Prothrombin Induced By Vitamin K absence-II Research Articles

Effect of PIVKA-II and AFP secretion status on early recurrence of hepatocellular carcinoma after open and laparoscopic surgery.

Prothrombin induced by vitamin K absence-II (PIVKA-II) and Alpha-fetoprotein (AFP) have been widely used as diagnostic markers in hepatocellular carcinoma (HCC), but the prognostic values of the two serum markers and their clinical usefulness in patient selection for different surgical approaches remain largely unclear. HCC patients received surgical treatment between 2015 and 2019 were included. Patients were divided into four statuses according to the serum PIVKA-II and AFP secretion status: PIVKA-II (-) AFP (-) (status 1); PIVKA-II (+) AFP (-) (status 2); PIVKA-II (-) AFP (+) (status 3); PIVKA-II (+) AFP (+) (status 4). Kaplan-Meier analyses were conducted to compare the survivals of the four groups and the HCC patients received different surgical interventions; time-dependent AUC curves were introduced to evaluate the prognostic value of the PIV-AFP status; Cox regression model was used to identify prognostic indexes for overall survival (OS) and recurrence-free survival (RFS). A total of 518 patients were included. Patients with PIVKA-II (+) and APF (+) presented significantly decreased OS and RFS comparing to the other statuses. The areas under ROC curves of PIV-AFP status in predicting OS and RFS were superior to the PIVKA-II or the AFP alone. The HCC patients in early stages with PIVKA-II (+) and APF (+) had worse RFS when received laparoscopic hepatectomy than those who received open hepatectomy, whereas there was no difference in other secretion statuses. The PIVKA-II (+) and AFP (+) secretion status was an independent risk factor for OS, RFS. The PIV-AFP secretion status is of favorable clinical utility in predicting the OS and RFS of the HCC patients; extra caution is needed when applicated the laparoscopic approach in the HCC patients with PIVKA-II (+) and AFP (+).

SP70 is a novel biomarker of hepatocellular carcinoma.

Tumor-specific protein 70 (SP70) was identified as a new biomarker associated with the proliferation and invasion of cancer cells. This study aimed to investigate the expression of SP70 in hepatocellular carcinoma (HCC) and assess its clinical value in the diagnosis and prediction of early HCC recurrence. A total of 1049 subjects from the First Affiliated Hospital of Nanjing Medical University were recruited in this study. Serum SP70, alpha-fetoprotein (AFP) and prothrombin induced by vitamin K absence II (PIVKA-II) were measured. The diagnostic performance for HCC was obtained using the receiver operating characteristic (ROC) curve, and recurrence-free survival (RFS) was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify predictive factors of RFS. SP70 was highly expressed in HCC cells and HCC tissue. Serum SP70 levels in the HCC group were significantly higher than in the benign liver diseases group and healthy control group (P<0.001). SP70 combined with AFP showed the best diagnostic performance (AUC=0.909, 95%CI [confidence interval]=0.890-0.929). Kaplan-Meier analysis revealed that patients with high SP70 levels had shorter median RFS than those with low SP70 levels (P=0.003). In addition, high SP70 levels were significantly associated with shorter RFS (P=0.037) in the AFP-negative subgroup. Univariate and multivariate analyses confirmed that preoperative serum SP70 level, serum AFP, tumor diameter and microvascular invasion were independent prognostic factors of RFS. SP70 is a promising biomarker in diagnosing HCC. High preoperative serum SP70 level is associated with an increased risk of early relapse and could be used as a valuable marker to predict early recurrence of HCC after resection.

Prothrombin induced by vitamin K Absence-II versus alpha-fetoprotein in detection of both resectable hepatocellular carcinoma and early recurrence after curative liver resection: A retrospective cohort study

BackgroundAlpha-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). MethodsData 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. ResultsAmong 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. ConclusionsAFP 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.

Usefulness of AFP, PIVKA-II, and Their Combination in Diagnosing Hepatocellular Carcinoma Based on Upconversion Luminescence Immunochromatography.

