Changes in Liver and Spleen Stiffness by Virtual Touch Quantification Technique after Balloon-Occluded Retrograde Transvenous Obliteration of Gastric Varices and Exacerbation of Esophageal Varices: A Preliminary Study.

PURPOSE: To assess liver stiffness (LS) and spleen stiffness (SS) values measured by virtual touch quantification (VTQ) technique in the monitoring of portal pressure and their usefulness for the prediction of the exacerbation of esophageal varices (EV) in patients with gastric varices undergoing balloon-occluded retrograde transvenous obliteration (B-RTO). MATERIALS AND METHODS: The LS, SS, and hepatic venous pressure gradient (HVPG) were measured in 20 patients both before and after B-RTO. The change in each parameter between the two groups (EV exacerbation and non-exacerbation groups) was compared by analysis of variance. The efficacy of the parameters for the prediction of the exacerbation of EV was analyzed using a receiver operating characteristic (ROC) curve analysis. RESULTS: 9 patients (40.9 %) exhibited an exacerbation of EV within 24 months after B-RTO. Significant changes were observed in the HVPG and SS after B-RTO between the two groups (EV exacerbation group vs. non-exacerbation group: HVPG before 12.7 ±â€Š4.4 mmHg vs. 11.0 ±â€Š4.4 mmHg; HVPG after 19.6 ±â€Š6.0 mmHg vs. 13.6 ±â€Š3.1 mmHg P = 0.003; SS before 3.40 ±â€Š0.50 m/s vs. 3.20 ±â€Š0.51 m/s; SS after 3.74 ± 0.53 m/s vs. 3.34 ±â€Š0.43 m/s P = 0.016). However, no significant changes in LS were observed between the two groups. The area under the ROC curves of elevation in HVPG and SS for the prediction of the exacerbation of EV after B-RTO were 0.833 and 0.818, respectively. CONCLUSION: Elevation of the HVPG and SS measured by VTQ after B-RTO was useful for the prediction of the exacerbation of EV.

Monitoring serum proangiogenic cytokines from hepatocellular carcinoma patients treated with sorafenib.

BACKGROUND AND AIM: Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements before treatment. METHODS: We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. RESULTS: Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen. CONCLUSIONS: Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib.

Measurement of Spleen Stiffness With Acoustic Radiation Force Impulse Imaging Predicts Mortality and Hepatic Decompensation in Patients With Liver Cirrhosis.

BACKGROUND & AIMS: Hepatic venous pressure gradient can predict mortality and hepatic decompensation in patients with cirrhosis. Measurement of hepatic venous pressure gradient requires an invasive procedure; therefore, prognostic markers are needed that do not require invasive procedures. We investigated whether measurements of spleen stiffness, made by acoustic radiation force impulse (ARFI) imaging, associated with mortality and decompensation in patients with cirrhosis, compared with liver stiffness and other markers. METHODS: We measured spleen stiffness in 393 patients diagnosed with cirrhosis (based on histologic or physical, laboratory, and radiologic findings) at a hospital in Japan from September 2010 through August 2013 (280 patients with compensated and 113 patients with decompensated cirrhosis). Patients underwent biochemical, ARFI, ultrasonography, and endoscopy evaluations every 3 or 6 months to screen for liver-related complications until their death, liver transplantation, or the end of the study period (October 2015). The primary outcome was the accuracy of spleen stiffness in predicting mortality and decompensation, measured by Cox proportional hazards model analysis. We compared spleen stiffness with other noninvasive parameters using the Harrell's C-index analysis. RESULTS: During a median follow-up period of 44.6 months, 67 patients died and 35 patients developed hepatic decompensation. In the multivariate analysis, spleen stiffness was an independent parameter associated with mortality, after adjustment for levels of alanine aminotransferase and serum sodium, and the model for end-stage liver disease score (P < .001). Spleen stiffness was associated independently with decompensation after adjustment for Child-Pugh score and model for end-stage liver disease score (P < .001). Spleen stiffness predicted mortality and decompensation with greater accuracy than other parameters (C-indexes for predicting mortality and decompensation were 0.824 and 0.843, respectively). A spleen stiffness cut-off value of 3.43 m/s identified the death of patients with a 95.3% negative predictive value and 75.8% accuracy. A spleen stiffness cut-off value of 3.25 m/s identified patients with decompensation with a 98.8% negative predictive value and 68.9% accuracy. CONCLUSIONS: Spleen stiffness, measured by ARFI imaging, can predict death of patients with cirrhosis with almost 76% accuracy and hepatic decompensation with almost 70% accuracy. It might be a useful noninvasive test to predict patient outcome. UMIN Clinical Trials Registry no. UMIN000004363.

