Normal Serum AFP Research Articles

Paediatric Mesenchymal Hamartoma of Liver-A Diagnostic Dilemma

Introduction and Importance: Benign tumors of the liver are relatively rare in children. Mesenchymal hamartoma (MH) is a benign tumor of the liver. It is the second most common benign pediatric hepatic tumor after infantile hemangioma. Mostly it is seen in children less than 2 years of age. The diagnosis of this tumor is difficult because of nonspecific clinical symptoms and lack of definitive laboratory studies. The precise diagnosis of mesenchymal hamartoma relies on histological evaluation of the tissue.We hereby present a rare case in a 2 year old child with mesenchymal hamartoma and its diagnostic challenges. Case presentation: A 2 year old previously healthy male was referred to our institution for evaluation of a liver mass. He complained of loss of apetite and abdominal distension since last 10 weeks. He had no complaints of fever/trauma. Clinical findings and Investigations: On per abdomen examination,there was a presence of large, non tender hepatomegaly with no shifting dullness present. On radiological evaluation, Ultrasound abdomen showed solitary right lobe mass. On further imaging, CT scan of the abdomen was done which showed a large multiloculated lesion in right lobe liver with arterial enhancing intervening septae within.The lesion was compressing and displacing right portal vein and right hepatic vein. At that time, laboratory evaluation showed normal liver function tests, serum AFP and other blood parameters. Differentials of liver cyst, hydatid cyst and biliary cystadenoma was made. Intervention and outcome: After discussion in multidisciplinary care, he was planned for surgery which would provide the exact histological diagnosis also in such cystic lesion of liver.He was optimized for surgery and subsequently underwent right hepatectomy with resection of the ~14× 12 cm mass. No major periperative complications developed and patient was discharged from hospital on POD6. The pathological review of the resected mass showed mixture of bile ducts, vessels, irregular liver cell plates and loose mesenchyme containing variable sized cysts consistent with a mesenchymal hamartoma. He is asymptomatic at the time of regular follow-up visits. Relevance and Impact: Benign tumors of the liver are relatively rare in children. The diagnosis of mesenchymal hamartoma still remains a challenge with non –specific complaints, normal laboratory findings and delay in diagnosis can lead to complications from local compression. Though advance imaging can diagnose this entity if index of suspicion is high but Differentiating it from other tumors such as an undifferentiated embryonal sarcoma is difficult on imaging alone. Hence surgical excision is the gold standard for diagnosing to reach the final histological diagnosis and treating these entities.

Evaluation of the Role of Serum Vimentin as a Diagnostic Biomarker for Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) is a major unresolved medical issue, which is considered as the seventh most common cancer globally and the fourth leading cause of cancer deaths, with approximately 700,000 deaths per year. Aim of the Work The aim of this study; to evaluate the role of serum vimentin as a diagnostic biomarker in patients with HCC. Patients and Methods This case control study enrolled 60 patients; divided into two groups: Group (I): included 20 patients with liver cirrhosis without HCC as a control group and Group (II): 20 patients divided into 2 subgroups: (IIa): includes 20 patients with HCC and serum AFP is high and (IIb): includes 20 patients with HCC and serum AFP is normal. Results The present study found statistical significant decrease in Hb level in group IIb compared to group I, there was high statistical significant decrease in platelet count in patients of group IIa and IIb compared to control group. a statistical significant elevation of total bilirubin and INR with decrease of albumin in group II compared to control group.There was high statistical significant elevation in AFP in group IIa and IIb compared to control group and in group IIa compared to group IIb, a high statistical significant elevation in Vimentin level in group IIa and IIb compared to control group while there was no statistical significant difference between group IIa and group IIb. Conclusion Vimentin can be considered as an important independent and discriminative serological biomarker for detecting early stage HCC in patients with normal serum AFP.

Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection.

