Prothrombin induced by vitamin K absence II (PIVKA-II) has recently been validated internationally as a diagnostic biomarker for hepatocellular carcinoma (HCC), as part of the GALAD model. However, ...its role as a treatment response biomarker has been less well explored. We, therefore, undertook a prospective study at a tertiary centre in the UK to evaluate the role of PIVKA-II as a treatment response biomarker in patients with early, intermediate and advanced stage HCC. In a cohort of 141 patients, we found that PIVKA-II levels tracked concordantly with treatment response in the majority of patients, across a range of different treatment modalities. We also found that rises in PIVKA-II levels almost always predated radiological progression. Among AFP non-secretors, PIVKA-II was found to be informative in 60% of cases. In a small cohort of patients undergoing liver transplantation, pre-transplant PIVKA-II levels predicted for microvascular invasion and poorer differentiation. Our results demonstrate the potential utility of PIVKA-II as a treatment response biomarker and in predicting microvascular invasion, in a Western population. PIVKA-II demonstrated improved performance over AFP but, as a single biomarker, its performance was still limited. Further larger prospective studies are recommended to evaluate PIVKA-II as a treatment response biomarker, within the GALAD model.
Aim
Microvascular invasion (MVI) is an important risk factor for early recurrence of hepatocellular carcinoma (HCC), but preoperative prediction of MVI is difficult.
Methods
A retrospective review ...was undertaken on 167 patients with primary solitary HCC who underwent initial hepatectomy. Independent predictors of MVI were identified, and factors affecting disease‐free survival in patients with MVI were clarified.
Results
Of the 167 patients, 20 patients (12%) had MVI. Recurrence rates of HCC after hepatectomy in MVI patients were significantly worse than in patients without MVI (P < 0.0361). Univariate analysis revealed that positive L3‐AFP, PIVKA‐II ≥ 150 mAU/mL and tumor size ≥3 cm preoperatively were associated with positive MVI. On multivariate analysis, independent predictors of MVI were PIVKA‐II ≥ 150 mAU/mL (odds ratio OR, 5.19; 95% confidence interval 95% CI, 1.44–24.87; P = 0.0109) and positive L3‐AFP (OR, 3.47; 95% CI, 1.19–10.75; P = 0.0229). Among the MVI‐positive group, the 1‐, 2‐ and 3‐year disease‐free survival rates were 78%, 58%, and 58% in patients with surgical margin (SM) ≥ 10 mm and 38%, 29%, and 29% in those with SM < 10 mm, respectively (P = 0.0263).
Conclusions
Patients with PIVKA‐II ≥ 150 mAU/mL and positive L3‐AFP on preoperative examination are at high risk for MVI.
Short‐term recurrence of hepatocellular carcinoma (HCC) after radical resection leads to dismal outcomes. To screen high‐recurrence risk patients to provide adjuvant treatment is necessary. Herein, ...based on our previous research, we further focused on the changes in the abundance of binuclear hepatocytes (ABH) in the paracancerous liver tissue to discuss the relationship between the attenuation of binuclear hepatocytes and postoperative short‐term recurrence, by combining with the assessment of the value of a reported independent early recurrence risk factor in HCC, protein induced by vitamin K absence or antagonist‐II (PIVKA‐II). A cohort of 142 paracancerous liver tissues from HCC patients who received radical resection was collected. Binuclear hepatocytes were reduced in the paracancerous liver tissues, compared with the liver tissues from normal donors. ABH was negatively correlated with clinical features such as tumor size, TNM stages, tumor microsatellite formation, venous invasion, and Alpha‐fetoprotein (AFP) level, as well as the expression of E2F7 and Anillin, which are two critical regulators concerning the hepatocyte polyploidization. According to the short‐term recurrence information, ABH value was laminated, and univariate and multivariate logistic regression was performed to analyze the relationship between paracancerous ABH and short‐term tumor relapse. Simultaneously, the predictive effectiveness of the ABH value was compared with the preoperative PIVKA‐II value. As observed, the paracancerous ABH value below 1.5% was found to be an independent risk factor for recurrence. In conclusion, the paracancerous ABH is a credible indicator of short‐term recurrence of HCC patients after radical resection, and regular assessment of ABH might help to prevent short‐term HCC recurrence.
In this article, we compared the abundance of binuclear hepatocytes in the paracancerous tissue of hepatocellular carcinoma (HCC) patients and normal liver tissue. We discovered for the first time that paracancerous abundance of binuclear hepatocytes (ABH) is dramatically reduced in HCC patients and correlates to E2F7 and Anillin expression, two known genes regulating ploidy in hepatocytes. Our findings indicate ABH can serve as a prognostic biomarker for short‐term recurrence after radical surgery.
An ultrasensitive immunosensor of Cys/Au@TiO2 based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed by utilizing ...Cystine (Cys) and nanocomposite Au@TiO2. Firstly, HAuCl4 underwent a reduction reaction with NaBH4, then Au nanoparticles were coated onto TiO2 nanoparticles. Followed, Cys/Au@TiO2 was formed through self-assembly of cysteine to allow the monoclonal antibody of abnormal thrombospondin to bound to the amino group on the surface of the composite by covalent bonding. The mechanism is to determine the changes in the current of the sensor caused by the specific binding of the abnormal prothrombin monoclonal antibody adsorbed by the complex with its antigen. The Cys/Au@TiO2 immunosensor was fully characterized by various analytical approaches and it showed a wide linear testing range of 1–10000 pg mL−1 (R2 = 0.991) and the limit of detection down to 0.77 pg ml−1, with highly sensitivity and specificity. The results showed that the developed immunosensor platform can effectively detect trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.
