Specific features of epitope-MIPs and whole-protein MIPs as illustrated for AFP and RBD of SARS-CoV-2.

Molecularly imprinted polymer (MIP) nanofilms for alpha-fetoprotein (AFP) and the receptor binding domain (RBD) of the spike protein of SARS-CoV-2 using either a peptide (epitope-MIP) or the whole protein (protein-MIP) as the template were prepared by electropolymerization of scopoletin. Conducting atomic force microscopy revealed after template removal and electrochemical deposition of gold a larger surface density of imprinted cavities for the epitope-imprinted polymers than when using the whole protein as template. However, comparable affinities towards the respective target protein (AFP and RBD) were obtained for both types of MIPs as expressed by the KD values in the lower nanomolar range. On the other hand, while the cross reactivity of both protein-MIPs towards human serum albumin (HSA) amounts to around 50% in the saturation region, the nonspecific binding to the respective epitope-MIPs is as low as that for the non-imprinted polymer (NIP). This effect might be caused by the different sizes of the imprinted cavities. Thus, in addition to the lower costs the reduced nonspecific binding is an advantage of epitope-imprinted polymers for the recognition of proteins.

AFP-L3 and DCP strongly predict early hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND & AIMS: Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant locoregional therapy. METHODS: This prospective cohort study included consecutive patients with HCC who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival. RESULTS: This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0 ng/ml (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0 ng/ml (0.3-2.8). Most (94.7%) patients received pre-LT locoregional therapy. After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 7 of 265 (2.6%) patients not meeting this threshold. The Kaplan-Meier recurrence-free survival rate at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p <0.001). CONCLUSIONS: Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk patients who require additional locoregional therapy prior to LT. IMPACT AND IMPLICATIONS: Alpha-fetoprotein (AFP) is used to predict hepatocellular carcinoma (HCC) recurrence after liver transplant, but it remains an imperfect biomarker. In this prospective study, the biomarkers DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) strongly predicted early HCC recurrence and outperformed AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted the majority of recurrences and could be used to further refine liver transplant eligibility criteria.

Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC). However, long-term survival outcomes and treatment response of HCC patients undergoing immunotherapy is unpredictable. The study aimed to evaluate the role of alpha-fetoprotein (AFP) combined with neutrophil-to-lymphocyte ratio (NLR) to predict the prognosis and treatment response of HCC patients receiving ICIs. METHODS: Patients with unresectable HCC who received ICI treatment were included. The HCC immunotherapy score was developed from a retrospective cohort at the Eastern Hepatobiliary Surgery Hospital to form the training cohort. The clinical variables independently associated with overall survival (OS) were identified using univariate and multivariate Cox regression analysis. Based on multivariate analysis of OS, a predictive score based on AFP and NLR was constructed, and patients were stratified into three risk groups according to this score. The clinical utility of this score to predict progression-free survival (PFS) and differentiate objective response rate (ORR) and disease control rate (DCR) was also performed. This score was validated in an independent external validation cohort at the First Affiliated Hospital of Wenzhou Medical University. RESULTS: Baseline AFP ≤ 400 ng/ml (hazard ratio [HR] 0.48; 95% CI, 0.24-0.97; P = 0.039) and NLR ≤ 2.77 (HR 0.11; 95% CI, 0.03-0.37; P<0.001) were found to be independent risk factors of OS. The two labolatory values were used to develop the score to predict survival outcomes and treatment response in HCC patients receiving immunotherapy, which assigned 1 point for AFP > 400 ng/ml and 3 points for NLR > 2.77. Patients with 0 point were classified as the low-risk group. Patients with 1-3 points were categorized as the intermediate-risk group. Patients with 4 points were classified as the high-risk group. In the training cohort, the median OS of the low-risk group was not reached. The median OS of the intermediate-risk group and high-risk group were 29.0 (95% CI 20.8-37.3) months and 16.0 (95% CI 10.8-21.2) months, respectively (P < 0.001). The median PFS of the low-risk group was not reached. The median PFS of the intermediate-risk group and high-risk group were 14.6 (95% CI 11.3-17.8) months and 7.6 (95% CI 3.6-11.7) months, respectively (P < 0.001). The ORR and DCR were highest in the low-risk group, followed by the intermediate-risk group and the high-risk group (P < 0.001, P = 0.007, respectively). This score also had good predictive power using the validation cohort. CONCLUSION: The HCC immunotherapy score based on AFP and NLR can predict survival outcomes and treatment response in patients receiving ICI treatments, suggesting that this score could serve as a useful tool for identification of HCC patients likely to benefit from immunotherapy.

