Arterial Phase Hyperenhancement Research Articles

Microvascular invasion-negative hepatocellular carcinoma: Prognostic value of qualitative and quantitative Gd-EOB-DTPA MRI analysis

ObjectivesThe purpose of this study was to establish a model for predicting the prognosis of patients with microvascular invasion (MVI)-negative hepatocellular carcinoma (HCC) based on qualitative and quantitative analyses of Gd-EOB-DTPA magnetic resonance imaging (MRI). Materials and methodsConsecutive patients with MVI-negative HCC who underwent preoperative Gd-EOB-DTPA MRI between January 2015 and December 2019 were retrospectively enrolled.In total, 122 patients were randomly assigned to the training and validation groups at a ratio of 7:3. Univariate and multivariate logistic regression analyses were performed to identify significant clinical parameters and MRI features, including quantitative and qualitative parameters associated with prognosis, which were incorporated into a predictive nomogram. The end-point of this study was recurrence-free survival. Outcomes were compared between groups using the Kaplan–Meier method with the log-rank test. ResultsDuring a median follow-up period of 58.86 months, 38 patients (31.15 %) experienced recurrence. Multivariate analysis revealed that lower relative enhancement ratio (RER), hepatobiliary phase hypointensity without arterial phase hyperenhancement, Liver Imaging Reporting and Data System category, mild-moderate T2 hyperintensity, and higher aspartate aminotransferase levels were risk factors associated with prognosis and then incorporated into the prognostic model. C-indices for training and validation groups were 0.732 and 0.692, respectively. The most appropriate cut-off value for RER was 1.197. Patients with RER ≤ 1.197 had significantly higher postoperative recurrence rates than those with RER > 1.197 (p = 0.004). ConclusionThe model integrating qualitative and quantitative imaging parameters and clinical parameters satisfactorily predicted the prognosis of patients with MVI-negative HCC.

Differentiating mass-forming intrahepatic cholangiocarcinoma from atypical hepatocellular carcinoma using Gd-EOB-DTPA-enhanced magnetic resonance imaging combined with serum markers in at-risk patients with hepatitis B virus.

The precise differentiation of intrahepatic cholangiocarcinoma (ICC) from atypical hepatocellular carcinoma (HCC) is vital for treatment strategy and prognostic prediction. In clinical practice, nearly 40% of HCCs demonstrate atypical manifestations, particularly HCCs with rim arterial phase hyperenhancement (APHE), which is challenging to differentiate from mass-forming ICC. Thus, we aimed to develop a diagnostic regimen of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast-enhanced magnetic resonance imaging (MRI) combined with serum tumor markers in differentiating mass-forming ICC from atypical HCC in at-risk patients with the hepatitis B virus (HBV). This study enrolled 129 patients with pathologically proven mass-forming ICCs (n=53) and atypical HCCs (n=76) who had undergone preoperative Gd-EOB-DTPA contrast-enhanced MRI. The clinical data and imaging findings were analyzed. Univariate and multivariate logistic analyses were performed to identify the independent predictors for differentiating mass-forming ICCs from atypical HCCs. The diagnostic performance was evaluated using receiver operating characteristic (ROC) curves, and DeLong test was used to compare the areas under curves of all independent predictors. Univariate logistic regression analysis revealed normal alpha fetoprotein (AFP), elevated carbohydrate antigen 19-9 (CA19-9) level, elevated carcinoma embryonic antigen (CEA) level, central hyperintensity on T2-weighted imaging (T2WI), central hypointensity on T2WI, and targetoid sign on hepatobiliary phase (HBP) and targetoid restriction on diffusion-weighted imaging (DWI) were more likely to be significant predictors favoring mass-forming ICCs (all P values <0.05). In contrast, multifocal hyperintensity on T2WI and capsule sign were more frequently seen in patients with atypical HCC (all P values <0.05). Multivariate analysis revealed normal AFP, elevated CA19-9 level, targetoid sign on HBP, and targetoid restriction on DWI (all P=0.001) were independent predictors for differentiating mass-forming ICCs from atypical HCCs; DeLong test showed that the area under curve (AUC) increased to 0.949 when the above predictors were combined (all P values <0.05), and the sensitivity, specificity, and accuracy of the combined independent predictors were 88.7%, 93.4%, and 91.5%, respectively. A diagnostic regimen integrating tumor markers (AFP, CA19-9) and imaging biomarkers (targetoid restriction on DWI and/or targetoid sign on HBP) using Gd-EOB-DTPA-enhanced MRI could help to differentiate mass-forming ICCs from atypical HCCs and achieve high diagnostic performance of mass-forming ICCs in at-risk patients with the HBV. Mass-forming intrahepatic cholangiocarcinoma (mass-forming ICC); atypical hepatocellular carcinoma (atypical HCC); magnetic resonance imaging (MRI); gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA); hepatobiliary phase (HBP).

Can absolute arterial phase hyperenhancement improve sensitivity of detection of hepatocellular carcinoma in indeterminate nodules on CT?

