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Abstract Background and Aims Prothrombin induced by vitamin K absence‐II (PIVKA‐II) is a serum biomarker linked to hepatocellular carcinoma (HCC), showing superiority to alpha‐fetoprotein (AFP) for early disease detection. We aimed to assess the clinical and analytical performance of the Elecsys® PIVKA‐II immunoassay in diagnosing HCC and evaluate PIVKA‐II's technical performance. Methods Serum samples from adult cases (i.e. patients with a first‐time HCC diagnosis; n = 168) and disease controls (i.e. patients without HCC with an at‐risk condition; n = 208) were assessed. An AFP cut‐off of 20 ng/mL was used to differentiate between HCC cases and disease controls. Clinical performance of the Elecsys PIVKA‐II assay was compared with that of comparator assays (Lumipulse G PIVKA‐II, μTASWako DCP, ARCHITECT PIVKA‐II) using receiver operating characteristic curve analysis to determine the area under the curve (AUC) values. Results The Elecsys PIVKA‐II assay compared favorably with comparator assays. Using a 28.4 ng/mL cut‐off, the Elecsys PIVKA‐II assay detected HCC with 86.9% sensitivity and 83.7% specificity. Clinical performance of the Elecsys PIVKA‐II assay (AUC: 90.8%) was equivalent to that of comparator assays (AUC: 88.3–89.6%). Relatively high PIVKA‐II concentrations were observed for cholangiocarcinoma and pancreatic cancer with the Elecsys assay in specificity panel analyses, indicating that high PIVKA‐II concentrations should not be used alone in the absence of other clinical data. Conclusions The Elecsys PIVKA‐II assay showed good analytical performance under routine laboratory conditions, comparing favorably with comparator assays. These findings support the suitability of the Elecsys PIVKA‐II assay as an aid in HCC diagnosis.

Background and Aims: Prothrombin induced by vitamin K absence‐II (PIVKA‐II) is a serum biomarker linked to hepatocellular carcinoma (HCC), showing superiority to alpha‐fetoprotein (AFP) for early disease detection. We aimed to assess the clinical and analytical performance of the Elecsys® PIVKA‐II immunoassay in diagnosing HCC and evaluate PIVKA‐II's technical performance. Methods: Serum samples from adult cases (i.e. patients with a first‐time HCC diagnosis; n = 168) and disease controls (i.e. patients without HCC with an at‐risk condition; n = 208) were assessed. An AFP cut‐off of 20 ng/mL was used to differentiate between HCC cases and disease controls. Clinical performance of the Elecsys PIVKA‐II assay was compared with that of comparator assays (Lumipulse G PIVKA‐II, μTASWako DCP, ARCHITECT PIVKA‐II) using receiver operating characteristic curve analysis to determine the area under the curve (AUC) values. Results: The Elecsys PIVKA‐II assay compared favorably with comparator assays. Using a 28.4 ng/mL cut‐off, the Elecsys PIVKA‐II assay detected HCC with 86.9% sensitivity and 83.7% specificity. Clinical performance of the Elecsys PIVKA‐II assay (AUC: 90.8%) was equivalent to that of comparator assays (AUC: 88.3–89.6%). Relatively high PIVKA‐II concentrations were observed for cholangiocarcinoma and pancreatic cancer with the Elecsys assay in specificity panel analyses, indicating that high PIVKA‐II concentrations should not be used alone in the absence of other clinical data. Conclusions: The Elecsys PIVKA‐II assay showed good analytical performance under routine laboratory conditions, comparing favorably with comparator assays. These findings support the suitability of the Elecsys PIVKA‐II assay as an aid in HCC diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression levels of prothrombin induced by vitamin K absence-II (PIVKA-II) and osteopontin (OPN) in patients with hepatocellular carcinoma (HCC) and cirrhosis, and to evaluate their potential as markers for cirrhosis severity., Methods: This retrospective study included 84 patients with HCC and cirrhosis treated at the Liver Disease Center of the 904th Hospital from January 2021 to December 2023, forming the cirrhosis group. Fifty healthy individuals undergoing routine physical examinations during the same period comprised the control group. We compared cirrhosis-related indicators and serum levels of PIVKA-II and OPN between the two groups and analyzed the relationships between these biomarkers, liver cancer-related indicators, Child-Pugh grades, tumor size, and their diagnostic value using receiver operating characteristic (ROC) curve analysis., Results: The cirrhosis group showed significantly higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin time (PT), total bilirubin (TBIL), alpha-fetoprotein (AFP), OPN, and PIVKA-II compared to the control group (all P < 0.05). Conversely, levels of hemoglobin (Hb), white blood cells (WBC), platelets (PLT), and albumin (ALB) were significantly lower (all P < 0.05). Serum levels of OPN, PIVKA-II, AFP, TBIL, PT, and Child-Pugh scores were positively correlated, with correlation coefficients (r values) of 0.678, 0.634, 0.529, 0.617, 0.479, 0.551, 0.620, and 0.054, respectively (all P < 0.05). These markers were negatively correlated with ALB levels, with r values of -0.480 and -0.533 (both P < 0.05). Additionally, higher PIVKA-II and OPN levels were associated with larger tumors (> 3 cm) and more advanced cirrhosis stages (P < 0.05). Over a two-year follow-up, 12 patient deaths were recorded, with deceased patients showing higher levels of PIVKA-II, OPN, and AFP than those in the control group. ROC curve analysis revealed that AFP had a sensitivity of 98.8% and specificity of 82.0% in diagnosing HCC with cirrhosis. OPN achieved a sensitivity of 93.82% and a specificity of 88.0% for diagnosing cirrhosis, while PIVKA-II showed a sensitivity of 98.8% and a specificity of 80.0%., Conclusion: Serum levels of PIVKA-II and OPN correlate significantly with HCC presence, cirrhosis severity, Child-Pugh grading, and patient prognosis. Their combined diagnostic use enhances detection rates of HCC with cirrhosis and holds substantial clinical value, recommending their incorporation into clinical practice., Competing Interests: None., (AJTR Copyright © 2024.)