Cell-free DNA (cfDNA)-based liquid biopsy is a promising approach for the early detection of cancer. A major hurdle is the limited yield of cfDNA from one blood draw, limiting the use of most samples to one test of either mutation or methylation. Here, we develop a technology, Mutation Capsule Plus (MCP), which enables multiplex profiling of one cfDNA sample, including simultaneous detection of genetic and epigenetic alterations and genome-wide discovery of methylation markers. With this technology, we performed de novo screening of methylation markers on cfDNA samples from 30 hepatocellular carcinoma (HCC) cases and 30 non-HCC controls. The methylation markers enriched in HCC cfDNA were further profiled in parallel with a panel of mutations on a training cohort of 60 HCC and 60 non-HCC cases, resulting in an HCC detection model. We validated the model in an independent retrospective cohort with 58 HCC and 198 non-HCC cases and got 90% sensitivity with 94% specificity. Furthermore, we applied the model to a prospective cohort of 311 asymptomatic hepatitis B virus carriers with normal liver ultrasonography and serum AFP concentration. The model detected four of the five HCC cases in the cohort, showing 80% sensitivity and 94% specificity. These findings demonstrate that the MCP technology has potential for the discovery and validation of multiomics biomarkers for the noninvasive detection of cancer. This study also provides a comprehensive database of genetic and epigenetic alterations in the cfDNA of a large cohort of HCC cases and high-risk non-HCC individuals.

Clinical characteristics of Hepatoid adenocarcinoma of the lung: Four case reports and literature review

PurposeHepatoid adenocarcinoma of the lung (HAL) is a rare form of lung cancer, which is characterized by its morphologic hepatoid features. The clinical characteristics and prognosis of this rare form of lung cancer remain obscure. MethodsThe clinical courses of four cases of HAL were reported. A literature search was performed up to December 31, 2020, using the electronic databases PubMed and Web of Science. ResultsIncluding the present 4 cases, a total of 42 cases of HAL have been reported in the literature. The median age was 58.5 years old (range, 36–73 years). 36 (85.7%) patients were male. 26 (61.9%) patients had a history of smoking, the median amount of smoking was 40 pack years (range, 8–180). The most common site of the primary tumor was the right upper lobe (22 cases, 52.3%) and the left upper lobe (10 cases, 23.8%). 21 patients (50%) had pretreatment serum AFP levels higher than the upper limit, and 4 patients (9.5%) had normal pretreatment serum AFP levels. Treatment of HAL included surgery, chemotherapy, radiotherapy, tyrosine kinase inhibitors (TKIs), anti-angiogenesis therapy, and anti-PD-1/PD-L1 monoclonal antibody. Overall, the prognosis of HAL was poor, with median overall survival (OS) of 14 months. ConclusionsHAL is an aggressive tumor, with a poor prognosis and male predominance, which tends to occur in heavy smokers and affects the right upper lobe of the lung.

Abstract 6336: Non-canonical activation of Gli-2 by TGF-β/Smad3 signaling pathway in modulation of chemoresistance of hepatocellular carcinoma

Abstract BACKGROUND: It has been demonstrated in our previous study that poorly-differentiated hepatoma cells with low α-feto-protein (AFP) expression and a CD133-/EpCAM- surface profile exhibited aberrant hedgehog signaling (Hh) activity, epithelial-mesenchymal transition and chemoresistance. However, expression of canonical Hh molecules (Sonic ligand and SMO) was not increased in poorly-differentiated hepatoma cells in contrast to well-differentiated hepatoma cells, indicating that Hh transcription factors Gli-1/2 may be activated through a non-classic pathway. The present study aims to investigate whether the TGF-β/Smad3 pathway is responsible for Gli-2 activation through a non-canonical pathway. METHODS: Expression of Sonic Hh (Shh) and Smad3 was assessed in both hepatoma cells and HCC specimens. Gli-2 and Smad3 expression was suppressed by lentiviral vector-mediated RNA interference in poorly-differentiated hepatoma Huh-7-DN and HLE cells. Chemosensitivity was evaluated in hepatoma cells with a Gli-2 or Smad3 inhibitor. RESULTS: Significantly increased Gli-1 and Gli-2 protein levels were observed in 78% (11 out of 14) and 50% (7 out of 14) HCC specimens. In 7 HCC patients with a normal serum AFP value (<20 μg/L), Gli-1/2 protein levels were obviously higher than their pericancerous tissue. Moreover, increased Gli-2 and ABCC1 protein levels were accompanied with increased TGF-β1 and p-Smad3 protein levels in 5 out 7 HCC specimens; whereas Shh protein levels were similar to paired pericancerous tissue. Consistent with the findings from HCC specimens, significantly higher Gli-2 and p-Smad3 nuclear protein levels were associated with increased ABCC1 protein levels in poorly-differentiated hepatoma cells (Huh-7-trans, Huh-7-DN, HLE and HLF); whereas Shh and SMO protein levels were not significantly different from well-differentiated hepatoma Huh-7 and Hep3B cells. Suppressing Gli-2 expression by specific shRNA caused marked decreased expression of Gli-2 and ABCC1 in Huh-7-DN, Huh-7-trans and HLE cells. In addition, expression of Smad3, Gli-2 and ABCC1 was significantly down-regulated in HLE cells after infected with a lentiviral vector harboring shSmad3, indicating that Gli-2 is a downstream target of Smad3. Sorafenib IC50 was significantly reduced from 35.76 to 17.45 μM or 14.04 μM in HLE cells when treated with a GLI inhibitor (GANT-61) or a Smad3 inhibitor (SIS3) at 5 μM. A potential GLI-binding site in the ABCC1 promoter was identified. ABCC1-Gli-luciferase reporter activity was increased up to 39-fold in HLE cells when transfected with constructs containing the potential GLI-binding site, compared to the construct that lacked a GLI-binding site. CONCLUSION: TGF-β/Smad3 activated Gli-2 and its direct transcriptional target ABCC1 in poorly-differentiated and chemoresistant hepatoma cells. Suppressing TGF-β/Smad3/Gli-2 signaling activity confers a potential molecular target in partially alleviating Sorafenib resistance for the treatment of refractory hepatoma. Citation Format: Jia Ding, Hui-yan Li, Li Zhang, Xiao-tian Zhou, Jian Wu. Non-canonical activation of Gli-2 by TGF-β/Smad3 signaling pathway in modulation of chemoresistance of hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6336.