A simple, sensitive, label-free electrochemical immunosensor based on the chitosan-coated silver/cerium oxide (CS@Ag/CeO2) nanocomposites for the detection of alpha-fetoprotein (AFP).

Metal oxide-based sensors have the benefit of inexpensive, quick response, and high sensitivity in detecting specific biological species. In this article, a simple electrochemical immunosensor was fabricated using antibody-chitosan coated silver/cerium oxide (Ab-CS@Ag/CeO2) nanocomposites on a gold electrode for sensitive alpha-fetoprotein (AFP) diagnosis in human serum samples. Successfully synthesis of AFP antibody-CS@Ag/CeO2conjugates was confirmed through Fourier transform infrared spectra of the prototype. The amine coupling bond chemistry was then used to immobilize the resultant conjugate on a gold electrode surface. It was observed that the interaction of the synthesized Ab-CS@Ag/CeO2nanocomposites with AFP prevented an electron transfer and reduced the voltammetric Fe(CN)63-/4-peak current, which was proportional to the amount of AFP. The linear ranges of AFP concentration were found from 10-12-10-6g.ml-1. The limit of detection was calculated using the calibration curve and came out to be 0.57 pg.ml-1. The designed label-free immunosensor successfully detected AFP in human serum samples. As a result, the resulting immunosensor is a promising sensor plate form for AFP detection and could be used in clinical bioanalysis.

Chinese expert consensus statement on the clinical application of AFP/AFP-L3%/DCP using GALAD and GALAD-like algorithm in HCC.

BACKGROUND: Primary hepatocellular carcinoma (HCC) is one of the most prevalent world-wide malignancies. Half of the newly developed HCC occurs in China. Optimizing the strategies for high-risk surveillance and early diagnosis are pivotal for improving 5-year survival. Constructing the scientific non-invasive detection technologies feasible for medical and healthcare institutions is among the key routes for elevating the efficacies of HCC identification and follow-up. RESULTS: Based on the Chinese and international guidelines, expert consensus statements, literatures and evidence-based clinical practice experiences, this consensus statement puts forward the clinical implications, application subjects, detection techniques and results interpretations of the triple-biomarker (AFP, AFP-L3%, DCP) based GALAD, GALAD like models for liver cancer. CONCLUSIONS: The compile of this consensus statement aims to address and push the reasonable application of the triple-biomarker (AFP, AFP-L3%, DCP) detections thus to maximize the clinical benefits and help improving the high risk surveillance, early diagnosis and prognosis of HCC.

Optimal threshold of alpha-fetoprotein response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Alpha-fetoprotein (AFP) response (relative decline in AFP) is associated with imaging response evaluated by response evaluation criteria in solid tumors ver1.1 (RECIST) and survival in treatment for hepatocellular carcinoma (HCC). However, the optimal threshold of AFP response is still unknown, especially in atezolizumab and bevacizumab (Atez/Bev) treatment. In this prospective multicenter study, we aimed to investigate an optimal threshold of AFP response in Atez/Bev treatment. Out of 284 patients with unresectable HCC who were treated with Atez/Bev, 91 patients with AFP ≥ 10 ng/ml were enrolled in the multicenter study. We investigated the relationship between various AFP response thresholds (relative decline ≥ 20%, ≥ 50%, and ≥ 75%) and treatment response and progression-free survival (PFS). An AFP relative decrease of ≥ 50% was associated with an overall response rate (ORR) with an odds ratio (95% confidence interval [CI]) of 5.7 (1.9-17). Disease control rate (DCR) was associated with an AFP relative decrease of ≥ 20%, with a 100% positive predictive value and a 52.0% sensitivity. AFP relative decreases of ≥ 50% and ≥ 20% were significantly associated with PFS with a hazard ratio (HR) of 5.60 (95% CI: 1.6-19, p = 0.006) and a HR of 4.44 (95% CI: 1.9-10, p < 0.001), respectively. AFP response of ≥ 50% and ≥ 20% were related to ORR and DCR, respectively, and both of these responses were also associated with PFS. AFP can be used as a real-time monitor during Atez/Bev treatment and is helpful for treatment optimization.

