The prognostic value of protein induced by vitamin K absence or antagonist-II in hepatocellular carcinoma patients undergoing surgical resection.

Background:Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are classical tumor markers in clinical practice. However, the relationship between tumor markers and prognosis in hepatocellular carcinoma (HCC) patients receiving immune checkpoint inhibitor (ICI) therapy remains unclear.Objectives:This study aims to explore the prognostic value of AFP and PIVKA-II in HCC patients treated with ICIs.Design:This study was a single-center, retrospective investigation aimed to assess the prognostic value of AFP and PIVKA-II in HCC patients receiving immune checkpoint inhibitors.Methods:This retrospective study included HCC patients who received ICIs treatment at Wuhan Union Hospital between July 2020 and March 2024. Serum AFP and PIVKA-II levels were collected before treatment. Patients were stratified into two groups based on AFP ⩾ 400 μg/L (yes = 1, no = 0) and PIVKA-II ⩾ 40 mAU/mL (yes = 1, no = 0). A total of 61% (114/186) of patients scored ⩽ 1, while 39% (72/186) scored 2. The objective response rate (ORR) and disease control rate (DCR) were calculated for both groups. Kaplan–Meier survival curves and Cox regression models were used to analyze overall survival (OS) and progression-free survival (PFS). Receiver operating characteristic curves were generated to demonstrate the predictive ability of combined independent prognostic factors for long-term survival.Results:The cohort consisted of 186 patients, divided into the low-risk group (n = 114) and the high-risk group (n = 72). Among all patients, 34.4% (64/186) achieved complete or partial response. Concurrent elevation of AFP and PIVKA-II was inversely associated with ORR (p = 0.012). The high-risk group exhibited significantly shorter OS (adjusted HR: 2.226 (95% CI: 1.410–3.513); p < 0.001) compared to the low-risk group. The integrated model combining AFP, PIVKA-II, and Barcelona Clinic liver cancer stage demonstrated moderate to good predictive capability for long-term risk stratification, with time-dependent area under the curves of 0.78 (9-month), 0.68 (12-month), and 0.63 (15-month).Conclusion:Concurrent elevation of AFP and PIVKA-II is significantly associated with shorter survival outcomes in HCC patients following ICI therapy.

BackgroundLiver cancers are common malignancies that primarily include hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Currently, the most commonly used serum markers for HCC are alpha fetoprotein (AFP), AFP-L3% and protein induced by vitamin K absence or antagonist-II (PIVKA-II), while the most commonly used serum markers for CCA are carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). In recent years, many HCC diagnostic models using the combined detection of serum AFP, AFP-L3% and PIVKA-II have been established. For serum AFP, AFP-L3%, PIVKA-II and their many diagnostic models, there has been no clear guidance on the selection of these markers and their various combinations in the diagnosis of liver cancers. The aim of this study was to evaluate and compare the efficacy of these markers and the models that incorporate them in diagnosing HCC and CCA. This could assist in identifying the optimal patterns of serum AFP, AFP-L3% and PIVKA-II for the diagnosis of liver cancers.MethodsClinical data and the results of serum AFP, AFP-L3%, PIVKA-II, CEA and CA19-9 were collected from 117 patients with HCC, 28 patients with CCA and 101 patients with benign liver diseases. Laboratory tests and detection of serum tumor markers in liver cancer patients were conducted prior to treatments. Recently published diagnostic models for AFP, AFP-L3% and PIVKA-II detection were collected; these included GALAD, ASAP, GALAD-C, GAAP, C-GALAD, C-GALAD II and GAP-TALAD.ResultsLevels of AFP-L3%, PIVKA-II, GALAD, ASAP, GALAD-C, GAAP, C-GALAD and C-GALAD II significantly differed between the patient cohorts, with the highest levels seen in HCC, followed by CCA and with the lowest levels seen in benign liver diseases (p < 0.05). Levels of CEA and CA19-9 significantly differed between cohorts, with the highest levels seen in CCA, followed by HCC and with the lowest levels seen in benign liver diseases (p < 0.05). Levels of AFP and GAP-TALAD in HCC patients were significantly higher than those in patients with CCA and patients with benign liver diseases (p < 0.05), but there were no significant differences in levels of AFP and GAP-TALAD between patients with CCA and benign liver diseases (p > 0.05). In the diagnosis of HCC, GAP-TALAD, GALAD, C-GALAD, ASAP and GALAD-C showed the highest efficacy. In the diagnosis of overall liver cancers (HCC and CCA), GALAD-C, GAAP, GALAD, ASAP and C-GALAD showed the highest efficacy. In the diagnosis of early liver cancers (early HCC and CCA), GALAD, GALAD-C, GAAP, C-GALAD and ASAP showed the highest efficacy.ConclusionsFor serum AFP, AFP-L3% and PIVKA-II, diagnostic models of combined marker detection improved efficacy in the diagnosis of liver cancers. Diagnostic models GALAD, ASAP, GALAD-C and C-GALAD showed the highest efficacy in the diagnosis of HCC, overall liver cancers (HCC + CCA) and early liver cancers, and can be used preferentially in clinical practice.

