Novel clinical insights and frontier issues in alpha- fetoprotein-producing gastric cancer

BackgroundTo explore the value of alpha fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in diagnosis of HBV-related hepatocellular carcinoma (HCC) and their relationship with vascular invasion, tumor differentiation and size.MethodsA total of 433 participants were enrolled in this study including 266 cases with HBV-related HCC, 87 cases with HBV DNA positive benign liver disease and 80 healthy individuals. Then we explored the correlation between AFP, PIVKA-II serum level and several pathological features such as vascular invasion, tumor differentiation and size. The value of these two markers used singly or jointly in diagnosing HBV-related HCC was evaluated by receiver operating characteristic (ROC) curve. The ROC curve was also plotted to identify AFP, PIVKA-II serum cut-off values that would best distinguish HBV-related HCC patients with and without vascular invasion.ResultsThe level of AFP and PIVKA-II in HBV-related HCC group was significantly higher (Z was 7.428, 11.243 respectively, all P < 0.01). When AFP and PIVKA-II were used as the individual tumor marker, the areas under the ROC curve (AUC) of HBV-related HCC diagnosis were 0.765 (95% CI, 0.713 ~ 0.8170) for AFP, 0.901 (95% CI, 0.868 ~ 0.935) for PIVKA-II, and 0.917 (95% CI, 0.886 ~ 0.948) for AFP and PIVKA-II simultaneously. The serum levels of AFP and PIVKA-II were positively correlated with tumor differentiation and size. High AFP and PIVKA-II expression was significantly associated with the presence of vascular invasion (P was 0.007 and 0.014 respectively). The AFP level > 64.4 ng/ml or PIVKA-II level > 957.61mAU/ml was the best critical value to predict the presence of vascular invasion.ConclusionOur results validate that AFP and PIVKA-II play a significant role in the diagnosis of HBV-related HCC. The diagnostic value of AFP and PIVKA-II combined detection or single assay of PIVKA-II is higher than that of separate assay of AFP. Moreover, their concentration has important clinical value in judging tumor size, tumor cell differentiation and vascular invasion.

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

High serum alpha-fetoprotein (AFP) level is a predictor of poor prognosis in patients with gastric cancer (GC). AFP-producing GC (AFP-GC) is an aggressive subtype of GC characterized by a high incidence of liver metastasis and high c-Met expression. High expression of metastasis-associated colon cancer 1 (MACC1), which is the transcription activator of c-Met, also predicts a poor prognosis of GC. c-Met is known to be involved in tumor progression into malignant invasive phenotypes. Considering that high c-Met expression is simultaneously positively correlated with high AFP and MACC1 expression levels and that high expression of AFP or MACC1 predicts poor prognosis in GC, we hypothesized that an interaction may exist between AFP and MACC1. In the present study, GC cell lines with AFP-overexpression, MACC1-downregulation and the combination of both transfections were used as experimental models. The relative mRNA and protein expression of c-Met, AFP and MACC1 were analyzed using reverse transcription quantitative PCR and western blotting, respectively. Cell viability was evaluated using Cell Counting Kit-8 assay. Cell invasion and cell migration were examined using Transwell migration assay with and without Matrigel, respectively. The results demonstrated that, compared with the control group, the mRNA and protein expression of MACC1was significantly elevated in the AFP-overexpressed group and in the group with AFP overexpressed and MACC1 downregulated. Furthermore, a significantly enhanced cell viability, migration and invasion were observed in the AFP-overexpressing group, whereas opposite effects were found in the MACC1-downregulating group. In summary, the results from this study indicated that AFP may promote GC progression by stimulating MACC1. This finding may help illustrating the aggressive behaviors of GC in patients with high AFP serum level and AFP-GC.