To evaluate the prognostic values of serum PIVKA-II (prothrombin induced by vitamin K absence-II) and α-fetoprotein (AFP) and the combination of these analytes for identifying hepatocellular carcinoma (HCC), and to analyze the correlation between biomarkers and clinicopathological features of HCC. The levels of PIVKA-II and AFP in 331 case individuals were determined by upconverting phosphor technology-based immune lateral flow (UPT-LF) assay. We used the ROC curve to determine the diagnostic value; the relationships between the biomarkers and clinicopathological features of HCC also were analyzed. AFP and PIVKA-II have good diagnostic performance in the diagnosis of HCC; the best AUC was 0.76, 0.74. High levels of PIVKA-II were more advantageous than AFP in predicting tumor size, portal-vein embolism, and vascular invasion (all P <.05). Levels of PIVKA-II and AFP showed good diagnostic value for HCC, but the level of PIVKA-II was more closely related to the clinicopathological features of HCC.

The potential of PIVKA-II as a treatment response biomarker in hepatocellular carcinoma: a prospective United Kingdom cohort study.

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.

Progressionof Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma.

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.

Пребывают ли младенцы, которых кормят исключительно грудным молоком, в состоянии дефицита витамина К? (К 20-летию истории вопроса)

Актуальность. «Are breast-fed infants vitamin K deficient?» — этот вопрос F.R. Greer сформулировал в 2001 году в исследовании, ставшем классическим. Цель: определение концентрации субстанции Рrotein induced by vitamin K absence ІІ (PIVKA-II) и протромбинового комплекса как маркеров скрытого дефицита витамина К у детей первых 6 месяцев жизни, получающих исключительно естественное вскармливание. Материалы и методы. Всего исследованы 264 ребенка в возрасте от рождения до 6 месяцев, которые находились в удовлетворительном состоянии и не имели изменений в общих анализах крови и результатах тестов гепатобилиарной системы. Результаты. В раннем неонатальном периоде 62 (83,8 %) ребенка из 74, не получавших витамин К, имели показатели PIVKA-II больше нормы, составляющей 40 усл.ед/мл. У 17 (77,3 %) из 22 детей в возрасте от 8 до 28 суток жизни, не получавших витамин К после рождения, уровень PIVKA-II был в пределах нормы. Из 31 младенца, которые получили профилактический болюс витамина К1, на первой неделе жизни 92 % имеют показатели PIVKA-II в пределах нормы. У 12 (54,5 %) из 22 детей в возрасте от 28 до 180 дней, обследованных после лечения антибиотиками, показатели PIVKA-II были выше нормы. Применение антибиотиков у детей было ассоциировано с повышенным концентрациями РIVKA-II, что может свидетельствовать о скрытом приобретенном дефиците витамина К, или о его возобновлении после рождения. Исследование протромбинового комплекса у этих же детей установило по медианам и квартальным оценкам (Me 25–75) снижение содержания протромбина по Квику до 62 % (18–91 %), удлинение протромбинового времени до 18 с (13–22 с) и увеличение международного нормализованного отношения до 1,4 (1,1–2,6). Выводы. Таким образом, у детей указанной группы возникло состояние гипокоагуляции, при совпадении других неблагоприятных обстоятельств вполне достаточное для развития поздней геморрагической болезни.

Clinical Utility of Protein Induced by Vitamin K Absence-II in Patients with Hepatocellular Carcinoma.

