Evaluation of the ablation margin of hepatocellular carcinoma using CEUS-CT/MR image fusion in a phantom model and in patients
Li et al. BMC Cancer
Evaluation of the ablation margin of hepatocellular carcinoma using CEUS-CT/ MR image fusion in a phantom model and in patients
Kai Li 0
Zhongzhen Su 0
0 Equal contributors Department of Ultrasound, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou 510630, Guangdong Province , People's Republic of China
Background: To assess the accuracy of contrast-enhanced ultrasound (CEUS)-CT/MR image fusion in evaluating the radiofrequency ablative margin (AM) of hepatocellular carcinoma (HCC) based on a custom-made phantom model and in HCC patients. Methods: Twenty-four phantoms were randomly divided into a complete ablation group (n = 6) and an incomplete ablation group (n = 18). After radiofrequency ablation (RFA), the AM was evaluated using ultrasound (US)-CT image fusion, and the results were compared with the AM results that were directly measured in a gross specimen. CEUS-CT/MR image fusion and CT-CT / MR-MR image fusion were used to evaluate the AM in 37 tumors from 33 HCC patients who underwent RFA. Results: The sensitivity, specificity, and accuracy of US-CT image fusion for evaluating AM in the phantom model were 93.8, 85.7 and 91.3%, respectively. The maximal thicknesses of the residual AM were 3.5 ± 2.0 mm and 3.2 ± 2.0 mm in the US-CT image fusion and gross specimen, respectively. No significant difference was observed between the US-CT image fusion and direct measurements of the AM of HCC. In the clinical study, the success rate of the AM evaluation was 100% for both CEUS-CT/MR and CT-CT/MR-MR, and the duration was 8.5 ± 2.8 min (range: 4-12 min) and 13.5 ± 4.5 min (range: 8-16 min) for CEUS-CT/MR and CT-CT/MR-MR, respectively. The sensitivity, specificity, and accuracy of CEUS-CT/MR imaging for evaluating the AM were 100.0, 80.0, and 90.0%, respectively. Conclusions: A phantom model composed of carrageenan gel and additives was suitable for the evaluation of HCC AM. CEUS-CT/MR image fusion can be used to evaluate HCC AM with high accuracy.
Tumor ablation; Phantom model; CEUS; CT; Image fusion
Radiofrequency ablation (RFA) is a radical treatment for
hepatocellular carcinoma (HCC) and has a relatively low
risk [1, 2]. However, recent studies have shown that
HCC patients undergoing RFA have a higher rate of
local tumor progression (LTP) compared with HCC
patients treated with resection [3–6]. Independent factors
associated with LTP include tumor size, sub-capsular
location, blood vessel proximity, and an insufficient
ablation margin (AM) [7–15]. The term “ablative margin”
refers to the 0.5 to 1.0-cm-wide region of normal tissue
around the tumor that should ideally be removed during
tumor ablation [16, 17]. Therefore, AM is one of the
most important factors for the prediction of LTP in
HCC patients after RFA [18–20]. However, regular
medical imaging methods, including CT, MR, and
contrastenhanced ultrasound (CEUS), are not able to accurately
evaluate AM because the tumor and surrounding
normal liver tissue mix and merge in the ablative area, and
the boundary between normal tissue and the ablative
area is difficult to identify. Thus, using the current
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imaging methods, it is challenging to determine whether
the zone of ablation encompasses the range of the AM
around the index tumor.
In recent years, novel medical imaging methods have
been explored to assess AM in HCC patients after
ablation, including CT-CT image fusion [21, 22], MR-MR
image fusion [23, 24], contrast-enhanced ultrasound
(CEUS)-CT/MR image fusion [18, 25], MR with
impaired clearance of ferucarbotran [26, 27], and MR with
gadolinium ethoxybenzyl diethylene triamine pentaacetic
acid . Our group has reported that CEUS-CT/MR
image fusion, which can be applied intraoperatively, is
useful for assessing AM in HCC patients receiving
ablation . An accurate evaluation of AM based on
CEUS-CT/MR image fusion allows physicians to
perform supplementary ablation, increasing the number of
adequate AM and reducing the probability of LTP.