Alpha-fetoprotein-producing gastric cancer (AFPGC) is a subtype of gastric cancer (GC) with more aggressive biological behavior. As a highly specific tight junction component exclusively present in gastric mucosa and gastric adenocarcinomas, claudin-18.2 (CLDN18.2) has become an emerging target in GC. In this study, we aimed to provide insight into AFPGC and investigate the expression and the clinical implications of CLDN18.2 in AFPGC. We retrospectively collected 98 cases of AFPGC and reviewed their clinical, morphological, and immunohistochemical features. Another 356 patients with stage-matched conventional GC (cGC) were enrolled as a control group. We further surveyed CLDN18.2 expression by immunohistochemistry (IHC) in 51 AFPGC tissues and explained its association with the clinicopathological parameters of AFPGC. Our results showed that AFPGC was a unique GC type with elevated serum alpha-fetoprotein (AFP), which was a predictor of a worse prognosis. AFPGC showed typical morphological features and positive staining of at least 1 hepatocytic or enteroblastic marker. The expression rate of CLDN18.2 was low, with a positivity rate of 21.6%, which was much lower than that observed in cGC tissues (38.5%). A significant correlation was found between CLDN18.2 expression and the differentiation of AFPGC. CLDN18.2 expression was negatively correlated with the serum AFP level of AFPGC. We also found that AFPGC with a hepatoid type (HPT) component showed a significantly lower CLDN18.2 expression than those without. This study demonstrated that CLDN18.2 was significantly decreased in AFPGC and was negatively correlated with the patient's preoperative serum AFP level. The negative correlation between AFP and CLDN18.2 could be explained by retro-differentiation of AFPGC. Special treatment strategies might be needed for this unique tumor type.

Alpha-Fetoprotein Producing Gastric Cancer (AFPGC) is an aggressive subgroup of gastric cancer. Recently ramucirumab has shown survival benefits in hepatocellular carcinoma, but only in those with higher Alpha-Fetoprotein (AFP) levels. However, the efficacy of ramucirumab-containing chemotherapy in AFPGC remains unclear. We retrospectively assessed 352 patients who received ramucirumab-containing chemotherapy between June 2015 and December 2019. AFPGC was defined when serum AFP levels were elevated at diagnosis and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal at diagnosis. Among the 352 patients, 28 patients were defined as AFPGC and 246 patients were defined as non-AFPGC. AFPGC was characterized by high frequency of liver metastasis and low frequency of peritoneal metastasis compared to non-AFPGC. Ramucirumab containing chemotherapy showed higher response rates in AFPGC (39.1% vs 24.8%, p = 0.198) and disease control rates (86.9% vs 61.5%, p = 0.028) than those of non-AFPGC, respectively. Median progression-free survival (PFS) was 5.5months (95%CI 3.9-7.1) in AFPGC and 4.0months (95%CI 3.6-4.6) in non-AFPGC (HR: 0.91, 95% CI 0.61-1.36, p = 0.66), and median overall survival (OS) was 10.7months (95% CI 7.4-20.8) in AFPGC and 9.2months (95% CI 8.1-10.4) in non-AFPGC (HR: 0.72, 95% CI 0.48-1.08, p = 0.11), respectively. In multivariate analysis, AFPGC was not a negative prognostic factor both for PFS and OS. Ramucirumab containing chemotherapy showed higher response and comparable survival in AFPGC compared to those of non-AFPGC. Considering the generally poor prognosis of AFPGC, ramucirumab-containing chemotherapy might be a promising treatment option in AFPGC.

The prognosis of hepatocellular carcinoma (HCC) is closely related to the diagnostic stage. Due to the difficulty diagnosing early-stage HCC, most patients with HCC are diagnosed at the advanced stage. In this study, we used protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) combined with aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T-Bil) to establish a novel diagnostic model for early-stage hepatitis B virus (HBV)-related HCC. The serum levels of PIVKA-II, AFP, AST, ALT, and T-Bil were measured in 148 patients with early-stage HBV-related HCC and 940 patients with chronic hepatitis B. The receiver operating characteristic (ROC) curves were used to verify the diagnostic efficacy of the novel diagnostic model for early-stage HBV-related HCC. The mathematical model of [1.5 x PIVKA-II/(AST x T-Bil) + AFP/(ALT x T-Bil)] was selected as the novel diagnostic model. The areas under ROC curves (AUROCs) of the novel diagnostic model for detecting early-stage HBV-related HCC were significantly higher than those of PIVKA-II, AFP, and PIVKA-II combined with AFP (HCC ≤ 5 cm: 0.925 vs. 0.826, 0.666, and 0.821; HCC < 3 cm: 0.896 vs. 0.741, 0.651, and 0.765, respectively) (all p < 0.001). Using serum levels of AFP ≥ 20 ng/mL, the diagnostic model had the highest AUROC values of 0.960 and 0.933 for HCC ≤ 5 cm (89 cases) and HCC < 3 cm (40 cases), respectively, with a sensitivity of 83.15%, and 77.50% and specificity of 95.34% and 90.69%, respectively. The novel diagnostic model is superior to PIVKA-II and AFP for diagnosing early-stage HBV-related HCC, especially in patients with abnormal serum AFP levels.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally, largely due to delayed diagnosis. Alpha-fetoprotein (AFP), a traditional biomarker for HCC, suffers from limited sensitivity and specificity, particularly in early-stage disease. Protein induced by vitamin K absence or antagonist-II (PIVKA-II) has emerged as a promising complementary marker. This study aimed to evaluate the diagnostic performance of AFP and PIVKA-II, individually and in combination, in HCC detection. A total of 210 HCC patients and 270 chronic hepatitis B (CHB) patients were enrolled between June 2021 and February 2023. Additionally, 91 HCC patients and 88 CHB patients were included as a validation cohort. Serum levels of AFP and PIVKA-II were measured, and their diagnostic efficacy was assessed using receiver operating characteristic (ROC) curve analysis. A multivariate logistic regression model incorporating clinical features and biomarkers was developed and validated. A meta-analysis of relevant studies was also conducted to further confirm the diagnostic value of AFP. PIVKA-II levels were significantly higher in HCC patients compared to CHB controls and showed superior diagnostic performance [area under the curve (AUC) =0.970] compared to AFP (AUC =0.890). The combination of AFP and PIVKA-II significantly improved sensitivity (98.6%) and specificity (91.1%). A predictive model integrating AFP, PIVKA-II, age, sex, aspartate aminotransferase (AST), and albumin (ALB) demonstrated excellent diagnostic accuracy (AUC =0.995) and was successfully validated (AUC =0.986). Meta-analysis supported AFP as a reliable biomarker for HCC, although with heterogeneity across studies. PIVKA-II was also effective in monitoring treatment response, with postoperative levels markedly decreasing in patients undergoing hepatectomy. PIVKA-II offers superior diagnostic accuracy for HCC and complements AFP to enhance early detection, especially in AFP-insensitive cases. The combined biomarker strategy and predictive model provide a robust framework for clinical screening and early intervention. Integration of PIVKA-II into routine diagnostic workflows could improve patient outcomes and reduce diagnostic delays in HCC.

Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) is rare and associated with a suboptimal prognosis. The aim of this retrospective study was to identify prognostic factors, with a particular focus on the dynamics of serum AFP levels during treatment, in AFPGC patients.Data of patients with pathologically diagnosed primary gastric cancer treated with various modalities electronically collected in the medical management systems of 2 hospitals (ie, Shihezi People's Hospital and Shihezi Hospital) in Shihezi city, northwest China, from January 2007 to October 2018 were reviewed. Patients with AFPGC were identified based on serum AFP levels. Associations of the change in serum AFP levels and clinicopathological parameters with treatment response, including the overall response rate and disease control rate, and outcomes, including overall survival (OS) and progression-free survival (PFS), were compared among different groups.Of 2354 patients diagnosed with gastric cancer, 96 patients with AFPGC were identified. The objective response rate and disease control rate were significantly higher in patients whose AFP level decreased by ≥50% than in patients whose AFP level decreased by <50% (68.8% vs. 40.6%, and 87.5% vs. 53.1%, respectively, both P < .05). The median OS and PFS were 32.0 (4-74) and 24.0 (1-66) months, respectively, in patients with a ≥50% decline in AFP, and 12.5 (0-69) and 9.0 (0-63) months, respectively, in those with a <50% decline in AFP (both P < .05). On univariate and multivariate analyses, tumor, node, metastasis staging classification stage, liver metastasis, curable surgery, and the decline in the serum AFP level were associated with OS and PFS.A significant decline in the serum AFP level was associated with good treatment response and prognosis in AFPGC. Along with a decline in the serum AFP level, tumor, node, metastasis staging classification stage, liver metastasis, and curable surgery were also independent factors associated with prognosis.

