Burst MRI in Cancer
— GR/M60613 and GR/M52533 Joint Final Report
This Final report describes research carried out during a 36-month period at two sites,
The University of Surrey (UniS), Guildford, Surrey and The Institute of Cancer Research
(ICR), Sutton, Surrey (with the Royal Marsden Hospital). On a day-to-day basis, the project was managed at both sites by Dr S Doran , who supervised Ms C Domenig , the project student recruited at UniS under the grant, and advised Dr M Bourgeois , the post-doc recruited at ICR.
Prof M Leach retained overall responsibility at ICR and provided scientific input and advice at all stages of the grant. This project represents the first research council grant received by Dr Doran.
The project sought to develop and evaluate an emerging Magnetic Resonance
Imaging technique, Burst . In the initial proposal, two platforms for the technique were envisaged: an existing 1.5 T clinical imaging scanner and a new 11.7 T research scanner, funding for which had already been secured at the time of writing of the grant. However, for reasons beyond the control of the applicants, installation of the high-field system was severely delayed and it did not, in fact, become fully operational until Summer 2002. This entailed a major — but, as it happily turned out, extremely fruitful — change in direction. This is fully detailed in Section C.
In terms of its revised remit, the project was extremely successful. Few imaging centres are given authorisation by the scanner manufacturers to modify imaging source code.
Of those that are, most incorporate only minor changes to the imaging module, leaving the internal looping and data storage structures unchanged. Implementation of an entirely new imaging method on a clinical scanner is a highly challenging task, particularly compared with the same task on a research scanner, whose programming architecture is very different. It often requires much sophisticated “trickery” to “persuade” the scanner to perform measurements that it has not been designed to do. We have achieved something that is normally attempted only by the manufacturers themselves and without the benefit of much proprietary technical information.
Both the scientists recruited were of high quality and performed well. As a result of the efforts of Dr Bourgeois, the development of Burst has been pushed to a point where it is limited either by the Physics of the processes involved (e.g., we have reached the intrinsic signal-to-noise limitations of the technique) or by the capabilities of the particular scanner
(e.g., the scanner’s gradient system fails to reproduce correctly the magnetic fields specified in the “pulse program”, leading to residual image artifacts).
The project has had a significant clinical , as well as technical , impact. Dr Doran and
Ms Domenig were key members of the team that showed for the first time ( The Lancet , 360,
307 –308 (2002)) that the diffusion coefficient of tumour water, measured prior to treatment, may predict the response to combined radiotherapy and chemotherapy treatment. This work has been widely publicised and a new clinical trial has been arranged to confirm these results.
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Burst MRI in Cancer
— GR/M60613 and GR/M52533 Joint Final Report
SNR=19 SNR=72 SNR~150
“Original” Burst “New” Burst “Best” EPI
Figure 1: Demonstration of improved image quality of our new Burst sequence over the original, and comparison with EPI, the fastest competitor method. The three images of a resolution phantom were all acquired in a single shot (original Burst 100 ms, 64

64 matrix, TE eff
~10 ms; new Burst 205 ms, 128

128, TE eff
= 22 ms; EPI 312 ms, 128

128, TE eff
= 85 ms) and are displayed with no additional smoothing applied. Image profiles demonstrate the capability of the sequence to resolve small features in the image and were measured on the ninth row of rods from the bottom (diameter 2.5 mm). The nominal resolution of the imaging methods is 4 mm for the original Burst and 2 mm for each of the other techniques. The new
Burst image has lower SNR than EPI and a low-level multiple ghost artifact, but EPI is slower (due to the need for fat-saturation) and has a less uniform image profile because of the coherent N/2 ghost artifact.
The primary aim of the project was to develop an improved version of the Burst sequence with improved spatial resolution and signal-to-noise ratio (SNR). This has been comprehensively achieved by Dr Bourgeois, who performed all the development, optimisation and testing of the Burst single-shot imaging sequences. The outcome, as detailed below, is at the upper limit of our original estimates in the grant application.
Our first task was to review the existing literature on all variants of the Burst technique and to develop calculations for the SNR at different spatial resolutions. The “original Burst” method (also known as OUFIS [1]) performs moderately well at low resolutions, but the SNR decreases very rapidly with increasing resolution. Although each of the techniques considered has merits in different situations, we chose to implement the version known as partial-Fourier, multi-refocusing Burst, which has by far the best SNR. Two authors [2, 3] had previously described similar methods, but our results demonstrate considerably superior resolution.
Figure 1 shows three images of the same phantom (test object). The new Burst sequence has a pixel area 4 times smaller than the original, yet an SNR a factor of almost 4 higher. One of the motivations for studying Burst was that it might provide an improvement over other ultra high-speed imaging sequences, so, throughout, we have compared our results with the best alternatives supplied by the scanner manufacturer, according to four key
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Burst MRI in Cancer
— GR/M60613 and GR/M52533 Joint Final Report
“Original” Burst “New” Burst
EPI HASTE
Figure 2: Comparison for different single-shot imaging sequences of the acquisition time, nominal resolution and normalised signal-to-noise as measured in the cerebellum, defined by SNRN = SNR/((acq. time) 1/2 area)): Original Burst 100 ms, 3.6

