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

DETECT: Development of Technologies for Early HCC Detection

α-Fetoprotein for Hepatocellular Carcinoma Diagnosis: The Demise of a Brilliant Star

Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis

Screening for hepatocellular carcinoma: Good enough but best yet to come

Impact of Surveillance on Survival of Patients With Initial Hepatocellular Carcinoma: A Study From Japan

BACKGROUNDResearchers have investigated the diagnostic value of protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), and obtained abundant clinical diagnostic data. However, PIVKA-II and AFP have unsatisfactory specificity and sensitivity in the diagnosis of early-stage HBV-related HCC. Gamma-glutamyltransferase (γ-GT) and aspartate aminotransferase (AST) are common biomarkers for evaluating liver function, and we hypothesized that the γ-GT/AST ratio in combination with PIVKA-II and AFP would improve the diagnosis of early-stage HBV-related HCC.AIMTo evaluate the diagnostic value of γ-GT/AST ratio alone or in combination with PIVKA-II and AFP in HBV-related HCC.METHODSSerum levels of γ-GT, AST, PIVKA-II, and AFP were detected and analysed in 176 patients with HBV-related HCC and in 359 patients with chronic hepatitis B. According to tumour size and serum level of HBV DNA, HBV-related HCC patients were divided into the following categories: Early-stage HCC patients, HCC patients, HBV DNA positive (HBV DNA+) HCC patients, and HBV DNA negative (HBV DNA-) HCC patients. Receiver-operating characteristic (ROC) curves were used to analyse and compare the diagnostic value of the single and combined detection of various biomarkers in different types of HBV-related HCC.RESULTSTumour size was positively correlated with serum levels of PIVKA-II and AFP in HCC patients (r = 0.529, aP < 0.001 and r = 0.270, bP < 0.001, respectively), but there was no correlation between tumour size and the γ-GT/AST ratio (r = 0.073, P = 0.336). The areas under the receiver-operating characteristic curves (AUROCs) of the γ-GT/AST ratio in early-stage HCC patients, HBV DNA+ HCC patients and HBV DNA- HCC patients were not significantly different from that in the total HCC patients (0.754, 0.802, and 0.705 vs 0.779, respectively; P > 0.05). When PIVKA-II was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, and HBV DNA+ HCC, the AUROCs of PIVKA-II increased, with values of 0.857 vs 0.835, 0.925 vs 0.913, and 0.958 vs 0.954, respectively. When AFP was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, HBV DNA+ HCC, and HBV DNA- HCC, the AUROCs of AFP increased, with values of 0.757 vs 0.621, 0.837 vs 0.744, 0.868 vs 0.757, and 0.840 vs 0.828, respectively.CONCLUSIONThe γ-GT/AST ratio may be better than PIVKA-II and AFP in the diagnosis of early-stage HBV-related HCC, and its combination with PIVKA-II and AFP can improve the diagnostic value for HBV-related HCC.

A modified TNM-based Japan Integrated Score combined with AFP level may serve as a better staging system for early-stage predominant hepatocellular carcinoma patients

To compare immunologic phenotypes between (1) hepatocellular carcinoma (HCC) patients and a healthy population and (2) more advanced and early stage HCC patients, we studied 45 HCC patients and 46 healthy controls from January 2006 to January 2008. Using fluorescent activated cell sorter (FACS) analysis, HCC patients were demonstrated to exhibit stronger phagocytosis of granulocytes and monocytes and more peripheral blood mononuclear cells (PBMCs) in the G2/M phase compared with healthy volunteers. By contrast, lower percentages of B and T h lymphocytes were also found in the peripheral blood of HCC patients than in the healthy population. Most importantly, a higher percentage of B cells was found in patients with advanced HCC than in those with early HCC in terms of TNM stage (II and III vs I, p = 0.004), the Japanese Integrated Scoring system (2–3 vs 0–1, p = 0.0235), and tumor numbers (≥2 vs 1, p = 0.005). In conclusion, our findings suggested that HCC patients might exhibit enhanced innate immunity and reduced adaptive immunity compared with healthy volunteers. A higher percentage of B cells was found in patients with more advanced HCC compared with patients with early stage HCC, which might serve as an indicator of the severity of HCC.

Ultrasound‐based surveillance has suboptimal sensitivity for early detection of hepatocellular carcinoma (HCC) in patients with cirrhosis. There are several emerging alternatives, including a novel multitarget HCC blood test (Mt‐HBT). We compared performance of mt‐HBT against ultrasound with or without alpha‐fetoprotein (AFP) for early HCC detection in patients with cirrhosis. Per the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) guidelines, two reviewers searched PubMed, Cochrane, Embase, and clinicaltrials.gov databases from January 1990 through December 2020 to identify studies reporting sensitivity and/or specificity of ultrasound and AFP for overall and early stage HCC detection in patients with cirrhosis. Mt‐HBT diagnostic performance was derived from a clinical validation study. A network meta‐analysis model was built for comparative assessment, and pooled estimates of sensitivity at a fixed specificity were estimated based on Bayesian binormal receiver operating characteristic models for each modality. Forty‐one studies (comprising 62,517 patients with cirrhosis) met inclusion criteria. Ultrasound‐alone sensitivity was 51.6% (95% credible interval [CrI], 43.3%–60.5%) for early stage HCC detection, which increased with the addition of AFP to 74.1% (95% CrI, 62.6%–82.4%); however, this was offset by decreased specificity (87.9% vs. 83.9%, respectively). With specificity fixed at 90%, mt‐HBT sensitivity for early stage HCC detection was higher than ultrasound alone (18.2%; 95% CrI, 0.2%–37.7%) and similar to ultrasound with AFP (−3.3%; 95% CrI, −22.3%–17.4%). Pairwise posterior probabilities suggested a preference for mt‐HBT over ultrasound alone in 97.4% of cases but only 36.3% of cases versus ultrasound with AFP. Conclusion: A blood‐based mt‐HBT has higher sensitivity than ultrasound alone for early stage HCC detection but similar sensitivity compared to ultrasound and AFP. Mt‐HBT could be a comparable alternative to existing methods for HCC surveillance in patients who are at risk.

