High-Mechanical Index (MI) Flash Imaging during Late Phase of Contrast-enhanced Ultrasound (CEUS): A Novel Approach to Enhance Differential Diagnosis of Malignant and Benign Focal Liver Lesions (FLLs)

High-Mechanical Index (MI) Flash Imaging during Late Phase of Contrast-enhanced Ultrasound (CEUS): A Novel Approach to Enhance Differential Diagnosis of Malignant and Benign Focal Liver Lesions (FLLs) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article High-Mechanical Index (MI) Flash Imaging during Late Phase of Contrast-enhanced Ultrasound (CEUS): A Novel Approach to Enhance Differential Diagnosis of Malignant and Benign Focal Liver Lesions (FLLs) Dan Zuo, Kai Yuan, Feihang Wang, Yanni Chen, Ping Yang, Xi Wang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8156677/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and aim: Although contrast-enhanced ultrasound (CEUS) is highly accurate, approximately 20% of focal liver lesions (FLLs) remain inconclusive. High-Mechanical Index (MI) flash imaging in the late phase of CEUS provides diagnostic information, yet its value is unexplored. We therefore conducted a prospective study to assess its feasibility and performance for differentiating malignant from benign FLLs. Methods: From January 2024 to April 2025, 155 consecutive patients with a single FLL underwent CEUS (MI: 0.12) followed by high-MI flash imaging (MI: 1.2). Hypo-echogenicity on flash imaging was served as the diagnostic criterion for malignant FLLs. Technical successful rate, observer agreement and diagnostic performance of flash imaging were assessed. The clinical value of flash imaging was determined in CEUS-inconclusive cases. Results: Flash imaging was technically successful in 143 (92.3%) FLLs (102 malignant; 41 benign). Hypo-echogenicity was present in 96.1% (98/102) malignant versus 34.1% (14/41) benign FLLs on flash imaging ( p < 0.001). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of flash imaging were 96.1%, 65.9%, 87.5%, 87.1%, and 87.4%, respectively. Inter- and intra-observer agreement were both excellent (inter: 92.3%; intra: 93.0 and 93.7%). Flash imaging achieved 80.0% differential diagnostic accuracy in CEUS-inconclusive cases. When CEUS and flash imaging were integrated, the overall differential diagnostic accuracy increased from 82.5% to 97.9% ( p < 0.001). Conclusion: High-MI flash imaging during late phase of CEUS demonstrates high technical success, excellent reproducibility and significant discriminative ability for FLLs, especially enhancing the discriminative ability of CEUS in CEUS-inconclusive cases. Focal liver lesions (FLLs) Flash imaging Contrast-enhancement ultrasound (CEUS) Differential diagnosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Focal liver lesions (FLLs) encompass a broad histopathological range with markedly divergent intra-tumoral microvascular signatures. Hepatocellular carcinoma (HCC) constitutes approximately 75–85% of malignant FLLs and remains the third leading cause of cancer-related death worldwide ( 1 ). Contrast-enhanced ultrasound (CEUS) is currently one of the most recommended modalities for FLLs, with the advantages of being radiation-free and providing continuous real-time visualization ( 2 , 3 ). Although a meta-analysis reported that the diagnosis accuracy of CEUS for differentiating malignant and benign FLL reached an overall 88% sensitivity and 81% specificity, which is similar to the diagnostic efficiency of CT or MRI, yet its performance drops markedly in small lesions ( 4 , 5 ). Moreover, 12–26% of HCCs arise in patients without cirrhosis and 37% of benign FLLs demonstrate late phase hypo-enhancement on CEUS, leaving a substantial proportion of cases in diagnostic gray zone and underscoring the need for a more reliable imaging modality ( 6 , 7 ). Different from conventional CEUS, which uses continuous low-mechanical index (MI) pulses to preserve microbubble integrity and prolong the observation window, flash imaging applies transient high-MI pulses to trigger controlled microbubble collapse, thereby enhancing the conspicuity of small or poorly visualized FLLs ( 8 ). In 1999, Kamiyama et al. first employed high-MI pulses to destroy microbubbles and quantified hepatic blood flow from the subsequent replenishment curve, establishing the "microbubble-destruction and replenishment" paradigm of flash imaging ( 9 ). In 2019, Wakui et al. turned their attention to the microbubble destruction itself. They observed that a wave-like hyperechoic band produced by microbubble destruction migrates steadily into deeper tissue, proving that diagnostic information can be obtained solely from the destruction event ( 10 ). However, to our knowledge no systematic investigation has explored the potential of flash imaging for differential diagnosis of malignant versus benign FLLs. In this study, we aim to assess the feasibility and diagnostic performance of high-MI flash imaging performed during the late phase of CEUS for differentiating malignant from benign FLLs, based solely on the microbubble destruction without replenishment imaging. Materials and Methods This prospective study was approved by the institutional ethics committee (No. B2022-223). Written informed consent was obtained from all participants prior to CEUS examinations. Patients From January 2024 to July 2025, consecutive patients who planned to accept both CEUS and flash imaging for FLL were prospectively enrolled. The gold standard for malignant FLLs was surgical or biopsy histopathology. Benign FLLs were confirmed either by histopathology or by composite imaging criteria (typical benign enhancement on both CEUS and contrast-enhanced CT/MRI) together with stability or decrease in size over ≥ 6 months of imaging follow-up (cut-off date: 30 April 2025). The exclusive criteria were as follows: ( 1 ) Patient with multiple FLLs; ( 2 ) Patient accepted any systemic or locoregional therapy for target FLL, including chemotherapy, targeted therapy, immunotherapy, local thermal ablation or transhepatic arterial chemotherapy and embolization; ( 3 ) Absence of gold-standard confirmation. Ultrasonography Examination and Flash Imaging All ultrasound examinations including B-mode ultrasound (BMUS), CEUS and flash imaging were performed by an experienced ultrasound operator (W. W. P., with 20 years of experience in liver CEUS examination) using a Mindray Resona R9 Super system with a 1–6 MHz convex-array transducer (Mindray Medical International Limited, Shenzhen, China). The contrast agent was Sonazoid (GE Healthcare AS, Oslo, Norway). A bolus of 0.6–1.0 mL was injected intravenously via the median cubital vein, followed by an immediate injection of 5 mL of 0.9% saline. A high-MI BMUS scan was firstly performed to localize and characterize any potential FLLs (transmit frequency: 2.8MHz; depth: 15 cm; MI: 1.2; frame rate: 25 fps; gain: 70%; dynamic range: 105dB). After intravenous administration of contrast agent, each identified FLL was continuously observed for 2 minutes under CEUS mode with low-MI (MI: 0.12; frame rate: 10 fps; gain: 50%; dynamic range: 110dB). During the late phase, the entire liver was systematically re-examined to detect any additional FLLs. Approximately 5 minutes after microbubble injection, the system was then one-click returned to high-MI B-mode (all parameters were identical to BMUS) to initiate flash imaging. Moving microbubble destruction generated a wave-like hyperechoic band that propagated from the capsule toward deeper parenchyma (Fig. 1) . The frame and clip in which this advancing hyperechoic wavefront overlapped target FLL was stored for subsequent analysis. Image Interpretation of Flash Imaging Prior to flash image interpretation, each flash frame was screened for qualification against the following three criteria: ( 1 ) a clearly visible, wave-like hyperechoic band moving from the near to the deep field; ( 2 ) demonstrable overlap between the hyperechoic band and the target FLL; ( 3 ) simultaneous visualization of perilesional liver parenchyma within the advancing hyperechoic wavefront. The technical successful rate (qualified frames/total frames × 100%) was then calculated. A senior ultrasound radiologist (W. W. P.) and a junior ultrasound radiologist (Y. K. with 1 year of experience in liver CEUS examination) independently reviewed the images, blinded to clinical, image and pathological data. Discrepancies were resolved by consensus. Inter-observer reliability was assessed by having the 2 observers review the images independently. Intra-observer reliability was evaluated by having each observer review the images again after a one-month interval. When the wavefront simultaneously covered the FLL and adjacent liver parenchyma, the lesion was classified as iso-echogenicity (indistinguishable from background parenchyma) or hypo-echogenicity (lower echogenicity than surrounding liver). Hypo-echogenicity on flash imaging was considered as a diagnostic criterion for malignant FLLs and iso-echogenicity for benign FLLs ( Fig. 1) . Diagnostic Criteria of CEUS for Differentiating Malignant and Benign FLLs According to the latest WFUMB-EFSUMB guideline, malignant FLLs are defined by any arterial phase hyper-enhancement (uniform, peripheral rim, heterogeneous or patchy) followed by wash-out in the portal venous or late phases, whereas typical benign FLLs show arterial iso- or hyper-enhancement (peripheral nodular centripetal fill, centrifugal spoke-wheel, or homogeneous) followed by sustained enhancement without wash-out ( 2 ). Any enhancement pattern failing to fulfil the aforementioned malignant or benign criteria is considered inconclusive on CEUS. Statistical Analysis Statistical analyses were performed with IBM SPSS 27.0 (IBM Corp., Armonk, NY, USA) and