Protein Induced By Vitamin K antagonist-II Research Articles

PIVKA-II combined with alpha-fetoprotein for the diagnostic value of hepatic tumors in children: a multicenter, prospective observational study

BackgroundTo investigate whether protein induced by vitamin K antagonist-II (PIVKA-II) combined with alpha-fetoprotein (AFP) can improve the diagnostic and differential diagnostic accuracy of childhood hepatic tumors.MethodsA multi-center prospective observational study was performed at nine regional institutions around China. Children with hepatic mass (Group T) were divided into hepatoblastoma group (Group THB) and hemangioendothelioma group (Group THE), children with extrahepatic abdominal mass (Group C). Peripheral blood was collected from each patient prior to surgery or chemotherapy. The area under the curve (AUROC) was used to evaluate the diagnostic efficiency of PIVKA-II and the combined tumor markers with AFP.ResultsThe mean levels of PIVKA-II and AFP were both significantly higher in Group T than Group C (p = 0.001, p < 0.001), in Group THB than Group THE (p = 0.018, p = 0.013) and in advanced HB than non-advanced HB (p = 0.001, p = 0.021). For the diagnosis of childhood hepatic tumors, AUROC of PIVKA-II (cut-off value 32.6 mAU/mL) and AFP (cut-off value 120 ng/mL) was 0.867 and 0.857. The differential diagnostic value of PIVKA-II and AFP in hepatoblastoma from hemangioendothelioma was further assessed, AUROC of PIVKA-II (cut-off value 47.1mAU/mL) and AFP (cut-off value 560 ng/mL) was 0.876 and 0.743. The combined markers showed higher AUROC (0.891, 0.895 respectively) than PIVKA-II or AFP alone.ConclusionsThe serum level of PIVKA-II was significantly higher in children with hepatic tumors, especially those with malignant tumors. The combination of PIVKA-II with AFP further increased the diagnostic performance.Trial registrationClinical Trials, NCT03645655. Registered 20 August 2018, https://www.clinicaltrials.gov/ct2/show/NCT03645655.

Glasgow Prognostic Score Predicts Survival and Recurrence Pattern in Patients With Hepatocellular Carcinoma After Hepatectomy.

The prognostic significance of the Glasgow Prognostic Score (GPS) on outcomes of liver resection for hepatocellular carcinoma (HCC) remains unclear; the aim of the study was to assess its significance. A total of 480 patients with HCC who underwent liver resection with curative intent at the Yokohama City University Hospital and Medical Center were enrolled in the study. Patients were classified into three groups: GPS-0, C-reactive protein (CRP) ≤1.0 mg/dl serum albumin ≥3.5 g/dl; GPS-1, CRP >1.0 mg/dl or serum albumin <3.5 g/dl; and GPS-2, CRP >1.0 mg/dl, serum albumin <3.5 g/dl. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. The recurrence pattern was also investigated using GPS. Of the 480 patients, 382 (79.6%), 81 (16.9%), and 17 (3.5%) were assigned to GPS-0, GPS-1, and GPS-2, respectively. Elevated GPS, indocyanine green retention rate at 15 min, and protein induced by vitamin K antagonist-II (PIVKA-II) were significantly associated with a poor OS. Elevated GPS, alpha-fetoprotein, and PIVKA-II were significantly associated with a poor DFS by multivariate analysis. The number of patients with liver-only recurrence in GPS-0, GPS-1, and GPS-2 was 179 (86.1%), 40 (78.4%), and 9 (69.2%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-0, GPS-1, and GPS-2 groups, was 33 (17.9%), 11 (27.5%), and 8 (88.9%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-2 group was significantly higher (p<0.001). Preoperative GPS is a useful predictor of OS and recurrence pattern after liver resection with a curative intent for HCC.

A nomogram to predict microvascular invasion in early hepatocellular carcinoma.