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•An ultrasensitive immunosensor of Cys/Au@TiO2 for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed.•Cys/Au@TiO2 immunosensor has good performance in detecting PIVKA-II.•Cys/Au@TiO2 immunosensor has good stability and selectivity.•Cys/Au@TiO2 immunosensor platform effectively detects trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.
Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including ...accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers. (Clin Mol Hepatol 2023;29:277-292)
To explore the diagnostic value of abnormal prothrombin Ⅱ (PIVKA-Ⅱ) and alpha-fetoprotein (AFP) in primary hepatocellular carcinoma (HCC).
From 2018 0.01 to 2020.01, there were 158 patients with ...primary liver cancer caused by chronic hepatitis B (male 116, women 42) and 62 patients with chronic hepatitis B (male 34, female 28). The levels of serum PIVKA-Ⅱ and AFP were measured, and the results were statistically analyzed.
The value of PIVKA-Ⅱin liver cancer group was distinctly higher than that in chronic viral hepatitis B group, the difference is statistically significant (P < 0.05). So does the value of AFP. Draw the subject working characteristic curve (ROC curve), the area under the curve of AFP and PIVKA-Ⅱ is 0.799 and 0.836, and that of the combination of AFP and PIVKA-Ⅱ is 0.854, the sensitivity is 57.6%,68.4%,72.2%,respectively, the specificity is 93.5%, 98.4%, 96.8%, respectively. After operation or interventional therapy, the value of PIVKA-Ⅱ in liver cancer group was clearly lower than that before treatment, and the difference was statistically significant.
In the diagnostic value of primary liver cancer, PIVKA-II combined with AFP is higher than PIVKA-II, while AFP has the lowest benefit. We also find that PIVKA-II has higher disease monitoring value than AFP.
Background
Early diagnosis decreases the mortality of hepatocellular carcinoma (HCC). We aimed to investigate the usefulness of PIVKA‐II, AFP, AFP‐L3, CEA, and their combinations in the diagnosis of ...primary and metastatic HCC.
Methods
One hundred and twenty patients with primary HCC (PHC), 115 with metastatic HCC (MHC), 89 with chronic liver disease (CLD), and 116 healthy volunteers were included. The diagnostic values of each marker and their combinations for HCC diagnosis were represented by ROC curve analyses.
Results
PIVKA‐II, AFP, and AFP‐L3 levels in PHC group were higher than that in normal control, CLD, and MHC groups. CEA levels in MHC group were higher than that in the other three groups. When the four markers were analyzed individually, PIVKA‐II showed the highest positive rate in PHC group (76.7%) and CEA showed the highest positive rate in MHC group (69.6%). PIVKA‐ II showed the largest area under ROC curve (AUC = 0.835) to discriminate PHC group from CLD group. Combined PIVKA‐II with AFP‐L3 increased the AUC to 0.910. CEA showed the highest AUC (0.849) to discriminate MHC group from CLD group. Combined CEA with PIVKA‐II increased the AUC to 0.866. AFP‐L3 alone showed the highest AUC (0.890) to discriminate MHC group from PHC group. Combined PIVKA‐II with AFP‐L3, and CEA increased the AUC to 0.957.
Conclusion
PIVKA‐II, AFP‐L3, AFP, and CEA are effective biomarkers for the diagnosis of PHC and MHC. Their combinations could improve the diagnostic performance compared with each marker used alone in detecting PHC and MHC.
Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification ...inhibitor of the arterial wall; its activity depends on vitamin K–dependent γ-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin K–dependent proteins in hemodialysis patients, assessed by circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II protein induced by vitamin K absence II).
Interventional randomized non–placebo-controlled trial with 3 parallel groups.
53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls.
Menaquinone-7 (vitamin K
2) treatment at 45, 135, or 360 μg/d for 6 weeks.
Plasma levels of dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II.
Plasma levels were assessed using enzyme-linked immunosorbent assays.
At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated-uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K
2 supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 μg and 360 μg of menaquinone-7, respectively.
Small sample size.
This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K
2 supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation.
Alpha-fetoprotein (AFP), Lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are widely used as tumor markers for the ...diagnosis of hepatocellular carcinoma (HCC). This study compared the diagnostic values of AFP, AFP-L3, and PIVKA-II individually and in combination to find the best biomarker or biomarker panel.Seventy-nine patients with newly diagnosed HCC and 77 non-HCC control patients with liver cirrhosis were enrolled. AFP, AFP-L3, and PIVKA-II were measured in the same serum samples using microchip capillary electrophoresis and a liquid-phase binding assay on an automatic analyzer. Receiver-operating characteristic curve analyses were also applied to all combinations of the markers.When the 3 biomarkers were analyzed individually, AFP showed the largest area under the receiver-operating characteristic curve (AUC) (0.751). For combinations of the biomarkers, the AUC was highest (0.765) for "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL." The combination of "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL and AFP-L3 > 10%" had worse sensitivity and lower AUC (P = 0.001). The highest AUC of a single biomarker was highest for AFP and of a combination was "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL," with this also being the case when the cut-off value of AFP and AFP-L3 was changed.Alpha-fetoprotein showed the best diagnostic performance as a single biomarker for HCC. The diagnostic value of AFP was improved by combining it with PIVKA-II, but adding AFP-L3 did not contribute to the ability to distinguish between HCC and non-HCC liver cirrhosis. These findings were not altered when the cut-off value of AFP and AFP-L3 was changed.
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