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Investigating the Accuracy of Ultrasound-Ultrasound Fusion Imaging for Evaluating the Ablation Effect via Special Phantom-Simulated Liver Tumors
ARTICLE IN PRESS Ultrasound in Med. & Biol., Vol. 00, No. 00, pp. 18, 2019 Copyright © 2019 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) Printed in the USA. All rights reserved. 0301-5629/$ - see front matter
https://doi.org/10.1016/j.ultrasmedbio.2019.07.415
Technical Note INVESTIGATING THE ACCURACY OF ULTRASOUND-ULTRASOUND FUSION IMAGING FOR EVALUATING THE ABLATION EFFECT VIA SPECIAL PHANTOMSIMULATED LIVER TUMORS AGEDPS T HUMIN
LV,*,y YINGLIN LONG,* ZHONGZHEN SU,*,z RONGQIN ZHENG,* KAI LI,* HUICHAO ZHOU,* CHEN QIU,* TINGHUI YIN,* and ERJIAO XU*TAGEDEN
* Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China; y Department of Medical Ultrasonics, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong Province, China; and z Department of Medical Ultrasonics, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China (Received 14 August 2018; revised 15 July 2019; in final from 21 July 2019)
Abstract—The goal of this study was to investigate the accuracy of ultrasound-ultrasound (US-US) fusion imaging for evaluating the ablation effect via phantom-simulated liver tumors. Twenty special phantom models were established, ablated and divided into a complete ablation group (n = 10) and an incomplete ablation group (n = 10). US-US fusion imaging was performed to evaluate the ablation effect. Gross specimens were observed as a standard reference. In this US-US fusion imaging study, the registration success rate was 100% (20/20), and the assessment time was 3.8 § 0.9 min. The accuracy rate of the evaluation was 100% (20/20). There was no significant difference in the residual pseudo-tumoral area between the evaluation with US-US fusion imaging and gross specimen observation (p = 0.811), and the measurement error was 1.1 § 0.6 mm. In conclusion, the feasibility and accuracy of US-US fusion imaging when evaluating the ablation effect can be investigated with this phantomsimulated liver tumor ablation model in an ideal state. (E-mail: [email protected]) © 2019 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/). Key Words: Fusion imaging, Ultrasound, Ablation, Liver tumor, Phantom.
multi-planar images using 3-D data together with a position tracking system that uses magnetic navigation. With this technology, real-time US can be fused with corresponding planar images obtained with computed tomography (CT), magnetic resonance imaging (MRI), or even US volume data (Makino et al. 2012; Ewertsen et al. 2013; Toshikuni et al. 2014). The most common mode is CT/MRI-US fusion imaging, which has been reported to be feasible and valuable in liver ablation procedures, including detection, planning, guidance and evaluation, by several studies (Zhong-Zhen et al. 2012; Lee et al. 2013; Song et al. 2013; Minami and Kudo 2014; Mauri et al. 2015; Bo et al. 2016; Li et al. 2016, 2017). According to our previous study, CT/MRI-US fusion imaging is valuable for the intra-operative immediate evaluation of the liver ablation effect (Li et al. 2016, 2017). With the help of real-time contrast-enhanced ultrasound (CEUS) and overlap with corresponding CT/MRI images, the liver ablation effect can be assessed precisely with multi-planar
INTRODUCTION Given its high efficacy and few complications, imageguided thermal ablation has been widely used as an important treatment option to manage liver tumors (Bruix and Sherman 2011; Verslype et al. 2012; Ahmed et al. 2014). Because of its convenience, real-time manner, low cost and lack of radiation, ultrasound (US) is the most common imaging modality used to guide liver tumor ablation. The ablation of an entire tumor and the precise evaluation of the ablation effect are critical problems for improving the thermal ablation effect. Fusion imaging is a technique that fuses two different images obtained from different modalities or the same imaging modality and reconstructs high-resolution Address correspondence to: Erjiao Xu, Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Key Laboratory of Liver Disease Research, No. 600, Tianhe Road, Guangzhou 510630, China. E-mail: [email protected]
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comparison in CT/MRI-US fusion imaging. The insufficient ablation zone can undergo supplementary ablation immediately to reduce the incidence rate of residual and local tumor progression (LTP). Recently, ultrasound-ultrasound (US-US) fusion imaging has been reported in a few publications (Toshikuni et al. 2013; Park et al. 2015; Su et al. 2015; Minami et al. 2016; Xu et al. 2018). Compared with CT/MRI-US fusion imaging, in US-US fusion imaging, 3-D US images before ablation are used as reference images instead of CT/MRI images to fuse with real-time US. Since US is the most common guidance and monitoring tool during liver tumor ablation procedures, USUS fusion imaging is expected to be a more convenient technique for the precise evaluation of the liver ablation effect. Only US images are used, and the 3-D US images can be fused with real-time US images automatically because of the magnetic position tracking system, which makes the US-US fusion imaging procedure easier and quicker. Our previous study also proved that US-US fusion imaging is feasible and valuable in the evaluation of the liver ablation effect (Xu et al. 2018). However, the evaluation accuracy of US-US fusion imaging can be confirmed only by the CT/MRI results obtained 1 mo after ablation in clinical studies, and it is impossible to observe the actual ablation zone directly. An accurate evaluation of the ablation effect is essential for its safety and high efficacy. Inaccuracies in the evaluation may lead to a residual tumor or the inadvertent ablation of normal liver parenchyma. However, the registration error of fusion imaging is inevitable. As a relatively novel technique, confirmation of the accuracy of US-US fusion imaging is necessary. In this study, we designed a special phantom model that could be ablated, and the actual ablation zone was directly observed to simulate the liver tumor ablation procedure and to investigate the accuracy of US-US fusion imaging for the evaluation of the ablation effect. MATERIALS AND METHODS Establishment of phantom models Design. A special phantom model that could be ablated and used to evaluate the ablation effect was established. Generally, a liver tumor becomes poorly defined after ablation on US images. To simulate this clinical situation, the phantom tumor model was designed to be well defined before ablation but poorly defined after ablation via conventional US. The residual tumor model after ablation could be simultaneously distinguished from the ablated tumor model and the surrounding matrix via gross specimen observation. Therefore, the gross specimen could be used as a standard reference to verify the evaluation accuracy of the US-US fusion imaging.
