Hepatocellular Carcinoma Incidences and Risk Factors in Hepatitis C Patients: Interferon versus Direct-Acting Agents.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a significant concern for patients with chronic hepatitis C (HCV), even after achieving a sustained virological response (SVR) with direct-acting antivirals (DAAs) or interferon (IFN)-based therapies. This study compared the risk of HCC in patients with HCV who achieved SVR through the DAA versus IFN regimens. METHODS: A retrospective analysis was conducted on 4806 HCV patients, without coinfection nor prior HCC history, treated at the Chang Gung Memorial Hospital, Taiwan (DAA: 2825, IFN: 1981). Kaplan-Meier and Cox regression analyses with propensity score matching (PSM) were used to adjust for baseline differences. RESULTS: DAA-treated patients exhibited a higher incidence of HCC than IFN-treated patients before and after PSM (after PSM: annual: 1% vs. 0.5%; 6-year: 6% vs. 3%, p = 0.01). Both DAA and IFN patients had a decreased HCC incidence during follow-up (>3 vs. <3 years from the end of treatment: DAA: 1.43% vs. 1.00% per year; IFN: 0.47% vs. 0.36% per year, both p < 0.05). HCC incidence was higher in the first three years post-SVR in DAA-treated ACLD patients and then decreased (3.26% vs. 1.39% per year, p < 0.01). In contrast, HCC incidence remained constant in the non-ACLD and IFN-treated groups. Multivariate Cox regression identified age ≥ 60, male sex, BMI, AFP ≥ 6 ng/mL, FIB-4, and ACLD status as independent risk factors for HCC, but antiviral regimens were not an independent factor for HCC. CONCLUSION: DAA treatment significantly affects HCC risk primarily within three years post-treatment, especially in younger HCV patients with ACLD. HCC incidence was reduced after three years in ACLD patients treated by DAA, but continued surveillance was still necessary. However, patients under 60 without advanced liver disease may require less intensive follow-up.

Ultrasonic Assessment of Liver Fibrosis Using One-Dimensional Convolutional Neural Networks Based on Frequency Spectra of Radiofrequency Signals with Deep Learning Segmentation of Liver Regions in B-Mode Images: A Feasibility Study.

The early detection of liver fibrosis is of significant importance. Deep learning analysis of ultrasound backscattered radiofrequency (RF) signals is emerging for tissue characterization as the RF signals carry abundant information related to tissue microstructures. However, the existing methods only used the time-domain information of the RF signals for liver fibrosis assessment, and the liver region of interest (ROI) is outlined manually. In this study, we proposed an approach for liver fibrosis assessment using deep learning models on ultrasound RF signals. The proposed method consisted of two-dimensional (2D) convolutional neural networks (CNNs) for automatic liver ROI segmentation from reconstructed B-mode ultrasound images and one-dimensional (1D) CNNs for liver fibrosis stage classification based on the frequency spectra (amplitude, phase, and power) of the segmented ROI signals. The Fourier transform was used to obtain the three kinds of frequency spectra. Two classical 2D CNNs were employed for liver ROI segmentation: U-Net and Attention U-Net. ROI spectrum signals were normalized and augmented using a sliding window technique. Ultrasound RF signals collected (with a 3-MHz transducer) from 613 participants (Group A) were included for liver ROI segmentation and those from 237 participants (Group B) for liver fibrosis stage classification, with a liver biopsy as the reference standard (Fibrosis stage: F0 = 27, F1 = 49, F2 = 51, F3 = 49, F4 = 61). In the test set of Group A, U-Net and Attention U-Net yielded Dice similarity coefficients of 95.05% and 94.68%, respectively. In the test set of Group B, the 1D CNN performed the best when using ROI phase spectrum signals to evaluate liver fibrosis stages ≥F1 (area under the receive operating characteristic curve, AUC: 0.957; accuracy: 89.19%; sensitivity: 85.17%; specificity: 93.75%), ≥F2 (AUC: 0.808; accuracy: 83.34%; sensitivity: 87.50%; specificity: 78.57%), and ≥F4 (AUC: 0.876; accuracy: 85.71%; sensitivity: 77.78%; specificity: 94.12%), and when using the power spectrum signals to evaluate ≥F3 (AUC: 0.729; accuracy: 77.14%; sensitivity: 77.27%; specificity: 76.92%). The experimental results demonstrated the feasibility of both the 2D and 1D CNNs in liver parenchyma detection and liver fibrosis characterization. The proposed methods have provided a new strategy for liver fibrosis assessment based on ultrasound RF signals, especially for early fibrosis detection. The findings of this study shed light on deep learning analysis of ultrasound RF signals in the frequency domain with automatic ROI segmentation.