3.6 mm 2 , TE eff
. (pixel
~10 ms, SNRN=0.09; New Burst 230 ms, 1.8

1.8 mm 2 ,
SNRN = 0.37, TE mm 2 eff
~25 ms; EPI 248 ms, 1.8

1.8 mm 2 , SNRN = 0.45, TE eff
90 ms; HASTE 344 ms, 1.25

1.25
, SNRN = 1.58, TE eff
=59 ms; FLASH (image not shown) 1070 ms, 1.8

1.8 mm 2 , SNRN = 0.16, TE eff
=4.1 ms. The improvement of the new over the original Burst sequence is clear. The echo-planar image shows geometrical distortion artifacts, to which Burst is not susceptible. The HASTE image is noticeably blurred because of T
2
decay during the acquisition, so that the true resolution is worse than 1.25 mm. criteria: (i) spatial resolution; (ii) SNR; (iii) imaging speed; (iv) the presence of image artifacts.
The EPI image in Figure 2 has the same nominal resolution (2 mm) as our new Burst sequence, but the horizontal profile in the resolution test object clearly demonstrates better actual resolution by Burst. Burst acquires the data 35% faster than EPI, whilst the EPI shows a SNR advantage of approximately a factor of two. The EPI image demonstrates a clear N/2 ghost artifact, while Burst shows a lower level artifact that causes a slight blurring in the phase-encoding direction. Depending on the particular application, either one or other of these artifacts might be the more serious.
In addition to the new technique described above, our original application set as measureable objectives the development of two other types of Burst, a 3-D variant and the socalled STEAM-Burst technique [4]. This was done and, in all, some 10 –15 different variants of the method were programmed and tested on the scanner. Having selected the best approach, three target regions, brain, liver and pelvis, were selected. The performance of Burst was tested in each and compared with the competitor rapid imaging sequences EPI and HASTE.
Figure 2 shows a summary of the results obtained in the brain . The relative merits of the various techniques depend strongly on the local NMR relaxation times and the weighting desired. However, Burst is able to achieve a much shorter effective echo time than EPI and
EPI + “fat sat”
“New” Burst HASTE
Figure 3: Results obtained in the pelvis. Although of somewhat lower quality, the Burst images may be acquired acquiring up to 5 times as quickly as HASTE. Note that in both the pelvis and abdomen, EPI requires fat saturation to avoid severe ghosting artifacts. This means that the image contrast, and consequently the information available, are very different.
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Burst MRI in Cancer
— GR/M60613 and GR/M52533 Joint Final Report so, in the cerebellum, the SNR values (normalised to image acquisition time and nominal image resolution) are simila. There is no distortion artifact as with EPI. HASTE produces images with much higher SNR, but considerable blurring in the phase-encode direction.
In the liver , Burst did not prove to be competitive. We doubled the resolution and improved the SNR, but motion of the liver meant that techniques used in the brain and pelvis to compensate for gradient system imperfections and software limitations of the scanner were unsuccessful. More modern scanners would not exhibit this problem.
Figure 3 shows a comparison of images obtained in the pelvis . Although the nominal resolution of Burst is lower than for HASTE, there is significant blurring of the HASTE images in the phase-encoding direction due to T
2
decay during the acquisition. The acquisition time of
HASTE in the pelvis is rather long (up to 5 times more than Burst), primarily for regulatory reasons concerning RF power deposition. (Quantitative comparisons were not made because the scans were done on different volunteers.)
As described in Section C, measurements made early on in the project were extremely exciting and the project focus was changed to reflect this. The Burst quantitative diffusion sequence (described in the original proposal and previously programmed on the clinical scanner by Dr J Wolber) was incorporated into a very detailed protocol, that aimed to probe tissue morphology, function and metabolism. The protocol was applied to rectal carcinoma patients and produced a wide range of information on tumour change during treatment.
Analysis of the Burst data by Ms Domenig revealed a striking result: the apparent diffusion coefficient (ADC) of the tumour region measured before treatment was strongly correlated with the response to treatment [5] (Fig. 4a). Closer analysis revealed that, via a mechanism known as Intra-Voxel Incoherent Motion (IVIM), we may be able to measure simultaneously both the tissue diffusion coefficient and the tissue perfusion (Fig. 4b). Re-examining our initial data, we concluded that the key factor in our previous correlation was not the diffusion coefficient per se but the diffusion fraction (Fig. 4c) [6].
Work was performed by both Dr Bourgeois and Ms Domenig to generate an optimal quantitative diffusion sequence. The original Burst sequence had a number of major limitations, including poor SNR, linkage of the diffusion weighting to the field-of-view chosen and sensitivity to motion. The first two problems were solved but, whilst a navigator-echo version of the sequence was implemented to eliminate motion, further work is still required.
Whilst diffusion imaging of the brain has been successfully used for many years, quantitative diffusion measurements in the abdomen and pelvis are still technically challenging and there is as yet no consensus on the ideal MRI sequence for making them.
The group investigated three other possibilities as well as Burst: Ms Domenig developed segmented-EPI, whilst Dr Bourgeois investigated the application of PSIF and made the first application of the split-echo HASTE sequence to abdominal diffusion measurements. Dr
Bourgeois was also able to obtain encouraging preliminary data that should enable us to quantify diffusion anisotropy in the prostate.
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a
Burst MRI in Cancer
— GR/M60613 and GR/M52533 Joint Final Report b
0.0