Using Lamin B1 mRNA for the early diagnosis of hepatocellular carcinoma: a cross-sectional diagnostic accuracy study

Background : Hepatocellular carcinoma (HCC) is vital medical issue in Egypt. It accounts for 70.48% of all liver tumors among Egyptians. The aim of this study was to determine the diagnostic role of plasma levels of mRNA of lamin B1 by RT-qPCR as an early marker of HCC. Methods: This study was conducted at the Clinical Pathology Department in collaboration with the Department of Tropical Medicine and Infectious Diseases at Ain Shams University Hospitals. It included 30 patients with primary HCC and viral cirrhosis (all were hepatitis C virus-positive) (Group I), in addition to 10 patients with chronic liver diseases (Group II) and 10 healthy age- and sex-matched subjects (Group III). Group I was further classified according to the Barcelona-Clinic Liver Cancer Staging System. Serum α-fetoprotein (AFP) chemiluminescent-immunoassays and RT-qPCR analysis of plasma lamin B1 mRNA levels were performed for all participants. Results: AFP and lamin B1 significantly elevated in patients with HCC compared to those in the other studied groups. AFP and lamin B1 status could discriminate group I from group II and III. A significant increase was found among the three Barcelona stages with regards to AFP and lamin B1 levels. A significant decrease was found between group II and stage 0, A and B with regards to AFP and lamin B1. Lamin B1 and AFP could both differentiate HCC patients with one tumor nodule (T1) from those with two or more tumor nodules (T2&Tm), as well as between those with tumor sizes >3 cm and ≤3 cm. Conclusion: Measurement of lamin B1 mRNA is recommended in patients with chronic liver disease with normal serum AFP, especially in known cirrhotic patients that deteriorate rapidly without any apparent etiology.

Using Lamin B1 mRNA for the early diagnosis of hepatocellular carcinoma: a cross-sectional diagnostic accuracy study.

Background: Hepatocellular carcinoma (HCC) is vital medical issue in Egypt. It accounts for 70.48% of all liver tumors among Egyptians. The aim of this study was to determine the diagnostic role of plasma levels of mRNA of lamin B1 by RT-qPCR as an early marker of HCC. Methods: This study was conducted at the Clinical Pathology Department in collaboration with the Department of Tropical Medicine and Infectious Diseases at Ain Shams University Hospitals. It included 30 patients with primary HCC and viral cirrhosis (all were hepatitis C virus-positive) (Group I), in addition to 10 patients with chronic liver diseases (Group II) and 10 healthy age- and sex-matched subjects (Group III). Group I was further classified according to the Barcelona-Clinic Liver Cancer Staging System. Serum α-fetoprotein (AFP) chemiluminescent-immunoassays and RT-qPCR analysis of plasma lamin B1 mRNA levels were performed for all participants. Results: AFP and lamin B1 significantly elevated in patients with HCC compared to those in the other studied groups. AFP and lamin B1 status could discriminate group I from group II and III. A significant increase was found among the three Barcelona stages with regards to AFP and lamin B1 levels. A significant decrease was found between group II and stage 0, A and B with regards to AFP and lamin B1. Lamin B1 and AFP could both differentiate HCC patients with one tumor nodule (T1) from those with two or more tumor nodules (T2&Tm), as well as between those with tumor sizes >3 cm and ≤3 cm. Conclusion: Measurement of lamin B1 mRNA is recommended in patients with chronic liver disease with normal serum AFP, especially in known cirrhotic patients that deteriorate rapidly without any apparent etiology.

