This study was in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of the Xijing Hospital of Air Force Military Medical University. The informed consent was obtained from all participants before collecting information. Data were analyzed and interpreted by the authors. All the authors reviewed the manuscript and vouch for the accuracy and completeness of the data and for the adherence of the study to the protocol.
66 volunteers were recruited to participate the study from May 2019 to February 2020. To be included in this study, subjects had to meet the following inclusion criteria: more than 18 years old, healthy and with normal pancreatic function, no any disease influencing pancreas. Exclusion criteria included common exclusion criteria for MRI scans and the use of Gd-related contrast agent, subjects with atherosclerotic disease influencing AIF, and poor DCE-MRI image quality. Poor image quality should mainly meet the criteria：severe motion artifacts appeared in enhanced MRI images and thus cannot be used for further evaluation. Finally, among 66 volunteers, four were excluded due to undesirable image quality, eight were excluded due to atherosclerosis, 54 volunteers were in the final cohort.
Prior to MR scanning, subjects were requested to fast at least 4 hours. MR images of the pancreases were acquired on a whole body 3.0 T MR scanner (Discovery MR750, GE Medical Systems, Chicago, IL, USA) with an eight-channel phased-array Torso coil. Using variable flip angle T1 mapping, pre-contrast three-dimensional spoiled gradient recalled echo sequence series were performed with flip angles of 3°, 6°, 9° and 12°. The other imaging parameters of T1 mapping were set as follows: repetition time (TR) = 3.2 msec, echo time (TE) = 1.5 msec, slice thickness = 4 mm, matrix = 260 x 160, field of view (FOV) = 360 x 360 mm2. Then, DCE-MRI scans were performed by a three-dimensional fast spoiled gradient recalled echo sequence for liver acquisition with volume acceleration (LAVA) with the following parameters: TR = 3.2 msec, TE = 1.5 msec, flip angle = 12°, FOV = 360 x 360 mm2, matrix = 260 x 160, slice thickness = 4 mm, bandwidth = 83.33 Hz/pixel. It took 240 sec to complete the DCE-MRI scanning with 40 phases acquired and 6 sec for each phase. After three pre-contrast phases were obtained, 0.1 mmol/kg of Gd-DTPA (Omniscan, GE Healthcare Co., Ltd., Shanghai, China) was administrated with a venous cannula at a rate of 2 ml/sec followed by a 20-ml saline flush at the same rate.
The DCE-MRI images were post-processed by Markov random fields (MRF) 3D non-rigid registration algorithms to correct motion artifacts. Then the images were transmitted to a workstation for quantitative analysis using DCE-MRI OK software package (Omni Kinetics, Version 2.00, GE Healthcare Co., Ltd.). The analysis process has the following steps. Firstly, the individual AIF was obtained from a region of interest (ROI) in abdominal aorta. Secondly, ROIs were manually drawn on pancreatic enhanced images on multiple slices without reaching the perimeter to avoid partial volume effect, meanwhile without inclusion of vessel and main pancreatic duct. Finally, ETL model[9, 10] was used to calculate the quantitative parameters: Ktrans, kep, ve and vp. The mean of each parameter in the ROIs was used for statistical analysis.
The first observer (XXX) measured DCE-MRI pharmacokinetic parameters thrice (by a time interval of at least one week to eliminate memory effect) to evaluate intra-observer reproducibility. Then, each of the three observers (observer 1, XXX, observer 2, YYY, and observer 3, ZZZ) measured parameters once to examine inter-observer reproducibility.
All subjects were divided into three groups owing to pancreatic region: pancreatic head (n = 54), body (n = 54) and tail (n = 54). Then, they were divided into three groups according to age: young (18 < age ≤ 40, median age 31, n = 18), middle (40 < age ≤ 60, median age 52, n = 18) and old-aged (age > 60, median age 68, n = 18), and two groups according to gender: male (n = 29) and female (n = 25).
Intra- and inter-observer differences in pharmacokinetic parameters
Intra- and inter-observer differences were evaluated using one-way analysis of variance (ANOVA). Intra- and inter-observer agreements of pharmacokinetic parameters were evaluated using the inter-class correlation coefficient (ICC). The agreement was defined as good (ICC > 0.75), moderate (ICC = 0.5 - 0.75), or poor (ICC < 0.5). Coefficients of variation (CoV) were computed as the proportion of the standard deviation of the mean (standard deviation/mean, expressed as percentage). For CoVs concerning the intra-observer variability, standard deviation was computed over three measurements by one observer. For CoVs describing the inter-observer variability, standard deviation was computed over each parameter obtained by all three observers.
Differences of pharmacokinetic parameters among different region, age and gender groups
Shapiro Wilk test was used for the normality distribution test. If the data conformed to the normal distribution, One-way ANOVA test and Independent Two-sample t test were used to evaluate the differences of pancreatic pharmacokinetic parameters obtained by observer 1. The former test was performed to evaluate the differences of pancreatic pharmacokinetic parameters among different pancreatic regions and different age groups. And the latter was used to exam the differences of parameters between male and female groups.
All statistical analyses were performed with the SPSS software Version 19.0. P values < 0.05 were considered to indicate a statistically significant difference.