To determine if quantitative assessment of relative (R) and absolute (A) arterial phase hyperenhancement (APHE) and washout (WO) applied to indeterminate nodules on CT would improve the overall sensitivity of detection of hepatocellular carcinoma (HCC). One-hundred and fourteen patients (90 male; mean age, 65years) with 210 treatment-naïve HCC nodules (190 HCCs, 20 benign) who underwent 4-phase CT were included in this retrospective study. Four radiologists independently assigned a qualitative LR (LI-RADS) category per nodule. LR-3/4 nodules were then quantitatively analyzed by the 4 readers, placing ROIs within nodules and adjacent liver parenchyma. A/R-APHE and WO were calculated, and per-reader sensitivity and specificity updated. Interobserver agreement and AUCs were calculated per reader. Qualitative readers 1-4 categorized 57, 69, 57, and 63 nodules as LR-3/4 respectively with moderate to substantial agreement in LR category (kappa 0.56-0.69, p < 0.0001); their diagnostic performances in the detection of HCC were 80%, 73.2%, 77.4%, and 77.4% sensitivity, and 100%, 95%, 70%, and 100% specificity, respectively. A threshold of ≥ 20 HU for A-APHE increased overall sensitivity of HCC detection by 0.5-3.1% without changing specificity for the subset of nodules APHE - /WO + on qualitative read, with 2, 6, 6, and 1 additional HCC detected by readers 1-4. Relative and various A-WO formulae and thresholds all increased sensitivity, but with a drop in specificity for some/all readers. Quantitatively assessed A-APHE showed potential to increase sensitivity and maintain specificity of HCC diagnosis when selectively applied to indeterminate nodules demonstrating WO without subjective APHE. Quantitatively assessed R and A-WO increased sensitivity, however reduced specificity. A workflow using selective quantification of absolute arterial enhancement is routinely employed in the CT assessment of renal and adrenal nodules. Quantitatively assessed absolute arterial enhancement is a simple tool which may be used as an adjunct to help increase sensitivity and maintain specificity of HCC diagnosis in indeterminate nodules demonstrating WO without subjective APHE. • In indeterminate nodules categorized as LI-RADS 3/4 due to absent subjective arterial phase hyperenhancement, a cut-off for absolute arterial phase hyperenhancement of ≥ 20 HU may increase the overall sensitivity of detection of HCC by 0.5-3.1% without affecting specificity. • Relative and various absolute washout formulae and cut-offs increased sensitivity of HCC detection, but with a drop in specificity for some/all readers.

Impact of Hepatocellular Carcinoma Tumor Size on Sonazoid Contrast-Enhanced Ultrasound Enhancement Features

The aim of the work described here was to evaluate the impact of hepatocellular carcinoma (HCC) tumor size on Sonazoid contrast-enhanced ultrasound (CEUS) enhancement features, especially in tumors with diameters ≤30 mm and <10 mm. In this retrospective study, we included patients with histopathologically confirmed HCC lesions and divided them into three groups on the basis of tumor size. All patients underwent Sonazoid-enhanced CEUS examinations before surgery. B-mode ultrasound (BMUS) features and CEUS enhancement patterns were evaluated according to current World Federation for Ultrasound in Medicine and Biology Guidelines criteria. The χ2- and Student t-tests were used to compare differences between groups. We included 132 patients with histopathologically confirmed HCC lesions from November 2020 to September 2022. On the basis of tumor size, patients were divided into group 1 (<10 mm, n=5), group 2 (10-30 mm, n=54) and group 3 (>30 mm, n=73). On BMUS, most HCCs appeared heterogeneous but predominantly hypo-echoic (61.4%, 81/132) with ill-defined margins and irregular shapes. Meanwhile, iso-echoic features were more common in small HCCs ≤30 mm (15.3%, 9/59), but a mixed hyper- and hypo-echoic appearance was more common in HCCs >30 mm (17.8%, 13/73) (p=0.003). On Sonazoid-enhanced CEUS, all HCCs presented arterial phase hyperenhancement (APHE) (100.0%, 132/132). Most HCCs >30 mm exhibited heterogeneous hyperenhancement (86.3%, 63/73), whereas nearly one-third of small HCCs ≤30 mm exhibited homogeneous hyperenhancement (35.6%, 21/59) (p=0.003). In the portal venous phase, there was a significantly higher proportion of washout in HCCs >30 mm (84.9%, 62/73) than in small HCCs ≤30 mm (64.4%, 38/59) (p=0.006). During the Kupffer phase, 11 additional hypo-enhanced lesions (mean size: 14.1 ± 4.1 mm, iso-echoic on BMUS), which were also suspected to be HCC lesions, were detected in 5 patients with small HCCs ≤30 mm and 4 patients with HCCs >30 mm. All 5 cases of HCCs <10 mm exhibited APHE and late washout (>60 s). The majority (3/5, 60%) exhibited washout in the portal venous phase (70, 74 and 75 s), one case did so in the late phase (125 s) and another in the Kupffer phase (420 s). Tumor size had a significant impact on the washout features of HCC lesions on Sonazoid-enhanced CEUS. Small HCC lesions ≤30 mm had a higher proportion of relatively late washout in comparison to larger lesions. Sonazoid-enhanced CEUS might be helpful in the detection and characterization of HCC lesions <10 mm.

