Culinaris Agglutinin-reactive Fraction Of Alpha-fetoprotein Research Articles

New predictors of microvascular invasion for small hepatocellular carcinoma ≤ 3cm.

Microvascular invasion (MVI) is a risk factor for postoperative recurrence of hepatocellular carcinoma (HCC), even in early-stage HCC. In small HCC ≤ 3cm, treatment options include anatomical resection or non-anatomical resection, and MVI has a major effect on treatment decisions. We aimed to identify the predictors of MVI in small HCC ≤ 3cm. We retrospectively studied 129 patients with very early or early-stage HCC ≤ 3cm who had undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography and subsequent hepatic resection from January 2016 to August 2023. These patients were divided into the derivation cohort (n = 86) and validation cohort (n = 43). We examined the risk factors for MVI using logistic regression analysis, and established a predictive scoring system in the derivation cohort. We evaluated the accuracy of our scoring system in the validation cohort. In the derivation cohort, a Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), prothrombin induced by vitamin K deficiency or antagonist-II (PIVKA-II), and metabolic tumor volume (MTV) were independent predictors of MVI. We established the scoring system using these three factors. In the validation test, there were no MVI-positive cases with a score of 0 and 1, and all cases were MVI-positive with a score of 4. Moreover, with a score ≥ 2, the sensitivity, specificity, and accuracy of our scoring system were 100%, 71.4%, and 81.4%, respectively. Our scoring system can accurately predict MVI in small HCC ≤ 3cm, and could contribute to establishing an appropriate treatment strategy.

Diagnostic accuracy of serological and imaging tests used in surveillance for hepatocellular carcinoma in adults with cirrhosis: a systematic review protocol

Background Liver cirrhosis is the largest risk factor for developing hepatocellular carcinoma (HCC), and surveillance is therefore recommended among this population. Current guidance recommends surveillance with ultrasound, with or without alpha-fetoprotein (AFP). This review is part of a larger project looking at benefits, harms and costs of surveillance for HCC in people with cirrhosis. It aims to synthesise the evidence on the diagnostic accuracy of imaging or biomarker tests, alone or in combination, to identify HCC in adults with liver cirrhosis in a surveillance programme. Methods We will identify studies through a 2021 Cochrane review with similar eligibility criteria, and a database search of MEDLINE, Embase and the Cochrane Database of Systematic Reviews. We will include diagnostic test accuracy studies with adult cirrhosis patients of any aetiology. Studies must assess at least one of the following index tests: ultrasound (US), magnetic resonance imaging (MRI), computerised tomography (CT), alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), a genomic biomarker, or a diagnostic prediction model incorporating at least one of the above-mentioned tests. We will assess studies for risk of bias using QUADAS-2 and QUADAS-C. We will combine data using bivariate random effects meta-analyses. For tests evaluated across varying diagnostic thresholds, we will produce pooled estimates of sensitivity and specificity across the full range of numerical thresholds, where possible. Where sufficient studies compare two or more index tests, we will perform additional analyses to compare the accuracy of different tests. Where feasible, we will stratify all meta-analyses by tumour size and patient characteristics, including cirrhosis aetiology and liver disease severity. Discussion This review will synthesise evidence across the full range of possible surveillance tests, using advanced statistical methods to summarise accuracy across all thresholds and to compare the accuracy of different tests. PROSPERO registration CRD42022357163

Role of the Clinical Features and MRI Parameters on Ki-67 Expression in Hepatocellular Carcinoma Patients: Development of a Predictive Nomogram.

To develop a nomogram using clinical features and the MRI parameters for preoperatively predicting the expression of Ki-67 in patients with hepatocellular carcinoma (HCC). One hundred and forty patients (training cohorts: n = 108; validation cohorts: n = 32) with confirmed HCC were investigated. Mann-Whitney U test, independent sample t-test, and chi-squared test were used to analyze the continuous and categorical variables. Univariate and multivariate logistic regression analyses were performed to examine the clinical variables and parameters from MRI associated with Ki-67 expression. As a result, a nomogram was developed based on these associations in patients with HCC. The performance of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration curves. In the training set, multivariable logistic regression analysis revealed that lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) levels, protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels, and tumor shape were independent predictors for Ki-67 expression (p < 0.05). These three variables and the apparent diffusion coefficient (ADC) value were used to establish a nomogram, while the ADC value was found to be a marginal significant predictor. The model demonstrated a strong ability to discriminate Ki-67 expression in both the training and validation cohorts (AUC = 0.862, 0.877). A non-invasive preoperative prediction method, which incorporates MRI variables and clinical features was developed, and showed effectiveness in evaluating Ki-67 expression in HCC patients.

