Identification of the suitable candidates for EOB-MRI with the high risk of the presence of non-hypervascular hypointense nodules in patients with HCV infection.

OBJECTIVES: Non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of progressing to hepatocellular carcinoma (HCC). The presence of NHHNs is a strong risk factor for HCC development in patients with chronic hepatitis C virus (HCV) infection after the achievement of sustained virologic response (SVR). However, it is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection. We therefore explored serum markers that potentially indicate the presence of NHHNs. METHODS: Three serum markers, alpha-fetoprotein (AFP), FIB-4 index, and Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi), were measured in 481 patients with HCV infection and no history of HCC who underwent EOB-MRI. The associations between these serum marker levels and the presence of NHHNs were investigated. RESULTS: All three markers were associated with the presence of NHHNs. M2BPGi predicted the presence of NHHNs more accurately than AFP and FBB-4 index; M2BPGi had the highest area under the receiver operating characteristic curve. Multivariate analysis identified male gender and high M2BPGi as factors associated with the presence of NHHNs. When patients were stratified by the degree of liver fibrosis, M2BPGi increased with the progression of fibrosis. In addition, NHHNs were more prevalently detected in patients with higher M2BPGi (COI > 3.46) in patients with similar fibrosis degree. CONCLUSIONS: M2BPGi is a serum marker that potentially identifies HCV patients with high risk of the presence of NHHNs, for whom EOB-MRI should be considered. KEY POINTS: • Non-hypervascular hypointense nodule on EOB-DTPA-enhanced MRI is pre-HCC nodule with high likelihood of progressing to HCC, which is a strong predictor for HCC that develops after the eradication of HCV in patients with HCV infection. • It is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection due to limited access, limited availability of MRI equipment, and high costs. • Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi) levels effectively indicate the presence of NHHNs and can be used to identify patients with high risk of their presence, for whom EOB-DTPA-enhanced MRI should be considered.

Pretreatment non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI as a predictor of hepatocellular carcinoma development after sustained virologic response in HCV infection.

BACKGROUND: Identification of risk factors for the development of hepatocellular carcinoma (HCC) after a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection is urgently needed for HCC surveillance. AIMS: To evaluate whether the presence of non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) before direct-acting antivirals (DAAs) therapy is a risk factor for de novo HCC development after SVR. METHODS: The presence of NHHNs was examined with EOB-MRI before the start of DAA therapy in 383 patients with HCV infection who achieved SVR. The incidence of de novo HCC after SVR was compared between patients with versus without NHHNs. RESULTS: NHHNs were detected before DAA therapy in 32 patients (8.4%). The incidence of de novo HCC after SVR was significantly higher in patients with NHHNs than in those without (1-, 3-, 5-year incidence, 9.8%, 24.2% and 41.6% vs. 0%, 1.2% and 4.4%, P < 0.0001). The presence of NHHNs before DAA therapy (adjusted HR, 10.86; 95% CI, 4.03-31.64) and cirrhosis (adjusted HR, 7.23; 95% CI, 1.88-35.85) were independently associated with a higher incidence of HCC after SVR. A higher incidence of de novo HCC after SVR remained after adjustment for age, gender, regular alcohol intake, diabetes, cirrhosis, FIB-4 index and serum alpha-foetoprotein with inverse probability of treatment weighting. CONCLUSIONS: This study confirmed that the presence of NHHNs before DAA therapy is a strong risk factor for the development of de novo HCC after SVR.

Prediction of Hepatocellular Carcinoma by Liver Stiffness Measurements Using Magnetic Resonance Elastography After Eradicating Hepatitis C Virus.