R 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were expressed as mean ± SD or median (IQR). Categorical variables were reported as n (%). Between-group comparisons used independent-samples T test or Mann-Whitney U test for continuous variables and χ² or Fisher’s exact test for categorical variables. Intra- and inter-observer agreement were assessed with Cohen’s κ ( 0.80 excellent). Two-tailed p < 0.05 was considered significant. The diagnostic performance of flash imaging was calculated against the gold standard. McNemar’s test was used to compare the diagnostic accuracy in the paired dataset; 95% CIs were calculated with Wilson score interval. Subgroup analyses were stratified by liver background (normal, fatty liver, cirrhosis, or fatty liver + cirrhosis), lesion size (≤ 3 cm, 3–5 cm, > 5 cm), baseline echogenicity on BMUS (hypoechoic, isoechoic, or hyperechoic), and depth (distance from the FLL center to the liver capsule: ≤3 cm, 3–6 cm, > 6 cm). Results Patients Between January 2024 and April 2025, 195 consecutive patients with FLLs who underwent CEUS and flash imaging were prospectively enrolled. After excluding 40 patients (multiple lesions, n = 15; received prior systemic/locoregional therapy, n = 6; lacked gold-standard confirmation, n = 19), a total of 155 patients with a single treatment-naïve FLL constituted the primary cohort (Fig. 2) . Technical success of flash imaging was achieved in 143 of 155 (92.3%) cases. Flash imaging of 12 FLLs was considered inadequate: 4 lesions because the wave-like hyperechoic zone wasn't generated, and 8 lesions because the advancing wavefront failed to simultaneously display both the target lesion and adjacent liver parenchyma (superficial location, n = 2; extreme deep location, n = 2; large lesion, n = 4). Consequently, the final analytical dataset comprised 143 patients with evaluable flash imaging (48 females, 95 males; median age 56 years, IQR 48–64), with 102 malignant and 41 benign FLLs ( Table 1) .Details of the final diagnoses and BMUS and conventional CEUS findings are provided in the Supplementary Materials Table S1 . Intra- and Inter-observer Reliabilities of Flash Imaging Features Both Inter- and intra-observer agreement values indicate excellent reliability. Inter-observer agreement was 92.3%, and Cohen’s kappa was κ = 0.77 (95 % CI: 0.63 - 0.90, p < 0.001). One month later, each observer re-assessed the same images. The junior and senior ultrasound radiologist showed intra-observer agreement of 93.0 %, κ = 0.81 (95 % CI: 0.69–0.92, p < 0.001) and 93.7%, κ = 0.83 (95 % CI: 0.72–0.93, p < 0.001), respectively. Flash Imaging Features of Malignant and Benign FLLs Among the 143 FLLs, 112 (78.3%) lesions exhibited hypo-echogenicity on flash imaging, while 31 (21.7%) lesions appeared iso-echogenicity (Table 2) . Among the 102 malignant FLLs, 98 (96.1%) lesions were hypo-echogenicity (Fig. 3, Video 1) and 4 (3.9%) were iso-echogenicity. In contrast, among the 41 benign FLLs, 27 (65.9%) lesions were iso-echogenicity on flash imaging (Fig. 4, Video 2) , and 14 (34.1%) were hypo-echogenicity. The hypo-echogenicity rate was significantly higher in malignant than in benign FLLs (96.1% vs. 34.1%, p < 0.001). Flash imaging features for individual FLL subtype are provided in Supplementary Materials Table S2 . Diagnostic Performance of Flash Imaging in Differentiating Malignant and Benign FLLs Setting hypo-echogenicity on flash imaging as indicative of malignant FLLs and iso-echogenicity of benign correctly classified 98 (96.1%) malignant FLLs and 27 (65.9%) benign FLLs, yielding a sensitivity of 96.1% (95 % CI: 90.0–99.2), specificity of 65.9% (95 % CI: 47.4–81.7), positive predictive value (PPV) of 87.5% (95 % CI: 80.0–92.3), negative predictive value (NPV) of 87.1 % (95 % CI: 70.5–95.0) and overall accuracy of 87.4 % (95 % CI: 79.8–92.3). Sensitivity and specificity were comparable across liver-background subgroups, but accuracy differed significantly ( p = 0.02). Pair-wise comparisons revealed that accuracy in the fatty liver group (78.4%; 95 % CI: 64.4–88.2) was markedly lower than in both the cirrhosis group (94.0%; 95% CI: 83.5–98.7), ( p = 0.02) and the combined cirrhosis + fatty liver group (94.4%; 95% CI: 72.7–99.9), ( p = 0.02). Sensitivity varied among groups with different baseline echogenicity on BMUS ( p = 0.04), while specificity and overall accuracy were unaffected. FLLs that appeared hyperechoic on BMUS demonstrated a lower sensitivity (82.6%; 95% CI: 61.2–95.0) than both hypoechoic (100%; 95% CI: 93.3–100, p = 0.02) and isoechoic lesions (100%; 95% CI: 86.8–100, p = 0.03). Neither size nor depth of FLLs significantly influenced sensitivity, specificity or accuracy of flash imaging in differentiating malignant and benign FLLs. Full details are provided in Table 3 . Practical Value of Flash Imaging Added to CEUS Among the 143 FLLs, CEUS correctly classified 86 malignant and 32 benign FLLs, yielding an overall diagnostic accuracy of 82.5%. However, 25 FLLs remained inconclusive on CEUS. In this inconclusive subgroup, flash imaging reclassified 16/16 malignancies as hypoechoic (Fig. 5) and 6/9 benign lesions as isoechoic (Fig. 6) , achieving 80.0% accuracy. When CEUS and flash imaging features were integrated, the overall diagnostic accuracy increased to 97.9%, which was significantly higher than CEUS alone ( p < 0.001). Discussion Despite CEUS being a guideline recommended image modality for FLLs, the rising incidence of HCC among individuals not traditionally high-risk, coupled with diverse imaging features of benign and malignant FLLs across different pathologies, adds to complexity of preoperative diagnosis ( 6 , 11 ). Flash imaging performed after the observation of CEUS late phase, is an convenient and efficient modality. No extra contrast agent or parameter adjustment is required—simply revert to high-MI B-mode after completing the CEUS sequence, capture the flash image in an easy scan, and add only seconds to the examination while markedly boosting diagnostic yield. We reported the first prospective study to evaluate flash imaging for differentiating malignant and benign FLLs. It reveals a high technical successful rate of 92.3% and excellent observer agreement of 92.3–93.7%, confirming feasibility and reproducibility. Flash imaging is a characteristic acoustic signature of rapid microbubble collapse, which is induced by a high-MI ultrasound pulse. Although microbubble rupture was triggered by various contrast agents, only sulfur-hexafluoride microbubbles consistently generate a stable, mobile hyper-echoic band under flash conditions, significantly enhancing lesion conspicuity and detection rates ( 9 , 10 , 12 ). Pathologically, benign FLLs retain the sinusoidal micro-architecture, whereas malignant FLLs show progressive loss of sinusoidal spaces owing to infiltrative tumour growth and capillarization( 13 ). These microvascular perfusion differences determine the late-phase CEUS signature: persistent iso- or hyper-enhancement in benign FLLs versus wash-out with hypo-enhancement appearance in malignant counterparts ( 14 ). Leveraging the late-phase contrast gradient between lesion and liver, flash imaging converts microbubble collapse into an accentuated wash-out signature. Theoretically, flash imaging improves diagnosis by unveiling late-phase wash-out of malignant FLLs invisible to unaided eye ( 12 ). Thus, a hypoechoic appearance on flash imaging may serve as a highly sensitive marker of malignant FLLs, with sensitivity 96.1% (95% CI: 90.0–99.2), specificity 65.9% (95% CI: 47.4–81.7), PPV 87.5% (95% CI: 80.0–92.3), NPV 87.1% (95% CI: 70.5–95.0) and accuracy 87.4% (95% CI: 79.8–92.3). The high sensitivity and NPV underscore its strength in detecting early or atypical malignant FLLs, while modest specificity reflects false positives from benign entities clarified by follow-up, preserving clinical benefit of minimal false negatives. Moreover, subgroup analysis showed that liver background significantly influenced flash imaging accuracy: 78.4% in fatty liver versus 94.0% in cirrhosis and 94.4% in combined disease ( p = 0.02). This reduction in fatty liver group reflects skewed FLL distribution—benign lesions predominated in fatty liver, whereas malignancies clustered in cirrhotic parenchyma—lowering accuracy without affecting sensitivity or specificity and indicating case-mix effect rather than technical limitation. Baseline BMUS echogenicity modestly reduced sensitivity for BMUS hyperechoic FLLs compared with BMUS hypo- and isoechoic lesions, because of decreased conspicuity against hyperechoic flash background, whereas specificity and overall accuracy remained unchanged. Lesion size and depth did not significantly affect diagnostic efficacy. Flash imaging exhibits robust diagnostic performance across malignant FLLs of divergent histotypes; in contrast, its behavior varies among benign entities, reflecting heterogeneous microvascular perfusion characteristics inherent to each pathological subtype. Hepatic focal nodular hyperplasia (FNH) consists of normal hepatocytes arrayed around richly vascularised fibrous septa. On CEUS it displays a spoke-wheel hyper-enhancement during arterial phase and a central non-enhancing scar in 1/3 to 1/2 cases; pooled diagnostic accuracy is 90% ( 15 , 16 ). In our cohort, 16 (88.9%) hepatic FNH exhibited iso-echogenicity on flash imaging, rendering them indistinguishable from surrounding liver—a concordance rate fully comparable to published CEUS benchmarks. Hepatic haemangiomas comprise endothelial-lined cavernous channels, variable arteriovenous shunts and organised thrombi that slow intralesional flow. These structural features generate the characteristic CEUS pattern of discontinuous, peripheral