Elevated serum alpha fetoprotein levels promote pathological progression of hepatocellular carcinoma

AIM:To investigate the biological role of alpha fetoprotein (AFP) and its clinical signif icance in carcinogenesis of hepatocellular carcinoma (HCC).METHODS:Clinical analysis of HCC patients and im-munohistochemical examination were conducted to evaluate the relationship between serum AFP level and patient mortality. Confocal microscopy,Western blotting, dimethylthiahzolyl-2,5-diphenyl-tetrazolium bromide,Cell Counting Kit-8 assays and flow cytometry were performed to explore the possible mechanism.RESULTS: Among the 160 HCC patients enrolled in this study,130 patients survived 2 years (81.25%),with a survival rate of 86.8% in AFP < 2 0 μg/L group,88.9% in AFP 20-250 μg/L group,and 69.6% in AFP > 250 μg/L group, demonstrating a higher mortality rate in HCC patients with higher AFP levels. Surgical treatment was benef icial only in patients with low AFP levels.The mortality rate of HCC patients with high AFP levels who were treated surgically was apparently higher than those treated with conservative management.The results of immunohistochemistry showed that AFP and AFP receptor were merely expressed in tissues of HCC patients with positive serum AFP.Consistently,in vitro analysis showed that AFP and AFPS were expressed in HepG2 but not in HLE cells. AFP showed a capability to promote cell growth,and this was more apparent in HepG2 cells,in which the proliferation was increased by 3.5 folds. Cell cycle analysis showed that the percent-age of HepG2 cells in S phase after exposure to AFP was modestly increased.CONCLUSION:HCC patients with higher AFP levels show a higher mortality rate,which appears to be attributable to the growth promoting properties of AFP.

CHANGES OF SERUM ALPHA FETOPROTEIN BEFORE AND AFTER RADIOIMMUNOTHERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA

Thirtytwo patients with surgically verified unresectable table hepatocellular carcinoma (HCC) have been treated by radioimmunotherapy (RIT) using intrahepatic arterial administration of￣(131)I anti HCC monoclonal antibody (Hepama1) combined with hepetic artery ligation. Twenty of them had abnormal serum alpha fetoprotein (AFP,>20 ng/ml). Single photon emission computed tomography (SPECT) scan and quantitative assay of AFP were performed after RIT. The results revealed that when the tumor to liver ratio (T/L) was higher than 3.5 (Group A , n =3) , the serum AFP level declined markedly and then kept in stable for a tongtime; when the T/L ratio was less than 1.2 (Group C ,n=5), the serum AFP level did not change evidently within 2 months postinfusion; while the T/L ratio was between 1. 2 3. 5 (Group B, n= 12) , the serum AFP level increased transiently and then decreased within 2 4 weeks postinfusion. Sequentiat resection was achieved in all of the 3 patients of Group A, in 6 patients (50%) of Group B, and none in Group C. The correlation of serum AFP and effective treatment demonstrates the usefulness of this oncofetal protein marker as an indicator of neoplastic activity for HCC and T/L ratio might be a good indicator to predict tumor response to RIT in patients with

The Combined Diagnostic Accuracy of Serum Alpha Fetoprotein and Des-Gamma Carboxyprothrombin in Hepatocellular Carcinoma among Chronic Liver Disease Patients in Ilorin

