Microvascular Flow Imaging Of Residual Or Recurrent .

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Original Article Gastrointestinal ImagingeISSN an J Radiol 2019;20(7):1114-1123Microvascular Flow Imaging of Residual or RecurrentHepatocellular Carcinoma after TransarterialChemoembolization: Comparison with Color/PowerDoppler ImagingHyo-Jin Kang, MD1, 2, Jeong Min Lee, MD1, 2, Sun Kyung Jeon, MD1, Hwaseong Ryu, MD3,Jeongin Yoo, MD1, Jae Keun Lee, BS4, Joon Koo Han, MD1, 2, 51Department of Radiology, Seoul National University Hospital, Seoul, Korea; 2Department of Radiology, Seoul National University College ofMedicine, Seoul, Korea; 3Department of Radiology, Pusan National University Yangsan Hospital, Yangsan, Korea; 4Samsung Medison Co., Ltd.,Seoul, Korea; 5Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, KoreaObjective: To determine the feasibility of microvascular flow imaging (MVFI) in comparison with color/power Doppler imaging(CDI/PDI) for detection of intratumoral vascularity in suspected post-transarterial chemoembolization (TACE) residual orrecurrent hepatocellular carcinomas (HCCs) by using contrast-enhanced ultrasonography (CEUS) or hepatic angiography (HA)findings as the reference standard.Materials and Methods: One hundred HCCs (mean size, 2.2 cm) in 100 patients treated with TACE were included in thisprospective study. CDI, PDI, and MVFI were performed in tandem for evaluating intratumoral vascularity of the lesions by usingan RS85 ultrasound scanner (Samsung Medison Co., Ltd.). Intratumoral vascularity in each technique was assessed by tworadiologists in consensus by using a 5-point scale. Then, one of the two radiologists and another radiologist performedadditional image review in the reverse order (MVFI-PDI-CDI) for evaluation of intra- and interobserver agreements. Resultswere then compared with those of either HA or CEUS as the reference. The McNemar test, logistic regression analysis, andintraclass correlation coefficient (ICC) were used.Results: CEUS or HA revealed intratumoral vascularity in 87% (87/100) of the tumors. Sensitivity (79.3%, 69/87) and accuracy(80.0%, 80/100) of MVFI were significantly higher than those of CDI (sensitivity, 27.6% [24/87]; accuracy, 37.0% [37/100])or PDI (sensitivity, 36.8% [32/87]; accuracy, 44.0% [44/100]) (all p 0.05). CDI, PDI, and MVFI presented excellent intraobserver(ICCs 0.9) and good interobserver agreements (ICCs 0.6).Conclusion: MVFI demonstrated significantly higher sensitivity and accuracy than did CDI and PDI for the detection ofintratumoral vascularity in suspected residual or recurrent HCCs after TACE.Keywords: Hepatocellular carcinoma; Transarterial chemoembolization; Microvascular flow imaging; Doppler imaging; Blood flowINTRODUCTIONUltrasonography (US) has been utilized as the firstline imaging modality for surveillance of hepatocellularcarcinoma (HCC) in patients with liver cirrhosis aswell as for follow-up of liver lesions (1, 2). However,characterization of focal liver lesions or detection of residualviable tumors after locoregional treatments on B-modeUS often remains difficult (3-6). In this regard, Dopplertechniques such as color Doppler imaging (CDI) and powerReceived December 31, 2018; accepted after revision April 7, 2019.This study was supoorted by a research grant from Samsung Medison Co., Ltd (06-2018-0110).Corresponding author: Jeong Min Lee, MD, Department of Radiology, Seoul National University College of Medicine, 101 Daehak-ro,Jongno-gu, Seoul 03080, Korea. Tel: (822) 2072-3154 Fax: (822) 743-6385 E-mail: jmsh@snu.ac.krThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium,provided the original work is properly cited.1114Copyright 2019 The Korean Society of Radiology