Serologic Detection of Hepatocellular Carcinoma: Application of Machine Learning and Implications for Diagnostic Models.

The gender, age, lens culinaris agglutinin-reactive fraction of alphafetoprotein, alphafetoprotein, des-gamma-carboxyprothrombin (GALAD) score is a biomarker-based statistical model for the serologic diagnosis of hepatocellular carcinoma (HCC) that has been developed and validated using the case-control approach with a view to early detection. Performance has, however, been suboptimal in the first prospective studies which better reflect the real-world situation. In this article, we report the application of machine learning to a large, prospectively accrued, HCC surveillance data set. Models were built on a cohort of 3,473 patients with chronic liver disease within a rigorous surveillance program between 1998 and 2014, during which 459 patients with HCC were detected. Two random forest (RF) models were trained. The first RF model uses the same variables as the original GALAD model (GALAD-RF); the second is based on routinely available clinical and laboratory features (RF-practical). For comparison, we evaluated a logistic regression GALAD model trained on this longitudinal prospective data set (termed GALAD-Ogaki). Models were evaluated using a repetitive cross-validation approach with the metrics averaged over 100 independent runs. As judged by area under the receiver operator curve (AUROC) and F1 score, the GALAD RF model significantly outperformed the original GALAD model. The RF-practical model also outperformed the original GALAD model in terms of both AUROC and F1 score, and both models outperformed the individual biomarkers. An online web application that implemented the GALAD-RF and RF-practical models is presented. RF-based models improve on the diagnostic performance of the original GALAD model in the setting of a standard HCC surveillance program. Further prospective validation studies are warranted using these models and could be expanded to offer prediction of risk of HCC development over defined periods of time.

Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review

The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.

The Application of Liquid Biopsy Techniques in High-Risk Population for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has a 5-year overall survival rate of 14.1%. Many HCC patients are diagnosed at an advanced stage, and thus early screening is essential for reducing the mortality of HCC. In addition to commonly used detection indicators such as serum alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and abnormal prothrombin (protein induced by vitamin K absence II, PIVKA-II), liquid biopsy techniques have been demonstrated to have diagnostic value in HCC detection. Compared with invasive procedures, liquid biopsy can detect circulatory metabolites of malignant neoplasms. Liquid biopsy techniques can detect circulating tumor cells, circulating tumor DNA, circulating RNA and exosomes and have been used in the early screening, diagnosis and prognostic evaluation of HCC. This paper reviews the molecular biological characteristics and application of different liquid biopsy techniques, and aim to highlight promising biomarkers that may be feasible options for early-stage HCC evaluation to improve early screening in populations at high risk for HCC.

Diagnostic Performance of AFP, AFP-L3, or PIVKA-II for Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Multicenter Analysis.

Background and Aim: Alpha-fetoprotein (AFP), a lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), is a protein that is induced by vitamin K deficiency or antagonist-II (PIVKA-II) that has been clinically used as a serum biomarker for early detection and diagnosis of hepatocellular carcinoma (HCC). Diagnostic performance of each serum biomarker alone, or their combinations for the detection of hepatitis C virus (HCV)-associated HCC were compared. Methods: Serum AFP, AFP-L3, and PIVKA-II levels were evaluated in patients with HCV-associated HCC, and those with chronic HCV infection without HCC (HCV-controls). The areas under the curve (AUC), sensitivity, and specificity were compared to identify the diagnostic performance of each serum HCC biomarker alone or in combination. Results: Overall, 172 HCV controls and 105 patients with HCV-associated HCC were enrolled. The AFP, AFP-L3, and PIVKA-II levels were significantly increased among patients with HCV-associated HCC when compared with HCV patients without HCC (p < 0.001). When these biomarkers were analyzed individually, PIVKA-II revealed the best predictive performance (AUC: PIVKA-II 0.90 vs. AFP 0.80 vs. AFP-L3 0.69, p < 0.001). In evaluating the combinations of any two biomarkers, the best predictive performance was found in PIVKA-II + AFP (0.93 vs. AFP + AFP-L3 0.78, p = 0.001; and PIVKA-II + AFP-L3 0.89, p < 0.001), which had no difference compared to the predictive performance of the combination of all three serum biomarkers (AFP + AFP-L3 + PIVKA-II 0.93, p = 0.277). Similar results were identified in the subgroups of patients with HCV-induced cirrhosis, and among patients with early-stage HCC defined by BCLC and TNM staging. Conclusions: The addition of the PIVKA-II test to routine AFP test maybe provide a more suitable biomarker approach to detect HCV-induced HCC in patients with HCV infection undergoing HCC surveillance.

