Serum Α-fetoprotein Research Articles

SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression.

Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1, also known as PTPN6) is a nonreceptor protein tyrosine phosphatase that acts as a negative regulator of inflammation. Emerging evidence indicates that SHP-1 plays a role in inhibiting the progression of hepatocellular carcinoma (HCC). However, the role of SHP-1 in hepatocarcinogenesis remains unknown. Here, we find that levels of SHP-1 are significantly downregulated in human HCC tissues compared with those in noncancerous tissues (P < 0.001) and inversely correlate with tumor diameters (r = -0.4130, P = 0.0002) and serum α-fetoprotein levels (P = 0.047). Reduced SHP-1 expression was associated with shorter overall survival of patients with HCC with HBV infection. Overexpression of SHP-1 suppressed proliferation, migration, invasion, and tumorigenicity of HCC cells, whereas knockdown of SHP-1 enhanced the malignant phenotype. Moreover, knockout of Ptpn6 in hepatocytes (Ptpn6HKO ) enhanced hepatocarcinogenesis induced by diethylnitrosamine (DEN) as well as metastasis of primary liver cancer in mice. Furthermore, systemic delivery of SHP-1 by an adenovirus expression vector exerted a therapeutic effect in an orthotopic model of HCC in NOD/SCID mice and DEN-induced primary liver cancers in Ptpn6HKO mice. In addition, SHP-1 inhibited the activation of JAK/STAT, NF-κB, and AKT signaling pathways, but not the MAPK pathway in primary hepatocytes from DEN-treated mice and human HCC cells. Together, our data implicate SHP-1 as a tumor suppressor of hepatocarcinogenesis and HCC progression and propose it as a novel prognostic biomarker and therapeutic target of HCC.Significance: The nonreceptor protein tyrosine phosphatase SHP-1 acts as a tumor suppressor in hepatocellular carcinoma. Cancer Res; 78(16); 4680-91. ©2018 AACR.

Novel strategy of sirolimus plus thymalfasin and huaier granule on tumor recurrence of hepatocellular carcinoma beyond the UCSF criteria following liver transplantation: A single center experience

Although liver transplantation (LT) lengthens the survival time of patients with hepatocellular carcinoma (HCC), LT patients exhibit a high recurrence rate; particularly those that had advanced HCC associated with the tumor biological characteristics and long-term application of immunosuppressants. A consensus on optimal prophylaxis and treatment for recurrent HCC following LT does not currently exist. The present study retrospectively analyzed data from 36 non-University of California at San Francisco criteria-eligible patients with advanced HCC who underwent LT, and then treated them with sirolimus (SRL)-based therapy with thymalfasin and huaier granules (SRL+, n=18), or with tacrolimus-based therapy (controls; n=18). The SRL+ group had significantly longer recurrence times (P=0.008) and survival times (P<0.0001) (OS, 1-year: 100%, 3-year: 94.4%, 5-year: 77.8%; DFS, 1-year: 88.9%, 3-year: 55.6%, 5-year: 50.0%). Furthermore, compared with pre-LT values and the control group, the SRL+ group had significantly lower serum α-fetoprotein (AFP) levels (both P<0.0001) and percentage of Forkhead box P3 (FoxP3)+ Treg lymphocytes (P<0.001) during the first year. In the SRL+ group, FoxP3+/cluster of differentiation (CD)8+ Treg lymphocyte percentages decreased significantly following LT (P<0.001); however, CD8+/CD3+ T-cells significantly increased (P<0.001). Levels of serum AFP and FoxP3+ Treg cells increased when tumors relapsed, and decreased to near-normal when relapse foci were cured or stabilized. SRL+ therapy may decrease AFP and Treg levels, while increasing CD8+ T cells, indicating an associated mechanism among them. In conclusion, SRL+ therapy appears to be safe and effective in preventing HCC recurrence following LT with no significant adverse events, and warrants further investigation.