Introduction :Chronic liver disease (CLD) is a disease of public health importance. CLD is defined as a clinical syndrome of liver disease lasting for at least six months with histology showing varying degree of hepatocellular necro-inflammation and fibrosis with or without neoplastic transformation. The disease is a spectrum that manifests initially as chronic hepatitis which may progress to liver cirrhosis and ultimately hepatocellular carcinoma (HCC). The current practice in the field of Gastroenterology has shifted from invasive methods of diagnosing HCC to non-invasive methods using tumor biomarkers. Various biomarkers of HCC have been proposed, but the largest body of evidence exists with alpha-fetoprotein (AFP). Most of the studies on the combined diagnostic accuracy of AFP and des-gamma-carboxyprothrombin (DCP) were done in other populations outside Nigeria. It is necessary to determine the combined diagnostic accuracy of the two tumor markers for early detection of HCC in North-central Nigeria. Materials and Methods: This study was a cross-sectional study and ethical clearance was obtained from the ethical and research committee of UITH, Ilorin. A total of 190 participants consisting of 125 cases and 65 healthy controls that were age and sex-matched were studied. Patients with extra-hepatic malignancies were excluded. The serum levels of AFP and DCP were determined using the enzyme-linked immunoassay (ELISA) technique. A detailed questionnaire was used to document the socio-demographic characteristics, clinical features as well as results of laboratory/radiologic parameters. Percutaneous liver biopsy was carried out on patients that were fit. Test of association between categorical variables was carried out using the Chi-Square Test. The sensitivity, specificity, positive and negative predictive values of the two tumor markers were determined by the area under curve (AUC) at various cut-off levels using the receiver operating characteristic (ROC) curve analysis. Statistical significance was set at p value < 0.05. AFP Quantitative test kit (alfabeto-RiakiDainabot Radioisotope laboratory, Japan) and DCP Qualitative test kit (EiTest MONO P-II kit) were used to assay AFP and DCP respectively. Liver biopsy needle (Menghini needle) was used to carry out liver biopsy. Results: Using a cut-off of 400 ng/ml, the sensitivity of serum AFP for diagnosing HCC was 51.3%. The specificity of AFP at the same cut-off was 87.8%. The positive and negative predictive values were 92.8% and 49.3% respectively. Using a cut-off of 7.5 ng/ml, the sensitivity of serum DCP for diagnosing HCC was 57.1%. The specificity of DCP at the same cut-off was 63.4%. The positive and negative predictive values were 76.2% and 41.9% respectively while the accuracy was 59.2%. The diagnostic accuracy of combined serum AFP and DCP for diagnosis of HCC in University of Ilorin Teaching Hospital, Ilorin was 64.9%. The sensitivity of combined serum AFP and DCP for diagnosing HCC was 55.6%. The specificity of combined serum AFP and DCP was 95.6%. The positive and negative predictive values were 96.2% and 52.3% respectively. Conclusion: Combining these two tumour markers does not significantly improve the diagnostic accuracy of HCC and chronic HBV remains a strong aetiological agent of HCC in UITH, Ilorin.

Construction of retroviral vector carrying HSV tk gene under control of human AFP enhancer core sequence and human pgk promotor *

AIM Tenstruct retroviral vector bringing HSV tk gene under control by human AFP enhancer core sequence and human pgk promotor.

Detection of blood AFPmRNA in nude mice bearing human HCC using nested RT-PCR and its significance

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Neutrophil to lymphocyte ratio and albumin bilirubin grade in hepatocellular carcinoma: A systematic review

BACKGROUND Hepatocellular carcinoma(HCC)is a frequent cause of cancer related death globally.Neutrophil to lymphocyte ratio(NLR)and albumin bilirubin(ALBI)grade are emerging prognostic indicators in HCC.AIM To study published literature of NLR and ALBI over the last five years,and to validate NLR and ALBI locally in our centre as indicators of HCC survival.METHODS A systematic review of the published literature on PubMed of NLR and ALBI in HCC over the last five years.The search followed the guidelines of the preferred reporting items for systematic reviews and meta-analyses.Additionally,we also investigated HCC cases between December 2013 and December 2018 in our centre.RESULTS There were 54 studies describing the relation between HCC and NLR and 95 studies describing the relation between HCC and ALBI grade over the last five years.Our local cohort of patients showed NLR to have a significant negative relationship to survival(P=0.011).There was also significant inverse relationship between the size of the largest HCC nodule and survival(P=0.009).Median survival with alpha fetoprotein(AFP)<10 KU/L was 20 mo and with AFP>10 KU/L was 5 mo.We found that AFP was inversely related to survival,this relationship was not statically significant(P=0.132).Mean survival for ALBI grade 1 was 37.7 mo,ALBI grade 2 was 13.4 months and ALBI grade 3 was 4.5mo.ALBI grades performed better than Child Turcotte Pugh score in detecting death from HCC.CONCLUSION NLR and ALBI grade in HCC predict survival better than the conventional alpha fetoprotein.ALBI grade performs better than Child Turcotte Pugh score.These markers are done as part of routine clinical care and in cases of normal alpha fetoprotein,these markers could give a better understanding of the patient disease progression.NLR and ALBI grade could have a role in modified easier to learn staging and prognostic systems for HCC.