INTRODUCTION: Liver fibrosis stage is one of the most important factors in stratifying the risk of developing hepatocellular carcinoma (HCC). We evaluated the usefulness of liver stiffness measured by magnetic resonance elastography (MRE) to stratify the risk of developing HCC in patients who underwent MRE before receiving direct-acting antivirals (DAAs) and subsequently achieved sustained virological response (SVR). METHODS: A total of 537 consecutive patients with persistent hepatitis C virus who underwent initial MRE before DAA therapy and achieved SVR were enrolled. Factors associated with HCC development were analyzed by univariate and multivariate Cox proportional hazards models. RESULTS: Albumin-bilirubin score ≥ -2.60 (adjusted hazard ratio [aHR] 6.303), fibrosis-4 (FIB-4) score >3.25 (aHR 7.676), and MRE value ≥4.5 kPa (aHR 13.190) were associated with HCC development according to a univariate Cox proportional hazards model. A multivariate Cox proportional hazards model showed that an MRE value ≥4.5 kPa (aHR 7.301) was the only factor independently associated with HCC development. Even in patients with an FIB-4 score >3.25, the cumulative incidence rate of HCC development in those with an MRE value <4.5 kPa was significantly lower than that in patients with an MRE value ≥4.5 kPa. DISCUSSION: Liver stiffness measured by MRE before DAA therapy was an excellent marker for predicting subsequent HCC development in patients with hepatitis C virus infection who achieved SVR. The same results were observed in patients with high FIB-4 scores.

Texture Analysis Using Preoperative Positron Emission Tomography Images May Predict the Prognosis of Patients With Resectable Oral Squamous Cell Carcinoma.

PURPOSE: Texture analysis is a computer-assisted technique used to measure intratumoral heterogeneity, which is known to have important roles in cancer research. This study aimed to assess the potential prognostic values of textural features extracted from preoperative 18F-fluorodeoxyglucose positron emission tomography images in patients with resectable oral squamous cell carcinoma. PATIENTS AND METHODS: This retrospective cohort study included patients with oral squamous cell carcinoma who underwent resection surgery. We extracted 31 textural indices from preoperative positron emission tomography images. Overall survival (OS) and disease-free survival (DFS) were chosen as the primary outcome variables, and the primary predictor variables were age, sex, primary tumor location, pathological T and N classification, histologic differentiation, resected margin, perineural and lymphovascular invasion, maximum standardized uptake value, and the 14 textural indices selected in the factor analysis. We analyzed OS and DFS using Kaplan-Meier curves, and the differences between survival curves were determined using a log-rank test. The independent prognostic factors were assessed using the Cox-proportional hazards model. RESULTS: We enrolled 81 patients (median age, 67.3 years; range, 32 to 88 years). The median follow-up duration was 50.1 months (range, 6.3 to 133.7 months). The univariable and multivariable analyses revealed that higher entropy values (≥1.91) were associated with worse OS (hazard ratio, 21.49; 95% confidence interval, 1.36 to 340.71; P = .03) and DFS (hazard ratio, 50.69; 95% confidence interval, 5.23 to 491.18; P = .001). CONCLUSIONS: This study showed that entropy is a statistically significant prognostic factor of both OS and DFS. Texture analysis using preoperative positron emission tomography images may contribute to risk stratification.

Liver stiffness does not affect ultrasound-guided attenuation coefficient measurement in the evaluation of hepatic steatosis.

AIM: Recently, a new method has been developed to diagnose hepatic steatosis with attenuation coefficients based on the ultrasound-guided attenuation parameter (UGAP). We investigated whether fibrosis identified by hepatic stiffness measurements based on magnetic resonance elastography (MRE) affects attenuation coefficient measurement using UGAP for the evaluation of hepatic steatosis. METHODS: A total of 608 patients with chronic liver disease were analyzed. Correlations between magnetic resonance imaging-determined proton density fat fraction (PDFF) or MRE value and attenuation coefficients were evaluated. In addition, the interaction between hepatic fibrosis and the attenuation coefficient was analyzed. RESULTS: The correlation coefficient (r) between PDFF values and attenuation coefficient values was 0.724, indicating a strong relationship. Conversely, the r between MRE values and attenuation coefficient values was -0.187, indicating almost no relationship. In the multiple regression assessment of the effect of PDFF and MRE on the attenuation coefficient based on UGAP, the P-values for PDFF, MRE, and PDFF × MRE were < 0.001, 0.277, and 0.903, respectively. In patients with non-alcoholic fatty liver disease (n = 169), the r between PDFF values and attenuation coefficient values was 0.695, indicating a moderate relationship. Conversely, the r between MRE values and attenuation coefficient values was -0.068, indicating almost no relationship. In the multiple regression assessment of the effect of PDFF and MRE on the attenuation coefficient based on UGAP, the P-values for PDFF, MRE, and PDFF × MRE were <0.001, 0.948, and 0.706, respectively. CONCLUSION: UGAP-determined attenuation coefficient was weakly affected by liver stiffness, an indicator of hepatic fibrosis.