nodular enhancement with gradual centripetal progression and incomplete late-phase fill-in ( 2 ). In a 1,153-patient Romanian multicenter study, CEUS delivered 90% sensitivity and 99% specificity for hepatic hemangioma, giving 97% diagnostic accuracy ( 17 ). However, flash imaging provided limited support for characterizing hepatic haemangiomas in our series, and the frequent hypo-echogenic appearance may reflect incomplete contrast replenishment related to the lesions’ unique architecture. Typical CEUS patterns remain more reassuring. Hepatic angiomyolipoma (HAML) is a rare benign mesenchymal neoplasm composed of haphazardly arranged smooth muscle bundles, thick-walled vessels and mature adipocytes, is richly vascularized yet lacks the characteristic sinusoidal architecture of hepatic parenchyma ( 18 ). On CEUS, HAML typically demonstrates marked arterial hyper-enhancement followed by persistent late-phase hypo-enhancement, a temporal pattern that closely mimics malignant FLLs ( 19 ). Nevertheless, although identification of intralesional fat on CT/MRI may offer a valuable diagnostic clue, high-quality prospective evidence is still lacking. In our cohort, among 6 HAML, 5 lesions appeared hypoechoic on flash imaging, yielding a flash-to-pathology concordance of only 16.7%. Owing to this limited specificity, confident characterization of HAML should integrate clinical context, multimodal imaging features, and CEUS perfusion findings to minimize misdiagnosis. Performed immediately after conventional CEUS as a one-click adjunct, flash imaging complements—rather than replaces—CEUS in the characterization of FLLs. We explored its added value in 25 CEUS-inconclusive FLLs, where flash imaging achieved 80% accuracy and correctly identified all malignant lesions. Integrating flash findings into CEUS assessment, overall accuracy rose from 82.5% to 97.9% ( p < 0.001), a margin comparable with published CT/MRI comparisons ( 20 ). These preliminary data suggest that flash imaging may enhance diagnostic confidence and accelerate therapeutic decision-making for early-stage liver cancer. However, flash imaging carries an inherent limitation: the high-MI pulse instantly destroys majority of micro-bubbles, rendering the examination "terminal" and precluding further vascular-phase assessment. Overall, flash imaging demonstrated a high technical success rate; suboptimal studies were encountered in only 12 (7.7%) cases. Inadequacy was attributable to absence of the characteristic hyperechoic band or failure to visualize simultaneously both the FLL and adjacent liver parenchyma (lesion too superficial, too deep, or exceeding the field of view). These limitations are inherent to conventional CEUS and can be overcome by standardized scanning protocols; they did not compromise the overall diagnostic performance of the technique. Limitations Limitations: ( 1 ) Reference-standard contamination confined to the benign subset: all 106 malignant FLLs were histopathologically verified, whereas 43.9% (18/41) of benign lesions were diagnosed by combined imaging follow up, risking mis-classification bias. ( 2 ) Spectrum bias: This study was performed at a tertiary referral centre, where the cohort was enriched with surgical candidates, yielding a malignancy fraction of 70% (vs ≈ 30% reported for incidental FLL in community cohorts( 21 )). Post-hoc bootstrap adjustment assuming a 30% malignant prevalence showed specificity remained 61%, indicating minimal net effect. ( 3 ) Single-centre, single-vendor design: all acquisitions were obtained on one Mindray Resona R9 Super system; multicentre, multi-platform validation is imperative to confirm external reproducibility. Conclusion High-MI flash imaging, when utilized during the late phase of CEUS, is not only easy to perform but also achieves high technical success and substantial observer agreement, markedly enhancing the ability of CEUS to discriminate malignant and benign FLLs. This improvement is particularly pronounced in the assessment of CEUS inconclusive FLLs, thereby highlighting its potential to augment diagnostic precision in challenging cases. Declarations Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Author Contributions: Dan Zuo conducted study conception, literature search and wrote the first draft of the manuscript. Kai Yuan and Ping Yang performed data analysis. Kai Yuan and Wenping Wang interpreted the images. Feihang Wang and Yanni Chen collected the data. Xi Wang reviewed and edited the manuscript. Wenping Wang performed all CEUS examinations and supervised the study. All authors critically reviewed the manuscript and approved the final version for publication. Funding Statement: This work was supported by National Natural Science Foundation of China (Grant No. 82472004). All funding departments had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Conflict of Interest Statement: The authors declare that they have no relevant financial or non-financial interests that may be perceived as having influenced the results or discussion reported in this manuscript.· References Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63. Lee JY, Minami Y, Choi BI, Lee WJ, Chou YH, Jeong WK, et al. The AFSUMB Consensus Statements and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound using Sonazoid. Ultrasonography. 2020;39(3):191-220. Tang Y, Sasaki SI, Hawley J, Peillon A, Sjostrom A, Fuentes-Alburo A, et al. Diagnostic Test Accuracy of Contrast-Enhanced Ultrasound With Sonazoid for Assessment of Focal Liver Lesions: A Systematic Review and Meta-Analysis. J Clin Ultrasound. 2025;53(3):510-24. Guang Y, Xie L, Ding H, Cai A, Huang Y. 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Combining CEUS and CT/MRI LI-RADS major imaging features: diagnostic accuracy for classification of indeterminate liver observations in patients at risk for HCC. Abdom Radiol (NY). 2025;50(5):2066-77. Dietrich CF, Nolsoe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, et al. Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020;46(10):2579-604. Tables Table 1 Clinical Characteristics of Patients with Qualified Flash Imaging Characteristics Overall (n = 143) Age (years) 56 (IQR: 48-64) Gender (%) Male Female 95 (66.4%) 48 (33.6%) Symptom (%) Asymptomatic Abdominal pain Abdominal distend 127 (88.8%) 9 (6.3%) 7 (4.9%) Elevated Tumor Maker (%) * AFP (n = 131) CA19-9 (n = 130) AFP- L3 (n = 118) DCP (n = 128) 31 (23.7%) 19 (14.6%) 34 (28.8%) 44 (34.4%) HBV Infection (%) Yes No 82 (57.3%) 61 42.7%) Diagnostic Method (%) Surgery Biopsy Image 106 (74.1%) 19 (13.3%) 18 (12.6%) Final Diagnosis (%) Malignant FLLs Benign FLLs 102 (71.3%) 41 (40.2%) * Note: Tumor markers were tested in a subset of patients. alpha-fetoprotein (APF); carbohydrate antigen 19-9 (CA19-9); alpha-fetoprotein L3 fraction (AFP-L3); des-γ-carboxy prothrombin (DCP). Table 2 Diagnostic Performance of Flash Imaging Flash Imaging Feature Gold Standard of FLLs Total Malignant Benign Hypo-echogenicity 98 14 112 Iso-echogenicity 4 27 31 Total 102 41 143 Table 3 Subgroup Analysis of Flash Imaging Diagnostic Performance for Malignant vs Benign FLLs Sensitivity % (95 %CI) p value Pairwise p * Specificity % (95 %CI) p value Accuracy % (95 %CI) p value Pairwise p * Liver background Normal Fatty liver Cirrhosis Fatty liver + cirrhosis 100.0 (78.2–100.0) 96.0 (79.6–99.9) 93.6 (82.5–98.7) 100.0 (78.2–100.0) 0.56 70 (34.8–93.3) 61.5 (40.6–79.8) 100.0 (29.2–100.0) 50.0 (1.3–98.7) 0.07 87.5 (67.6–95.9) 78.4 (64.4–88.2) 94.0 (83.5–98.7) 94.4 (72.7–99.9) 0.02 0.02 a 0.02 b Depth ≤ 3cm 3 - 6 cm > 6 cm 100.0 (83.2–100.0) 94.4 (85.2–98.8) 96.4 (81.7–99.9) 0.55 64.3 (35.6–85.8) 61.9 (38.4–81.9) 83.3 (35.9–99.6) 0.52 85.3 (68.5–94.3) 85.3 (75.2–92.4) 94.1 (84.2–99.9) 0.36 Size ≤ 3cm 3 - 5 cm > 5cm 95.7 (85.5–99.5) 100.0 (85.7–100.0) 93.8 (79.2–99.2) 0.55 72.7 (49.8–89.3) 42.9 (9.9–81.6) 75.0 (42.8–94.5) 0.52 87.0 (74.3–94.4) 86.7 (69.3–96.2) 88.6 (73.3–96.7) 0.92 Echogenicity on BMUS Hypoechoic Isoechoic Hyperechoic 100.0 (93.3–100.0) 100.0 (86.8–100.0) 82.6 (61.2–95.0) 0.04 0.02 c 0.03 d 66.7 (44.7–84.4) 66.7 (29.9–92.5) 62.5 (24.5–91.5) 0.89 89.6 (80.3–95.0) 91.4 (76.9–98.2) 77.4 (58.9–90.4) 0.21 Overall 96.1 (90.0–99.2) 65.9 (47.4–81.7) 87.4 (79.8–92.3) *: Holm correction was applied to two-tailed Fisher exact tests for multiple comparisons. a: p values by two-tailed Fisher exact test between cirrhosis and fatty liver. b: p value by two-tailed Fisher exact test between fatty liver + cirrhosis and fatty liver. c: p values by two-tailed Fisher exact test between hyperechoic and hypoechoic. d: p values by two-tailed Fisher exact test between hyperechoic and isoechoic. Supplementary Files GraphicAbstract.docx SupplementaryMaterials.docx SupplementaryVideo1.mp4 SupplementaryVideo2.mp4 SupplementaryVideo3.mp4 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8156677","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":563952056,"identity":"4ee0a370-1408-4f50-a3a6-3be350a109eb","order_by":0,"name":"Dan Zuo","email":"","orcid":"","institution":"Zhongshan Hospital Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Zuo","suffix":""},{"id":563952057,"identity":"9e0e2582-ea4d-4e65-ac60-f855c1227520","order_by":1,"name":"Kai Yuan","email":"","orcid":"","institution":"Zhongshan Hospital Fudan 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1","display":"","copyAsset":false,"role":"figure","size":743822,"visible":true,"origin":"","legend":"\u003cp\u003eschematic showing the flash phenomenon: following the CEUS late phase, the ultrasound system was switched back to high-MI B-mode (a), a wave-like hyperechoic band propagates from the near field towards the deep liver parenchyma (b, c, d). When the advancing wavefront overlaps the target FLL and surrounding liver parenchyma, malignant lesions appear hypo-echogenicity (g, left), whereas benign lesions remain iso-echogenicity (g, right) relative to the surrounding liver parenchyma (yellow arrow). Once the hyperechoic band has moved deeper, the target FLL reverts to its original BMUS appearance (h).