To construct an integrated nomogram combining protein induced by vitamin K antagonist-II (PIVKA-II), alpha fetoprotein (AFP) and other clinical factors to detect microvascular invasion (MVI) in early hepatocellular carcinoma (HCC) patients with single nodule. One hundred and eleven early HCC patients were enrolled in the present study and 43 early HCC patients were diagnosed with MVI. Serum levels of PIVKA-II, AFP and other laboratory indicators were detected. Chi-squared test, t-test and logistic regression were employed in statistic analysis. A nomogram combining independent predictors was constructed and internal validated. In early HCC patients with MVI, PIVKA-II serum level was significantly higher than those without MVI (385.97 mAU/ml vs 67.08 mAU/ml; P < 0.01), as well as AFP serum level (81.6 ng/mL vs 9.15 ng/mL P = 0.001). PIVAK-II, AFP serum levels and tumor size were independent risk factors for MVI in early HCC, which was employed to develop a logistic regression model. The area under the ROC curve (AUROC) of the model was 0.74 (95%CI 0.65 - 0.84). A nomogram combining PIVKA-II, AFP and tumor size was constructed and calibration curves showed that the model was accurate in predicting the risk of MVI in early HCC patients. The present study indicates that a preoperative nomogram combining PIVKA-II, AFP and tumor size could estimate the preoperative probability of MVI in early HCC patients, which may help clinicians in choosing treatment options and prognosis evaluation.

A Novel LC-MS/MS Assay for Quantification of Des-carboxy Prothrombin and Characterization of Warfarin-Induced Changes.

Warfarin is a narrow therapeutic index anticoagulant drug and its use is associated with infrequent but significant adverse bleeding events. The international normalized ratio (INR) is the most commonly used biomarker to monitor and titrate warfarin therapy. However, INR is derived from a functional assay, which determines clotting efficiency at the time of measurement and is susceptible to technical variability. Protein induced by vitamin K antagonist‐II (PIVKA‐II) has been suggested as a biomarker of long‐term vitamin K status, providing mechanistic insights about variation in the functional assay. However, the currently available antibody‐based PIVKA‐II assay does not inform on the position and number of des‐carboxylation sites in prothrombin. The assay presented in this paper provides simultaneous quantification of carboxy and des‐carboxy prothrombin that are essential for monitoring early changes in INR and, thus, serves as the superior tool for managing warfarin therapy. Additionally, this assay permits the quantification of total prothrombin level, which is affected by warfarin treatment. Prothrombin recovery from plasma was 95% and the liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay was linear (r 2 = 0.98) with a dynamic range of 1–100 µg/mL. The assay interday precision was within 20%. A des‐carboxy peptide of prothrombin (GNLER) was negatively correlated with active prothrombin (Pearson r = 0.99, P < 0.0001), whereas its association was positively linked with INR values (Pearson r = 0.75, P < 0.015). This novel LC‐MS/MS assay for active and inactive prothrombin quantification can be applied to titrate anticoagulant therapy and to monitor the impact of diseases, such as hepatocellular carcinoma on clotting physiology.

Development And Validation Of A Simple Model For Detection Of Early Hepatocellular Carcinoma In A Liver Cirrhosis Cohort.

AimWe aimed to develop a simple model combining protein induced by vitamin K antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) to detect early hepatocellular carcinoma (HCC) in liver cirrhosis (LC) patients.MethodOne hundred and sixty-nine newly diagnosed early HCC patients and 242 LC patients without HCC were enrolled in the current case-control study. All subjects were randomly divided into analysis group and validation group. Serum levels of PIVKA-II, AFP and other laboratory parameters were detected. Chi-squared test, t-test and logistic regression were employed in statistical analysis.ResultsPIVKA-II level in early HCC was significantly higher than that in LC (90.97 mAU/mL vs 18.00 mAU/mL, P < 0.01), as well as AFP level (15.00 ng/mL vs 2.00 ng/mL, P < 0.01) in analysis groups. Multivariate analysis showed that PIVAK-II, AFP, gender, and age were independent risk factors for early HCC detection among LC patients. A logistic regression model and a simple model combining PIVKA and AFP were conducted to detect early HCC. The ROC curve showed that among analysis groups, the area under the ROC curve (AUROC) of the logistic regression model and the simple model were 0.96 (95% CI 0.94–0.98) and 0.94 (95% CI 0.92–0.97), respectively. At a cut-off value of 56.03 the sensitivity and specificity of the simple model were 81.1% and 91.4%, respectively. In the validation group, the sensitivity and specificity of the simple model was 82.4% and 94.2%, respectively. The two models are comparable statistically for early HCC detection, but the logistic regression requires complex calculation.ConclusionThe present study indicates that the simple model combining PIVKA-II and AFP has comparable diagnostic efficiency in contrast to the logistic model but is easy to use clinically. It might be helpful for early HCC detection among liver cirrhosis patients.