Combined measurement of serum tumor markers in patients with hepatocellular carcinoma

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The re-emergence of the GP73 and fucosylated liver cancer biomarkers

The study shows that GP73 alone may not be sufficient to achieve the discrimination in every population. This is because many other clinical factors may influence the levels of the biomarker. This review attempts to identify some of these clinical variables,and helps provide a means of using these clinical values,in combination with GP73,to achieve the best use of the entire clinical biomarker family.

Clinical Significance of a Rise in AFP in Lung Adenocarcinoma Patients with Liver Metastasis:One Case Report and Literatures Review

IntroductionUsually the alpha fetoprotein （AFP） concentration of patients with metastatic liver cancer is slightly raised. Most of the levels are lower than 400 ug/L. Following biopsies of lung and liver neoplasms, one patient with a clinical diagnosis of lung cancer plus liver metastasis was pathologically diagnosed having an adenocarcinoma. His serum AFP value was 100-300 times the normal value. In order to further explore the clinical significance of an elevation of the AFP level in patients with lung adenocarcinoma plus liver metastasis, and to precisely distinguish a simple liver metastasis from lung adenocarcinoma or from lung hepatoid adenocarcinoma （HAC）, a clinical analysis of the patient, and a literature review was conducted.

Maternal seru m screening for Down syndro me in a teaching hospitalin Hong Kong

Objective To study prospectively the use of maternal serum alpha fetoprotein (AFP) and total β human chorionic gonadotropin (hCG) concentrations for screening of Down syndrome in Hong Kong.Methods AFP and total β hCG were measured in serum samples from 1638 singleton Chinese pregnancies at 14-22 weeks of gestation, recruited over a twelve month period. Gestational ages were determined by ultrasonographic parameters measured at the same visit as the test for all cases. The gestational age specific and weight adjusted medians for serum AFP and total β hCG were calculated. Risk for fetal Down syndrome (FDS) was derived by mathematical modeling of the medians together with maternal age. Amniocenteses were offered to women with a calculated FDS risk of 1∶270 or greater.Results The gestational age specific and weight adjusted medians for maternal serum AFP were similar to previous studies while that of total β hCG were higher. A total of 101 patients (6.1%) were classified as being high risk for FDS, including 3.4% (48/1394) of those younger than 35 years of age and 21.7% (53/244) of those who were 35 or above. There were 4 cases of Down syndrome, 1 case of Turner syndrome and 1 of Edward syndrome. Three out of the four cases of Down syndrome were screened positive, corresponding to a detection rate of FDS of 75%. A case of Turner syndrome was also screened positive. A case of trisomy 18 was found to have very low levels of AFP [0.262 multiple of median (MoM)] and total β hCG (0.115 MoM).Conclusions Maternal serum screening using double biochemical markers (AFP and total β hCG) in combination with gestational dating by ultrasonography is effective in the detection of fetal Down syndrome and possibly other chromosomal disorders in Chinese pregnant women.

A versatile biosensing platform coupling CRISPR-Cas12a and aptamers for detection of diverse analytes

Rapid and sensitive detection of various analytes is in high demand.Apart from its application in genome editing,CRISPR-Cas also shows promises in nucleic acid detection applications.To further exploit the potential of CRISPR-Cas for detection of diverse analytes,we present a versatile biosensing platform that couples the excellent affinity of aptamers for broad-range analytes with the collateral single-strand DNA cleavage activity of CRISPR-Cas12 a.We demonstrated that the biosensors developed by this platform can be used to detect protein and small molecule in human serum with a complicated background,i.e.,the tumor marker alpha fetoprotein and cocaine with the detection limits of 0.07 fmol/L and 0.34 lmol/L,respectively,highlighting the advantages of simplicity,sensitivity,short detection time,and low cost compared with the state-of-the-art biosensing approaches.Altogether,this biosensing platform with plug-and-play design show great potential in the detection of diverse analytes.

