Measurement Of Serum Alpha-fetoprotein Research Articles

B-333 Optimizing AFP Cutoffs for Hepatocellular Carcinoma Screening: Insights from the National Cancer Screening Program in Korea

Abstract Background The incidence rate and mortality rate of liver cancer were 11.6 (ranked 8th among cancers) and 10.7 (4th) per 100,000 individuals respectively globally in 2020, whereas in Korea, they were higher at 29.5 (7th) and 20.6 (2nd) per 100,000 individuals. The National Cancer Screening Program (NCSP) in Korea conducts biannual concurrent liver ultrasound and serum alpha-fetoprotein (AFP) measurement for hepatocellular carcinoma (HCC) surveillance in high-risk groups, including those with chronic hepatitis B and C, and liver cirrhosis. The effectiveness of surveillance is impacted by varying AFP cutoffs; however, within the NCSP, different cutoffs are being used, and it is not clear which cutoffs are being employed. Harmonization of AFP test results by major reagent manufacturers have been achieved, enabling the adoption of a uniform threshold. This study aims to assess the variation of AFP cutoffs among institutions within the NCSP and suggest a unified and optimal AFP threshold. Methods This study examined HCC screening results from the NCSP between 2018 and 2020, investigating unit and cutoff usage for AFP test across institutions each year (number of institutions were 4452 for 2018, 4754 for 2019, and 4847 for 2020). To determine the optimal AFP cutoff for HCC screening, datasets comprised unique patient results from 2018 to 2020 (number of patients = 819,644). Receiver operating characteristic (ROC) curve analyses were conducted for determine best AFP cutoffs. Cancer diagnosis was defined by billing records indicating HCC within one year post-screening. Results More than 96% of institutions used ng/mL as a unit of AFP test. Among institutions using ng/mL, the most frequently used AFP cutoff was 7 ng/mL, with frequency percentages of 75.7%, 72.2%, and 62.2% in 2018, 2019, 2020, respectively. The percentiles (1st, 10th, 90th, 99th) of AFP cutoff usage for the years 2018, 2019, and 2020 were (7, 7, 8.8, 15), (7, 7, 8.9, 15), and (7, 7, 9, 15) respectively. The AUC of ROC was 0.824 and some cut-off points with their sensitivity and specificity values were as follows: 5 ng/mL (0.648, 0.874); 10 (0.457, 0.976); 20 (0.327, 0.993); 40 (0.246, 0.997); 100 (0.169, 0.998); 200 (0.123, 0.999); 400 (0.084, 1). Conclusions Different cutoffs observed across institutions in NCSP. Our study cautiously suggests that the optimal AFP value for screening HCC in NCSP may range from 10 to 20 ng/mL, considering sensitivity and specificity when AFP is combined with ultrasound in regions with a high prevalence of HCC. For a more suitable AFP cutoff recommendation, additional analyses based on ultrasound findings and underlying diseases should be considered.

Ultrasonography in surveillance for hepatocellular carcinoma in patients with non-alcoholic fatty liver disease

International guidelines recommend six monthly ultrasounds as the primary surveillance tool for patients at risk of hepatocellular carcinoma (HCC). The dominant driver of liver disease in HCC surveillance populations is shifting, particularly in Europe and the United States, from chronic viral hepatitis (B or C), towards non-alcoholic fatty liver disease (NAFLD). Today, the population requiring HCC surveillance is also characterised by a high prevalence of overweight/obesity. These patient characteristics significantly impair ultrasound quality which can impede the detection of early HCC lesions. This diagnostic limitation has significant implications considering that eligibility for curative treatment depends upon the stage at which the cancer is detected. In this narrative review, we provide a comprehensive overview of the published evidence and national/international guidelines regarding ultrasound surveillance for HCC in people with NAFLD. We examine ultrasound sensitivity in this cohort for the detection of all stage and early HCC, the impact of steatosis and abdominal obesity on ultrasound performance, evidence for the addition of serum alpha-fetoprotein measurement, optimal timing of surveillance, emerging modalities for risk stratification and screening, and outline the challenges of case finding and surveillance eligibility criteria in this patient cohort. Finally, amalgamating all available evidence, we propose a pragmatic surveillance pathway for patients with NAFLD.

Diagnostic implication of a circulating serum-based three-microRNA signature in hepatocellular carcinoma.

