Experimental And Clinical Study Of The MSCT Imaging Of Blood Supply Correlated With Pathology In Brain Gliomas

Background and Objective:The biological behaviour was closely correlated to angiogenesis in gliomas and other tumors. Tumor angiogenesis is well recognized as an essential process for tumor growth, invasion and metastasis. However, the tumor-associated and newly grown capillary vessels were immature and could ascend regional blood volume and vasopermeability. Previous studies indicated that there was conspicuous positive correlation between growth, invasive power and capillary permeability in malignant gliomas and that a specific antiangiogenic approach could efficiently cut down the microvascular permeability and step down the growth velocity of tumors.Nowadays, a large number of agents were under development targeting different points in the angiogenic process of the glioma and hoped to be used in clinical practice in recent years. For these reasons, the simple anatomical and morphological evaluation of the glioma with radiologic techniques was unable to satisfy development of modern medical science. Studies based on the tumor angiogenesis is one of the significant directions of the radiologic development.With widespread clinical application of antiangiogenic and genic therapies in the near future, developments in angiogenesis imaging have gained greater impetus. The need for imaging surrogates that inform on drug action noninvasively has been widely recognized. With advent of fast and multi-slice spiral computed tomography (MSCT) scanners, CT perfusion (CTP) imaging technique is able to assess human tumors with respect to their angiogenic status in vivo, and has a world of applied perspective for expectancy grading and evaluation of therapeutic effect of gliomas.But, because of its restricted anatomic coverage at the initial stage, CTP was seldomly used to study the angiogenesis of gliomas so far. The CTP parameters of the healthy adult brain and the animal brain correlated to glioma models, so it was a necessity to completely establish normal value data. Only a few reports focused on the haemodynamic investiga- tions of the human cerebrum and basal ganglia. In the meantime, the reproducibility of CTP applied small animal has also not been validated. As a favourable technique, CT angiography (CTA) was used to display blood vessels, it may be used to quantitatively study the new vessels of gliomas.The study aimed directly to study the above-mentioned shortages in blood supply imaging territory of gliomas, achieve the normal CTP hemodynamic parameters in rat brain with a 64-slice MSCT scanner, and evaluate the precision and accuracy of the multislice CTP applied small experimental animals. Moreover, the C6 brain gliomas of Wistar rat were inoculated, and MRI, CTP and pathologic techniques were used to observe the growing and angiogenic patterns of these C6 gliomas. The relationship of the radiologic and pathologic results was also analyzed statistically. Eventually, the angiogenesis of 30 human brain astrocytic tumors was detected by CTA and CTP techniques, and the obtained results were compared with postoperative pathologic results. With a ROC analytical method, the sensitivity and specificity of astrocytic tumor grading with the CTA and CTP could also be computed easilly.Study Methods:1.Fifteen health Wistar rats underwent CTP scanning twice with a 2-day interval between scans. CTP data were processed by 2 radiologists. For assessment of intra- and inter- observer variability, and consistency of 2 CTP results, each observer repeated processing of 2 CT perfusion data sets.2.Forty adult Wistar rats underwent intracerebral inoculation with C6 cells by a stereotaxic apparatus. MRI, CTP and pathologic techniques were used to observe the growing and angiogenic patterns of C6 gliomas in three different periods with 5-10 d, 10-15 d and 15-20 d post inoculation. The relationship of the radiologic and pathologic results was analyzed statistically.3.Fifty-three patients with brain tumors underwent CTP and CTA examination, and the astrocytic tumors confirmed by operation and pathology were selected as the object of this study. The main observation contents included the tumor vessel contents (TVC), maximum perfusion regional CTP parameters and MVD in tumor areas, and the cerebral vessel contents (CVC) and CTP parameters of normal brain tissue in opposite side. Finally, these obtained data were used to evaluate the relationship among TVC, CTP parameters and MVD, the difference of various kinds indicators between low and high grade astrocytic tumors, and the sensitivity and specificity of astrocytic tumor grading with the TVC and CTP parameters.Study Results:1.There was significant difference (P<0.05 or 0.01) in the CBF and CBV parameters among different areas of the Wistar rat brain. The maximum CBF and CBV area was cerebellum, next basal ganglia and bulbus medullae, the minimum CBF and CBV area was cerebral cortex. Nevertheless, there was no significant difference in the MTT parameters among different areas (P>0.05). When raw data were analyzed by two different radiologists, simple regression analyses performed on combined intra- and interobserver variability data indicated a strong linear relationship in both cases for values of CBV, CBF and MTT. CT