Proton Beam Therapy for HCC Exceeding up-to-Seven Criteria

Whilst standard treatment for intermediate-stage hepatocellular carcinoma (HCC) is transcatheter arterial chemoembolization (TACE), those exceeding "up-to-seven" criteria don't respond as such as those within, and systemic therapy is suggested to be more beneficial. This is sought to be both because of the limited efficacy of TACE and its hepatic toxicity. Proton beam therapy (PBT) offers high local control and low toxicity rates, and we hypothesize that the same can be said in this patient group also. We here present the outcome of PBT for primary HCC exceeding "up-to-seven" criteria. Primary HCC treated with PBT between 2010 and 2018 were extracted from an all-in treatment database and retrospectively reviewed. (Maximum diameter of the largest tumor in centimeters) + (tumor count) > 7 was considered as exceeding "up-to-seven" criteria. Local recurrence was defined as tumor re-enlargement or the appearance of arterial phase hyperenhancement. Adverse events were evaluated by CTCAE v5.0. Overall survival and recurrence-free survival were determined by the Kaplan-Meier method, and local recurrence was analyzed as cumulative incidence with death as a competing risk. All statistical analyses were done using R. Out of 202 primary cases, 79 exceeded the "up-to-seven" criteria. The median tumor diameter was 8.0 cm (range 3.1 - 20 cm) and macroscopic vascular invasion (MVI) was observed in 26 cases. For tumor count, 36 were solitary, 28 were between 2 - 3, and 15 had 4 or more. According to the modified ALBI grade, 38 were grade 1, 18 were grade 2a and 23 were 2b. The prescribed dose was 66 Gy / 10 Fr for 6, 72.6 Gy / 22 Fr for 60, 74 Gy / 37 Fr for 12 and 60 Gy / 15 Fr for one case after relative biological effect weighting of 1.1. With a median follow-up period of 33 months (IQR 15 - 57 months), 2-year overall survival was 62% (95% C.I. 50 - 72%) and median survival time was 37 months (95% C.I. 30 - 52 months). 2-year recurrence-free survival and local recurrence rate were 42% (95% C.I. 30 - 53%) and 8% (95% C.I. 3 - 15%) respectively. Cox regression analysis revealed modified ALBI grade as the only significant risk factor for survival (hazard ratio 1.80, 95% C.I. 1.27 - 2.55, p = 0.0010) among age, sex, alpha-fetoprotein level, MVI, tumor count, and size. Other than one case of early death (2 weeks after treatment) with an unknown causal relationship, there were no adverse events of grade 4 or higher observed. PBT for primary HCC exceeding "up-to-seven" criteria appears to be safe and effective. Local control of intrahepatic lesions may be beneficial even in intermediate-stage cases, while results of this study suggests that suppression of out-of-field recurrence is required for further survival prolongment.

Outcome of Proton Beam Therapy for Primary Hepatocellular Carcinoma with “Unfavorable” Macroscopic Classification

Transcatheter arterial chemoembolization (TACE) is the standard treatment for early to intermediate-stage hepatocellular carcinoma (HCC) unfit for hepatectomy or radiofrequency/microwave ablation (RFA/MWA). Putting aside its hepatic toxicity, local control of TACE is far from satisfactory, especially with non- "simple nodular type" appearances, to an extent where systemic therapy is suggested to be more beneficial. We here analyzed the outcome of proton beam therapy (PBT) for primary HCC by macroscopic classification. Primary HCC treated with PBT between 2010 and 2018 were extracted from an all-in treatment database. The macroscopic classification was defined by CT or MRI prior to PBT. Local recurrence was defined as tumor re-enlargement or the appearance of arterial phase hyperenhancement. Adverse events were evaluated by CTCAE v5.0. Overall survival, local control, intrahepatic recurrence-free survival, and extrahepatic recurrence-free survival were determined by the Kaplan-Meier method, and the association with treatment factors was analyzed by log-rank and cox regression model. A total of 202 primary HCC cases were extracted, all not a candidate for hepatectomy nor RFA/MWA. Out of them, 75 cases were simple nodular type, 79 were simple nodular type with extranodular growth, 38 were confluent multinodular type, and 10 were infiltrative type. 26 cases were HBV positive, and 84 cases were HCV positive. 35 cases had macroscopic vascular invasion (MVI). With a median follow-up period of 3.72 years (IQR: 1.79-5.85years), the 3-year overall survival rate was 68.1% (95% CI 61.0 - 74.3%), the 3-year local control rate was 89.6% (95% CI 83.4-93.5), the 3-year intrahepatic recurrence-free survival rate was 53.7% (95% CI 45.9-60.8%), and the 3-year extrahepatic recurrence-free survival rate was 87.4% (95% CI: 81.5-91.6%). Simple nodular type had better overall survival (73.2% vs 65.2% p = 0.012) and extrahepatic recurrence free survival (96.9% vs 81.9% p<0.01), but there was no statistically significant difference in local control (92.7% vs 87.6% p = 0.06) and intrahepatic recurrence-free survival (62.0% vs 48.5% p = 0.114). Multivariate analysis of risk factors against OS, including age, sex, AFP, MVI, and macroscopic classification, revealed age and macroscopic classification as independent risk factors. Adverse events of grade 3 included 2 cases of gastrointestinal bleeding, 7 cases of liver function disorder, 1 cases of biliary hemorrhage, and 1 case of pleural effusion. Other than one case of early death (2 weeks after treatment) with an unknown causal relationship, there were no adverse events of grade 4 or severe. PBT for non- "simple nodular type" primary HCC appears to be safe and effective, whilst suppression of out-of-field recurrence is needed for further survival prolongment.

Long-term evolution of LR-2, LR-3 and LR-4 observations in HBV-related cirrhosis based on LI-RADS v2018 using gadoxetic acid-enhanced MRI.