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

BackgroundCurrent surveillance strategies for hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) are insufficient. This study aimed to investigate the diagnostic performance of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and their combinations in HCC underlying NAFLD patients. MethodsSerologic AFP, AFP-L3, and PIVKA-II levels in NAFLD patients with and without HCC were measured. By receiver operating characteristic (ROC) analyses, the area under the curve (AUC), sensitivity, and specificity were obtained to evaluate the diagnostic accuracy of each biomarker and their combinations. ResultsThis study was conducted on 139 patients with NAFLD-HCC and 345 NAFLD controls. The elevation of these three biomarkers was observed in patients with NAFLD-HCC compared to those in NAFLD controls (all P < 0.001). When they were analyzed individually, PIVKA-II showed the best performance in diagnosing any-stage HCC with an AUC of 0.869, followed by AFP (0.763; vs. PIVKA-II, P < 0.001) and AFP-L3 (0.689; vs. PIVKA-II, P < 0.001). When they were analyzed in combination, AFP + PIVKA-II yielded the highest AUC (0.906), followed by AFP + PIVKA-II + AFP-L3 (0.904; vs. AFP + PIVKA-II, P = 0.086), PIVKA-II + AFP-L3 (0.881; vs. AFP + PIVKA-II, P < 0.001), and AFP + AFP-L3 (0.759; vs. AFP + PIVKA-II, P < 0.001). Similar findings were obtained in the subgroup with early-stage NAFLD-HCC, as well as the non-cirrhotic subgroup. ConclusionsThese data validated the better diagnostic ability of PIVKA-II than AFP or AFP-L3 alone for diagnosing any-stage HCC among patients with NAFLD, and the combination of AFP + PIVKA-II significantly improved the diagnostic accuracy of NAFLD-HCC.