\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/73e0e72e2664dcedb809da12.png"},{"id":99192290,"identity":"af1e2937-0c9a-4e8b-bda2-fef25e1a3383","added_by":"auto","created_at":"2025-12-30 01:03:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1837052,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of this study.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/c25ece2c64dd74abb6deecf5.png"},{"id":99192288,"identity":"57446ca8-9f79-4471-9ce8-705febea7540","added_by":"auto","created_at":"2025-12-30 01:03:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1146361,"visible":true,"origin":"","legend":"\u003cp\u003eThis is a 40-year-old man with a history of HBV infection and elevated AFP levels. BMUS revealed a 45mm × 34mm hypoechoic lesion in the right lobe of liver (a). After injection of the ultrasound contrast agent, the lesion showed heterogeneous hyper-enhancement during the arterial phase with an irregular non-enhancing area (c), followed by hypo-enhancement during the portal venous and late phases (d, e). Flash imaging demonstrated hypo-echogenicity (b), indicating a high suspicion for malignancy (See \u003cstrong\u003eSupplementary Video 1\u003c/strong\u003e for real-time flash imaging). The final pathological diagnosis was an HCC with central necrosis.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/a27f4e348d2435ca3e1926fc.png"},{"id":99319280,"identity":"0590219d-3096-4590-b84a-35b5435cd7ff","added_by":"auto","created_at":"2025-12-31 16:36:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1136076,"visible":true,"origin":"","legend":"\u003cp\u003eThis is a 43-year-old woman without hepatitis virus infection. Tumor markers were within normal limits. BMUS revealed a 43mm × 36mm slightly hypoechoic lesion in the left lobe of the liver (a). After injection of the ultrasound contrast agent, the lesion showed centrifugal hyper-enhancement during arterial phase (c, d), without washout during the delayed phase (e). Flash imaging demonstrated iso-echogenicity with hypoechoic central scar (b), indicating a high probability of benignity (See \u003cstrong\u003eSupplementary Video 2\u003c/strong\u003e for real-time flash imaging). The final pathological diagnosis was an hepatic FNH.\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/ce22236ac3f0b167c039b5ff.png"},{"id":99316463,"identity":"0ddf1cfb-1b90-4e0b-945a-99fb4d825290","added_by":"auto","created_at":"2025-12-31 16:28:29","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1113014,"visible":true,"origin":"","legend":"\u003cp\u003eA CEUS-inconclusive case. This is a 51-year-old man without a history of HBV infection. Tumor markers were within normal limits. BMUS revealed a 24mm × 20mm slightly hypoechoic lesion in the right lobe of liver (a). After injection of the ultrasound contrast agent, the lesion showed homogeneous hyper-enhancement during arterial phase (c), followed by iso-enhancement during portal venous and late phases (d, e). Flash imaging demonstrated hypo-echogenicity (b), indicating a moderate suspicion for malignancy (See \u003cstrong\u003eSupplementary\u003c/strong\u003e \u003cstrong\u003eVideo 3\u003c/strong\u003e for real-time flash imaging). The final pathological diagnosis was an HCC.\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/be6ef6c58b8fcb72c2962c07.png"},{"id":99192302,"identity":"31db8935-8ab6-47d9-bc59-45d04427ae70","added_by":"auto","created_at":"2025-12-30 01:03:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1116362,"visible":true,"origin":"","legend":"\u003cp\u003eA CEUS-inconclusive case. This is a 43-year-old man without hepatitis virus infection. Tumor markers were within normal limits. BMUS revealed a 43mm × 34mm hypoechoic lesion in the right lobe of liver (a). After injection of the ultrasound contrast agent, the lesion showed slightly heterogeneous hyper-enhancement during arterial phase (c), iso-enhancement during portal venous phase (d) and hypo-enhancement during late phases (e). Flash imaging demonstrated iso-echogenicity (b), indicating a high suspicion of a benignity. The final pathological diagnosis was an HAML.\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/cfbc50f8123330481e6be394.png"},{"id":100357099,"identity":"03bc581f-a65a-4bc5-b0f9-7ffcfd3fd9e2","added_by":"auto","created_at":"2026-01-16 07:18:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8165737,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/1e1226ac-5f47-4cca-80a0-64231abc8a31.pdf"},{"id":99319294,"identity":"eb934b89-aa4c-4564-a800-b80379773543","added_by":"auto","created_at":"2025-12-31 16:36:50","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":615663,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicAbstract.docx","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/f7b6113a218aa94c492194e7.docx"},{"id":99317000,"identity":"d627c0b2-5878-4754-8992-3ce2b6f9e738","added_by":"auto","created_at":"2025-12-31 16:29:34","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":44199,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/cf5c4f515c8179aff7328ae0.docx"},{"id":99192298,"identity":"f2c01e59-d23a-4d7f-a416-5217a73663a7","added_by":"auto","created_at":"2025-12-30 01:03:30","extension":"mp4","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":7526692,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryVideo1.mp4","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/c2e9b54b4d30ce30e7cf5fc5.mp4"},{"id":99192300,"identity":"7de034e3-ef48-497a-b7cd-b0d7763055a9","added_by":"auto","created_at":"2025-12-30 01:03:30","extension":"mp4","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":12817621,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryVideo2.mp4","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/7f89f3310c64fdaa6e5019fb.mp4"},{"id":99318512,"identity":"b19d3019-0bf7-4991-9be8-ce1fd83b12fe","added_by":"auto","created_at":"2025-12-31 16:33:30","extension":"mp4","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":12817621,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryVideo3.mp4","url":"https://assets-eu.researchsquare.com/files/rs-8156677/v1/7344ac2c494bc4632e9d2a07.mp4"}],"financialInterests":"","formattedTitle":"High-Mechanical Index (MI) Flash Imaging during Late Phase of Contrast-enhanced Ultrasound (CEUS): A Novel Approach to Enhance Differential Diagnosis of Malignant and Benign Focal Liver Lesions (FLLs)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFocal liver lesions (FLLs) encompass a broad histopathological range with markedly divergent intra-tumoral microvascular signatures. Hepatocellular carcinoma (HCC) constitutes approximately 75\u0026ndash;85% of malignant FLLs and remains the third leading cause of cancer-related death worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Contrast-enhanced ultrasound (CEUS) is currently one of the most recommended modalities for FLLs, with the advantages of being radiation-free and providing continuous real-time visualization (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Although a meta-analysis reported that the diagnosis accuracy of CEUS for differentiating malignant and benign FLL reached an overall 88% sensitivity and 81% specificity, which is similar to the diagnostic efficiency of CT or MRI, yet its performance drops markedly in small lesions (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Moreover, 12\u0026ndash;26% of HCCs arise in patients without cirrhosis and 37% of benign FLLs demonstrate late phase hypo-enhancement on CEUS, leaving a substantial proportion of cases in diagnostic gray zone and underscoring the need for a more reliable imaging modality (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDifferent from conventional CEUS, which uses continuous low-mechanical index (MI) pulses to preserve microbubble integrity and prolong the observation window, flash imaging applies transient high-MI pulses to trigger controlled microbubble collapse, thereby enhancing the conspicuity of small or poorly visualized FLLs (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In 1999, Kamiyama et al. first employed high-MI pulses to destroy microbubbles and quantified hepatic blood flow from the subsequent replenishment curve, establishing the \"microbubble-destruction and replenishment\" paradigm of flash imaging (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In 2019, Wakui et al. turned their attention to the microbubble destruction itself. They observed that a wave-like hyperechoic band produced by microbubble destruction migrates steadily into deeper tissue, proving that diagnostic information can be obtained solely from the destruction event (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, to our knowledge no systematic investigation has explored the potential of flash imaging for differential diagnosis of malignant versus benign FLLs.\u003c/p\u003e \u003cp\u003eIn this study, we aim to assess the feasibility and diagnostic performance of high-MI flash imaging performed during the late phase of CEUS for differentiating malignant from benign FLLs, based solely on the microbubble destruction without replenishment imaging.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis prospective study was approved by the institutional ethics committee (No. B2022-223). Written informed consent was obtained from all participants prior to CEUS examinations.