Objective. The role of serum prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) in the early detection of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection has not yet been clearly identified. The purpose of the study was to evaluate the sensitivity and specificity of PIVKA-II, alone or in combination with alpha-fetoprotein (AFP), for the detection of HCC during surveillance, and to determine whether PIVKA-II was a significant risk factor for patient survival. Material and methods. During surveillance, 106 HCC cases and 100 non-HCC cases of chronic HBV infection were included. Sensitivity and specificity of AFP and PIVKA-II were obtained through cut-off values of 20 ng/ml and 40 mAU/ml, respectively. The Cox proportional hazards model was used to determine whether PIVKA-II would be a significant risk factor for patient survival. Results. The sensitivity rates of AFP and PIVKA-II were 57.5% (61/106) and 51.9% (55/106), respectively. Of 45 patients negative for AFP, 22 were positive for PIVKA-II. A combination of AFP and PIVKA-II increased the sensitivity to 78.3% (83/106). The specificities of AFP and PIVKA-II were 88.0% and 97.0%, respectively. PIVKA-II was not a significant risk factor for patient survival after multivariate analysis. Conclusions. PIVKA-II can be used as a tumor marker for the early detection of HCC in patients with chronic HBV infection, especially in combination with AFP.

Measurement of serum alpha-fetoprotein (AFP) and abdominal ultrasound (US) examination are used for the early detection of hepatocellular carcinoma (HCC) in chronic liver disease patients. However, the accuracy and usefulness of these tests in a clinical setting in the United States of America have not been clarified. We conducted a 7-year prospective surveillance study by using both AFP and US to detect HCC in 602 patients with chronic viral hepatitis. Our main goal was to determine the optimal test for detection of early HCC. We also assessed the clinical outcome of HCC patients identified during this time period. Thirty-one cases of HCC were detected. Serum AFP levels were elevated in 74% of HCC patients, but was also high in 10% of patients who did not develop HCC. The positive predictive value for AFP to detect HCC was only 12% or less for all AFP cut-off values, and the maximum joint sensitivity and specificity as determined by receiver operator characteristic analysis was approximately 65 and 90%, respectively. Abdominal US identified all 31 cases of HCC. The positive predictive value for US examinations to detect HCC was 78%, while the sensitivity and specificity was 100 and 98%, respectively. After detection of HCC, 24 (77%) patients died within a mean of 16.7 +/- 19.4 months. Our study indicates that US examination was more accurate in detecting HCC. Because of its poor predictive value and low sensitivity, serum AFP should not be used as the only test for screening and surveillance for HCC.

If diagnosed at early stages, patients with hepatocellular carcinoma (HCC) can receive curative therapies, whereas therapeutic options at later stages are very limited. Here, we addressed the potential of soluble Axl (sAxl) as a biomarker of early HCC by analyzing levels of sAxl in 311 HCC and 237 control serum samples from centers in Europe and China. Serum concentrations of sAxl were significantly increased in HCC (18.575 ng/mL) as compared to healthy (13.388 ng/mL) or cirrhotic (12.169 ng/mL) controls. Receiver operating characteristic curve analysis of sAxl in very early stage HCC patients (BCLC 0) showed an area under the curve (AUC) of 0.848, with a sensitivity of 76.9% and a specificity of 69.2%. α-Fetoprotein (AFP)-negative HCC patients displayed an AUC of 0.803, with sensitivity and specificity of 73% and 70.8%. Combination of sAxl and AFP improved diagnostic accuracy to 0.936 in very early HCC patients and to 0.937 in all HCC. Differential diagnosis of very early HCC versus liver cirrhosis showed a combined performance for sAxl and AFP of 0.901 with a sensitivity of 88.5% and a specificity of 76.7%. Furthermore, sAxl levels failed to be elevated in primary ovarian, colorectal and breast carcinomas as well as in secondary hepatic malignancies derived from colon. In summary, sAxl outperforms AFP in detecting very early HCC as compared to healthy or cirrhotic controls and shows high diagnostic accuracy for AFP-negative patients. sAxl is specific for HCC and suggested as a biomarker for routine clinical use.

Treatment for Hepatocellular Carcinoma in South Asia

Alpha-Fetoprotein in Early Hepatocellular Carcinoma

The aim of this study was to explore the value of autoantibody to GNAS in the early detection of hepatocellular carcinoma (HCC). In a large-scale sample set of 912 participants (228 cases in each of HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NCs) groups), autoantibody to GNAS was detected with a positive result in 47.8% of HCC patients, which was significantly higher than that in patients with LC (35.1%), CHB (19.7%), and NCs (19.7%). Further analysis showed that the frequency of autoantibody to GNAS started increasing in compensated cirrhosis patients (37.0%) with a jump in decompensated cirrhosis patients (53.2%) and reached a peak in early HCC patients (62.4%). The increasing autoantibody response to GNAS in patients at different stages was closely associated with the progression of chronic liver lesions. The result from 44 human serial sera demonstrated that 5 of 11 (45.5%) HCC patients had elevated autoantibody to GNAS before and/or at diagnosis of HCC. Moreover, 46.1% and 62.4% of high positive rates in alpha-fetoprotein (AFP) negative and early-stage HCC patients can supplement AFP in early detection of HCC. These findings suggest that autoantibody to GNAS could be used as a potential biomarker for the early detection of HCC.