Evaluating the GALAD Score in Diagnosing Hepatocellular Carcinoma

This paper aims to evaluate the GALAD score in diagnosing hepatocellular carcinoma. The paper conducted a retrospective study of 86 Hepatocellular Carcinoma patients who underwent AFP, AFP-L3, and PIVKA II. The results show that the average age of the patients was 57.7 ± 11.14, the ratio of male/female was 11.34/1. The median values of AFP, AFP-L3, and PIVKA-II before treatment were 196 ng/mL, 16.2%, and 3154.5 mAU/mL, respectively. The sensitivity of AFP, AFP-L3, and PIVKA-II was 80.2%; 58.1%; and 88.4%, respectively. The combination of the three markers also showed a high sensitivity of 94.2%. The mean value of GALAD in the patients was 5.83 ± 5.3. The liver cancer probability index was 0.8485 ± 0.276. Overall, the paper results suggest that using the BALAD score is both easy to practice and economical, which is highly useful for the early detection of hepatocellular carcinoma.&#x0D; Keywords:&#x0D; Hepatocellular carcinoma, PIVKA-II, GALAD score.&#x0D; References&#x0D; [1] H. Sung, J. Ferlay, M. E. Rebecca, L. Siegel et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA: aA Cancer Journal For Clinicians, 2021.[2] M. Makuuchi et al., Development of Evidence‐based Clinical Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma in Japan Hepatology Research, Vol. 38, No. 1, 2008, pp. 37-51. 7[3] M. Makuuchi, Clinical Practice Guidelines for Hepatocellular Carcinoma-the Japan Society of Hepatology 2009 update, Hepatol Res, Vol. 40, No. 1, 2010, pp. 2-144. [4] G. M. N. O. Wongjarupong, N. R. Chaiteerakij et al., Model Combining Pre-transplant Tumor Biomarkers and Tumor Size Shows More Utility Iin Predicting Hepatocellular Carcinoma Recurrence and Survival than the BALAD Models, World Journal of Gastroenterology, Vol. 24, No. 12, 2018, pp. 1321-1331. [5] L. R. Roberts, Current Status of the GALAD and BALAD Biomarker Models for Hepatocellular Carcinoma, Gastroenterology &amp; Hepatology, Vol. 15, No. 12, 2019, pp. 672-675. [6] L.N. Khue, M.T. Khoa at el 2020, Guideline about Diagnosis and Treatment some type of Cancer, Ministry of Health, 2020, pp. 900-935. [7] National Comprehensive Cancer Network, Hepatocellular Carcinoma, 2020. [8] J. D. Yang, B. D. Addissie, K. C. Mara et al., GALAD Score for Hepatocellular Carcinoma Detection in Comparison with Liver Ultrasound and Proposal of GALADUS Score, Cancer Epidemiol Biomarkers Prev, Vol. 28, No. 3, 2019, pp. 531-538. [9] T. T. Ngoc, Studying the Role of Alpha-fetoprotein, Alpha-fetoprotein-L3 and Des-gamma-carboxy Prothrombin in Diagnosis and Treatment Of Hepatocellular Carcinoma, Thesis of PhD, Hanoi Medical University, 2020. [10] G. P. Caviglia, M. L. Abate, E. Petrini et al., Highly Sensitive Alpha-fetoprotein, Lens Culinaris Agglutinin-reactive Fraction of Alpha-fetoprotein and Des-gamma-carboxyprothrombin for Hepatocellular Carcinoma Detection, Hepatol Res, Vol. 46, No. 3, 2016, pp. E130-E135. [11] S. Berhane, H. Toyoda, T. Tada et al., Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients, Vol. 14, No. 6, 2016, pp. 875-886. e6. [12] J. Best, L. P. Bechmann, J. P. Sowa et al., GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients with Nonalcoholic Steatohepatitis, Clin Gastroenterol Hepatol, Vol. 18, No. 3, 2020, pp. 728-735.e4.

Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein improves diagnostic accuracy for hepatocellular carcinoma.

BACKGROUNDDiagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated.AIMTo evaluate the diagnostic accuracy of alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) and their combination for HCC diagnosis.METHODSPatients with newly detected liver mass or elevated serum AFP levels were considered eligible. Serum AFP level, AFP-L3 fraction, and PIVKA-II level were measured at the first visit.RESULTSIn total, 622 patients were included; 355 patients (57.1%) had chronic liver disease, and 208 (33.4%) had liver cirrhosis. HCC was diagnosed in 160 patients (25.7%). The area under the receiver operating characteristics curves (AUROCs) of the serum AFP, AFP-L3 fraction, AFP-L3, and PIVKA-II levels for the diagnosis of HCC were 0.775, 0.792, 0.814, and 0.834, respectively. A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets. Using the binary regression analysis of the training cohort, the AFP, AFP-L3 fraction, and PIVKA-II (ALPs) score was calculated as follows: ALPs score = 3.8 × [serum AFP level (ng/mL) × AFP-L3 fraction (%) × 0.01] + 0.2 × PIVKA-II level (mAU/mL). The AUROC of the ALPs score for diagnosis of HCC was 0.878, significantly higher than that of serum AFP level (P < 0.001), AFP-L3 fraction (P < 0.001), PIVKA-II level (P = 0.036), and AFP-L3 level (P = 0.006). The optimal ALPs score cut-off was 5.3 (sensitivity, 85.0%, specificity 80.1%). The validation cohort showed similar results.CONCLUSIONThe ALPs score calculated using serum AFP level, AFP-L3 fraction, and PIVKA-II level showed improved accuracy in HCC diagnosis.

A Practical Model is Equivalent to the BALAD or BALAD-2 Score in Predicting Long-term Survival after Hepatectomy in Chinese Patients with Hepatocellular Carcinoma.