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eFrom January 2024 to July 2025, consecutive patients who planned to accept both CEUS and flash imaging for FLL were prospectively enrolled. The gold standard for malignant FLLs was surgical or biopsy histopathology. Benign FLLs were confirmed either by histopathology or by composite imaging criteria (typical benign enhancement on both CEUS and contrast-enhanced CT/MRI) together with stability or decrease in size over \u0026ge;\u0026thinsp;6 months of imaging follow-up (cut-off date: 30 April 2025). The exclusive criteria were as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Patient with multiple FLLs; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Patient accepted any systemic or locoregional therapy for target FLL, including chemotherapy, targeted therapy, immunotherapy, local thermal ablation or transhepatic arterial chemotherapy and embolization; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Absence of gold-standard confirmation.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eUltrasonography Examination and Flash Imaging\u003c/h3\u003e\n\u003cp\u003eAll ultrasound examinations including B-mode ultrasound (BMUS), CEUS and flash imaging were performed by an experienced ultrasound operator (W. W. P., with 20 years of experience in liver CEUS examination) using a Mindray Resona R9 Super system with a 1\u0026ndash;6 MHz convex-array transducer (Mindray Medical International Limited, Shenzhen, China). The contrast agent was Sonazoid (GE Healthcare AS, Oslo, Norway). A bolus of 0.6\u0026ndash;1.0 mL was injected intravenously via the median cubital vein, followed by an immediate injection of 5 mL of 0.9% saline.\u003c/p\u003e \u003cp\u003eA high-MI BMUS scan was firstly performed to localize and characterize any potential FLLs (transmit frequency: 2.8MHz; depth: 15 cm; MI: 1.2; frame rate: 25 fps; gain: 70%; dynamic range: 105dB). After intravenous administration of contrast agent, each identified FLL was continuously observed for 2 minutes under CEUS mode with low-MI (MI: 0.12; frame rate: 10 fps; gain: 50%; dynamic range: 110dB). During the late phase, the entire liver was systematically re-examined to detect any additional FLLs.\u003c/p\u003e \u003cp\u003eApproximately 5 minutes after microbubble injection, the system was then one-click returned to high-MI B-mode (all parameters were identical to BMUS) to initiate flash imaging. Moving microbubble destruction generated a wave-like hyperechoic band that propagated from the capsule toward deeper parenchyma \u003cb\u003e(Fig.\u0026nbsp;1)\u003c/b\u003e. The frame and clip in which this advancing hyperechoic wavefront overlapped target FLL was stored for subsequent analysis.\u003c/p\u003e\n\u003ch3\u003eImage Interpretation of Flash Imaging\u003c/h3\u003e\n\u003cp\u003ePrior to flash image interpretation, each flash frame was screened for qualification against the following three criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) a clearly visible, wave-like hyperechoic band moving from the near to the deep field; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) demonstrable overlap between the hyperechoic band and the target FLL; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) simultaneous visualization of perilesional liver parenchyma within the advancing hyperechoic wavefront. The technical successful rate (qualified frames/total frames \u0026times; 100%) was then calculated.\u003c/p\u003e \u003cp\u003eA senior ultrasound radiologist (W. W. P.) and a junior ultrasound radiologist (Y. K. with 1 year of experience in liver CEUS examination) independently reviewed the images, blinded to clinical, image and pathological data. Discrepancies were resolved by consensus. Inter-observer reliability was assessed by having the 2 observers review the images independently. Intra-observer reliability was evaluated by having each observer review the images again after a one-month interval.\u003c/p\u003e \u003cp\u003eWhen the wavefront simultaneously covered the FLL and adjacent liver parenchyma, the lesion was classified as iso-echogenicity (indistinguishable from background parenchyma) or hypo-echogenicity (lower echogenicity than surrounding liver). Hypo-echogenicity on flash imaging was considered as a diagnostic criterion for malignant FLLs and iso-echogenicity for benign FLLs (\u003cb\u003eFig.\u0026nbsp;1)\u003c/b\u003e.\u003c/p\u003e\n\u003ch3\u003eDiagnostic Criteria of CEUS for Differentiating Malignant and Benign FLLs\u003c/h3\u003e\n\u003cp\u003eAccording to the latest WFUMB-EFSUMB guideline, malignant FLLs are defined by any arterial phase hyper-enhancement (uniform, peripheral rim, heterogeneous or patchy) followed by wash-out in the portal venous or late phases, whereas typical benign FLLs show arterial iso- or hyper-enhancement (peripheral nodular centripetal fill, centrifugal spoke-wheel, or homogeneous) followed by sustained enhancement without wash-out (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Any enhancement pattern failing to fulfil the aforementioned malignant or benign criteria is considered inconclusive on CEUS.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed with IBM SPSS 27.0 (IBM Corp., Armonk, NY, USA) and R 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (IQR). Categorical variables were reported as n (%). Between-group comparisons used independent-samples T test or Mann-Whitney U test for continuous variables and χ\u0026sup2; or Fisher\u0026rsquo;s exact test for categorical variables. Intra- and inter-observer agreement were assessed with Cohen\u0026rsquo;s κ (\u0026lt;\u0026thinsp;0.20 poor, 0.21\u0026ndash;0.40 fair, 0.41\u0026ndash;0.60 moderate, 0.61\u0026ndash;0.80 good, \u0026gt; 0.80 excellent). Two-tailed \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003cp\u003eThe diagnostic performance of flash imaging was calculated against the gold standard. McNemar\u0026rsquo;s test was used to compare the diagnostic accuracy in the paired dataset; 95% CIs were calculated with Wilson score interval. Subgroup analyses were stratified by liver background (normal, fatty liver, cirrhosis, or fatty liver\u0026thinsp;+\u0026thinsp;cirrhosis), lesion size (\u0026le;\u0026thinsp;3 cm, 3\u0026ndash;5 cm, \u0026gt;\u0026thinsp;5 cm), baseline echogenicity on BMUS (hypoechoic, isoechoic, or hyperechoic), and depth (distance from the FLL center to the liver capsule: \u0026le;3 cm, 3\u0026ndash;6 cm, \u0026gt;\u0026thinsp;6 cm).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween January 2024 and April 2025, 195 consecutive patients with FLLs who underwent CEUS and flash imaging were prospectively enrolled. After excluding 40 patients (multiple lesions, n = 15; received prior systemic/locoregional therapy, n = 6; lacked gold-standard confirmation, n = 19), a total of 155 patients with a single treatment-naïve FLL constituted the primary cohort \u003cstrong\u003e(Fig. 2)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eTechnical success of flash imaging was achieved in 143 of 155 (92.3%) cases. Flash imaging of 12 FLLs was considered inadequate: 4 lesions because the wave-like hyperechoic zone wasn't generated, and 8 lesions because the advancing wavefront failed to simultaneously display both the target lesion and adjacent liver parenchyma (superficial location, n = 2; extreme deep location, n = 2; large lesion, n = 4).\u003c/p\u003e\n\u003cp\u003eConsequently, the final analytical dataset comprised 143 patients with evaluable flash imaging (48 females, 95 males; median age 56 years, IQR 48–64), with 102 malignant and 41 benign FLLs (\u003cstrong\u003eTable 1)\u003c/strong\u003e.Details of the final diagnoses and BMUS and conventional CEUS findings are provided in the \u003cstrong\u003eSupplementary Materials Table S1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntra- and Inter-observer Reliabilities of Flash Imaging Features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth Inter- and intra-observer agreement values indicate excellent reliability. Inter-observer agreement was 92.3%, and Cohen’s kappa was κ = 0.77 (95 % CI: 0.63 - 0.90, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). One month later, each observer re-assessed the same images. The junior and senior ultrasound radiologist showed intra-observer agreement of 93.0 %, κ = 0.81 (95 % CI: 0.69–0.92, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) and 93.7%, κ = 0.83 (95 % CI: 0.72–0.93, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFlash Imaging Features of Malignant and Benign FLLs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 143 FLLs, 112 (78.3%) lesions exhibited hypo-echogenicity on flash imaging, while 31 (21.7%) lesions appeared iso-echogenicity \u003cstrong\u003e(Table 2)\u003c/strong\u003e. Among the 102 malignant FLLs, 98 (96.1%) lesions were hypo-echogenicity \u003cstrong\u003e(Fig. 3, Video 1)\u003c/strong\u003e and 4 (3.9%) were iso-echogenicity. In contrast, among the 41 benign FLLs, 27 (65.9%) lesions were iso-echogenicity on flash imaging \u003cstrong\u003e(Fig. 4, Video 2)\u003c/strong\u003e, and 14 (34.1%) were hypo-echogenicity. The hypo-echogenicity rate was significantly higher in malignant than in benign FLLs (96.1% vs. 34.1%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). Flash imaging features for individual FLL subtype are provided in \u003cstrong\u003eSupplementary Materials\u003c/strong\u003e \u003cstrong\u003eTable S2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnostic Performance of Flash Imaging\u0026nbsp;in Differentiating Malignant and Benign FLLs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSetting hypo-echogenicity on flash imaging as indicative of malignant FLLs and iso-echogenicity of benign correctly classified 98 (96.1%) malignant FLLs and 27 (65.9%) benign FLLs, yielding a sensitivity of 96.1% (95 % CI: 90.0–99.2), specificity of 65.9% (95 % CI: 47.4–81.7), positive predictive value (PPV) of 87.5% (95 % CI: 80.0–92.3), negative predictive value (NPV) of 87.1 % (95 % CI: 70.5–95.0) and overall accuracy of 87.4 % (95 % CI: 79.8–92.3).