MVFI for Blood Flow Signal Detection in Residual or Recurrent HCC after TACEDoppler imaging (PDI), which can detect relatively fastintratumoral blood flows, have been used to differentiatehypervascular tumors in the liver (7, 8) or to evaluatethe post-treatment response of HCCs in a noninvasivemanner (9). Unfortunately, however, CDI and PDI havebeen shown to be limited in detecting slow flows or theflow in small vessels as they adopt a wall filter to minimizeclutter artifacts, leading to elimination of informationregarding low Doppler frequency shifts (10-12). Indeed,this limitation has been a major obstacle for the widerapplication of Doppler examinations in assessing hepatictumor hemodynamics. Several studies have demonstratedthe diagnostic value of contrast-enhanced ultrasonography(CEUS) in revealing the vascularity of residual tumors aftertransarterial chemoembolization (TACE) (13-16). However,CEUS requires intravenous cannulation, as well as additionalnurses or ultrasound technicians and the additional expensefor contrast agents. Therefore, there is an unmet clinicalneed to depict slow-flow vascular signals from small vesselsin focal hepatic malignancies by using a noninvasiveDoppler technique.In order to improve the depiction of slow blood flowusing the Doppler technique, several novel modified powerDoppler-based techniques that operate at very low velocityscales using advanced clutter suppression have beendeveloped, including superb microvascular imaging (SMI,Canon Medical Systems, Otawara, Japan), microflow imaging(MFI, Philips Healthcare, Best, The Netherlands), andmicrovascular flow imaging (MVFI) (MV-FlowTM, SamsungMedison Co., Ltd., Seoul, Korea). These techniques canseparate slow or small-vessel flow signals from clutterartifacts that arise from voluntary and involuntary motionby using a vendor-specific adaptive filter and can displayflow information at a high spatial resolution and framerate (17). Until now, several studies have demonstratedthe diagnostic value of the SMI technique in characterizingfocal lesions in the thyroid and breast by revealing lowvelocity flow in small vessels within the tumor (18-20).However, only a limited number of studies have exploredthese techniques to reveal tumor vessels in the liver, andthese studies had limitations such as small patient numbersor the lack of data comparing the diagnostic performancewith that of CDI or PDI (21, 22). Since residual HCCsafter locoregional treatments would increase intratumoralvascularity, we hypothesized that MVFI could sensitivelydepict intratumoral vascularity in residual or recurrentHCCs after TACE. Therefore, the purpose of our study 932to determine the feasibility of MVFI in comparison withCDI and PDI for the detection of intratumoral vascularityin suspected post-TACE residual or recurrent HCCs by usingCEUS or hepatic angiography (HA) findings as the referencestandard.MATERIALS AND METHODSThis prospective study was approved by the InstitutionalReview Board of our hospital, and all patients providedwritten informed consent for participation in this study.Financial support and the investigational US platform forthis study were provided by Samsung Medison Co., Ltd.However, the authors maintained full control of the dataat all times and the information submitted for publication,which remained unbiased by industry.PatientsFrom January 2018 to May 2018, patients with suspiciouspost-TACE residual or recurrent HCCs on follow-up CT or MRIwere prospectively screened for enrollment in this study.Inclusion criteria were as follows: 1) suspected residualor recurrent tumors in adult patients on follow-up CT/MRI after TACE according to the Liver Imaging ReportingAnd Data System (LI-RADS) v2017 treatment responsealgorithm (23); 2) diagnostic image quality on dynamic CT/MRI performed within 3 months of study enrollment; 3)absence of severe cardiovascular dysfunction; and 4) visibletumor(s) on either B-mode US or real-time multimodalityPatients with suspicion of residual or recurred HCC after TACEon follow-up CT or MRI using LI-RADS v2017 treatmentresponse algorithm between January 2018 and May 2018Exclusion for enrollment (n 8)1) Invisible lesion on B-mode US even after real-timeimaging fusion with CT or MRI (n 2)2) Suboptimal image quality of CT of MRI (n 2)3) Impairment of cardiopulmonary system (n 1)4) Refuse to enroll (n 3)One hundred patients (100 HCCs) were prospectively enrolledand performed same day CDI, PDI, MVFI, and CEUS/TACE- Hypervascular on subsequent TACE/CEUS (n 87)- Tumor size: mean, 2.2 cm; range 0.8–7.8 cmFig. 