To investigate the long-term evolution of LR-2, LR-3 and LR-4 observations in patients with hepatitis B virus (HBV)-related cirrhosis based on LI-RADS v2018 and identify predictors of progression to a malignant category on serial gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI). This retrospective study included 179 cirrhosis patients with untreated indeterminate observations who underwent Gd-EOB-MRI exams at baseline and during the follow-up period between June 2016 and December 2021. Two radiologists independently assessed the major features, ancillary features, and LI-RADS category of each observation at baseline and follow-up. In cases of disagreement, a third radiologist was consulted for consensus. Cumulative incidences for progression to a malignant category (LR-5 or LR-M) and to LR-4 or higher were analyzed for each index category using Kaplan‒Meier methods and compared using log-rank tests. The risk factors for malignant progression were evaluated using a Cox proportional hazard model. A total of 213 observations, including 74 (34.7%) LR-2, 95 (44.6%) LR-3, and 44 (20.7%) LR-4, were evaluated. The overall cumulative incidence of progression to a malignant category was significantly higher for LR-4 observations than for LR-3 or LR-2 observations (each P < 0.001), and significantly higher for LR-3 observations than for LR-2 observations (P < 0.001); at 3-, 6-, and 12-month follow-ups, the cumulative incidence of progression to a malignant category was 11.4%, 29.5%, and 39.3% for LR-4 observations, 0.0%, 8.5%, and 19.6% for LR-3 observations, and 0.0%, 0.0%, and 0.0% for LR-2 observations, respectively. The cumulative incidence of progression to LR-4 or higher was higher for LR-3 observations than for LR-2 observations (P < 0.001); at 3-, 6-, and 12-month follow-ups, the cumulative incidence of progression to LR-4 or higher was 0.0%, 8.5%, and 24.6% for LR-3 observations, and 0.0%, 0.0%, and 0.0% for LR-2 observations, respectively. In multivariable analysis, nonrim arterial phase hyperenhancement (APHE) [hazard ratio (HR) = 2.13, 95% CI 1.04-4.36; P = 0.038], threshold growth (HR = 6.50, 95% CI 2.88-14.65; P <0.001), and HBP hypointensity (HR = 16.83, 95% CI 3.97-71.34; P <0.001) were significant independent predictors of malignant progression. The higher LI-RADS v2018 categories had an increasing risk of progression to a malignant category during long-term evolution. Nonrim APHE, threshold growth, and HBP hypointensity were the imaging features that were significantly predictive of malignant progression.

A multivariate model based on gadoxetic acid-enhanced MRI using Li-RADS v2018 and other imaging features for preoperative prediction of dual‑phenotype hepatocellular carcinoma.

To investigate the diagnostic value of liver imaging reporting and data system (LI-RADS) v2018 and other imaging features in dual-phenotype hepatocellular carcinoma (DPHCC), establish a prediagnostic model based on gadoxetic acid-enhanced MRI, and explore the prognostic significance after surgery of the DPHCC. Preoperative enhanced MRI findings and the clinical and pathological data of patients with surgically confirmed HCC were analysed retrospectively. Image analysis was based on LI-RADS v2018 and other image features. Univariate analysis was used to screen for predictive factors of DPHCC, and multivariate logistic regression analysis was used to determine the predictive factors. A regression diagnostic model was established. Receiver operating characteristic (ROC) curve analysis was used to determine the critical value, area under curve (AUC), and the corresponding 95% confidence interval (95% CI). The diagnostic performance was verified by fivefold cross-validation. Cox regression analysis was used to determine the prognostic factors associated with early recurrence after surgical resection. In total, 158 patients were included, of whom 79 had DPHCC and 79 had non-DPHCC. Multivariate analysis showed that rim arterial phase hyperenhancement (Rim APHE) and targetoid restriction were independent risk factors for DPHCC (P < 0.05). The AUC (95% CI) of the model was 0.862 (0.807-0.918), sensitivity was 81.01%, and specificity was 89.874%. Cox regression analysis showed that DPHCC, microvascular invasion, tumour diameter, and an increase of alpha-fetoprotein were independent factors for recurrence. Rim APHE and targetoid restriction were sensitive imaging features of DPHCC before surgery, and the identification of DPHCC has important prognostic significance for early recurrence.

Added value of CE-CT radiomics to predict high Ki-67 expression in hepatocellular carcinoma

BackgroundThis study aimed to develop a computed tomography (CT) model to predict Ki-67 expression in hepatocellular carcinoma (HCC) and to examine the added value of radiomics to clinico-radiological features.MethodsA total of 208 patients (training set, n = 120; internal test set, n = 51; external validation set, n = 37) with pathologically confirmed HCC who underwent contrast-enhanced CT (CE-CT) within 1 month before surgery were retrospectively included from January 2014 to September 2021. Radiomics features were extracted and selected from three phases of CE-CT images, least absolute shrinkage and selection operator regression (LASSO) was used to select features, and the rad-score was calculated. CE-CT imaging and clinical features were selected using univariate and multivariate analyses, respectively. Three prediction models, including clinic-radiologic (CR) model, rad-score (R) model, and clinic-radiologic-radiomic (CRR) model, were developed and validated using logistic regression analysis. The performance of different models for predicting Ki-67 expression was evaluated using the area under the receiver operating characteristic curve (AUROC) and decision curve analysis (DCA).ResultsHCCs with high Ki-67 expression were more likely to have high serum α-fetoprotein levels (P = 0.041, odds ratio [OR] 2.54, 95% confidence interval [CI]: 1.04–6.21), non-rim arterial phase hyperenhancement (P = 0.001, OR 15.13, 95% CI 2.87–79.76), portal vein tumor thrombus (P = 0.035, OR 3.19, 95% CI: 1.08–9.37), and two-trait predictor of venous invasion (P = 0.026, OR 14.04, 95% CI: 1.39–144.32). The CR model achieved relatively good and stable performance compared with the R model (AUC, 0.805 [95% CI: 0.683–0.926] vs. 0.678 [95% CI: 0.536–0.839], P = 0.211; and 0.805 [95% CI: 0.657–0.953] vs. 0.667 [95% CI: 0.495–0.839], P = 0.135) in the internal and external validation sets. After combining the CR model with the R model, the AUC of the CRR model increased to 0.903 (95% CI: 0.849–0.956) in the training set, which was significantly higher than that of the CR model (P = 0.0148). However, no significant differences were found between the CRR and CR models in the internal and external validation sets (P = 0.264 and P = 0.084, respectively).ConclusionsPreoperative models based on clinical and CE-CT imaging features can be used to predict HCC with high Ki-67 expression accurately. However, radiomics cannot provide added value.

