Detection Of Hepatocellular Carcinoma In Patients Research Articles

Validation of the Hepatocellular Carcinoma Early Detection Screening (HES) Algorithm in a Cohort of Veterans With Cirrhosis

Early detection of hepatocellular carcinoma (HCC) through surveillance reduces mortality associated with this cancer. Guidelines recommend HCC surveillance every 6 months for patientswith cirrhosis, via ultrasonography, with or without measurement of serum level of alpha fetoprotein (AFP). We previously developed and internally validated an HCC early detection screening (HES) algorithm that included patient's current level of AFP, rate of AFP change, age, level of alanine aminotransferase, and platelet count in a department of Veterans affairs (VA) cohort with active hepatitis C virus-related cirrhosis. HES score was associated with 3.84% absolute improvement in sensitivity of detection of HCC compared with AFP alone, at 90% specificity, within 6 months prior to diagnosis of this cancer. We externally validated the HES algorithm in a cohort of 38,431 patients with cirrhosis of any etiology evaluated at a VA medical center from 2010 through2015. A total of 4804 cases of HCC developed during a median follow-up time of 3.12 years. At 90% specificity, the HES algorithm identified patients with HCC with 52.56% sensitivity, compared to 48.13% sensitivity for the AFP assay alone, within 6 months prior to diagnosis; this was an absolute improvement of 4.43% (P < .0005). In HCC screening, a positive result leads to follow-up evaluation by computed tomography or magnetic resonance imaging. We estimated that the number of HCC cases detected per 1000 imaging analyses was 198.57 for the HES algorithm vs 185.52 for the AFP assay alone, or detection of 13 additional cases of HCC (P < .0005). We validated the HES algorithm in detection of HCC in patients with cirrhosis of any etiology evaluated at VA medical centers. The algorithm offers a modest but useful advantage over AFP alone in HCC surveillance.

Performance of protein induced by vitamin K absence or antagonist-II assessed by chemiluminescence enzyme immunoassay for hepatocellular carcinoma detection: a meta-analysis

Objectives: In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development.Materials and methods: We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA).Results: A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746–0.837) and 0.767 (0.732–0.803), respectively. The combination of PIVKA-II + AFP results in a sAUC of 0.859 (0.837–0.882). The performance for HCC detection of PIVKA-II + AFP was significantly superior to each biomarker used alone (ΔsAUC = 0.068, p = .032 and ΔsAUC = 0.092, p < .001, respectively).Conclusion: In clinical practice, the use of PIVKA-II + AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.

Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis

Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the performance of surveillance imaging, with or without alpha fetoprotein (AFP), for early detection of HCC in patients with cirrhosis. Two reviewers searched MEDLINE and SCOPUS from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Thirty-two studies (comprising 13,367 patients) characterized sensitivity of imaging with or without AFP measurement for detection of HCC in patients with cirrhosis. Ultrasound detected any stage HCC with 84% sensitivity (95% confidence interval [CI] 76%-92%), but early-stage HCC with only 47% sensitivity (95% CI 33%-61%). In studies comparing ultrasound with vs without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR] 0.88; 95% CI0.83-0.93) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR 0.81; 95% CI 0.71-0.93). However, ultrasound alone detected HCC with a higher levelof specificity than ultrasound plus AFP measurement (RR1.08; 95% CI 1.05-1.09). Ultrasound with vs without AFP detected early-stage HCC with 63% sensitivity (95% CI 48%-75%) and 45% sensitivity (95% CI 30%-62%), respectively (P=.002). Only 4 studies evaluated computed tomography or magnetic resonance image-based surveillance, which detected HCC with 84% sensitivity (95% CI 70%-92%). We found ultrasound alone has a low sensitivity to detect early stage HCC in patients with cirrhosis. Addition of AFP to ultrasound significantly increases sensitivity of early HCC detection in clinical practice.