However, direct measurement of AM in HCC patients is not
feasible because the gross specimen is usually
unavailable in ablation patients. Therefore, the rate of LTP has
been widely used as the standard to evaluate the
accuracy of AM in most studies. Tumor tissues that are not
covered by AM during HCC ablation are usually a major
cause of LTP. However, AM is not the only independent
factor associated with LTP after ablation. Therefore, the
accuracy of CEUS-CT/MR image fusion in assessing
AM should be further evaluated.
In this study, we established a phantom model to
evaluate AM based on US-CT image fusion. The aim of
this study was to assess the accuracy of CEUS-CT/MR
image fusion for the evaluation of the AM of liver
tumors, both in an in vitro phantom model and in the
clinic. The gross specimen of the phantom after RFA
was used as a gold standard. The clinical AM results
obtained using CEUS-CT/MR image fusion and MR-MR/
CT-CT image fusion were compared.
The materials used to construct the phantom model
included carrageenan (Dehui Marine Biological Technology
Cor., Ltd., Qingdao, China) and a number of additives such
as oral ultrasonic contrast agent (Hangzhou Huqingyutang
Medical Technology Cor., Ltd., Hangzhou, China), gastric
window contrast agent (Huqingyutang Cor., Hangzhou,
China), milk, and Congo red.
Establishment of the phantom model
The phantom model included a spherical tumor model
(2 cm in diameter, Fig. 1a), an AM model (a 5-mm layer
of AM gel around the tumor model, Fig. 1b), and a
cylindrical parenchyma model (10 cm in height and
diameter, Fig. 1c), in which the AM model was embedded
(Fig. 1d). Bamboo sticks in the parenchyma model were
used as registration and positional marks.
The shape, height, and gradient of the phantom model
were tested at 1 h, 6 h, and 12 h after construction of
the model. The structure of the phantom model and the
position of the marks were checked using both
ultrasound and observation of the gross specimen.
A total of 24 phantom models were randomly divided
into two groups, including a complete ablation group
(n = 6) in which the ablative area was covered by AM and
an incomplete ablation group (n = 18) in which the
ablative area was not covered by AM.
RFA was performed with a cooled-tip RFA system
(Covidien, Mansfield, MA, USA) using a 17-gauge,
Fig. 1 a A spherical tumor model (2 cm in diameter) made of carrageenan in red. b Section of the AM model: the carrageenan tumor model
surrounded by the 5-mm AM gel in white. c Cylindrical-shaped parenchyma model (10 cm in height and 10 cm in diameter of the upper and
lower plane). d Section of the cylindrical-shaped parenchyma model. e CT image showing the tumor. The scope of AM could not accurately
evaluated. f US image showing the tumor. The boundary between the tumor and AM gel was not clear
internally cooled-tip electrode with a 3-cm tip. A MyLab
Twice ultrasound machine (Esoate, Genoa, Italy) and a
linear probe LA332 (frequency range from 3 to 11 MHz)
with imaging fusion (Virtual Navigation System) and
three-dimensional software were employed for
ultrasound guidance and exploration.
An ablative area model was established by ablating the
tumor model. Electrodes were inserted into the
cylindrical model parenchyma via ultrasound guidance by an
experienced ultrasound interventional doctor. The RFA
was set in impedance mode with maximum output.
According to our pilot studies, the duration of ablation was
4 and 6 min for the incomplete and complete ablation
groups, respectively. After ablation, the liver tumor
model together with the AM model and a portion of the
parenchyma model were melted and mixed. An ablative
area model was established after cooling and solidifying
the melted gel.
Evaluation of AM by US-CT image fusion
Each phantom CT scan was performed without contrast
medium prior to ablation. The CT scan was performed
using a 64-row multi-detector CT scanner (VCT 64
slices; GE Medical Systems). The following CT
parameters were applied to acquire dynamic data: 1-s
gantry rotation time, 120 kV, 80 mA, acquisition in 264
transverse mode (64 sections per gantry rotation), and
2.5-mm reconstructed section thickness (Fig. 2A-1, B-1).
The model was positioned horizontally with the
guidance of a horizontal laser instrument.