Objective:Despite moderate sensitivity, alpha fetoprotein (AFP) is widely used in screening and prognostication for hepatocellular carcinoma (HCC). The objective of the current study was to assess clinical utility of Prothrombin induced by Vitamin K absence-II (PIVKAII) in addition to AFP in patients with HCC. Methods:We retrospectively reviewed 244 patients with documented AFP, PIVKA II and dynamic imaging of the liver. Using ROC curves, cutoff values for AFP and PIVKAII for HCC detection, tumor grade and microvascular invasion (MVI) were assessed. In patients who underwent liver transplantation (LT) for HCC, survival was determined using Kaplan Meier curves. Results:The median PIVKAII in healthy living donors was 28.6mAU/ml (15.9-55). In cirrhotics, the sensitivity of an AFP cutoff of 7.6 ng/ml or PIVKAII cutoff of 250 mAU/ml for HCC detection was 91.7% (176/192) and specificity was 62.9%(68/108) (P<0.0001). In patients with HCC, PIVKAII values were significantly elevated with tumor size > 5 cm (P < 0.0001), tumor nodules > 3(P=0.01), and macrovascular invasion(P<0.0001). The high risk group (patients with AFP ≥ 40 ng/ml + PIVKAII ≥ 350 mAU/ml), had a sensitivity of (23/33) 69.6% and specificity of (22/22)100% for MVI (P <0.001). The estimated 3 year RFS after LT in the low risk group (AFP <40 ng/ml or PIVKAII< 350 mAU/ml) was 100% versus 63%(P=0.001). The estimated 3 year RFS based with and without MVI was 80% and 100% (P=0.03). Conclusion:PIVKAII in combination with AFP, appears to have a promising role in surveillance and prognostication for HCC. It also allows improved patient selection for liver transplantation.

Association between Prothrombin Induced by Vitamin K Absence-II (PIVKA-II) and Barcelona Clinic Liver Cancer (BCLC) Stage, Tumor Size, Portal Venous Thrombosis in Hepatocellular Carcinoma Patients

Hepatocellular carcinoma is one of the major cancer problems in the world because of the low early screening awareness in patients. Serum alpha-fetoprotein is not adequate as a single screening tool, especially for small HCCs, thus, prothrombin induced by vitamin K absence-II (PIVKA-II) can help in detecting small HCCs. Barcelona Clinic Liver Cancer (BCLC) stage remains to be the preferred HCC classification because it can predict the outcome and help in choosing available treatment options according to stages. This study aims to investigate the association between PIVKA-II levels with BCLC stage, tumor size, portal venous thrombosis in HCC patients. We enrolled patients with newly diagnosed HCC at the Adam Malik General Hospital, Medan, Indonesia from January to December 2018. Patients with HCC were classified according to BCLC stages, findings of portal venous thrombosis and tumor size from triphasic CT scan were noted, and serum PIVKA-II levels were measured. Sixty patients were included in this study. There were significant differences in serum PIVKA-II levels with different stages of BCLC (p &lt; 0.001). Significantly higher serum PIVKA-II levels were detected in patients with portal venous thrombosis (p &lt; 0.001) and larger size tumors (p &lt; 0.003). Our study shows that serum PIVKA-II levels can help to diagnose, differentiate between stages of BCLC, and determine the prognosis in patients with HCC.

The Diagnostic Value of Serum PIVKA-II Alone or in Combination with AFP in Chinese Hepatocellular Carcinoma Patients.

Background At present, the diagnostic accuracy of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is insufficient. It remains controversial whether prothrombin induced by vitamin K absence II (PIVKA-II) has a better diagnostic value than AFP for HCC patients. Objective To investigate the diagnostic role of PIVKA-II alone or in combination with AFP in Chinese HCC patients. Methods Serum AFP and PIVKA-II levels were detected and analyzed in 308 HCC afflicted patients and 120 unafflicted controls. The receiver operator curve (ROC) and area under the curve (AUC) were conducted to evaluate the clinical value of AFP and PIVKA-II for diagnosing HCC and early HCC. Results In the whole HCC cohort, the diagnostic values of PIVKA-II were better than that of AFP. The AUC of PIVKA-II and AFP was 0.90 (95% CI 0.87-0.94) and 0.79 (95% CI 0.74-0.84), respectively. “AFP + PIVKA-II” yielded a high sensitivity of 95.1% and a specificity of 83.3%, with the AUC 0.89 (95% CI 0.85-0.93). In the early stage HCC group, the diagnostic accuracy of PIVKA-II was also better than that of AFP. The AUC of PIVKA-II and AFP was 0.83 (95% CI 0.77-0.89) and 0.75 (95% CI 0.68-0.81), respectively. “AFP + PIVKA-II” achieved the sensitivity of 83.3% and specificity of 89.1%, with an AUC of 0.86 (95% CI 0.81-0.91). Moreover, for AFP-negative HCC patients, serum PIVKA-II showed good diagnostic performance, with an AUC of 0.804 (95% CI 0.720-0.887). Besides, elevated PIVKA-II level was a strong independent risk factor for HCC patients with portal vein tumor thrombus (PVTT) (OR = 4.890, P = 0.020). Conclusion PIVKA-II is superior to AFP in HCC screening, and AFP in combination with PIVKA-II significantly improves the diagnostic value for Chinese HCC patients. PIVKA-II could effectively indicate HCC accompanied by PVTT and help to optimize the therapeutic strategy.