Ultrasound normalized cumulative residual entropy imaging: Theory, methodology, and application.

BACKGROUND AND OBJECTIVE: Ultrasound information entropy imaging is an emerging quantitative ultrasound technique for characterizing local tissue scatterer concentrations and arrangements. However, the commonly used ultrasound Shannon entropy imaging based on histogram-derived discrete probability estimation suffers from the drawbacks of histogram settings dependence and unknown estimator performance. In this paper, we introduced the information-theoretic cumulative residual entropy (CRE) defined in a continuous distribution of cumulative distribution functions as a new entropy measure of ultrasound backscatter envelope uncertainty or complexity, and proposed ultrasound CRE imaging for tissue characterization. METHODS: We theoretically analyzed the CRE for Rayleigh and Nakagami distributions and proposed a normalized CRE for characterizing scatterer distribution patterns. We proposed a method based on an empirical cumulative distribution function estimator and a trapezoidal numerical integration for estimating the normalized CRE from ultrasound backscatter envelope signals. We presented an ultrasound normalized CRE imaging scheme based on the normalized CRE estimator and the parallel computation technique. We also conducted theoretical analysis of the differential entropy which is an extension of the Shannon entropy to a continuous distribution, and introduced a method for ultrasound differential entropy estimation and imaging. Monte-Carlo simulation experiments were performed to evaluate the estimation accuracy of the normalized CRE and differential entropy estimators. Phantom simulation and clinical experiments were conducted to evaluate the performance of the proposed normalized CRE imaging in characterizing scatterer concentrations and hepatic steatosis (n = 204), respectively. RESULTS: The theoretical normalized CRE for the Rayleigh distribution was π/4, corresponding to the case where there were ≥10 randomly distributed scatterers within the resolution cell of an ultrasound transducer. The theoretical normalized CRE for the Nakagami distribution decreased as the Nakagami parameter m increased, corresponding to that the ultrasound backscattered statistics varied from pre-Rayleigh to Rayleigh and to post-Rayleigh distributions. Monte-Carlo simulation experiments showed that the proposed normalized CRE and differential entropy estimators can produce a satisfying estimation accuracy even when the size of the test samples is small. Phantom simulation experiments showed that the proposed normalized CRE and differential entropy imaging can characterize scatterer concentrations. Clinical experiments showed that the proposed ultrasound normalized CRE imaging is capable to quantitatively characterize hepatic steatosis, outperforming ultrasound differential entropy imaging and being comparable to ultrasound Shannon entropy and Nakagami imaging. CONCLUSION: This study sheds light on the theory and methodology of ultrasound normalized CRE. The proposed ultrasound normalized CRE can serve as a new, flexible quantitative ultrasound envelope statistics parameter. The proposed ultrasound normalized CRE imaging may find applications in quantified characterization of biological tissues. Our code will be made available publicly at https://github.com/zhouzhuhuang.

Modified multi-Rayleigh model-based statistical analysis of ultrasound envelope for quantification of liver steatosis and fibrosis.