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Due to the lack of efficient tools for early detection, asymptomatic HCC patients are diagnosed at an advanced stage, leading to a poor prognosis. To improve survival, serum biomarker prothrombin induced by vitamin K absence-II (PIVKA-II) was under investigation. PIVKA-II is an abnormal protein produced in HCC. The coagulation function was insufficient due to the lack of Gla residues. Elevated PIVKA-II was associated with bad tumor behavior in terms of proliferation, metastasis, and invasion. Three major signaling pathways were proposed to clarify the mechanism. With the advantages including affordability, minimal invasiveness, convenience, and efficiency, PIVKA-II could improve HCC management consisting of four aspects. First, PIVKA-II was an effective and dynamic tool for improving HCC surveillance in high-risk population. Changes in the serum levels of PIVKA-II provided valuable molecular alteration information before imaging discovery. Second, PIVKA-II offered a complementary approach for HCC early detection. Compared to traditional diagnostic approaches, the combination of PIVKA-II and other biomarkers had better performance. Third, PIVKA-II was an indicator for the assessment of response to treatment in HCC. Preoperative assessment was for selecting personalized therapy, and postoperative measurement was for assessing treatment efficacy. Fourth, PIVKA-II was considered as a prognostic predictor for HCC. Patients with elevated PIVKA-II were more likely to develop microvascular invasion, metastasis, and recurrence.

