Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 28, 2016; 22(24): 5520-5531
Published online Jun 28, 2016. doi: 10.3748/wjg.v22.i24.5520
Intravoxel incoherent motion diffusion-weighted imaging for monitoring chemotherapeutic efficacy in gastric cancer
Xiao-Li Song, Heoung Keun Kang, Gwang Woo Jeong, Kyu Youn Ahn, Yong Yeon Jeong, Yang Joon Kang, Hye Jung Cho, Chung Man Moon
Xiao-Li Song, Heoung Keun Kang, Yong Yeon Jeong, Yang Joon Kang, Department of Radiology, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, South Korea
Gwang Woo Jeong, Chung Man Moon, Department of Radiology, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 501-757, South Korea
Kyu Youn Ahn, Hye Jung Cho, Department of Anatomy, Chonnam National University Medical School, Gwangju 501-746, South Korea
Author contributions: Song XL and Jeong YY designed the studies; Song XL, Kang YJ and Moon CM performed the majority of experiments; Song XL, Ahn KY, Kang YJ and Cho HJ contributed to the analysis and interpretation of imaging date and histological examination; Song XL wrote the first draft of the manuscript; Jeong GW and Kang HK have approved the final manuscript and completed manuscript; Also, all authors agree with the content of the manuscript.
Supported by National Research Foundation of South Korea, No. NRF-2013R1A1A2013878 and No. 2015R1A2A2A01007827.
Institutional animal care and use committee statement: All procedures involved animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Chonnam National University [CNU IACUC-H-2015-41].
Conflict-of-interest statement: The authors declared that they have no conflicts of interest to this work.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Heoung Keun Kang, MD, Professor of Medicine, Department of Radiology, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, South Korea. hkkang@jnu.ac.kr
Telephone: +82-61-3797101 Fax: +82-61-3797133
Received: February 24, 2016
Peer-review started: February 25, 2016
First decision: March 31, 2016
Revised: April 12, 2016
Accepted: April 20, 2016
Article in press: April 20, 2016
Published online: June 28, 2016
Abstract

AIM: To assess intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for monitoring early efficacy of chemotherapy in a human gastric cancer mouse model.

METHODS: IVIM-DWI was performed with 12 b-values (0-800 s/mm2) in 25 human gastric cancer-bearing nude mice at baseline (day 0), and then they were randomly divided into control and 1-, 3-, 5- and 7-d treatment groups (n = 5 per group). The control group underwent longitudinal MRI scans at days 1, 3, 5 and 7, and the treatment groups underwent subsequent MRI scans after a specified 5-fluorouracil/calcium folinate treatment. Together with tumor volumes (TV), the apparent diffusion coefficient (ADC) and IVIM parameters [true water molecular diffusion coefficient (D), perfusion fraction (f) and pseudo-related diffusion coefficient (D*)] were measured. The differences in those parameters from baseline to each measurement (ΔTV%, ΔADC%, ΔD%, Δf% and ΔD*%) were calculated. After image acquisition, tumor necrosis, microvessel density (MVD) and cellular apoptosis were evaluated by hematoxylin-eosin (HE), CD31 and terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining respectively, to confirm the imaging findings. Mann-Whitney test and Spearman's correlation coefficient analysis were performed.

RESULTS: The observed relative volume increase (ΔTV%) in the treatment group were significantly smaller than those in the control group at day 5 (ΔTVtreatment% = 19.63% ± 3.01% and ΔTVcontrol% = 83.60% ± 14.87%, P = 0.008) and day 7 (ΔTVtreatment% = 29.07% ± 10.01% and ΔTVcontrol% = 177.06% ± 63.00%, P = 0.008). The difference in ΔTV% between the treatment and the control groups was not significant at days 1 and 3 after a short duration of treatment. Increases in ADC in the treatment group (ΔADC%treatment, median, 30.10% ± 18.32%, 36.11% ± 21.82%, 45.22% ± 24.36%) were significantly higher compared with the control group (ΔADC%control, median, 4.98% ± 3.39%, 6.26% ± 3.08%, 9.24% ± 6.33%) at days 3, 5 and 7 (P = 0.008, P = 0.016, P = 0.008, respectively). Increases in D in the treatment group (ΔD%treatment, median 17.12% ± 8.20%, 24.16% ± 16.87%, 38.54% ± 19.36%) were higher than those in the control group (ΔD%control, median -0.13% ± 4.23%, 5.89% ± 4.56%, 5.54% ± 4.44%) at days 1, 3, and 5 (P = 0.032, P = 0.008, P = 0.016, respectively). Relative changes in f were significantly lower in the treatment group compared with the control group at days 1, 3, 5 and 7 follow-up (median, -34.13% ± 16.61% vs 1.68% ± 3.40%, P = 0.016; -50.64% ± 6.82% vs 3.01% ± 6.50%, P = 0.008; -49.93% ± 6.05% vs 0.97% ± 4.38%, P = 0.008, and -46.22% ± 7.75% vs 8.14% ± 6.75%, P = 0.008, respectively). D* in the treatment group decreased significantly compared to those in the control group at all time points (median, -32.10% ± 12.22% vs 1.85% ± 5.54%, P = 0.008; -44.14% ± 14.83% vs 2.29% ± 10.38%, P = 0.008; -59.06% ± 19.10% vs 3.86% ± 5.10%, P = 0.008 and -47.20% ± 20.48% vs 7.13% ± 9.88%, P = 0.016, respectively). Furthermore, histopathologic findings showed positive correlations with ADC and D and tumor necrosis (rs = 0.720, P < 0.001; rs = 0.522, P = 0.007, respectively). The cellular apoptosis of the tumor also showed positive correlations with ADC and D (rs = 0.626, P = 0.001; rs = 0.542, P = 0.005, respectively). Perfusion-related parameters (f and D*) were positively correlated to MVD (rs = 0.618, P = 0.001; rs = 0.538, P = 0.006, respectively), and negatively correlated to cellular apoptosis of the tumor (rs = -0.550, P = 0.004; rs = -0.692, P < 0.001, respectively).

CONCLUSION: IVIM-DWI is potentially useful for predicting the early efficacy of chemotherapy in a human gastric cancer mouse model.

Keywords: Gastric cancer, Microvessel density, Nude mouse model, Intravoxel incoherent motion diffusion-weighted imaging, Terminal-deoxynucleoitidyl transferase mediated nick end labeling

Core tip: Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) is useful for monitoring changes of molecular diffusion and microcirculation in gastric cancer at the early stage of chemotherapy. The apparent diffusion coefficient (ADC) and IVIM parameters of true water molecular diffusion coefficient (D) could be reliable marker to detect the necrosis and cellular apoptosis, while perfusion-related IVIM parameters of perfusion fraction (f) and pseudo-related diffusion coefficient (D*) are capable of noninvasive assessment of angiogenesis activity in gastric cancer undergoing chemotherapy.