PIVKA_II a useful biomarker for hepatocellular carcinoma in caucasian HCV cirrhotic patients treated with direct-acting antivirals

Introduction: Prothrombin induced by vitamin K absence-II (PIVKA-II) performance as hepatocellular carcinoma (HCC) marker in HCV cirrhotics treated with direct-acting antivirals (DAA) is unknown.

Diagnostic performance of protein induced by vitamin K absence II for chronic hepatitis B-related hepatocellular carcinoma

Background: The aim of this study was to assess the diagnostic value of prothrombin induced by vitamin K absence-II (PIVKA-II) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in a Chinese population. Methods: In this study, receiver operating characteristics (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated to assess the diagnostic performance of serum PIVKA-II levels for HBV-related HCC (n=134) with negative or mildly elevated α-fetoprotein (AFP) relative to chronic hepatitis B (CHB, n=119) patients or healthy controls (n=100). Results: Serum levels of PIVKA-II were significantly greater in the HBV-related HCC patients compared to the CHB patients (P Conclusions: PIVKA-II shows high discriminatory ability and improvement of the detection rate for HBV-related HCC in a Chinese population with normal or mildly elevated AFP.

Unique Biological Activity and Potential Role of Monomeric Laminin-γ2 as a Novel Biomarker for Hepatocellular Carcinoma: A Review.

Laminin (Ln)-332 consists of α3, β3, and γ2 chains, which mediate epithelial cell adhesion to the basement membrane. Ln-γ2, a component of Ln-332, is frequently expressed as a monomer in the invasion front of several types of malignant tissues without simultaneous expression of Ln-α3 and/or Ln-β3 chains. Moreover, monomeric Ln-γ2 induces tumor cell proliferation and migration in vitro. These unique biological activities indicate that monomeric Ln-γ2 could be a candidate biomarker for early cancer surveillance. However, the present immune method for monomeric Ln-γ2 detection can only predict its expression, since no antibody that specifically reacts with monomeric γ2, but not with heterotrimeric γ2 chain, is commercially available. We have, therefore, developed monoclonal antibodies to specifically detect monomeric Ln-γ2, and devised a highly sensitive method to measure serum monomeric Ln-γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). We evaluated its diagnostic value in sera from patients with several digestive cancers, including hepatocellular carcinoma (HCC), and found serum monomeric Ln-γ2 to be a clinically available biomarker for HCC surveillance. The combination of monomeric Ln-γ2 and prothrombin induced by Vitamin K Absence II (PIVKA-II) may be more sensitive for clinical diagnosis of HCC than any currently used combination.

Diagnostic value of serum PIVKA-II levels for BCLC early hepatocellular carcinoma and correlation with HBV DNA.

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. 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. 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 onehealthy controls, 37chronic hepatitis patients, 43cirrhotic patients and 143HCC 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). 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 > 166mAU/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. PIVKA-II was more efficient than AFP for the diagnosis of early HCC and has no correlation with serum HBV DNA levels.

Prognostic value of PIVKA-II in hepatocellular carcinoma patients receiving curative ablation: A systematic review and meta-analysis.