Owing to the diagnostic dilemma, the prognosis of hepatocellular carcinoma (HCC) remains impoverished, contributing to the globally high mortality rate. Currently, HCC diagnosis depends on the combination of imaging modalities and the measurement of serum alpha-fetoprotein (AFP) levels. Nevertheless, these conventional modalities exhibit poor performance in detecting HCC at early stages. Thus, there is a pressing need to identify novel circulating biomarkers to promote diagnostic accuracy and surveillance. Circulating miRNAs are emerging as promising diagnostic tools in screening various cancers, including HCC. However, because of heterogenous and, at times, contradictory reports, the universality of miRNAs in clinical settings remains elusive. Consequently, we proposed to explore the diagnostic potential of ten miRNAs selected on a candidate-based approach in HCC diagnosis. The expression of ten candidate miRNAs (Let-7a, miR-15a, miR-26a, miR-124, miR-126, miR-155, miR-219, miR-221, miR-222, and miR-340) was investigated in serum and tissue of 66 subjects, including 33 HCC patients and 33 healthy controls (HC), by rt-PCR. Receiver operating characteristic curve (ROC) analysis was used to determine the diagnostic accuracy of the prospective serum miRNA panel. To anticipate the potential biological roles of a three-miRNA signature, the target genes were evaluated using the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway. The serum and tissue expression of miRNAs (Let-7a, miR-26a, miR-124, miR-155, miR-221, miR-222, and miR-340) were differentially expressed in HCC patients (p < 0.05). The ROC analysis revealed promising diagnostic performance of Let-7a (AUC = 0.801), miR-221 (AUC = 0.786), and miR-2 (AUC = 0.758) in discriminating HCC from HC. Furthermore, in a logistic regression equation, we identified a three-miRNA panel (Let-7a, miR-221, and miR-222; AUC = 0.932) with improved diagnostic efficiency in differentiating HCC from HC. Remarkably, the combination of AFP and a three-miRNA panel offered a higher accuracy of HCC diagnosis (AUC = 0.961) than AFP alone. The functional enrichment analysis demonstrated that target genes may contribute to pathways associated with HCC and cell-cycle regulation, indicating possible crosstalk of miRNAs with HCC development. To conclude, the combined classifier of a three-miRNA panel and AFP could be indispensable circulating biomarkers for HCC diagnosis. Furthermore, targeting predicted genes may provide new therapeutic clues for the treatment of aggressive HCC.

A Retrospective Multicentric Study of 34 Patients with Niemann–Pick Type C Disease and Early Liver Involvement in France

To describe the clinical features and course of liver involvement in a cohort of patients with Niemann-Pick type C disease (NP-C), a severe lysosomal storage disorder. Patients with genetically confirmed NP-C (NPC1, n=31; NPC2, n=3) and liver involvement before age 6months were retrospectively included. Clinical, laboratory test, and imaging data were collected until the last follow-up or death; available liver biopsy specimens were studied using anti-CD68 immunostaining. At initial evaluation (median age, 17days of life), all patients had hepatomegaly, 33 had splenomegaly, and 30 had neonatal cholestasis. Portal hypertension and liver failure developed in 9 and 4 patients, respectively. Liver biopsy studies, performed in 16 patients, revealed significant fibrosis in all 16 and CD68+ storage cells in 15. Serum alpha-fetoprotein concentration measured in 21 patients was elevated in 17. Plasma oxysterol concentrations were increased in the 16 patients tested. Four patients died within 6months of life, including 3 from liver involvement. In patients who survived beyond age 6months (median follow-up, 6.1years), cholestasis regressed in all, and portal hypertension regressed in all but 1; 25 patients developed neurologic involvement, which was fatal in 16 patients. Liver involvement in NP-C consisted of transient neonatal cholestasis with hepatosplenomegaly, was associated with liver fibrosis, and was responsible for death in 9% of patients. The combination of liver anti-CD68 immunostaining, serum alpha-fetoprotein measurement, and studies of plasma biomarkers should facilitate early identification of NP-C.

Limb Body Wall Complex: A Case Report

Limb-body wall complex (LBWC) is a rare, congenital defect defined by lateral body-wall defects, limb reduction abnormalities and/or craniofacial defects. The developmental pathogenesis as well as the etiology of LBW complex is controversial and has no sex or familial predilection. The poor prognosis of LBWC necessitates an early antenatal diagnosis. Serum alpha-fetoprotein measurement and ultrasonographic examination is the key to prenatal diagnosis. Prenatally, the abnormal fetoplacental attachment can be detected ultrasonographically by the end of the first gestational trimester. Postnatal, the examination of placenta, umbilical cord and membranes is crucial in confirming the diagnosis of LBWC. The present case is associated with amniotic adhesive bands, thoraco-abdominoschisis, minor encephalocele, and belongs to the category of LBWC with craniofacial defects.

Current Status and Future Directions of Hepatocellular Carcinoma Surveillance Test Based on Cost-effective Analysis

Detection of hepatocellular carcinoma (HCC) at an early stage enables patients to receive curative treatment with survival gains. Current international liver society guidelines recommend the enrollment of patients at high risk for HCC in surveillance programs. In Korea, surveillance for HCC advocated for patients with chronic hepatitis B, chronic hepatitis C, and liver cirrhosis. The established surveillance tool for HCC is liver ultrasonography plus serum alpha-fetoprotein measurement every 6 months. However, there would be obstacles to the improvement of efficacy and cost-effectiveness of the HCC surveillance test. Assessing who is at risk of developing HCC remains incompletely validated. Also, which surveillance tools to use according to patients' characteristics are controversial. The present paper reviews the latest knowledge regarding the strategies and cost-effectiveness of HCC surveillance.