PURPOSE: Quantitative diagnosis of the degree of fibrosis progression is currently a focus of attention for fatty liver in nonalcoholic steatohepatitis (NASH). However, previous studies have focused on either lipid droplets or fibrotic tissue, and few have reported the evaluation of both in patients whose livers contain adipose and fibrous features. Our aim was to evaluate fibrosis tissue and lipid droplets in the liver. METHODS: We used an analytical method combining the multi-Rayleigh (MRA) model and a healthy liver structure filter (HLSF) as a technique for statistical analysis of the amplitude envelope to estimate fat and fibrotic volumes in clinical datasets with different degrees of fat and fibrosis progression. RESULTS: Fat mass was estimated based on the non-MRA fraction corresponding to the signal characteristics of aggregated lipid droplets. Non-MRA fraction has a positive correlation with fat mass and is effective for detecting moderate and severe fatty livers. Progression of fibrosis was estimated using MRA parameters in combination with the HLSF. The proposed method was used to extract non-healthy areas with characteristics of fibrotic tissue. Fibrosis in early fatty liver suggested the possibility of evaluation. On the other hand, fat was identified as a factor that reduced the accuracy of estimating fibrosis progression in moderate and severe fatty livers. CONCLUSION: The proposed method was used to simultaneously evaluate fat mass and fibrosis progression in early fatty liver, suggesting the possibility of quantitative evaluation for discriminating between lipid droplets and fibrous tissue in the early fatty liver.

Ultrasound Entropy Imaging Based on the Kernel Density Estimation: A New Approach to Hepatic Steatosis Characterization.

In this paper, we present the kernel density estimation (KDE)-based parallelized ultrasound entropy imaging and apply it for hepatic steatosis characterization. A KDE technique was used to estimate the probability density function (PDF) of ultrasound backscattered signals. The estimated PDF was utilized to estimate the Shannon entropy to construct parametric images. In addition, the parallel computation technique was incorporated. Clinical experiments of hepatic steatosis were conducted to validate the feasibility of the proposed method. Seventy-two participants and 204 patients with different grades of hepatic steatosis were included. The experimental results show that the KDE-based entropy parameter correlates with log10 (hepatic fat fractions) measured by magnetic resonance spectroscopy in the 72 participants (Pearson's r = 0.52, p < 0.0001), and its areas under the receiver operating characteristic curves for diagnosing hepatic steatosis grades ≥ mild, ≥moderate, and ≥severe are 0.65, 0.73, and 0.80, respectively, for the 204 patients. The proposed method overcomes the drawbacks of conventional histogram-based ultrasound entropy imaging, including limited dynamic ranges and histogram settings dependence, although the diagnostic performance is slightly worse than conventional histogram-based entropy imaging. The proposed KDE-based parallelized ultrasound entropy imaging technique may be used as a new ultrasound entropy imaging method for hepatic steatosis characterization.

Steatosis Quantification on Ultrasound Images by a Deep Learning Algorithm on Patients Undergoing Weight Changes.

INTRODUCTION: A deep learning algorithm to quantify steatosis from ultrasound images may change a subjective diagnosis to objective quantification. We evaluate this algorithm in patients with weight changes. MATERIALS AND METHODS: Patients (N = 101) who experienced weight changes ≥ 5% were selected for the study, using serial ultrasound studies retrospectively collected from 2013 to 2021. After applying our exclusion criteria, 74 patients from 239 studies were included. We classified images into four scanning views and applied the algorithm. Mean values from 3-5 images in each group were used for the results and correlated against weight changes. RESULTS: Images from the left lobe (G1) in 45 patients, right intercostal view (G2) in 67 patients, and subcostal view (G4) in 46 patients were collected. In a head-to-head comparison, G1 versus G2 or G2 versus G4 views showed identical steatosis scores (R2 > 0.86, p < 0.001). The body weight and steatosis scores were significantly correlated (R2 = 0.62, p < 0.001). Significant differences in steatosis scores between the highest and lowest body weight timepoints were found (p < 0.001). Men showed a higher liver steatosis/BMI ratio than women (p = 0.026). CONCLUSIONS: The best scanning conditions are 3-5 images from the right intercostal view. The algorithm objectively quantified liver steatosis, which correlated with body weight changes and gender.