Management of pure metastatic teratoma in chemotherapy naïve testis cancer patients.

e16043 Background: Management of metastatic testicular cancer often requires post-chemotherapy resection of teratoma. This is well known and described in literature. However, the ability of teratoma to metastasize independently is not as well appreciated, making chemotherapy futile in patients with pure metastatic teratoma. Methods: 15 patients with metastatic teratoma were identified of which 13 had only teratoma in the orchiectomy and 2 had predominantly teratoma. All 15 had normal serum hCG and AFP. Cases were derived from a retrospective review of patients seen from 1989-2016. Results: Mean age of patients was 27 years. 12 patients presented initially with Stage II disease and 2 presented with stage III disease. Median RP mass size was 6 cm with a range of 1.5-24 cm. 2 of 15 patients were treated initially with a single course of chemotherapy with BEP and showed no response. The remaining 13 patients only received resection(s). All 15 patients underwent RPLND with 2 patients requiring additional mediastinal and retrocrural resection and 1 requiring lobectomy. All surgical specimens showed pure teratoma on pathology with no other active germ cells. Patients were followed for a median duration of 5 years and all 15 remain with no evidence of disease at most recent follow up. However, 1 patient needed subsequent surgery for a late relapse of teratoma and 1 patient had a second extra-gonadal primary. Conclusions: Teratoma can metastasize in the absence of other germ cells. Surgical treatment alone for patients with pure metastatic teratoma of any stage can result in cure for the majority of patients and this approach can help avoid unnecessary chemotherapy.

ITPKA expression is a novel prognostic factor in hepatocellular carcinoma.

BackgroundInositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) has recently been found to be implicated in the tumor progression of various cancers. However, the expression and the prognostic value of ITPKA in hepatocellular carcinoma (HCC) remains unexplored. The aim of this study is to investigate the clinical significance of ITPKA expression in HCC.MethodsWe determined the expression level of ITPKA in 135 cases of HCC tissues and the matched adjacent nontumorous tissues by quantitative real-time RT-PCR. The correlation between ITPKA expression and prognosis of HCC patients was further evaluated by univariate and multivariate analysis. Multivariate analysis of the prognostic factors was performed with Cox proportional hazards model.ResultsUp-regulation of ITPKA occurred in 48.9 % of primary HCCs compared with their nontumor counterparts (P < 0.001). In addition, high expression of ITPKA was significantly associated with vascular invasion (P = 0.001) and TNM stage (P = 0.005). Kaplan–Meier analysis showed that the 5-year overall survival (OS) and relapse-free survival (RFS) rate in the group with high expression of ITPKA is poorer than that in low expression group (32.2 and 26.8 % versus 59.2 and 57.7 %). Univariate and multivariate analyses revealed that ITPKA was an independent prognostic factor for OS and RFS. Moreover, Stratified analysis revealed that its prognostic significance still existed within the subgroup of patients with early clinical stage (TNM stage I) or normal serum AFP level (≤25 μg/L).ConclusionOur data indicated that ITPKA expression was significantly up-regulated in HCC and could serve as a potential novel prognostic biomarker for HCC patients after surgery.

Expression of NEDD9 in hepatocellular carcinoma and its clinical significance.

Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) plays an integral role in natural and pathological cell biology. Overexpression of NEDD9 protein has been correlated with poor prognosis in various types of cancer. However, few available data address the precise function of the NEDD9 gene in hepatocellular carcinoma (HCC). In the present study, we investigated NEDD9 expression in 40 primary human HCC tissues compared with matched adjacent non-tumor hepatic tissues using RT-qPCR and western blot analysis. Immunohistochemistry was performed to analyze the correlations between NEDD9 expression and clinicopathological factors. Statistical analyses were applied to derive prognostic values of NEDD9 in HCC. The results showed that the NEDD9 mRNA and protein expression levels in HCC tissues were significantly higher than those in matched adjacent non-tumor hepatic tissues. High NEDD9 expression was correlated with larger tumor size, advanced tumor grade, metastasis, intrahepatic venous invasion and high UICC TNM stages in HCC patients. Patients with high NEDD9 expression levels exhibited poorer recurrence-free and overall survival than those with a low NEDD9 expression. Additionally, NEDD9 expression status was an independent prognostic factor for survival. This correlation remained significant in patients with early-stage HCC or with normal serum AFP levels. The results of this study suggest that NEDD9 may be a valuable prognostic biomarker for HCC, including early-stage and AFP-normal patients.

Non-invasive Analysis of Genomic Copy Number Variation in Patients with Hepatocellular Carcinoma by Next Generation DNA Sequencing.

To explore new molecular diagnosis approaches for early detection and differential diagnosis of hepatocellular carcinoma (HCC), we analyzed genomic copy number variations (CNV) using plasma cell-free DNA from patients with HCC by next generation DNA sequencing. Plasma samples from 31 patients with HCC and 8 patients with chronic hepatitis or cirrhosis were analyzed. In HCC group, most samples with large tumor size (tumor dimension greater than 50 mm) showed CNVs that are visually recognizable at chromosome CNV plots, few samples with small tumor and none samples with chronic liver diseases showed CNVs recognizable at CNV plots. CNV Z score analysis showed significant CNVs in samples with HCC and chronic liver diseases although more significant changes were found in HCC group, some are differentially valuable (such as gain in 1q, 7q, and 19q in HCC), while others are less differentially valuable (such as loss in 4q, 13q, gain in 17q, 22q). We proposed a CNV scoring method that generated positive result in 26 of the 31 HCC patients (83.9%) or 11 of the 16 HCC with tumor dimension 50 mm or less (68.8%) or 4 of the 7 HCC with tumor dimension 30 mm or less (57.1%), while all the 8 samples with chronic hepatitis or cirrhosis scored negative. Ten HCC patients had normal or low serum AFP levels, among them, 7 were scored positive by CNV analysis, including 4 with tumor dimension 50 mm or less. Our study suggested that non-invasive genomic CNV analysis using plasma samples could be a valuable tool for early detection and differential diagnosis of HCC. Although CNV analysis itself cannot establish the diagnosis, it can help identify patients at high risk for HCC among patients with chronic liver diseases, which would prompt closer and more frequent surveillance for early tumor detection and intervention.

Clinical significance of α- fetoprotein in initial diagnosis of primary hepatic cancer

Objective To investigate the value ofα- fetoprotein ( AFP) in the initial diagnosis of primary hepatic cancer ( PHC) . Methods A retrospective analysis was performed on the initial AFP measurement results and imaging findings of 177 patients who had relatively complete clinical data and had a confirmed diagnosis of PHC; 98 patients with chronic hepatitis B ( CHB) and 82 patients with post- hepatitis B cirrhosis ( PHBC) , who were admitted to our department in 2011, were enrolled as controls. The obtained data were subjected to statistical analysis using SAS software; the enumeration data were subjected to chi- square test. Results In the initial examination for the 177PHC patients, 93 ( 52. 54%) had a serum AFP level not lower than 400 ng / ml, 38 ( 21. 47%) had a serum AFP level between 20 ng / ml and 400 ng / ml, and 46 ( 25. 99%) had a normal serum AFP level; the abnormal rate of AFP level was 74. 01%, which was significantly higher than those of CHB group ( χ2= 106. 07, P

Prognostic value of preoperative peripheral neutrophil-to-lymphocyte ratio in patients with HBV-associated hepatocellular carcinoma after radical hepatectomy

Neutrophil-to-lymphocyte ratio (NLR), an inflammation index, is considered a prognostic predictor of hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic value of preoperative peripheral NLR in patients with hepatitis B virus (HBV)-associated HCC after radical hepatectomy. Clinical data were collected from patients with HBV-associated HCC who underwent radical hepatectomy. NLR was calculated from lymphocyte and neutrophil counts on preoperative routine blood tests. Demographics, laboratory analyses, and histopathological data were analyzed. A total of 282 patients were selected and divided by the cutoff NLR value of 2. Multivariate analysis showed that NLR > 2 was an independent prognostic predictor of poor disease-free survival [hazard ratio (HR) = 1.362; 95% confidence interval (CI) 1.025-1.811; P = 0.033] and overall survival (HR = 1.434; 95% CI 1.044-1.970; P = 0.023). NLR had a good predictive value for prognosis in patients with HBV-associated HCC who had normal serum AFP level. These results suggested that NLR is an independent indicator of both disease-free survival and overall survival in patients with HBV-associated HCC after radical hepatectomy, including AFP-normal patients.

