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High-resolution in-vivo analysis of normal brain response to cranial irradiation.

ABSTRACT: Radiation therapy (RT) is a widely accepted treatment strategy for many central nervous system (CNS) pathologies. However, despite recognized therapeutic success, significant negative consequences are associated with cranial irradiation (CR), which manifests months to years post-RT. The pathophysiology and molecular alterations that culminate in the long-term detrimental effects of CR are poorly understood, though it is thought that endothelial injury plays a pivotal role in triggering cranial injury. We therefore explored the contribution of bone marrow derived cells (BMDCs) in their capacity to repair and contribute to neo-vascularization following CR. Using high-resolution in vivo optical imaging we have studied, at single-cell resolution, the spatio-temporal response of BMDCs in normal brain following CR. We demonstrate that BMDCs are recruited specifically to the site of CR, in a radiation dose and temporal-spatial manner. We establish that BMDCs do not form endothelial cells but rather they differentiate predominantly into inflammatory cells and microglia. Most notably we provide evidence that more than 50% of the microglia in the irradiated region of the brain are not resident microglia but recruited from the bone marrow following CR. These results have invaluable therapeutic implications as BMDCs may be a primary therapeutic target to block acute and long-term inflammatory response following CR. Identifying the critical steps involved in the sustained recruitment and differentiation of BMDCs into microglia at the site of CR can provide new insights into the mechanisms of injury following CR offering potential therapeutic strategies to counteract the long-term adverse effects of CR.

SUBMITTER: Burrell K

PROVIDER: S-EPMC3366930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION:This systematic review aims to elucidate the diagnostic accuracy of radiological examinations to distinguish between brain radiation necrosis (BRN) and tumor progression (TP). METHODS:We divided diagnostic approaches into two categories as follows-conventional radiological imaging [computed tomography (CT) and magnetic resonance imaging (MRI): review question (RQ) 1] and nuclear medicine studies [single photon emission CT (SPECT) and positron emission tomography (PET): RQ2]-and queried. Our librarians conducted a comprehensive systematic search on PubMed, the Cochrane Library, and the Japan Medical Abstracts Society up to March 2015. We estimated summary statistics using the bivariate random effects model and performed subanalysis by dividing into tumor types-gliomas and metastatic brain tumors. RESULTS:Of 188 and 239 records extracted from the database, we included 20 and 26 studies in the analysis for RQ1 and RQ2, respectively. In RQ1, we used gadolinium (Gd)-enhanced MRI, diffusion-weighted image, MR spectroscopy, and perfusion CT/MRI to diagnose BRN in RQ1. In RQ2, 201Tl-, 99mTc-MIBI-, and 99mTc-GHA-SPECT, and 18F-FDG-, 11C-MET-, 18F-FET-, and 18F-BPA-PET were used. In meta-analysis, Gd-enhanced MRI exhibited the lowest sensitivity [63%; 95% confidence interval (CI): 28-89%] and diagnostic odds ratio (DOR), and combined multiple imaging studies displayed the highest sensitivity (96%; 95% CI: 83-99%) and DOR among all imaging studies. In subanalysis for gliomas, Gd-enhanced MRI and 18F-FDG-PET revealed low DOR. Conversely, we observed no difference in DOR among radiological imaging in metastatic brain tumors. However, diagnostic parameters and study subjects often differed among the same imaging studies. All studies enrolled a small number of patients, and only 10 were prospective studies without randomization. CONCLUSIONS:Differentiating BRN from TP using Gd-enhanced MRI and 18F-FDG-PET is challenging for patients with glioma. Conversely, BRN could be diagnosed by any radiological imaging in metastatic brain tumors. This review suggests that combined multiparametric imaging, including lesional metabolism and blood flow, could enhance diagnostic accuracy, compared with a single imaging study. Nevertheless, a substantial risk of bias and indirectness of reviewed studies hindered drawing firm conclusion about the best imaging technique for diagnosing BRN.

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High-resolution in-vivo analysis of normal brain response to cranial irradiation.

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