Identification of long non-coding RNA ZFAS1 as a novel biomarker for diagnosis of HCC

Hepatocellular carcinoma (HCC) is the third major cause of cancer-related deaths. Abundant research show that long non-coding RNAs (lncRNAs) play critical roles in the initiation and progression of HCC and may serve as diagnostic markers for HCC. In the present study, six lncRNAs were chosen as candidate genes on the basis of previous literature to evaluate their diagnostic value on HCC by qRT-PCR. Experiment was first carried out in 22 pairs of tissues from HCC and then those were differently expressed in tissues were further tested in plasma from 20 HCC patients and 20 control cases. At last, ZFAS1 was chosen to be further analyzed in another 214 plasma samples including 79 control cases, 75 hepatitis B and cirrhosis patients, and 60 HCC patients. The levels of plasma ZFAS1 in HCC were significantly higher than those in healthy controls (P<0.001), and in patients with cirrhosis and hepatitis B (P<0.001), and was positively associated with serum α-fetoprotein (AFP). Meanwhile, the area under the receiver operating characteristic curve (AUC) of ZFAS1 was 0.801 to diagnose HCC from healthy controls, while AFP was 0.798 and the combined AUC of ZFAS1 and AFP was 0.891 (95% CI: 0.829–0.953), slightly higher than ZFAS1 alone. In conclusion, our results indicated that ZFAS1 could serve as a biomarker for diagnosing HCC.

Prognostic value of heterogeneous ribonucleoprotein A1 expression and inflammatory indicators for patients with surgically resected hepatocellular carcinoma: Perspectives from a high occurrence area of hepatocellular carcinoma in China.

Heterogeneous ribonucleoproteinA1 (hnRNPA1) is a documented tumor biomarker known to be aberrantly expressed in a number of types of human cancer. However, to the best of our knowledge, its prognostic value for surgically resected HCC (RHCC) in the high incidence areas of China has not been described; the association between hnRNPA1 expression, pre-operative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) is also not understood. In the present study, hnRNPA1 expression was retrospectively measured in two independent cohorts of patients with hepatocellular carcinoma (HCC) who underwent surgery to remove the primary cancer at one center in Fujian, an area with a high incidence of HCC in China. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC) were used to quantify hnRNPA1 expression in RHCC tissues. The survival curves were plotted using the Kaplan-Meier method, and the prognostic significance of hnRNPA1, NLR and PLR was analyzed using the log-rank test. The relevant prognostic factors were identified by multivariate Cox regression analysis. RT-qPCR and western blotting revealed that hnRNPA1 was upregulated in HCC tissues (P<0.001), and particularly overexpressed in tumor tissues of patients with recurrent HCC (P<0.001) (cohort 1; 54 patients). Differential hnRNPA1 expression was measured in 426HCC tissues with IHC; 259 exhibited high hnRNPA1 expression and 167 exhibited low expression. High hnRNPA1 expression was significantly associated with Tumor-Node-Metastasis stage (P=0.024), tumor size (P=0.027), vascular invasion (P<0.001), Edmonson grade (P<0.001), pre-operative serum α-fetoprotein (AFP) (P<0.001), NLR (P<0.001) and PLR (P<0.001). In addition, multivariate Cox regression analysis confirmed that high hnRNPA1 expression was associated with relapse-free survival (RFS; HR, 0.685; 95% CI, 0.506–0.928; P=0.015) and overall survival (OS; HR, 0.629; 95% CI, 0.454–0.871; P=0.005). Multivariate analysis confirmed that higher pre-operative serum AFP had an unfavorable impact on RFS (HR, 1.350; 95% CI, 1.006–1.811; P=0.045) and OS (HR=1.564; 95% CI, 1.151–2.126; P=0.004), while higher pre-operative NLR had an unfavorable impact on OS (HR, 1.758; 95% CI, 1.161–2.661; P=0.008) (cohort 2;426 patients). The expression of hnRNPA1 was also positively correlated with NLR (Spearman's correlation; r=0.122, P=0.012) and PLR (Spearman's correlation; r=0.140, P=0.004). In conclusion, high hnRNPA1 expression was revealed as prognostic for poor survival in patients with RHCC, and detection of hnRNPA1 protein in tumor tissues demonstrated potential in estimating survival for patients with RHCC in areas with high incidence rates. Furthermore, the combination of high hnRNPA1 expression and pre-operative serum AFP levels (>400 µg) proved to be a good diagnostic and prognostic biomarker for this specific population of patients. Finally, a correlation may also exist between hnRNPA1 expression and other markers of systemic inflammation.