MACC1 as a Prognostic Biomarker for Early-Stage and AFP-Normal Hepatocellular Carcinoma

BackgroundThe metastasis-associated in colon cancer 1 gene (MACC1) has been found to be associated with cancer development and progression. The aim of this study was to investigate the prognostic value of MACC1 in early-stage and AFP-normal hepatocellular carcinoma (HCC).MethodsmRNA and protein levels of MACC1 expression in one normal liver epithelial cells THLE3 and 15 HCC cell lines were examined using reverse transcription-PCR and Western blot. MACC1 expression was also comparatively studied in 6 paired HCC lesions and the adjacent non-cancerous tissue samples. Immunohistochemistry was employed to analyze MACC1 expression in 308 clinicopathologically characterized HCC cases. Statistical analyses were applied to derive association between MACC1 expression scores and clinical staging as well as patient survival.ResultsLevels of MACC1 mRNA and protein were higher in HCC cell lines and HCC lesions than in normal liver epithelial cells and the paired adjacent noncancerous tissues. Significant difference in MACC1 expression was found in patients of different TNM stages (P<0.001). Overall survival analysis showed that high MACC1 expression level correlated with lower survival rate (P = 0.001). Importantly, an inverse correlation between MACC1 level and patient survival remained significant in subjects with early-stage HCC or with normal serum AFP level.ConclusionsMACC1 protein may represent a promising biomarker for predicting the prognosis of HCC, including in early-stage and AFP-normal patients.

687 SERUM IP-10 LEVEL ASSOCIATED WITH HEPATOCELLULAR CARCINOMA DEVELOPMENT IN PATIENTS WITH CHRONIC HEPATITIS B

correlation remained significant in patients with early-stage HCC or with normal serum AFP level. Multivariate analysis indicated that LARP1 expression might be an independent prognostic indicator of the survival of patients with HCC. Furthermore, we found that ectopic expression of LARP1 induced, while silencing LARP1 inhibited, cell invasion and anchorage-independent growth ability. Moreover, we demonstrated that the upregulation of LARP1 could reduce the expression of e-cadherin and induce the expression of fibronectin. Conclusions: Our findings suggest that the LARP1 protein is a valuable marker of HCC progression and may represent a novel prognostic biomarker and therapeutic target for the disease.

688 CO-EXPRESSION OF MST1R AND MET RECEPTORS AND DISTANT METASTASIS IN STAGE I HEPATOCELLULAR CARCINOMA

correlation remained significant in patients with early-stage HCC or with normal serum AFP level. Multivariate analysis indicated that LARP1 expression might be an independent prognostic indicator of the survival of patients with HCC. Furthermore, we found that ectopic expression of LARP1 induced, while silencing LARP1 inhibited, cell invasion and anchorage-independent growth ability. Moreover, we demonstrated that the upregulation of LARP1 could reduce the expression of e-cadherin and induce the expression of fibronectin. Conclusions: Our findings suggest that the LARP1 protein is a valuable marker of HCC progression and may represent a novel prognostic biomarker and therapeutic target for the disease.

689 THE HUMAN DEVELOPMENT INDEX IS ASSOCIATED WITH THE GLOBAL INCIDENCE AND MORTALITY RATES OF LIVER CANCER

correlation remained significant in patients with early-stage HCC or with normal serum AFP level. Multivariate analysis indicated that LARP1 expression might be an independent prognostic indicator of the survival of patients with HCC. Furthermore, we found that ectopic expression of LARP1 induced, while silencing LARP1 inhibited, cell invasion and anchorage-independent growth ability. Moreover, we demonstrated that the upregulation of LARP1 could reduce the expression of e-cadherin and induce the expression of fibronectin. Conclusions: Our findings suggest that the LARP1 protein is a valuable marker of HCC progression and may represent a novel prognostic biomarker and therapeutic target for the disease.