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Materials. The materials for the phantom model included carrageenan and additives, such as a homemade US contrast agent, a gastric window contrast agent (Huqingyutang Corp., Hangzhou, China), milk and red dye. Carrageenan is a hydrophilic colloid derived from algae seaweed with good thermal reversibility. It solidifies at room temperature, with good acoustics, and melts into a liquid when the temperature rises above 70˚C. After cooling, the solid gel was restored. The homemade US contrast agent was a type of liposome-encapsulated C3F8 gas microbubble that was described in our previously published research (Yin et al. 2013). Process of manufacture. First, the mixed liquid containing carrageenan, the homemade US contrast agent, the gastric window contrast agent and milk was injected into a spherical mold and solidified into a spherical tumor model (3 cm in diameter) after cooling. Then, the spherical tumor model and three crossings of surgical sutures were fixed in a cylindrical mold. The sutures, which were used as registration marks, simulated the hepatic vessel bifurcations (the most common registration marks during the fusion imaging procedure). Finally, the mixed liquid containing carrageenan and the gastric window contrast agent was poured into the cylindrical mold and solidified into a matrix model after cooling. The depth of the tumor model from the surface was approximately 3.5 cm. Phantom model testing. The appearance, height and gradient of the phantom models were tested 1, 6 and 12 h after production. The structures of the phantom models, including the tumor model, matrix model and registration marks, were analyzed via US and gross observation. Ablation Equipment. Radiofrequency ablation (RFA) was performed using a cooled-tip RFA system (Covidien, Mansfield, MA, USA) with a 17-gauge, internally cooled-tip electrode and a 3 cm tip. A MyLab Twice US system with Virtual Navigator (Esaote, Genoa, Italy), an LA332 linear transducer (frequency range from 3 to 11 MHz) and an electromagnetic signal transmitter system were used for fusion imaging. Grouping. In total, 20 phantom models were created and randomly divided into a complete ablation group (n = 10) and an incomplete ablation group (n = 10) via drawing. RFA procedure. An experienced US interventional physician inserted the electrode into the tumor model under US guidance. The RFA was set in
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impedance mode with maximum output. According to pilot studies, the ablation duration for each model was 4 min for the incomplete ablation group and 6 min for the complete ablation group. Post-processing of models. The ablation zone was replaced subsequently because the margin between the ablation zone and the residual tumor model was difficult to distinguish on both the US images and the gross specimen. After ablation, the ablation zone remained in a liquid state for approximately 5-10 min because of the high temperature, and then it slowly re-solidified as the temperature dropped. The replacement procedure was performed immediately (within 5 min) after ablation, when the ablation zone remained in the liquid state. A syringe with a long needle was used to extract the original liquid of the ablation zone, and then the same volume of red liquid containing a high concentration of the gastric window contrast agent was injected. The long needle was inserted slowly into the phantom following the original path of the electrode to avoid disturbing the phantom during the replacement procedure. After cooling, the red liquid of the ablation zone solidified for evaluation. As a result, the ablation zone could be easily distinguished on both the US images and the gross specimen. Evaluation of the ablation effect using US-US fusion imaging Acquisition and registration. Another experienced US physician who was blinded to the ablation procedures performed the fusion imaging procedures. Before ablation, the 3-D US volume images of the tumor model were acquired in freehand scanning mode with a slow uniform speed. These 3-D US volume images were used as reference images and to outline the margin of the tumor model. The cross-sections of the volume images were selected based on the largest diameter dimension of the tumor in three perpendicular planes. The margin of the tumor was outlined with a sphere. Since the 3-D US volume images were acquired in the magnetic position tracking system, the location information was recorded in the 3-D US volume images. When the transducer with the magnetic positioning sensor was placed on the phantom, the real-time US images were automatically fused with the 3-D US volume images. US-US fusion imaging evaluation. After ablation, real-time US was performed in the same place and fused with the reference 3-D US images. If three registration marks of the crossings of surgical sutures were not fully matched between the real-time US images and the 3-D US volume images, which indicated that registration errors existed, manual alignment (fine tuning) by moving
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or rotating the images was performed to improve the registration precision. Then, the ablation effect of the tumor model was assessed. During the whole experimental process, the orientation of the phantom model was fixed via marking. Moreover, the tumor model was equally divided into eight quadrants, designated as Q1Q8, by three orthogonal transverse, coronal and sagittal planes crossing the center of the tumor model. In the incomplete ablation group, the quadrant of the residual tumor and the maximum thickness of the residual tumor were recorded by US-US fusion imaging. Finally, the results were compared with those from the gross specimens. Standard reference assessment. After the US-US fusion imaging evaluation, the phantom model was cut along the scanning direction of the real-time US. The ablation effect was evaluated on the gross specimen. In the incomplete ablation group, the quadrant of the residual tumor and the maximum thickness of the residual tumor were also recorded on the gross specimen. Data analysis 1. Registration success rate. The registration was considered successful when the registration marks were fully matched between the real-time US images and the 3-D US volume images after the ablation procedure. 2. The assessment time of US-US fusion imaging. TaggedPThe assessment time included the acquisition of 3-D US images, outline of the tumor margin, registration and evaluation of the ablation effect. 3. Accuracy rate of evaluation. The evaluation was considered accurate in the following situations: (i) the tumor model was assessed as complete ablation by US-US fusion imaging when the gross specimen also showed complete ablation, and (ii) the tumor model was assessed as incomplete ablation by US-US fusion imaging when the gross specimen also showed incomplete ablation. Moreover, when the quadrants of the residual pseudo-tumor were not consistent between the assessment of US-US fusion imaging and the gross specimen, the evaluation was considered inaccurate. 4. Measurement error of the residual pseudotumoral area. If both the tumor model assessed by USUS fusion imaging and the gross specimen were evaluated as incomplete ablation in the same quadrant, the maximum thickness of the residual pseudo-tumoral area was measured. The measurement error was defined as the difference in the maximum thickness of the residual pseudo-tumoral area between the measurement on the US images and that on the gross specimen.
