High Serum Alpha-fetoprotein Level Research Articles

Association between alpha-fetoprotein and metabolic syndrome in a Chinese asymptomatic population: a cross-sectional study.

BackgroundMetabolic syndrome is closely associated with an increased risk for fatty liver disease morbidity and mortality. Recently, studies have reported that participants with fatty liver disease have higher serum alpha-fetoprotein levels than those without. We investigated the association between alpha-fetoprotein levels and the prevalence of metabolic syndrome in a Chinese asymptomatic population.MethodsA cross-sectional study was performed with 7 755 participants who underwent individual health examinations. Clinical and anthropometric parameters were collected and serum alpha-fetoprotein levels and other clinical and laboratory parameters were measured. Logistic regression analysis was used to examine associations between alpha-fetoprotein and metabolic syndrome.ResultsParticipants with metabolic syndrome had significantly higher (p < 0.001) alpha-fetoprotein levels than those without, though all alpha-fetoprotein levels were within the reference interval. The association between the components of metabolic syndrome (central obesity, elevated blood pressure, elevated triglycerides, reduced high-density lipoprotein cholesterol, and elevated fasting plasma glucose) and alpha-fetoprotein levels was evaluated. Alpha-fetoprotein levels in the elevated triglycerides, reduced high-density lipoprotein cholesterol, and elevated fasting plasma glucose groups were significantly different (p=0.002, p < 0.001, p=0.020) compared with alpha-fetoprotein in the normal triglycerides, high-density lipoprotein cholesterol, and fasting plasma glucose groups. Logistic regression analyses showed an association between alpha-fetoprotein levels and increased risk for metabolic syndrome, the presence of reduced high-density lipoprotein cholesterol, and elevated fasting plasma glucose, but not with obesity, elevated blood pressure, or triglycerides.ConclusionsThese results suggest a significant association between alpha-fetoprotein and metabolic syndrome.

Effects of combining transarterial chemoembolization with percutaneous microwave coagulation therapy for hepatocellular carcinoma abutting the diaphragm

Objective: This study aims to explore the clinical effectiveness of a combination therapy of transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) in treating hepatocellular carcinoma (HCC) abutting the diaphragm. Material and methods: Six cases with HCC were treated with TACE followed by PMCT one month later with the aid of artificial pneumothorax. Results: CT/MRI revealed complete necrosis in the tumor lesions and the treated tumor margins (≥5 mm). Serum alpha-fetoprotein (AFP) levels markedly declined in patients who originally had higher serum AFP levels. Postoperative complications such as fever, mild hepatic dysfunction and pleural effusion were alleviated within a short period of time. All patients were closely monitored through follow-up; all patients survived, except for one patient who received a liver transplantation. Conclusions: As lesions are either invisible or poorly visible in sonography, determining an effective treatment for HCC abutting the diaphragm remains a particular challenge. TACE and PMCT combined therapy with the aid of artificial pneumothorax proved to be an available treatment option.

High level of serum AFP is an independent negative prognostic factor in gastric cancer.

Gastric cancer with a high level of serum alpha fetoprotein (AFP) is uncommon and has unique clinicopathological features and a poorer prognosis. The aim of this research was to elucidate the clinicopathological and prognostic features of gastric cancer with a high level of AFP. The sera from 1,286 patients with gastric cancer treated at Qilu Hospital of Shandong University from January 2004 to December 2008 were analyzed preoperatively for AFP, CEA and CA19-9 levels after excluding active or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma as well as preoperative distant metastasis. Patients were divided into 2 groups: 86 serum AFP-positive patients and 1,200 serum AFP-negative patients according to a cutoff of 20 ng/mL. The clinicopathological features and prognostic factors were compared between the groups. A higher incidence of serosal invasion, lymph node metastasis and liver metastasis and poorer prognosis was observed in the AFP-positive group compared with the AFP-negative group (all p&lt;0.05). Serum AFP showed the highest specificity (93.66%) and diagnostic accuracy (92.38%) for predicting liver metastasis among the 3 tumor markers examined. Multivariate survival analysis revealed that AFP positivity was an independent prognostic factor in all 1,286 gastric cancer patients. The prognosis of AFP-positive gastric cancer was poorer than that of AFP-negative gastric cancer (p&lt;0.05). A high level of serum AFP is an independent prognostic factor in gastric cancer and can be used for evaluating the prognosis of gastric cancers whether in the presence or absence of liver metastasis.