Therapy of Patient with Recurrent HCC After Liver Transplantation with T-cells transiently expressing HBV-specific TCR

Background Hepatitis B virus (HBV) antigen expression frequently occurs in HBV-related hepatocellular carcinoma (HCC). We are performing a phase 1 trial to evaluate the safety and efficacy of activated autologous T cells, that express transiently an HBsAg/HLA-class I restricted specific T cell receptor (HBV/TCR-T cell) trough mRNA TCR electroporation. Here we report the first case of our trial. METHODS: The patient was given an intravenous injection of 4 doses of escalating HBV/TCR-T cell (1x104, 1x105, 1x106, and 5x106/kg) in the first treatment cycle, followed by a second treatment cycle of 4 doses of 5x106/kg one month later. The patient was evaluated every 8 weeks by radiologic imaging. Patients’ immune responses were monitored using an interferon-gamma enzyme-linked immunospot assay. Results The patient was a 41-year-old man with HBV associated HCC and undergone liver transplant at Jan 22nd, 2016. HCC relapse at the T12 thoracic vertebra was found 10 months after liver transplant, followed by a vertebral metastasis resection and radiotherapy. At 3 months after the resection, a new T9 metastasis was detected and treated with heavy ion radiotherapy once again. However, the serum α-fetoprotein (AFP) was increased from 167 to 2536 ng/ml and the tumor diameter increased from 3.6 to 5.8 cm within 4 months during the treatment. Then the first cycle of the HBV/TCR-T cell was given with serum HBV-DNA detected negative. The serum AFP drop from 2629 to 488 ng/ml after the first treatment cycle. However, the AFP was then gradually increased to 821 ng/ml after the second treatment cycle. HBV-DNA coding for HBV antigen was detected on the primary HCC. mRNA TCR-redirected T cells infusion was associated with a reduction in AFP levels without exacerbation of liver inflammation or other toxicity. During the HBV/TCR-T cell therapy, the metastasis tumor diameter was not increased without new lesions detected, which mean the disease stabilized in this case according to the Response Evaluation Criteria In Solid Tumors criteria. This clinical response continued for 5 months after the initiation of HBV/TCR-T cell therapy. We did not observe any serious adverse reactions to the immunotherapy, which was well tolerated. Conclusion We provide initial evidence of the safety and antitumor activity of autologous TCR-redirected immunotherapy in patients with recurrent hepatitis B-associated HCC after liver transplantation.

Preoperative computed tomography and serum α-fetoprotein to predict microvascular invasion in hepatocellular carcinoma.

To determine the diagnostic value of computed tomography (CT) for prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). Preoperative CTs for 160 patients with 57 MVI-positive and 103 MVI-negative HCCs diagnosed by surgical pathology were reviewed retrospectively. CT parameters and serum α-fetoprotein (AFP) level were analyzed in SPSS 16.0. Although univariate analysis showed that tumor size (P = .012), grade (Z = −2.114, P = .034), and peritumoral enhancement (χ2 = 4.464, P = .035) were associated with MVI, multiple logistic regression analysis showed that capsular invasion (odds ratio [OR] = 23.469, P < .001), margins (OR = 6.751, P < .001), and serum AFP level (OR = 1.001, P = .038) were associated with MVI in HCC (P < .05). Radiographic hepatic capsular invasion and nonsmooth tumor margins identified by preoperative CT images, along with AFP levels greater than 232.2 ng/mL, are important predictors of MVI.

Voltammetric immunoassay for α-fetoprotein by using a gold nanoparticle/dendrimer conjugate and a ferrocene derived ionic liquid.

An immunosensor is described for the voltammetric determination of α-fetoprotein. It is making use of an AuNP-dendrimer conjugate and an ionic liquid. A gold electrode was first modified with chitosan. Then, the AuNP-dendrimer conjugate was covalently immobilized on the electrode. Following this, an ionic liquid was placed on the electrode via formation of a covalent bond between the amino groups of PAMAM and the aldehyde groups of an ionic liquid containing ferrocene. Thus, the redox probe ferrocene becomes immobilized on the electrode surface. PAMAM increases the amount of ferrocene immobilized on the electrode due to its globular shape and rich amino groups. The use of AuNPs improves the conductivity of the electrode. The modified electrode was applied to the determination of α-fetoprotein in human serum and has a linear response that covers the 0.05 to 30ngmL-1 α-fetoprotein concentration range, with a detection limit of 0.02ngmL-1. This assay is stable, selective and reproducible. It is perceived to provide a powerful tool for the early detection of cancer markers. Graphical abstract Schematic of a voltammetric immunoassay for α-fetoprotein based on a gold nanoparticle/dendrimer conjugate and ionic liquids anchored with both aldehyde and ferrocene. Chit: chitosan; GA: glutaraldehyde ; PAMAM: G4 polyamidoaminic dendrimers; AuNP: Au nanoparticle; Fc: ferrocene; IL: ionic liquid. PB: phosphate buffer solution.