Glypican-3-Targeted 227Th α-Therapy Reduces Tumor Burden in an Orthotopic Xenograft Murine Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide, with limited therapeutic options for advanced disease. Targeted α-therapy is an emerging class of targeted cancer therapy in which α-particle-emitting radionuclides, such as 227Th, are delivered specifically to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and invivo efficacy of a 227Th-labeled GPC3-targeting antibody conjugate (227Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. Methods: The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3-targeting antibody (αGPC3) for subsequent 227Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227Th. In vitro stability was evaluated by measuring the percentage of protein-bound 227Th by γ-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2-Red-FLuc cells was developed. Biodistribution and blood clearance of 227Th-octapa-αGPC3 were evaluated in tumor-bearing mice. The efficacy of 227Th-octapa-αGPC3 was assessed in tumor-bearing animals with serial measurement of serum α-fetoprotein at 23 d after injection. Results: Octapa-conjugated αGPC3 provided up to 70% 227Th labeling yield in 2 h at room temperature. In the presence of ascorbate, at least 97.8% of 227Th was bound to αGPC3-octapa after 14 d in phosphate-buffered saline. In HepG2-Red-FLuc tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. Twenty-three days after treatment, a significant reduction in tumor burden was observed in mice receiving a 500 kBq/kg dose of 227Th-octapa-αGPC3 by tail-vein injection. No acute off-target toxicity was observed, and no animals died before termination of the study. Conclusion:227Th-octapa-αGPC3 was observed to be stable invitro; maintain high specificity for GPC3, with favorable biodistribution invivo; and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.

Abstract 928: Glypican-3 targeted thorium-227 alpha therapy reduces tumor burden in an orthotopic xenograft model of hepatocellular carcinoma

Abstract The purpose of this study is to develop a thorium-227 (227Th) antibody radioimmunoconjugate targeting glypican-3 (GPC3) and to test its therapeutic efficacy in a hepatocellular carcinoma (HCC) orthotopic xenograft model. GPC3 targeting antibody (αGPC3) was conjugated to bifunctional chelator p-SCN-Bn-H4octapa (octapa), and αGPC3-octapa binding affinity for GPC3 was evaluated by flow cytometry. 227Th radiolabeling of this conjugate was optimized, and in vitro stability of 227Th-αGPC3-octapa was evaluated in PBS with and without free radical scavenging agent over 14 days. For in vivo evaluation, an orthotopic xenograft model was generated by hepatic subcapsular injection of human HCC HepG2 cells. In vivo biodistribution was assessed in blood, tumor and organs at 1, 7 and 21 days after tail vein injection of 227Th-αGPC3-octapa (500 KBq/kg). To test therapeutic efficacy, tumor-bearing animals were injected with 227Th-αGPC3-octapa (250 kBq/kg or 500 kBq/kg) and compared to an irrelevant control antibody, 227Th-αBHV1-octapa (500 kBq/kg), and to a no-treatment control. Tumor burden was assessed with serial serum alpha-fetoprotein (AFP) measurements, a marker of tumor burden validated in this model. Toxicity to 227Th-αGPC3-octapa was measured by serum comprehensive metabolic panel obtained 21 days after injection. GPC3 binding affinity was highest after conjugation of αGPC3 with 10 equivalents of octapa. The protein recovery from the conjugation process was &amp;gt;85%, and mass spectral analysis indicated an average of 3.3 octapa moieties per molecule of αGPC3-octapa. After two weeks, &amp;gt;98% of αGPC3-octapa and αBHV1-octapa had 227Th bound in the presence of scavenging agent. αGPC3-octapa maintained high affinity for GPC3 as measured by flow cytometry, indicating the octapa conjugation reaction did not alter immunoreactivity of αGPC3. In vivo, 227Th-αGPC3-octapa accumulated in the tumor over time and cleared from normal tissues with a %ID/g of &amp;lt;5% by 21 days after injection. Significant antitumor activity was observed after treatment with 227Th-αGPC3-octapa (500 kBq/kg) with mean AFP level of 10,696 ± 19,754ng/mL compared to 308,175 ± 362,372ng/mL and 145,154 ± 166,780ng/mL in the 227Th-αBHV1-octapa and no-treatment control group, respectively. Reductions in serum AFP was observed in all but one tumor-bearing mouse after 500kBq/kg 227Th-αGPC3-octapa therapy. Organ-specific toxicity was not observed after treatment with 227Th-αGPC3-octapa (500 KBq/kg) compared to no-treatment control. In conclusion, we report the development of a GPC3 targeted thorium conjugate and demonstrate its in vivo therapeutic efficacy in a murine orthotopic xenograft model of hepatocellular carcinoma. Citation Format: Kevin P. Labadie, Donald K. Hamlin, Aimee Kenoyer, Sara K. Daniel, Alan F. Utria, Andrew D. Ludwig, Heidi L. Kenerson, Delphine L. Chen, Johnnie Orozco, Raymond S. Yeung, Lily Li, Chris Orvig, Yawen Li, D Scott Wilbur, James O. Park. Glypican-3 targeted thorium-227 alpha therapy reduces tumor burden in an orthotopic xenograft model of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 928.