Hepatoid carcinoma of the pancreas:a case report

In 1970, a gastric adenocarcinoma patient with increased alpha fetoprotein （AFP） in his serum and liver metastatic tumor was reported by Bourreilile et al. At that time, it was realized that a gastric adenocarcinoma could produce AFP. In 1985, Ishikura et al reported a hepatocellular carcinoma （HCC）-like differentiation in a primary gastric tumor and first proposed the conception of a ＂hepatoid carcinoma＂. Subsequent documentation of this unique histopathologic feature has been made in other extrahepatic sites including the esophagus, papilla of Vater, colon, lung, gallbladder, adrenal gland, kidney, urinary bladder, ovary, uterus, vagina, testicle, and small intestine. However, the number of cases is very small. Hepatoid carcinoma is a primary extrahepatic neoplasm exhibiting features of hepatocellular carcinoma in terms of morphology, immunohistochemistry and biological behavior. But histopathologically it is very rare. Many but not all cases, present with an elevated serum AFP. Taking a wide view of various literatures it is evident that hepatoid carcinoma has mostly been found in the stomach and very rarely in the pancreas. To date, only eight cases of hepatoid carcinoma of the pancreas have been reported in the literature. We present a case of hepatoid carcinoma of the pancreas arising in an elderly man without evidence of residual disease eight months after local resection of the tumor.

Testicular germ cell tumors type 2 have high RNA expression of LDHB,the gene for lactate dehydrogenase subunit B

This study analyzed RNA expression of genes for three serum tumor markers,alpha fetoprotein(AFP),human chorionic gonadotropin(hCG),and lactate dehydrogenase(LDH),in patients with testicular germ cell tumors(TGCT)type 2.The gene AFP encodes AFP,the gene for chorionic gonadotropin beta polypeptide 5(CGB5)encodes a major part of the specific beta subunit of hCG,and the genes for LDH subunit A(LDHA),LDH subunit B(LDHB),and LDH subunit C(LDHC)encode three different subunits of LDH.LDHB encodes the LDHB subunit present as a tetramer in LDH isoenzyme 1(LDH-1).We examined three datasets with 203 samples of normal testis tissue(NT)and TGCT type 2.Yolk sac tumor(YST)expressed RNA of AFP fourteen thousand times higher than seminoma(SE),embryonal carcinoma(EC),and teratoma(TER)combined(P=0.00015).In the second microarray,choriocarcinoma(CC)expressed RNA of CGB5 ten times higher than other histologic types of TGCT combined.EC expressed RNA of LDHB twice higher than SE,YST and TER combined(P=0.000041).EC expressed RNA of LDHB higher than that YST expressed RNA of AFP and that CC expressed RNA of CGB5.In conclusion,TGCT type 2 expressed RNA of LDHB markedly higher than the RNA of 23 other candidate genes for TGCT type 2.

Advances in early diagnosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most recurrent hepatic malignancy and the third in the cancer-related casualties in the west.The frequently-documented causes of HCC are chronic liver infections by hepatitis B virus or hepatitis C virus,nonalcoholic fatty liver disease,cirrhosis,exposure to aflatoxins and tobacco smocking,etc.Clinical presentation of this fatal disease ranges from asymptomatic to upper abdominal pain or common health conditions like weight loss or lethargy.Among current surveillance strategy for suspected patients,liver imaging and serum alpha fetoprotein estimation has been regularly recommended.However,sensitivity of this diagnostic methodology especially in early detections,often suffers from compromised sensitivity and selectivity.Various image based and serological biomarkers for HCC has been introduced in recent decades with varied sensitivity as stand-alone or combined diagnostic protocol.The current article will review the status of HCC diagnosis with respect to common diagnostic protocol,and upcoming novel biomarkers.

Evaluation and impact of different biomarkers for early detection of hepatocellular carcinoma

Worldwide,hepatocellular carcinoma(HCC)is a frequent complication of liver diseases and remains a major cause of cancer-related mortality.In addition,the prevalence of nonalcoholic steatohepatitis(NASH)as prerequisite of hepatocarcinogenesis,even in the absence of cirrhosis,is rising rapidly.The early detection of HCC has been crucial in improving the survival outcomes of those patients.However,in the mostly obese NASH population,diagnostic sensitivity of ultrasound-based HCC screening approaches is limited.On the other hand,biomarkers for HCC show promising potential to improve early detection,providing reproducible,investigator-independent results that can be used either alone or integrated with other biomarkers for scoring models.In the past,validation has been limited due to a lack of prospective longitudinal cohort studies.At present,large-scale retrospective phase-III-biomarker-development gives hope for the availability of biomarker-based screening approaches in the near future.This review focuses on the potential impact of biomarkers on surveillance strategies,potentially allowing for earlier HCC diagnosis.