The emergence of non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI in patients with chronic hepatitis C.

BACKGROUND: Intrahepatic non-hypervascular hypointense nodules (NHHNs) detected during the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have the potential to transition into typical hypervascular hepatocellular carcinoma (HCC). However, the incidence and risk factors for the emergence of these nodules in patients with chronic hepatitis C virus (HCV) infection are unknown. AIM: To investigate the incidence and risk factors for NHHNs in patients with chronic HCV infection in a longitudinal follow-up study METHODS: EOB-MRI was performed in 608 patients with chronic HCV infection and no history of HCC. The characteristics of patients with and without NHHNs were compared. In patients without NHHNs at baseline, the incidence of NHHN emergence and associated risk factors were analysed. RESULTS: NHHNs were detected at baseline in 93 of 608 patients (15.3%). Among 515 patients without NHHNs at baseline, the 1-year, 3-year and 5-year incidence of NHHN emergence was 1.8%, 9.8% and 16.4%, respectively. Only FIB-4 index was independently associated with the emergence of NHHNs in multivariate analyses. Whereas NHHNs emerged in 24.1% of patients with FIB-4 index ≥ 3.25 at 5 years, none emerged in patients with FIB-4 index < 1.45. CONCLUSION: In patients with chronic HCV infection, advanced liver fibrosis is an important risk factor for the presence or emergence of NHHNs.

The course of elderly patients with persistent hepatitis C virus infection without hepatocellular carcinoma.

BACKGROUND: Little is known about the course of elderly patients with persistent hepatitis C virus (HCV) infection. We investigated the course of HCV infection in this patient population. METHODS: Among 9,126 HCV antibody-positive patients who visited our hospital between 1995 and 2015, there were 453 patients with continuous follow-up who survived to age 80. They were included in the study following the inclusion criteria: confirmed persistent detection of HCV RNA, no HCV eradication if anti-HCV therapy occurred before enrollment, and no development of hepatocellular carcinoma (HCC) before enrollment. For all study patients, baseline was defined as the date when they turned 80. Mortality rates after the age of 80 years and cause of death were analyzed. RESULTS: During the study period, 155 patients (34.2%) died. Median survival time (MST) after age 80 was 8.8 years, which was comparable to that of the general population (10.1 years). Among 155 deceased patients, the majority (115 patients, 74.2%) died due to non-liver-related disease, followed by HCC (28 patients, 18.1%) and liver-related disease other than HCC (12 patients, 7.7%). Patients with advanced liver fibrosis (FIB-4 index > 3.25, n = 245) had shorter MST than patients with mild liver fibrosis (FIB-4 index ≤ 3.25, n = 208) (7.1 vs. 10.2 years; p = 0.020) due to a higher mortality rate from liver-related complications, including HCC. CONCLUSION: Most elderly HCV patients die from non-liver-related disease, especially those with less advanced liver fibrosis.