A comparison of clinical pathologic characteristics between alpha-fetoprotein negative and positive hepatocellular carcinoma patients from Eastern and Southern China.

BACKGROUND: Alpha-fetoprotein (AFP) is a biomarker used in clinical management of hepatocellular carcinoma (HCC), however, approximately 40% of HCC patients do not present with elevated serum AFP levels. This study aimed to investigate the clinical and pathologic characteristics between AFP positive and negative HCC patients to allow for improved clinical management and prognostication of the disease. METHODS: This study observed a cohort of HCC patients from Eastern and Southern China with comparisons of the clinical and pathologic features between serum AFP positive and negative patient groups; patients with decompensated hepatic cirrhosis, those with chronic hepatitis B, and hepatitis B virus (HBV) asymptomatic carrier patients were used as controls. Data included the laboratory results, pathology diagnosis, clinical staging and scores were obtained from routine clinical diagnostic methods. RESULTS: Patients with HCC, larger tumor sizes, liver cancer with hepatic cirrhosis, portal vein thrombosis, metastasis, high Child-Pugh score, high Barcelona-Clínic Liver Cancer (BCLC) stage, and advanced clinical stage had significantly higher serum AFP levels. Also, patients with HBsAg and HBeAg positive, high HBV DNA levels had significantly higher serum AFP levels. Patients with high serum AFP levels had higher protein induced by vitamin K absence or antagonist-II (PIVKA-II), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alpha-l-fucosidase (AFU), gamma-glutamyl transpeptidase (γ-GT), γ-GT /ALT, direct bilirubin (DBIL), indirect bilirubin (IDBIL), fibrinogen, and D-dimer levels. Patients with AFP positive had higher white blood cells (WBC), neutrophil, monocyte, and platelet count and neutrophil to lymphocyte ratio (NLR). CONCLUSIONS: The are significant differences in clinical pathologic characteristics between AFP positive and negative HCC patients which may be helpful for the management and prognostication of the disease.

Second trimester prediction of gestational diabetes: maternal analytes as an additional screening tool.

OBJECTIVES: Early diagnosis of gestational diabetes can lead to greater optimization of glucose control. We evaluated associations between maternal serum analytes (alpha-fetoprotein [AFP], free beta-human chorionic gonadotropin [beta-hCG], inhibin, and estriol) and the development of gestational diabetes mellitus (GDM). METHODS: This retrospective cohort study identified single-ton pregnancies with available second trimester serum analytes between 2009 and 2017. GDM was identified by ICD-9 and -10 codes. We examined the associations between analyte levels and GDM and to adjust for potential confounders routinely collected during genetic serum screening (maternal age, BMI, and race) using logistic regression. Optimal logistic regression predictive modeling for GDM was then performed using the analyte levels and the above mentioned potential confounders. The performance of the model was assessed by receiver operator curves. RESULTS: Out of 5,709 patients, 660 (11.6%) were diagnosed with GDM. Increasing AFP and estriol were associated with decreasing risk of GDM, aOR 0.76 [95% CI 0.60-0.95] and aOR 0.67 [95% CI 0.50-0.89] respectively. Increasing beta-hCG was associated with a decreasing risk for GDM(aOR 0.84 [95% CI 0.73-0.97]). There was no association with inhibin. The most predictive GDM predictive model included beta-hCG and estriol in addition to the clinical variables of age, BMI, and race (area under the curve (AUC 0.75), buy this was not statistically different than using clinical variables alone (AUC 0.74) (p=0.26). CONCLUSIONS: Increasing second trimester AFP, beta-hCG, and estriol are associated with decreasing risks of GDM, though do not improve the predictive ability for GDM when added to clinical risk factors of age, BMI, and race.