Portal Hypertension in Patients with Liver Cirrhosis: Diagnostic Accuracy of Spleen Stiffness.

PURPOSE: To evaluate the accuracy of spleen stiffness (SS) and liver stiffness (LS) measured by using acoustic radiation force impulse imaging in the diagnosis of portal hypertension in patients with liver cirrhosis, with the hepatic venous pressure gradient (HVPG) as a reference standard. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this prospective single-center study. From February 2012 to August 2013, 60 patients with liver cirrhosis (mean age, 70.8 years; age range, 34-88 years; 34 men, 26 women) with HVPG, LS, and SS measurements and gastrointestinal endoscopy and laboratory data were included if they met the following criteria: no recent episodes of gastrointestinal bleeding, no history of splenectomy, no history of partial splenic embolization, no history of ß-blocker therapy, and absence of portal thrombosis. The efficacy of the parameters for the evaluation of portal hypertension was analyzed by using the Spearman rank-order correlation coefficient and receiver operating characteristic (ROC) curve analysis. RESULTS: The correlation coefficient between SS and HVPG (r = 0.876) was significantly better than that between LS and HVPG (r = 0.609, P < .0001). The areas under the ROC curve of SS for the identification of clinically important portal hypertension (HVPG ≥ 10 mm Hg), severe portal hypertension (HVPG ≥ 12 mm Hg), esophageal varices (EVs), and high-risk EVs were significantly higher (0.943, 0.963, 0.937, and 0.955, respectively) than those of LS, spleen diameter, platelet count, and platelet count to spleen diameter ratio (P < .05 for all). SS could be used to accurately rule out the presence of clinically important portal hypertension, severe portal hypertension, EVs, and high-risk EVs (negative likelihood ratios, 0.051, 0.056, 0.054, and 0.074, respectively). CONCLUSION: SS is reliable and has better diagnostic performance than LS for identifying portal hypertension in liver cirrhosis.

Management of gastroesophageal varices in cirrhotic patients: current status and future directions.

Bleeding from gastroesophageal varices (GEV) is a serious event in cirrhotic patients and can cause death. According to the explosion theory, progressive portal hypertension is the primary mechanism underlying variceal bleeding. There are two approaches for treating GEV: primary prophylaxis to manage bleeding or emergency treatment for bleeding followed by secondary prophylaxis. Treatment methods can be classified into two categories: 1) Those used to decrease portal pressure, such as medication (i.e., nonselective ß-blockers), radiological intervention [transjugular intrahepatic portosystemic shunt (TIPS)] or a surgical approach (i.e., portacaval shunt), and 2) Those used to obstruct GEV, such as endoscopy [endoscopic variceal ligation (EVL), endoscopic injection sclerotherapy (EIS), and tissue adhesive injection] or radiological intervention [balloon-occluded retrograde transvenous obliteration (BRTO)]. Clinicians should choose a treatment method based on an understanding of its efficacy and limitations. Furthermore, elastography techniques and serum biomarkers are noninvasive methods for estimating portal pressure and may be helpful in managing GEV. The impact of these advances in cirrhosis therapy should be evaluated for their effectiveness in treating GEV.

