Lukas Carl Lundholm^{1}, Mikael Montelius^{1}, Oscar Jalnefjord^{1}, Emman Shubbar^{1}, Eva ForssellAronsson^{1}, and Maria Ljungberg^{1}
^{1}Department of Radiation Physics, Institute of Clinical Sciences, GĂ¶teborg, Sweden
Synopsis
Diffusion
MRI methods to characterize tumour tissue could facilitate early assessment of radiotherapy
response. In this study mouse models of human small intestine neuroendocrine
tumours were irradiated externally, and posttreatment effects were studied
over two weeks using VERDICT and kurtosis analysis of diffusion MRI measurements.
Results showed multiple correlations between tumour treatment response and
parameters estimated from the models, suggesting that a decrease of cell
density and microstructural barriers early after treatment indicates a more substantial
response. Both VERDICT and kurtosis analysis shows great potential for early
assessment of treatment response to external radiation therapy in the studied tumour
model.
Introduction
Noninvasive
methods for tumour tissue characterization would facilitate prediction and
early assessment of therapy response and thereby personalized treatment
planning. Diffusion weighted MRI (dMRI) is a promising technique for this
purpose and holds the potential to indirectly estimate microstructural
parameters beyond the conventional resolution limits of MRI. Two suggested dMRI
based models are the Vascular, Extracellular, and Restricted Diffusion for
Cytometry in Tumours (VERDICT)^{1} and kurtosis (DKI) models. VERDICT aims
to separate the MR signal coming from different tissue compartments and
utilizes multiple diffusion gradient timings and strengths to estimate
microstructural parameters such as cell size, intracellular (IC), vascular
(VASC) and extracellular extravascular (EES) volume fractions. DKI estimates
the presence of microstructural barriers and compartments by modelling the nongaussian
behaviour of the diffusing water molecules. DKI also provides estimates of the kurtosiscorrected
apparent diffusion coefficient.
To our
knowledge, studies using VERDICT and DKI for assessment of therapy response in
smallintestine neuroendocrine tumours (SINET) have not been conducted. The
aim of this study was to investigate if VERDICT and DKI analysis can be used
for early and longitudinal assessment of external radiation therapy response in
SINETs.Subjects and methods
Balb/C nude
mice (n=20) with subcutaneous SINET (GOT1) xenografts were irradiated
externally with an absorbed dose of 8 Gy to the tumour on day 0, using a 6 MV
photon beam (Varian Medical Systems). In
vivo dMRI experiments were conducted on days 1, 2, 3 as well as one week
(day 6 or 7) and two weeks (day 15) after the treatment using a 7T preclinical
MR system (Bruker, Biospec), table 1. The kurtosis model was fitted using an
inhouse built MATLAB (MathWorks, Natick, USA) software to the subset of the dMRI
experiments with TE=39 ms. The VERDICT model was fitted to the full set of dMRI
experiments using the AMICO framework^{2} where the EES and IC
compartments were described using the BallSphere model, and the VASC
compartment was described using a model which separates the blood flow from the
diffusion of the blood^{3}. To make the model fit more robust some
parameters of the VERDICT model were fixed. A grid search was used to find the
fixed parameter combination which yielded the lowest fitting cost function for
the entire data set (dIC=1x109
m^{2}/s, dEES=1.5x109 m^{2}/s, dVASC=1.75x109
m^{2}/s, vdVASC=0.6x103 m/s).
Tumour volumes were measured externally on days 4,
1, 0, 2, 3, 7, and 15 using callipers. The tumour treatment response (TTR) was
calculated according to
$$TTR=ln\left(\frac{V_{15}}{V'_{15}}\right)$$
where V_{15} is the measured tumour volume on day 15 and V'_{15} is the hypothetical nontreated tumour volume on
day 15 assuming an exponential growth based on volume measurements prior to the
treatment^{4}. Linear correlations between TTR
and estimated diffusion parameters were analysed using the Pearson correlation
coefficient (r).
The
Gothenburg Ethical Committee on Animal Research approved this study.Results & discussion
Out of the
parameters estimated by VERDICT, the IC and EES volume fractions showed the
most prominent trends early after treatment where the IC volume fraction tended
to decrease and the EES volume fraction tended to increase during the first
week (Fig 1), possibly indicating a reduction in cell density. The same trends
could also be qualitatively analysed and observed in parameter maps of the
estimated parameters (Fig 3), where the heterogeneity of the tumour tissues was
revealed as well.
Trends were
also observed for the parameters estimated with DKI where the kurtosiscorrected
diffusion coefficient (D_{k}) tended to increase and the kurtosis (K) tended to decrease during the
first week (Fig 2), suggesting a reduction in microscopical compartments and diffusion
barriers. After day 7 the progression of both VERDICT and DKI parameters showed
a more scattered result.
Multiple linear
correlations were found between TTR and estimated diffusion parameters early
after treatment (Fig 4). A relative increase of D_{k} (r = 0.60) and
EES volume fraction (r = 0.57) from day 1 to day 3 correlated with a higher
TTR. On the contrary, a relative decrease of K (r = 0.61) and IC volume
fraction (r = 0.67) from day 1 to day 3 correlated with a higher TTR. These
results suggest that early signs of reduced cell density and microscopical
barriers after treatment may indicate a more substantial response.
Additionally, a higher cell radius on day 3 correlated with a higher TTR (r =
0.54).Conclusion
Our results
show that VERDICT and kurtosis modelling of dMRI data holds great potential for
early assessment of tumour response to external radiation therapy in the GOT1
tumour model.Acknowledgements
No acknowledgement found.References

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