Study of siRNA Delivery via Polymeric Nanoparticles in Combination with Angiogenesis Inhibitor for The Treatment of AFP-Related Liver Cancer.

Angiogenesis inhibitor drugs have been explored as important pharmacological agents for cancer therapy, including hepatocellular carcinoma. These agents have several drawbacks, such as drug resistance, nonspecific toxicity, and systemic side effects. Therefore, combination therapy of the drug and small interfering RNA could be a promising option to achieve high therapeutic efficacy while allowing a lower systemic dose. Therefore, we studied adding an alpha-fetoprotein siRNA (AFP-siRNA) incorporated on polymeric nanoparticles (NPs) along with angiogenesis inhibitor drugs. The AFP siRNA-loaded NPs were successfully synthesized at an average size of 242.00 ± 2.54 nm. Combination treatment of AFP-siRNA NPs and a low dose of sunitinib produced a synergistic effect in decreasing cell viability in an in vitro hepatocellular carcinoma (HCC) model. AFP-siRNA NPs together with sorafenib or sunitinib greatly inhibited cell proliferation, showing only 39.29 ± 2.72 and 44.04 ± 3.05% cell viability, respectively. Moreover, quantitative reverse transcription PCR (qRT-PCR) demonstrated that AFP-siRNA incorporated with NPs could significantly silence AFP-mRNA expression compared to unloaded NPs. Interestingly, the expression level of AFP-mRNA was further decreased to 28.53 ± 5.10% when sunitinib was added. Therefore, this finding was considered a new promising candidate for HCC treatment in reducing cell proliferation and enhancing therapeutic outcomes.

Fetal Programming of the Endocrine Pancreas: Impact of a Maternal Low-Protein Diet on Gene Expression in the Perinatal Rat Pancreas.

In rats, the time of birth is characterized by a transient rise in beta cell replication, as well as beta cell neogenesis and the functional maturation of the endocrine pancreas. However, the knowledge of the gene expression during this period of beta cell expansion is incomplete. The aim was to characterize the perinatal rat pancreas transcriptome and to identify regulatory pathways differentially regulated at the whole organ level in the offspring of mothers fed a regular control diet (CO) and of mothers fed a low-protein diet (LP). We performed mRNA expression profiling via the microarray analysis of total rat pancreas samples at embryonic day (E) 20 and postnatal days (P) 0 and 2. In the CO group, pancreas metabolic pathways related to sterol and lipid metabolism were highly enriched, whereas the LP diet induced changes in transcripts involved in RNA transcription and gene regulation, as well as cell migration and apoptosis. Moreover, a number of individual transcripts were markedly upregulated at P0 in the CO pancreas: growth arrest specific 6 (Gas6), legumain (Lgmn), Ets variant gene 5 (Etv5), alpha-fetoprotein (Afp), dual-specificity phosphatase 6 (Dusp6), and angiopoietin-like 4 (Angptl4). The LP diet induced the downregulation of a large number of transcripts, including neurogenin 3 (Neurog3), Etv5, Gas6, Dusp6, signaling transducer and activator of transcription 3 (Stat3), growth hormone receptor (Ghr), prolactin receptor (Prlr), and Gas6 receptor (AXL receptor tyrosine kinase; Axl), whereas upregulated transcripts were related to inflammatory responses and cell motility. We identified differentially regulated genes and transcriptional networks in the perinatal pancreas. These data revealed marked adaptations of exocrine and endocrine in the pancreas to the low-protein diet, and the data can contribute to identifying novel regulators of beta cell mass expansion and functional maturation and may provide a valuable tool in the generation of fully functional beta cells from stem cells to be used in replacement therapy.

A novel waitlist dropout score for hepatocellular carcinoma - identifying a threshold that predicts worse post-transplant survival.

