocytomas (DAs) and glioblastomas (GBs), and whether it can contribute to the differentiation of MTs from GBs. Methods: Color PADRE images of 11 patients with MTs, nine with DAs and 17 with GBs were created by combining tissue-enhanced, vessel-enhanced and magnitude images of PADRE, and then retrospectively reviewed. First, predominant visibility of superficial white matter and deep medullary veins within non-gadolinium-enhancing T2-hyperintense regions were compared among the three groups. Then, the discriminatory power to differentiate MTs from GBs was assessed using receiver operating characteristic analysis. Results: The degree of visibility of superficial white matter was significantly better in MTs than in GBs (p = 0.017), better in GBs than in DAs (p = 0.014), and better in MTs than in DAs (p = 0.0021). On the contrary, the difference in the visibility of deep medullary veins was not significant (p = 0.065). The area under the receiver operating characteristic curve to discriminate MTs from GBs was 0.76 with a sensitivity of 80% and specificity of 64%. Conclusion: Visibility of superficial white matter on Color PADRE reflects inferred differences in the proportion of vasogenic edema and tumoral infiltration within non-gadolinium-enhancing T2-hyperintense regions of MTs, DAs and GBs. Evaluation of peritumoral areas on Color PADRE can help to distinguish MTs from GBs.
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Project description:Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.
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