Image fusion was performed by an experienced
ultrasound doctor who was blinded to the ablation. A series of
CT data in DICOM format were uploaded in fusion mode
into the ultrasound system to automatically generate
images. The areas of the tumor model and 5-mm AM in the
3D CT images were outlined using red and blue circles,
respectively. At the beginning of image fusion, the
Fig. 2 (A-1) and (B-1): CT images of the models. (A-2) and (B-2): US-CT image fusion of the area of ablation (left arrow). The AM was not fully
encompassed by the area of ablation (right arrow, A-2). The tumor and AM were completely encompassed by the area of ablation (B-2). (A-3): The
AM was not completely encompassed by the area of ablation in the gross specimen (left arrow). (B-3): The AM was completely encompassed by
the area of ablation in the gross specimen. The tumor is shown in blue, and the AM gel is indicated in red (5 mm)
registration marks in the phantom models were used to
choose one transverse section of the CT image and the
ultrasound image of the same section. The CT and
ultrasound images were then overlapped and fused. After
registration of this section, additional fine tuning was
performed to enable a more precise adaptation. The
distance between the CT and ultrasound images of the same
registration mark in overlapping mode could be measured
and used as the error of image fusion. A successful image
fusion was defined when the error of image fusion of all
registration marks was less than 2 mm. Otherwise, the
registration was repeated. The image fusion was
considered a failure if a successful fusion could not be achieved
after three attempts. In overlapping mode, inclusion of the
tumor within the ablative area of the model and the AM
mode could be decided. The position and thickness of the
thickest part of the AM model was recorded if the AM
was not completely covered (Fig. 2A-2, B-2).
Evaluation of the AM in the gross specimen
The phantom was cut along the section showing the
thickest residue in the AM model by image fusion.
Whether the AM model had been fully ablated was
examined, and the maximal thickness of the AM model
residue was measured. In addition, the results of the
US-CT image fusion and gross specimen were compared
to calculate the sensitivity, specificity, and accuracy of
US-CT image fusion for the evaluation of AM model
residue (Fig. 2A-3, B-3).
Ethics statement and study populations
This study was approved by the Institute Research
Medical Ethics Committee of the Third Affiliated
Hospital of Sun Yat-Sen University and was in
compliance with the Declaration of Helsinki. Informed consent
was obtained from all participants. From January 2014
to April 2014, a total of 33 HCC patients who
underwent RFA in our hospital were enrolled in this study. All
liver lesions meeting the Milan criteria were
pathologically or clinically diagnosed as HCC . Inclusion
criteria were as follows: the ablation zone of the tumors
was evaluated by CEUS-CT/MR image fusion after RFA.
Exclusion criteria were as follows: 1) failure to obtain
CT/MR data in DICOM format from the patient
preoperatively; 2) the patient did not receive a CT/MR
examination 1–2 months after RFA; 3) different image
methods (CT and MR) were applied preoperatively and
postoperatively, precluding image fusion; 4) ultrasound
and CT/MR images could not be successfully fused; 5)
the patient was allergic to ultrasound contrast agents.
was performed under endotracheal anesthesia. All RFA
procedures were performed by two experienced
ultrasound physicians with more than 5 years of RFA
experience. According to the routine examination, previously
determined plan, and multiple needle ablations for larger
tumors, all HCC lesions, including the 5-mm AM, were
successfully ablated. CEUS-CT/MR image fusion was
performed approximately 10 min after RFA to evaluate
the efficacy of RFA and to guide the supplementary
CEUS-CT/MR image fusion
CEUS-CT/MR image fusion was performed using the
MyLab Twice (Esaote, Italy) ultrasound unit and convex
array transducer CA431 (4–10 MHz) 10–15 min after
ablation. Virtual Navigator was the image fusion
program and CnTI (MI <0.05) was the imaging technique
for contrast-enhanced ultrasound in the ultrasound unit.
SonoVue (Bracco, Italy) was used as the contrast agent.
For each application, 2.4 ml of SonoVue was
administered through the antecubital vein and flushed by 5 ml
of normal saline.
The method of CEUS- CT/MR image fusion used in
this study had been reported in our former article .
The CT/MR image series in DICOM format were
transferred into the navigation system and 3D image volume
was generated. Different colors were used to outline the
tumor and 5-mm AM (Figs. 3A-2, 4A-2). After planar
registration, more precise fusion was acquired through
additional refinement. Then CEUS was performed and
the image of CEUS was overlapped with the CT/MR
image to see whether the area of CEUS had covered the
tumor as well as the AM region.