The Clinicopathologic and Prognostic Significance of Gross Classification on Solitary Hepatocellular Carcinoma After Hepatectomy.

The prevalence of hepatitis B virus (HBV) infection is extremely high in China. We aimed to investigate the clinicopathologic and prognostic significance of gross classification on solitary hepatocellular carcinoma (HCC) after hepatectomy.A total of 144 patients with solitary HCC who underwent hepatectomy were identified retrospectively. Based on the gross appearance, the tumors were divided into single nodular (SN), single nodular with extranodular growth (SNEG), confluent multinodular (CMN), and infiltrative types. Clinicopathologic variables and survival information were compared among patients with those 4 types.The 144 tumors composed of 25 SN, 34 SNEG, 33 CMN, and 52 infiltrative types. The serum alpha-fetoprotein (AFP) level and HBV infection rate of infiltrative type were significantly higher than other 3 types. The disease-free and overall survival times of infiltrative type were significantly shorter than other 3 types. Univariate and multivariate analysis showed that gross classification, microvascular invasion, and T stage were independent risk factors.In Chinese patients with solitary HCC, the infiltrative type accounted for a much higher proportion compared with other regions of the world. Infiltrative HCC had higher serum AFP level, HBV infection, and microvascular invasion rates with poorer prognosis compared with other 3 types.

Clinical outcomes of patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective study of routine clinical practice in multi-institutions.

BackgroundSorafenib is an orally administered multikinase inhibitor with antiangiogenic and antiproliferative properties. The results of large clinical trials demonstrate that sorafenib prolongs survival and the time to progression of patients with advanced hepatocellular carcinoma (HCC). The aim of the present study was to determine the outcomes of such patients who were routinely treated with sorafenib at multi-institutions in Korea, in contrast to formal clinical trials.MethodsBetween August 2007 and March 2012, patients with advanced HCC in seven referral medical centers in Daejeon-Chungcheong Province of Korea were retrospectively enrolled to evaluate treatment response, survival, and tolerability following administration of sorafenib. The treatment response was assessed in accordance with the Response Evaluation Criteria in Solid Tumor 1.1 guidelines.ResultsAmong 116 patients, 66 (57%) had undergone treatment for HCC, and 77 (66%) were accompanied with Child-Pugh A cirrhosis. The median duration of sorafenib treatment was 67 days (range 14–452 days). Median overall survival and median time to progression were 141 days and 90 days, respectively. Complete response, partial response, and stable disease were achieved for 0%, 2%, and 29% of patients, respectively. Overall median survival, but not the median time to progression, was significantly shorter for patients with Child-Pugh B cirrhosis compared with those with Child-Pugh A cirrhosis (64 days vs 168 days, P = 0.004). Child-Pugh B cirrhosis (P = 0.024) and a high level of serum alpha-fetoprotein (P = 0.039) were independent risk factors for poor overall survival. Thirty-nine (34%) patients experienced grade 3/4 adverse events such as hand-foot skin reactions and diarrhea that required dose adjustment.ConclusionsThe clinical outcomes of sorafenib-treated patients with advanced HCC were comparable to those reported by formal clinical trial conducted in the Asia-Pacific region. Underlying hepatic dysfunction was the most important risk factor for shorter survival.

MicroRNA-34a expression is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma.