1. Flow diagram of patient population. CDI colorDoppler imaging, CEUS contrast-enhanced ultrasonography, HCC hepatocellular carcinoma, LI-RADS Liver Imaging ReportingAnd Data System, MVFI microvascular flow imaging, PDI powerDoppler imaging, TACE transarterial chemoembolization, US ultrasonography1115

Kang et al.US fusion. Eight patients were excluded from the screeningdue to the following reasons: invisible lesions on B-modeUS even after real-time imaging fusion with CT or MRI (n 2), suboptimal image quality on CT/MRI (n 2), impairmentof the cardiopulmonary system (n 1), and refusal to enrollin the study (n 3) (Fig. 1). Finally, a total of 100 patients(77 men and 23 women; mean age, 64.9 years; age range,36–73 years) with suspicious post-TACE residual or recurrentHCCs (locally recurred, n 47; remotely recurred, n 53) onfollow-up CT/MRI were enrolled in this study.All patients underwent subsequent CEUS (n 68) or HA (n 32) as the reference assessment for hypervascularity. When CTor MRI showed multiple tumors, one representative tumor perpatient was analyzed. The representative tumor was selectedon the basis of the following criteria: 1) better visibility onB-mode US, 2) closer from skin (tumor depth), 3) manageabletumor size (range, 2–5 cm). Mean tumor size was 2.8 cm(range, 0.8–8.1 cm), and the mean size of the viable portionwas 2.2 cm (range, 0.8–7.8 cm). The HCCs were located in theleft lateral (n 19), left medial (n 11), right anterior (n 37), and the right posterior (n 33) sections.US ExaminationAll US examinations were performed by one of the twoboard-certified abdominal radiologists (with 25 and 8 years’experience in abdominal US examinations, respectively)on an RS85 ultrasound scanner (Samsung Medison Co.,Ltd.) using a CA1-7A (Samsung Medison Co., Ltd.) convexprobe. First, after localizing the target tumor, CDI and PDIwere performed using an appropriate field of view (FOV)with optimal parameters for evaluation of the target tumor.Second, a MVFI was obtained using the same FOV with andwithout blending of background tissue signals. All imageswere obtained perpendicular to the skin surface, whichallowed the best visualization of the target tumor. Allsettings including gain, wall filter, and scale were optimizedin each tumor to obtain the best image possible. DetailedTable 1. Imaging Parameters of Each Doppler Technique andCEUSTechniqueCDIPDIMVFICEUSMI1.31.31.20.08Gain ��1226–32N/ADoppler Scale (kHz)0.8–2.30.8–2.30.15N/ACDI color Doppler imaging, CEUS contrast-enhancedultrasonography, MI mechanical index, MVFI microvascular flowimaging, N/A not assessed, PDI power Doppler imaging1116parameters of each US technique are noted in Table 1.Imaging AnalysisIntratumoral vascular flow was assessed on CDI, PDI, andMVFI on a 5-point scale as shown in Table 2. A flow scoreof 3 or higher was assumed to be positive for the detectionof intratumoral flow. The intratumoral vascular flow wasdetermined by the consensus reading of the two operatorsusing stored videos and images.In addition, to evaluate the possible factors affectingintratumoral flow detection, skin-to-tumor depth, liversurface-to-tumor depth, and presence of motion artifacts(binary scale) were analyzed. Motion artifact was definedas all the artifacts degrading image quality by motion, suchas clutter and blurring (24, 25). When the motion artifactswere regular and synchronized with cardiac pulsation, theywere regarded as pulsating artifacts.For interobserver agreement, another board-certifiedabdominal