472 G6PD deficiency is associated with decreased maternal serum Alpha-fetoprotein levels

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited X-linked recessive disorder, being the most common enzymatic defect of erythrocytes in humans. Since G6PD deficiency has been associated with metabolic comorbidities and placental dysfunction, we aimed to examine whether this disorder can affect the levels of maternal serum biochemical screening markers. For this retrospective study, we collected data of all pregnant women delivering in our medical center between January 2015 to December 2019. The inclusion criteria were any documentation of maternal serum biochemical screening markers: free beta-human chorionic gonadotropin (HCG), pregnancy-associated plasma protein A (PAPP-A), maternal serum alpha-fetoprotein (AFP), HCG and unconjugated estriol. Overall, 6,186 women with documented maternal serum biochemical screening markers were detected, 63 of these (1.0%) with G6PD deficiency. No difference in demographic or obstetrical characteristics was noted between G6PD-deficient women to the remaining cohort (including maternal age, body mass index, gestational age and birth weight). In G6PD-deficient women, significantly lower levels of maternal AFP were found compared to the remaining cohort (0.87±0.28 vs. 1.05±0.28 multiples of median, respectively, p<0.001, Table 1). In addition, marginally lower second trimester HCG levels were found in G6PD deficiency (1.0±0.58 vs. 1.15±0.69 multiples of median in the remaining cohort, p=0.07). Since the placenta plays a major role in HCG synthesis, as well as in transferring the fetal AFP to maternal circulation, the placental effects of G6PD deficiency may explain lower levels of these markers. As maternal serum AFP measurement serves as a screening tool for neural tube defects, as well as a component of biochemical screening for Down syndrome, G6PD status may affect the screening results. Thus, the findings of our study may be of great importance in prenatal surveillance, and should be further explored.

Screening for hepatocellular carcinoma in chronic liver disease: a systematic review and meta-analysis of randomized controlled trials comparing screening methodologies

Background Globally, hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second most common cause of cancer-related mortality. HCC is often asymptomatic until an advanced stage. Current guidelines recommend ultrasound surveillance with or without measurement of serum alpha-fetoprotein. Our objective was to determine if screening for HCC is beneficial or harmful in patients with chronic liver disease. Primary outcomes were all-cause mortality and quality of life. Secondary outcomes were mortality due to HCC, the number of cases of HCC detected, and adverse events. Methods This is a systematic review and meta-analysis of data from randomized controlled trials. To be included trials had to randomize patients to either an HCC screening group or non-screening group, randomize patients to different screening frequencies or randomize patients to different screening methods. All published reports of randomized trials on screening for HCC were eligible for inclusion, irrespective of the language of publication. Studies had to include patients with chronic liver disease. Data extraction were performed independently by two reviewers. Results When screening with six-monthly alpha-fetoprotein and ultrasound abdomen was compared to no screening there was no evidence of difference in HCC related mortality when adjusted for clustering across a range of intracluster correlation coefficients (Intracluster coefficient (ICC) 0.02, odds ratio (OR) 0.60, 95% confidence interval (CI) 0.31-1.15). Screening with six-monthly alpha-fetoprotein when compared to a single alpha-fetoprotein check did not result in a statistically significant difference in all-cause mortality (OR 1.02, 95% confidence interval (CI) 0.65-1.60), mortality due to HCC (OR 1.01, 95% CI 0.57-1.78) or the number of HCC detected (OR 1.11 95% CI 0.64-1.92). There was no evidence of difference in all-cause mortality (OR 0.81, 95% CI 0.26-2.53), mortality due to hepatocellular carcinoma (OR 0.81, 95% CI 0.26-2.53) or the number of patients with HCC detected (OR 1.09 95% CI 0.40-2.99) when twice-a-year ultrasound was compared with annual CT. There was no statistically significant difference when screening more frequently was compared to less frequently in terms of all-cause mortality (OR 0.86, 95% CI 0.56-1.32), mortality due to hepatocellular carcinoma (OR 1.42, 95% CI 0.55-3.64) and the number of cases of hepatocellular carcinoma detected (OR 0.90 95% CI 0.47-1.71). Conclusion There is currently insufficient evidence from randomized controlled trials to support routine screening for HCC in patients with chronic liver disease.