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Statistical analysis All statistical analyses were performed using SPSS for Microsoft Windows (version 13.0; SPSS Inc. Chicago, IL, USA). The measurement data are presented as the mean § standard deviation (range). A paired samples t-test was used to compare the maximum thickness of the residual tumor model between the US image and the gross specimen in the incomplete ablation group. The significance level was set at a p value less than 0.05.
RESULTS The success rate of establishing the phantom models was 100% (20/20). The phantom models were faint yellow and translucent cylindrical colloids. In this phantom model study, the hyperechoic tumor model with a homemade US contrast agent gradually became an isoechoic zone. The majority of the hyperechoic tumor model faded away in 2 min during the ablation process. After the ablation, the hyperechoic tumor model became an isoechoic zone. The performances of the phantom model before and after ablation as well as the replacement of the post-process model on US scanning and gross specimen analyses are presented in Figure 1 and Figure 2. The registration success rate was 100% (20/20). The assessment time of US-US fusion imaging was 3.8 § 0.9 min (range, 2.56.8 min). After ablation, in the complete ablation group, all 10 phantom models were assessed as complete ablation by US-US fusion imaging and confirmed in the gross specimens. In the incomplete
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ablation group, another 10 phantom models were assessed as incomplete ablation by US-US fusion imaging, and these results were also verified in the gross specimens (Fig. 3). Moreover, the quadrants of the residual pseudo-tumor were consistent between the assessment of US-US fusion imaging and the gross specimen. As a result, the accuracy rate of the evaluation with USUS fusion imaging was 100% (20/20). In the incomplete ablation group, the measurement error of the residual pseudo-tumoral area was 1.1 § 0.6 mm (range, 02 mm). No significant difference was observed between the evaluation of US-US fusion imaging and the gross specimen (p = 0.811). The details of the results are shown in Table 1.
DISCUSSION In this study, phantom models were used to validate the feasibility and accuracy of US-US fusion imaging. Phantom studies have several advantages over animal or clinical studies. For example, certain interfering factors, such as respiratory movement and the non-cooperation of animals, could be effectively excluded. In this study, the phantom models were idealized based on our requirements that the tumor model was visible before ablation but invisible after ablation. The tumor model was hyperechoic because the homemade US contrast agent was added. Our homemade US contrast agent had similar acoustic properties to SonoVue (Bracco, Milan, Italy), which is already on the market in China. However, according to our preliminary experiments, our homemade US contrast agent had higher homogeneity and
Fig. 1. Phantom model performance before ablation. (A) The tumor model presented as a hyperechoic sphere and was easy to distinguish from the matrix model, which was isoechoic on US images. (B) The tumor model presented as a white sphere and was easy to distinguish from the surrounding matrix on the gross specimen. (C) 3-D US volume images of the liver tumor model. The margin of the tumor model was outlined. US = ultrasound.