Aim: To evaluate the predictive value of the BALAD and BALAD-2 scores on long-term survival after hepatectomy in Chinese hepatocellular carcinoma (HCC) patients and to attempt to establish a more practical or effective model.Methods: A total of 251 HCC patients underwent hepatectomy were recruited. The BALAD and BALAD-2 scores were calculated with total bilirubin, albumin, alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxyprothrombin. The associations of the two scores and their components with the overall survival were analyzed. Finally, three prediction models were explored and constructed.Results: We observed that HCC patients had 5-year survival rates that worsened with increasement of BALAD and BALAD-2 scores. The BALAD and BALAD-2 scores demonstrated fine value in predicting overall survival with Harrell-C statistics of 0.665 (0.618-0.712) and 0.603 (0.554-0.636). After two variables, largest tumor size and BMI, were included in BALAD [0.720 (0.671-0.769)] or BALAD-2 [0.701 (0.649-0.751)] multivariate models, the Harrell-C statistic increased significantly than BALAD (P=0.048) or BALAD-2 (P<0.001) alone. Taking into account availability and expense, an equivalent BAA-BS model was established based on total bilirubin, albumin, AFP, BMI and largest tumor size. The Harrell-C statistic of BAA-BS model [0.723(0.674-0.772)] was similar to that of BALAD (P=0.820) or BALAD-2 (P=0.209) multivariate model. And, the continuous net reclassification index and integrated discriminatory improvement were not statistically different. Finally, a nomogram of the equivalent BAA-BS model was constructed to assist surgeons and patients in predicting 5-year survival rates.Conclusion: Both BALAD and BALAD-2 scores were highly suitable for predicting long-term survival after hepatectomy in Chinese HCC patients. A significant increase in predictive efficacy was observed after the addition of largest tumor size and BMI to BALAD or BALAD-2 score. Even if AFP-L3 and DCP are not detected, an equivalent BAA-BS model also obtained an excellent discriminatory performance.

Does Hepatocellular Carcinoma Surveillance Increase Survival in At-Risk Populations? Patient Selection, Biomarkers, and Barriers.

Hepatocellular carcinoma (HCC) is a highly morbid and prevalent cancer globally. While high quality evidence for mortality benefit of HCC surveillance is lacking, early detection of HCC is likely beneficial as prognosis is highly correlated with tumor stage. High risk populations, including patients with cirrhosis and subgroups with Hepatitis B, should undergo surveillance with ultrasound ± alpha-fetoprotein (AFP) at 6-month intervals. In addition, emerging data suggest that patients with Hepatitis C cirrhosis who achieve sustained virologic response should continue surveillance. Further research is needed to determine the value of surveillance in patients with nonalcoholic fatty liver disease in the absence of cirrhosis or with advanced fibrosis of other etiologies. Newer biomarkers and models such as Lens culinaris agglutinin-reactive fraction of AFP, des-γ-carboxy prothrombin, and the GALAD score are increasingly utilized in the diagnosis and prognostication of HCC. The role of these biomarkers in surveillance is still under investigation but may potentially offer a more practical alternative to traditional image-based surveillance. Despite recommendations from multiple professional society guidelines, many at-risk patients do not receive HCC surveillance due to barriers at the patient, clinician, and health care system levels. Strategies such as implementing patient navigation services, educating clinicians about surveillance guidelines, and creating automated outreach systems, may improve surveillance rates and ultimately reduce morbidity and mortality from HCC.

VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma

BackgroundTo investigate the von Willebrand factor to ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma (HCC) in cirrhosis.MethodsSerum levels of alpha-fetoprotein, des-γ-carboxy prothrombin, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (alpha-fetoprotein-L3%), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, as well as the plasma levels of von Willebrand factor antigen (von Willebrand factor: Ag) and ADAMTS13 activity (ADAMTS13:AC), were evaluated in 41 cirrhotic patients with HCC undergoing radiofrequency ablation and in 20 cirrhotic patients without HCC. The diagnostic accuracy of each biomarker was evaluated using the receiver operating characteristic curve analysis.ResultsThe von Willebrand factor: Ag and von Willebrand factor: Ag/ADAMTS13:AC ratios were significantly higher in cirrhotic patients with HCC than in those without HCC (p < 0.05 and p < 0.01, respectively), whereas ADAMTS13:AC was significantly lower in those with HCC than those without HCC (p < 0.05). However, no relationship was observed between the von Willebrand factor: Ag/ADAMTS13:AC ratio and serum tumor markers such as alpha-fetoprotein, des-γ-carboxy prothrombin, and alpha-fetoprotein-L3%. Multivariate regression analysis identified von Willebrand factor: Ag/ADAMTS13:AC ratio and alpha-fetoprotein-L3% as significant factors of HCC development. Receiver operating characteristic analysis showed that the von Willebrand factor: Ag/ADAMTS13:AC ratio and alpha-fetoprotein-L3% had a better performance than alpha-fetoprotein, des-γ-carboxy prothrombin, alpha-fetoprotein-L3%, vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, von Willebrand factor: Ag, and ADAMTS13:AC. The von Willebrand factor: Ag/ADAMTS13:AC ratio was exclusively correlated with tumor volume and stage as well as serum vascular endothelial growth factor levels.ConclusionsThe von Willebrand factor: Ag/ADAMTS13:AC ratio can potentially serve as a novel biomarker for early diagnosis of HCC in cirrhotic patients.