Serum peroxiredoxin-3 as a useful biomarker for detection of hepatocellular carcinoma

Objective The aim of this study is to evaluate serum peroxiredoxin-3 (PRDX3) as a noninvasive serum marker for the diagnosis of hepatocellular carcinoma (HCC). Background Early diagnosis of HCC is the most important step in successful treatment. However, it is usually rare because of the lack of a highly sensitive and specific biomarker so that the HCC is usually fatal within a few months after diagnosis. PRDX3 is a c-Myc target gene that is required for mitochondrial homeostasis and neoplastic transformation. In our study, we attempted to evaluate the value of PRDX3 as a useful serum biomarker for the detection of HCC. Patients and methods PRDX3, α-fetoprotein (AFP), and other biochemical parameters were measured in serum samples from 50 patients. They were subdivided into three groups: 20 patients with cirrhosis and HCC (group I), 20 patients with liver cirrhosis (LC) without HCC (group II), and 10 healthy controls (group III). Correlations between serum PRDX3 expression and clinicopathological variables were analyzed. Results Serum PRDX3 was significantly higher in HCC patients than in the LC and healthy control groups. The sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 84.2 and 79.8%, respectively, at a cutoff of 162 ng/ml and the area under the curve was 0.877 compared with that of AFP (0.721) with a sensitivity of 70.1% and a specificity of 60%. Moreover, serum PRDX3 expression was strongly associated with AFP levels and focal lesion size. Conclusion Serum PRDX3 level, at a cutoff value of 162 ng/ml, could be a valuable marker for the detection of HCC in patients with LC.

Metabolomic Characterization of Hepatocellular Carcinoma in Patients with Liver Cirrhosis for Biomarker Discovery

Background: Metabolomics plays an important role in providing insight into the etiology and mechanisms of hepatocellular carcinoma (HCC). This is accomplished by a comprehensive analysis of patterns involved in metabolic alterations in human specimens. This study compares the levels of plasma metabolites in HCC cases versus cirrhotic patients and evaluates the ability of candidate metabolites in distinguishing the two groups. Also, it investigates the combined use of metabolites and clinical covariates for detection of HCC in patients with liver cirrhosis.Methods: Untargeted analysis of metabolites in plasma from 128 subjects (63 HCC cases and 65 cirrhotic controls) was conducted using gas chromatography coupled to mass spectrometry (GC-MS). This was followed by targeted evaluation of selected metabolites. LASSO regression was used to select a set of metabolites and clinical covariates that are associated with HCC. The performance of candidate biomarkers in distinguishing HCC from cirrhosis was evaluated through a leave-one-out cross-validation based on area under the receiver operating characteristics (ROC) curve.Results: We identified 11 metabolites and three clinical covariates that differentiated HCC cases from cirrhotic controls. Combining these features in a panel for disease classification using support vector machines (SVM) yielded better area under the ROC curve compared with alpha-fetoprotein (AFP).Conclusions: This study demonstrates the combination of metabolites and clinical covariates as an effective approach for early detection of HCC in patients with liver cirrhosis.Impact: Further investigation of these findings may improve understanding of HCC pathophysiology and possible implication of the metabolites in HCC prevention and diagnosis. Cancer Epidemiol Biomarkers Prev; 26(5); 675-83. ©2016 AACR.

Deregulation of miR-34a and Its Chaperon Hsp70 in Hepatitis C virus-Induced Liver Cirrhosis and Hepatocellular Carcinoma Patients

Background:MicroRNA deregulation may occur during hepatocellular carcinoma (HCC) genesis and progression stages. MicroRNA-34a (miR-34a) functions as a tumor suppressor and is down-regulated or silenced in a variety of human cancers, while heat shock proteins (Hsps) play important roles in assisting protein folding and preventing both protein aggregation and transport across membranes. The present study aimed to evaluating serum expression of miR-34a and its target Hsp70 for early detection of HCC in patients with liver cirrhosis (LC), focusing on correlations with clinicopathological features.Methods:A total of 180 patients were included: 120 with HCC on top of LC (60 with either early or late HCC) and 60 patients with HCV-related LC. In addition, 60 healthy individuals were considered as controls. Real-time polymerase chain reactions were performed for expression profiling of serum miR-34a and Hsp70 and for allelic discrimination of the promotor variant (rs2763979, C/T). In addition, in silico analysis was carried out.Results:All participants were heterozygote for the promotor polymorphism. miR-34a serum levels were significantly under-expressed in LC and especially HCC patients as compared to controls. Associations with a high Child-Turcotte-Pugh (CTP) score, advanced cancer stage, and number of masses were noted. In contrast the target Hsp70 was significantly overexpressed in cancer patients but not in LC group and inversely correlated with miR-34a levels.Conclusion:Utility of circulating miRNAs as biomarkers for early detection of HCC was raised. Future large-scale studies are warranted to confirm the current findings.