Serum and tissue PIVKA-II expression reflect the biological malignant potential of small hepatocellular carcinoma

Protein induced by vitamin K absence or antagonist II as a prognostic marker in hepatocellular carcinoma patients with normal serum alpha-fetoprotein levels.

Simple SummaryCirculating biomarkers for the early detection and prediction of hepatocellular carcinoma development are an unmet need. In the present study, we observed that serum values of three biomarkers (namely AFP, PIVKA-II and GPC-3) were significantly different between patients with cirrhosis and those with hepatocellular carcinoma; the best accuracy for the detection of tumors was achieved by a combination of AFP + PIVKA-II. However, PIVKA-II resulted as the only biomarker able to identify patients with cirrhosis at increased risk of hepatocellular carcinoma development. The measurement of PIVKA-II in patients with cirrhosis at risk of tumor development may be useful to tailor personalized surveillance strategies and thus to improve patients’ survival.International guidelines recommend the use of ultrasound as a surveillance tool for hepatocellular carcinoma (HCC) in patients with cirrhosis, while the role of serum biomarkers is still debated. We investigated serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II) and glypican-3 (GPC-3) diagnostic accuracy for HCC detection and prediction in patients with liver cirrhosis of viral etiology under surveillance. A total of 349 patients (200 cirrhosis and 149 HCC) were enrolled. The 200 patients with cirrhosis consisted of 114 patients still HCC-free after 36 months of follow-up and 86 patients that developed HCC after 13.8 (11.0–19.8) months. AFP, PIVKA-II and GPC-3 were measured in serum samples collected at tumor diagnosis in the 149 patients with HCC, and at the beginning of follow-up in the 200 patients with cirrhosis. The higher performance for HCC detection was observed for PIVKA-II (area under the curve (AUC) = 0.790), followed by AFP (AUC = 0.737) and GPC-3 (AUC = 0.637); the combination of AFP + PIVKA-II improved the diagnostic accuracy to AUC = 0.822. Serum PIVKA-II values, but not AFP and GPC-3, were significantly higher in the 86 cirrhotics that developed HCC compared with the 114 cirrhotics still HCC-free after 36 months of follow-up (p = 0.020). PIVKA-II ≥ 55 mAU/mL allowed to identify patients with cirrhosis at higher risk of HCC development (Log-rank test, p < 0.001; adjusted Hazard Ratio = 1.99, p = 0.001). In conclusion, the measurement of PIVKA-II in patients with cirrhosis may be useful to tailor personalized surveillance strategies.

Objective To investigate the diagnostic value and biological features of protein induced by vitamin K absence or antagonist Ⅱ (PIVKA-Ⅱ) and alpha-fetoprotein (AFP) in hepatocellular carcinoma (HCC). Methods Serum samples of 72 patients with HCC (HCC group), 54 patients with hepatitis B cirrhosis (cirrhosis group) and 30 patients with chronic hepatitis B (CHB) without cirrhosis (CHB group) were tested with the PIVKA-Ⅱ and AFP detection kits. Diagnostic efficacies of PIVKA-Ⅱ and AFP were evaluated by receiver-operating characteristic curve (ROC). The cut-off value of PIVKA-Ⅱ for diagnose HCC was also determined. Sensitivities and specificities of PIVKA-Ⅱ and AFP were compared. Results The medians of PIVKA-Ⅱ levels in HCC group, cirrhosis group and CHB group were 14.36, 11.21, and 329.88 mAU/mL, respectively. The serum PIVKA-Ⅱ level in the HCC group was significantly higher than that in cirrhosis group (U=342.50, P 0.05). The serum PIVKA-Ⅱ levels in patients with BCLC stage A, B, C in HCC group were 22.13, 345.46, and 13 057.72 mAU/mL, respectively. After comparison of stage A and C with stage B, the differences were both statistically significant (stage A to B: U=119.0, P<0.01; stage B to C: U=158.0, P<0.01). The sensitivity and specificity of PIVKA-Ⅱ with a cut-off value of 30.01 mAU/mL by means of Youden index were 0.750 and 1.000, respectively. When combined PIVKA-Ⅱ with AFP, the sensitivity and specificity were 0.800 and 0.964, respectively. The area under the curve (AUC) was highest (AUC=0.930, 95%CI: 0.852—0.974), and significantly higher than that using PIVKA-Ⅱ alone (AUC=0.892, 95%CI: 0.834—0.950, χ2=21.43, P<0.01). Conclusions The diagnostic value of serum PIVKA-Ⅱ is superior to AFP. Combined with AFP, serum PIVKA-Ⅱ can improve the detection rate of HCC, and has advantages during the development of HCC and can be used to monitor the condition of HCC patients. Key words: PIVKA-Ⅱ; Carcinoma, hepatocellular; Diagnosis