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Fig. 2. The performances of the ablation zone before and after replacement. (A) Before replacement, the ablation zone presented as an isoechoic ellipsoid and was difficult to distinguish from the residual tumor model and the matrix model on US. (B) Before replacement, the ablation zone presented as a white ellipsoid and was difficult to distinguish from the residual tumor model (arrow) in the gross specimen. (C) After replacement, the ablation zone presented as a hyperechoic ellipsoid because of the higher concentration of the gastric window contrast agent and was easy to distinguish from the residual tumor model and the matrix model, which were isoechoic areas on US. (D) After replacement, the ablation zone presented as a red ellipsoid and was easy to distinguish from the residual tumor model, which was noted in the white area (arrow) in the gross specimen. US = ultrasound
stability than SonoVue. This finding may be because of the smaller microbubble diameter and the higher resonance frequency of our homemade US contrast agent (Yin et al. 2013). Because of the high temperature of ablation, the hyperechoic tumor model with the homemade US contrast agent became an isoechoic zone after ablation as the microbubbles were destroyed with the passage of time. The majority of the hyperechoic tumor model faded away in 2 min. Finally, the ablation zone gradually presented as an isoechoic zone without a clear margin. As the matrix model was isoechoic, the margin of the tumor model was invisible after ablation. As a result, the operator could not estimate the ablation zone or the residual foci during and after the ablation procedure, which could avoid bias. After the ablation procedure, the red liquid containing a high concentration of
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the gastric window contrast agent was used to replace the isoechoic ablation zone. By taking advantage of the good thermal reversibility of carrageenan, we were able to visualize the margin of the ablation zone on both the US images and the gross specimen for the subsequent evaluation. In this way, the ablation zone could be assessed by US-US fusion imaging intuitively. Moreover, the standard reference of the gross specimen could be obtained to confirm the actual ablation effect, which is not practical in a clinical study. A few reports have investigated the feasibility and accuracy of the registration of fusion imaging using a phantom model (Toshikuni et al. 2013; Burgmans et al. 2017; Li et al. 2017). In the reports of Toshikuni et al. (2013) and Burgmans et al. (2017), a phantom model was used to determine the registration accuracy of USUS fusion imaging and US-CT fusion imaging, respectively. However, the registration accuracy after ablation was lacking. The registration accuracy after ablation is important because some errors might occur during the ablation procedure. In another report by Li et al. (2017), the phantom models were ablated and evaluated using US-CT fusion imaging to assess the accuracy of US-CT fusion imaging in evaluating the ablative margin (AM) of the tumor. Compared with the phantom models in Li et al.’s (2017) report, our tumor models became poorly defined after ablation on US images, which might have reduced subjective bias during assessment. To the best of our knowledge, there have been no reports on the feasibility and accuracy of US-US fusion imaging after ablation using a phantom model. Additionally, there is no similar phantom model that can be ablated and assessed with US-US fusion imaging. Based on the present study, the registration success rate was 100% using US-US fusion imaging. Only 3.8 § 0.9 min was required to finish this procedure. The procedure of fusing post-ablation real-time US images with pre-ablation 3-D US images was more convenient and quicker, because the mono-modality images using US made image recognition and alignment easier and dependent on less experience. Moreover, US-US fusion imaging was also accurate for distinguishing the complete ablation models from the incomplete ablation models. According to the evaluation results of the US images and the gross specimens in the incomplete ablation group, the quadrant of the residual tumor was consistent in each phantom model, and the measurement error of the residual pseudo-tumoral area was only 02 mm. No significant difference was observed between the evaluation of US-US fusion imaging and the gross specimen (p = 0.811). The measurement error may be related to the registration error or the manual measurement error. Although the quadrant and the maximum thickness of the residual tumor were different in each phantom
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Fig. 3. Assessment of the ablation effect of the tumor model based on US-US fusion imaging and the gross specimen of the phantom model. (A) Complete ablation. US-US fusion imaging showed that the ablation zone covered the entire tumor model, suggesting complete ablation. (B) The gross specimen of the phantom model showed complete ablation of the tumor model. (C) Incomplete ablation. US-US fusion imaging showed that the ablation zone did not cover the entire tumor model, suggesting incomplete ablation. (D) The gross specimen of the phantom model showed incomplete ablation of the tumor model. The maximum thickness of the residual tumor model (arrow) between the US images and the gross specimen of the phantom model was similar. US = ultrasound’
model, the evaluation results of the US-US fusion imaging were accurate compared with the gross specimen results. These results indicate that US-US fusion imaging is feasible in the evaluation of tumor ablation and able to assess the ablation effect precisely. The exact results of the US-US fusion imaging evaluation can be realized
directly in phantom study by comparison with gross specimens. The registration errors of US fusion imaging are inevitable during the registration procedure. In clinical practice, in addition to system registration errors, registration errors may also be caused by a patient’s motion
Table 1. Comparison of the US-US fusion imaging and gross specimen results in the incomplete ablation group Phantom model
1 2 3 4 5 6 7 8 9 10 US = ultrasound
Evaluation results of the US images
Evaluation results of the gross specimen
Quadrant
Maximum thickness of the residual tumor (mm)
Quadrant
Maximum thickness of the residual tumor (mm)
7/8 8 2 7 6 8 8 4 7 4
24 8 4 4 3 6 11 11 7 4
7/8 8 2 7 6 8 8 4 7 4
22 7 5 6 4 6 12 12 6 3
Difference value (mm)
2 1 1 2 1 0 1 1 1 1
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or breathing and tissue deformation. The imaging conditions of this study represent an ideal state. In this study, compared with the gross specimens, the measurement errors were less than 2 mm (1.1 § 0.6 mm). In our opinion, such small measurement errors are inevitable and acceptable. Registration errors may increase in clinical practice. The operators must be aware of the existence of registration errors and take measures to reduce them, such as controlling the patient’s breathing or selecting anatomic markers close to the target lesion for registration. This study had several limitations. First, the phantom study was performed in an ideal state (no blood flow, no respiratory movement, etc.), and the performance of the US system in clinical practice may differ from the results obtained in this phantom study. The registration success rate is expected to be lower in clinical studies because patient motion and breathing and tissue deformation may induce registration errors. Second, we investigated only the performance of the Esaote MyLab Twice, and the study findings may thus not be extrapolated to other systems. Third, unified phantom models were used in this phantom study. We could not provide the measurement error depending on the changes in the tumor model’s depth, size or shape. However, diverse models were not the focus of our study, which would increase the complexity of the present study. Further studies with diverse models are necessary. CONCLUSIONS The feasibility and accuracy of US-US fusion imaging in the evaluation of the ablation effect can be investigated by this phantom-simulated liver tumor ablation model in an ideal state. Acknowledgments—This work was supported by the National Key R&D Program of China (No. 2017 YFC0112000); the National Natural Science Foundation of China (No. 81401434 and No. 81430038); the Science and Technology Planning Project of Guangdong Province, China (No. 2015 A020214009, No. 2017 A020215082 and No. 2017 A020215137); the Medical Scientific Research Foundation of Guangdong Province, China (No. A2015257); and the Science and Technology Program of Guangzhou, China (No. 201704020164). Conflict of interest disclosure—The authors declare no competing interests.