Washout appearance of hepatocellular carcinomas using standardized contrast-enhanced ultrasound (CEUS) including an extended late phase observation - Real-world data from the prospective multicentre DEGUM study.

Non-invasive diagnosis of hepatocellular carcinoma (HCC) in contrast-enhanced ultrasound (CEUS) is based on the combination of arterial phase hyperenhancement (APHE) and subsequent late (>60 seconds) and mild contrast washout (WO). Whereas APHE is seen in the majority of HCC, wash-out pattern may vary in onset and intensity. In some HCC lesions, even no washout is seen at all. Our prospective multicentre DEGUM HCC CEUS study aimed at identifying typical and atypical washout appearance of HCC in a real-life setting. High-risked patients for HCC with focal liver lesions upon B-mode ultrasound were recruited prospectively. In a multicentre real-life setting, a standardised CEUS examination including an extended late phase up to 6 minutes was performed. CEUS patterns of HCC were recorded, and onset and intensity of washout appearance were assessed with respect to patient and tumour characteristics. Histological findings served as reference standard. In 230/316 HCC (72.8%), a CEUS pattern of APHE followed by WO was observed. In 158 cases (68.7%), WO was typical (onset > 60 seconds, mild intensity). 72 cases (31.3%) showed marked and / or early WO, whereas in 41 HCCs (13%), APHE was followed by sustained isoenhancement.Atypical WO upon CEUS was associated with macroinvasion of the liver vessels, portal vein thrombosis and diffuse growth pattern, but not tumour size and histological grading. In a prospective multicentre real-life setting, APHE is followed by atypical washout appearance or no washout at all in almost half of the HCCs with APHE. The examiner has to bear in mind that in spite of a characteristic APHE in HCCs, washout appearance can be atypical in CEUS, especially in HCCs with macrovascular invasion or diffuse growth pattern.

Magnetic resonance imaging-based risk factors of hepatocellular carcinoma after direct-acting antiviral therapy: A multicenter observational study.

To determine risk factors associated with hepatocellular carcinoma (HCC) development following direct-acting antiviral (DAA) therapy. We enrolled patients with chronic hepatitisC who underwent direct-acting antiviral therapy and achieved sustained virologic response at 12weeks between 2012 and 2018. Subsequently, patients were followed up. The primary endpoint was the development of HCC or the date of the last follow up when the absence of HCC was confirmed. Uni- and multivariate Cox proportional hazards models were used to identify factors contributing to HCC development, including gadoxetic acid-enhanced magnetic resonance imaging findings. The cumulative incidence rates of HCC development were calculated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. The final study cohort comprised 482 patients (median age 70.5years; 242 men). The median follow-up period was 36.8months. Among 482 patients, 96 developed HCC (19.9%). The 1-, 3-, and 5-year cumulative rates of HCC development were 4.9%, 18.6%, and 30.5%, respectively. Multivariate analysis revealed that age, male sex, history of HCC, and hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were independent risk factors significantly associated with HCC development (p<0.001-0.04). The highest risk group included patients with both a history of HCC and the presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement (the 1- and 3-year cumulative HCC development rates were 14.2% and 62.2%, respectively). History of HCC and presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were strong risk factors for HCC development following direct-acting antiviral therapy.

Quantification of Hepatocellular Carcinoma Vascular Dynamics With Contrast-Enhanced Ultrasound for LI-RADS Implementation.

The aim of this study is to describe a comprehensive contrast-enhanced ultrasound (CEUS) imaging protocol and analysis method to implement CEUS LI-RADS (Liver Imaging Reporting and Data System) in a quantifiable manner. The methods that are validated with a prospective single-center study aim to simplify CEUS LI-RADS evaluation, remove observer bias, and potentially improve the sensitivity of CEUS LI-RADS. This prospective single-center study enrolled patients with hepatocellular carcinoma (April 2021-June 2022; N = 31; mean age ± SD, 67 ± 6 years; 24 men/7 women). For each patient, at least 2 CEUS loops spanning over 5 minutes were collected for different lesion scan planes using an articulated arm to hold the transducer. Automatic respiratory gating and motion compensation algorithms removed errors due to breathing motion. The long axis of the lesion was measured in the contrast and fundamental images to capture nodule size. Parametric processing of time-intensity curve analysis on linearized data provided quantifiable information of the wash-in and washout dynamics via rise time ( RT ) and degree of washout ( DW ) parameters extracted from the time-intensity curve, respectively. A Welch t test was performed between lesion and parenchyma RT for each lesion to confirm statistically significant differences. P values for bootstrapped 95% confidence intervals of the relative degree of washout ( rDW ), ratio of DW between the lesion and surrounding parenchyma, were computed to quantify lesion washout. Coefficient of variation (COV) of RT , DW , and rDW was calculated for each patient between injections for both the lesion and surrounding parenchyma to gauge reproducibility of these metrics. Spearman rank correlation tests were performed among size, RT , DW , and rDW values to evaluate statistical dependence between the variables. The mean ± SD lesion diameter was 23 ± 8 mm. The RT for all lesions, capturing arterial phase hyperenhancement, was shorter than that of surrounding liver parenchyma ( P < 0.05). All lesions also demonstrated significant ( P < 0.05) but variable levels of washout at both 2-minute and 5-minute time points, quantified in rDW . The COV of RT for the lesion and surrounding parenchyma were both 11%, and the COV of DW and rDW at 2 and 5 minutes ranged from 22% to 31%. Statistically significant relationships between lesion and parenchyma RT and between lesion RT and lesion DW at the 2- and 5-minute time points were found ( P < 0.05). The imaging protocol and analysis method presented provide robust, quantitative metrics that describe the dynamic vascular patterns of LI-RADS 5 lesions classified as hepatocellular carcinomas. The RT of the bolus transit quantifies the arterial phase hyperenhancement, and the DW and rDW parameters quantify the washout from linearized CEUS intensity data. This unique methodology is able to implement the CEUS-LIRADS scheme in a quantifiable manner for the first time and remove its existing issues of currently being qualitative and suffering from subjective evaluations.