Several studies have been conducted to evaluate the prognostic value of prothrombin induced by vitamin K absence-II (PIVKA-II) overexpression in hepatocellular carcinoma patients treated with curative ablation. However, the results remain controversial. The purpose of this meta-analysis was to explore the correlation between PIVKA-II expression and survival outcomes in these patients. We performed a systematic literature search in PubMed, EMBASE, Medline, Cochrane Library, and Web of Science to identify the relevant articles investigating the prognostic value of PIVKA-II in patients with hepatocellular carcinoma. Combined hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival and recurrence-free survival were calculated as the analysis endpoints. A total of 15 cohorts encompassing 5647 patients were included. The results indicated that elevated PIVKA-II was significantly associated with poorer overall survival (HR 1.59; 95% CI 1.40, 1.82; P < 0.001) and recurrence-free survival (HR 1.76; 95% CI 1.42, 2.17; P < 0.001). Similar results were observed in the subgroup analysis based on sample size, analytical method, treatment modality, and cut-off value. This meta-analysis suggests that elevated PIVKA-II is a predictor of unfavorable overall survival and recurrence-free survival in hepatocellular carcinoma patients receiving curative ablation. More rigorous studies are warranted to confirm the clinical utility of PIVKA-II in determining hepatocellular carcinoma prognosis.

Significance of PIVKA-II levels for predicting microvascular invasion and tumor cell proliferation in Chinese patients with hepatitis B virus-associated hepatocellular carcinoma.

The present study aimed to determine the levels of prothrombin induced by vitamin K absence-II (PIVKA-II) according to the Barcelona Clinic Liver Cancer (BCLC) staging system, to develop an appropriate strategy for managing hepatocellular carcinoma (HCC), particularly early HCC, and to investigate the value of PIVKA-II for predicting prognosis-associated pathological parameters. Clinical information of 117 patients with hepatitis B-associated HCC was retrospectively collected. Preoperative serum PIVKA-II and α-fetoprotein (AFP) levels were measured using a chemiluminescence method. The efficiency of PIVKA-II levels for predicting pathological parameters was evaluated using step-wise logistic regression. The receiver operator characteristic curve was used to evaluate the predictive performance of PIVKA-II levels. It was demonstrated that except for the difference between stages B and C HCC (P=0.923), serum PIVKA-II levels significantly increased according to BCLC stage (P<0.050), however AFP levels did not. In early HCC (stage 0+A), the correlation between PIVKA-II and AFP levels (dual-positive, 64.70% in stage 0; 46.97% in stage A) was relatively weak (r=0.410). PIVKA-II >40 mAU/ml was an independent predictor of microvascular invasion [hazard ratio (HR), 3.77; 95% confidence interval (CI), 1.31–10.88; P=0.014; and high Ki67 expression in situ (HR, 2.99; 95% CI, 1.19–7.52; P=0.020). Combined analysis of PIVKA and AFP levels may contribute to an effective strategy for the management of patients with early HCC, as high PIVKA-II levels indicated a more aggressive tumor phenotype. Further investigation of PIVKA-II levels may provide novel insights into the mechanism underlying the metastasis of HCC cells and facilitate the development of novel therapeutic strategies for HCC.

Diagnostic Value of PIVKA-II in Detecting Hepatocellular Carcinoma

Aim: Evaluation of prothrombin induced by vitamin K absence-II (PIVKA-II) in detecting hepatitis B virus-associated hepatocellular carcinoma (HCC). Materials &amp; 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 (&lt;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.

Evaluation of prothrombin induced by vitamin K absence, macrophage migration inhibitory factor and Golgi protein-73 versus alpha fetoprotein for hepatocellular carcinoma diagnosis and surveillance

Hepatocellular carcinoma (HCC) represents a challenging malignancy of worldwide importance. It is the third most common cause of cancer-related death globally as most patients present with unresectable disease. Alpha-fetoprotein (AFP) is the widely and solely used biomarker for HCC diagnosis; yet, its usefulness is hampered by low sensitivity and specificity. We aimed to identify more sensitive biomarkers for HCC diagnosis and a surveillance algorithm that may facilitate early detection of HCC. A total of 305 Egyptian and Saudi participants grouped as healthy controls, cancer controls, benign hepatic lesions, chronic viral hepatitis and HCC were included. Serum AFP, prothrombin induced by vitamin K absence-II (PIVKA-II), macrophage migration inhibitory factor (MIF) and Golgi protein-73 (GP-73) levels were quantitated by enzyme immunoassay. Significantly higher levels of GP-73 and PIVKA-II were detected in the HCC group than in all other groups, while MIF showed a highly significant increase in HCC from all groups except the cancer control group. The HCC group showed no significant difference between the studied biomarkers and the type of chronic viral hepatitis. On the basis of multiple ROC curve analyses, GP-73 and PIVKA-II showed the highest sensitivity and specificity for surveillance and diagnosis. In conclusion, PIVKA-II and GP-73 offer an effective approach for early HCC diagnosis and surveillance of high-risk groups with a higher accuracy than AFP. MIF may serve as a promising screening tumor marker for the detection of gastrointestinal tract (GIT) malignancy.