BACKGROUNDResearchers have investigated the diagnostic value of protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), and obtained abundant clinical diagnostic data. However, PIVKA-II and AFP have unsatisfactory specificity and sensitivity in the diagnosis of early-stage HBV-related HCC. Gamma-glutamyltransferase (γ-GT) and aspartate aminotransferase (AST) are common biomarkers for evaluating liver function, and we hypothesized that the γ-GT/AST ratio in combination with PIVKA-II and AFP would improve the diagnosis of early-stage HBV-related HCC.AIMTo evaluate the diagnostic value of γ-GT/AST ratio alone or in combination with PIVKA-II and AFP in HBV-related HCC.METHODSSerum levels of γ-GT, AST, PIVKA-II, and AFP were detected and analysed in 176 patients with HBV-related HCC and in 359 patients with chronic hepatitis B. According to tumour size and serum level of HBV DNA, HBV-related HCC patients were divided into the following categories: Early-stage HCC patients, HCC patients, HBV DNA positive (HBV DNA+) HCC patients, and HBV DNA negative (HBV DNA-) HCC patients. Receiver-operating characteristic (ROC) curves were used to analyse and compare the diagnostic value of the single and combined detection of various biomarkers in different types of HBV-related HCC.RESULTSTumour size was positively correlated with serum levels of PIVKA-II and AFP in HCC patients (r = 0.529, aP < 0.001 and r = 0.270, bP < 0.001, respectively), but there was no correlation between tumour size and the γ-GT/AST ratio (r = 0.073, P = 0.336). The areas under the receiver-operating characteristic curves (AUROCs) of the γ-GT/AST ratio in early-stage HCC patients, HBV DNA+ HCC patients and HBV DNA- HCC patients were not significantly different from that in the total HCC patients (0.754, 0.802, and 0.705 vs 0.779, respectively; P > 0.05). When PIVKA-II was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, and HBV DNA+ HCC, the AUROCs of PIVKA-II increased, with values of 0.857 vs 0.835, 0.925 vs 0.913, and 0.958 vs 0.954, respectively. When AFP was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, HBV DNA+ HCC, and HBV DNA- HCC, the AUROCs of AFP increased, with values of 0.757 vs 0.621, 0.837 vs 0.744, 0.868 vs 0.757, and 0.840 vs 0.828, respectively.CONCLUSIONThe γ-GT/AST ratio may be better than PIVKA-II and AFP in the diagnosis of early-stage HBV-related HCC, and its combination with PIVKA-II and AFP can improve the diagnostic value for HBV-related HCC.

Hepatocellular carcinoma is a common type of malignancy with a poor prognosis. Identification and utilisation of markers for monitoring and diagnosis are urgently needed. Alpha-fetoprotein (AFP) and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) have been proved to be efficient biomarkers for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The combination of the two markers could improve the detection rate. However, these indicators cannot meet the need of clinical diagnosis.It is necessary to discover novel serological markers and more cost-effective, appropriate combination of these markers for the diagnosis and surveillance of HBV-related HCC. Accordingly, in this study, we aimed to evaluate the diagnostic value of γ-glutamyltransferase (γ-GT) to alanine amino transferase (ALT) ratio alone or in combination with AFP and PIVKA-II for HBV-related HCC. 234 patients with HBV-related HCC and 396 patients with chronic hepatitis B (CHB) were enrolled in this study and approved by the institutional review board. Our results showed levels of AFP and PIVKA-II, and γ-GT/ALT ratio in cases with early-stage HCC, HCC, HCC plus HBV DNA positivity, and HCC plus HBV DNA negativity were higher than those in the corresponding CHB control group. Additionally, the levels of serum AFP and PIVKA-II, and the γ-GT/ALT ratio were positively correlated with tumour sizes in patients with HBV-related HCC. The areas under the ROC curves (AUROCs) of the γ-GT/ALT ratio in patients with early-stage HCC, HCC, HCC plus HBV DNA positivity, and HCC plus HBV DNA negativity were 0.795, 0.846,0.855, and 0.837, respectively; AUROCs of combination of the γ-GT/ALT ratio and PIVKA-II were 0.858, 0.928, 0.948, and 0.902, respectively; AUROCs of combination of the γ-GT/ALT ratio and AFP were 0.822, 0.886, 0.896, and 0.873, respectively;AUROCs of combination of the γ-GT/ALT ratio and PIVKA-II with AFP were 0.857, 0.928, 0.946, and 0.907, respectively, and AUROCs of combination of PIVKA-II and AFP were 0.804, 0.904, 0.942, and 0.863, respectively. In conclusion, the γ-GT/ALT ratio was a useful biomarker for the diagnosis of HBV-related HCC and that the combination of AFP and PIVKA-II with the γ-GT/ALT ratio could improve the diagnostic value of these biomarkers for HBV-related HCC. Moreover, the ratio of γ-GT/ALT may be a useful index in monitoring patients for progression of HBV-related HCC.

Alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II, lens culinaris agglutinin-reactive fraction of alpha-fetoprotein alone and in combination for early detection of hepatocellular carcinoma from nonalcoholic fatty liver disease: A multicenter analysis

Inflammation-related markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and prognostic nutritional index (PNI) could reflect tumor immune microenvironment and predict prognosis of cancers. However, it had not been explored in alpha-fetoprotein (AFP) producing gastric cancer (GC). To determine the predictive value of inflammation-related peripheral blood markers including as NLR, PLR, MLR, SII, SIRI and PNI in the prognosis of AFP- producing GC (AFPGC). Besides, this study would also compare the differences in tumor immune microenvironment, clinical characteristics and prognosis between AFPGC and AFP- GC patients to improve the understanding of this disease. 573 patients enrolled were retrospectively studied. They were divided into AFP+ group (AFP ≥ 20 ng/mL) and AFP- group (AFP < 20 ng/mL), comparing the levels of NLR/PLR/MLR/SII/SIRI/PNI and prognosis. In AFP+ group, the impact of NLR/PLR/MLR/SII/SIRI/PNI and their dynamic changes on prognosis were further explored. Compared with AFP- patients, AFP+ patients had higher NLR/PLR/MLR/SII/SIRI and lower PNI levels and poorer overall survival (OS). In the AFP+ group, mortality was significantly lower in the lower NLR/PLR/MLR/SII/SIRI group and higher PNI group. Moreover, the dynamic increase (NLR/PLR/MLR/SII/SIRI) or decrease (PNI) was associated with the rise of mortality within 1 year of follow-up. Compared with AFP- patients, the level of inflammation-related peripheral blood markers significantly increased in AFP+ patients, which was correlated with OS of AFP+ patients. Also, the gradual increase of SII and SIRI was associated with the risk of death within one year in AFP+ patients. AFPGC should be considered as a separate type and distinguished from AFP- GC because of the difference in tumor immune microenvironment. It requires basic experiments and large clinical samples in the future.

Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are used as tumour markers for the diagnosis of hepatocellular carcinoma (HCC). We investigate whether combined liver function marker such as gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST) with alpha-fetoprotein (AFP) and PIVKA-II increase their diagnostic predictive value in diagnosis of HCC. The serum levels of PIVKA-II, AFP and GGT/AST ratio were analysed in 112 transplant candidates. Of these patients, 66 (59%) had HCC and 46 (41%) patients did not. Histological grade was positively correlated with serum levels of PIVKA-II and AFP (r = 0.255, P < 0.039 and r = 0.284, P < 0.021, respectively) and only tumour size positively correlated with the serum level of PIVKA-II (r = 0.270, P < 0.028), but no correlation between the number of tumour, Milan criteria and PIVKA-II (r = -0.002, P = 0.984 and r = 0.154, P = 0.216, respectively) with AFP (r = -0.024, P = 0.851 and r = 0.080, P = 0.522, respectively). Sensitivity and specificity of AFP, PIVKA-II and GGT/AST ratio at cutoff values of 6.08, 2.63 and 0.89, respectively, were as follows: 77, 77 vs 71, 83 vs 60 and 53%. The combination of AFP and PIVKA-II and GGT/AST ratio in HCC diagnosis increased AUROC values as follows; 0.860 vs 0.882 and 0.823 vs 0.840, respectively. This study showed that combined tumour markers such as AFP, PIVKA-II and GGT/AST ratio increase their sensitivity in HCC diagnosis.

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

Objectives To develop a novel diagnostic model combining bilirubin, protein induced by vitamin K absence or antagonist-II (PIVKA-II), and alpha-fetoprotein (AFP) to improve hepatocellular carcinoma (HCC) diagnosis. Methods The serum levels of PIVKA-Ⅱ, AFP, and bilirubin in 718 HCC patients and 2,763 benign liver disease (BLD) patients were measured. A mathematical model was used as the combined diagnostic model (PIVKA-Ⅱ, AFP, and bilirubin: PAB combination) for improving HCC diagnosis. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic value of the individual markers, the PIVKA-II and AFP (PA) combination, and the PAB combination for HCC diagnosis. Results With the increase in bilirubin, the positive predictive value (PPV) of bilirubin in HCC diagnosis decreased (p&lt;0.001) while the negative predictive value (NPV) increased (p&lt;0.001). The areas under the ROC curves (AUCs) of the PAB combination were 0.935 and 0.862 for the diagnosis of HCC and HCC&lt;3.0 cm, respectively, which were significantly higher than those of PIVKA-Ⅱ, AFP, and the PA combination (p&lt;0.001). The AUC values for PIVKA-Ⅱ, AFP, and the PA combination were significantly decreased for the diagnosis of HCC and HCC&lt;3.0 cm when serum levels of PIVKA-Ⅱ≥40 mAU/mL and/or AFP≥20 ng/mL were used for diagnosis, while the AUC value of the PAB combination increased. Conclusions Bilirubin is a superior biomarker for diagnosing HCC and distinguishing HCC from BLD. The combination of bilirubin with PIVKA-Ⅱ and AFP has superior diagnostic value for HCC and early-stage HCC.