Performance of current versus modified CEUS LI-RADS in the diagnosis of non-hepatocellular carcinoma malignancies.

The high proportion of HCC in CEUS LR-M decreases the sensitivity of LR-5 for the diagnosis of HCC. However, when modifying LR-M criteria to further improve the sensitivity of LR-5, it is also important not to compromise the diagnostic performance (especially sensitivity) of LR-M for non-hepatocellular carcinoma malignancies (non-HCCMs). The purpose of this study was to evaluate the diagnostic performance of CEUS LI-RADS (2017 version) for non-HCCMs and to explore the impact of modified CEUS LI-RADS on the diagnostic performance of LR-M. In this retrospective study, patients with pathologically confirmed non-HCCMs were evaluated. Two radiologists independently interpreted the major CEUS features and categorized the liver lesions. New LR-M criteria were applied: early washout (< 45 s) or marked washout (< 5 min). The sensitivity values of the current and modified CEUS LR-M were assessed and then compared using a paired χ2 test. Cohen's κ was used to compare the inter-reader agreement of the LI-RADS categories. A total of 131 non-HCCMs were ultimately selected, including 71 intrahepatic cholangiocarcinomas, 26 combined hepatocellular cholangiocarcinomas, 29 metastases, and 5 other non-HCCMs. The numbers of LR-M, LR-5, LR-4, and LR-3 in liver lesions were 111, 18, 1, and 1, respectively. The inter-reader agreement of the LI-RADS categories for non-HCCMs was 0.59. The sensitivity of the current CEUS LR-M in diagnosing non-HCCMs was 84.7%. By adjusting the early washout time to < 45 s, the sensitivity of LR-M was 80.9%. By adjusting the marked washout time within 5 min, the sensitivity of LR-M was 72.5%. CEUS LR-M has high sensitivity in diagnosing non-HCCMs. For LR-M nodules with nonrim arterial phase hyperenhancement and early washout, advancing the time of early washout to < 45 s has a minimal impact on the sensitivity of LR-M in diagnosing non-HCCMs compared to the condition of increasing the marked washout within 5 min.

Diagnosis of hepatocellular carcinoma using Sonazoid: a comprehensive review.

Sonazoid contrast-enhanced ultrasonography (CEUS) is a promising technique for the detection and diagnosis of focal liver lesions, particularly hepatocellular carcinoma (HCC). Recently, a collaborative effort between the Korean Society of Radiology and Korean Society of Abdominal Radiology resulted in the publication of guidelines for diagnosing HCC using Sonazoid CEUS. These guidelines propose specific criteria for identifying HCC based on the imaging characteristics observed during Sonazoid CEUS. The suggested diagnostic criteria include nonrim arterial phase hyperenhancement, and the presence of late and mild washout, or Kupffer phase washout under the premise that the early or marked washout should not occur during the portal venous phase. These criteria aim to improve the accuracy of HCC diagnosis using Sonazoid CEUS. This review offers a comprehensive overview of Sonazoid CEUS in the context of HCC diagnosis. It covers the fundamental principles of Sonazoid CEUS and its clinical applications, and introduces the recently published guidelines. By providing a summary of this emerging technique, this review contributes to a better understanding of the potential role of Sonazoid CEUS for diagnosing HCC.

Diagnostic performance of gadoxetic acid-enhanced abbreviated magnetic resonance imaging protocol in small hepatocellular carcinoma (≤2 cm) in high-risk patients.

Biannual Ultrasound showed insufficient sensitivity in detecting small or early-stage hepatocellular carcinoma (HCC). Abbreviated magnetic resonance imaging (A-MRI) protocols with fewer sequences demonstrated higher HCC detection sensitivity than ultrasound with acceptable cost and examination time. To compare the diagnostic performance of gadoxetic acid-enhanced A-MRI with a full sequence MRI (F-MRI) protocol for small HCC (≤2 cm) in cirrhotic or hepatitis B virus-infected high-risk patients. Two hundred and four consecutive patients with 166 pathologically confirmed small HCC who underwent preoperative gadoxetic acid-enhanced MRI were retrospectively included. A-MRI set comprised T1-weighted hepatobiliary phase imaging, T2-weighted imaging, diffusion-weighted imaging and apparent diffusion coefficient mapping. Two independent radiologists blinded to clinical data assessed the A-MRI set and F-MRI set. Per-patient HCC and per-lesion HCC diagnostic performance were compared. Per-patient HCC detection sensitivity of A-MRI set was 93.8% and 91.2% for observer 1 and observer 2, and, for the F-MRI set, the per-patient HCC detection sensitivity was 96.6% and 95.2%, respectively. There was no significant difference in per-patient sensitivity, specificity and per-lesion HCC detection sensitivity between the two imaging sets for both readers. (P = 0.06-0.25) The A-MRI set showed higher sensitivity on HCC without arterial phase hyperenhancement, and the F-MRI set demonstrated with higher sensitivity on HCC with arterial phase hyperenhancement (P < 0.05). A-MRI using diagnostic criteria including hypointensity on hepatobiliary phase plus mild to moderate hyperintensity on T2-weighted imaging or restricted diffusion demonstrated comparable sensitivity and specificity for small HCC compared to the F-MRI protocol in high-risk patients.