Cost-effectiveness Analysis of Screening Extremely Low Birth Weight Children for Hepatoblastoma Using Serum Alpha-fetoprotein

To evaluate the cost-effectiveness of screening children born at extremely low birth weight (ELBW) for hepatoblastoma using serial serum alpha-fetoprotein measurements. We created a decision tree to evaluate the cost effectiveness of screening children born at ELBW between 3 and 48months of age compared with current standard of care (no screening). Our model used discounted lifetime costs and monetary benefits in 2018 US dollars, based on estimates in the published literature. The effects of uncertainty in model parameters were also assessed using univariate sensitivity analyses, in which we changed the values for one parameter at a time to assess the effect on the estimated incremental cost-effectiveness ratio. For the estimated 55 699 children born at ELBW in the US each year, this screening is associated with 77.7 additional quality-adjusted life-years (QALYs) at a cost of $8.7 million. This results in an incremental cost-effectiveness ratio of about $112 000/QALY, which is considered cost effective from a US societal perspective. For children diagnosed with hepatoblastoma, our model finds that the screening regimen is associated with a 10.1% increase in survival, a 4.18% increase in expected QALYs, and a $245 184 decrease in expected cost. Screening ELBW children for hepatoblastoma between 3 and 48months of age dominates the alternative and is cost effective from a societal perspective.

Distinct clinical and genetic characteristics of AFP-negative hepatocellular carcinoma patients infected by HBV or HCV.

e16620 Background: The serum level of alpha-fetoprotein (AFP) is a key biomarker in hepatocellular carcinoma (HCC) screening regardless of the high false-negative rates. Studies have characterized AFP negative HCC patients, however, the differences between HBV and HCV infected AFP negative HCC patients have not been discussed. Methods: The clinical profiles and whole-exome sequencing data of 243 patients were downloaded from the TCGA database. Patients were divided into 4 groups based on their virus infection status and serum AFP measurements as indicated in the table. The mutation profiles and clinical features of the patients were analyzed. Results: In the HBV infected groups, the AFP+ patients carried significantly larger tumors (n = 17, 85.88±11.87 mm) compared to the AFP- patients (n = 13, 49.08±8.933 mm, p = 0.026). The HBV+ AFP+ group exhibited the prevalence of vascular invasion (VI, 76%, 13/17) while less than half of the patients in the HBV+ AFP- group developed VI (46%, 6/13). The WES results identified shared mutations in more than 10% of patients in each group. It appeared that 126 shared mutations were restricted to the HBV+ AFP+ group, they are involved in the regulation of ion transmembrane transport (p &lt; 0.001) and interaction between L1 and Ankyrins (p &lt; 0.0001). Only 51 shared mutations were exclusive to the HBV+ AFP- group, they majorly affect developmental growth (p &lt; 0.001) and skeletal system development (p &lt; 0.01). In contrast, the tumor sizes of HCV+ AFP+ and HCV+ AFP- patients are similar (55.18±7.781 vs 48.19±5.564, p = 0.47), while the VI rate is higher in the HCV+ AFP- group (63%, 17/29, Table). In total, 11 shared mutations were restricted to the HCV+ AFP+ group, several of the genes were involved in the generation of precursor metabolites and energy (p &lt; 0.01) and activation of immune response (p &lt; 0.01). 27 shared mutations were exclusive to the HCV+ AFP- group, the enrichment analysis showed that they are related to the regulation of synapse organization (p &lt; 0.0001) and the regulation of chromosome organization (p &lt; 0.01). Conclusions: HBV and HCV infection were associated with distinct clinical features among the AFP positive and AFP negative patients. The differences were underpinned by the mutations exclusive to each group, and they were involved in distinct molecular and cellular functions. [Table: see text]

Diagnostic Value of Serum Glypican 3 in Hepatocellular Carcinoma: A Case Control Study of Patients Seen at the University College Hospital, Ibadan, Nigeria

Hepatocellular carcinoma (HCC) is a major health problem which has been increasing in Nigeria with a doubling in the incidence rate in the past 10 years. Current diagnosis of HCC relies on clinical information, liver imaging and measurement of serum alpha-fetoprotein (AFP). The reported sensitivity and specificity of AFP are not sufficient for early diagnosis, and so additional and more sensitive markers are needed. One of such tumor markers is serum Glypican 3 (GPC3). So, this study aimed to determine the frequency of GPC3 in apparently healthy controls and patients with HCC, comparing the diagnostic efficacy of GPC3 to AFP in HCC and to assess the diagnostic accuracy of combined AFP and GPC3 in the diagnosis of HCC.Fifty patients with clinical, radiological and/or histological features of HCC, and fifty apparently healthy controls who were HBsAg and anti-HCV negative and had normal abdominal ultrasonography scan were recruited for the study. Serum estimation of AFP and GPC-3 were done for all the subjects. The sensitivity and specificity of GPC3 was 54 % and 44% respectively based on a receiver operating characteristic(ROC) curve –derived optimum cut-off level &gt;20 ng/ml. The sensitivity and specificity of AFP were 64% and 100% at an ROC derived optimum cut- off level of 20 ng/ml. The area under the receiver operating characteristic curve (AUROC) for AFP was 0.69 and was significantly larger than that of GPC3 which was 0.42(p &lt;0.001). The diagnostic value of GPC3 in our patients with advanced hepatocellular carcinoma is poor in comparison with AFP. Keywords : Glypican 3, Diagnostic value, Hepatocellular carcinoma, Nigeria DOI : 10.7176/JHMN/59-06