Type 2 diabetes mellitus: A risk factor for progression of liver fibrosis in middle-aged patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIM: The severity of liver fibrosis is strongly associated with prognosis in patients with non-alcoholic fatty liver disease (NAFLD). We evaluated clinical risk factors for progression of liver fibrosis in patients with NAFLD. METHODS: This study included 1562 middle-aged (36-64 years) patients with NAFLD and less severe liver fibrosis (fibrosis-4 index < 1.3). RESULTS: During follow-up, 186 patients progressed to advanced fibrosis (fibrosis-4 index > 2.67). The 3-, 5-, 7-, and 10-year cumulative incidence of progression to advanced fibrosis was 4.4%, 6.7%, 11.0%, and 16.7%, respectively. In the univariate analysis, age, albumin concentration, and type 2 diabetes mellitus (T2DM) were significantly associated with progression to advanced fibrosis. Multivariate analysis with adjustment for age, smoking, body mass index, albumin, estimated glomerular filtration rate, dyslipidemia, T2DM, and steatosis showed that age ≥ 50 years (hazard ratio [HR], 2.121; 95% confidence interval [CI], 1.462-3.076; P < 0.001), albumin concentration < 4.2 g/dL (HR, 1.802; 95% CI, 1.285-2.528; P < 0.001), and the presence of T2DM (HR, 1.879; 95% CI, 1.401-2.520; P < 0.001) were independently associated with progression to advanced fibrosis. Conversely, degree of steatosis was not associated with progression to advanced fibrosis. The respective 3-, 5-, 7-, and 10-year cumulative incidence of progression to advanced fibrosis was 3.6%, 5.0%, 8.2%, and 12.9% in patients without T2DM (n = 1077) and 6.1%, 10.4%, 16.7%, and 24.0% in patients with T2DM (n = 485) (P < 0.001). CONCLUSIONS: Type 2 diabetes mellitus is associated with progression to advanced liver fibrosis in middle-aged NAFLD patients, even those with less severe liver fibrosis.

The prognostic significance of intratumoral heterogeneity of 18F-FDG uptake in patients with oral cavity squamous cell carcinoma.

PURPOSE: This study aimed to evaluate the prognostic significance of two major indices of intratumoral heterogeneity of 18F-fluorodeoxyglucose uptake by positron emission tomography (PET)/computed tomography (CT), namely heterogeneity index (HI) and heterogeneity factor (HF), in patients with oral squamous cell carcinoma. METHODS: We performed a retrospective analysis of 62 patients who underwent resective surgery. HI, HF, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained from pretreatment PET. HI was obtained by dividing SUVmax by SUVmean for the primary lesion; HF was obtained by taking the derivative (dV/dT) of the volume-threshold function from 30 to 70%. Univariate and multivariate analyses for the overall survival (OS) and disease-free survival (DFS) were performed using PET and clinicopathological parameters. RESULTS: Univariate and multivariate analyses of OS revealed that higher HI levels (threshold for the SUVmean is 30% of the SUVmax) were associated with poorer OS [hazard ratio (HR) = 11.57; 95% confidence interval (CI) = 1.45-92.28; P = 0.021]. Moreover, univariate and multivariate analyses of DFS revealed that higher TLG levels (threshold for the MTV and SUVmean is 4.0 of the SUV) were associated with poorer DFS (HR = 14.48; 95% CI = 1.27-164.78; P = 0.031). CONCLUSIONS: HI and TLG may be statistically significant prognostic factors for OS and DFS, respectively.

Utility of Attenuation Coefficient Measurement Using an Ultrasound-Guided Attenuation Parameter for Evaluation of Hepatic Steatosis: Comparison With MRI-Determined Proton Density Fat Fraction.

