Hiroyuki Takabatake

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.

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.

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 β-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.

Soluble HLA Class I antigens in sera of patients with chronic hepatitis

SummarySoluble HLA Class I antigens in sera (serum-HLA Class I, s-HLA Class I) of patients with chronic hepatitis (CH) were measured with an enzyme-linked double determinant immunoassay (EDDIA). The mean titers of s-HLA Class I antigens of patients with CPH (mean±standard deviation, 2.22±1.60), CAH2A (2.24±1.65) or CAH2B (2.73±1.46) were significantly higher than that of normal subjects (0.36±0.27) (P< 0.01). The titer of s-HLA Class I correlated significantly with the level of serum glutamic pyruvic transaminase (s-GPT) (r=0.73), and weakly with serum level of β2-microglobulin (r=0.43). In patients with chronic hepatitis type B (CH-B) treated with human lymphoblastoid interferon alpha (IFNα), the titer of s-HLA Class I antigens increased. The increased level of s-HLA Class I antigens in the clinical course of chronic hepatitis may be caused by their release from necrotizing hepatocytes which have acquired the expression of HLA Class I antigens on the cell-surface membrane during viral infection.

Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma

Background:We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort.Methods:In the current retrospective cohort study, we measured serum levels of the eightcytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS).Results:Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21–2.81), and OS (HR, 1.95; 95% CI, 1.21–3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30–3.06) and OS (HR, 1.94; 95% CI, 1.19–3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis.Conclusion:High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.

Promotion of Spheroid Assembly of Adult Rat Hepatocytes by Some Factor(s) Present in the Initial 6-Hour Conditioned Medium of the Primary Culture

Adult rat hepatocytes are capable of assembling to form floating multicellular spheroids (spheroids) in a dish with a positively charged surface in primary culture. In this report we show that the conditioned medium of the early time period of the culture exhibited biologically defined activity that promoted the assembly of isolated hepatocytes to floating spheroid. This activity was present only in the initial 6-hour conditioned medium; it was highest in the initial 2 h of culture and gradually decreased over 6 h and was not detected thereafter for 7 days. The conditioned medium appeared to inhibit the disintegration of spheroids that occurred during transfer to a new positively charged dish in the presence of either new or conditioned medium collected after day 4. Furthermore, disintegrated spheroids again assembled to form floating spheroid in the presence of the conditioned medium. Since the activity present in the conditioned medium was linearly dose-responsive to the inoculated viable cell number but not to that of dead cells, some factors responsible for the activity were probably produced by the viable cells during only a short time in culture.

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.

Prediction of oesophageal variceal bleeding by measuring spleen stiffness in patients with liver cirrhosis

Letter to the Editor We read with interest the guidelines by Tripathi et al 1 and the leading article by Rosselli et al ,2 reporting the role of transient elastography for the diagnosis of oesophageal varices (OV). Before screening endoscopy, non-invasive measures are needed to ascertain cirrhotic patients at high risk for oesophageal variceal bleeding (OVB) to decrease the number receiving unnecessary prophylactic treatments. In our recent study,3 spleen stiffness (SS) evaluated by acoustic radiation force impulse (ARFI) imaging was shown to be closely correlated with the presence of OV. This study aimed to evaluate SS determined by ARFI imaging as a predictor of OVB. We measured SS in 446 cirrhotic patients and followed them prospectively at Kurashiki Central Hospital between 2010 and 2014. We examined the diagnostic accuracy of SS for predicting OVB …

Idiotypic diversity and variable region gene usage by mouse anti-HLA-DQ3 mAb

The anti-HLA-DQ3 monoclonal antibodies (mAb) KS13, SO1, SO2, SO3, SO4, and SO5 recognize spatially close but distinct antigenic determinants, since they crossinhibit each other in their binding to HLA-DQ3 antigens, but do not share idiotopes recognized in their antigen combining site by syngeneic and anti-id antisera and mAb. Furthermore, mAb SO1, SO3, SO4, and SO5 react also with HLA-DQ allospecificities other than HLA-DQ3. Sequence analysis of the heavy (VH) and light (VL) chain variable region of the six mAb revealed preferential usage of VH 36–60 and VK 12/13 gene families. However, the individual VH and VL germline gene usage by the six mAb is diverse and the utilization of D, JH, and JL gene segments is heterogeneous. The diverse usage of VH and VL gene segments and heterogeneous amino acid sequences of VH and VL CDR, together with the heterogeneous idiotypic profile, may reflect the complexity of the determinants recognized by the six mAb on HLA-DQ3 antigens. The results we have presented provide for the first time information about the structural basis of the diversity of antibodies recognizing human histocompatibility antigens.

Classification of hepatitis C virus into subgroups on the basis of sequence variations in the envelope protein

In order to investigate the possibility that hepatitis C virus (HCV) can be classified into subgroups based on the variations in the envelope region, the nucleotide and deduced amino acid sequences were compared among the reported viral isolates including HCV1, HCJ1, HCJ4, HCVJ, HCVBK, HCVNK and HCJ6. From the homology analysis, the HCV isolates were classified into three subgroups: group I (HCV1 and HCJ1); group II (HCJ4, HCVJ, HCVBK and HCVNK); and group III (HCJ6). Furthermore, two novel regions were found in the E1 envelope region. One is located at aa246–258 (intersubtype variable region 1; ISVR‐1) where the amino acid sequences were relatively conserved within each subgroup, while the sequences were extremely different among the subgroups. Another is located at aa315–328 (intersubgroup common region‐1; ISCR‐1) where the amino acid sequences were completely identical among all seven HCV isolates despite the fact that the marked variations were distributed throughout the envelope region. The results suggest that the combination of ISVR‐1 and ISCR‐1 can be utilized as marker sequences for the classification of HCV strains and that the letter region might be one of the candidates for the vaccine.