The Development of Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). NAFLD-related HCCs (NAFLD-HCCs) have the following clinical features: high body mass index, deranged lipid profiles, diabetes mellitus, hypertension, and metabolic syndrome. Among them, obesity, diabetes mellitus, and high Fe contents in the liver are risk factors of developing HCC in patients with NAFLD. Inflammatory cytokines, adipokines, insulin like growth factor-I, and lipotoxicity are intermingled and may cross react with each other to develop HCC. Because there is no guideline for early detection of HCC in patients with NAFLD, NAFLD-HCCs tend to be greater in size and in advanced stages when detected compared with hepatitis virus-related HCCs. Therefore, there is an urgent need of a surveillance program for the early detection of HCC. Treatment of NAFLD-HCCs is not different from other causes-related HCCs. However, patients with NAFLD-HCCs have cardiovascular disease and other metabolic problems, which may complicate treatment.

Glutathione species and metabolomic prints in subjects with liver disease as biological markers for the detection of hepatocellular carcinoma

BackgroundThe incidence of liver disease is increasing in USA. Animal models had shown glutathione species in plasma reflects liver glutathione state and it could be a surrogate for the detection of hepatocellular carcinoma (HCC). MethodsThe present study aimed to translate methods to the human and to explore the role of glutathione/metabolic prints in the progression of liver dysfunction and in the detection of HCC. Treated plasma from healthy subjects (n = 20), patients with liver disease (ESLD, n = 99) and patients after transplantation (LTx, n = 7) were analyzed by GC- or LC/MS. Glutathione labeling profile was measured by isotopomer analyzes of 2H2O enriched plasma. Principal Component Analyzes (PCA) were used to determined metabolic prints. ResultsThere was a significant difference in glutathione/metabolic profiles from patients with ESLD vs healthy subjects and patients after LTx. Similar significant differences were noted on patients with ESLD when stratified by the MELD score. PCA analyses showed myristic acid, citric acid, succinic acid, l-methionine, d-threitol, fumaric acid, pipecolic acid, isoleucine, hydroxy-butyrate and glycolic, steraric and hexanoic acids were discriminative metabolites for ESLD-HCC+ vs ESLD-HCC− subject status. ConclusionsGlutathione species and metabolic prints defined liver disease severity and may serve as surrogate for the detection of HCC in patients with established cirrhosis.

NAFLD-Associated Hepatocellular Carcinoma: a Threat to Patients with Metabolic Disorders

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its prevalence is increasing in relation to the epidemics of obesity and type 2 diabetes mellitus, via non-alcoholic fatty liver disease (NAFLD). Unhealthy lifestyles associated with metabolic disorders are per se risk conditions for NAFLD progression, and specific gene polymorphisms may also favor oncogenesis, particularly in the presence of advanced fibrosis or cryptogenic cirrhosis. However, NAFLD-associated HCC may also develop in non-cirrhotic NAFLD and is frequently diagnosed at a more advanced tumor stage, compared with virus/alcohol-related HCC. This highlights the need for screening programs and long-term surveillance for earlier HCC detection in patients with metabolic risk factors, a policy hindered by the large number of cases at risk, with costs unaffordable by National health systems. New screening tools and cost-utility studies are eagerly awaited to develop more appropriate programs for early detection and treatment of NAFLD-associated HCC.

Glutathione species and metabolomic prints in subjects with liver disease as biological markers for the early detection of hepatocellular carcinoma (HCC)

The incidence of liver disease is increasing mainly as a result of viral infections and obesity. The present study explored the role of glutathione sp. and metabolic prints in the progression of liver dysfunction and early detection of HCC. Three subsets of subjects were enrolled on IRB approved protocols: healthy subjects (n = 20), patients with end stge liver disease and diverse MELD score (n = 99) and patients after LTx (n = 29). Treated plasma was analyzed by LC/MS-MS and identification of metabolites was performed using metabolomic libraries. Glutathione sp. synthesis rate was calculated by isotopomer analyzes of 2H-labelled compounds. Parametric analytical tests were performed to compare groups and Principal Component Analyzes (PCA) were implemented to explain differences in metabolic prints. There was a significant difference in glutathione sp and Tier 1, 2, and 3 (3, 21 and 72 compounds) metabolic profiles from patients with ESLD when compared to healthy subjects and patients after LTx (p < 0.05). Patients with ESLD and HCC (+) had a significant different profile when compared to patients with ESLD and HCC (-, p < 0.05). Patients stratified by MELD score or by etiology showed a different metabolic profile. Patients with ESLD had a significant decreased in GSH synthesis and increased GSSG production when compared to healthy subjects and to patients after LTx (p < 0.05). Glutathione sp and metabolic prints may defined liver disease progression and served as surrogate for the early detection of HCC in patients with ESLD. Patients after LTx remained with significant metabolic disturbances no reflected in standard liver function tests.