radiologist (with 6 years of experience inabdominal US examinations) reviewed intratumoral vascularflow by using saved images and videos. In addition,intraobserver agreements were assessed in the reverse order(MVFI-PDI-CDI) to that of the prospective acquisition ofthe three examinations by the two radiologists respectively,with a 1-month interval between the assessments so as tominimize recall bias.Reference Standards of HypervascularityHADigital subtraction HA was performed using a 5-Frcatheter (RH catheter, Cook, Bloomington, IN, USA) placedat the common hepatic artery via the right femoral arteryin 32 patients. Cone-beam CT HA was also performed inall of these 32 patients to identify hypervascular tumorsand their feeding arteries (26) by using a uniplanar conebeam CT scanner (Syngo DynaCT; Siemens Healthineers,Table 2. Scoring System for Intratumoral Vascularity AssessmentScore12345DefinitionDefinite absence of flowProbable absence of flowIndeterminate, 1 or 2 intratumoral vessels presentProbable presence of flow, 3 intratumoral vesselspresentDefinite presence of flow, 4 or more intratumoralvessels ine.org

MVFI for Blood Flow Signal Detection in Residual or Recurrent HCC after TACEForchheim, Germany). Among these, 28 lesions (28/32,87.5%) presented hypervascularity on digital subtraction orcone-beam CT HA.CEUSCEUS was performed by using a contrast-specific UStechnique of the RS85 platform (Samsung Medison Co., Ltd.)and a CA1-7A convex probe under real-time multimodalityfusion guidance in 68 patients. The contrast media(SonoVue, Bracco, Milan, Italy) was prepared according tothe manufacturer’s recommendations. Next, 2.4 mL of theprepared contrast agent was injected manually followedby a saline flush of 10 mL via an antecubital venous line.Cine CEUS images of the target tumor were obtained forthe first 60 seconds after contrast injection, followed byinterval scans for 5 seconds at 30-second intervals over 5minutes. Among the 68 lesions in 68 patients, 59 (86.8%)presented hypervascularity on the arterial phase (not rimenhancement on the arterial phase).Statistical AnalysisAll values were expressed as mean standard deviation.Comparison of vascularity scores between US techniqueswas assessed using the paired t test. To compare the flowdetection rate with respect to sensitivity, specificity,positive predictive values, negative predictive values, andaccuracy between US techniques, the McNemar test wasused. To assess the possible factors affecting intratumoral5.0RESULTSIntratumoral Flow ScoreThe intratumoral flow score in MVFI was significantlyhigher than those in CDI and PDI (p 0.001), while 93.52.5**4.5ScoreScoreflow detection, skin-to-tumor depth, liver surface-totumor depth, tumor size, and patient age were analyzedusing the independent t test. In addition, the presence ofmotion artifacts, recurrence patterns (local/remote), andsex were assessed using the chi-squared test. Parametersproven to be significant on univariate analysis with twotailed p values of less than 0.10 were subsequently testedon multivariate analysis. For multivariate analysis, logisticregression was used to assess significant independentfactors of intratumoral flow detection in each US technique.Intra- and interobserver agreements for the vascular flowscore were assessed with intraclass correlation coefficientsand those for diagnostic performance were assessed withκ-statistics. The strength of the agreement was evaluatedas follows: 0.21–0.40, fair agreement; 0.41–0.60, moderateagreement; 0.61–0.80, good agreement; and 0.81–1.0,excellent agreement. All statistical analyses were performedusing commercially available statistical software (MedCalc,ver. 16.4, MedCalc Software bvba, Mariakerke, Belgium;SPSS, ver. 23, IBM Corp., Armonk, NY, USA), and twotailed p values less than 0.05 were considered to indicate astatistically significant DISubjective vascularity scoreMVFIMVFIPDICDISubjective vascularity score in reverse orderABFig. 2. Graphs showing subjective vascularity scores for intratumoral flow detection on CDI, PDI, and MVFI.A. Intratumoral flow score in MVFI (3.59 1.51) was shown to be significantly higher than that in CDI (1.76 1.20, p 0.001) and PDI (1.95 1.26, p 0.001). B. When reviewing images and videos in reverse order, intratumoral flow score was still significantly high in MVFI (3.05 1.55)than in CDI (1.75 1.20, p 0.001) and PDI (2.07 1.31, p 0.001). *p 0.05, **p 8.09321117