Background: A hepatocellular carcinoma (HCC) prediction model (ASAP), including age, sex, and the biomarkers alpha-fetoprotein and prothrombin induced by vitamin K absence-II, showed potential clinical value in the early detection of HCC. We validated and updated the model in a real-world cohort and promoted its transferability to daily clinical practice. Methods: This retrospective cohort analysis included 1012 of the 2479 eligible patients aged 35 years or older undergoing surveillance for HCC. The data were extracted from the electronic medical records. Biomarker values within the test-to-diagnosis interval were used to validate the ASAP model. Due to its unsatisfactory calibration, three logistic regression models were constructed to recalibrate and update the model. Their discrimination, calibration, and clinical utility were compared. The performance statistics of the final updated model at several risk thresholds are presented. The outcomes of 855 non-HCC patients were further assessed during a median of 10.2 months of follow-up. Statistical analyses were performed using packages in R software. Results: The ASAP model had superior discriminative performance in the validation cohort [C-statistic = 0.982, (95% confidence interval 0.972–0.992)] but significantly overestimated the risk of HCC (intercept − 3.243 and slope 1.192 in the calibration plot), reducing its clinical usefulness. Recalibration-in-the-large, which exhibited performance comparable to that of the refitted model revision, led to the retention of the excellent discrimination and substantial improvements in the calibration and clinical utility, achieving a sensitivity of 100% at the median prediction probability of the absence of HCC (1.3%). The probability threshold of 1.3% and the incidence of HCC in the cohort (15.5%) were used to stratify the patients into low-, medium-, and high-risk groups. The cumulative HCC incidences in the non-HCC patients significantly differed among the risk groups (log-rank test, p-value < 0.001). The 3-month, 6-month and 18-month cumulative incidences in the low-risk group were 0.6%, 0.9% and 0.9%, respectively. Conclusions: The ASAP model is an accurate tool for HCC risk estimation that requires recalibration before use in a new region because calibration varies with clinical environments. Additionally, rational risk stratification and risk-based management decision-making, e.g., 3-month follow-up recommendations for targeted individuals, helped improve HCC surveillance, which warrants assessment in larger cohorts. [ABSTRACT FROM AUTHOR]

OBJECTIVE: ApoE alleles have been shown to significantly correlate with vitamin K status, however, data concerning this phenomenon in cystic fibrosis (CF) are scarce. This study aimed to investigate the effect of ApoE polymorphism on vitamin K status in a unique group of CF patients who had never received vitamin K supplementation. PATIENTS AND METHODS: The study group consisted of 93 CF patients aged from 3 months to 32 years. Vitamin K status was assessed by the concentration of prothrombin induced by vitamin K absence (PIVKA-II) and the percentage of undercarboxylated osteocalcin (u-OC). The clinical status was evaluated in all patients. RESULTS: Fifty-four (65.1%) out of 83 patients had a pathological PIVKA-II concentration (≥2 ng/ml) and an abnormal percentage of u-OC (≥20%). There were no differences in the clinical parameters, including PIVKA-II concentration (p=0.7752) and u-OC percentage (p=0.8395), between patients with genotypes ApoE2/3, ApoE3/3 and ApoE3/4. Moreover, the frequency of vitamin K deficiency did not significantly differ in CF patients with ApoE2/3, ApoE3/3 and ApoE3/4 genotypes (66.7 vs. 69.9 vs. 80%, p=0.8411; 87.5 vs. 89.6 vs. 100%, p=1.000, respectively). CONCLUSIONS: The presence of the ApoE4 allele does not influence the vitamin K status in CF patients who have never received vitamin K supplementation. [ABSTRACT FROM AUTHOR]

