Elles Elschot1, Lieke van den Wildenberg1, Vitaly Khlebnikov1, Dennis Klomp1, and Jannie Wijnen1
1Radiology Department, UMC Utrecht, Utrecht, Netherlands
Synopsis
This study investigates
the relation between B1+ and signal amplitude of the APT and MT exchange pools in CEST MRI. We examined 19 breast
cancer patients that underwent NAC treatment with CEST MRI at 7T. The data
indicates evidence for an extra exchanging pool with strong B1
dependence, that is more abundant in tumor tissue compared to healthy tissue. By
identifying the exchanging components in this pool, a new biomarker for tumor
tissue could be found and used to understand changes in response to NAC early
during treatment.
Introduction
Nowadays neoadjuvant chemotherapy (NAC) is the preferred treatment for
early-stage breast cancer. NAC is a systemic therapy whereby cytotoxic drugs
are administered before surgery or radiation therapy, with the intention to
reduce tumor size and make breast conserving surgery possible for patients who
otherwise required mastectomy.1,2 However 30% of the patients do not
respond to NAC3 and for these patients it would be beneficial
to predict the pathological response early on in the course of treatment, to
properly adjust the treatment for every patient individually. In this study,
changes in metabolism of tumor tissue are investigated using amide proton
transfer (APT) CEST MRI at an ultra-high field MR system (7T). The
concentration of proteins and the intracellular exchange rate is
increased in tumor tissue.4,5 Dula et al. showed that NAC may have an effect on these features.6
APT CEST at high-field benefits from high signal to noise ratio (SNR) and
increased chemical shift dispersion, making the technique reproducible with a
high level of precision and improving the sensitivity of APT signals to
therapeutic response.7 Moreover, at higher field strengths, the
wavelength of the radio frequency pulse is reduced, resulting in transmit (B1+)
field inhomogeneities that can be used to study CEST contrast mechanism in
detail. This study was performed to evaluate the effect of B1+
on CEST MRI in breast cancer patients at an ultra-high-field MR system.Methods
CEST MRI was
performed in 19 breast cancer patients treated with NAC before and after the
first cycle of chemotherapy on a whole-body 7T MR scanner (Achieva, Philips
Health Care, Cleveland, OH, USA) in prone position using a dual-quadrature
double-tuned radiofrequency coil.8 A series of 20 sinc-Gauss RF-saturation
pulses (pulse duration: 100ms, inter pulse delay: 100ms, nominal B1+
peak amplitude: 2µT) resulting in a 4s saturation train (50% duty cycle)
followed by a gradient-echo readout.9 33 Frequency offsets were
acquired resulting in a scan time of 4:55min. These offsets were not equally
distributed over the frequencies; more offsets were obtained around the amide
peak (3.5 ppm) and the water peak (0.0 ppm) for better fitting of these
resonances. The frequency offsets associated with the nuclear Overhauser effect
(NOE) were not included due to signal distortions by unsuppressed lipid
resonances. CEST images were B0 corrected using the original CEST spectra as input for the WASSR method10
and quantified using a three-pool Lorentzian fit (water, APT and metabolic
transfer (MT)) of the Z-spectra in the tumor as well as in healthy tissue. The
calculated APT and MT maps were obtained using the amplitude of the fits. Tumor
tissue masks were obtained using a region growing algorithm on intensity
difference images of the first and last acquisition of a dynamic contrast
series (Figure 1). The correlation between B1+ and CEST
signal was investigated for APT and MT and compared between healthy and tumor
tissue. Because the quality of the B1+ maps acquired (AFI, TE=1.981ms, TR1=40ms, TR2=200ms,
FA=30°)
is suboptimal in some regions where B1+ is low, the
template approach developed by Rijssel et al. was used.11 The
simulated B1+ distribution of the generic template12 was scaled to patient specific values using a linear least squares approach
between the template and the measured B1+ maps for both
breasts separately.Results
Figure 2 shows the
results of the three pool Lorentzian fitting of the Z-spectrum of one patient. Looking
at the correlation between APT and B1+, healthy tissue
showed a positive correlation (R2=0.12747; Figure 3). However, in the tumor tissue a negative correlation between APT and
B1+ was observed (R2=0.50093). The MT signal
showed a positive correlation with B1+ in healthy tissue (R2=0.48253)
and an even stronger positive correlation in
tumor tissue (R2=0.70834; Figure 4). These results indicate that an
additional pool is present in the
tumor tissue, which might cause overfitting of MT and under fitting of APT.Discussion
As can be seen in
Figures 3 and 4 the B1+ field has a certain effect on the
data. An increase in absolute intrinsic signal is expected considering the
relation of B1+ with B1-. The remaining
effect could be explained by an additional exchange pool with strong B1+
dependence, which results in imperfect fitting of MT and APT. Further research is
needed to identify and quantify the exchanging metabolites in the “hidden pool”
we found in our data. The stronger increase at higher B1+ points to
a fast exchanging molecule at lower ppm.Conclusion
This study shows an indication for an exchange pool with strong B1+
dependence, that is more abundant in tumor tissue compared to healthy tissue.
By identifying the metabolites in this pool a new biomarker for tumor tissue could
be found and used to understand changes in response to NAC early during
treatment.Acknowledgements
We would like to thank the Dutch Cancer Society (Alpe d'Huzes project number: UU 2013‐6302) for
financial support.
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