CT-CT/MR-MR image fusion
Contrast-enhanced CT/MR was performed 1 month
before and after the RFA for all patients. AM was further
evaluated using CT-CT/MR-MR image fusion if the CT/
MR at 1 month after RFA revealed that the lesion was
One CT/MR portal or delayed phase series with a
clearly demonstrated hepatic vessel and ablative area
before RFA in DICOM format was transferred into the
navigation system in MyLab Twice. One month after
RFA, another series of CT/MR images were also
imported into the image fusion system. The system then
automatically displayed six pictures in two rows: the
upper row included the transaction, coronal and vertical
section CT/MR images before RFA, and the lower row
showed the corresponding CT/MR images after RFA.
The HCC lesion in the CT/MR before RFA was
manually outlined, and then a 5-mm AM was set
automatically in different colors (Figs. 3b, 4b).
Fig. 3 Medical images of case 1 in the clinical study. (A-1) CUES image of the area of ablation (dark). (A-2). Preoperative MR image (tumor shown
in blue, and 5-mm AM shown in yellow). (A-3) CEUS-MR fusion image. The tumor and 5-mm AM were fully encompassed by the area of ablation.
b MR-MR fusion image of case 1. Upper panel: preoperative MR images (tumor shown in blue, and 5-mm AM shown in yellow). Middle panel:
postoperative MR images (arrow, ablation area shown in dark color). Lower panel: MR-MR fusion images showing that the tumor and the 5-mm AM
were fully encompassed by the area of ablation
Image registration was performed by aligning two
overlaid CT/MR images. Translation and rotation were
performed in three reformed planes to maximize the image
similarity around the HCC lesion and the area of ablation.
The hepatic vein, hepatic artery portal complex and
hepatic contour near the lesion were used as landmarks for
fine adjustments to obtain a satisfactory registration. The
pre- and post-RFA CT/MR images were then overlapped
to assess whether the ablative area encompassed the HCC
lesion and the 5-mm AM. The standards of complete
registration included complete matching of three
corresponding anatomic landmarks adjacent to the tumor, and
the offset was less than 5 mm in each plane. Failed
registration was determined when the above standards
were not achieved after three attempts. The time spent on
registration for each lesion and the success rate of
MRMR image fusion were recorded. The results of the
CTCT/MR-MR image fusion as standard were used to
evaluate the accuracy of the CEUS-CT/MR image fusion.
The analyzed data included 1) the duration required for
the US-CT image fusion (phantom model study),
CEUSCT/MR image fusion, and MR-MR image fusion (clinical
study); 2) the success rate of US-CT image fusion
(phantom model study), CEUS-CT/MR image fusion and
CTFig. 4 Medical images of case 2 in the clinical study. (A-2) Preoperative MR image (tumor shown in blue and 5-mm AM in yellow). (A-1) CEUS-MR
fusion image showing that the area of ablation encompassed the tumor but not the entire AM due to the influence of vessels (white arrow).
b MR-MR fusion image from the same patient. Upper panel: preoperative MR images (tumor shown in blue and 5-mm AM in yellow). Middle panel:
postoperative MR images (arrow, area of ablation shown in dark color). Lower panel: MR-MR fusion images showing that the tumor and AM were
not fully encompassed by the area of ablation (white arrow)
CT/MR-MR image fusion (clinical study); 3) the
accuracy rate of the assessment, including the coincidence
rates of the assessment of complete ablation between
US-CT image fusion and the gross specimen (phantom
model study), and between CEUS-CT/MR image fusion
and CT-CT/MR-MR image fusion; and 4) the maximum
thickness of the residual AM in the US-CT image fusion
and the gross specimen.
Statistical analyses were performed using SPSS for Microsoft
Windows (version 13.0; SPSS Inc. Chicago, IL, USA). The
data are the mean ± standard deviation (range). The paired t
test was used to compare the maximum thickness of the
residual AM in the US-CT image fusion and the gross
specimen. A P value less than 0.05 was considered significant.