Blood gene signature for early hepatocellular carcinoma detection in patients with chronic hepatitis B.

Up to 25% of chronic hepatitis B (CHB) patients eventually develop hepatocellular carcinoma (HCC), a disease with poor prognosis unless detected early. This study identifies a blood-based RNA biomarker panel for early HCC detection in CHB. A genome-wide RNA expression study was performed using RNA extracted from blood samples from Malaysian patients (matched HCC, CHB, controls). Genes differentiating HCC from controls were selected for further testing using quantitative real-time polymerase chain reaction. Finally, a 6-gene biomarker panel was identified and characterized using a training set (cohort I = 126), and tested against 2 test sets (cohort II = 222; cohort III = 174). The total number of samples used for each group is: HCC + CHB = 143, CHB = 211, control = 168. Our gene panel displays a consistent trend distinguishing HCC from controls in our test sets, with an area under receiver-operating characteristic curve of 0.9 in cohort III. Our independent test set (cohort III) showed that the gene panel had a sensitivity of 70% with a specificity of 92%. The biomarker profile for HCC was consistently detected in a small subgroup of CHB patients, thus potentially predicting early, preclinical cases of cancer that should be screened more intensively. The biomarkers identified in this study can be used as the basis of a blood-based test for the detection of early HCC in CHB.

Detectability of hepatocellular carcinoma on gadoxetic acid-enhanced MRI at 3 T in patients with severe liver dysfunction: clinical impact of dual-source parallel radiofrequency excitation

AimTo clarify the detectability of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI at 3 T with dual-source parallel radiofrequency (RF) excitation. Materials and methodsTwelve patients with 26 HCCs who each underwent multidetector row CT (MDCT), gadoxetic acid-enhanced MRI with dual-source parallel RF excitation, and angiography-assisted CT prior to living related-liver transplantation. Three blinded readers independently reviewed the images obtained by each imaging technique for the presence of HCC on a segment-by-segment basis using a five-point confidence scale. The area under the receiver operating characteristic curve (Az), sensitivity, and specificity were compared among the three techniques. ResultsThe Az values of gadoxetic acid-enhanced MRI were highest for all readers, although no significant difference in Az value among the three methods was obtained. No significant differences in sensitivity or specificity were observed among the three techniques for each reader. ConclusionGadoxetic acid-enhanced MRI at 3 T with dual-source parallel RF excitation has relatively high-level diagnostic potential for the detection of HCC in patients with severe liver dysfunction, which was equivalent to that of MDCT and angiography-assisted CT. Dual-source parallel RF excitation would have a clinical impact on 3 T MRI of the liver.

Detection of hepatocellular carcinoma in transgenic mice by Gd-DTPA- and rhodamine 123-conjugated human serum albumin nanoparticles in T1 magnetic resonance imaging

Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1-weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In the present study, we investigated the possibility of employing novel non-toxic human serum albumin nanoparticles conjugated with Gd-DTPA and rhodamine 123 (Gd-Rho-HSA-NPs) for the detection of HCC by T1-weighted MRI. In addition, the influence of surface coating of the NPs with poloxamine 908, which alters the absorptive behavior of NPs and changes their distribution between the liver and tumor was examined. MRI of transgenic mice with endogenously formed HCCs following intravenous injection of Gd-Rho-HSA-NPs revealed a strong negative contrast of the tumors. Contrasting of the HCCs by NP-enhanced MRI required less Gd as compared to gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced MRI, which currently provides the most sensitive detection of HCC in patients. Immunohistochemical analyses revealed that the Gd-Rho-HSA-NPs were localized to macrophages, which were – similar to HCC in patients – fewer in number in HCC as compared to the liver tissue, which is in agreement with the negative contrasting of HCC in Gd-Rho-HSA-NP-enhanced MRI. Poloxamine-coated NPs showed lower accumulation in the tumor macrophages and caused a longer lasting enhancement of the MRI signal. These data indicate that Gd-Rho-HSA-NPs enable sensitive detection of HCC by T1-weighted MRI in mice with endogenous HCC through their uptake by macrophages. Poloxamine coating of the NPs delayed the tumor localization of the NPs.