Weighing the benefits of hepatocellular carcinoma surveillance against potential harms

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and usually occurs in people with liver cirrhosis. Both the incidence and mortality of HCC are increasing worldwide, making it a growing public health issue. HCC diagnosed at an early stage has a far better prognosis than HCC diagnosed at a late stage, mainly because early stage HCC can be treated with potentially curative therapies such as resection and transplantation. This makes surveillance for HCC in patients with liver cirrhosis an important strategy in improving outcomes. Serial measurements of serum alpha fetoprotein (AFP) and abdominal ultrasound (US) are the established methods of surveillance. Surveillance using a combination of these techniques has reasonable sensitivity and specificity and reduces mortality from HCC by varying degrees, depending on the patient population. However, there are potential harms. The main harms result from false-positive and false-negative results. False-positive results commit patients to undergo further, potentially invasive and ultimately unnecessary diagnostic testing – which has both financial and emotional costs. False-negative results can have devastating consequences for patients who later present with more advanced HCC. Obesity is increasingly prevalent and reduces the sensitivity of US in detecting HCC. Obesity-associated non-alcoholic fatty liver disease (NAFLD) presents an additional challenge, where HCC can develop in the absence of cirrhosis. As surveillance with US and AFP is not cost-effective in NAFLD without cirrhosis, it is not advocated. These aspects will be reviewed.

Serum Dickkopf-1 as A Biomarker for The Diagnosis and Prognosis of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma is one of the commonest cancers in world. It is one of the major health problems and its incidence is increasing. The main routinely used parameter for diagnosis of HCC is AFP, also it can be elevated in the liver cirrhosis. It represents a liver cell specific, not a tumor specific marker, for these reasons, we suggest use AFP as a supplementary marker for HCC diagnosis. So, identification of a sensitive biomarker to improve early diagnosis of HCC is in need. Aim of the work: this study was aimed to evaluate the clinical significance of serum Dickkopf-1 (DKK1) as a diagnostic and prognostic marker in hepatocellular carcinoma. Patients and Methods: in this study 100 subjects were included and divided into 3 groups, Group I: included 50 patients with HCC, and divided into 2 subgroups according to Barcelona Clinic Liver Cancer (BCLC) into early HCC (24 patients) and late HCC (18 patients). Group II: included 25 patients with liver cirrhosis. Group III: included 25 healthy subjects (control). Clinical assessment, routine laboratory evaluation, CT scan and measurements of serum alpha-fetoprotein (AFP) and DKK1 were performed to all patients and repeated to group I patients 1 month after treatment. Results: the current study showed that Serum DKK1 was significantly elevated in HCC group compared to liver cirrhosis and healthy control groups, with increased level in late than early stage. The optimum cut off values of DKK1 for diagnosis of HCC was 1.92 ng/mL (AUC 0.926, sensitivity 88% and specificity 83%). While the optimum cut off value for AFP was 102 ng/mL (AUC 0.904, 71% sensitivity and 84% specificity). Testing of both serum DKK1 and AFP increased the diagnostic accuracy for HCC (AUC 0.964, sensitivity 91%, and specificity 90%). Serum DKK1 level significantly decreases after HCC treatment with radio-frequency ablation. Conclusion: It could be concluded that Testing of both serum DKK1 and AFP significantly increased the diagnostic accuracy for HCC. Meanwhile, DKK1 can be used alone for diagnosis of HCC even in HCC with inconclusive AFP. Serum DKK1 might be a potential diagnostic and prognostic marker for HCC.

Risk Factors for Hepatocellular Carcinoma

Abstract Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, with incidence rising is expected to increase by another 81% by the year 2020, primarily due to the hepatitis C epidemic. The strongest risk factors for the development of HCC is a hepatitis B (HBV) and hepatitis C (HCV) virus infection, as well as cirrhosis of any cause. Other risk factors that have been reported include exposure to aflatoxin, alcohol, tobacco, obesity and diabetes. To detect potentially curable cases of hepatocellular carcinoma, outpatients with chronic liver disease who have been seen at the Dr. Ion Cantacuzino Hospital, since 10 years and examined periodically with real-time ultrasonography and measurement of serum alpha-fetoprotein.We analyzed the data on these patients for risk factors for hepatocellular carcinoma. The risk of liver cancer in men was 1.33 times higher than in women; patients in their 60s had significantly higher rate ratios (6.46) than patients in their 40s; patients with liver cirrhosis diagnosed at enrollment had significantly higher rate ratios for liver cancer (1.93) than patients with chronic hepatitis. The high serum alpha-fetoprotein level at enrollment was also confirmed as a significant marker for a high risk, regardless of the stage of disease (chronic hepatitis or liver cirrhosis). The serum markers for hepatitis virus -- HBsAg, and anti-HCV - were significantly associated with the risk of liver cancer: the adjusted rate ratios for HBsAg, anti-HBc, and anti-HCV were estimated to be 6.92, 4.54, and 4.09, respectively. Hepatitis B surface antigen (rate ratio 6,92; 95% CI: 2.92 to 16.39) and hepatitis C antibody (rate ratio 4.09; 95% CI: 1.30 to 12.85) showed the most risk for carcinoma. Further studies are required to clarify the roles of other risk factors, including drinking and smoking habits.