Planning Sonography Using Real-time Virtual Sonography and Contrast-enhanced Sonography for Radiofrequency Ablation of Inconspicuous Hepatocellular Carcinoma Nodules.

BACKGROUND/AIMS: Determining whether planning sonography, using real-time virtual sonography (RVS) and contrast-enhanced sonography (CEUS), enables the identification of inconspicuous HCC nodules on conventional sonography (US), during percutaneous radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODOLOGY: We examined the factors associated with poor conspicuity, identification rate of inconspicuous HCC nodules in planning US using RVS and CEUS, the success rate of RFA for such nodules and local recurrence rates. RESULTS: Sixty inconspicuous HCC nodules were analyzed. Factors associated with poor conspicuity included location of the nodules for 34 nodules, US findings of HCC nodules for 24 nodules, US findings of surrounding hepatic parenchyma for 26 nodules and local recurrence for 18 nodules. Fifty-five (90.0%) HCC nodules were identified with RVS. Of the remaining five HCC nodules, three were visualized with CEUS. Thus, 96.7% (58/60) of the inconspicuous HCC nodules were identified. Forty-six (79.3%) identified HCC nodules, were treated with RFA; the success rate was 95.7% (44/46). The cumulative local recurrence rates were 0%, 2.7% and 9.4% at 12, 24 and 36 months, respectively. CONCLUSIONS: This study suggested that planning US using RVS and CEUS permits the identification of most inconspicuous HCC nodules, thereby improving the success rate of RFA.

Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.

BACKGROUND & AIMS: We evaluated whether spleen stiffness (SS), measured by acoustic radiation force impulse imaging, can identify patients who have esophageal varices (EVs); those without EVs would not require endoscopic examination. METHODS: In a prospective study, we measured SS and liver stiffness (LS) in 340 patients with cirrhosis undergoing endoscopic screening for EVs and 16 healthy volunteers (controls) at the Kurashiki Central Hospital in Okayama, Japan. The diagnostic accuracy of SS for the presence of EVs was compared with that of other noninvasive parameters (LS, spleen diameter, and platelet count). Optimal cutoff values of SS were chosen to confidently rule out the presence of varices. RESULTS: Patients with cirrhosis had significantly higher SS and LS values than controls (P < .0001 and P < .0001, respectively). Levels of SS were higher among patients with EVs (n = 132) than controls, and values were highest among patients with high-risk EVs (n = 87). SS had the greatest diagnostic accuracy for the identification of patients with EVs or high-risk EVs compared with other noninvasive parameters, independent of the etiology of cirrhosis. An SS cutoff value of 3.18 m/s identified patients with EVs with a 98.4% negative predictive value, 98.5% sensitivity, 75.0% accuracy, and 0.025 negative likelihood ratio. An SS cutoff value of 3.30 m/s identified patients with high-risk EVs with a 99.4% negative predictive value, 98.9% sensitivity, 72.1% accuracy, and 0.018 negative likelihood ratio. SS values less than 3.3 m/s ruled out the presence of high-risk varices in patients with compensated or decompensated cirrhosis. SS could not be measured in 16 patients (4.5%). CONCLUSIONS: Measurements of SS can be used to identify patients with cirrhosis with EVs or high-risk EVs. A cutoff SS was identified that could rule out the presence of varices and could be used as an initial noninvasive screening test; UMIN Clinical Trials Registry number, UMIN000004363.

Efficacy of sorafenib beyond first progression in patients with metastatic hepatocellular carcinoma.

AIM: We investigated whether continuous sorafenib administration keeps suppressing the growth of hepatocellular carcinoma (HCC) after first progressive disease (PD), and whether it prolongs patients' survival. METHODS: The size of metastatic lesions was measured in 36 patients with advanced HCC treated with sorafenib. The tumor growth rates before and after radiological PD as well as survival were compared between the patients who continued (n = 23) and stopped (n = 13) sorafenib at first radiological PD. RESULTS: The growth rate did not differ between before and after PD in patients who continued sorafenib, while it increased after PD in patients who stopped sorafenib at PD (P = 0.002). Survival beyond first progression was longer in patients who continued sorafenib than in those who stopped it at PD (P = 0.012), and this tendency was observed even when the analysis was limited to Child-Pugh class A patients (P = 0.085). CONCLUSION: Sorafenib administration beyond first radiological PD could continuously suppress HCC growth and may have survival benefit.