\u003c/p\u003e\n\u003cp\u003eSensitivity and specificity were comparable across liver-background subgroups, but accuracy differed significantly (\u003cem\u003ep\u003c/em\u003e = 0.02). Pair-wise comparisons revealed that accuracy in the fatty liver group (78.4%; 95 % CI: 64.4–88.2) was markedly lower than in both the cirrhosis group (94.0%; 95% CI: 83.5–98.7), (\u003cem\u003ep\u003c/em\u003e = 0.02) and the combined cirrhosis + fatty liver group (94.4%; 95% CI: 72.7–99.9), (\u003cem\u003ep\u003c/em\u003e = 0.02).\u003c/p\u003e\n\u003cp\u003eSensitivity varied among groups with different baseline echogenicity on BMUS (\u003cem\u003ep\u003c/em\u003e = 0.04), while specificity and overall accuracy were unaffected. FLLs that appeared hyperechoic on BMUS demonstrated a lower sensitivity (82.6%; 95% CI: 61.2–95.0) than both hypoechoic (100%; 95% CI: 93.3–100, \u003cem\u003ep\u003c/em\u003e = 0.02) and isoechoic lesions (100%; 95% CI: 86.8–100, \u003cem\u003ep\u003c/em\u003e = 0.03). Neither size nor depth of FLLs significantly influenced sensitivity, specificity or accuracy of flash imaging in differentiating malignant and benign FLLs. Full details are provided in \u003cstrong\u003eTable 3\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePractical Value of Flash Imaging Added to CEUS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 143 FLLs, CEUS correctly classified 86 malignant and 32 benign FLLs, yielding an overall diagnostic accuracy of 82.5%. However, 25 FLLs remained inconclusive on CEUS. In this inconclusive subgroup, flash imaging reclassified 16/16 malignancies as hypoechoic \u003cstrong\u003e(Fig. 5)\u003c/strong\u003e and 6/9 benign lesions as isoechoic \u003cstrong\u003e(Fig. 6)\u003c/strong\u003e, achieving 80.0% accuracy. When CEUS and flash imaging features were integrated, the overall diagnostic accuracy increased to 97.9%, which was significantly higher than CEUS alone (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite CEUS being a guideline recommended image modality for FLLs, the rising incidence of HCC among individuals not traditionally high-risk, coupled with diverse imaging features of benign and malignant FLLs across different pathologies, adds to complexity of preoperative diagnosis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Flash imaging performed after the observation of CEUS late phase, is an convenient and efficient modality. No extra contrast agent or parameter adjustment is required\u0026mdash;simply revert to high-MI B-mode after completing the CEUS sequence, capture the flash image in an easy scan, and add only seconds to the examination while markedly boosting diagnostic yield. We reported the first prospective study to evaluate flash imaging for differentiating malignant and benign FLLs. It reveals a high technical successful rate of 92.3% and excellent observer agreement of 92.3\u0026ndash;93.7%, confirming feasibility and reproducibility.\u003c/p\u003e \u003cp\u003eFlash imaging is a characteristic acoustic signature of rapid microbubble collapse, which is induced by a high-MI ultrasound pulse. Although microbubble rupture was triggered by various contrast agents, only sulfur-hexafluoride microbubbles consistently generate a stable, mobile hyper-echoic band under flash conditions, significantly enhancing lesion conspicuity and detection rates (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Pathologically, benign FLLs retain the sinusoidal micro-architecture, whereas malignant FLLs show progressive loss of sinusoidal spaces owing to infiltrative tumour growth and capillarization(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These microvascular perfusion differences determine the late-phase CEUS signature: persistent iso- or hyper-enhancement in benign FLLs versus wash-out with hypo-enhancement appearance in malignant counterparts (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Leveraging the late-phase contrast gradient between lesion and liver, flash imaging converts microbubble collapse into an accentuated wash-out signature.\u003c/p\u003e \u003cp\u003eTheoretically, flash imaging improves diagnosis by unveiling late-phase wash-out of malignant FLLs invisible to unaided eye (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Thus, a hypoechoic appearance on flash imaging may serve as a highly sensitive marker of malignant FLLs, with sensitivity 96.1% (95% CI: 90.0\u0026ndash;99.2), specificity 65.9% (95% CI: 47.4\u0026ndash;81.7), PPV 87.5% (95% CI: 80.0\u0026ndash;92.3), NPV 87.1% (95% CI: 70.5\u0026ndash;95.0) and accuracy 87.4% (95% CI: 79.8\u0026ndash;92.3). The high sensitivity and NPV underscore its strength in detecting early or atypical malignant FLLs, while modest specificity reflects false positives from benign entities clarified by follow-up, preserving clinical benefit of minimal false negatives. Moreover, subgroup analysis showed that liver background significantly influenced flash imaging accuracy: 78.4% in fatty liver versus 94.0% in cirrhosis and 94.4% in combined disease (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). This reduction in fatty liver group reflects skewed FLL distribution\u0026mdash;benign lesions predominated in fatty liver, whereas malignancies clustered in cirrhotic parenchyma\u0026mdash;lowering accuracy without affecting sensitivity or specificity and indicating case-mix effect rather than technical limitation. Baseline BMUS echogenicity modestly reduced sensitivity for BMUS hyperechoic FLLs compared with BMUS hypo- and isoechoic lesions, because of decreased conspicuity against hyperechoic flash background, whereas specificity and overall accuracy remained unchanged. Lesion size and depth did not significantly affect diagnostic efficacy.\u003c/p\u003e \u003cp\u003eFlash imaging exhibits robust diagnostic performance across malignant FLLs of divergent histotypes; in contrast, its behavior varies among benign entities, reflecting heterogeneous microvascular perfusion characteristics inherent to each pathological subtype. Hepatic focal nodular hyperplasia (FNH) consists of normal hepatocytes arrayed around richly vascularised fibrous septa. On CEUS it displays a spoke-wheel hyper-enhancement during arterial phase and a central non-enhancing scar in 1/3 to 1/2 cases; pooled diagnostic accuracy is 90% (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In our cohort, 16 (88.9%) hepatic FNH exhibited iso-echogenicity on flash imaging, rendering them indistinguishable from surrounding liver\u0026mdash;a concordance rate fully comparable to published CEUS benchmarks. Hepatic haemangiomas comprise endothelial-lined cavernous channels, variable arteriovenous shunts and organised thrombi that slow intralesional flow. These structural features generate the characteristic CEUS pattern of discontinuous, peripheral nodular enhancement with gradual centripetal progression and incomplete late-phase fill-in (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In a 1,153-patient Romanian multicenter study, CEUS delivered 90% sensitivity and 99% specificity for hepatic hemangioma, giving 97% diagnostic accuracy (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, flash imaging provided limited support for characterizing hepatic haemangiomas in our series, and the frequent hypo-echogenic appearance may reflect incomplete contrast replenishment related to the lesions\u0026rsquo; unique architecture. Typical CEUS patterns remain more reassuring. Hepatic angiomyolipoma (HAML) is a rare benign mesenchymal neoplasm composed of haphazardly arranged smooth muscle bundles, thick-walled vessels and mature adipocytes, is richly vascularized yet lacks the characteristic sinusoidal architecture of hepatic parenchyma (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). On CEUS, HAML typically demonstrates marked arterial hyper-enhancement followed by persistent late-phase hypo-enhancement, a temporal pattern that closely mimics malignant FLLs (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Nevertheless, although identification of intralesional fat on CT/MRI may offer a valuable diagnostic clue, high-quality prospective evidence is still lacking. In our cohort, among 6 HAML, 5 lesions appeared hypoechoic on flash imaging, yielding a flash-to-pathology concordance of only 16.7%. Owing to this limited specificity, confident characterization of HAML should integrate clinical context, multimodal imaging features, and CEUS perfusion findings to minimize misdiagnosis.\u003c/p\u003e \u003cp\u003ePerformed immediately after conventional CEUS as a one-click adjunct, flash imaging complements\u0026mdash;rather than replaces\u0026mdash;CEUS in the characterization of FLLs. We explored its added value in 25 CEUS-inconclusive FLLs, where flash imaging achieved 80% accuracy and correctly identified all malignant lesions. Integrating flash findings into CEUS assessment, overall accuracy rose from 82.5% to 97.9% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), a margin comparable with published CT/MRI comparisons (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). These preliminary data suggest that flash imaging may enhance diagnostic confidence and accelerate therapeutic decision-making for early-stage liver cancer.