Triple-phase multidetector computed tomography:an evaluation of hepatic space occupying lesion in cirrhotic patients

Hepatocellular carcinoma (HCC) is a common tumor with an incidence of 1 - 6 % among cirrhotic patients. Dysplastic nodule often occurs within regenerative cirrhotic nodules. They can show low or high grade dysplasia. MRI best differentiates this iso-or hypo intense lesion from hyper intense HCC. The current study was designed to assess the usefulness of Triple-phase multiphasic multidetector computed tomography (MDCT) in evaluation of hepatic space occupying lesion in cirrhotic patients.This cross sectional study was carried out in Radiology and Imaging department in collaboration with Hepatology and Hepatobiliary surgery department, of Bangabandhu Sheikh Mujib Medical University, Dhaka during July 2014 to June 2016. A total of 62 cirrhotic patients with hepatic space occupying lesion were included in this study. MDCT was done in all these patients and they were followed-up from the admission up to post operative tissue diagnosis of hepatic space occupying lesion in respective pathology departments to assess the histopathological correlation. Patients with suspected hepatic space occupying lesion diagnosed by clinical andultrasonography and having high serum α-fetoprotein level were enrolled. The mean age was 50.0±13.6 years with ranged from 25 to 79 years. Male female ratio was 2.3:1.In MDCT, a total of 54 malignant cases were found, out of which 49(79.0%) patients had HCC, 4(6.5%) had metastases and 1(1.6%) had dysplastic nodule. In benign tumor group, 6(9.7%) patients had cirrrhotic nodule, 1(1.6%) had hepatic adenoma and 1(1.6%) had haemangioma. In histopahology, a total 53 malignant cases were found, out of them 48(77.5%) patients had HCC, 3(4.8%) had metastases and 2(3.2%) had dysplastic nodule. Triphasic MDCT in diagnosis of hepatic space occupying lesion in cirrhotic patients revealed a sensitivity of 98.1%, specificity of 77.8%, accuracy 95.2%, positive predictive values 96.3% and negative predictive values 87.5%. While the same diagnostic tool showed a sensitivity95.8%, specificity 78.6%, accuracy 91.9%, positive predictive values 93.9% and negative predictive values 84.6% in identification of HCC. In evaluation of metastasis MDCT had a sensitivity of 100.0%, specificity 98.3%, accuracy 98.4%, positive predictive values 75.0% and negative predictive values 100.0%. In evaluation of dysplastic nodule MDCT had sensitivity 50.0%, specificity 100.0%, accuracy 98.4%, positive predictive values 100.0% and negative predictive values 98.4%.So, MDCT can be an ideal diagnostic tool for detecting as well as characterizing the hepaticspace occupying lesion (SOLs) in cirrhotic patients.Bangladesh Med Res Counc Bull 2018; 44(1):23-29

Prognostic value of pretreatment PET/CT lean body mass-corrected parameters in patients with hepatocellular carcinoma.

This study was designed to investigate whether pretreatment fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) lean body mass-corrected parameters could predict the overall survival (OS) better than the established predictors in patients with hepatocellular carcinoma (HCC). We retrospectively analyzed 61 patients with HCC with pretreatment F-FDG-PET/CT. Besides obtaining clinical factors, we measured both lean body mass-corrected and body weight-corrected PET/CT parameters, including metabolic tumor volume, maximal standardized uptake value of the tumor, total lesion glycolysis, tumor-to-normal liver uptake ratio, and so on. The prognostic value of those factors for OS was assessed by statistical software. In the univariate analysis, PET/CT parameters, ascites, serum α-fetoprotein, alkaline phosphatase, aspartate transaminase (AST), tumor number, tumor size of the maximal one, vascular invasion, TNM stage, Child-Pugh class, Barcelona Clinic Liver Cancer (BCLC) staging, and Okuda staging were significant predictors of OS. In multivariate and Kaplan-Meier analyses, lean body mass-corrected maximum standardized uptake value (lbmSUVmax) more than 3.35 g/ml, AST more than 42.00 U/l, and BCLC staging B-C were significant independent predictors of poor OS. When BCLC staging variable was stratified by four categories instead of two in the multivariate analysis, it was not the statistically significant independent predictor anymore, but lbmSUVmax and AST still were. Pretreatment F-FDG-PET/CT lean body mass-corrected parameters can predict the OS in patients with HCC. Moreover, lbmSUVmax and AST, as the independent predictors of OS, could supplement the prognostic value of the BCLC staging system.