The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly associated with tumor recurrence. So far, no tissue biomarker of recurrence has been confirmed in biopsy specimens. Previous studies have reported that aberrant expression of microRNA-34a (miR-34a) is involved in oncogenesis and progression of HCC. The aim of this study was to investigate the prognostic value of tissue miR-34a expression in patients with HCC treated with RFA. Patients with early-stage single-nodule HCC treated with RFA were included, and tissue expression of miR-34a were assessed by quantitative reverse-transcription polymerase chain reaction. Main clinical endpoints were overall and early recurrence. The Kaplan-Meier method was used to plot recurrence curves and univariable and multivariable Cox regression analyses were performed to assess independent predictive factors for recurrence. Of 120 patients, recurrence occurred in 67 patients (55.8 %) with a median follow-up of 31 months. Forty-one patients (34.2 %) recurred within 2 years after RFA. The median miR-34a level was 0.87 (range 0.06-21.54). Low miR-34a level was associated with larger tumor size (P = 0.033) and higher serum alpha-fetoprotein (AFP) level (P = 0.004). When analyzed with a Cox regression model, the two independent predictive factors for overall recurrence were high serum AFP level (hazard ratio [HR] = 1.21; 95 % confidence interval [CI] = 1.04-1.36; P = 0.039) and low miR-34a level (HR = 1.44; 95 % CI = 1.13-1.72; P = 0.011). The expression of miR-34a was also an independent predictive factor for early recurrence (HR = 1.49; 95 % CI = 1.15-1.79; P = 0.008). Taken together, this study suggests that the expression of miR-34a in HCC biopsy specimens has an independent predictive value of early recurrence after RFA.

Associations between pregnancy outcomes and unexplained high and low maternal serum alpha-fetoprotein levels.

To determine the relationship between adverse pregnancy outcomes and maternal serum alpha-fetoprotein (MSAFP) levels. A retrospective cohort study was conducted on consecutive singleton pregnancies, screened for fetal Down syndrome, in the northern part of Thailand. The prospective database of our fetal Down screening program was assessed to recruit all consecutive records. Pregnancies with medical complication and fetal abnormality were excluded. The recruited women were categorized into three groups: normal (≥0.76 to ≤2.0 MoM), low (<0.76 MoM) and high (>2.0 MoM) MSAFP levels. Of 7,110 screened women, 5,486 met inclusion criteria, including 240; 5,016 and 230 in the group of high, normal and low MSAFP levels, respectively. The rates of preterm birth, pregnancy-induced hypertension (PIH), fetal growth restriction (FGR), fetal death, low birth weight (LBW) and low APGAR scores were significantly higher in women with high MSAFP levels (11.7 vs. 6.6 %, 7.5 vs. 3.3 %, 7.5 vs. 3.3 %, 2.1 vs. 0.3 %, 15.8 vs. 6.7 %, and 2.9 vs. 0.5 % respectively), with relative risk of 1.76, 2.28, 2.27, 7.46, 2.35 and 6.09, respectively. The rates of preterm birth, FGR and LBW were significantly lower in low MSAFP levels with relative risk of 0.39, 0.26 and 0.26, respectively, whereas the rates of PIH and fetal death and low Apgar scores were not significantly different. Pregnant women with high MSAFP levels had an increased risk of poor pregnancy outcomes, while those with low MSAFP levels had a significantly lower risk of such outcomes.

Clinicopathological features and prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgery

Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancer consisting of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of the rarity of this tumor, its feature is poorly understood. The present study aimed to evaluate the clinicopathological features and long-term prognosis of patients with cHCC-CC after surgery and to compare with those of the patients with stage-matched HCC and CC. The clinicopathological features of the patients who underwent surgery for cHCC-CC at our center during the period of 2001-2010 were retrospectively analyzed and compared with those of stage-matched HCC and CC patients. Cancer staging was performed according to the AJCC Cancer Staging Manual (6th ed.). Overall survival and disease-free survival were compared among the groups and prognostic factors of cHCC-CC were evaluated. Significant differences were observed in clinicopathological features among 42 patients with cHCC-CC, 90 patients with HCC and 45 patients with CC. Similar to HCC patients, cHCC-CC patients had frequent hepatitis B virus antigen positivity, microscopic vessel invasion, cirrhosis and high level of serum alpha-fetoprotein. Similar to CC patients, cHCC-CC patients showed increased bile duct invasion and decreased capsule. The 1-, 3-, and 5-year overall survival and disease-free survival of patients with cHCC-CC were not significantly different from those with stage-matched patients with CC; but significantly poorer than those with HCC. In subanalysis of patients with stage II, the overall survival in patients with cHCC-CC or CC was significantly poorer than that in patients with HCC. We did not find the difference in patients with other stages. Univariate analysis of overall and disease-free survival of patients with cHCC-CC showed that the vascular invasion and intrahepatic metastasis were the significant predictive factors. Patients with cHCC-CC showed similar clinicopathological features as those with HCC or CC, and patients with cHCC-CC or CC had a poorer prognosis compared with those with HCC, especially at matched stage II.