Real-time image fusion for successful percutaneous radiofrequency ablation of hepatocellular carcinoma.

Percutaneous radiofrequency ablation (RFA) is an established nonsurgical curative treatment for hepatocellular carcinoma (HCC). Because of its efficiency and safety, sonography is the most commonly used imaging modality when performing RFA. However, the presence of HCC nodules that are inconspicuous when using conventional sonography is a major drawback of RFA and limits its feasibility as a treatment for HCC. However, a new technology has been developed that synthesizes high-resolution multiplanar reconstruction images using 3-dimensional data and is combined with a position-tracking system using magnetic navigation. With this technology, real-time sonograms can be fused with corresponding computed tomographic, magnetic resonance imaging, or even sonographic volume data; this process is known as real-time image fusion. In this article, we describe this novel imaging method as a useful tool for successful RFA treatment of HCC.

Comparison of combined transcatheter arterial chemoembolization and radiofrequency ablation with surgical resection by using propensity score matching in patients with hepatocellular carcinoma within Milan criteria.

PURPOSE: To retrospectively compare the outcome of combined transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, TACE-RFA) with that of surgical resection (SR) in patients with hepatocellular carcinoma (HCC) within the Milan criteria. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. From January 2000 to December 2010, 154 patients (mean age, 69.9 years; age range, 50-89 years; 107 men, 47 women) underwent TACE-RFA, and 176 patients (mean age, 66.9 years; age range, 29-83 years; 128 men, 48 women) underwent SR. Patients with HCC who underwent TACE-RFA or SR were enrolled if they met the following inclusion criteria: no previous HCC treatment, one HCC lesion no larger than 5 cm or up to three nodules smaller than 3 cm without vascular invasion or extrahepatic metastasis, and Child-Pugh class A or B disease. Cumulative overall survival (OS) and disease-free survival (DFS) rates were compared after adjustment with propensity score matching. RESULTS: After this adjustment, OS rates were comparable between the groups (P = .393), but DFS was superior in the SR group (P < .048). Among patients with very early stage HCC (lesions <2 cm in diameter), OS and DFS rates in the SR group were significantly higher than those in the TACE-RFA group (P < .001 and P = .008, respectively). However, adjustment with propensity score matching yielded comparable OS and DFS rates between the two groups (P = .348 and P = .614, respectively). CONCLUSION: TACE-RFA may be a viable alternative treatment for early-stage HCC when SR is not feasible.

Needle electrode position assessed using three-dimensional ultrasonography and outcome of radiofrequency ablation in hepatocellular carcinoma.

BACKGROUND/AIMS: Radiofrequency ablation (RFA) is an established curative therapy for early-stage hepatocellular carcinoma (HCC). We assessed the positions of inserted needle electrodes using three-dimensional ultrasonography (3D-US) and examined the association between the electrode position and outcomes of RFA. METHODOLOGY: Forty-seven patients with 49 HCC nodules treated with a cooled-tip RFA system were enrolled. Immediately after the first insertion of electrodes, 3D volume data were acquired. After RFA completion, the electrode position was assessed using the data. RESULTS: There were 18 central and 31 marginal pattern nodules. The total number of electrode insertions was significantly greater for the marginal nodules than for the central nodules (p=0.032). In the first session of RFA, 36 HCC nodules (central, n=14; marginal, n=22) were treated with single insertion of electrodes. The ratio of incompletely ablated nodules after the first session was greater for the marginal nodules than for the central nodules (p=0.025). CONCLUSIONS: Our study demonstrated that inserted electrode positions assessed using 3D-US are closely associated with outcomes of RFA and the number of electrode insertions.