Increased expression of G9A contributes to carcinogenesis and indicates poor prognosis in hepatocellular carcinoma.

Euchromatic histone-lysine N-methyltransferase (G9A), the primary histone methyltransferase for histone H3 Lys9, has been identified to be upregulated in numerous types of cancer. The aim of the present study was to analyze the clinical significance of G9A, and preliminarily explore its function in hepatocellular carcinoma (HCC). An increased expression level of G9A was demonstrated in the HCC samples and also in 5 publically available datasets. By analyzing GSE14520, it was revealed that its expression level was significantly associated with serum α-fetoprotein level of patients with HCC, and may serve as a potential prognostic indicator for patients with multinodular HCC. Bioinformatics tools were utilized to predict the potential function of G9A, and the results indicated that G9A may modulate gene sets involved in RNA processing and DNA replication. G9A inhibition may suppress cell proliferation by arresting cells in G1 phase and increasing the expression level of microtubule-associated protein light chain 3β (MAP1LC3B) in Huh7 and HepG2 cells. In addition, an inverse association between the expression of G9A and LC3B was demonstrated in HCC tumor samples in the publically available GSE14520 dataset, which indicated that G9A may also have the potential to regulate MAP1LC3B expression in HCC tumor tissues. The results of the present study led to hypothesis that the G9A expression level may be of assistance in diagnosing HCC, and be a potential therapeutic target for HCC. The results provided novel evidence for additional understanding of the crucial role of G9A in tumorigenesis.

Deciphering hepatocellular carcinoma through metabolomics: from biomarker discovery to therapy evaluation.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer, with increasing prevalence worldwide. The mortality rate of HCC is similar to its incidence rate, which reflects its poor prognosis. At present, the diagnosis of HCC is still mostly dependent on invasive biopsy, imaging methods, and serum α-fetoprotein (AFP) testing. Because of the asymptomatic nature of early HCC, biopsy and imaging methods usually detect HCC at the middle–late stages. AFP has limited sensitivity and specificity, as many other nonmalignant liver diseases can also result in a very high serum level of AFP. Therefore, better biomarkers with higher sensitivity and specificity at earlier stages are greatly needed. Since metabolic reprogramming is an essential hallmark of cancer and the liver is the metabolic hub of living systems, it is useful to investigate HCC from a metabolic perspective. As a noninvasive and nondestructive approach, metabolomics provides holistic information on dynamically metabolic responses of living systems to both endogenous and exogenous factors. Therefore, it would be conducive to apply metabolomics in investigating HCC. In this review, we summarize recent metabolomic studies on HCC cellular, animal, and clinicopathologic models with attention to metabolomics as a biomarker in cancer diagnosis. Recent applications of metabolomics with respect to therapeutic and prognostic evaluation of HCC are also covered, with emphasis on the potential of treatment by drugs from natural products. In the last section, the current challenges and trends of future development of metabolomics on HCC are discussed. Overall, metabolomics provides us with novel insight into the diagnosis, prognosis, and therapeutic evaluation of HCC.

Significance of PIVKA-II levels for predicting microvascular invasion and tumor cell proliferation in Chinese patients with hepatitis B virus-associated hepatocellular carcinoma.

The present study aimed to determine the levels of prothrombin induced by vitamin K absence-II (PIVKA-II) according to the Barcelona Clinic Liver Cancer (BCLC) staging system, to develop an appropriate strategy for managing hepatocellular carcinoma (HCC), particularly early HCC, and to investigate the value of PIVKA-II for predicting prognosis-associated pathological parameters. Clinical information of 117 patients with hepatitis B-associated HCC was retrospectively collected. Preoperative serum PIVKA-II and α-fetoprotein (AFP) levels were measured using a chemiluminescence method. The efficiency of PIVKA-II levels for predicting pathological parameters was evaluated using step-wise logistic regression. The receiver operator characteristic curve was used to evaluate the predictive performance of PIVKA-II levels. It was demonstrated that except for the difference between stages B and C HCC (P=0.923), serum PIVKA-II levels significantly increased according to BCLC stage (P<0.050), however AFP levels did not. In early HCC (stage 0+A), the correlation between PIVKA-II and AFP levels (dual-positive, 64.70% in stage 0; 46.97% in stage A) was relatively weak (r=0.410). PIVKA-II >40 mAU/ml was an independent predictor of microvascular invasion [hazard ratio (HR), 3.77; 95% confidence interval (CI), 1.31–10.88; P=0.014; and high Ki67 expression in situ (HR, 2.99; 95% CI, 1.19–7.52; P=0.020). Combined analysis of PIVKA and AFP levels may contribute to an effective strategy for the management of patients with early HCC, as high PIVKA-II levels indicated a more aggressive tumor phenotype. Further investigation of PIVKA-II levels may provide novel insights into the mechanism underlying the metastasis of HCC cells and facilitate the development of novel therapeutic strategies for HCC.