0.2

0.4

0.6

0.8

1.0
0 50 100 150 200 250
Normalised b-value / s mm
300
-2
350 400 c
1.0
Figure 4: (a) Striking correlation in rectal carcinoma patients between tumour regression after chemo-radiation and pre-treatment tumour
ADC; (b) analysis of the Burst diffusion data for the tumour region-of-interest, suggesting that we may be observing a multi-exponential decay, as predicted by the IVIM model, in well perfused rectal tumours; (c) observed correlation between diffusion fraction and response to chemoradiation.
0.9
0.8
0.7
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0.5
-20 0 20 40 60
% regression in tumour size after combined CRT
80 100
All of the project milestones concerning the 1.5 T scanner were achieved, as specified in the timetable of our original grant application. Patient trials of quantitative Burst sequences occurred only for diffusion measurements, as the potential of Burst is still under investigation for quantitative perfusion mapping. An additional highlight of the Burst single-shot imaging programme was a successful collaboration with Prof R Ordidge (UCL), which demonstrated
Burst imaging on a 4.7 T whole-body imaging system. Initial results were extremely promising and future work is planned using the sequences later developed at 1.5 T.
As alluded to earlier, the 11.7 T scanner was not finally commissioned until 2½ years into the project. Three of the original co-applicants of the proposal (Drs Bifone, Padhani and
Rowland) left the Institute of Cancer Research early in the lifetime of the grant. Without the high-field machine, the expertise of Dr Rowland in pre-clinical work with contrast agents and the input of Dr Bifone on hyperpolarised xenon imaging, this part of the project could not proceed. By contrast, Dr A Dzik-Jurasz, Consultant Radiologist, coordinator of the rectal carcinoma study took a keen interest in the Burst project and gave valuable input during all three years. Under his supervision, Ms Domenig’s research topic was altered to “Development of a clinically useful diffusion imaging sequence for quantitative extracranial measurements”.
The change of emphasis of the project led to a number of achievements that had not been envisaged in the original project plan, most notably, the quantitative comparison of four different method of diffusion imaging (Burst, segmented-EPI, split-echo HASTE and PSIF) and the ability to compare Burst diffusion measurements with other functional and metabolic indices.
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Burst MRI in Cancer
— GR/M60613 and GR/M52533 Joint Final Report
In terms of reaching the largest number of people, the greatest impact of the project has undoubtedly been our finding concerning diffusion data in rectal cancers., which appeared in The Lancet [5], as an ICR Press Release [7], on the BBC [8] and in the UniS Physics
Department’s and the ICR’s Annual Reports. The diffusion measurement would not have been included in the original MRI study without Dr Doran’s interest in Burst and the data would not have been analysed in this way without the work of Ms Domenig. Work on Burst by the group, has been selected for presentation either orally or as a poster in every annual meeting of the International Society of Magnetic Resonance in Medicine (ISMRM) between 2000 and
2003, as well as at a number of other meetings. Publications have been submitted and more are in preparation (see IGR form). Other sources of dissemination have been the supply of