BACKGROUND: It is reported that prothrombin induced by vitamin K absence-II (PIVKA-II) has a better performance of diagnosis for HCC, and has also been known to be an independent risk factor for vascular invasion. Few studies study the relationship between PIVKA-II and HBV DNA. OBJECTIVE: To determine the clinical value of serum Prothrombin induced by vitamin K absence-II (PIVKA-II) in early hepatocellular carcinoma (HCC), and to explore its relationship with vascular invasion and HBV DNA. METHODS: In a Chinese cohort, we conducted a case-control study to compare the performances of a-fetoprotein (AFP) and PIVKA-II serum levels for diagnosis of HCC and early HCC. Fifty one healthy controls, 37 chronic hepatitis patients, 43 cirrhotic patients and 143 HCC cases of which 48 (33.57%) had early stage HCC (n = 19 very early, n = 29 early) were enrolled. We explored the correlation between PIVKA-II serum level and several pathological features such as vascular invasion. The serum levels of and AFP were measured by chemiluminescence assay (CLIA) and electrochemiluminescence assay (ECLA). RESULTS: The serum levels of both PIVKA-II and AFP in HCC group were higher than that in chronic hepatitis, cirrhosis and healthy control groups. The sensitivity, specificity, positive predictive value, negative predictive value and kappa of PIVKA-II were higher than AFP in the diagnosis of HCC. Serum PIVKA-II level was correlated with tumor size, tumor cell differentiation and BCLC staging (P < 0.05). For the diagnosis of early HCC, the combination of PIVKA-II (AUC 0.812; 95% CI, 0.702–0.894) and AFP (0.797; 95% CI, 0.686–0.883) slightly improve the diagnostic performance for early HCC(AUC 0.849; 95% CI, 0.745–0.923). PIVKA-II > 166 mAU/ml is an independent risk factor for vascular invasion. The serum HBV DNA level in cirrhosis and HCC patients was significantly higher than in chronic hepatitis patients. We detected a negative association between serum PIVKA-II and serum HBV DNA levels. CONCLUSIONS: PIVKA-II was more efficient than AFP for the diagnosis of early HCC and has no correlation with serum HBV DNA levels. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Microvascular invasion (mVI) is a major prognostic factor in hepatocellular carcinoma (HCC) that cannot be detected before surgery. Predictive biomarkers of mVI are thus urgently needed. We have developed an original approach of virtual biopsy to assess the performance of an immunohistochemical panel comprising three biomarkers of mVI (H4K16ac, H4K20me2, PIVKA‐II) for the prediction of mVI in HCC core needle biopsies (CNB). Methods: A test set of HCC surgical specimens (n = 64) and an independent validation set of HCC CNB (n = 42) were retrospectively constituted. Immunostainings were first quantified in the test set on the whole tissue section, to determine optimal cut‐off values for each marker. From the digitised image of the whole section, three virtual biopsies were provided. Immunostainings and accuracy of the panel for the prediction of mVI were further assessed in virtual biopsies and in the validation set of CNB. Results: In virtual biopsies, PIVKA‐II/H4K16ac had the best performance for prediction of mVI, with sensitivity, specificity, predictive positive value (PPV), and predictive negative value (PNV) of 30%, 97%, 91%, 56%, respectively. In CNB, PIVKA‐II/H4K20me2 showed the best accuracy for prediction of mVI, with sensitivity, specificity, PPV, and NPV of 43%, 95%, 90%, and 62%, respectively. The two panels were independent predictive factors of mVI (PIVKA‐II/H4K16ac, P = .037; PIVKA‐II/H4K20me2, P = .026). Conclusion: This study shows that a panel of two markers is able to predict mVI in HCC CNB, and pave the way for the future development of prognostic biomarkers in HCC that could guide the therapeutic strategy. [ABSTRACT FROM AUTHOR]

Aim: Evaluation of prothrombin induced by vitamin K absence-II (PIVKA-II) in detecting hepatitis B virus-associated hepatocellular carcinoma (HCC). Materials & methods: PIVKA-II and AFP levels were measured in 366 Chinese subjects (176 HCC, 98 liver cirrhosis and 92 noncirrhotic chronic hepatitis B patients). Results: PIVKA-II showed a sensitivity of 82.4% and a specificity of 95.9% at a cut-off value of 40.5 mAU/ml versus 73.9 and 82.9% for AFP at a cut-off value of 12.3 ng/ml for differentiating HCC from non-HCC. In detecting small-sized HCC (<3 cm), the sensitivity of PIVKA-II, AFP and their combination was 63.6, 75.8 and 84.8%, respectively. Conclusion: PIVKA-II was more efficient than AFP in detecting HBV-associated HCC, and their combination could improve the detection sensitivity. [ABSTRACT FROM AUTHOR]

Background & Aims Prothrombin induced by vitamin K absence-II (PIVKA-II) is a diagnostic and surveillance marker for HCC mainly used in Asia, and has also been shown to be a predictor of microvascular invasion (MVI), a major prognostic factor in HCC. However, experience with PIVKA-II in Europe remains limited. Methods In a French cohort, we conducted a case-control study to compare the performances of α-fetoprotein (AFP) and PIVKA-II serum levels for diagnosis of early stage HCC, and we determined the value of PIVKA-II serum and tissue expression in pre-operative detection of MVI. 43 cirrhotic control patients and 85 HCC cases were included, of which 54 (63.5%) had early stage HCC (n = 22 very early, n = 32 early). PIVKA-II tissue expression was assessed by immunohistochemistry in HCC surgical samples. Results For the diagnosis of early HCC, PIVKA-II had a sensitivity of 77% and a specificity of 82% at a cut-off of 42 mAU/ml, vs. 61% and 50% for AFP at a cut-off of 5.5 ng/ml (AUC 0.81 vs. 0.58, respectively). A PIVKA-II level >90 mAU/ml was an independent predictor of MVI (HR 3.5; 95% CI 1.08–11.8; p = 0.043). High PIVKA-II tissue expression was significantly associated with the presence of MVI ( p = 0.001). When combining PIVKA-II immunostaining with the PIVKA-II serum level, sensitivity and specificity for the diagnosis of MVI increased from 70% to 87% and 63% to 90%, respectively. Conclusions PIVKA-II was more efficient than AFP for the diagnosis of early HCC, and could be used as a predictive biomarker of MVI. [ABSTRACT FROM AUTHOR]