Serum soluble urokinase plasminogen activator receptor as a screening test for the early diagnosis of hepatocellular carcinoma.

Early detection of hepatocellular carcinoma (HCC) before imaging signs appear remains an unmet medical need. Former publications suggest that soluble urokinase plasminogen activator receptor (suPAR) is a non-specific cancer marker. suPAR was validated for the detection of patients at risk for HCC. After an initial training set in 23 patients with extreme disease phenotypes, a prospective test set was conducted in which 267 patients without any imaging signs of HCC were followed up for 7 years. Patients were divided into low risk and high risk for the development of HCC by the EASL criteria. suPAR was measured at the beginning of follow-up. All patients underwent liver biopsy to define staging of fibrosis. The primary study endpoint was to define a cut-off among high-risk patients by the EASL criteria that can early discriminate those at real risk for HCC. The training set showed that suPAR was significantly greater in patients with HCC even in the absence of underlying cirrhosis compared with patients with minimal liver inflammation because of fatty deposition. The test set showed that among the high-risk EASL subgroup, suPAR more than 9.56 ng/ml had sensitivity 76.0%, specificity 90.4%, positive predictive value 54.3% and negative predictive value 96.2% for the development of HCC (odds ratio: 29.88, P < 0.0001). In survival analysis, patients with suPAR above 9.56 ng/ml at baseline progressed earlier to HCC. The specificity and negative predictive value make serum suPAR a potential screening tool for the early detection of HCC in patients with chronic liver disorders.

Is Liver-Specific Gadoxetic Acid-Enhanced Magnetic Resonance Imaging a Reliable Tool for Detection of Hepatocellular Carcinoma in Patients with Chronic Liver Disease?

Gadoxetic acid is a recently developed hepatobiliary-specific contrast material used for magnetic resonance imaging (MRI) which enables highly sensitive detection of hepatocellular carcinoma (HCC). We performed a meta-analysis of all available studies of the diagnostic performance of gadoxetic acid-enhanced MRI (Gd-EOB-MRI) for detection of HCC in patients with chronic liver disease. Databases including MEDLINE and EMBASE were searched for relevant original articles published from January 2000 to April 2012. Pooled estimation and subgroup analysis data were obtained by statistical analysis. Across 10 studies of 570 patients, Gd-EOB-MRI sensitivity was 0.91 (95 % CI 0.77, 0.97) and specificity was 0.93 (95 % CI 0.85, 0.97). Overall, LR+ was 13.6 (95 % CI 5.6, 33.2), LR- was 0.10 (95 % CI 0.04, 0.27), and DOR was 140.36 (95 % CI 28, 696). Among patients with high pre-test probabilities, MRI enabled confirmation of HCC; among patients with low pre-test probabilities, MRI enabled exclusion of HCC. Worst-case-scenario (pre-test probability, 50 %) post-test probabilities were 93 and 9 % for positive and negative MRI results, respectively. In studies in which both Gd-EOB-MRI and contrast enhanced computed tomography (CE-CT) were performed, Gd-EOB-MRI was more sensitive than CE-CT (0.93 vs. 0.78; p < 0.05). Subgroup analysis suggested average lesion size (<2 vs. >2 cm) did not affect the diagnostic accuracy of the test (p > 0.05). A limited number of small studies suggest Gd-EOB-MRI has good diagnostic performance in the detection of HCC among patients with chronic liver disease. It is also confirmed to be a reliable tool for evaluation of small early-stage HCC.

