Diagnostic detection of diffuse glioma tumors in vivo with molecular fluorescent probe-based transmission spectroscopy
(a) Segmented mouse head boundary with skin, brain, and bone regions defined. (b) Mouse head mesh with slice showing the skin, brain, bone, and adipose regions. In (c) a fiber optic source-detector pair is shown for transmittance measurement. In (d) positioning of eight fiber optics are shown. The signal relative to tumor size and the tumor contrast is plotted with the measured contrast in the color scales of (e)–(h). In (e) is the contrast with tumor positioned at the center of brain using a single source-detector pair for measurement. In (f) the same tumor position was used, with eight sources and detectors and averaged measurements. In (g) the contrast from an off center tumor, using a single source-detector pair is shown, and in (h) the signal from the off center tumor is shown with all eight fiber measurements averaged together.
Three representative examples of mice implanted with U251-GFP brain tumors. The first three rows illustrate ex vivo data, with the top row showing PpIX fluorescence and the second row showing GPF fluorescence and the third row showing the corresponding image. The bottom two rows illustrate in vivo T1 turbospin echo (TSE) contrast enhanced (CE) MRI, with the next to the bottom row showing MRI 29 days after tumor implantation and the bottom row showing MRI 35 days following implantation. All three cases show that the PpIX fluorescence images, the GFP images and images show tumor at the same location. The MRI image in (a) shows the tumor is well demarcated by T1 TSE CE MRI. However, this is an anomalous case and most U251-GFP tumors are most similar to those shown in (b) and (c) where the tumor is not well demarcated in the T1 TSE CE MRI and very difficult to visualize.
Three representative examples of mice implanted with 9L-GFP brain tumors. The first three rows illustrate ex vivo data, with the top row showing PpIX fluorescence, the second row showing GPF fluorescence, and the third row showing the corresponding image. The bottom row illustrate in vivo T1 turbospin echo (TSE) contrast enhanced (CE) MRI. In (a) it can be seen that the PpIX fluorescence is largely confined to the bulk tumor, although a portion of the tumor tissue does not appear to have PpIX production as compared to the corresponding GFP and images. However, most of the examples of this tumor line show PpIX production patterns more similar to those illustrated in (b) and (c) where the PpIX fluorescence is only in the periphery of the tumor tissue and not necessarily in the bulk tumor. As can be seen in (a)–(c), the 9L-GFP tumor is well demarcated by T1 TSE CE MRI.
All graphs show tumor signal/signal on contralateral side of brain, with an inset ROC curve comparing the control animals with each tumor-bearing group. (a) TI TSE CE MRI for 9L-GFP, U251, and U251-GFP tumor-bearing mice. The control mice did not have implanted tumors, but did have sham surgery. (b) T2 TSE MR for 9L-GFP, U251, U251-GFP, and control mice. The T1 TSE CE and T2 TSE MRI allow for visualization of the 9L-GFP and U251 tumor-bearing mice as compared to the control mice. However, both conventional imaging sequences fail to discern the U251-GFP tumors in the mice. Additional MR imaging sequences were conducted for the U251-GFP mice, the contrasts of which are illustrated in (c). The MRI sequences included T1 TSE with contrast and T1 TSE without contrast, providing the ability for difference imaging, T1 fast field echo (FFE), T2 fluid attenuated inversion recovery (T2 FLAIR), and T1 inversion recovery (TI IR).
PpIX and EGF-IRDye fluorescence spectroscopy measurements were collected for mice with diffuse growing and bulk growing tumor tissue. (a) In vivo PpIX fluorescence 2 h after the administration of ALA. (b) In vivo EGF-IRDye fluorescence 24 h following intravenous administration. ROC curves are inset to illustrate detection of each tumor type over non-tumor-bearing control mice for each fluorophore.
Example EGF-IRDye detection of 9L-GFP and U251-GFP intracranial tumors. (a) Ex vivo EGF-IRDye, GFP, and sections of a representative mouse from the U251-GFP group are shown in the first row. Qualitatively corresponding in vivo MRI images of the same section are shown in the second row. (b) Ex vivo EGF-IRDye, GFP, and sections of a representative mouse from the 9L-GFP group are shown in the first row. Qualitatively corresponding in vivo MRI images of the same section are shown in the second row.
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