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https://doi.org/10.1016/j.ultrasmedbio.2019.07.415
Technical Note INVESTIGATING THE ACCURACY OF ULTRASOUND-ULTRASOUND FUSION IMAGING FOR EVALUATING THE ABLATION EFFECT VIA SPECIAL PHANTOMSIMULATED LIVER TUMORS AGEDPS T HUMIN
LV,*,y YINGLIN LONG,* ZHONGZHEN SU,*,z RONGQIN ZHENG,* KAI LI,* HUICHAO ZHOU,* CHEN QIU,* TINGHUI YIN,* and ERJIAO XU*TAGEDEN
* Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China; y Department of Medical Ultrasonics, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong Province, China; and z Department of Medical Ultrasonics, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China (Received 14 August 2018; revised 15 July 2019; in final from 21 July 2019)
Abstract—The goal of this study was to investigate the accuracy of ultrasound-ultrasound (US-US) fusion imaging for evaluating the ablation effect via phantom-simulated liver tumors. Twenty special phantom models were established, ablated and divided into a complete ablation group (n = 10) and an incomplete ablation group (n = 10). US-US fusion imaging was performed to evaluate the ablation effect. Gross specimens were observed as a standard reference. In this US-US fusion imaging study, the registration success rate was 100% (20/20), and the assessment time was 3.8 § 0.9 min. The accuracy rate of the evaluation was 100% (20/20). There was no significant difference in the residual pseudo-tumoral area between the evaluation with US-US fusion imaging and gross specimen observation (p = 0.811), and the measurement error was 1.1 § 0.6 mm. In conclusion, the feasibility and accuracy of US-US fusion imaging when evaluating the ablation effect can be investigated with this phantomsimulated liver tumor ablation model in an ideal state. (E-mail: [email protected]) © 2019 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/). Key Words: Fusion imaging, Ultrasound, Ablation, Liver tumor, Phantom.
multi-planar images using 3-D data together with a position tracking system that uses magnetic navigation. With this technology, real-time US can be fused with corresponding planar images obtained with computed tomography (CT), magnetic resonance imaging (MRI), or even US volume data (Makino et al. 2012; Ewertsen et al. 2013; Toshikuni et al. 2014). The most common mode is CT/MRI-US fusion imaging, which has been reported to be feasible and valuable in liver ablation procedures, including detection, planning, guidance and evaluation, by several studies (Zhong-Zhen et al. 2012; Lee et al. 2013; Song et al. 2013; Minami and Kudo 2014; Mauri et al. 2015; Bo et al. 2016; Li et al. 2016, 2017). According to our previous study, CT/MRI-US fusion imaging is valuable for the intra-operative immediate evaluation of the liver ablation effect (Li et al. 2016, 2017). With the help of real-time contrast-enhanced ultrasound (CEUS) and overlap with corresponding CT/MRI images, the liver ablation effect can be assessed precisely with multi-planar
INTRODUCTION Given its high efficacy and few complications, imageguided thermal ablation has been widely used as an important treatment option to manage liver tumors (Bruix and Sherman 2011; Verslype et al. 2012; Ahmed et al. 2014). Because of its convenience, real-time manner, low cost and lack of radiation, ultrasound (US) is the most common imaging modality used to guide liver tumor ablation. The ablation of an entire tumor and the precise evaluation of the ablation effect are critical problems for improving the thermal ablation effect. Fusion imaging is a technique that fuses two different images obtained from different modalities or the same imaging modality and reconstructs high-resolution Address correspondence to: Erjiao Xu, Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Key Laboratory of Liver Disease Research, No. 600, Tianhe Road, Guangzhou 510630, China. E-mail: [email protected]
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comparison in CT/MRI-US fusion imaging. The insufficient ablation zone can undergo supplementary ablation immediately to reduce the incidence rate of residual and local tumor progression (LTP). Recently, ultrasound-ultrasound (US-US) fusion imaging has been reported in a few publications (Toshikuni et al. 2013; Park et al. 2015; Su et al. 2015; Minami et al. 2016; Xu et al. 2018). Compared with CT/MRI-US fusion imaging, in US-US fusion imaging, 3-D US images before ablation are used as reference images instead of CT/MRI images to fuse with real-time US. Since US is the most common guidance and monitoring tool during liver tumor ablation procedures, USUS fusion imaging is expected to be a more convenient technique for the precise evaluation of the liver ablation effect. Only US images are used, and the 3-D US images can be fused with real-time US images automatically because of the magnetic position tracking system, which makes the US-US fusion imaging procedure easier and quicker. Our previous study also proved that US-US fusion imaging is feasible and valuable in the evaluation of the liver ablation effect (Xu et al. 2018). However, the evaluation accuracy of US-US fusion imaging can be confirmed only by the CT/MRI results obtained 1 mo after ablation in clinical studies, and it is impossible to observe the actual ablation zone directly. An accurate evaluation of the ablation effect is essential for its safety and high efficacy. Inaccuracies in the evaluation may lead to a residual tumor or the inadvertent ablation of normal liver parenchyma. However, the registration error of fusion imaging is inevitable. As a relatively novel technique, confirmation of the accuracy of US-US fusion imaging is necessary. In this study, we designed a special phantom model that could be ablated, and the actual ablation zone was directly observed to simulate the liver tumor ablation procedure and to investigate the accuracy of US-US fusion imaging for the evaluation of the ablation effect. MATERIALS AND METHODS Establishment of phantom models Design. A special phantom model that could be ablated and used to evaluate the ablation effect was established. Generally, a liver tumor becomes poorly defined after ablation on US images. To simulate this clinical situation, the phantom tumor model was designed to be well defined before ablation but poorly defined after ablation via conventional US. The residual tumor model after ablation could be simultaneously distinguished from the ablated tumor model and the surrounding matrix via gross specimen observation. Therefore, the gross specimen could be used as a standard reference to verify the evaluation accuracy of the US-US fusion imaging.
