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Characterizing tumor response to chemotherapy at various length scales using temporal diffusion spectroscopy.

Xu J, Li K, Smith RA, Waterton JC, Zhao P, Chen H, Does MD, Manning HC, Gore JC - PLoS ONE (2012)

Bottom Line: Following treatment, the ADC values obtained by both the PGSE and low frequency OGSE methods increased.This work is the first study to probe intracellular microstructural variations due to polyploidy following treatment using diffusion MRI in vivo.It is also the first observation of post-treatment ADC changes occurring in opposite directions at short and long diffusion times.

View Article: PubMed Central - PubMed

Affiliation: Institute of Imaging Science, Vanderbilt University, Nashville, Tennessee, United States of America. junzhong.xu@vanderbilt.edu

ABSTRACT
Measurements of apparent diffusion coefficient (ADC) using magnetic resonance imaging (MRI) have been suggested as potential imaging biomarkers for monitoring tumor response to treatment. However, conventional pulsed-gradient spin echo (PGSE) methods incorporate relatively long diffusion times, and are usually sensitive to changes in cell density and necrosis. Diffusion temporal spectroscopy using the oscillating gradient spin echo (OGSE) sequence is capable of probing short length scales, and may detect significant intracellular microstructural changes independent of gross cell density changes following anti-cancer treatment. To test this hypothesis, SW620 xenografts were treated by barasertib (AZD1152), a selective inhibitor of Aurora B kinase which causes SW620 cancer cells to develop polyploidy and increase in size following treatment, ultimately leading to cell death through apoptosis. Following treatment, the ADC values obtained by both the PGSE and low frequency OGSE methods increased. However, the ADC values at high gradient frequency (i.e. short diffusion times) were significantly lower in treated tumors, consistent with increased intracellular restrictions/hindrances. This suggests that ADC values at long diffusion times are dominated by tumor microstructure at long length scales, and may not convey unambiguous information of subcellular space. While the diffusion temporal spectroscopy provides more comprehensive means to probe tumor microstructure at various length scales. This work is the first study to probe intracellular microstructural variations due to polyploidy following treatment using diffusion MRI in vivo. It is also the first observation of post-treatment ADC changes occurring in opposite directions at short and long diffusion times. The current study suggests that temporal diffusion spectroscopy potentially provides pharmacodynamic biomarkers of tumor early response which distinguish microstructural variations following treatment at both the subcellular and supracellular length scales.

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The R values in all four imaging group measured by the OGSE method.CT2 and CT4 are 2- and 4-day control groups; and TX2 and TX4 are 2- and 4-day treatment groups.
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pone-0041714-g005: The R values in all four imaging group measured by the OGSE method.CT2 and CT4 are 2- and 4-day control groups; and TX2 and TX4 are 2- and 4-day treatment groups.

Mentions: The ADC measurements from 50 Hz to 250 Hz were fit to a straight line by linear regression and the slope R was calculated. Figure 5 shows the percentage change in R values in all four imaging groups (CT2, CT4, TX2 and TX4). For both the 2-day and 4-day control groups, and the 2-day treatment group, R did not change significantly after the injections of drug/vehicle, while for the 4-day treatment group R decreased significantly after the treatment (−44% in mean with 95%CI = (−53%, −35%), p = 0.016 given by the Wilcoxon signed-rank test). The Kruskal-Wallis test gives p = 0.002 for all four groups, and the Wilcoxon rank sum test shows that the percentage change in R values of 4-day treatment group is significantly different from those of all other three groups (CT2, CT4 and TX2), indicating that ΔR was able to capture the microstructural variations of tumors in 4-day treatment group. The relatively large percentage change of R (−44% in mean) compared to ΔADC obtained by the PGSE method (%29 in mean) and OGSE at f = 250 Hz (−13% in mean) may imply that R might be a more sensitive probe for assessing tumor response because it incorporates changes in both cellularity and intracellular structures. This is consistent with previous ex vivo findings that the rate of ADC changes can reveal more subtle structural differences between different types of mouse brain tissues [26].