Longitudinal assessment of hepatocellular carcinoma response to stereotactic body radiation using gadoxetate-enhanced MRI: A case series

PurposeTo describe the longitudinal response in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) and who underwent liver transplant (LT) using gadoxetate-enhanced MRI. MethodsFive men (median age 61y, range 57–64y) with 6 HCCs treated with SBRT (median dose 50 Gy) who subsequently underwent LT were included in this retrospective study. Patients underwent gadoxetate-enhanced MRI before and after SBRT over a period of 3–18 months. Response was assessed using RECIST1.1, mRECIST, LI-RADS and image subtraction, by 2 observers in consensus. Percentage of pathologic tumor necrosis was evaluated. ResultsLT was performed 278 days (IQR, 148–418d) after completion of SBRT and 48d after the last MRI. Histopathology demonstrated tumor necrosis of 48 ± 42% (range, 10–100%). Mean tumor size at baseline and last post-treatment MRIs pre-LT were 2.6 ± 0.8 cm and 2.4 ± 0.9 cm. Enhancing tumor component size at baseline MRI and last post-treatment MRI pre-LT were 1.6 ± 0.8 cm and 0.9 ± 1.0 cm. Responses assessed at the last LRI pre-LT were: partial response (PR, n = 3), stable disease (SD, n = 3) using RECIST1.1; complete response (CR, n = 2), partial response (PR, n = 2), stable disease (SD, n = 2) using mRECIST; and LR-TR viable (n = 4), LR-TR non-viable (n = 2) using LI-RADS. At the last MRI pre-LT, per-lesion features of arterial phase hyperenhancement (APHE, 4/6), portal venous washout (3/6) and capsule (3/6) were observed. 5/6 lesions displayed a hypointense perilesional halo on hepatobiliary phase with a mean delay of 3.1 months post-SBRT. ConclusionsThis case-series showed decreased size, persistent APHE, and incomplete pathologic necrosis in most HCCs treated with SBRT undergoing transplant.

MRI Using Gadoxetic Acid in the Work-Up of Liver Nodules Not Conclusively Benign in Budd-Chiari Syndrome: A Prospective Long-Term Follow-Up

Introduction: The incidence of hepatocellular carcinoma (HCC) in Budd-Chiari syndrome (BCS) is unknown and there is no validated diagnostic work-up to define the liver nodules with arterial phase hyperenhancement (APHE), suggesting malignancy. This prospective study evaluates HCC incidence in a Western cohort of patients with BCS and assesses the performance of MRI with hepatobiliary contrast (HB-MRI) for nodule characterization. Methods: Patients with BCS followed in our hospital were prospectively evaluated by MRI with extracellular contrast (EC-MRI). Nodules with APHE categorized as non-conclusively benign by 2 radiologists were studied by HB-MRI and reviewed by 2 radiologists blinded to the EC-MRI results. A new EC-MRI 1 year later and clinical, analytical, and sonographic follow-up every 6 months for a median of 10 years was performed. Results: A total of 55 non-conclusively benign nodules with APHE were detected at EC-MRI in 41 patients. While 32 of them were suggestive of HCC by EC-MRI, all the 55 nodules showed increased uptake of hepatobiliary contrast. An unequivocal central scar was seen in 12/55 nodules at HB-MRI regardless of it was not detected on the EC-MRI. None of the nodules was hypointense in the hepatobiliary phase (HBP). HCC was not detected during a median of 10 years of follow-up. Conclusions: Detection of nodules with APHE is frequent in patients with BCS, but HCC is rare in Western patients with BCS. While EC-MRI may detect nodules suggesting malignancy, the identification of contrast uptake in the HBP at HB-MRI may help categorize them as benign.

Feeding artery: a valuable feature for differentiation of regenerative nodule, dysplastic nodules and small hepatocellular carcinoma in CEUS LI-RADS.

To investigate whether the feeding artery (FA) feature can aid in discriminating small hepatocellular carcinoma (HCC) using the contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) from precancerous lesions. Between June 2017 and May 2021, a total of 347 patients with 351 precancerous liver lesions or small HCCs who underwent CEUS were enrolled. Two independent radiologists assigned LI-RADS categories to all lesions and assessed the presence of the FA feature, which was used as an ancillary feature to either upgrade or downgrade the LI-RADS category. The diagnostic performance of CEUS LI-RADS, both with and without the FA feature, was evaluated based on accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. The FA feature was found to be more prevalent in HCC (85.54%, p < 0.001) than in regenerative nodules (RNs, 29.73%), low-grade dysplastic nodules (LGDNs, 33.33%), and high-grade dysplastic nodules (HGDNs, 55.26%). Furthermore, the presence of arterial phase hyperenhancement (APHE), washout (WO), and FA in liver nodules was associated with a higher expression of GPC-3 and Ki-67 compared to the group without these features (p < 0.001). After adjusting, the sensitivity and accuracy of LR-5 for HCC improved from 68.67% (95%CI: 62.46%, 74.30%) to 77.51% (95%CI: 71.72%, 82.44%) and from 69.23% (95%CI: 64.11%, 74.02%) to 73.79% (95%CI: 68.86%, 78.31%), respectively. The FA feature is a valuable feature for distinguishing small HCC and precancerous lesions and could be added as a possible ancillary feature in CEUS LI-RADS which was backed up by biomarkers. The presence of a feeding artery is a valuable imaging feature in the differentiation of HCC and precancerous lesions. Incorporating this characteristic in the CEUS LI-RADS can enhance the diagnostic ability. • Feeding artery is more frequent in HCC than in regenerative nodules, low-grade dysplastic nodules, and high-grade dysplastic nodules. • Feeding artery feature is a valuable ancillary feature for CEUS LI-RADS to differentiate regenerative nodules, low-grade dysplastic nodules, high-grade dysplastic nodules, and HCC. • The existence of feeding artery, arterial phase hyperenhancement, and washout is associated with more GPC-3 positive expression and higher Ki-67 expression than the group without these features.