[Radiofrequency ablation for hepatocellular carcinoma in elderly patients].

The efficacy and safety of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) were compared between elderly (age≥75 years, n=82) and non-elderly groups (age<75 years, n=158). No significant differences were observed in complications between the two groups. Elderly patients had a lower survival rate compared to the non-elderly patients. Multivariate analysis showed that age was not a significant factor for survival on tumor recurrence. Matching by propensity score revealed no significant differences were observed in survival on tumor recurrence rate. The prognosis of elderly patients undergoing RFA might be considered poorer than that of non-elderly patients. However, when considering the clinical background, RFA might be safe and effective in elderly patients, as well as non-elderly patients.

Prognostic factors in hepatitis C patients with a single small hepatocellular carcinoma after radiofrequency ablation.

BACKGROUND/AIMS: Hepatitis C is a major cause of hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) has been widely performed as a curative treatment for small HCC. The knowledge of prognostic factors in hepatitis C patients with small HCC after RFA is therefore important. METHODOLOGY: One hundred consecutive hepatitis C patients with a single HCC3cm or less treated with RFA were enrolled. The cumulative recurrence and survival rates were calculated using Kaplan-Meier analysis. Prognostic factors were investigated using the Cox proportional hazard mod-el. RESULTS: Five-year local and distant intra hepatic recurrence rates were 10.4% and 70.9%, respectively. Five-year overall survival and recurrence-free survival rates were 60.3% and 15.9%, respectively. Multivarlate analysis revealed that an age of 75 years or more[relative hazard (RH) 1.61, p=0.019] and a serum al-bumin level less than 3.5g/dL (RH 1.61, p=0.016)were significant factors for decreased overall survival. Furthermore, a serum albumin level less than 3.5g/dL (RH 1.50, p=0.003) was the only significant factor for decreased recurrence-free survival. CONCLUSIONS: This study suggests that host-related factors (age and serum albumin level) are important in predicting survival in hepatitis C patients with a single small HCC af-ter RFA.

Outcomes after curative treatment for cryptogenic cirrhosis-associated hepatocellular carcinoma satisfying the Milan criteria.

BACKGROUND AND AIM: The prognosis of cryptogenic cirrhosis-associated hepatocellular carcinoma (CC-HCC) was reported to be poor because many of them were discovered at the advanced stage. The aim of this study is to reveal the clinical features of early CC-HCC. METHODS: Consecutive 36 curatively treated CC-HCC patients satisfying the Milan Criteria were compared with corresponding 211 HCV-associated HCC (HCV-HCC) patients. The clinical background, tumor recurrence rate, overall survival rate, and prognostic values of the patients were assessed. RESULTS: The size of CC-HCCs was larger than that of HCV-HCCs (P = 0.01). The respective tumor recurrence rates at 1, 3, and 5 years were 11%, 32%, and 46% in the CC-HCC, and 21%, 59%, and 81% in the HCV-HCC. The respective overall survival rates at 1, 3, and 5 years were 94%, 85%, and 80% in the CC-HCC, and 98%, 81%, and 61% in the HCV-HCC. CC-HCC patients had a lower tumor recurrence rate and a higher survival rate compared to the HCV-HCC patients (P = 0.001 and P = 0.02, respectively). Via multivariate analysis, significant factors for high recurrence rate were number of HCCs (P = 0.02) and serum alpha fetoprotein levels (P = 0.03) in CC-HCC, whereas multiple tumors (P < 0.001), large tumor size (P = 0.01), and high alanine aminotransferase (P = 0.04) in HCV-HCC. The factor for survival was albumin in both groups. CONCLUSION: The size of CC-HCC was larger than that of HCV-HCC even in patients who received curative treatment; however, the risk for recurrence and the mortality of the patients with CC-HCC was lower than those with HCV-HCC.

