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The development and application of functional nuclear magnetic resonance to in vivo therapeutic anticancer research

2002 Sir Godfrey Hounsfield lecture delivered at the President's Day, Manchester

The Cancer Research UK Clinical Magnetic Resonance Research Group, Institute of Cancer Research and the Royal Marsden NHS Trust, Sutton, Surrey SM2 5PT, UK

View larger version (63K): [in a new window]   Figure 1. Sir Godfrey Hounsfield (left) and the title of his 1979 Nobel lecture (top right) together with a diagram illustrating the variation in precessional frequency in nuclei exposed to a magnetic gradient orthogonal to the main field (bottom right) from the same lecture. © The Nobel Foundation.

View larger version (16K): [in a new window]   Figure 2. Behaviour of NMR signal intensity in response to a bolus intravenous dose of paramagnetic contrast agent. The signal intensity was derived from the tumour that had previously been outlined. The T1 weighted sequence records a rise in signal intensity due to shortening of the spin-lattice relaxation time of water protons. With a T2* weighted sequence there is a transient loss of signal intensity due to the sequence detecting a first pass effect of the contrast agent. The rapid change in the local magnetic fields induced by the first pass of contrast agent induces a strong susceptibility effect. The area under the T2* curve is theoretically related to the blood volume in the region of interest.

View larger version (14K): [in a new window]   Figure 3. Association of the measured capillary permeability in the locally advanced rectal cancers in our study with response following chemotherapy. The association indicates that tumours exhibiting a greater capillary permeability (as measured by Ktrans) are more likely to respond to treatment than those that are not. If this association does reflect underlying biology then it may be related to drug delivery. Alternatively it may simply be reflecting a particularly susceptible phenotype. Ktrans is expressed as the logarithm since the transform resulted in a normal distribution of the data.

View larger version (124K): [in a new window]   Figure 4. Example of two locally advanced rectal tumours with (a), (b) high and (c), (d) low permeability. The top images are the anatomical axial T2 images whilst the lower two demonstrate a "permeability" (capillary leakiness) map overlaying the two tumours. The colour scale is shown on the left of images (b) and (d) and permits an appreciation of the extent of capillary leakiness within individual voxels based on modelling kinetic contrast agent data (in this case Gd-DTPA, gadolinium(III) diethylenetriamine pentaacetic acid). Our results indicate that rectal tumours with a higher permeability (b) are more likely to respond to chemotherapy than those with low permeability (d). Our findings are independent of original tumour size.

View larger version (124K): [in a new window]   Figure 5. Tumours with a greater relative blood volume were more likely to respond to chemotherapy than those with a lower or no recordable blood volume. The top images (a and c) are the T2 weighted axial anatomical images of the tumours and the lower two images are the relative blood volume or "susceptibility" maps. The "susceptibility" maps arise from a first pass effect of contrast agent through the tumour inducing a susceptibility effect. Although the physical effect is manifest as a signal loss, the scale has been inverted to highlight the areas of signal loss. The tumour illustrated on the left (a and b) demonstrates a strong "susceptibility" effect whilst there was no recordable signal loss in the tumour on the right (c and d). The tumour on the right is less likely to respond to chemotherapy than the one on the right.

View larger version (85K): [in a new window]   Figure 6. Results of studying locally advanced rectal cancer using quantitative diffusion weighted imaging. A typical low-b value image (top left) of a large tumour and the resulting diffusion image (top right). The two graphs demonstrate that those tumours with a low apparent diffusion coefficient (ADC) (and by implication of higher cellularity) prior to treatment are more likely to respond to chemotherapy (bottom left) and chemoradiation (bottom right) than those that are not. Based on evidence from animal tumours we have argued that the ADC measurements in this situation are a surrogate marker for necrosis. Graphs reprinted with permission from Elsevier [11].

View larger version (12K): [in a new window]   Figure 7. Association between the measure of capillary permeability (Ktrans) and the serum vascular endothelial growth factor (VEGF) platelet ratio. The association supports, though far from proves, that MR based measures of vascularity, in this case capillary permeability are related to the underlying angiogenic process. Platelets normally carry VEGF and therefore we were concerned to account for the patient's platelet count, hence the expression of the ratio.

View larger version (70K): [in a new window]   Figure 8. A short (echo time (TE)=20 ms) (top) and long (TE=135 ms) (bottom) single voxel 1H-MR spectrum (repetition time (TR)=1500 ms in both cases) from a locally advanced rectal cancer. The principal resonances are labelled and include "choline" (due to trimethylamine protons -N+(CH3)3) a marker of cell membrane turnover and the methyl (-CH2-) and methylene (-CH3) resonances of saturated lipid. The long T2 of the "choline" species compared with that of the lipids explains the relatively greater persistence of the "choline" peak over that of lipids in the long echo time spectrum (bottom left). The three orthogonal T1 localizer images are shown on the right and demonstrate the voxel sited within the confines of the tumour. Reproduced with permission, John Wiley & Sons, Inc.

View larger version (12K): [in a new window]   Figure 9. The catabolic pathway of 5-fluorouracil (5FU). The majority of this process occurs in the liver and the rate-limiting step is the conversion of 5FU to dihydrofluorouracil by the enzyme dihydropyrimidine dehydrogenase. The principal catabolite is -fluoro--alanine that is predominantly excreted in urine. The species carboxy-fluoro-beta alanine (carboxy-FBAL) is rarely encountered since its formation is highly pH dependent. It would normally form under acidic conditions, which is rarely found in the liver and almost never in bile.

View larger version (167K): [in a new window]   Figure 10. Exclusive 19F resonance arising from the gallbladder of an individual receiving protracted venous infusion of 5-fluorouracil (5FU). This example demonstrates a half Fourier single-shot turbo spin echo (HASTE) image of the upper abdomen with the 19F chemical shift imaging (CSI) grid overlain. The high signal intensity structure in the middle left grid is the gallbladder. In CSI, signals are acquired from each of the grids. Note the absence of a 19F resonance from the liver. The methodological set-up allowed the accurate determination of the resonant frequency of a particular chemical 19F species. We now believe the gallbladder resonance is due to bile acid conjugated -fluoro--alanine. Reproduced with permission, John Wiley & Sons, Inc [39].

View larger version (28K): [in a new window]   Figure 11. (a) Unlocalized and (b and c) single voxel 19F experiments in a patient receiving a bolus dose of 5-fluorouracil (5FU). The two black arrows indicate the expected resonance of -fluoro--alanine (right arrow) and bile acid conjugated -fluoro--alanine (left arrow). Note how both resonances are visible in the (a) unlocalized sequence. As expected, -fluoro--alanine is detected in the liver (b) and note the single resonance detected in the gallbladder centred on the expected resonance of bile acid conjugated -fluoro--alanine.