Recent topics on α‐fetoprotein

Zinc-fingers and homeoboxes 2 (ZHX2) and zinc-finger and BTB domain containing 20 (ZBTB20) repress the postnatal expression of α-fetoprotein (AFP) by interacting with the AFP gene promoter regions. ZHX2 inhibits the expression of AFP and cyclins A and E. ZBTB20 is negatively regulated by CUX1, which promotes cell-cycle progression, suggesting that AFP reactivation is closely linked to hepatocyte proliferation. A slight elevation in the serum AFP level often occurs in patients with chronic hepatitis C in the absence of hepatocellular carcinoma (HCC) and is an independent risk factor for HCC development to complement the fibrosis stage. In addition, the sustained elevation of AFP after interferon therapy is a risk factor of HCC development. AFP levels are clinically useful in predicting the outcomes of liver transplantation and sorafenib therapy for HCC patients. A low preoperative AFP level is a predictor of long-term survival and is associated with a low recurrence rate of HCC after liver transplantation. AFP response (≥20% decrease in AFP during 6-8 weeks of treatment) rather than radiological outcomes is a significant prognostic factor for survival in sorafenib-treated HCC patients. Highly sensitive Lens culinaris agglutinin-reactive AFP (AFP-L3) is 5-10 times more sensitive than conventional AFP-L3, and useful for early detection of HCC in patients with total AFP below 20 ng/mL.

A pooled analysis of diffusion‐weighted imaging in the diagnosis of hepatocellular carcinoma in chronic liver diseases

The purpose of this study was to perform a meta-analysis of all available studies of the diagnostic performance of diffusion-weighted imaging (DWI) in the detection of hepatocellular carcinoma (HCC) in patients with chronic liver disease. Databases including MEDLINE and EMBASE were searched for relevant original articles published from January 2000 to April 2012. Pooled estimation and subgroup analysis data were obtained by statistical analysis. Across the nine studies (476 patients), DWI sensitivity was 81% (95%CI: 67%-90%), and specificity was 89% (95% CI: 76%-95%). Overall, positive likelihood ratio was 7.11 (95%CI: 3.50, 14.48), negative likelihood ratio was 0.21 (95%CI: 0.12-0.37), and the diagnostic odds ratio (DOR) was 33.48 (95%CI: 16.67-67.25). The area under the curve of the summary receiver operator characteristic (ROC) was 0.92 (95% CI:0.89-0.94). In studies in which both DWI and conventional contrast-enhanced magnetic resonance imaging (CE-MRI) were performed, the comparison of DWI performance with that of conventional CE-MRI suggested no major differences against these two methods (P > 0.05). DWI combined CE-MRI had higher pooled sensitivity than DWI alone (93% vs 73%) (P < 0.05). DWI has good diagnostic performance in the detection of HCC in patients with chronic liver disease and equivalent to conventional CE-MRI. Combination of CE-MRI and DWI can improve the diagnostic accuracy of MRI. Further larger prospective studies are still needed to establish its value for detecting HCC in patients with chronic liver disease.

Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP

To evaluate diagnostic value of α-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-II (PIVKA-II) in hepatocellular carcinoma (HCC). One hundred and sixty-eight patients during routine HCC surveillance were included in this study. Of the 168 patients, 90 (53.6%) had HCC including newly developed HCC (n = 82) or recurrent HCC after treatment (n = 8). Sera were obtained during their first evaluation for HCC development and at the time of HCC diagnosis before commencing HCC treatment. HCC was diagnosed by histological examination, appropriate imaging characteristics-computed tomography or magnetic resonance imaging. Control sera were collected from 78 patients with benign liver disease (BLD), which were obtained during routine surveillance with a suspicion of HCC. AFP, AFP-L3 and PIVKA-II were measured in the same serum by microchip capillary electrophoresis and liquid-phase binding assay on a micro-total analysis system Wako i30 auto analyzer. The performance characteristics of three tests and combined tests for the diagnosis of HCC were obtained using receiver operating characteristic curves in all populations and subgroups with AFP < 20 ng/mL. Of 90 HCC patients, 38 (42.2%) patients had AFP < 20 ng/mL, 20 (22.2%) patients had AFP 20-200 ng/mL and 32 (35.6%) patients had AFP > 200 ng/mL. Of the 78 BLD patients, 74 (94.9%) patients had AFP < 20 ng/mL. After adjustment for age and HBV infection status, AFP-L3 levels were higher in HCC than in BLD among patients with low AFP levels (< 20 ng/mL) (P < 0.001). In a total of 168 patients, areas under the curve (AUC) for HCC were 0.879, 0.887, 0.801 and 0.939 for AFP, AFP-L3, PIVKA-II and the combined markers, respectively. The combined AUC for three markers showed higher value than the AUCs of individual marker (P < 0.05). AFP-L3 had higher AUC value than PIVKA-II for HCC detection in entire patients (P = 0.043). With combination of AFP-L3 (cut-off > 5%) and PIVKA-II (cut-off > 40 AU/L), the sensitivity were 94.4% and specificity were 75.6% in all patients. In 112 patients with low AFP levels (< 20 ng/mL), AUCs of AFP-L3, PIVKA-II and combine AFP-L3 and PIVKA-II tests were 0.824, 0.774 and 0.939, respectively. AFP-L3 with a cut-off value of 5% showed sensitivity of 71.1% and specificity of 83.8%, and PIVKA-II with a cut-off value of 40 AU/L had sensitivity of 57.9% and specificity of 95.9% in patients with low AFP levels. The combination of AFP-L3 and PIVKA-II increased the sensitivity and specificity up to 92.1% and 79.7%, respectively, in low AFP group. Combined markers detected 81.8% of early stage HCC (Union for International Cancer Control stage I), 86.7% of small sized tumor (< 2 cm) and 91.7% of single tumor of HCC in the low AFP group. In multivariate analysis, AFP-L3 was correlated with AFP and tumor size, and PIVKA-II was correlated with laboratory tests including serum aspartate aminotransferase, total bilirubin, platelets and albumin levels. PIVKA-II had no correlation with AFP, AFP-L3 or tumor characteristics. Combined determination of AFP-L3 and PIVKA-II could improve the diagnostic value for HCC detection in patients with or without increased AFP levels.