Transient increases in serum α fetoprotein and protein induced by vitamin K antagonist II levels following proton therapy does not necessarily indicate progression of hepatocellular carcinoma.

Transient increases in α-fetoprotein (AFP) and protein induced by vitamin K antagonist II (PIVKA-II), so-called flares, are frequently observed after treatment of hepatocellular carcinoma (HCC). In the present study, changes in AFP and PIVKA-II levels after proton therapy (PT), and the relationship between the flare phenomenon and clinical response were investigated. In 82 patients with stage I/II HCC (59 with no recurrence and 23 with out-of-field recurrence within 1 year), serum AFP and PIVKA-II levels were measured at 1, 3, 6, 9 and 12 months post-PT. AFP and PIVKA-II flares were defined as a >20% increase from the preceding serum level above 20 ng/ml (AFP) or 40 mAU/ml (PIVKA-II), followed by a >20% drop. Among the 59 patients with no recurrence, 3 (5.1%) had an AFP flare, while 23 (39%) had a PIVKA-II flare. The median time to AFP and PIVKA-II flare peaks was 1 and 6 months, respectively. In 4 patients, PIVKA-II flares were observed twice during follow-up. In 1 patient, AFP and PIVKA-II flares were observed simultaneously at 1 month post-PT. The PIVKA-II level pre-PT was significantly higher in the PIVKA-II flare-positive group compared with that in the flare-negative group (P=0.015, odds ratio 4.3, 95% confidence interval, 1.3-14.0). In the 23 patients with out-of-field recurrence, the median increase rate of PIVKA-II (203%) was higher than that in the PIVKA-II-flare-positive group (111%, P=0.035) and the time to recurrence (median, 9 months) was longer than the time to peak AFP level (1 month) in the AFP-flare-positive group (P=0.033). There was no significant association between flares and clinical response. Increases in AFP and PIVKA-II levels following PT should be assessed with caution to avoid misinterpretation of therapeutic outcome.

Incidental microscopic bile duct tumor thrombi in hepatocellular carcinoma after curative hepatectomy: a matched study.

In patients with hepatocellular carcinoma (HCC), the presence of bile duct tumor thrombi (BDTT) in the major bile ducts indicates poor prognosis compared with that of HCC patients without BDTT. However, the prognostic significance of incidental microscopic BDTT in the peripheral bile ducts after curative liver resection is not known. We compared the outcomes of HCC patients with and without microscopic BDTT in the peripheral bile ducts who underwent hepatectomy.The electronic medical records of 31 patients with microscopic BDTT (BDTT group) were retrospectively reviewed. To compare the surgical outcomes, 62 patients (No BDTT group) were randomly chosen from the remaining HCC patients without BDTT based on age, sex, etiology of HCC, tumor size, tumor number, and modified Union for International Cancer Control T staging.The 1-year, 2-year, and 3-year disease-free survival rates and overall survival rates were 54.8%, 34.0%, 34.0% and 90.1%, 69.2%, 61.0% in the BDTT group and 66.8%, 59.2%, 42.3% and 86.4%, 84.4%, 84.4% in the No BDTT group (P = 0.089 and P = 0.014, respectively). The overall survival curve in the No BDTT group was higher than that in the BDTT group. Multivariate analysis revealed that predisposing factors for tumor recurrence after curative liver resection included increased levels of the protein induced by vitamin K antagonist-II (PIVKA-II), tumor grades 3 and 4, and the presence of BDTT.This study demonstrates that HCC prognosis is worse in patients with incidental microscopic BDTT in the peripheral bile ducts than it is in those without BDTT. The presence of BDTT should therefore be considered when evaluating a patient's HCC prognosis after curative hepatectomy.