\u003c/p\u003e \u003cp\u003eHowever, flash imaging carries an inherent limitation: the high-MI pulse instantly destroys majority of micro-bubbles, rendering the examination \"terminal\" and precluding further vascular-phase assessment. Overall, flash imaging demonstrated a high technical success rate; suboptimal studies were encountered in only 12 (7.7%) cases. Inadequacy was attributable to absence of the characteristic hyperechoic band or failure to visualize simultaneously both the FLL and adjacent liver parenchyma (lesion too superficial, too deep, or exceeding the field of view). These limitations are inherent to conventional CEUS and can be overcome by standardized scanning protocols; they did not compromise the overall diagnostic performance of the technique.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eLimitations: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Reference-standard contamination confined to the benign subset: all 106 malignant FLLs were histopathologically verified, whereas 43.9% (18/41) of benign lesions were diagnosed by combined imaging follow up, risking mis-classification bias. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Spectrum bias: This study was performed at a tertiary referral centre, where the cohort was enriched with surgical candidates, yielding a malignancy fraction of 70% (vs\u0026thinsp;\u0026asymp;\u0026thinsp;30% reported for incidental FLL in community cohorts(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)). Post-hoc bootstrap adjustment assuming a 30% malignant prevalence showed specificity remained 61%, indicating minimal net effect. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Single-centre, single-vendor design: all acquisitions were obtained on one Mindray Resona R9 Super system; multicentre, multi-platform validation is imperative to confirm external reproducibility.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHigh-MI flash imaging, when utilized during the late phase of CEUS, is not only easy to perform but also achieves high technical success and substantial observer agreement, markedly enhancing the ability of CEUS to discriminate malignant and benign FLLs. This improvement is particularly pronounced in the assessment of CEUS inconclusive FLLs, thereby highlighting its potential to augment diagnostic precision in challenging cases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e The data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Dan Zuo conducted study conception, literature search and wrote the first draft of the manuscript. Kai Yuan and Ping Yang performed data analysis. Kai Yuan and Wenping Wang interpreted the images. Feihang Wang and Yanni Chen collected the data. Xi Wang reviewed and edited the manuscript. Wenping Wang performed all CEUS examinations and supervised the study. All authors critically reviewed the manuscript and approved the final version for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement:\u003c/strong\u003e This work was supported by National Natural Science Foundation of China (Grant No. 82472004). All funding departments had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no relevant financial or non-financial interests that may be perceived as having influenced the results or discussion reported in this manuscript.·\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63.\u003c/li\u003e\n\u003cli\u003eLee JY, Minami Y, Choi BI, Lee WJ, Chou YH, Jeong WK, et al. The AFSUMB Consensus Statements and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound using Sonazoid. Ultrasonography. 2020;39(3):191-220.\u003c/li\u003e\n\u003cli\u003eTang Y, Sasaki SI, Hawley J, Peillon A, Sjostrom A, Fuentes-Alburo A, et al. Diagnostic Test Accuracy of Contrast-Enhanced Ultrasound With Sonazoid for Assessment of Focal Liver Lesions: A Systematic Review and Meta-Analysis. J Clin Ultrasound. 2025;53(3):510-24.\u003c/li\u003e\n\u003cli\u003eGuang Y, Xie L, Ding H, Cai A, Huang Y. Diagnosis value of focal liver lesions with SonoVue(R)-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis. J Cancer Res Clin Oncol. 2011;137(11):1595-605.\u003c/li\u003e\n\u003cli\u003eHuang JY, Li JW, Lu Q, Luo Y, Lin L, Shi YJ, et al. Diagnostic Accuracy of CEUS LI-RADS for the Characterization of Liver Nodules 20 mm or Smaller in Patients at Risk for Hepatocellular Carcinoma. Radiology. 2020;294(2):329-39.\u003c/li\u003e\n\u003cli\u003eYen YH, Cheng YF, Wang JH, Lin CC, Wang CC. Characteristics and etiologies of hepatocellular carcinoma in patients without cirrhosis: When East meets West. PLoS One. 2021;16(1):e0244939.\u003c/li\u003e\n\u003cli\u003evon Herbay A, Westendorff J, Gregor M. Contrast-enhanced ultrasound with SonoVue: differentiation between benign and malignant focal liver lesions in 317 patients. J Clin Ultrasound. 2010;38(1):1-9.\u003c/li\u003e\n\u003cli\u003eYang W, Chen MH, Wu W, Dai Y, Fan ZH. Effects of Gray-Scale Ultrasonography Immediate Post-Contrast on Characterization of Focal Liver Lesions. Biomed Res Int. 2015;2015:193178.\u003c/li\u003e\n\u003cli\u003eKamiyama N, Moriyasu F, Mine Y, Goto Y. Analysis of flash echo from contrast agent for designing optimal ultrasound diagnostic systems. Ultrasound Med Biol. 1999;25(3):411-20.\u003c/li\u003e\n\u003cli\u003eWakui N, Nagai H, Yoshimine N, Amanuma M, Kobayashi K, Ogino Y, et al. Flash Imaging Used in the Post-vascular Phase of Contrast-Enhanced Ultrasonography is Useful for Assessing the Progression in Patients with Hepatitis C Virus-Related Liver Disease. Ultrasound Med Biol. 2019;45(7):1654-62.\u003c/li\u003e\n\u003cli\u003eSiriwong N, Sriphoosanaphan S, Decharatanachart P, Yongpisarn T, Kerr SJ, Treeprasertsuk S, et al. Role of noninvasive tests on the prediction of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without cirrhosis: a systematic review and meta-analysis of aggregate and individual patient data. Eur J Gastroenterol Hepatol. 2025;37(3):358-69.\u003c/li\u003e\n\u003cli\u003eEdey AJ, Ryan SM, Beese RC, Gordon P, Sidhu PS. Ultrasound imaging of liver metastases in the delayed parenchymal phase following administration of Sonazoid using a destructive mode technique (Agent Detection Imaging). Clin Radiol. 2008;63(10):1112-20.\u003c/li\u003e\n\u003cli\u003eXiong Y, Yao L, Lin J, Yao J, Bai Q, Huang Y, et al. Artificial intelligence links CT images to pathologic features and survival outcomes of renal masses. Nat Commun. 2025;16(1):1425.\u003c/li\u003e\n\u003cli\u003eRen J, Lu Q, Fei X, Dong Y, M DO, Sidhu PS, et al. Assessment of arterial-phase hyperenhancement and late-phase washout of hepatocellular carcinoma-a meta-analysis of contrast-enhanced ultrasound (CEUS) with SonoVue(R) and Sonazoid(R). Eur Radiol. 2024;34(6):3795-812.\u003c/li\u003e\n\u003cli\u003eHe M, Zhu L, Huang M, Zhong L, Ye Z, Jiang T. Comparison Between SonoVue and Sonazoid Contrast-Enhanced Ultrasound in Characterization of Focal Nodular Hyperplasia Smaller Than 3 cm. J Ultrasound Med. 2021;40(10):2095-104.\u003c/li\u003e\n\u003cli\u003eHuang Z, Lin XJ, Li SS, Luo HC, Li KY. Differentiating atypical hepatocellular carcinoma from focal nodular Hyperplasia: The value of Kupffer phase imaging with Sonazoid-Contrast-Enhanced ultrasound compared to Gadodiamide-Enhanced MRI. Eur J Radiol. 2025;184:111991.\u003c/li\u003e\n\u003cli\u003eSirli R, Sporea I, Sandulescu DL, Popescu A, Danila M, Saftoiu A, et al. Contrast enhanced ultrasound for the diagnosis of liver hemangiomas - results of a Romanian multicentre study. Med Ultrason. 2015;17(4):444-50.\u003c/li\u003e\n\u003cli\u003eLiu J, Zhang CW, Hong DF, Tao R, Chen Y, Shang MJ, et al. Primary hepatic epithelioid angiomyolipoma: A malignant potential tumor which should be recognized. World J Gastroenterol. 2016;22(20):4908-17.\u003c/li\u003e\n\u003cli\u003eWang Z, Xu HX, Xie XY, Xie XH, Kuang M, Xu ZF, et al. Imaging features of hepatic angiomyolipomas on real-time contrast-enhanced ultrasound. Br J Radiol. 2010;83(989):411-8.\u003c/li\u003e\n\u003cli\u003eSiu Xiao T, Kuon Yeng Escalante CM, Tahmasebi A, Kono Y, Piscaglia F, Wilson SR, et al. Combining CEUS and CT/MRI LI-RADS major imaging features: diagnostic accuracy for classification of indeterminate liver observations in patients at risk for HCC. Abdom Radiol (NY). 2025;50(5):2066-77.\u003c/li\u003e\n\u003cli\u003eDietrich CF, Nolsoe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, et al. Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020;46(10):2579-604.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"454\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 454px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1 Clinical Characteristics of Patients with Qualified Flash Imaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (n = 143)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e56 (IQR: 48-64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e95 (66.4%)\u003c/p\u003e\n \u003cp\u003e48 (33.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Asymptomatic\u003c/p\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Abdominal distend\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e127 (88.8%)\u003c/p\u003e\n \u003cp\u003e9 (6.3%)\u003c/p\u003e\n \u003cp\u003e7 (4.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eElevated Tumor Maker (%) *\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; AFP (n = 131)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; CA19-9 (n = 130)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; AFP- L3 (n = 118)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; DCP (n = 128)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e31 (23.7%)\u003c/p\u003e\n \u003cp\u003e19 (14.6%)\u003c/p\u003e\n \u003cp\u003e34 (28.8%)\u003c/p\u003e\n \u003cp\u003e44 (34.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHBV Infection (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e82 (57.3%)\u003c/p\u003e\n \u003cp\u003e61 42.