Automated CT LI-RADS v2018 scoring of liver observations using machine learning: A multivendor, multicentre retrospective study

Assessment of computed tomography (CT)/magnetic resonance imaging Liver Imaging Reporting and Data System (LI-RADS) v2018 major features leads to substantial inter-reader variability and potential decrease in hepatocellular carcinoma diagnostic accuracy. We assessed the performance and added-value of a machine learning (ML)-based algorithm in assessing CT LI-RADS major features and categorisation of liver observations compared with qualitative assessment performed by a panel of radiologists. High-risk patients as per LI-RADS v2018 with pathologically proven liver lesions who underwent multiphase contrast-enhanced CT at diagnosis between January 2015 and March 2019 in seven centres in five countries were retrospectively included and randomly divided into a training set (n= 84 lesions) and a test set (n= 345 lesions). An ML algorithm was trained to classify non-rim arterial phase hyperenhancement, washout, and enhancing capsule as present, absent, or of uncertain presence. LI-RADS major features and categories were compared with qualitative assessment of two independent readers. The performance of a sequential use of the ML algorithm and independent readers were also evaluated in a triage and an add-on scenario in LR-3/4 lesions. The combined evaluation of three other senior readers was used as reference standard. A total of 318 patients bearing 429 lesions were included. Sensitivity and specificity for LR-5 in the test set were 0.67 (95% CI, 0.62-0.72) and 0.91 (95% CI, 0.87-0.96) respectively, with 242 (70.1%) lesions accurately categorised. Using the ML algorithm in a triage scenario improved the overall performance for LR-5. (0.86 and 0.93 sensitivity, 0.82 and 0.76 specificity, 78% and 82.3% accuracy for the two independent readers). Quantitative assessment of CT LI-RADS v2018 major features is feasible and diagnoses LR-5 observations with high performance especially in combination with the radiologist's visual analysis in patients at high-risk for HCC. Assessment of CT/MRI LI-RADS v2018 major features leads to substantial inter-reader variability and potential decrease in hepatocellular carcinoma diagnostic accuracy. Rather than replacing radiologists, our results highlight the potential benefit from the radiologist-artificial intelligence interaction in improving focal liver lesions characterisation by using the developed algorithm as a triage tool to the radiologist's visual analysis. Such an AI-enriched diagnostic pathway may help standardise and improve the quality of analysis of liver lesions in patients at high risk for HCC, especially in non-expert centres in liver imaging. It may also impact the clinical decision-making and guide the clinician in identifying the lesions to be biopsied, for instance in patients with multiple liver focal lesions.

Surveillance for malignant progression of LI-RADS version 2017 category 3/4 nodules using contrast-enhanced ultrasound.

To identify the risk factors for predicting the malignant progression of LR-3/4 observations on the baseline and contrast-enhanced ultrasound (CEUS). In total, 245 liver nodules assigned to LR-3/4 in 192 patients from January 2010 to December 2016 were followed up by baseline US and CEUS. The differences in the rate and time of progression to hepatocellular carcinoma (HCC) among subcategories (defined as P1-P7) of LR-3/4 in CEUS Liver Imaging Reporting and Data System (LI-RADS) were analyzed. The risk factors to predict progression to HCC were analyzed by univariate and multivariate Cox proportional hazard model analysis. A total of 40.3% of LR-3 nodules and 78.9% of LR-4 nodules eventually progressed to HCC. The cumulative incidence of progression was significantly higher for LR-4 than LR-3 (p < 0.001). The rate of progression was 81.2% in nodules with arterial phase hyperenhancement (APHE), 64.7% in nodules with late and mild washout, and 100% in nodules with both characteristics. The overall progression rate and median progression time of subcategory P1 nodules (LR-3a) were lower (38.0% vs. 47.6-100.0%) and later (25.1months vs. 2.0-16.3months) than those of other subcategories. The cumulative incidence of progression of LR-3a (P1), LR-3b (P2/3/4), and LR-4 (P5/6/7) categories were 38.0%, 52.9%, and 78.9%. The risk factors of HCC progression were Visualization score B/C, CEUS characteristics (APHE, washout), LR-4 classification, echo changes, and definite growth. CEUS is a useful surveillance tool for nodules at risk of HCC. CEUS characteristics, LI-RADS classification, and changes in nodules provide useful information for the progress of LR-3/4 nodules. CEUS characteristics, LI-RADS classification, and nodule changes provide important predictions for LR-3/4 nodule progression to HCC, which may stratify the risk of malignant progression to provide a more optimized and refined, more cost-effective, and time-efficient management strategy for patients. • CEUS is a useful surveillance tool for nodules at risk of HCC, CEUS LI-RADS successfully stratified the risks that progress to HCC. • CEUS characteristics, LI-RADS classification, and changes in nodules can provide important information on the progression of LR-3/4 nodules, which may be helpful for a more optimized and refined management strategy.