Tumor-derived alpha-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells

Several tumor-derived factors have been implicated in DC dysfunction in cancer patients. Alpha-fetoprotein (AFP) is an oncofetal antigen that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC compared to patients with low serum AFP levels and healthy donors, suggesting that AFP alters DC differentiation in vivo. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function was assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DC expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular weight (LMW) species that i) co-purify with tAFP, and ii) are abundant in the LMW fractions of both tumor and non-tumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for ubiquitous LMW molecules, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes.

Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma

The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in ∼15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n=70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n=109). This noninvasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease.

The role of unexplained high serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) levels in the second trimester to determine poor obstetric outcomes.

Objective:To investigate the relationship between gestational complications and high levels of maternal serum alfa-fetoprotein (MSAFP) and/or beta human chorionic gonadotropin (hCG) and to determine whether these markers are effective predictors of poor pregnancy outcomes.Materials and Methods:In this study, we enrolled a total of 679 women at 15-20 gestational weeks with MSAFP and hCG below or above 2.0 multiples of the median (MoM); of those, 200 women with normal MSAFP and hCG MoM formed the control group. Pre-eclampsia, intrauterine growth retardation (IUGR), preterm labor, preterm delivery, placental abruption, placenta previa, placenta accreta, preterm premature rupture of the membranes (PPROM), intrauterine fetal death, as well as neonatal and perinatal morbidity rates were evaluated.Results:A significant relationship was found between adverse pregnancy outcomes and abnormal elevation of hCG and AFP levels in the second trimester. In cases of isolated elevation of hCG, preeclampsia and preterm labor/spontaneous preterm birth rate were slightly higher than in the control group (p=0.043, p=0.015), while IUGR, PPROM, placental abruption, and intrauterine fetal death rates were all similar (p=0.063, p=0.318, p=1.00, p=0.556).In case having an elevation in both markers, increased rate of obstetric complications have been observed. A significant relationship was found between the high levels of maternal serum AFP and hCG MoM and poor pregnancy outcomes like preeclampsia, IUGR, PPROM, intrauterine fetal death (p=0.003, p=0.001, p=0.040, p=0.006).Conclusion:To our knowledge, up to now, no definitive follow-up and treatment protocols have been established for patients at increased risk. In light of these findings, it is recommended to inform and educate patients about the most likely signs and symptoms of complications, to make more often antenatal visits, to perform more frequent ultrasound examination (fetal growth, AFI, etc.), NST, arterial/venous doppler, biophysical profile, and cervical length measurements in high-risk group.

Risk factors for 1-year mortality in patients with intermediate-stage hepatocellular carcinoma treated solely with transcatheter arterial chemoembolization