OBJECTIVE: Recently, a new method was developed to diagnose hepatic steatosis by measuring attenuation coefficients that are based on the ultrasound-guided attenuation parameter (UGAP). We investigated the diagnostic ability of these coefficients to detect steatosis that was identified using the proton density fat fraction (PDFF) on MRI in patients with chronic liver disease. MATERIALS AND METHODS: A total of 126 patients with chronic liver disease (non-hepatitis B, non-hepatitis C) were analyzed. The diagnostic ability of UGAP-determined attenuation coefficients was evaluated using ROC curve analysis, and the correlation between MRI-determined PDFF values and attenuation coefficient values was determined. RESULTS: The correlation coefficient (r) between PDFF values and attenuation coefficient values was 0.746 (95% CI, 0.657-0.815) (p < 0.001), corresponding to a strong relationship. The diagnostic ability of attenuation coefficients for steatosis grades ≥ 1, ≥ 2, and 3 as determined by PDFF were 0.922 (95% CI, 0.870-0.973), 0.874 (95% CI, 0.814-0.934), and 0.892 (95% CI, 0.835-0.949), respectively. The r between PDFF values and attenuation coefficient values was 0.559 (95% CI, 0.391-0.705) (p < 0.001) in patients with mild or no steatosis (grade ≤ 1). In addition, the r between PDFF values and attenuation coefficient values was 0.773 (95% CI, 0.657-0.853) (p < 0.001) in obese patients (body mass index [weight in kilograms divided by the square of height in meters] ≥ 25). The diagnostic ability of attenuation coefficients for patients with steatosis grades ≥ 1, ≥ 2, and 3 as determined by PDFF were 0.884 (95% CI, 0.792-0.976), 0.863 (95% CI, 0.778-0.947), and 0.889 (95% CI, 0.813-0.965), respectively. CONCLUSION: UGAP-determined attenuation coefficient values had a good diagnostic ability to detect hepatic steatosis.

Functional expansion of a TCA cycle operon mRNA by a 3' end-derived small RNA.

Global RNA profiling studies in bacteria have predicted the existence of many of small noncoding RNAs (sRNAs) that are processed off mRNA 3' ends to regulate other mRNAs via the RNA chaperones Hfq and ProQ. Here, we present targets of SdhX (RybD), an Hfq-dependent sRNA that is generated by RNase E mediated 3' processing of the ∼10 000-nt mRNA of the TCA cycle operon sdhCDAB-sucABCD in enteric bacteria. An in silico search predicted ackA mRNA, which encodes acetate kinase, as a conserved primary target of SdhX. Through base pairing, SdhX represses AckA synthesis during growth of Salmonella on acetate. Repression can be achieved by a naturally occurring 38-nucleotide SdhX variant, revealing the shortest functional Hfq-associated sRNA yet. Salmonella SdhX also targets the mRNAs of fumB (anaerobic fumarase) and yfbV, a gene of unknown function adjacent to ackA. Instead, through a slightly different seed sequence, SdhX can repress other targets in Escherichia coli, namely katG (catalase) and fdoG (aerobic formate dehydrogenase). This study illustrates how a key operon from central metabolism is functionally connected to other metabolic pathways through a 3' appended sRNA, and supports the notion that mRNA 3'UTRs are a playground for the evolution of regulatory RNA networks in bacteria.

The impact of HCV eradication by direct-acting antivirals on the transition of precancerous hepatic nodules to HCC: A prospective observational study.

BACKGROUND & AIMS: It remains controversial whether the eradication of hepatitis C virus (HCV) by interferon (IFN)-free anti-HCV therapy using direct-acting antivirals (DAAs) suppresses or promotes hepatocellular carcinoma (HCC) development. We investigated the influence of HCV eradication by DAA therapy on HCC development, by observing changes of non-hypervascular hypointense nodules (NHHNs) by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI). METHODS: A total of 401 patients treated with DAA therapy who did not have a history of HCC were enrolled in this prospective cohort study. All patients underwent EOB-MRI prior to the start of DAA therapy and were followed up periodically after therapy. The progression of NHHNs detected at baseline to typical HCC, as indicated by hypervascularization and the incidence of newly emergent NHHNs, was analyzed. RESULTS: In comparison of patients who achieved sustained virologic response (SVR) with propensity score-matched patients with persistent HCV infection, there was no difference in the incidence of hypervascularization of NHHNs to typical HCC among patients who had NHHNs at baseline. Among patients who did not have NHHNs at baseline, the incidence of the new emergence of NHHNs did not differ between study patients and propensity score-matched patients with persistent HCV infection. CONCLUSIONS: During a 2-year observation period after SVR, the eradication of HCV by IFN-free DAA therapy did not suppress or enhance HCC development. (UMIN000017020).