Multiplication of alpha-fetoprotein and protein induced by vitamin K absence-II is a powerful predictor of prognosis and recurrence in hepatocellular carcinoma patients after a hepatectomy.

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.

Serum protein induced by vitamin K absence or antagonist II (PIVKAII), hepatoma-specific band of serum gamma-glutamyl transferase (GGTII), and α-fetoprotein (AFP) levels were determined in 120 patients with hepatocellular carcinoma (HCC) and 90 patients with cirrhosis. The mean serum concentration of PIVKAII in HCC patients was higher than that in cirrhotic patients. A total of 53.3% of patients (64 out of 120) with HCC had PIVKAII levels above 40 mAU ml−1. However, only 13 patients with cirrhosis had higher PIVKA II levels. Of 32 small HCC patients, 13 (40.6%) had PIVKAII values above 40 mAU ml−1. An increased concentration of AFP (i.e. 20 ng ml−1) was observed in 70 out of 120 (58.3%) patients with HCC and in 33 out of 90 (36.7%) patients with cirrhosis. Positive GGTII was found in 74.0% (89 out of 120) cases of HCC (sensitivity), in 16 of 90 cases of cirrhosis, and 14 of 32 (43.8%) small HCC patients had GGTII positive. No significant correlation was found between serum levels of AFP and PIVKAII. Combining the information from PIVKAII, AFP, and GGTII significantly increases the sensitivity over AFP alone. PIVKAII and GGTII are useful tumour markers complementary to AFP for diagnosis of HCC.

We read with great interest the Editorial by Su et al. regarding our study [1, 2], and we fully agree with the authors that evidence-based tools for hepatocellular carcinoma (HCC) risk stratification are an unmet medical need. In recent years, great efforts have been made to promote the transition from standard HCC surveillance (ultrasound [US] ± alpha-fetoprotein [AFP]) to personalised screening approaches. In this regard, an increasing body of evidence supports the cost-effectiveness of circulating biomarkers as potential tools for implementing risk-based surveillance strategies [3, 4]. Thus, we took the opportunity to highlight the potential value of protein induced by vitamin K absence or antagonist II (PIVKA-II) to stratify HCC risk in patients with advanced liver disease of any aetiology. A recent meta-analysis including 53 case–control studies showed that PIVKA-II outperformed AFP in distinguishing between patients with and without HCC (summary area under the curve [sAUC] = 0.89 vs. 0.78, respectively), independently from ethnicity and liver disease aetiology [5]. More recently, two independent phase III validation studies demonstrated that PIVKA-II was able to identify patients at different risk of HCC. In patients with hepatitis C virus (HCV)-related cirrhosis treated with direct-acting antivirals (DAA), end-of-treatment PIVKA-II was significantly associated to HCC occurrence (HR = 9.49, 3.58–25.14) [6], while in patients with hepatitis B virus (HBV)-related cirrhosis on nucleos(t)ide analogues, PIVKA-II measured at virological remission predicted HCC development (HR = 2.46, 1.35–4.49) [7]. In our study, we investigated whether changes in serum PIVKA-II from month 1 (M1) of antiviral treatment to 12 weeks after DAA completion (SVR12) were associated with HCC development during follow-up (FU), in patients with a pre-treatment diagnosis of cirrhosis. After performing propensity score matching for several baseline variables (age, gender, baseline HCV RNA, HCV genotype, alanine aminotransferase, aspartate aminotransferase, platelet count, Child-Turcotte-Pugh score, and liver stiffness measurement), we compared serum M1 PIVKA-II with SVR12 levels, as well as their variations, in 75 patients who developed HCC during FU (median time to HCC: 28.4, 15.8–43.0 months) vs. 75 patients who did not (median FU: 42.0, 15.0–55.6 months) (Table S1). We observed significantly higher PIVKA-II values at M1 (53, 42–97 mAU/mL vs. 47, 38–60 mAU/mL, p = 0.016) and SVR12 (58, 40–117 mAU/mL vs. 46, 37–62 mAU/mL, p = 0.014) in HCC patients compared to those who remained HCC-free. Moreover, we observed a significant increase of PIVKA-II values from M1 to SVR12 in HCC but not in HCC-free patients during FU (p = 0.011 and p = 0.747, respectively) (Figure 1). Our results align with Ricco et al. [8], who investigated the time-related variability of PIVKA-II in 418 cirrhotics (31.1% HBV, 58.6% HCV, 10.3% non-viral aetiology) undergoing US surveillance. The authors observed that in patients developing HCC, PIVKA-II values showed an increasing trend over time, while in patients not developing HCC during FU, PIVKA-II variations were minimal. Taken together, our and other results provide further evidence supporting the value of serum PIVKA-II monitoring in patients with advanced liver disease at risk of HCC. Gian Paolo Caviglia: formal analysis, investigation, writing – original draft. Roberta D'Ambrosio: writing – review and editing. Piero Colombatto: writing – review and editing. Alessia Ciancio: writing – review and editing. The authors' declarations of personal and financial interest are unchanged from those in the original article [2]. This article is linked to Caviglia et al papers. To view these articles, visit https://doi.org/10.1111/apt.18409 and https://doi.org/10.1111/apt.18444. The data that support the findings of this study are available from the corresponding author upon reasonable request. TABLE S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUNDSerum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance.AIMTo identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC.METHODSThis study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively.RESULTSElevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone.CONCLUSIONSerum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.