Transarterial embolization for ruptured hepatocellular carcinoma: survival predictors.

BACKGROUND/AIMS: Survival predictors in patients with ruptured hepatocellular carcinoma (HCC) treated by transarterial embolization (TAE), have not been fully investigated. METHODOLOGY: Predictors of short-term (< or = 30 days) and long-term (>30 days) survival were evaluated by using the logistic regression model and the Cox proportional hazard model, respectively. RESULTS: Forty-eight patients treated by emergency TAE were enrolled. The median survival time was 231 days. Although hemostasis was attained by TAE in 44 patients (91.7%), 15 patients (31.3%) died within 30 days. In a multivariate analysis, low serum creatinine level (p=0.018) was the only significant predictor of increased short-term survival. Of the 33 patients who survived more than 30 days after TAE, he patic resection was performed in 8, transarterial chemoembolization or chemotherapy in 8, and conservative treatment in 17. In a multivariate analysis, among the 33 who survived, unilateral location of tumors (p=0.041) and low a-fetoprotein level (p=0.004) were significant predictors of increased long-term survival. CONCLUSIONS: Short-term survival of patients with ruptured HCC who were treated by TAE depended on serum creatinine level on arrival. Long-term survival of patients who survived more than 30 days after TAE, was influenced by tumor location and a-fetoprotein level.

[Helicobacter pylori infection and liver diseases].

Recently, it has been shown that Helicobacter infections are associated not only with upper gastrointestinal tract diseases but also with extra-gastrointestinal diseases such as cardiovascular, liver or biliary diseases. The contributions of H. pylori to the development of hepatic encephalopathy and hyperammonemia were reported. Some studies demonstrated the effectiveness of H. pylori eradication therapy in hepatic encephalopathy, but these results have not been supported by other reports. H. pylori eradication therapy for the treatment of hyperammonemia and hepatic encephalopathy has not been recommended. The role of H. pylori infection in cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) is uncertain. Furthermore, the question of whether H. pylori could play a role in the development of hepatoma remains controversial. Our study demonstrated that H. pylori infection was one of the independent risk factors for the development of nonalcoholic fatty liver disease (NAFLD). Further investigation is warranted.

Nomograms to Predict the Disease-free Survival and Overall Survival after Radiofrequency Ablation for Hepatocellular Carcinoma.

Objective The purpose of this study was to construct nomograms for the disease-free survival (DFS) and overall survival (OS) of post-radiofrequency ablation (RFA) patients with hepatocellular carcinoma (HCC). Furthermore, we compared the prognostic predictive ability of these nomograms for estimating per-patient outcomes with that of traditional staging systems. Methods We retrospectively enrolled 298 patients in the training set and 272 patients in the validation set who underwent RFA for HCC. The nomograms for the DFS and OS were constructed from the training set using the multivariate Cox proportional hazards model. The discriminatory accuracy of the models was compared with traditional staging systems by analyzing the Harrell's C-index. Results The DFS nomogram was developed based on the tumor size, tumor number, aspartate aminotransferase (AST), albumin, age, and α-fetoprotein. The OS nomogram was developed based on the tumor size, the model for end-stage liver disease, AST, and albumin. Our DFS and OS nomograms had good calibration and discriminatory abilities in the training set, with C-indexes of 0.640 and 0.692, respectively, that were greater than those of traditional staging systems. The C-indexes of our DFS and OS nomograms were also greater than those of traditional staging systems in the validation set, with C-indexes of 0.614 and 0.657, respectively. RFA patients were stratified into low- and high-risk groups based on the median nomogram scores. High-risk patients receiving surgical resection (SR) were associated with a better DFS and OS than those undergoing RFA. However, the DFS and OS were similar between the low-risk RFA and SR groups. Conclusion We constructed reliable and useful nomograms that accurately predict the DFS and OS after RFA for early-stage HCC patients. These graphical tools are easy to use and will assist physicians during the therapeutic decision-making process.