Acoustic radiation force impulse predicts long-term outcomes in a large-scale cohort: High liver cancer, low comorbidity in hepatitis B virus.

BACKGROUND: Acoustic radiation force impulse (ARFI) is used to measure liver fibrosis and predict outcomes. The performance of elastography in assessment of fibrosis is poorer in hepatitis B virus (HBV) than in other etiologies of chronic liver disease. AIM: To evaluate the performance of ARFI in long-term outcome prediction among different etiologies of chronic liver disease. METHODS: Consecutive patients who received an ARFI study between 2011 and 2018 were enrolled. After excluding dual infection, alcoholism, autoimmune hepatitis, and others with incomplete data, this retrospective cohort were divided into hepatitis B (HBV, n = 1064), hepatitis C (HCV, n = 507), and non-HBV, non-HCV (NBNC, n = 391) groups. The indexed cases were linked to cancer registration (1987-2020) and national mortality databases. The differences in morbidity and mortality among the groups were analyzed. RESULTS: At the enrollment, the HBV group showed more males (77.5%), a higher prevalence of pre-diagnosed hepatocellular carcinoma (HCC), and a lower prevalence of comorbidities than the other groups (P < 0.001). The HCV group was older and had a lower platelet count and higher ARFI score than the other groups (P < 0.001). The NBNC group showed a higher body mass index and platelet count, a higher prevalence of pre-diagnosed non-HCC cancers (P < 0.001), especially breast cancer, and a lower prevalence of cirrhosis. Male gender, ARFI score, and HBV were independent predictors of HCC. The 5-year risk of HCC was 5.9% and 9.8% for those ARFI-graded with severe fibrosis and cirrhosis. ARFI alone had an area under the receiver operating characteristic curve (AUROC) of 0.742 for prediction of HCC in 5 years. AUROC increased to 0.828 after adding etiology, gender, age, and platelet score. No difference was found in mortality rate among the groups. CONCLUSION: The HBV group showed a higher prevalence of HCC but lower comorbidity that made mortality similar among the groups. Those patients with ARFI-graded severe fibrosis or cirrhosis should receive regular surveillance.

Parallelized ultrasound homodyned-K imaging based on a generalized artificial neural network estimator.

The homodyned-K (HK) distribution model is a generalized backscatter envelope statistical model for ultrasound tissue characterization, whose parameters are of physical meaning. To estimate the HK parameters is an inverse problem, and is quite complicated. Previously, we proposed an artificial neural network (ANN) estimator and an improved ANN (iANN) estimator for estimating the HK parameters, which are fast and flexible. However, a drawback of the conventional ANN and iANN estimators consists in that they use Monte Carlo simulations under known values of HK parameters to generate training samples, and thus the ANN and iANN models have to be re-trained when the size of the test sets (or of the envelope samples to be estimated) varies. In addition, conventional ultrasound HK imaging uses a sliding window technique, which is non-vectorized and does not support parallel computation, so HK image resolution is usually sacrificed to ensure a reasonable computation cost. To this end, we proposed a generalized ANN (gANN) estimator in this paper, which took the theoretical derivations of feature vectors for network training, and thus it is independent from the size of the test sets. Further, we proposed a parallelized HK imaging method that is based on the gANN estimator, which used a block-based parallel computation method, rather than the conventional sliding window technique. The gANN-based parallelized HK imaging method allowed a higher image resolution and a faster computation at the same time. Computer simulation experiments showed that the gANN estimator was generally comparable to the conventional ANN estimator in terms of HK parameter estimation performance. Clinical experiments of hepatic steatosis showed that the gANN-based parallelized HK imaging could be used to visually and quantitatively characterize hepatic steatosis, with similar performance to the conventional ANN-based HK imaging that used the sliding window technique, but the gANN-based parallelized HK imaging was over 3 times faster than the conventional ANN-based HK imaging. The parallelized computation method presented in this work can be easily extended to other quantitative ultrasound imaging applications.