SummaryBackground/aimsTranscatheter arterial chemoembolization (TACE) is a main therapy for patients with intermediate‐stage hepatocellular carcinoma (HCC). The purpose of our study was to determine the risk factors for 1‐year mortality in patients treated solely with TACE.MethodsA total of 123 patients with intermediate‐stage HCC treated solely with TACE were recruited from Ren‐ai Branch, Taipei City hospital during the period from January 1998 to June 2013. Baseline characteristics and factors associated with 1‐year mortality were analyzed.ResultsThere were 94 men (76.4%) and 29 women (23.6%) among 123 newly diagnosed intermediate‐stage HCC patients treated solely with TACE. The mean age was 63 ± 11 years (range, 31–92 years). The 1–5‐year overall cumulative survival rates were 65.9%, 46%, 33.2%, 22%, and 18.4% [median: 23 months, 95% confidence interval (CI): 16.4–29.6 months], respectively. Of these, 42 (34.1%) and 81 (65.9%) patients had survival time shorter (Group 1) and longer (Group 2) than 1 year, respectively. There were no significant differences in sex, age, hepatitis B virus/hepatitis C virus positive rate and tumor number between Group 1 and Group 2 patients. Compared to Group 2, Group 1 patients had a significantly larger mean maximum tumor size (6.8 ± 3.2 cm vs. 5.3 ± 3.1 cm, p = 0.024), lower serum albumin level (3.4 ± 0.45 g/dL vs. 3.6 ± 0.46 g/dL, p = 0.011), higher serum bilirubin level (1.52 ± 1.07 mg/dL vs. 1.07 ± 0.59 mg/dL, p = 0.023), higher ratio of serum alpha‐fetoprotein (AFP) &gt; 400 ng/mL (52.4% vs. 24.7%, p = 0.003), and higher ratio of Child‐Turcotte‐Pugh (CTP) class B cirrhosis (26.2% vs. 6.2%, p = 0.003). Multivariate analysis revealed that AFP level &gt; 400 ng/mL [hazard ratio (HR): 2.663, 95% CI: 1.143–6.205, p = 0.023], CTP class B cirrhosis (HR: 4.69, 95% CI: 1.399–15.715, p = 0.012) and tumor size (HR: 1.153 for each 1 cm increase, 95% CI: 1.015–1.310, p = 0.029) were independently associated with 1‐year mortality.ConclusionOne‐year mortality in patients with intermediate‐stage HCC treated solely with TACE is not uncommon. High serum AFP level (&gt; 400 ng/mL), CTP class B cirrhosis, and tumor size are independent risk factors for 1‐year mortality in those patients.

Association between serum alpha-fetoprotein levels and fatty liver disease: a cross-sectional study.

To investigate the association between serum alpha-fetoprotein (AFP) levels and fatty liver disease (FLD) in a Chinese population. A cross-sectional study was performed among subjects who presented for a health examination at the First Affiliated Hospital, College of Medicine, Zhejiang University in 2013. FLD was diagnosed based on an ultrasonography examination. Serum AFP levels were measured with a chemiluminescence immunoassay. Of the 9800 subjects enrolled, 2601 were diagnosed with FLD. Subjects with FLD had higher serum AFP levels than those without the disease. Subjects with high serum AFP levels had a higher prevalence of FLD, metabolic syndrome, and its components. Univariate logistic analysis showed that elevated serum AFP levels were associated with an increased risk of FLD (OR = 1.057, 95%CI: 1.031-1.084). However, after adjusting for covariates, AFP no longer remained significantly associated with the risk factors for FLD. Our results suggest that serum AFP levels are significantly associated with FLD and that AFP acts as a cofactor, but not as an independent factor, for FLD.

Aberrant p16INK4A methylation: Relation to viral related chronic liver disease and hepatocellular carcinoma

Background:Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the third leading cause of cancer related deaths. Several studies have shown that the tumor suppressor gene p16INK4A is frequently downregulated by aberrant methylation of the 5’-cytosine-phosphoguanine island within the promoter region.Aim:To find out the frequency of methylated p16INK4A in the peripheral blood of HCC and cirrhotic patients and to evaluate its role in hepatocarcinogenesis.Patients and Methods:This study was performed on 58 subjects: 30 HCC patients, 20 cirrhotic patients, and eight healthy volunteers. Methylation of p16INK4A was examined using methylation specific polymerase chain reaction (PCR) (MSP). Comparison of quantitative variables between the study groups was done using Mann-Whitney U test for independent samples when not normally distributed. For comparing categorical data, Chi-square (χ2) test was performed. Exact test was used instead when the expected frequency was less than 5.Results:Methylation of p16INK4A was found in 6.7% of HCC patients, 5% of liver cirrhosis (LC) patients, and none of the healthy volunteers; 66.67% of the p16INK4A-methylated cases (2/3) were positive for anti-hepatitis C virus (HCV) antibodies (one of them had HCC). All HCC cases with aberrant p16INK4A methylation show very high serum alpha fetoprotein (AFP) level (9,080; 30,000 μg/mL). There were no significant associations between the status of p16INK4A methylation and tumor size.Conclusion:Hypermethylation of p16INK4A was found to be infrequent among Egyptian patients with HCC.