Characterizing tumor response to chemotherapy at various length scales using temporal diffusion spectroscopy.

Xu J, Li K, Smith RA, Waterton JC, Zhao P, Chen H, Does MD, Manning HC, Gore JC - PLoS ONE (2012)

The R values in all four imaging group measured by the OGSE method.CT2 and CT4 are 2- and 4-day control groups; and TX2 and TX4 are 2- and 4-day treatment groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404000&req=5

pone-0041714-g005: The R values in all four imaging group measured by the OGSE method.CT2 and CT4 are 2- and 4-day control groups; and TX2 and TX4 are 2- and 4-day treatment groups.
Mentions: The ADC measurements from 50 Hz to 250 Hz were fit to a straight line by linear regression and the slope R was calculated. Figure 5 shows the percentage change in R values in all four imaging groups (CT2, CT4, TX2 and TX4). For both the 2-day and 4-day control groups, and the 2-day treatment group, R did not change significantly after the injections of drug/vehicle, while for the 4-day treatment group R decreased significantly after the treatment (−44% in mean with 95%CI = (−53%, −35%), p = 0.016 given by the Wilcoxon signed-rank test). The Kruskal-Wallis test gives p = 0.002 for all four groups, and the Wilcoxon rank sum test shows that the percentage change in R values of 4-day treatment group is significantly different from those of all other three groups (CT2, CT4 and TX2), indicating that ΔR was able to capture the microstructural variations of tumors in 4-day treatment group. The relatively large percentage change of R (−44% in mean) compared to ΔADC obtained by the PGSE method (%29 in mean) and OGSE at f = 250 Hz (−13% in mean) may imply that R might be a more sensitive probe for assessing tumor response because it incorporates changes in both cellularity and intracellular structures. This is consistent with previous ex vivo findings that the rate of ADC changes can reveal more subtle structural differences between different types of mouse brain tissues [26].

Bottom Line: Following treatment, the ADC values obtained by both the PGSE and low frequency OGSE methods increased.This work is the first study to probe intracellular microstructural variations due to polyploidy following treatment using diffusion MRI in vivo.It is also the first observation of post-treatment ADC changes occurring in opposite directions at short and long diffusion times.

View Article: PubMed Central - PubMed

Affiliation: Institute of Imaging Science, Vanderbilt University, Nashville, Tennessee, United States of America. junzhong.xu@vanderbilt.edu

ABSTRACT
Measurements of apparent diffusion coefficient (ADC) using magnetic resonance imaging (MRI) have been suggested as potential imaging biomarkers for monitoring tumor response to treatment. However, conventional pulsed-gradient spin echo (PGSE) methods incorporate relatively long diffusion times, and are usually sensitive to changes in cell density and necrosis. Diffusion temporal spectroscopy using the oscillating gradient spin echo (OGSE) sequence is capable of probing short length scales, and may detect significant intracellular microstructural changes independent of gross cell density changes following anti-cancer treatment. To test this hypothesis, SW620 xenografts were treated by barasertib (AZD1152), a selective inhibitor of Aurora B kinase which causes SW620 cancer cells to develop polyploidy and increase in size following treatment, ultimately leading to cell death through apoptosis. Following treatment, the ADC values obtained by both the PGSE and low frequency OGSE methods increased. However, the ADC values at high gradient frequency (i.e. short diffusion times) were significantly lower in treated tumors, consistent with increased intracellular restrictions/hindrances. This suggests that ADC values at long diffusion times are dominated by tumor microstructure at long length scales, and may not convey unambiguous information of subcellular space. While the diffusion temporal spectroscopy provides more comprehensive means to probe tumor microstructure at various length scales. This work is the first study to probe intracellular microstructural variations due to polyploidy following treatment using diffusion MRI in vivo. It is also the first observation of post-treatment ADC changes occurring in opposite directions at short and long diffusion times. The current study suggests that temporal diffusion spectroscopy potentially provides pharmacodynamic biomarkers of tumor early response which distinguish microstructural variations following treatment at both the subcellular and supracellular length scales.

Show MeSH
Related in: MedlinePlus