The Use of Serum Survivin and AFP-L3 and their Combination in Improving Hepatocellular Carcinoma Diagnosis Especially in Patients with Low Serum AFP

AbstractBackground: Hepatocellular carcinoma (HCC) is respon-sible for about 4.7% of chronic liver disease in Egypt. Survivin is an essential element in apoptosis inhibition. Survivin is present in fetal and malignant adult tissue and is absent in non malignant tissues. A diagnostic and prognostic HCC marker is the alpha-fetoprotein (AFP) binding to Lens culinaris agglutinin (AFP-L3%) percentage. There is a need for HCC marker that is better than AFP especially in those low AFP.Aim of Study: To detect the role of determination of serum Survivin gene, AFP-L3% and their combination in HCC diagnosis.Subjects and Methods: Fifty HCC patients and 20 healthy control persons were subjected for measurement of serum AFP, survivin gene and AFP-L3%. Reverse transcription-polymerase chain reaction (RT-PCR) was used for detection of serum survivin gene. AFP-L3% was measured by a liquid-phase binding assay on the Wako LiBASys clinical auto analyzer.Results: Serum Survivin gene was positive in 27 (54%) HCC cases and negative in 23 (46%) cases. AFP-L3% was detected in 36 (72%) HCC cases. The combined use of serum servivin gene and AFP-L3% were positive in 43 (86%) of HCC cases. In 22 HCC cases with serum AFP below 200 ng/ml serum servivin gene was detected in 9 (40.9%) cases but AFP-L3% was positive in 13 (59.9%) cases and the combined use of positive serum servivin and AFP-L3 were present in 18 cases (81.18%).Conclusions: The combined use of serum survivin gene and AFP-L3% could have a valuable diagnostic role in HCC especially in those with low AFP.

Alpha-fetoprotein dynamics in the waiting list as a biomarker of hepatocellular carcinoma recurrence and mortality after liver transplant

Introduction: There is a lack of information on the impact that serum alpha-fetoprotein(AFP)dynamics may have on hepatocellular carcinoma(HCC)recurrence and survival after liver transplantation(LT).We aimed to assess if this could serve as a surrogate of tumor biology. Methods: We assessed all patients who underwent LT for HCC between January 2004 and December 2014.Only patients with a measurement of serum AFP at listing and at LT were included.AFP ratio was defined as AFP at LT/AFP at listing.Patients with more than 2-times increase in AFP were compared to those with less than 2-times increase and those with a decrease or no change in AFP.The primary outcomes were overall survival(OS)and disease-free survival(DFS).Multivariate Cox regression was applied to identify predictors of post-LT outcomes. Results: 506 patients were transplanted for HCC;442 patients were included in the study.There were 292 patients(66.1%)with a decrease or no change in AFP(Group1),86(19.4%)with an increase< double(Group2)and 64(14.5%)with a double increase(Group3). These 3 groups were comparable.The 5-years DFS was 71.3%for Group1 vs 66.4%for Group2 and 52.2%for Group3,p=0.018.The 5-years OS was 75.7% for Group1 vs 72.9%for Group2 vs. 54.3% for Group3,p=0.03. The sole risk factors for recurrence after adjusting for confounders were double increase in the AFP ratio[HR2.4(1.4-4.1),p=0.001]and maximum tumor size at listing[HR1.12(1.06-1.19),p< 0.001];however the only risk factor for death was a double increase in AFP[HR1.60(1.04-2.4),p=0.001]after adjusting for confounders. Conclusion: Double increase in the serum AFP while patients are waiting for LT is a strong predictor of outcomes. This dynamic serum AFP biomarker may serve to expand the“size and number criteria” without impairing the results of LT.Tabled 1FP16-01 Table [Patient characteristics]AFP RatioN (442)Group 1 ≤ (292, 66.1%)Group 2 1-2 (86, 19.4%)Group 3 ≥ (64, 14.5%)p valueAge, y*58 (53-62)58 (53-62)58 (52-62)57 (50-61)0.661Male, %369 (83.5)243 (83.2)75 (87.2)51 (79.7)0.461Bridging therapy, %329 (74.4)227 (77.7)58 (67.4)44 (68.8)0.083 Radiofrequency ablation, %208 (63.2)150 (66.1)31 (53.4)27 (61.4)0.197 Transarterial79 (24.0)51 (22.5)15 (25.9)23 (52.3)0.001chemoembolization, %MELD at listing*10 (8-14)10 (8-13)10 (8-13)11 (9-14)0.654Waiting time (months)*6 (2-11)6 (2-11)6 (2-11)6 (3-12)0.651Listing max. tumor size, cm*2.5 (1.5-3.9)2.5 (1.5-3.9)2.5 (1.4-3.9)2.5 (1.5-3.9)0.835PreLT max. tumor size, cm*2.0 (0.0-3.2)1.8 (0-3.0)1.8 (0-3.3)2.4 (1.3-3.4)0.106Listing tumor number*1 (1-2)1 (1-2)1 (1-2)1 (1-3)0.292PreLT tumor number*1 (0-2)1 (0-2)1 (0-2)2 (1-3)0.028Listing AFP*13 (5-47)11 (5-47)18 (7-50)21 (9-63)0.196PreLT AFP*11 (5-44)7 (5-16)20 (9-63)76 (27-522)<0.001AFP difference*0 (-5-3)-2 (-14-0)4 (2-13)59 (18-426)<0.001*median (IQR)Abbreviation: BMI: Body mass index; MELD: Model for End-Stage Liver Disease; AFP: alpha-fetoprotein: Open table in a new tab *median (IQR) Abbreviation: BMI: Body mass index; MELD: Model for End-Stage Liver Disease; AFP: alpha-fetoprotein:

Des-γ carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T^{1762}, A^{1764}), a prospective study.

The accuracy of des-γ -carboxyprothrombin (DCP) in the detection of hepatocellular carcinoma (HCC) in those infected hepatitis B virus (HBV) from cross-sectional or case-control studies is contradictory. To resolve this contradiction using a prospective study. Three hundred male individuals persistently infected with HBV were recruited from the Chinese cohort and followed up once per year from 2012 to 2015. Each subject was screened for HCC by measurements of serum alpha-fetoprotein (AFP), lectin-bound α -fetoprotein (AFP-L3), DCP concentrations and ultrasonographic examinations. Nineteen HCC cases were identified. The area under receiver operating characteristic (AUROC) at first, second and third visit for AFP, AFP-L3 and DCP ranges from 0.710-0.897, 0.566-0.637 and 0.520-0.595, respectively. The rate of elevated DCP is not significantly different between the HCC cases and controls (52.6% vs. 47.4%) (P > 0.05). The incidence of HCC in subjects with elevated DCP is not significantly higher than that of those with normal DCP (9.5% vs. 4.6%) (P > 0.05). The AUROC of combinations of these biomarkers was higher than that of AFP alone at the first visit. However, it was reduced at the second visit. At the third visit, the AUROCs of AFP + DCP and AFP + AFP-L3 + DCP, but not that of AFP + AFP-L3, were higher than that of AFP alone. AFP but DCP or AFP-L3 remains a valuable biomarker for HCC in those chronically infected with HBV. The combination with AFP-L3 and DCP may not increase the accuracy of AFP in differentiating HCC cases from controls, among those infected with HBV.

The Clinical Significance of Serum Alpha-fetoprotein in Diagnosing Hepatocellular Carcinoma in a Health Screening Population

Serum alpha-fetoprotein (AFP) measurement is commonly included in a health check-up program in Korea. However, its benefits remain uncertain. We analyzed whether AFP measurement should be included in a general health check-up program to screen for hepatocellular carcinoma (HCC). A total of 36,552 adults aged 18 years or older-who participated in a routine health examination including AFP determination between January 2009 and December 2009 at the Health Promotion Center, Samsung Medical Center, South Korea-were analyzed. High risk of HCC was defined as positivity for hepatitis B surface antigen, anti-hepatitis C virus antibody or having liver cirrhosis. AFP level >10 ng/mL was observed in 27 participants (0.1%) and primary liver cancer was diagnosed in 9 patients (6 HCC and 3 cholangiocarcinoma). Among 1,619 participants with high risk factors of HCC, AFP level >10 ng/mL was observed in 16 participants, of which, 4 diagnoses were made. Sensitivity, specificity, positive predictive value, and negative predictive value of AFP for HCC was 0.66, 0.99, 0.25 and 0.99, respectively, for high risk participants. Among 34,933 participants without risk factors for HCC, 11 patients (<0.1%) showed elevated AFP levels above 10 ng/mL, and no case was diagnosed with primary liver cancer during a median follow-up period of 36 months (range: 0-48 months). AFP elevation was rare in participants without risk factors for HCC, and was unable to screen for HCC in this population. We discourage routine AFP measurements for asymptomatic adults without risk factors of HCC.