Ethics
This prospective single-center cohort was approved by our hospital's institutional review board and followed the ethical guidelines of the Declaration of Helsinki. Written informed consent was obtained from each patient before inclusion.
Study population
This study was conducted from February 2019 to January 2020. Fourteen patients with diagnosed HCC, according to the BCLC classification system, were enrolled initially and underwent pretreatment MRI examinations. Inclusion criteria were as follows (1) previously untreated tumor, (2) BLCB stage B tumor without vascular invasion and extrahepatic spread, (3) Child–Pugh grade A or B liver disease, (4) no contraindication for MRI examinations, who were candidates TACE palliative or bridging therapy. Exclusion criteria consisted of (1) glomerular filtration rate < 60, (2) Child–Pugh grade C, (3) total bilirubin > 4.0 mg/dL, (4) platelet count < 50/000/mL, (5) serum creatinine > 2.0 mg/dL. Two patients were excluded because of limited diffusion imaging quality, rendering interpretation impossible. Post-treatment MRI (30–45 days) scanning was evaluated based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) [19]. Patients with stable disease (SD) or progressive disease (PD) were classified into the nonresponse group, and patients with partial response (PR) or complete response (CR) were classified into the response group.
MRI technique
MRI investigations were performed on a 3.0 T scanner (GE-DISCOVERY MR750W; GE Healthcare) using a commercially available phased array body coil. All patients had fasted for at least 4–6 h before examination and coached on breathing and breath-holding techniques. Conventional MR imaging protocols included breath-hold 2D spin-echo (SE) T1-weighted sequence (TE/TR: 109 ms/4.2 ms, flip angle (FA): 90°, field of view (FOV): 252 × 325 mm, slice thickness: 5 mm, slice gap: 1 mm). T2-weighted GRE sequence (2D multi-echo fast GRE, TE/TR: 47.7 ms/1.4 ms, FA: 25°, FOV: 296 × 3040, matrix size: 128 × 128, slice thickness: 8 mm, slice gap: 1 mm) sequences with breath-hold. The diffusion-weighted imaging was performed by using a respiratory triggered single-shot SE echo-planar imaging (EPI) sequence in the transverse plane. Fifteen b values from 0 to 1500 s/mm2 (0, 10, 20, 30, 40, 50, 70, 90, 100, 120, 150, 500, 600, 1000, and 1500) were applied. The acquisition parameters of DWI sequences were as follows: FA: 90°, FOV: 192 × 160 mm, TR /TE: 5000–12,000/73 ms, number of slices: 14, slice thickness: 7 mm, slice gap: 1 mm.
TACE treatment
Patients received TACE from two interventional radiologists with 15 and 20 years of experience. Angiography was performed by femoral artery puncture, and the catheter advanced to celiac artery, which was further placed in the tumor-feeding arteries through selective access of the catheter into the feeding artery. Once the catheter was accurately positioned, an angiogram was used to visualize the tumor. Then, an emulsion consisting of doxorubicin (60 mg), mitomycin (6 mg), and lipiodol (80 mg) was delivered into the catheter and released inside the feeder artery. After surgery, the catheters were pulled out, followed by local compression and pressure bandaging.
Quantification of MR images
The ADC values were estimated by fitting diffusion-weighted signals at all b values (0–1500 s/mm2) to the following mono-exponential equation:
$$\frac{{S_{b} }}{{S_{0} }} = \exp \left( { - b \cdot ADC} \right)$$
where Sb is the signal intensity at a given b value, and S0 is the signal intensity without diffusion weighting. Diffusion signal is affected by blood flow in the capillary network and cerebrospinal fluids at low b values (i.e., less than 100–200 s/mm2). Here to calculate coefficients of diffusion, a bi-exponential IVIM quantification model was used as follows [18]:
$$\frac{{S_{b} }}{{S_{0} }} = \left( {1 - f} \right) \cdot \exp \left( { - b \cdot D} \right) + f \cdot \left( { - b \cdot D*} \right)$$
where \(S_{0}\) is the signal at b value of zero, \(f\) (fraction of perfusion) is the percentage of a voxel volume occupied by capillaries, D (true diffusion coefficient) is the diffusion parameter representing pure molecular diffusion (“1-f” reflects the extravascular space where only diffusion effects), and \(D^{*}\) (pseudo-diffusion coefficient) is the proportion of the pseudo-diffusion and reflects dephasing due to perfusion in semi-randomly organized capillaries.
A board-certified abdominal radiologist, who was blinded to all clinical, laboratory, and follow-up information, delineated the regions of interest (ROIs) on the HCC lesions. Borders were drawn along the edge of the tumor on the original images of the DWI sequences by referring to the conventional T1-and T2-weighted images. Tumor size was defined as the maximum diameter of each lesion. The ROIs were automatically copied to the ADC and IVIM maps to obtain the mean apparent diffusion coefficient (ADC), true molecular diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) values for each ROI. For each parameter, the average value of all ROIs was calculated.
Statistical analysis
We performed analyses in SPSS (Windows ver. 18; IBM SPSS Inc.) Descriptive data are presented in mean ± SD /frequency and percentage. We evaluated data normality by Kolmogorov–Smirnov test. We acquired an Independent sample t test for continuous variables with normal distribution, Mann–Whitney U test for continuous not-normal, and Chi-square test for nominal variables. Univariate and multivariate logistic regression analyses were used to identify independent factors for tumor response to TACE in the response group. The final prediction model was derived from the multivariate (backward stepwise) logistic regression analysis results. To define optimum cutoff values for most significant parameters for tumor response to TACE, receiver-operating characteristic (ROC) curves were drawn, and Youden’s J index [20] was used. All p values less than 0.05 were considered statistically significant.