Downregulation of BRAF-activated non-protein coding RNA in patients with hepatitis B virus-associated hepatocellular carcinoma.

Long non-coding RNAs (lncRNAs) have been investigated as a novel class of regulators of cellular processes, including cell growth, apoptosis and carcinogenesis. lncRNA BRAF-activated non-protein coding RNA (BANCR) has recently been revealed to be involved in tumorigenesis of numerous types of cancer, including papillary thyroid carcinoma, melanoma, non-small cell lung cancer and colorectal cancer. However, the expression profiles and biological relevance of lncRNA BANCR in hepatocellular carcinoma (HCC) has not yet been reported. In the present study, the expression level of BANCR in tumor tissues and para-cancerous tissues was determined by reverse transcription-quantitative polymerase chain reaction in patients with hepatitis B virus (HBV)-associated HCC, and its association with clinicopathological characteristics of patients was analyzed. The results demonstrated that the expression level of BANCR was significantly reduced in tumor tissues in comparison with in para-cancerous tissues (P<0.001). Furthermore, the present study demonstrated that BANCR expression level was closely associated with serum α-fetoprotein levels (P<0.01) and HCC tumor number (P<0.05). To the best of our knowledge, these results revealed for the first time that BANCR downregulated in patients with HBV-associated HCC and BANCR expression level may be a potential valuable diagnosis and therapeutic biomarker in HCC.

Quels sont l’objectif réel et la portée du dépistage des aneuploïdies ?

In France, the recommended method for Down syndrome screening is the first trimester combined test, the risk assessment, based on maternal age, ultrasound measurement of fetal nuchal translucency and maternal serum markers (free β-hCG and PAPP-A). The Down syndrome detection rate is 78.7% at a screen positive rate of 5%. However, the best screening test is the integrated test using a combination of first trimester combined test and second trimester quadruple test (serum α-fetoprotein, human chorionic gonadotropin, unconjugated E3, and dimeric inhibin-A) and being able to achieve a detection rate for Down syndrome of approximately 96% at a screen-positive rate of 5%. In recent years, the isolation of small fragments of “fetal” cell-free DNA in the maternal blood dramatically changed the screening strategy paradigm allowing a Down syndrome detection rate and false positive rate of 99.2 and 0.09%, respectively. However, aneuploidy screening based on cell-free DNA presents two major limitations which must be taken into account because they considerably limit its benefit: (i) not every woman will receive an interpretable result and that those who fail to receive a result are at increased risk for fetal aneuploidy: whether an inconclusive result is treated as screen positive or screen negative affects the overall detection rate (sensitivity) and false-positive rate (specificity) of the test; (ii) the limited number of targeted aneuploidies (trisomies 21, 18, 13 and common sex chromosome aneuploidies) in contrast to conventional noninvasive screening which is also able to detect rare aneuploidies, duplications, deletions, and other structural rearrangements. Of course, genetic counseling has to include a discussion about benefits and limitations of aneuploidy screening based on cell-free DNA. However, it should not be considered as a new screening test to substitute for conventional noninvasive screening. Moreover, if the ultimate goal is to deliver the most information about potential risk of various chromosomal abnormalities associated with adverse perinatal outcomes, then current cell-free DNA screening strategies may not be the best approach. These data highlight the limitations of cell-free DNA screening and the importance of a clear and fair information during pretest genetic counseling about benefits and limitations of any prenatal noninvasive screening (whether conventional or by cell-free DNA), but also about risks and benefits of invasive diagnostic procedures (in first- or second-line), especially since the cytogenetic analysis with chromosomal microarray analysis has improved the detection of genome microdeletions and microduplications (variants of the copy number) that can not be detected by standard cytogenetic analysis.