The prognosis in cases of hepatocellular carcinoma after hepatectomy: young patients versus older patients.

Backgrounds/AimsHepatocellular carcinoma (HCC) is uncommon in young adults and the prognosis of these patients is still unclear. In this retrospective study, we compared the clinicopathological characteristics and outcomes of young patients with HCC with those of older patients with HCC.MethodsWe retrospectively reviewed the clinicopathological characteristics of a total of 1,124 patients with HCC who underwent hepatectomy at our institution between 2006 and 2010. Patients ≤40 years of age at the time of HCC diagnosis were classified in the younger group.ResultsOne hundred and three patients (9.2%) were classified in the younger group. whereas, 1021 patients were classified in the older group. The incidences of hepatitis B virus infection, alpha-fetoprotein (AFP) levels, and indocyanine green retention test were all higher in younger patients than in older patients (p<0.05). Disease-free survival and overall survival were longer in older patients than in younger patients, without statistical significance. In younger patients, increased levels of protein induced by vitamin K antagonist-II (PIVKA-II) and alkaline phosphatase, portal vein tumor thrombosis, and intrahepatic metastasis were all predisposing factors for tumor recurrence after hepatectomy.ConclusionsAlthough the AFP levels were higher in younger patients with HCC than in older patients with HCC, disease-free survival and overall survival after liver resection were not significantly different between the two groups.

Differences Between Hepatocellular Carcinoma and Hepatitis B Virus Infection in Patients With and Without Cirrhosis

In patients with hepatitis B virus (HBV) infections, differences in hepatocellular carcinoma (HCC) between those with liver cirrhosis and those without cirrhosis have not been elucidated. The aim of this study was to compare clinicopathological characteristics and survival between noncirrhotic and cirrhotic patients and to determine prognostic factors for tumor recurrence after hepatectomy in patients with HBV and HCC. Between 2005 and 2010, 441 curative hepatectomies for HCC in patients with cirrhosis and 454 for HCC in patients without cirrhosis were performed. Cirrhotic patients had lower platelet counts, protein induced by vitamin K antagonist-II (PIVKA-II) levels, and tumor size than noncirrhotic patients. HCC differentiation in noncirrhotic patients was poorer than in cirrhotic patients. The 1-, 2-, and 3-year disease-free survival rates were 72.0, 65.6, and 61.0% in noncirrhotic patients, and 68.6, 56.5, and 51.5% in cirrhotic patients, respectively (P = 0.013). However, the 1-, 2-, and 3-year overall survival rates were 92.4, 85.5, and 81.7% in noncirrhotic patients, and 91.9, 86.1, and 82.4% in cirrhotic patients, respectively (P = 0.683). Risk factors for tumor recurrence in each group varied in multivariate analyses. Increased age, high platelet counts, microvascular invasion, serosal invasion, and intrahepatic metastasis predisposed to tumor recurrence in noncirrhotic patients, but elevated PIVKA-II and alkaline phosphatase levels, low serum albumin levels, portal vein invasion, intrahepatic metastasis, and tumor size were predisposing factors for recurrence in cirrhotic patients. The clinicopathologic characteristics and risk factors for tumor recurrence in cirrhotic and noncirrhotic HCC patients with HBV infection differ.

Protein Induced by Vitamin K Antagonist‐II (PIVKA‐II) Is a Reliable Prognostic Factor in Small Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) <2 cm in diameter has a favorable prognosis. Therefore surgical resection of small HCC is associated with good outcomes. However, the predisposing factors of prognosis following resection of HCC remain ill-defined. The aims of the present study were to identify the clinicopathologic characteristics and outcomes of patients with small HCC and analyze the predisposing factors for tumor recurrence after surgery. We retrospectively reviewed 180 patients with small HCC who underwent hepatectomy between 2006 and 2010. Independent predictors of tumor recurrence were identified with Cox regression analysis. The 1-year, 3-year, and 5-year disease-free survival rates and overall survival rates were 83.7, 68.0, 65.3, and 98.9, 96.5, 92.7 %, respectively. Multivariate analysis reported that protein induced by the vitamin K antagonist-II (PIVKA-II) ≥ 200 mAU/mL, alkaline phosphatase (ALP) ≥ 80 IU/mL, and microvascular invasion were important predisposing factors for tumor recurrence. Elevated serum PIVKA-II level was associated with microvascular invasion in small HCC, which was a powerful predisposing factor. Although small HCC is generally associated with a good prognosis, serum PIVKA-II level ≥ 200 mAU/mL, ALP ≥ 80 IU/L, and microvascular invasion were predisposing factors for tumor recurrence. These factors can be used to stratify patients with respect to recurrence after resection. Elevated PIVKA-II was closely associated with microvascular invasion in small HCC. These data emphasize the importance of PIVKA-II in small HCC.