Successful establishment of the phantom models
The echogenicity, density, and color of different
components of the phantom models met the requirements
(Table 1). The appearance, height, and gradient of the
phantom models were stable at 1 h, 6 h, and 12 h after
Table 1 The ultrasound echo, CT density and color of the phantom models
aThese two had the same echogenecity, bthese two had the same density
US-CT image fusion detected residual AM with high
sensitivity, specificity, and accuracy in the phantom
Of the 24 phantom models, one phantom was
accidentally damaged, and 23 phantoms were used in all
followup experiments. Image fusion was successfully obtained
from the 23 phantoms. The success rate of image fusion
was 100% (23/23). The average time used for image
fusion was 5–12 min (median = 7 min). Compared with
the gross specimen, the sensitivity, specificity, and
accuracy of the US-CT image fusion for the detection of
residual AM were 100.0, 93.8 and 95.7%, respectively
(Table 2). In one case, the US-CT image fusion showed
that AM was completely encompassed by the ablative
area, but a 1-mm residual AM was still observed in the
gross specimen. The maximal thicknesses of residual
AM calculated by the US-CT image fusion and
measured in the gross specimen were 3.5 ± 2.0 mm and
3.2 ± 2.0 mm, respectively, which suggested that there
was no significant difference (P = 0.705).
CEUS-CT/MR image fusion revealed residual AM with a
high sensitivity, specificity, and accuracy in the clinical
A total of 30 tumors from 26 patients were enrolled in
the clinical study. The clinical characteristics of the
participants and HCC lesions are shown in Table 3. Seven
patients were excluded from the study, including three
patients without a postoperative CT/MR examination
and three patients with inconsistent preoperative and
postoperative imaging methods. In addition, one patient
was excluded from the clinical study due to the
Table 2 The results of AM evaluated by US-CT image fusion
and gross specimen (P > 0.05)
formation of a local abscess in the ablation zone after
RFA, which could bias the AM assessment.
CT-CT image fusion was conducted for one lesion, and
MR-MR image fusion was applied for the remaining
lesions. The success rate of CEUS-CT/MR image fusion and
CT-CT/MR-MR image fusion were both 100% (30/30).
The duration was 8.5 ± 2.8 min (range: 4–12 min) and
13.5 ± 4.5 min (range: 8–16 min) for the CEUS-CT/MR
and CT-CT/MR-MR image fusions, respectively. The
results of the AM evaluation based on CEUS-CT/MR and
MR/MR image fusions are shown in Table 4. An
inadequate AM was caused by blood vessels in seven cases
(46.7%) and an inadequate ablation zone in eight cases
(53.3%). Compared with CT-CT/MR-MR image fusion, the
sensitivity, specificity, and accuracy of CEUS-CT/MR
image fusion for the evaluation of AM were 100.0, 80.0,
and 90.0%, respectively.
Phantoms have been widely used to evaluate the effects
of thermal treatments. Previous studies, however, have
mainly focused on other topics, such as temperature
monitoring, energy distribution, the relationship
between RF and electrical conductivity, and development
of the heating algorithm applied in drug delivery. It is
not clear whether phantoms are good models for the
evaluation of AM using a CEUS-CT/MR image fusion
system. Therefore, in the present study, we established a
phantom model to evaluate AM using CEUS-CT/MR
image fusion. In our study, we found that the peculiarly
Age (mean ± standard deviation, years)
Tumor diameter (mean ± SD, mm)
HCC hepatocellular carcinoma, M median, QR interquartile range
AM not covered 0
AM covered AM not covered
Table 4 The results of AM evaluated by CEUS-CT/MR image
fusion and MR/MR image fusion
thermal invertibility and thermal sensitivity of the
carrageenan gel were useful for distinguishing the ablative
zone, the remaining ‘tumor’, and the AM after RFA.
While the carrageenan hybrid gel used in the present
study was not the best material for the evaluation of
thermal ablation, especially for temperature variation
and energy distribution, we took full advantage of the
physical properties of the carrageenan gel. To the best of
our knowledge, this is the first report to assess the
accuracy of the evaluation of complete RF using an image
fusion system that matched pre-RFA and post-RFA
images in a tissue-mimicking phantom.