Clinical Predictors of Liver Fibrosis in Patients With Chronic Hepatitis B Virus Infection From Children to Adults.

This study aimed to elucidate predictors of liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. Transient elastography was performed to define liver stiffness in 533 patients with chronic HBV infection (mean age ± standard deviation, 30.72 ± 0.57 years). Protein array was performed on serum samples and lysates of Huh7 cells transfected with HBV mutants; the results were confirmed by enzyme-linked immunosorbent assay. Single-nucleotide polymorphisms in the gene encoding interleukin 1β (IL-1β) were examined in patients with chronic HBV infection with and without liver fibrosis. Male sex, age ≥18 years, and serum α-fetoprotein level >3.6 ng/mL were independent predictors of a liver stiffness measurement of ≥7 kPa (P = .005, .019, and <.001, respectively). HBV e antigen (HBeAg)-negative hepatitis is associated with increased liver stiffness (P < .001). Elevation of the serum IL-1β level was demonstrated in subjects with liver fibrosis. IL-1β was upregulated in Huh7 cells transfected with HBV mutants associated with HBeAg-negative hepatitis. The AA genotype at rs16944 and the CC genotype at rs1143627 in the gene encoding IL-1β were associated with higher serum IL-1β levels and liver fibrosis. Male sex, age ≥18 years, elevated α-fetoprotein level, and HBeAg-negative hepatitis are risk factors for liver fibrosis. IL-1β is involved in the progression of liver fibrosis in subjects with HBeAg-negative hepatitis.

Carbohydrate Antigen 19-9 Increases the Predictive Efficiency of a-Fetoprotein for Prognosis of Resected Hepatocellular Carcinoma

Serum α-fetoprotein (AFP) is a classical biomarker for both diagnosis and prognosis of hepatocellular carcinoma (HCC). However, its predictive efficiency for prognosis remains unsatisfactory. This study explores whether integrating AFP and carbohydrate antigen (CA) 19-9/carcinoembryonic antigen (CEA) increase its prognostic efficiency in HCC. A total of 67 HCC patients with complete record of AFP, CA19-9, and CEA, who underwent radical hepatectomy, were included. The sole and combined evaluations for prognostic significance of the three markers were performed. In the first, it was found by one-factor analysis that AFP was a univariate prognostic indicator for disease-free survival, but not overall survival, whereas CEA and CA19-9 were not statistically significant, although the latter was of marginally predictive significance for disease-free survival. Subsequently, it was revealed that combined evaluation of AFP and CA19-9, rather than AFP and CEA, distinguished overall and disease-free survival more effectively, compared with single ones. However, this combination was not significant in multivariate Cox regression analysis, thus needing further validation, especially in large-scale prospective investigations. The addition of vascular invasion to AFP/CA19-9 combination might provide enhanced predictive power for disease-free survival. Collectively, these results preliminarily suggest that CA19-9 increases the predictive efficiency of AFP for prognosis of HCC after resection.

Elevated TEAD1 Expression is not an Independent Prognosis Factor of Hepatocellular Carcinoma.

To explore the expression pattern and clinical significance of TEAD1 in hepatocellular carcinoma (HCC). The prognostic significance of TEAD-1 expression is also evaluated. TEAD1 expression was detected by the immunohistochemistry (IHC) method and western blot. The association between TEAD1 expression of HCC tissues and clinical variables was evaluated by Chi-squared test. Survival analysis was used to determine the prognosis effect of TEAD1. Expression of TEAD1 is significantly increased in HCC tissues compared with adjacent normal liver tissues by IHC (p = 0.002) and western blot (p = 0.020). The difference for the ratio of low, medium, and high staining between HCC and normal tissues is significant (p < 0.001). Higher TEAD1 expression is related to worse histological grade (p = 0.013), bigger tumor size (p = 0.033), and higher serum a-fetoprotein (AFP) level of HCC patients (p = 0.026). No association is found between TEAD1 expression and other clinical features. No statistical difference is found for the overall survival among the low, medium, and high TEAD1 expression groups (p = 0.122). TEAD1 expression is highly expressed in HCC. TEAD1 overexpression is involved in the growth and differentiation of HCC. TEAD1 expression is unable to act as an independent prognosis factor for HCC patients.

Efficacy of Sorafenib for the Treatment of Post-Transplant Hepatocellular Carcinoma Recurrence.