Impact of previously cured hepatocellular carcinoma (HCC) on new development of HCC after eradication of hepatitis C infection with non-interferon-based treatments.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in patients with a history of curatively-treated HCC is higher than in patients with no history of HCC even after sustained virologic response (SVR). AIM: To investigate differences in the patterns of HCC development after SVR in patients with a history of curatively-treated HCC and those with no history of HCC, based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) findings. METHODS: EOB-MRI was performed in 164 patients with HCV cirrhosis who achieved SVR by interferon-free direct-acting antiviral (DAA) therapy just before the start of therapy. Changes in EOB-MRI findings after SVR were compared prospectively between patients with (n = 62) and without (n = 102) a history of HCC. RESULTS: The incidence of HCC after SVR was higher in patients with a history of HCC (P < 0.0001). The prevalence of nonhypervascular hypointense nodules (NHHNs) by EOB-MRI was significantly higher in patients with a history of HCC at baseline (P = 0.05). Although there was no difference in the incidence of the hypervascularisation of baseline NHHNs to typical hypervascular HCC between patients with and without a history of HCC, the incidence of direct emergence of hypervascular HCC despite the absence of NHHNs at baseline was significantly higher in patients with a history of HCC (P < 0.0001). CONCLUSION: Direct emergence of hypervascular HCC and a higher prevalence of NHHNs before DD therapy contributed to the higher incidence of HCC after SVR. (UMIN000017020).

Differences in the impact of prognostic factors for hepatocellular carcinoma over time.

The aim of the present study was to evaluate the prognostic significance of serum markers that reflect tumor progression, liver function, or liver fibrosis in patients with hepatocellular carcinoma (HCC), focusing on how their impact changes over time after diagnosis. Alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), albumin-bilirubin (ALBI) score, aspartate aminotransferase to platelet ratio index (APRI), and FIB-4 index were measured at the time of initial non-recurrent HCC diagnosis in 1669 patients between 1997 and 2016. Survival rates after diagnosis were compared after stratifying patients by these markers. Time-dependent receiver-operating characteristics (ROC) analysis was carried out to assess how these markers predict patient survival or death. Serum AFP and DCP levels, ALBI score, and APRI and FIB-4 index were strongly correlated with HCC progression, liver function, and degree of liver fibrosis, respectively. Survival rates after diagnosis were significantly different when patients were stratified by these markers. In the time-dependent ROC analysis, AFP and DCP had a high prognostic impact within 3 years of diagnosis but the impact decreased thereafter. In contrast, APRI and FIB-4 index had higher prognostic impact 10 years after diagnosis. ALBI score had a high prognostic impact throughout the study period. Time-dependent ROC analysis clearly showed changes in the prognostic importance of serum markers based on the duration after diagnosis. Whereas the prognostic impact of tumor progression markers was strong in the short term, liver fibrosis markers had higher prognostic impact long after diagnosis. Liver function had constant prognostic impact on patient survival after diagnosis.

Improvement of liver stiffness in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response.

BACKGROUND AND AIM: There is insufficient research on whether direct-acting antiviral (DAA) therapy can improve liver fibrosis in patients with chronic hepatitis C virus (HCV). We evaluated sequential changes in liver stiffness using shear wave elastography in patients with HCV who received DAA therapy. METHODS: A total of 210 patients with HCV who received daclatasvir and asunaprevir therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness, as evaluated by shear wave elastography, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), and at 24 weeks after EOT (SVR24). RESULTS: Alanine aminotransferase levels (ALT) decreased over time, and there were significant differences between baseline and EOT and between EOT and SVR24. Although platelet counts did not significantly differ between baseline and EOT, they increased significantly from EOT to SVR24. The median (interquartile range) liver stiffness values at baseline, EOT, and SVR24 were 10.2 (7.7-14.7), 8.8 (7.1-12.1), and 7.6 (6.3-10.3) kPa, respectively (P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). Additionally, in patients with ALT ≤ 30 (indicating low necroinflammatory activity in the liver) and Fibrosis-4 index > 2.0 (n = 75), the liver stiffness values at baseline, EOT, and SVR24 were 9.6 (7.7-15.2), 9.2 (7.3-12.1), and 7.7 (6.3-10.1) kPa, respectively (P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). CONCLUSION: These results suggest that early improvement of liver stiffness starts during the administration of DAAs in patients who achieve SVR, and this effect is particularly pronounced in patients with progressive liver fibrosis.