Abstract 3143: A functional interaction between alpha-fetoprotein and miRNA-29 modulates the HCC epigenome.

Abstract Globally, hepatocellular carcinoma (HCC) accounts for 70-85% of primary liver cancers and ranks second in the leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally expressed during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors may differ biologically and have different prognosis in HCC patients. Using microarray-based global microRNA and mRNA profiling, we found that members of the miR-29 family are the most significantly (p&amp;lt;1E-5) down-regulated miRs in AFP+ tumors (n=242). Physiologically, during mouse embryonic development, miR-29 family expression is low but gradually increases after birth, contrary to AFP expression which dramatically decreases after birth. In addition, a member of the DNA methyltransferase (DNMT) family, DNMT3A, is one of the most significantly (p=8E-6) up-regulated genes in AFP+ HCC. Interestingly, there is a significant inverse correlation (p&amp;lt;1E-4) between miR-29 and DNMT gene expression, suggesting that they may be functionally antagonistic, which is consistent with the finding showing that DNMT3A and DNMT3B are direct targets of miR-29. Experimentally, we found that increased AFP expression or the addition of AFP+ media to AFP- cells inhibits miR-29a expression in HCC cell lines. We also found that AFP transcriptionally regulates the promoter of miR-29a. Moreover, global DNA methylation array profiling reveals increased methylation in HCC patients with high levels of serum AFP. These results support our hypothesis that AFP inhibits miR-29, which modulates epigenetic changes that contribute to poor outcome. Taken together, this study elucidates the mechanisms that link AFP and miR-29 expression to epigenetic alterations and may aid in the development of novel therapeutic agents to improve survival of HCC patients. Citation Format: Sonya Parpart, Stephanie Roessler, Fei Dong, Vinay Rao, Christopher Loffredo, Xin Wei Wang. A functional interaction between alpha-fetoprotein and miRNA-29 modulates the HCC epigenome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3143. doi:10.1158/1538-7445.AM2013-3143

Predisposing Factors of Hepatocellular Carcinoma Recurrence Following Complete Remission in Response to Transarterial Chemoembolization

The aim of our study was to determine the predictors of recurrences in hepatocellular carcinoma (HCC) patients who had achieved complete remission (CR) by transarterial chemoembolization (TACE). A total of 220 consecutive HCC patients who had achieved CR by TACE were followed for a median 72 months. CR was defined as complete lipiodol uptake based on the results of lipiodol-computed tomography 4 weeks after TACE and no additional tumor staining on the follow-up angiography. Recurrence patterns were classified as local recurrence and secondary tumor, respectively, in relation to the location of recurrence; early and late recurrence were classified in relation to recurrence time. Recurrence of HCC was observed in 169 patients (77 %), of whom 91 (54 %) had local recurrences, 61 (36 %) had secondary tumor, and 17 (10 %) had both. There were 45 (27 %) early and 124 (73 %) late recurrences. Local recurrence developed more frequently in patients with early recurrence than in those with late recurrence (62 vs. 51 %, respectively), while secondary tumor was detected more commonly in patients with late recurrence than in those with early recurrence (39 vs. 29 %, respectively; P < 0.001). In multivariate analyses, multinodularity [hazard ratio (HR) 2.351, P = 0.023] and a persistently high serum alpha-fetoprotein level following CR (HR 3.173, P < 0.001) were significant predictors of early recurrence. Older age (≥ 60 years; HR 1.531, P = 0.043), advanced Child-Pugh class (HR 1.983, P = 0.002), and the association with cirrhosis (HR 1.756, P = 0.028) were predictors of late recurrence following CR. Early recurrences following CR by TACE may be due mainly to undetectable remaining tumors, whereas late recurrences may be caused by newly appearing tumors in patients with a background of advanced cirrhotic liver.

An isolate alpha-fetoprotein producing gastric cancer liver metastasis emerged in a patient previously affected by radiation induced liver disease

We report a case of an isolated hepatic neoplasia which originated in a site of the liver previously affected by radiation induced liver disease (RILD) in a patient resected for gastric cancer and referred to us for high serum alpha-fetoprotein (AFP) levels. This case challenged us in distiguishing, even histologically, between primary liver cancer and AFP producing gastric cancer metastasis. Only a panel of immunohistochemical markers allowed the definitive diagnosis of liver metastasis of endodermal stem cell-derived and AFP producing gastric cancer. We discuss the criteria for a differential diagnosis, as well as the possible link between RILD and emergence of liver neoplasia.