A quantitative analytical method for PIVKA-II using multiple reaction monitoring-mass spectrometry for early diagnosis of hepatocellular carcinoma.

Prothrombin induced by vitamin K absence-II (PIVKA-II) is an effective tumor marker for hepatocellular carcinoma (HCC). We have developed a novel targeted mass spectrometric (MS) assay for quantifying PIVKA-II in human serum. The ideal signature peptide was selected to measure PIVKA-II concentrations on a triple quadrupole (QqQ) mass spectrometer, and the chromatography gradient was optimized for the peptide separation to minimize elution interference. Using multiple reaction monitoring-mass spectrometry (MRM-MS), good linearity (R 2 = 0.9988) was obtained for PIVKA-II over a range of 3 orders. We achieved a limit of detection (LOD) of 0.45nM (31.72ng/mL), a limit of quantification (LOQ) of 0.93nM (65.31ng/mL), a lower limit of quantification (LLOQ) of 0.49nM (34.32ng/mL), and an upper limit of quantification (ULOQ) of 1000.00nM (70,037.00ng/mL). The intra-day and inter-day precisions were within ±14.96%, and the accuracy ranged from 87.66 to 114.29% for QC samples at four concentrations. Compared with an established immunoassay, the correlation (R = 0.8335) was good for the measurements of PIVKA-II concentrations. This method was successfully applied to the analysis of clinical samples for normal control (n = 50), chronic hepatitis (n = 50), liver cirrhosis (n = 50), HCC (n = 50), and recovery (n = 50) serum. Graphical Abstract MRM-MS assay development for determining concentration of PIVKA-II in serum and a comparison between MRM-MS assay and immunoassay with high correlation.

Predictors of Micrometastases in Patients with Barcelona Clinic Liver Cancer Classification B Hepatocellular Carcinoma.

PurposeTransarterial chemoembolization (TACE) is indicated for Barcelona Clinic Liver Cancer (BCLC) B hepatocellular carcinoma (HCC). Whether TACE provides any long-term survival benefits remains unclear. We aimed to investigate micrometastases predictors with which to identify patients who would benefit from surgical resection (SR).Materials and MethodsFirst, we analyzed risk factors of micrometastases, microvascular invasion, and poor histologic grade in 38 patients with newly diagnosed resectable BCLC stage B HCC limited to one or two segments with well-preserved liver function and who underwent SR between January 2006 and December 2013. Second, we validated identified risk factors in 54 newly diagnosed resectable BCLC B HCC patients with well-preserved liver function who underwent TACE during the same period to determine their influence on survival.ResultsRisk factors of micrometastases in SR patients were α-fetoprotein (AFP) ≥110 [hazard ratio (HR)=5.166; 95% confidence interval (CI), 1.031–25.897; p=0.046] and prothrombin induced by vitamin K absence-II (PIVKA-II) ≥800 (HR=5.166; 95% CI, 1.031–25.897; p=0.046). The cumulative probability of tumor recurrence (p=0.009) after SR differed according to levels of AFP and PIVKA-II. After validation of these risk factors in the TACE group, patients with SR and AFP <110 and PIVKA-II <800 had superior survival outcomes than other patients (HR=0.116; 95% CI, 0.027–0.497; p=0.004).ConclusionAFP and PIVKA-II levels predict micrometastases and survival. Therefore, they should be considered when selecting SR for BCLC B HCC.