BACKGROUND & AIMS: It has been suggested that patients with hepatocellular carcinoma (HCC) at high risk of wait-list dropout would have done poorly after liver transplantation (LT) because of tumour aggressiveness. To test this hypothesis, we analysed risk of wait-list dropout among patients with HCC in long-wait regions (LWRs) to create a dropout risk score, and applied this score in short (SWRs) and mid-wait regions (MWRs) to evaluate post-LT outcomes. We sought to identify a threshold in dropout risk that predicts worse post-LT outcome. METHODS: Using the United Network for Organ Sharing database, including all patients with T2 HCC receiving priority listing from 2010 to 2014, a dropout risk score was created from a developmental cohort of 2,092 patients in LWRs, and tested in a validation cohort of 1,735 patients in SWRs and 2,894 patients in MWRs. RESULTS: On multivariable analysis, 1 tumour (3.1-5 cm) or 2-3 tumours, alpha-fetoprotein (AFP) >20 ng/ml, and increasing Child-Pugh and model for end-stage liver disease-sodium scores significantly predicted wait-list dropout. A dropout risk score using these 4 variables (C-statistic 0.74) was able to stratify 1-year cumulative incidence of dropout from 7.1% with a score ≤7 to 39.5% with a score >23. Patients with a dropout risk score >30 had 5-year post-LT survival of 60.1% vs. 71.8% for those with a score ≤30 (p = 0.004). There were no significant differences in post-LT survival below this threshold. CONCLUSIONS: This study provided evidence that patients with HCC with the highest dropout risk have aggressive tumour biology that would also result in poor post-LT outcomes when transplanted quickly. Below this threshold risk score of ≤30, priority status for organ allocation could be stratified based on the predicted risks of wait-list dropout without significant differences in post-LT survival. LAY SUMMARY: Prioritising patients with hepatocellular carcinoma for liver transplant based on risk of wait-list dropout has been considered but may lead to inferior post-transplant survival. In this study of nearly 7,000 patients, we created a threshold dropout risk score based on tumour and liver-related factors beyond which patients with hepatocellular carcinoma will likely have poor post-liver transplant outcomes (60% at 5 years). For patients below this risk score threshold, priority status could be stratified based on the predicted risk of wait-list dropout without compromising post-transplant survival.

Alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC): a retrospective study of 27 cases.

OBJECTIVE: The aim of the study was to investigate the relative risk factors associated with the prognosis and effective treatments of alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC). METHOD: We presented three cases of AFP-producing EOC and performed a brief review to summarize the clinicopathological features and prognostic factors of 24 cases that have been previously reported. We evaluated the correlations among prognostic and clinical parameters, such as stage, pathology and chemotherapy regimens. In addition, a retrospective review of these 27 cases was conducted, and survival curves were estimated using the Kaplan-Meier method. RESULTS: The patients were aged between 23 and 77 years. The median overall survival was 10 months, and ten (37.04%) patients died within 18 months. We compared the overall mean survival times of all patients in different stages, and the results suggest that the postoperative pathological staging is hardly correlated with prognosis (P = 0.76). There was a correlation between pathology and prognosis (P = 0.0018). The mean survival time was longer for patients who had undergone chemotherapy than for those without chemotherapy (14.88 vs 0.65 months) (P < 0.0001). Moreover, although patients had a good response to the regimens for PEB and TC (P = 0.004), there was no significant difference between PEB and TC (P = 0.386). CONCLUSIONS: AFP-producing EOC is uncommon and regarded as an extremely malignant type of tumor. Patients with chemotherapy may have a longer survival time; additionally, PEB and TC may be an optimal selection for this kind of tumor. Further large-scale studies are needed to confirm our findings.

Effect of Alpha-Fetoprotein on Differentiation of Myeloid Supressor Cells.