LARP1 predict the prognosis for early-stage and AFP-normal hepatocellular carcinoma

BackgroundThe La-related protein 1 (LARP1) has been found to be a RNA binding protein and was related to spermatogenesis, embryogenesis and cell-cycle progression. The aim of this study was to investigate the prognostic value of LARP1 in hepatocellular carcinoma (HCC).MethodsLARP1 expression was examined in 15 HCC cell lines and 272 clinical specimens using real-time PCR, immunohistochemistry (IHC) and western blot analysis (WB). LARP1 expression was also studied in 6 paired HCC lesions and the adjacent non-cancerous tissue samples. Statistical analyses were applied to derive association between LARP1 expression scores and clinical characters as well as patient survival.ResultsmRNA and protein levels of LARP1 were higher in HCC cell lines and HCC lesions than in normal liver epithelial cells and the paired adjacent noncancerous tissues. LARP1 expression was correlated to survival time, vital status, tumor size and Child-Pugh score. Overall survival analysis showed HCC patients with high LARP1 expression level had lower survival rate (P < 0.01). Importantly, this correlation remained significant in patients with early-stage HCC or with normal serum AFP level.ConclusionsLARP1 protein may represent a promising biomarker for predicting the prognosis of HCC, including in early-stage and AFP-normal patients.

Validity of plasma macrophage migration inhibitory factor for diagnosis and prognosis of hepatocellular carcinoma

We performed our study to determine whether plasma macrophage migration inhibitory factor (MIF) levels have diagnostic and prognostic value in hepatocellular carcinoma (HCC) patients. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to measure the expression of MIF in plasma and tissues, respectively. Plasma MIF levels were compared to HCC occurrence, clinicopathological features and outcomes. Cutpoints of plasma MIF levels for diagnosis and prognosis were, respectively, determined by receiver operating characteristic analysis and X-tile in corresponding training cohort, and then were confirmed in the validation cohort. The postoperative plasma MIF levels of HCC patients were detected in an independent cohort (80 HCC patients). As a result, MIF expression in situ was mainly observed in the cytoplasm of HCC cells. Intratumoral MIF expression was positively correlated with plasma MIF levels (r = 0.759, p < 0.001). Compared to serum α-fetoprotein (AFP), plasma MIF had a higher diagnostic value for discrimination of HCC from controls at 35.3 ng/ml. With determined cutpoints, plasma MIF levels demonstrated a significant association with overall survival (OS) and disease-free survival (DFS) of HCC patients even in patients with normal serum AFP levels and Tumor Node Metastasis (TNM) stage I. In addition, the plasma MIF levels were identified as an independent factor for OS [hazard ratio (HR) = 1.754; p = 0.012] and DFS (HR = 2.121; p < 0.001). Plasma MIF levels decreased markedly within 30 days after tumor resection (p < 0.001). Therefore, plasma MIF levels have potential as a diagnostic and prognostic factor for HCC.

Gene Expression Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), a common cancer worldwide, has a dismal outcome partly due to the poor identification of early-stage HCC. Currently, one third of HCC patients present with low serum alpha-fetoprotein (AFP) levels, the only clinically available diagnostic marker for HCC. The aim of this study was to identify new diagnostic molecular markers for HCC, especially for individuals with low serum AFP. We used the microarray technique to determine the expression profiles of 218 HCC specimens from patients with either high or low serum AFP. From the microarray study, we selected five candidate genes (i.e., GPC3, PEG10, MDK, SERPINI1, and QP-C), which were overexpressed in HCCs. Using quantitative real-time PCR analyses, we validated the expression of these five genes in 50 AFP-normal and 8 AFP-positive HCC specimens and 36 cirrhotic noncancerous hepatic specimens, which include 52 independent specimens not used in microarray analysis. A significant increase in the expression of the five candidate genes could be detected in most of the HCC samples, including those with normal serum AFP and small tumors. GPC3, MDK, and SERPINI1 encode known serum proteins. Consistently, a significant increase in serum midkine, encoded by MDK, was associated with HCC patients, including those with normal serum AFP. Using prediction analysis of microarray, we showed that a combined score of these five genes can accurately classify noncancerous hepatic tissues (100%) and HCC (71%). We suggest that a diagnostic signature approach using a combined score of these five biomarkers rather than a single marker may improve the prediction accuracy of HCC patients, including those with normal serum AFP and smaller-sized tumors.