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Materials. The materials for the phantom model included carrageenan and additives, such as a homemade US contrast agent, a gastric window contrast agent (Huqingyutang Corp., Hangzhou, China), milk and red dye. Carrageenan is a hydrophilic colloid derived from algae seaweed with good thermal reversibility. It solidifies at room temperature, with good acoustics, and melts into a liquid when the temperature rises above 70˚C. After cooling, the solid gel was restored. The homemade US contrast agent was a type of liposome-encapsulated C3F8 gas microbubble that was described in our previously published research (Yin et al. 2013). Process of manufacture. First, the mixed liquid containing carrageenan, the homemade US contrast agent, the gastric window contrast agent and milk was injected into a spherical mold and solidified into a spherical tumor model (3 cm in diameter) after cooling. Then, the spherical tumor model and three crossings of surgical sutures were fixed in a cylindrical mold. The sutures, which were used as registration marks, simulated the hepatic vessel bifurcations (the most common registration marks during the fusion imaging procedure). Finally, the mixed liquid containing carrageenan and the gastric window contrast agent was poured into the cylindrical mold and solidified into a matrix model after cooling. The depth of the tumor model from the surface was approximately 3.5 cm. Phantom model testing. The appearance, height and gradient of the phantom models were tested 1, 6 and 12 h after production. The structures of the phantom models, including the tumor model, matrix model and registration marks, were analyzed via US and gross observation. Ablation Equipment. Radiofrequency ablation (RFA) was performed using a cooled-tip RFA system (Covidien, Mansfield, MA, USA) with a 17-gauge, internally cooled-tip electrode and a 3 cm tip. A MyLab Twice US system with Virtual Navigator (Esaote, Genoa, Italy), an LA332 linear transducer (frequency range from 3 to 11 MHz) and an electromagnetic signal transmitter system were used for fusion imaging. Grouping. In total, 20 phantom models were created and randomly divided into a complete ablation group (n = 10) and an incomplete ablation group (n = 10) via drawing. RFA procedure. An experienced US interventional physician inserted the electrode into the tumor model under US guidance. The RFA was set in
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impedance mode with maximum output. According to pilot studies, the ablation duration for each model was 4 min for the incomplete ablation group and 6 min for the complete ablation group. Post-processing of models. The ablation zone was replaced subsequently because the margin between the ablation zone and the residual tumor model was difficult to distinguish on both the US images and the gross specimen. After ablation, the ablation zone remained in a liquid state for approximately 5-10 min because of the high temperature, and then it slowly re-solidified as the temperature dropped. The replacement procedure was performed immediately (within 5 min) after ablation, when the ablation zone remained in the liquid state. A syringe with a long needle was used to extract the original liquid of the ablation zone, and then the same volume of red liquid containing a high concentration of the gastric window contrast agent was injected. The long needle was inserted slowly into the phantom following the original path of the electrode to avoid disturbing the phantom during the replacement procedure. After cooling, the red liquid of the ablation zone solidified for evaluation. As a result, the ablation zone could be easily distinguished on both the US images and the gross specimen. Evaluation of the ablation effect using US-US fusion imaging Acquisition and registration. Another experienced US physician who was blinded to the ablation procedures performed the fusion imaging procedures. Before ablation, the 3-D US volume images of the tumor model were acquired in freehand scanning mode with a slow uniform speed. These 3-D US volume images were used as reference images and to outline the margin of the tumor model. The cross-sections of the volume images were selected based on the largest diameter dimension of the tumor in three perpendicular planes. The margin of the tumor was outlined with a sphere. Since the 3-D US volume images were acquired in the magnetic position tracking system, the location information was recorded in the 3-D US volume images. When the transducer with the magnetic positioning sensor was placed on the phantom, the real-time US images were automatically fused with the 3-D US volume images. US-US fusion imaging evaluation. After ablation, real-time US was performed in the same place and fused with the reference 3-D US images. If three registration marks of the crossings of surgical sutures were not fully matched between the real-time US images and the 3-D US volume images, which indicated that registration errors existed, manual alignment (fine tuning) by moving
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or rotating the images was performed to improve the registration precision. Then, the ablation effect of the tumor model was assessed. During the whole experimental process, the orientation of the phantom model was fixed via marking. Moreover, the tumor model was equally divided into eight quadrants, designated as Q1Q8, by three orthogonal transverse, coronal and sagittal planes crossing the center of the tumor model. In the incomplete ablation group, the quadrant of the residual tumor and the maximum thickness of the residual tumor were recorded by US-US fusion imaging. Finally, the results were compared with those from the gross specimens. Standard reference assessment. After the US-US fusion imaging evaluation, the phantom model was cut along the scanning direction of the real-time US. The ablation effect was evaluated on the gross specimen. In the incomplete ablation group, the quadrant of the residual tumor and the maximum thickness of the residual tumor were also recorded on the gross specimen. Data analysis 1. Registration success rate. The registration was considered successful when the registration marks were fully matched between the real-time US images and the 3-D US volume images after the ablation procedure. 2. The assessment time of US-US fusion imaging. TaggedPThe assessment time included the acquisition of 3-D US images, outline of the tumor margin, registration and evaluation of the ablation effect. 3. Accuracy rate of evaluation. The evaluation was considered accurate in the following situations: (i) the tumor model was assessed as complete ablation by US-US fusion imaging when the gross specimen also showed complete ablation, and (ii) the tumor model was assessed as incomplete ablation by US-US fusion imaging when the gross specimen also showed incomplete ablation. Moreover, when the quadrants of the residual pseudo-tumor were not consistent between the assessment of US-US fusion imaging and the gross specimen, the evaluation was considered inaccurate. 4. Measurement error of the residual pseudotumoral area. If both the tumor model assessed by USUS fusion imaging and the gross specimen were evaluated as incomplete ablation in the same quadrant, the maximum thickness of the residual pseudo-tumoral area was measured. The measurement error was defined as the difference in the maximum thickness of the residual pseudo-tumoral area between the measurement on the US images and that on the gross specimen.