perfusion imaging also demonstrated little variability within individuals when studied on two occasions within 2 days.2.After rat intracerebral inoculation with C6 cells, the gross tumor volume showed exponential growth with time. There was significant difference (P<0.01) in the gross tumor volume between radiologic and pathologic measurement results of the comparatively large tumors in the 15-20 d stage. In the 5-15 d stage, the angiogenesis of the rat C6 gliomas showed proliferation progressively and reached a peak in the 10-15 d period. Soon after, the blood vessel numbers decreased gradually in the 15-20 d stage. But, the tumor PS value might be ascending constantly. When simple regression analyses performed on CTP parameters and MVD value of rat C6 gliomas, CBF and CBV with strongly and positively correlated with tumor MVD and Pearson correlations, respectively, were as follows: CBF and MVD, r=0.730, P<0.01; CBV and MVD, r=0.917, P<0.01; but, PS and MTT without correlated with tumor MVD: PS and MVD, r=0.067, P>0.05; MTT and MVD, r=0.002, P>0.05.3.When CBF, CBV, PS, TVC and MVD were compared among the human brain high and low grade astrocytic tumors, and normal brain tissue in opposite side, with significant difference (P<0.01). But, the MTT wasn't significantly different (P>0.05) among high and low grade astrocytic tumors, and normal brain tissue in opposite side. When Spearman rank correlated analyses was performed on CTP parameters and TVC values of astrocytic tumors; CBF, CBV and PS with strongly and positively correlated with tumor TVC, Spearman rank correlations, respectively, were as follows: CBF and TVC, rs=0.792, P<0.01; CBV and TVC, rs=0.687, P<0.01; PS and TVC, rs=0.666, P<0.01; but, MTT without correlated with TVC (rs=-0.357, P>0.05). When simple regression analyses performed on CTP parameters and MVD values of astrocytic tumors, CBF, CBV and PS with strongly and positively correlated with tumor MVD, Pearson correlations, respectively, were as follows: CBF and MVD, r=0.819, P<0.01; CBV and MVD, r=0.862, P<0.01; PS and MVD, r=0.776, P<0.01; but, MTT without correlated with MVD (r=-0.320, P>0.05). In addition, a strongly and positively rank correlation was also foud between TVC and MVD (rs=0.805, P<0.01).4.The under-ROC curve areas of the CBF, CBV, PS and TVC values used to differentiate high and low grade astrocytic tumors were respectively 0.914, 0.876, 0.914 and 0.928. When the optimal limit values of these indicators for differentiation of high and low grade astrocytic tumors were selected as follows: CBF=62.635 ml·min?1·100g?1, CBV= 4.310 ml·100g?1, PS=5.925 ml·min?1·100g?1 and TVC=48.295%, the sensitivity was 84.2% uniformly and the specificity was 81.8%, 81.8%, 91.9% and 91.9% respectively. Only MTT was unable to differentiate high and low grade astrocytic tumors, its under-ROC curve areas was 0.455 (P>0.05).Study Conclusion:1.Multi-slice spiral CTP has a high degree of precision and accuracy for measure- ments of cerebral hemodynamics in normal Wistar rats and hence is fully suitable to study the hemodynamics and angiogenesis of small animal models. The distribution of cerebral blood flow shows a world of difference in the Wistar rat brain. The maximum regional hemoperfusion was cerebellum, next basal ganglia and bulbus medullae. But, there is a lower hemoperfusion with the cerebral cortex.2.After rat intracerebral inoculation with C6 cells, the volume of tumor enlarges in an exponential manner with time. The fast voluminal increase of tumors and PS values may be the main factors leading to a deteriorative pathogenetic condition with the inoculated rats in advanced stage, which slao supports that the development of clinical symptoms is closely correlated to the growing pattern of tumors and the impaired degree of BBB after rat intracerebral inoculation with C6 cells. In CTP parameters, the PS value is one of important indicators to reflect the peculiarity of tumor vessels, the CBF and CBV are very sensitive indicators to reflect the microvessel numbers, and these parametric values are determined the tumorous category and malignant degree. Therefore, multiple utilization of CTP para- meters may be helpful to more accurately identify the category and malignant degree of human tumors.3.With regard to the angiogenesis of rat C6 glioma model, because the tumors take place vascular proliferation only within 15 days, and minority rats may present autoimm- unity activity resulting in the spontaneous regression of the C6 gliomas, the angiogenic characteristics itself and the potential autoimmunity activity should be considered in selection of the intervention time and observation period when the model is used to estimate therapeutic effect of new drugs.4.By detecting microcirculation, the multislice CTP is able to quantitatively evaluate the angiogenesis of glioma. The CTP parameters are strongly correlated with tumor MVD and high sensitivity and specificity for differential diagnosis of high and low grade astrocytic tumors, which are very important indicators reflecting the angiogenesis and malignant degree of glioma. Moreover, TVC (one of CTA tumor vessel contents) with strong and positive correlation with tumor MVD, CBF, CBV and PS values may be a valuable adjunct indicator for evaluation of proliferative vessels and malignant degree of glioma.