Discrepant imaging findings of portal vein thrombosis with dynamic computed tomography and computed tomography during arterial portography in hepatocellular carcinoma: possible cause leading to inappropriate treatment selection.

We encountered a patient with hepatocellular carcinoma who had discrepant imaging findings on portal vein thrombosis with portal phase dynamic computed tomography (CT) and CT during arterial portography (CTAP). CTAP, via the superior mesenteric artery and via the splenic artery, both showed a portal perfusion defect in the right hepatic lobe, indicating portal vein thrombosis in the main trunk of the right portal vein. Portal phase dynamic CT clearly depicted portal perfusion of the same hepatic area. Transarterial chemoembolization was successfully performed, but it was associated with severe liver injury. Clinicians should be cautious about this possible discrepancy based on imaging technique. The inaccurate evaluation of portal vein thrombosis may result in inappropriate treatment selection, which can worsen patient prognosis.

Progression of liver fibrosis is associated with non-liver-related mortality in patients with nonalcoholic fatty liver disease.

In patients with nonalcoholic fatty liver disease (NAFLD), prognosis and outcome, especially non-liver-related mortality, remain incompletely elucidated. We clarified the mortality from all causes in patients with NAFLD. A total of 4,073 patients with NAFLD diagnosed by ultrasonography were enrolled. We investigated the causes of death and analyzed the mortality from non-liver-related diseases according to the degrees of steatosis and fibrosis using the competing risk method. We used the NAFLD fibrosis score (NFS) to assess fibrosis severity and the ultrasonography fatty liver score to evaluate steatosis severity. The numbers of patients with NFS indicating low, intermediate, and high probabilities of advanced fibrosis were 2,451 (60.2%), 1,462 (35.9%), and 160 (3.9%), respectively. Of the 4,073 patients, 179 died during follow-up, but only nine deaths were due to liver-related diseases. Of the remaining 170 patients who died due to non-liver-related diseases, 83 (48.8%), 42 (24.7%), and 45 (26.5%) patients died due to malignancies, cerebrovascular and cardiovascular diseases, and benign diseases (excluding cerebrovascular and cardiovascular diseases), respectively. Multivariate analysis showed that the intermediate and high NFS groups were independently associated with each disease category: hazard ratio (HR) 2.163 (95% confidence interval [CI], 1.354-3.457) and HR 4.814 (95% CI, 2.323-9.977) for malignancies; HR 2.265 (95% CI, 1.141-4.497) and HR 8.482 (95% CI, 3.558-20.220) for cerebrovascular and cardiovascular diseases; and HR 3.216 (95% CI, 1.641-6.303) and HR 5.558 (95% CI, 1.923-16.070) for benign diseases, respectively. Conversely, the status of steatosis was not associated with risk of mortality in multivariate analysis. Conclusion: Progression of liver fibrosis severity was associated with mortality from various non-liver-related causes in patients with NAFLD. (Hepatology Communications 2017;1:928-945).

Extra-hepatic feeding arteries of hepatocellular carcinoma: An investigation based on intra-arterial CT aortography images using an angio-MDCT system.

