title: Intravoxel incoherent motion diffusion-weighted imaging for monitoring chemotherapeutic efficacy in gastric cancer.
abstract: OBJECTIVE
  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/mm(2)) 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 (r s = 0.720, P < 0.001; r s = 0.522, P = 0.007, respectively). The cellular apoptosis of the tumor also showed positive correlations with ADC and D (r s = 0.626, P = 0.001; r s = 0.542, P = 0.005, respectively). Perfusion-related parameters (f and D(*)) were positively correlated to MVD (r s = 0.618, P = 0.001; r s = 0.538, P = 0.006, respectively), and negatively correlated to cellular apoptosis of the tumor (r s = -0.550, P = 0.004; r s = -0.692, P < 0.001, respectively).
  
  
  CONCLUSIONS
  IVIM-DWI is potentially useful for predicting the early efficacy of chemotherapy in a human gastric cancer mouse model.
authors.affiliation: 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.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Heoung Keun
authors.initials: HK
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Gwang Woo
authors.initials: GW
authors.lastname: Jeong
authors.affiliation: 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.
authors.forename: Kyu Youn
authors.initials: KY
authors.lastname: Ahn
authors.affiliation: 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.
authors.forename: Yong Yeon
authors.initials: YY
authors.lastname: Jeong
authors.affiliation: 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.
authors.forename: Yang Joon
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: 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.
authors.forename: Chung Man
authors.initials: CM
authors.lastname: Moon
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D020287:In Situ Nick-End Labeling; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D002955:Leucovorin; D005472:Fluorouracil
keywords: Gastric cancer; Intravoxel incoherent motion diffusion-weighted imaging; Microvessel density; Nude mouse model; Terminal-deoxynucleoitidyl transferase mediated nick end labeling