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Statistical analysis All statistical analyses were performed using SPSS for Microsoft Windows (version 13.0; SPSS Inc. Chicago, IL, USA). The measurement data are presented as the mean § standard deviation (range). A paired samples t-test was used to compare the maximum thickness of the residual tumor model between the US image and the gross specimen in the incomplete ablation group. The significance level was set at a p value less than 0.05.
RESULTS The success rate of establishing the phantom models was 100% (20/20). The phantom models were faint yellow and translucent cylindrical colloids. In this phantom model study, the hyperechoic tumor model with a homemade US contrast agent gradually became an isoechoic zone. The majority of the hyperechoic tumor model faded away in 2 min during the ablation process. After the ablation, the hyperechoic tumor model became an isoechoic zone. The performances of the phantom model before and after ablation as well as the replacement of the post-process model on US scanning and gross specimen analyses are presented in Figure 1 and Figure 2. The registration success rate was 100% (20/20). The assessment time of US-US fusion imaging was 3.8 § 0.9 min (range, 2.56.8 min). After ablation, in the complete ablation group, all 10 phantom models were assessed as complete ablation by US-US fusion imaging and confirmed in the gross specimens. In the incomplete
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ablation group, another 10 phantom models were assessed as incomplete ablation by US-US fusion imaging, and these results were also verified in the gross specimens (Fig. 3). Moreover, the quadrants of the residual pseudo-tumor were consistent between the assessment of US-US fusion imaging and the gross specimen. As a result, the accuracy rate of the evaluation with USUS fusion imaging was 100% (20/20). In the incomplete ablation group, the measurement error of the residual pseudo-tumoral area was 1.1 § 0.6 mm (range, 02 mm). No significant difference was observed between the evaluation of US-US fusion imaging and the gross specimen (p = 0.811). The details of the results are shown in Table 1.
DISCUSSION In this study, phantom models were used to validate the feasibility and accuracy of US-US fusion imaging. Phantom studies have several advantages over animal or clinical studies. For example, certain interfering factors, such as respiratory movement and the non-cooperation of animals, could be effectively excluded. In this study, the phantom models were idealized based on our requirements that the tumor model was visible before ablation but invisible after ablation. The tumor model was hyperechoic because the homemade US contrast agent was added. Our homemade US contrast agent had similar acoustic properties to SonoVue (Bracco, Milan, Italy), which is already on the market in China. However, according to our preliminary experiments, our homemade US contrast agent had higher homogeneity and
Fig. 1. Phantom model performance before ablation. (A) The tumor model presented as a hyperechoic sphere and was easy to distinguish from the matrix model, which was isoechoic on US images. (B) The tumor model presented as a white sphere and was easy to distinguish from the surrounding matrix on the gross specimen. (C) 3-D US volume images of the liver tumor model. The margin of the tumor model was outlined. US = ultrasound.
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Fig. 2. The performances of the ablation zone before and after replacement. (A) Before replacement, the ablation zone presented as an isoechoic ellipsoid and was difficult to distinguish from the residual tumor model and the matrix model on US. (B) Before replacement, the ablation zone presented as a white ellipsoid and was difficult to distinguish from the residual tumor model (arrow) in the gross specimen. (C) After replacement, the ablation zone presented as a hyperechoic ellipsoid because of the higher concentration of the gastric window contrast agent and was easy to distinguish from the residual tumor model and the matrix model, which were isoechoic areas on US. (D) After replacement, the ablation zone presented as a red ellipsoid and was easy to distinguish from the residual tumor model, which was noted in the white area (arrow) in the gross specimen. US = ultrasound
stability than SonoVue. This finding may be because of the smaller microbubble diameter and the higher resonance frequency of our homemade US contrast agent (Yin et al. 2013). Because of the high temperature of ablation, the hyperechoic tumor model with the homemade US contrast agent became an isoechoic zone after ablation as the microbubbles were destroyed with the passage of time. The majority of the hyperechoic tumor model faded away in 2 min. Finally, the ablation zone gradually presented as an isoechoic zone without a clear margin. As the matrix model was isoechoic, the margin of the tumor model was invisible after ablation. As a result, the operator could not estimate the ablation zone or the residual foci during and after the ablation procedure, which could avoid bias. After the ablation procedure, the red liquid containing a high concentration of
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the gastric window contrast agent was used to replace the isoechoic ablation zone. By taking advantage of the good thermal reversibility of carrageenan, we were able to visualize the margin of the ablation zone on both the US images and the gross specimen for the subsequent evaluation. In this way, the ablation zone could be assessed by US-US fusion imaging intuitively. Moreover, the standard reference of the gross specimen could be obtained to confirm the actual ablation effect, which is not practical in a clinical study. A few reports have investigated the feasibility and accuracy of the registration of fusion imaging using a phantom model (Toshikuni et al. 2013; Burgmans et al. 2017; Li et al. 2017). In the reports of Toshikuni et al. (2013) and Burgmans et al. (2017), a phantom model was used to determine the registration accuracy of USUS fusion imaging and US-CT fusion