The effect of recombinant alpha-fetoprotein (AFP) on human myeloid suppressor cell (MDSC) differentiation was studied in vitro in the presence of cytokines IL-6 (10 ng/mL) and GM-CSF (10 ng/mL). It was found that AFP at concentrations of 50 and 100 IU/mL increased the number of MDSC (CD33+ HLA-DR-/lowCD11b+) in culture. Analysis of MDSC subpopulations showed that the increase was due to monocytic M-MDSC (HLA-DR-/lowCD33+CD11b+CD14+CD66b-). There was no modulating effect of AFP on granulocytic PMN-MDSC (HLA-DR-/lowCD33+CD11b+CD14-CD66b+). The effects of recombinant AFP on MDSC differentiation were thus demonstrated for the first time.

A core fucose specific lectin from Cephalosporium curvulum induces cellular apoptosis in hepatocellular and pancreatic cancer cells and effective in detecting AFP.

Cephalosporium curvulum lectin (CSL), a lectin from pathogenic fungus has exquisite specificity towards α1-6 linkage of core fucosylated glycans, expressed in hepatocellular and pancreatic cancer. Interaction and effect of CSL and other fucose specific lectins LCA and AOL on HepG2 and PANC-1 cells was investigated. CSL, LCA and AOL exhibited strong binding to PANC-1 cells which could be effectively blocked by competing glycoprotein mucin. Effect of CSL, LCA and AOL on PANC-1 and HepG2 cells was determined by MTT assay and all the three lectins inhibited the cell growth which could be blocked by mucin, cell cycle analysis revealed that CSL increased hypodiploid HepG2 cell population indicating cellular apoptosis. CSL induced apoptosis in HepG2 cells was confirmed by Annexin V/PI assay. CSL induced increase in early apoptotic HepG2 cell population, a time dependent increase in the expression of caspases-3, 9 and cytochrome-c was observed by western blotting suggesting the possible involvement of intrinsic caspase dependent apoptosis. Increase in ROS and decrease in MMP demonstrated involvement of intrinsic caspase dependent apoptosis. Quantification of AFP in HCC patients using CSL lectin-antibody sandwich ELISA, supports diagnostic potential of CSL.

Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.

BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.

Ambulatory end-stage liver disease in Ghana; patient profile and utility of alpha fetoprotein and aspartate aminotransferase: platelet ratio index.

BACKGROUND: End-stage liver disease (ESLD) is a major burden on public health, particularly in sub-Saharan Africa, where hepatitis B virus (HBV) is an important risk factor. We aimed to describe clinical characteristics of ESLD from cirrhosis or hepatocellular carcinoma (HCC) and the performance of aspartate aminotransferase (AST)-platelet ratio index (APRI) and alpha fetoprotein (AFP) in Ghana. METHODS: We performed an observational cross-sectional study in outpatient hepatology clinics at three teaching hospitals in Ghana, West Africa. One hundred and forty-one HCC, 216 cirrhosis and 218 chronic HBV patients were recruited by convenience sampling. Sociodemographic, history and examination, laboratory, and disease staging information were shown using descriptive statistics. Performance of the APRI score in diagnosis of cirrhosis and AFP in the diagnosis of HCC was determined using AUROC analysis. RESULTS: Median age at presentation was 44 years for HCC and 46 years for cirrhosis. HBV was found in 69.5% of HCC and 47.2% of cirrhosis cases, and HCV in 6.4% and 3.7% respectively. APRI cut-off of 2 had sensitivity of 45.4% and specificity of 95% in diagnosis of cirrhosis, and cut-off of 1 had sensitivity of 75.9% and specificity of 89%. AUC of AFP was 0.88 (95% CI 0.81-0.94) in diagnosis of HCC. Low monthly income was associated with lower odds of undertaking AFP. Thirty one percent of cirrhotic persons were Child-Pugh C, and 67.9% of HCC patients had advanced or terminal disease at presentation. CONCLUSIONS: Our findings emphasize the young age of ESLD patients in Ghana and the advanced nature at presentation. It highlights shortcomings in surveillance and the need for policies to address the burden and improve outcomes in Ghana.

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.

The Spatial Distribution Characteristics of the Tumor Biomarker Alpha-fetoprotein: A Cross-section Study.