We developed a hybrid gel phantom using carrageenan
and other substances, which have a number of important
properties, i.e., sufficient strength, low fragility, and low
cost. Carrageenan, a high-molecular-weight
polysaccharide extracted from red algae, consists of repeating
galactose and 3,6-anhydrogalactose units linked by alternating
α-1,3- and β-1,4-glycosidic linkages. Carrageenan can be
used in a phantom model because it is inexpensive and
safe, as well as broadly applied for the production of gel
products and other foods. Additive agents played
significant roles in the construction, imaging, and observation
by the naked eye. For example, NaCl was added to the
carrageenan gels to adjust the gel conductivity. US
contrast agent and iodipin were used to improve the echo or
to enhance attenuation. In addition, Congo red, an
indicator used for the diagnosis of amyloidosis by generating a
bright and distinct red color, was easily distinguished from
the opaque gel. The red color may have infiltrated the
peripheral gel due to the diffusion of Congo red. However, we
believe that Congo red has no influence on the results of
the AM evaluation if the whole procedure, including
manufacturing, RFA, and assessment of the ablative zone,
is completed within 6 h. Using carrageenan together with
other substances, we were able to create a large and robust
phantom model with excellent shape retention. The
turbidity and low fragility of the carrageenan gel in the
phantom model ensured accurate image registration. In
addition, we designed a phantom that mimicked the
tumor lesion (i.e., a visible sphere) to assess the AM using
the fusion imaging system after RF. The easy heating and
coagulation of the phantom model allowed us to assess
the post-RFA destructive zone more accurately. Improved
visualization of the target by US and CT, as well as the
distinct color of the materials, also improved the ablation
assessment. Therefore, the phantom model established
herein was successfully used for the evaluation of the AM
of the HCC tumor.
The present experimental study results suggest that
the US-CT fusion image system can be used to
accurately and effectively evaluate AM. However, in one case,
US-CT image fusion revealed that the AM was
completely covered by the ablative area, and even less than a
1-mm AM was observed in the gross specimen. The
false-positive case could be caused by registration error
and magnetic positioning system error. Given that the
phantom model was idealized to evaluate AM, the
feasibility and accuracy was further validated in a clinical
In our clinical study, the sensitivity, specificity, and
accuracy of CEUS-CT/MR image fusion for the evaluation
of AM were 100.0, 80.0 and 90.0%, respectively, suggesting
that CEUS-CT/MR image fusion is a good tool for
evaluating AM after HCC ablation. CEUS-CT/MR image
fusion combines the advantages of CEUS and CT/MR and
expands the use of both imaging methods, including the
high spatial contrast resolution of CT/MR and real-time
guidance, accessibility, and practicality of ultrasound. In
addition, CEUS-CT/MR image fusion greatly improves
intraoperative AM evaluation and the localization of tumor
lesions compared with MR-MR image fusion.
We discovered three false-positive cases in the clinical
study, which might be due to the ability of CEUS to only
demonstrate blood perfusion of tissues rather than
necrosis. The high temperature of the local zone of
ablation may cause swollen tissues and small vessel
occlusion, limiting the infiltration of blood into the ablated
area. However, occluded small vessels can be reperfused
after the local tissue temperature decreases, suggesting
that the ablation zone may be over-measured by
The present study has several limitations. First, the
phantom model cannot completely mimic dynamic
tissues and organs, such as respiratory movements, which
may reduce the accuracy of the registration for image
fusion and affect the imaging assessment. While the
assessment was performed successfully in the idealized
phantom model, some unknown problems may be
present in the in vivo experiments, which must be
identified and resolved. Second, the phantom models applied
in the present study were used for US-CT image fusion,
whereas most of the clinical cases were evaluated by
CEUS-CT/MR image fusion. Thus, the accuracy of the
results may be biased. Third, all of the patients enrolled
in this study were male, which may also bias the results.
Therefore, further studies with more experience, a larger
sampling size and better technology are needed.
In conclusion, we successfully established a phantom
model for the evaluation of AM using US-CT/MR image
fusion. Our results suggest that US-CT/MR image
fusion is an accurate approach for evaluating AM after
tumor ablation based on both an in vitro model and a
AM: Ablative margin; CEUS: Contrast-enhanced ultrasound; HCC: Hepatocellular
carcinoma; LTP: Local tumor progression; RFA: Radiofrequency ablation
RZ contributed to the conception of the study. KL and ZS performed the
experiments. QH and QZ were responsible for gathering data. EX and KL
analyzed the data. KL wrote the manuscript. All authors read and approved
the final manuscript.
Ethics approval and consent to participate
This study was approved by the Institute Research Medical Ethics Committee of
the Third Affiliated Hospital of Sun Yat-Sen University and was in compliance
with the Declaration of Helsinki. Informed consent was obtained from all
participants. All subjects signed informed consents prior to their inclusion in
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