imaging, respectively. However, the registration accuracy after ablation was lacking. The registration accuracy after ablation is important because some errors might occur during the ablation procedure. In another report by Li et al. (2017), the phantom models were ablated and evaluated using US-CT fusion imaging to assess the accuracy of US-CT fusion imaging in evaluating the ablative margin (AM) of the tumor. Compared with the phantom models in Li et al.’s (2017) report, our tumor models became poorly defined after ablation on US images, which might have reduced subjective bias during assessment. To the best of our knowledge, there have been no reports on the feasibility and accuracy of US-US fusion imaging after ablation using a phantom model. Additionally, there is no similar phantom model that can be ablated and assessed with US-US fusion imaging. Based on the present study, the registration success rate was 100% using US-US fusion imaging. Only 3.8 § 0.9 min was required to finish this procedure. The procedure of fusing post-ablation real-time US images with pre-ablation 3-D US images was more convenient and quicker, because the mono-modality images using US made image recognition and alignment easier and dependent on less experience. Moreover, US-US fusion imaging was also accurate for distinguishing the complete ablation models from the incomplete ablation models. According to the evaluation results of the US images and the gross specimens in the incomplete ablation group, the quadrant of the residual tumor was consistent in each phantom model, and the measurement error of the residual pseudo-tumoral area was only 02 mm. No significant difference was observed between the evaluation of US-US fusion imaging and the gross specimen (p = 0.811). The measurement error may be related to the registration error or the manual measurement error. Although the quadrant and the maximum thickness of the residual tumor were different in each phantom
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Fig. 3. Assessment of the ablation effect of the tumor model based on US-US fusion imaging and the gross specimen of the phantom model. (A) Complete ablation. US-US fusion imaging showed that the ablation zone covered the entire tumor model, suggesting complete ablation. (B) The gross specimen of the phantom model showed complete ablation of the tumor model. (C) Incomplete ablation. US-US fusion imaging showed that the ablation zone did not cover the entire tumor model, suggesting incomplete ablation. (D) The gross specimen of the phantom model showed incomplete ablation of the tumor model. The maximum thickness of the residual tumor model (arrow) between the US images and the gross specimen of the phantom model was similar. US = ultrasound’
model, the evaluation results of the US-US fusion imaging were accurate compared with the gross specimen results. These results indicate that US-US fusion imaging is feasible in the evaluation of tumor ablation and able to assess the ablation effect precisely. The exact results of the US-US fusion imaging evaluation can be realized
directly in phantom study by comparison with gross specimens. The registration errors of US fusion imaging are inevitable during the registration procedure. In clinical practice, in addition to system registration errors, registration errors may also be caused by a patient’s motion
Table 1. Comparison of the US-US fusion imaging and gross specimen results in the incomplete ablation group Phantom model
1 2 3 4 5 6 7 8 9 10 US = ultrasound
Evaluation results of the US images
Evaluation results of the gross specimen
Quadrant
Maximum thickness of the residual tumor (mm)
Quadrant
Maximum thickness of the residual tumor (mm)
7/8 8 2 7 6 8 8 4 7 4
24 8 4 4 3 6 11 11 7 4
7/8 8 2 7 6 8 8 4 7 4
22 7 5 6 4 6 12 12 6 3
Difference value (mm)
2 1 1 2 1 0 1 1 1 1
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or breathing and tissue deformation. The imaging conditions of this study represent an ideal state. In this study, compared with the gross specimens, the measurement errors were less than 2 mm (1.1 § 0.6 mm). In our opinion, such small measurement errors are inevitable and acceptable. Registration errors may increase in clinical practice. The operators must be aware of the existence of registration errors and take measures to reduce them, such as controlling the patient’s breathing or selecting anatomic markers close to the target lesion for registration. This study had several limitations. First, the phantom study was performed in an ideal state (no blood flow, no respiratory movement, etc.), and the performance of the US system in clinical practice may differ from the results obtained in this phantom study. The registration success rate is expected to be lower in clinical studies because patient motion and breathing and tissue deformation may induce registration errors. Second, we investigated only the performance of the Esaote MyLab Twice, and the study findings may thus not be extrapolated to other systems. Third, unified phantom models were used in this phantom study. We could not provide the measurement error depending on the changes in the tumor model’s depth, size or shape. However, diverse models were not the focus of our study, which would increase the complexity of the present study. Further studies with diverse models are necessary. CONCLUSIONS The feasibility and accuracy of US-US fusion imaging in the evaluation of the ablation effect can be investigated by this phantom-simulated liver tumor ablation model in an ideal state. Acknowledgments—This work was supported by the National Key R&D Program of China (No. 2017 YFC0112000); the National Natural Science Foundation of China (No. 81401434 and No. 81430038); the Science and Technology Planning Project of Guangdong Province, China (No. 2015 A020214009, No. 2017 A020215082 and No. 2017 A020215137); the Medical Scientific Research Foundation of Guangdong Province, China (No. A2015257); and the Science and Technology Program of Guangzhou, China (No. 201704020164). Conflict of interest disclosure—The authors declare no competing interests.
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