The Number of Positive Tumor Marker Status Is Beneficial for the Selection of Therapeutic Modalities in Patients with Hepatocellular Carcinoma.

Hepatic resection (HR) and radiofrequency ablation (RFA) are popular local therapies for early-stage hepatocellular carcinoma (HCC). Alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-c-carboxy prothrombin are well-known and useful tumor markers for HCC. The positive number status of these tumor markers has recently been demonstrated as beneficial for predicting outcome for HCC patients treated with local therapy. Although the normal ranges reported have differed by institution, the positivity of tumor markers is consistent and can easily be assessed. Kumamoto and Wakayama’s group clearly demonstrated the following: 1) Regardless of the degree of tumor stage, a triple-positive tumor marker profile can predict poor outcome in HCC patients undergoing HR; 2) For RFA alone, HCC patients with double- and triple-positive status, having less than three lesions and lesions ≤3 cm in diameter show comparably insufficient outcomes; 3) For HCC patients with lesions ≤5 cm in Child–Pugh grade A, HR is preferred over RFA; 4) Microvascular invasion rates increased even in the double-positive patients, while poorly differentiated HCC was frequently observed only in the triple-positive patients; and 5) RFA with chemoembolization, anatomical liver resection, and postoperative adjuvant chemoembolization or hepatic arterial chemotherapy might improve the outcome for patients with highly malignant HCC with multiple positive tumor markers. However, the impacts of these therapies still need to be evaluated in prospective comparative studies.

Research progress on the molecular biomarkers for patients with hepatocellular carcinoma recurrence after surgery

Tumor recurrence is the main factor affecting the postoperative prognosis of hepatocellular carcinoma. The forecast of tumor recurrence by monitoring biomarker can effectively improve the prognosis of such disease. To improve the detection rate of early cancer recurrence can be achieved by detecting the level of the alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin (DCP), or combined detection. In recent years, the researches on the miRNA and Long Noncoding RNAs (LncRNA), which are key regulators in the upstream of signal pathways, could provide a new way for HCC recurrence monitoring. The combined detection of biomarkers in different control levels, maybe is the effective measure to improve the tumor recurrence detection rate, and is also the focus of the further research. Key words: Hepatocellular carcinoma; Tumor recurrence; Molecular biomarker

Double- and Triple-Positive Tumor Markers Predict Early Recurrence and Poor Survival in Patients with Hepatocellular Carcinoma within the Milan Criteria and Child-Pugh Class A

The prognostic implications of the expression patterns of three tumor markers, alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-γ-carboxy prothrombin (DCP), have been evaluated in patients with hepatocellular carcinoma (HCC). From January 1994 to December 2014, 1182 consecutive patients underwent hepatic resection and surgical microwave ablation for HCC at our institution. This study analyzed 475 patients within the Milan criteria and Child–Pugh class A. Cumulative overall survival (OS) and disease-free survival (DFS) rates were analyzed relative to the number of positive tumor markers. OS and DFS at 5 years postoperatively were 85.3 and 44.2% in triple-negative patients, 79.4 and 48.0% in single-positive patients, 56.2 and 32.9% in double-positive patients, and 61.7 and 35.7% in triple-positive patients with statistical significance. OS in triple-negative or single-positive patients was 85.3%, and that in all double- or triple-positive patients was 58.0% (P < 0.0001); DFS at 5 years postoperatively in these two groups was 45.9 and 34.0%, respectively (P < 0.0013). Both double- and triple-positive tumor markers are associated with early recurrence and poor survival in HCC patients within the Milan criteria and Child–Pugh class A.