Hepatocellular carcinoma in patients with chronic liver disease: A comparison of gadoxetic acid-enhanced MRI and multiphasic MDCT

To compare the diagnostic performances of gadoxetic acid-enhanced magnetic resonance imaging (MRI) and multiphasic multidetector computed tomography (MDCT) in the detection of hepatocellular carcinoma (HCC) in patients with chronic liver disease. Institutional review board approval was obtained for this study and informed consent was obtained from all patients. Fifty-one patients (43 men, eight women; age range 32-80 years) with 73 HCCs underwent gadoxetic acid-enhanced MRI and multiphasic MDCT. Two readers independently analysed each image in three separate reading sessions. The alternative free-response receiver operating characteristic (AFROC) method was used to analyse the diagnostic accuracy. Positive and negative predictive values and sensitivity were evaluated. A total of 73 HCCs were detected in 51 patients. Although not significant (p>0.05), the areas under the receiver operating characteristic curves were 0.877 and 0.850 for MDCT, 0.918 and 0.911 for dynamic MRI, and 0.905 and 0.918 for combined interpretation of dynamic and hepatobiliary phase MR images. Differences in sensitivity, specificity, and positive and negative predictive values between the readers were not statistically significant (p>0.05). Combined interpretation of dynamic and hepatobiliary phase MRI images was more useful than MDCT in the detection of HCC lesions ≤1cm in diameter for one reader (p=0.043). Gadoxetic acid-enhanced MRI and MDCT show similar diagnostic performances for the detection of HCC in patients with chronic liver disease. However, the combined interpretation of dynamic and hepatobiliary phase MRI images may improve diagnostic accuracy in the detection of HCC lesions ≤1cm in diameter.

Utility of contrast‐enhanced ultrasonography with Sonazoid in radiofrequency ablation for hepatocellular carcinoma

Kupffer imaging in contrast-enhanced ultrasonography (CEUS) with Sonazoid, which lasts for 60 min or longer, may be useful in ultrasound-guided percutaneous tumor ablation. The utility of Sonazoid in radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) was investigated in this study. We analyzed a total of 716 HCC nodules that were detected on dynamic computed tomography in 316 patients. Detectability of these nodules was compared between CEUS and conventional ultrasonography. The effectiveness in the treatment was assessed by comparing the mean numbers of treatment sessions of RFA in patients treated with CEUS and that in historical controls matched for tumor and background conditions. Detectability of tumor nodule was 83.5% in conventional ultrasonography and 93.2% in CEUS (P=0.04). Sixty-nine nodules in 52 patients were additionally detected with CEUS. The number of additionally detected tumor nodules was positively correlated with serum albumin level (P=0.016). The number of RFA sessions was 1.33±0.45 with CEUS as compared to 1.49±0.76 in the historical controls (P=0.0019). CEUS with Sonazoid is useful for HCC detection in patients with a well-conserved liver function reservoir. The decrease in RFA session numbers indicated the utility of Sonazoid in RFA treatment of HCC.