Background: Alpha-fetoprotein (AFP) and prothrombin induced by vitamin K absence-II (PIVKA-II) are two commonly used biomarkers for detection and prognostic prediction of hepatocellular carcinoma (HCC). This study sought to evaluate and compare the use of these two biomarkers to detect HCC, as well as predict postoperative early recurrence (within 2 years after HCC resection).Methods: Data on consecutive patients who underwent curative resection for HCC between 2014 and 2020 was prospectively collected and reviewed. Serum AFP and PIVKA-II levels within one week before surgery or at the time of detection of early recurrence were assessed; preoperative AFP positivity (≥20 ng/ml) and preoperative PIVKA-II positivity (≥40 mAU/ml) were examined relative to recurrence using univariate and multivariate Cox-regression analyses.Results: Among 751 patients who underwent curative HCC resection, 589 (78.4%) patients had preoperative PIVKA-II positivity versus 498 (66.3%) patients had preoperative AFP positivity (P < 0.001). With a median follow-up of 41.6 months, 370 (50.1%) patients had an early HCC recurrence; among patients with an early recurrence, the proportion of patients with PIVKA-II positivity versus AFP positivity (76.5% vs. 60.0%, P = 0.002) was higher. On multivariate analysis, preoperative PIVKA-II positivity, but not preoperative AFP positivity was an independent risk factor to predict early recurrence after HCC resection.Conclusions: AFP and PIVKA-II are useful biomarkers to detect resectable HCC and predict early recurrence after HCC resection, with the latter showing higher rates of positivity. Preoperative PIVKA-II positivity was independently associated with early recurrence following HCC resection. [ABSTRACT FROM AUTHOR]

Aim: To determine the cutoff values and to compare the diagnostic role of alpha-fetoprotein (AFP) and prothrombin induced by vitamin K absence-II (PIVKA-II) in chronic hepatitis B (CHB)., Methods: A total of 1255 patients with CHB, including 157 patients with hepatocellular carcinoma (HCC), 879 with non-cirrhotic CHB and 219 with cirrhosis without HCC, were retrospectively enrolled. The areas under the receiver operating characteristic (AUROC) curves of PIVKA-II, AFP and their combination were calculated and compared., Results: The optimal cutoff values for PIVKA-II and AFP were 40 mAU/mL and 10 ng/mL, respectively, for the differentiation of HCC from nonmalignant CHB. The sensitivity and specificity were 73.9% and 89.7%, respectively, for PIVKA-II and 67.5% and 90.3% for AFP, respectively. The AUROC curves of both PIVKA-II and AFP were not significantly different (0.854 vs 0.853, P = 0.965) for the differentiation of HCC from nonmalignant CHB, whereas the AUROC of PIVKA-II was significantly better than that of AFP in patients with cirrhosis (0.870 vs 0.812, P = 0.042). When PIVKA-II and AFP were combined, the diagnostic power improved significantly compared to either AFP or PIVKA-II alone for the differentiation of HCC from nonmalignant CHB (P < 0.05), especially when cirrhosis was present (P < 0.05)., Conclusion: Serum PIVKA-II might be a better tumor marker than AFP, and its combination with AFP may enhance the early detection of HCC in patients with CHB.

Aim: To evaluate diagnostic value of α-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-II (PIVKA-II) in hepatocellular carcinoma (HCC)., Methods: 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., Results: 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., Conclusion: Combined determination of AFP-L3 and PIVKA-II could improve the diagnostic value for HCC detection in patients with or without increased AFP levels.