Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2017; 23(11): 1990-2001
Published online Mar 21, 2017. doi: 10.3748/wjg.v23.i11.1990
Chemotherapy response evaluation in a mouse model of gastric cancer using intravoxel incoherent motion diffusion-weighted MRI and histopathology
Jin Cheng, Yi Wang, Chun-Fang Zhang, He Wang, Wei-Zhen Wu, Feng Pan, Nan Hong, Jie Deng
Jin Cheng, Yi Wang, Wei-Zhen Wu, Feng Pan, Nan Hong, Department of Radiology, Peking University People’s Hospital, Beijing 100044, China
Chun-Fang Zhang, Clinical Epidemiology and Medical Statistics, Peking University People’s Hospital, Beijing 100044, China
He Wang, GE Healthcare, Shanghai 200050, China
Jie Deng, Department of Medical Imaging, Ann and Robert H. Lurie Children’s Hospital of Chicago, Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-2605, United States
Author contributions: Cheng J performed the animal experiments, reviewed the experimental and histological data, and wrote the manuscript; Wang Y designed the entire scientific research, instructed manuscript writing, and revised the manuscript; Zhang CF instructed the statistical analysis; Wang H adjusted the parameters of IVIM-DWI scanning; Wu WZ performed the animal experiments and recorded the experimental data; Pan F performed the animal experiments and recorded the experimental data; Hong N instructed the animal experiments and revised the manuscript; Deng J wrote the Metlab program of the bi-exponential IVIM model and analyzed the IVIM parameter data.
Institutional review board statement: The study was reviewed and approved by the Peking University People’s Hospital Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Peking University People’s Hospital (IACUC protocol number: 2013-0010).
Conflict-of-interest statement: All authors declared that there was no conflict of interest related to this study.
Data sharing statement: Technical appendix, statistical code, and dataset are available from the corresponding author at wangyi@pkuph.edu.cn. Participants gave informed consent for data sharing.
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: Yi Wang, MD, Department of Radiology, Peking University People’s Hospital, 11 Xizhimen South St., Beijing 100044, China. wangyi@pkuph.edu.cn
Telephone: +86-10-88325813 Fax: +86-10-68318386
Received: December 22, 2016
Peer-review started: December 23, 2016
First decision: January 10, 2017
Revised: January 19, 2017
Accepted: February 17, 2017
Article in press: February 17, 2017
Published online: March 21, 2017
Abstract
AIM

To determine the role of intravoxel incoherent motion (IVIM) diffusion-weighted (DW) magnetic resonance imaging (MRI) using a bi-exponential model in chemotherapy response evaluation in a gastric cancer mouse model.

METHODS

Mice bearing MKN-45 human gastric adenocarcinoma xenografts were divided into four treated groups (TG1, 2, 3 and 4, n = 5 in each group) which received Fluorouracil and Calcium Folinate and a control group (CG, n = 7). DW-MRI scans with 14 b-values (0-1500 s/mm2) were performed before and after treatment on days 3, 7, 14 and 21. Fast diffusion component (presumably pseudo-perfusion) parameters including the fast diffusion coefficient (D*) and fraction volume (fp), slow diffusion coefficient (D) and the conventional apparent diffusion coefficients (ADC) were calculated by fitting the IVIM model to the measured DW signals. The median changes from the baseline to each post-treatment time point for each measurement (ΔADC, ΔD* and Δfp) were calculated. The differences in the median changes between the two groups were compared using the mixed linear regression model by the restricted maximum likelihood method shown as z values. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. The median percentage changes were compared with the histopathological analyses between the pre- and post-treatment for each measurement.

RESULTS

Compared with the control group, D* in the treated group decreased significantly (ΔD*treated% = -30%, -34% and -20%, with z = -5.40, -4.18 and -1.95. P = 0.0001, 0.0001 and 0.0244) and fp increased significantly (Δfptreated% = 93%, 113% and 181%, with z = 4.63, 5.52, and 2.12, P = 0.001, 0.0001 and 0.0336) on day 3, 7 and 14, respectively. Increases in ADC in the treated group were higher than those in the control group on days 3 and 14 (z = 2.44 and 2.40, P = 0.0147 and P = 0.0164).

CONCLUSION

Fast diffusion measurements derived from the bi-exponential IVIM model may be more sensitive imaging biomarkers than ADC to assess chemotherapy response in gastric adenocarcinoma.

Keywords: Xenografts, Intravoxel incoherent diffusion-weighted magnetic resonance imaging, Chemotherapy, Treatment response, Gastric adenocarcinoma

Core tip: In a mouse gastric cancer model, we demonstrated that the intravoxel incoherent motion (IVIM)-derived tissue perfusion coefficient (D*) decreased, whereas perfusion fraction (PF) increased immediately after chemotherapy and during the treatment course. No considerable overlaps were observed in D* and PF measurements between the treated and control groups. IVIM-derived perfusion measurements offer a potential accurate evaluation of chemotherapeutic efficacy. This imaging study is ready to be translated into a clinical study and may facilitate individualized treatment strategy and prompt treatment adjustment in gastric cancer patients.