OBJECTIVES: This study aims to explore the spatial characteristics of the alpha-fetoprotein (AFP) reference value in healthy Chinese adults, and its relationship to geographical location. METHODS: A total of 9396 AFP reference values were collected from patients in 96 administrative units. A correlation analysis and support vector machine (SVM) were employed to extract dependent geographical factors and predict the reference values in the entire country, respectively. A geostatistics analysis was developed to reveal the spatial characteristics of the value. RESULTS: Under the long-term influence of geographical environment, AFP reference values show spatial autocorrelation and regional variation. The values are higher in western and northern areas than in eastern and southern areas of China. CONCLUSIONS: The AFP reference values show regional differences, and this difference should be considered in clinical practice.

Comparison of rapid immunoassays for rupture of fetal membranes.

BACKGROUND: Rupture of membranes (ROM) before the onset of uterine contractions, particularly in pregnancies less than 37 weeks gestational age, is a common diagnostic problem in obstetrical practice. Timely detection of ROM is vital to support gestational age-specific interventions to optimize perinatal outcomes and minimize the risk of serious complications such as preterm delivery, fetal distress and maternal/fetal infections. Rapid bedside immunoassay tests designed to detect amniotic fluid proteins in cervicovaginal fluids have emerged as valuable clinical tools to provide timely ROM diagnosis. METHODS: In this prospective observational study, two commercially-available immunoassay tests (ROM Plus®, AmniSure®) were evaluated concurrently in 111 pregnant women who presented with the chief complaint of ROM. Immunoassay results were compared to clinical parameters for determining ROM via comprehensive, retrospective clinical chart review. Diagnostic performance characteristics were calculated including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. RESULTS: Overall, diagnostic performance characteristics were robust and similar between ROM Plus® and AmniSure®, respectively: sensitivity (96.4 and 89.3%), specificity (98.8 and 100%), PPV (96.4 and 100%), NPV (98.8% and 96.5) and accuracy (98.2 and 97.3%). For term patients (≥37 weeks gestation), the sensitivities were 93.8 and 81.3% and specificities were 97.1 and 100% for ROM Plus® and AmniSure®, respectively. For preterm patients (<37 weeks gestation), both immunoassay tests provided exact concordance with clinical confirmation of ROM resulting in 100% diagnostic accuracy. CONCLUSIONS: Both rapid immunoassay tests provided similarly excellent diagnostic accuracy for the rapid detection of ROM with only two discrepant results for ROM Plus® and three discrepant results for AmniSure® compared to clinical confirmation. The findings from this study recommend these tests for pregnant women presenting with suspected ROM to guide correct clinical management decisions to improve obstetrical and neonatal outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02208011 (1 August 2014).

Combination of miR-125b and miR-27a enhances sensitivity and specificity of AFP-based diagnosis of hepatocellular carcinoma.

Non-invasive biomarkers of early-stage hepatocellular carcinoma (HCC) could offer immense benefits. Currently available tumor markers for HCC are of not much clinical relevance. In this study, we investigated the potential for using a panel of serum microRNAs (miRNAs) as novel tumor markers in conjunction with serum alpha-fetoprotein (AFP) for diagnosis of HCC. Serum expression of four miRNAs was assessed in 150 subjects (90 cases of HCC and 60 cases without cancer) by quantitative real-time polymerase chain reaction (qRT-PCR). Logistic regression analysis was performed to assess the potential use of miRNAs for detection of HCC. Receiver operating characteristic curves were used to evaluate diagnostic accuracy. A panel of serum miRNAs (miR-125b, miR-223, miR-27a, and miR-26a) used in conjunction with AFP helped differentiate HCC patients from those in the non-cancer group after adjusting for age and gender, with the area under the curve of 0.870. In addition, the use of miR-125b/miR-27a panel differentiated HBV-related early-stage HCC with a high sensitivity (80.0 %) and specificity (87.2 %) in AFP-negative (-) subjects. A combination of serum miR-125b, miR-223, miR-27a, and miR-26a as a second-line tests could help detect HCC in AFP (-) subjects. The panel of miR-125b/miR-27a/AFP had a higher sensitivity and specificity for diagnosis of early-stage HCC as compared to that of a single marker.