Factors Predisposing Metastatic Tumor Antigen 1 Overexpression in Hepatitis B Virus Associated Hepatocellular Carcinoma

Overexpression of metastatic tumor antigen-1 (MTA-1) is suggested to be associated with frequent postoperative recurrence and poor survival of hepatocellular carcinoma (HCC) patients. In this study, we intended to determine clinical factors predisposing the overexpression of MTA-1 in patients with hepatitis B virus (HBV)-associated HCC and also examine whether MTA-1 overexpression affects the survival periods of these patients treated with curative surgical resection. A total of 303 patients with HBV-associated HCC who underwent curative surgical resection were subjected. The expressions of MTA-1 in HCC and surrounding non-tumor liver tissues were evaluated using the immunohistochemical method. The clinical, radiological and histological characteristics of the patients were analyzed in relation to the expression of MTA-1 to find predisposing factors of MTA-1 overexpression. MTA-1 was overexpressed in 104 HCC tissues (34.3 %) and none of the surrounding non-tumor tissues. Clinically, MTA-1 overexpression was significantly associated with younger age, female gender, higher serum alpha-fetoprotein level, and Child-Turcotte-Pugh class A. Also, portal vein thrombosis, microvascular invasion, capsular invasion and poorly histological differentiation were associated with overexpression of MTA-1. The cumulative survival rates were significantly lower in patients with MTA-1 overexpression compared with those in the MTA-1 negative group (P = 0.03). In addition to the overexpression of MTA-1, the presence of microvascular or capsular invasion was a significant factor determining the poor survival of the patients with HBV-associated HCC after curative resection. MTA-1 is overexpressed in patients with HBV-associated HCC of invasive nature. MTA-1 overexpression is associated with shorter survival periods of patients with HBV-associated HCC after curative resection.

Synthesis of alpha-fetoprotein by human yolk sac tumor transplanted into nude mice.

All nude mice bearing primary or secondary transplants of a human yolk sac tumor exhibited a high serum alpha-fetoprotein level. This finding clearly indicates the synthesis of alpha-fetoprotein by the human yolk sac tumor and supports an idea that human yolk sac tumor simulates yolk sac endoderm not only morphologically but also functionally.

Adenoendocrine cell carcinoma of the gallbladder producing a high level of alpha-fetoprotein

We present the case of a 78-year-old Japanese woman with adenoendocrine cell carcinoma of the gallbladder accompanied by a high serum alpha-fetoprotein level. The patient visited our hospital with a complaint of a large mass in the right hypochondrium. Ultrasonography and computed tomography revealed multiple large hepatic tumors, swelling of lymph nodes in the hepatic hilum and para-aortic regions, and a slightly irregular gallbladder wall. The serum alpha-fetoprotein level was 157,428ng/mL. We initially suspected scirrhous hepatocellular carcinoma, sarcomatous hepatocellular carcinoma, biliary tract cancer, or pancreatic cancer. However, the hepatic tumor biopsy was histologically diagnosed as undifferentiated adenocarcinoma. Immunohistochemical analysis demonstrated that the tumor was positive for cytokeratin 19, focally positive for cytokeratin 7, but negative for hepatocyte paraffin 1 and cytokeratin 20, suggestive of biliary tract carcinoma. Although the patient received a course of hepatic arterial infusion chemotherapy with cisplatin, she died 2months after admission. Histopathological examination at autopsy revealed that the hepatic tumor was adenoendocrine cell carcinoma of the gallbladder, which was positive for cytokeratin 19, focally positive for cytokeratin 7, chromogranin A, synaptophysin, and weakly positive for alpha-fetoprotein. Labeling index of Ki-67 was 28%. Interestingly, this was the first case report of adenoendocrine cell carcinoma of the gallbladder that produced a high level of alpha-fetoprotein, which hampered correct diagnosis before autopsy.