Development and validation of the APTNM staging system: Integration of serum biomarkers with TNM classification for enhanced prognostic stratification following hepatectomy for hepatocellular carcinoma.

We have confirmed the diagnostic value of protein induced by vitamin K absence or antagonist-II (PIVKA-II) in a French cohort of patients with hepatocellular carcinoma (HCC). Herein, we aim to study the biological response under treatment and the prognostic value of PIVKA-II serum level in patients treated for HCC. Patients with primary HCC developed chronic liver disease with serum PIVKA-II, and alpha-fetoprotein (AFP) levels available at baseline and after first HCC treatment [within 3 months (M1-M3) and/or within 6-9 months (M6-M9)] were included. A total of 94 patients were included. Median follow-up was 23 months (range 11-31 months). PIVKA-II levels significantly decreased from baseline to M1-M3 (P = 0.002) and to M6-M9 (P = 0.035). By multivariate analysis, biological response (M1-M3/baseline PIVKA-II ratio) independently and significantly predicted overall survival (OS). A ratio below 0.73 was able to identify patients with the better prognosis in the total population [OS: 27 months (range 17-31) vs. 17 (range 9-25); P = 0.008] and in patients who had transarterial chemoembolization or selective internal radiation therapy as first treatment approach [OS: 26 months (range 14-31) vs. 16 (range 9-25); P = 0.002 and 2-year OS of 73% vs. 30%; P = 0.009]. PIVKA-II serum levels at baseline and PIVKA-II biological response were significantly associated with radiological response. PIVKA-II serum level seems to be a good prognostic and promising biomarker for early monitoring treatment outcomes for patients with HCC.

Many staging systems for hepatocellular carcinoma: evolution from Child-Pugh, Okuda to SLiDe.

Hepatocellular carcinoma (HCC) is one of the top five contributors to the cancer burden in China, with a poor prognosis and heavy disability-adjusted life year burden. The criteria used for HCC prognosis are complicated and therefore restricted in routine clinical practice. Multiple factors influence HCC malignancy and progression. In this study, we retrospectively evaluated 173 patients with HCC who underwent curative resection for 9 years to evaluate the correlation of a combination of γ-glutamyl transferase (γ-GT), protein induced by vitamin K absence or antagonist-II (PIVKA-II), and α-fetoprotein (AFP) with the long-term survival of patients with HCC. Multivariate analysis revealed that the γ-GT level was an independent prognostic factor for recurrence. The prediction rate of early recurrence with γ-GT, PIVKA-II, and AFP levels individually was 63.5%, 79.4%, and 39.7%, respectively, whereas the prediction rate of early recurrence was 95.2% with the combination of γ-GT, PIVKA-II, and AFP levels as a composite indicator. Our long-term retrospective study revealed that γ-GT, PIVKA-II, and AFP can aid in predicting long-term prognosis of HCC recurrence. The combination of γ-GT, PIVKA-II, and AFP can further aid in identifying patients with early recurrence. Together, γ-GT, PIVKA-II, and AFP may a be used to develop a new prediction method to improve the prognosis of patients with HCC, and our results indicate the requirement of more active HCC treatment strategies.