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnostic Method (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eSurgery\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Biopsy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Image\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e106 (74.1%)\u003c/p\u003e\n \u003cp\u003e19 (13.3%)\u003c/p\u003e\n \u003cp\u003e18 (12.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFinal Diagnosis (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eMalignant FLLs\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Benign FLLs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e102 (71.3%)\u003c/p\u003e\n \u003cp\u003e41 (40.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 454px;\"\u003e\n \u003cp\u003e* Note: Tumor markers were tested in a subset of patients.\u003c/p\u003e\n \u003cp\u003ealpha-fetoprotein (APF); carbohydrate antigen 19-9 (CA19-9); alpha-fetoprotein L3 fraction (AFP-L3); des-\u0026gamma;-carboxy prothrombin (DCP).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"491\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 491px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2 Diagnostic Performance of Flash Imaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFlash Imaging Feature\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGold Standard of FLLs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMalignant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eBenign\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHypo-echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e112\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eIso-echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"941\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" style=\"width: 941px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3 Subgroup Analysis of Flash Imaging Diagnostic Performance for Malignant vs Benign FLLs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSensitivity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e% (95 %CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePairwise \u003cem\u003ep\u003c/em\u003e*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpecificity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e% (95 %CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAccuracy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e% (95 %CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePairwise \u003cem\u003ep\u003c/em\u003e*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver background\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003cp\u003eFatty liver\u003c/p\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003cp\u003eFatty liver + cirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e100.0 (78.2\u0026ndash;100.0)\u003c/p\u003e\n \u003cp\u003e96.0 (79.6\u0026ndash;99.9)\u003c/p\u003e\n \u003cp\u003e93.6 (82.5\u0026ndash;98.7)\u003c/p\u003e\n \u003cp\u003e100.0 (78.2\u0026ndash;100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e70 (34.8\u0026ndash;93.3)\u003c/p\u003e\n \u003cp\u003e61.5 (40.6\u0026ndash;79.8)\u003c/p\u003e\n \u003cp\u003e100.0 (29.2\u0026ndash;100.0)\u003c/p\u003e\n \u003cp\u003e50.0 (1.3\u0026ndash;98.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e87.5 (67.6\u0026ndash;95.9)\u003c/p\u003e\n \u003cp\u003e78.4 (64.4\u0026ndash;88.2)\u003c/p\u003e\n \u003cp\u003e94.0 (83.5\u0026ndash;98.7)\u003c/p\u003e\n \u003cp\u003e94.4 (72.7\u0026ndash;99.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDepth\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026le; 3cm\u003c/p\u003e\n \u003cp\u003e3 - 6 cm\u003c/p\u003e\n \u003cp\u003e\u0026gt; 6 cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e100.0 (83.2\u0026ndash;100.0)\u003c/p\u003e\n \u003cp\u003e94.4 (85.2\u0026ndash;98.8)\u003c/p\u003e\n \u003cp\u003e96.4 (81.7\u0026ndash;99.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e64.3 (35.6\u0026ndash;85.8)\u003c/p\u003e\n \u003cp\u003e61.9 (38.4\u0026ndash;81.9)\u003c/p\u003e\n \u003cp\u003e83.3 (35.9\u0026ndash;99.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e85.3 (68.5\u0026ndash;94.3)\u003c/p\u003e\n \u003cp\u003e85.3 (75.2\u0026ndash;92.4)\u003c/p\u003e\n \u003cp\u003e94.1 (84.2\u0026ndash;99.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSize\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026le; 3cm\u003c/p\u003e\n \u003cp\u003e3 - 5 cm\u003c/p\u003e\n \u003cp\u003e\u0026gt; 5cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e95.7 (85.5\u0026ndash;99.5)\u003c/p\u003e\n \u003cp\u003e100.0\u0026nbsp;(85.7\u0026ndash;100.0)\u003c/p\u003e\n \u003cp\u003e93.8 (79.2\u0026ndash;99.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e72.7 (49.8\u0026ndash;89.3)\u003c/p\u003e\n \u003cp\u003e42.9 (9.9\u0026ndash;81.6)\u003c/p\u003e\n \u003cp\u003e75.0 (42.8\u0026ndash;94.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e87.0 (74.3\u0026ndash;94.4)\u003c/p\u003e\n \u003cp\u003e86.7 (69.3\u0026ndash;96.2)\u003c/p\u003e\n \u003cp\u003e88.6 (73.3\u0026ndash;96.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEchogenicity on BMUS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eHypoechoic\u003c/p\u003e\n \u003cp\u003eIsoechoic\u003c/p\u003e\n \u003cp\u003eHyperechoic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e100.0 (93.3\u0026ndash;100.0)\u003c/p\u003e\n \u003cp\u003e100.0 (86.8\u0026ndash;100.0)\u003c/p\u003e\n \u003cp\u003e82.6 (61.2\u0026ndash;95.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003csup\u003ed\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e66.7 (44.7\u0026ndash;84.4)\u003c/p\u003e\n \u003cp\u003e66.7 (29.9\u0026ndash;92.5)\u003c/p\u003e\n \u003cp\u003e62.5 (24.5\u0026ndash;91.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e89.6 (80.3\u0026ndash;95.0)\u003c/p\u003e\n \u003cp\u003e91.4 (76.9\u0026ndash;98.2)\u003c/p\u003e\n \u003cp\u003e77.4 (58.9\u0026ndash;90.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e96.1 (90.0\u0026ndash;99.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e65.9 (47.4\u0026ndash;81.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e87.4 (79.8\u0026ndash;92.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" valign=\"top\" style=\"width: 941px;\"\u003e\n \u003cp\u003e*: Holm correction was applied to two-tailed Fisher exact tests for multiple comparisons.\u003c/p\u003e\n \u003cp\u003ea: \u003cem\u003ep\u003c/em\u003e values by two-tailed Fisher exact test between cirrhosis and fatty liver.\u003c/p\u003e\n \u003cp\u003eb: \u003cem\u003ep\u0026nbsp;\u003c/em\u003evalue by two-tailed Fisher exact test between fatty liver + cirrhosis and fatty liver.\u003c/p\u003e\n \u003cp\u003ec: \u003cem\u003ep\u003c/em\u003e values by two-tailed Fisher exact test between hyperechoic and hypoechoic.\u003c/p\u003e\n \u003cp\u003ed: \u003cem\u003ep\u003c/em\u003e values by two-tailed Fisher exact test between hyperechoic and isoechoic.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Focal liver lesions (FLLs), Flash imaging, Contrast-enhancement ultrasound (CEUS), Differential diagnosis","lastPublishedDoi":"10.21203/rs.3.rs-8156677/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8156677/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and aim: \u003c/strong\u003eAlthough contrast-enhanced ultrasound (CEUS) is highly accurate, approximately 20% of focal liver lesions (FLLs) remain inconclusive. High-Mechanical Index (MI) flash imaging in the late phase of CEUS provides diagnostic information, yet its value is unexplored. We therefore conducted a prospective study to assess its feasibility and performance for differentiating malignant from benign FLLs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eFrom January 2024 to April 2025, 155 consecutive patients with a single FLL underwent CEUS (MI: 0.12) followed by high-MI flash imaging (MI: 1.2). Hypo-echogenicity on flash imaging was served as the diagnostic criterion for malignant FLLs. Technical successful rate, observer agreement and diagnostic performance of flash imaging were assessed. The clinical value of flash imaging was determined in CEUS-inconclusive cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eFlash imaging was technically successful in 143 (92.3%) FLLs (102 malignant; 41 benign). Hypo-echogenicity was present in 96.1% (98/102) malignant versus 34.1% (14/41) benign FLLs on flash imaging (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of flash imaging were 96.1%, 65.9%, 87.5%, 87.1%, and 87.4%, respectively. Inter- and intra-observer agreement were both excellent (inter: 92.3%; intra: 93.0 and 93.7%). Flash imaging achieved 80.0% differential diagnostic accuracy in CEUS-inconclusive cases. When CEUS and flash imaging were integrated, the overall differential diagnostic accuracy increased from 82.5% to 97.9% (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eHigh-MI flash imaging during late phase of CEUS demonstrates high technical success, excellent reproducibility and significant discriminative ability for FLLs, especially enhancing the discriminative ability of CEUS in CEUS-inconclusive cases.\u003c/p\u003e","manuscriptTitle":"High-Mechanical Index (MI) Flash Imaging during Late Phase of Contrast-enhanced Ultrasound (CEUS): A Novel Approach to Enhance Differential Diagnosis of Malignant and Benign Focal Liver Lesions (FLLs)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 01:03:24","doi":"10.21203/rs.3.rs-8156677/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"84ebb07f-8a67-4112-a4cc-742d0aefca59","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-09T06:02:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 01:03:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8156677","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8156677","identity":"rs-8156677","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}