High frequency of hepatocellular carcinoma in Mongolia; association with mono-, or Co-infection with hepatitis C, B, and delta viruses

To investigate the association between viral infection pattern and hepatocellular carcinoma (HCC), 292 chronic hepatitis patients, including 108 with developed HCC were screened using serological and molecular genetics methods. Viral etiology was established in 267 (91.4%), anti-HCV detected in 198 (67.8%), and HBsAg in 124 (42.5%) including 93 (74.4%) cases with HDV co-infection. HCV mono-infection predominated in both, "non-HCC" and "HCC" groups (54% and 39%, respectively) with higher frequency in the first group (P = 0.011), whereas HBV in co-infection with HDV was more frequent in HCC group (14% vs 25%, P = 0.017). Patients with HCV mono-infection were older than those with co-infection (P<0.02), had higher frequency of HCV-viraemia (82% vs 7%, P < 0.0001), and yet had significantly lower prevalence of HCC (29.6% vs. 49.1%, P = 0.003). Alpha-fetoprotein (AFP) and protein induced by vitamin K antagonist-II (PIVKA-II) were specifically elevated in 71% of HCC patients. In conclusion, although HCV monoinfection pattern predominates in Mongolia, co-infection with HBV and HDV had stronger association with HCC development at younger age. Liver tumor markers; AFP and PIVKA-II are useful tools for complex HCC-screening and clinical follow-up for chronic hepatitis patients in Mongolia.

Analysis of α-fetoprotein mRNA in peripheral blood: detection and semi-quantitation by reverse transcription polymerase chain reaction

The presence of α-fetoprotein (AFP) mRNA in mononuclear cells of the peripheral blood was examined in patients with hepatocellular carcinoma (HCC), liver cirrhosis, chronic hepatitis and normal volunteers using nested reverse transcription polymerase chain reaction (RT-PCR). Then, the AFP mRNA levels were quantitatively analyzed in AFP mRNA-positive patients with HCC. AFP mRNA was detected in 23 of 38 (60.5%) cases with HCC, 2 of 12 (16.7%) cases with cirrhosis, and 1 of 9 (11.1%) cases with chronic hepatitis, respectively. AFP mRNA was not demonstrated in six healthy volunteers. The frequency of positive cases in TNM stage III–IV (16/21, 76.2%) was significantly higher than that in stage I–II (7/17, 41.2%)( P<0.05). AFP mRNA was detected more frequently in patients with positive levels of serum protein induced by vitamin K antagonist II (PIVKA-II) (≥40 mAU/ml, 18/25, 72.0%) than in those with negative level (40 mAU/ml, 5/13, 38.5%) ( P<0.05). However, there was no significant correlation between detectable rate of AFP mRNA and serum AFP level. The frequency of AFP mRNA positive result was not closely associated with L. culinaris agglutinin A, a reactive α-fetoprotein (AFP L3). On the other hand, the expression levels of AFP mRNA were measured in 23 AFP mRNA-positive patients with HCC. Quantitative analysis of AFP mRNA was performed by comparing the amplification kinetic curve of AFP mRNA with that of β-actin mRNA as an internal control. The AFP mRNA levels were expressed as Δ cycle values by this method. Δ cycle values were significantly increased in patients with HCC in stages III–IV (4.7±2.4) compared with patients with HCC in stages I–II (−1.3±7.3) ( P<0.01). These results suggested that the detection and quantitation of AFP mRNA in peripheral blood may indicate the hematogenous spreading of tumor cells in patients with HCC.