Kang et al.presented a significantly higher score than did CDI (p 0.002) (Fig. 2A). When reviewing the images and videos inreverse order, intratumoral flow score was still significantlyhigher in MVFI than in CDI and PDI (p 0.001) (Fig. 2B).ARepresentative examples are presented in Figure 3.Sensitivity, Specificity, and Accuracy for Flow DetectionThirteen (13%) tumors did not show hypervascularity onBCDFig. 3. 73-year-old woman with 1.5-cm intrahepatic remote recurrent tumor in segment 6 who had previously been treated withTACE for HCC in another segment (not shown).On CDI (A) and PDI (B), intratumoral flow was detected and was graded as score of 4. On MVFI (C, D), multiple intratumoral vessels werevisualized and were graded as 5.Table 3. Sensitivity, Specificity, PPV, NPV, and Accuracy of Each Doppler Technique in Depiction of Intratumoral Vascularity ofTreated TumorsLocally Recurred (n 47)CDIPDIRemotely Recurred (n 53)MVFICDIPDIMVFITotalCDIPDIMVFISensitivity (%) 26.8 (11/41) 34.1 (14/41) 80.5 (33/41) 28.3 (13/46) 39.1 (18/46) 78.3 (36/46) 27.6 (24/87) 36.8 (32/87)79.3 (69/87)Specificity (%)100 (6/6)100 (6/6)100 (13/13) 92.3 (12/13)84.6 (11/13)PPV (%)100 (11/11)100 (14/14) 97.1 (33/34)100 (13/13) 94.7 (18/19) 97.3 (36/37)100 (24/24) 97.0 (32/33)97.2 (69/71)NPV (%)16.7 (6/36)18.2 (6/33)17.5 (7/40)17.1 (13/76) 17.9 (12/67)37.9 (11/29)Accuracy (%)36.2 (17/47) 42.6 (20/47) 80.9 (38/47) 37.7 (20/53) 45.3 (24/53) 79.2 (42/53) 37.0 (37/100) 44.0 (44/100) 80.0 (80/100)83.3 (5/6)38.5 (5/13)100 (7/7)85.7 (6/7)17.6 (6/34)85.7 (6/7)37.5 (6/16)Numbers in parentheses are numbers of tumors. NPV negative predictive value, PPV positive predictive nline.org

MVFI for Blood Flow Signal Detection in Residual or Recurrent HCC after TACEthe reference images (HA, n 4; CEUS, n 9), and therewere no significant differences between the referenceimages (p 0.63). Sensitivity, specificity, positivepredictive value, negative predictive value, and accuracy ofeach US technique are summarized in Table 3. MVFI showed79.3% sensitivity and 80.0% accuracy for intratumoral flowdetection, which was significantly higher than those of CDIand PDI (p 0.001) (Fig. 4). Representative examples arepresented in Figure 5. However, MVFI showed the lowestspecificity (84.6%), even though there were no significantdifferences in specificity among the Doppler techniques (p 0.05).MVFI showed 79.7% sensitivity for intratumoral flowdetection when using CEUS as the reference standard (n 68), which was significantly higher than those of CDI(13.6%) and PDI (25.4%) (p 0.001), without showing areduction in specificity (all specificities 100%). Likewise,MVFI showed 78.6% sensitivity when using HA as thereference standard (n 32), while CDI and PDI showed57.1% and 60.7% sensitivity (p 0.001), respectively. Inthis comparison, MVFI showed lower specificity (50.0%)than did CDI (100%) or PDI (75.0%) without statisticalsignificance (p 0.15).In the subgroup analysis by recurrence patterns, thesensitivities of MVFI were significantly higher than thoseof CDI and PDI. The speci

imaging fusion with CT or MRI (n 2) 2) Suboptimal image quality of CT of MRI (n 2) 3) Impairment of cardiopulmonary system (n 1) 4) Refuse to enroll (n 3) Fig. 1. Flow diagram of patient population. CDI color Doppler imaging, CEUS contrast-enhanced ultrasonography, HCC hepatocellular carcinoma, LI-RADS Liver Imaging Reporting

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