Combination of triple biomarkers AFP, AFP-L3, and PIVAKII for early detection of hepatocellular carcinoma in China: Expectation.

Hepatocellular carcinoma (HCC) remains a severe health threat in China. Early tumor detection is crucial for improving the prognosis of patients. Currently, ultrasound plus biomarker alpha fetoprotein (AFP) is recommended by Chinese Liver Cancer Diagnosis and Treatment Guidelines in China. However, most HCC continues to be diagnosed beyond an early stage due to insufficient sensitivity and specificity of current surveillance tools, highlighting the need for more accurate biomarkers to improve early HCC detection. In Japan, ultrasound plus triple biomarkers AFP, Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and prothrombin induced by vitamin K absence II (PIVKA II) has been routinely used for HCC surveillance and achieved increased early HCC detection rate. Very recently, the assay of triple biomarkers AFP, AFP-L3, and PIVKA II using μTASWako i30 immuno-analyzer was brought into China. The prospect of the modality of ultrasound plus triple biomarkers for early HCC detection in China is expected in the future.

Irregular vascular pattern by contrast-enhanced ultrasonography and high serum Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level predict poor outcome after successful radiofrequency ablation in patients with early-stage hepatocellular carcinoma.

Radiofrequency ablation (RFA) is considered the most effective treatment for early‐stage hepatocellular carcinoma (HCC) patients unsuitable for resection. However, poor outcome after RFA has occasionally been reported worldwide. To predict such an outcome, we investigated imaging findings using contrast‐enhanced ultrasonography (CEUS) with Sonazoid and serum tumor markers before RFA. This study included 176 early‐stage HCC patients who had initially achieved successful RFA. Patients were examined using CEUS; their levels of alpha‐fetoprotein (AFP), Lens culinaris agglutinin‐reactive fraction of AFP (AFP‐L3), and des‐gamma‐carboxy prothrombin before RFA were measured. Sonazoid provided parenchyma‐specific contrast imaging and facilitated tumor vascular architecture imaging through maximum intensity projection (MIP). Kaplan–Meier analysis examined cumulative rates of local tumor progression, intrasubsegmental recurrence, and survival; factors associated with these were determined with Cox proportional hazards analysis. Local tumor progression (n = 15), intrasubsegmental recurrence (n = 46), and death (n = 18) were observed. Irregular pattern in MIP classification and serum AFP‐L3 level (>10%) before RFA were identified as independent risk factors for local tumor progression and intrasubsegmental recurrence. These two factors were independently associated with poor survival after RFA (irregular pattern in MIP: hazard ratio, (HR) = 8.26; 95% confidence interval, (CI) = 2.24–30.3; P = 0.002 and AFP‐L3 > 10%: HR = 2.94; 95% CI = 1.09–7.94; P = 0.033). Irregular MIP pattern by CEUS and high level of serum AFP‐L3 were independent risk factors for poor outcome after successful RFA. The Patients with these findings should be considered as special high‐risk group in early‐stage HCC.

Biomarkers: evaluation of clinical utility in surveillance and early diagnosis for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second most common cause of death from cancer worldwide. Strategies to surveil and diagnose HCC in an earlier stage are urgently needed since this is when curable interventions can be offered to achieve long-term disease-free survival. Over the past few decades, research has suggested measuring alpha-fetoprotein (AFP) concentration and performing abdominal ultrasound (US) as part of routine surveillance of HCC every 6 months for high-risk patients, and many HCC guidelines worldwide have also recommended these examinations. Over the past 5 years, however, the role of serum biomarkers in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by some Western countries. In Asian countries, serum biomarkers such as AFP, the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxyprothrombin (DCP) are still recommended for HCC surveillance and are being used as an adjunctive diagnostic tool in accordance with HCC guidelines. Moreover, novel biomarkers including Dickkopf-1 (DKK1), midkine (MDK), and microRNA (miRNA) are being studied in this regard. China accounts for 50% of HCC cases worldwide, so identifying biomarkers of HCC is paramount. Recent studies have indicated the clinical utility of simultaneous measurement of AFP and DCP for the early detection of HCC in China. They are predominantly used for cases caused by HBV infection. Additional large-scale prospective studies should be conducted to establish the utility of these biomarkers.

Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma.

The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.