Burst sequences to other laboratories and visits by foreign researchers. On the strength of the diffusion work, Dr Doran has been asked to co-author a book chapter and, based on his work in rapid imaging, Dr Doran was invited to chair the session of Rapid Imaging at ISMRM 2001.
Expenditure on the project occurred largely as anticipated. However, three categories in the UniS budget require further explanation: (1) Travel: monies were requested for attendance of ISMRM 2002 in Honolulu. In the event the meeting coincided with the UniS
Physics undergraduate Board of Examiners and Dr Doran was unable to attend, with work being presented by Dr Bourgeois. Somewhat fewer journeys were made by car between UniS and ICR than anticipated, since electronic access between the two sites was so good.
(2) Equipment: During the course of the grant, one of the department’s pre-existing computers that had been used to analyse data for the project was required (by virtue of specialist equipment installed) to run another experiment. A new system for viewing the 3-D data generated was purchased to replace it. (3) Consumables: Only two consumable items were specified on the original form. In practice, a larger number of additional small spends was recorded (for example, manufacture of 35 mm slides at ~£100 per talk, and printing of A0 posters ~£100 each for conferences, purchase of a ZIP drive and disks for transfer of data from ICR to the University).
The diffusion methodology developed by this project has been incorporated into a new clinical imaging protocol for a currently active trial. Dr Doran will make a further application to
EPSRC for follow-up funding to make further developments. Further collaboration to implement the Burst single-shot imaging technique at 4.7 T is being discussed.
1. L. P. Zha and I. J. Lowe, Optimized Ultra-Fast Imaging Sequence (Oufis) , Magnetic Resonance in Medicine, 33 (3), 377-395 (1995)
2. L. Zha, W. Zhang, H. Avram, D. Goldhaber, R. Wagner and D. Kramer, T2-weighted multislice single-shot hybrid Burst spin echo imaging on a Standard 0.5T Scanner , in 5th ISMRM, Vancouver, 1997
3. P. Vangelderen, C. T. W. Moonen and J. H. Duyn, Susceptibility Insensitive Single-Shot Mri Combining Burst and Multiple Spin Echoes ,
Magnetic Resonance in Medicine, 33 (3), 439-442 (1995)
4. Y. Cremillieux, C. A. WheelerKingshott, A. Briguet and S. J. Doran, STEAM-Burst: A single-shot, multi-slice imaging sequence without rapid gradient switching , Magnetic Resonance in Medicine, 38 (4), 645-652 (1997)
5. A. Dzik-Jurasz, C. Domenig, M. George, J. Wolber, A. Padhani, G. Brown and S. Doran, Diffusion MRI: a potential tool for the prediction of response of locally advanced rectal cancer to neoadjuvant chemoradiation , The Lancet, 360 , 307-308 (2002)
6. C. Domenig, A. Dzik-Jurasz, M. O. Leach and S. J. Doran, Intravoxel Incoherent Motion Imaging: Evaluation of Diffusion and Pseudodiffusion Coefficients in Locally Advanced Rectal Tumours , Journal of Magnetic Resonance Imaging, (2002 (submitted))
7. I. o. C. Research, Researchers develop method of predicting success of treatment for rectal cancer patients , 14 January 2003, http://www.icr.ac.uk/press/releases/researchers.html
8. BBC, Cancer treatment success predicted , Monday, 13 January, 2003, 14:36 GMT, http://news.bbc.co.uk/1/hi/health/2654039.stm
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