OBJECTIVES: We investigated the frequencies and factors associated with the presence of extra-hepatic feeding arteries (EHFAs) of hepatocellular carcinoma (HCC) using intra-arterial CT aortography images. METHODS: A total of 173 patients with HCC who underwent transarterial chemoembolization (TACE) in our institution between January 2013 and March 2015 were enrolled. The types of EHFAs were evaluated by CT aortography images using an apparatus that combines multidetector-row computed tomography and angiography system. In addition, factors associated with the presence of EHFAs were determined. RESULTS: EHFAs were present in 22 (12.7%) patients with HCC. EHFAs most frequently branched from the right inferior phrenic artery (n=19), while others branched from the right adrenal artery (n=2), right renal artery (n=2), right internal thoracic artery (n=2), branches of the superior mesenteric artery (n=1), and an unknown artery from the aorta (n=1). Factors significantly associated with the presence of EHFAs in multivariate analysis were tumor size≥30mm (odds ratio (OR), 5.233 [95% confidence interval (CI), 1.507-17.413]; p=0.009) and number of prior TACE treatments≥3 (OR, 6.847 [95% CI, 1.928-24.311]; p=0.003). CONCLUSIONS: EHFAs of HCC were assessed with CT aortography images. Repeat TACE treatments and large tumor size were risk factors for the presence of EHFAs.

Utility of combined gray-scale and perflubutane contrast-enhanced ultrasound for diagnosing early hepatocellular carcinomas: Comparison of well differentiated and distinctly nodular types.

AIM: To clarify the value of gray-scale ultrasound (US) combined with contrast-enhanced US (CEUS) with perflubutane in diagnosing early hepatocellular carcinoma (HCC). METHODS: A total of 57 surgically resected, well differentiated HCCs were analyzed. Hepatocellular carcinomas were macroscopically diagnosed as vaguely nodular or distinctly nodular types, which correspond to early HCC or progressed HCC, respectively. Gray-scale US findings were evaluated in terms of shape (round or roundish, or irregular), border and contour (well-defined and smooth, or poorly defined), and intratumor echo levels (hyper, hypo, iso, heterogeneous, or mosaic). Contrast-enhanced US findings were evaluated during the arterial phase (vascularity [finely homogeneous, dendritic, or chaotic] and perfusion enhancement [homogeneous or heterogeneous]), portal phase (presence or absence of washout), and post-vascular phase (echo intensity level [defect, incomplete defect, or iso-enhancing]). RESULTS: Eighteen HCCs were categorized as early HCCs and the remaining 39 were categorized as progressed HCCs. Receiver operating characteristic curve analysis for the diagnosis of early HCC yielded area under the receiver operating characteristic curve (Az ) values for border and contour on gray-scale US and echo intensity level in the CEUS post-vascular phase of 0.782 and 0.828, respectively. Multiple logistic regression analysis also indicated that both of these gray-scale US and CEUS findings were independently associated with early HCC. The Az value for the combination of border and contour and echo intensity for the diagnosis of early HCC was 0.907, corresponding to a high diagnostic value. CONCLUSION: The combination of gray-scale US and CEUS can provide high-quality imaging assessment for diagnosing early HCC.

Utility of Contrast-enhanced Ultrasonography with Perflubutane for Determining Histologic Grade in Hepatocellular Carcinoma.

The purpose of this study was to clarify the diagnostic value of contrast-enhanced ultrasonography (CEUS) with perflubutane in determining the histologic grade in hepatocellular carcinoma (HCC). A total of 147 surgically resected HCCs were dichotomized as well differentiated HCC (wd-HCC) and moderately- or poorly-differentiated HCC (mp-HCC). CEUS findings were evaluated during the arterial phase (vascularity, level and shape of enhancement), portal phase (presence or absence of washout) and post-vascular phase (echo intensity and shape). Receiver operating characteristic (ROC) curve analysis for the diagnosis of mp-HCC yielded area under the ROC curve (Az) values for arterial phase vascularity and portal phase washout of 0.910 and 0.807, respectively. The Az value for the combination of vascularity and washout for the diagnosis of mp-HCC was 0.956 (95% confidence interval, 0.910-0.979), corresponding to high diagnostic value. In conclusion, CEUS can provide high-quality imaging assessment for determining the histologic grade of HCCs.