BackgroundThe role of sorafenib in patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been rarely studied. The aim of this study was to evaluate the efficacy of sorafenib in post-LT era.MethodsConsecutive patients with post-transplant HCC recurrence not eligible to resection or locoregional therapy were included. Patients receiving best supportive care (BSC) until 2007 were compared with those treated by sorafenib thereafter.ResultsOf a total of 65 patients, 20 patients received BSC and 45 received sorafenib. Clinical characteristics were similar between two groups except that sorafenib group received tacrolimus and mammalian target-of-rapamycin inhibitors more frequently than BSC group. Treatment with sorafenib conferred a survival advantage as compared with BSC for survival after recurrence (median, 14.2 vs. 6.8 months; P = 0.01). In multivariate analyses, high serum α-fetoprotein level, synchronous intrahepatic recurrence and distant metastasis at the time of recurrence, and BSC were independently associated with poorer survival after recurrence. Sorafenib treatment was associated with better survival after recurrence as compared with BSC (hazard ratio, 0.25; 95% confidence interval, 0.10–0.62; P = 0.002). In addition, sorafenib group showed tolerable toxicity in the post-transplant setting.ConclusionSorafenib may be beneficial in patients with post-transplant HCC recurrence.

Metabonomics of d-glucaro-1,4-lactone in preventing diethylnitrosamine-induced liver cancer in rats

Context: d-Glucaro-1,4-lactone (1,4-GL) exists in many vegetables and fruits. Metabonomics has not been used to investigate the role of 1,4-GL in preventing liver cancer.Objective: The pharmacological effects and metabolite alterations of 1,4-GL on the prevention of diethylnitrosamine (DEN)-induced liver cancer were investigated.Materials and methods: Ten healthy Sprague–Dawley rats served as control and 46 were used to establish rat liver cancer model. 1HNMR-based metabonomics was used to compare the effects of oral 1,4-GL (50 mg/kg) in liver cancer rats (n = 26) after 10 consecutive weeks of intervention. The amino acids in rat serum were quantified by HPLC-UV, and the changes in Fischer’s ratio were calculated.Results: The 20-week survival rate of DEN-induced liver cancer rats administered with oral 1,4-GL was increased from 45.0 to 70.0% with reduced carcinogenesis of the liver and significantly lowered serum α-fetoprotein level (14.28 ± 2.89 ng/mL vs. 18.56 ± 4.65 ng/mL, p = 0.012). The serum levels of leucine, valine, 3-hydroxybutyrate, lactate, acetate and glutamine in the DEN + 1,4-GL group returned to normal levels compared with those of the DEN group on week 20. Fischer’s ratio in the rat serum of DEN group was 1.62 ± 0.21, which was significantly lower than that in healthy rats (2.3 ± 0.12). However, Fischer’s ratio increased to 1.89 ± 0.22 in the DEN + 1,4-GL group.Discussion and conclusions: 1,4-GL exerted positive effects on liver carcinogenesis in rats by pathological examination and metabonomic analysis. Its mechanism may be related to the restoration of amino acid and energy metabolism.

Case 2: A Patient with Trisomy 21, Transient Abnormal Myelopoiesis, and Pneumoperitoneum

A 34-week-gestation male infant is born appropriate for gestational age to a 41-year-old gravida 3, para 3 woman. The patient’s mother had received limited prenatal care starting at 15 weeks, and is found to have a positive result on maternal serum α-fetoprotein screening test and an amniocentesis that confirms trisomy 21 (47,XY+21 karyotype) with no evidence of translocation or mosaicism. The infant is born at an outside hospital and has physical features characteristic of trisomy 21. He is transferred to our facility for respiratory distress and multiple episodes of apnea and bradycardia on the day of birth. Sepsis is ruled out on admission. His initial complete blood cell count is significant for a white blood cell count of 15,300/μL (15.3×109/L) with 25% blasts. He is also noted to have an enlarged liver that is 1 cm below the costal margin. Peripheral blood smear and flow cytometry findings are consistent with a diagnosis of transient abnormal myelopoiesis (TAM). Pediatric hematology is consulted and recommends complete blood cell counts which are obtained regularly until day 22 after birth, when the TAM spontaneously resolves. The infant is able to receive full enteral feedings until he develops abdominal distention and irritability on day 12 after birth. An abdominal radiograph is notable for pneumoperitoneum concerning for an acute bowel perforation without signs of …