High Alpha-fetoprotein Levels Research Articles

Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis.

The prognostic role of programmed death ligand-1 (PD-L1) expression in hepatocellular carcinoma (HCC) has been widely studied but the results are controversial. In this comprehensive meta-analysis, we elucidated the clinical value of PD-L1 in HCC. Relevant studies were systematically searched in the Cochrane Library, EMBASE, and PubMed until June 27, 2019. Eligible studies were validated for the prognostic effect of PD-L1 on the overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS) in HCC using a hazard ratio (HR) and its 95% confidence interval (95% CI). Twenty-three studies with 3529 patients were involved in this meta-analysis. The pooled results revealed that high membrane-bound PD-L1 (mPD-L1) expression was associated with poor OS (HR: 1.42; 95% CI: 1.12–1.80; P = 0.004) and had no significant correlation with RFS (HR: 1.14; 95% CI: 0.85–1.54; P = 0.39), and DFS (HR: 1.36; 95% CI: 0.81–2.28; P = 0.25). The results also indicated that high soluble PD-L1 (sPD-L1) levels were associated with worse OS (HR: 2.93; 95% CI: 2.20–3.91; P < 0.00001). In addition, high mPD-L1 expression was associated with high alpha-fetoprotein levels (AFP; OR = 1.46; 95% CI: 1.16–1.84; P = 0.001), hepatitis (OR = 0.72; 95% CI: 0.54–0.98; P = 0.03), poor tumor differentiation (OR = 0.68; 95% CI: 0.55–0.84; P = 0.03), and tumor-infiltrating lymphocytes (OR = 3.39; 95% CI: 1.06–10.91; P = 0.04). The mPD-L1 expression had no significant correlation with age, number of tumors, gender, tumor size, liver cirrhosis, vascular invasion, tumor encapsulation, or TNM stage. The study revealed that high mPD-L1 expression in the tumor tissue and high sPD-L1 levels were associated with shorter OS in HCC. Moreover, overexpression of mPD-L1 was significantly associated with poor tumor differentiation, hepatitis, AFP elevation, and tumor-infiltrating lymphocytes.

Alpha feto protein in obstetrics

Alpha-feto protein in obstetricsAbstractAll obstetricians have the primary objective of obtaining an optimum obstetric and perinatal result. Diagnosis of many obstetric complications, such as restriction of intrauterine development, preeclampsia; placental necrosis or early pregnancy abruption may be conducted through several safe tests to minimize maternal and fetal morbidity or mortality. Biochemical markers were used for the earl during the 1980s and 90s .Early detection of fetal genetic disorders was performed using biochemical markers. Soon after the establishment of maternal serum screening tests for early detection of fetal abnormalities, poor pregnancy results started to be reported after unexplained isolated alpha-fetoprotein (AFP) elevation was identified. This correlation was recorded between high AFP and poor obstetric outcomes Recorded over the last 20 years. In this paper, we attempt to investigate recently updated data on the relationship between high levels of maternal serum alpha-fetoprotein (MS-AFP) with various obstetric and fetal outcomes and to assess its significance as effective markers in predicting poor outcomes for pregnanciesThe aim of the study: The aim of our study was to detect the significance of AFP in obstetric medicine.Conclusion: As a result of our research, unexplained AFP rates have been discovered with unfavorable perinatal results. Pregnancies in which AFP rates increasing rapidly were complicated with adverse perinatal outcomes in a more serious manner.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Presenting with Primary Diagnosis of Hepatocellular Carcinoma

: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon systemic allergic reaction, which usually occurs due to a specific medication. The most common presentation is fever, skin eruption, and lymphadenopathy that presents two to eight weeks after exposure to the culprit drug. In some cases, evidence of internal organ involvement including renal failure, respiratory symptoms, or liver involvement may present. These symptoms may present weeks to months after the exposure or even discontinuing the drug, which makes the diagnosis challenging. This report presents a young man with first presentation of icter and elevated liver enzymes, whose laboratory and imaging studies failed to diagnose the disease. A liver biopsy was performed and the pathologist reported hepatocellular carcinoma (HCC). A high level of serum alpha-fetoprotein was consistent with the histologic findings, but concerning the uncommon clinical setting, the pathologic specimen was reviewed by another pathologist, which reported hepatocyte regeneration following hepatitis. This finding was consistent with elevated serum alpha-fetoprotein. A retrospective review revealed the history of using ceftriaxone nine months before the presentation and his final diagnosis was the DRESS syndrome with a dramatic response to corticosteroid treatment.

Hepatocyte-Specific Magnetic Resonance Imaging-Based Assessment of Indeterminate Hepatic Nodules in the Liver Transplant Evaluation of Patients With Cirrhosis.

We aimed to determine the identities in explants of indeterminate hepatic nodules (IDNs) that had been scanned by dynamic magnetic resonance imaging (MRI) to establish clinicoradiological parameters predicting which IDNs were hepatocellular carcinomas (HCCs). This study included 88 patients with cirrhosis who underwent gadoxetic acid-enhanced MRI in pre-liver transplantation (LT) workup followed within 90days by primary LT. The MRI detected 168 hepatic nodules that were classified into 6 benign tumors, 49 HCCs, and 113 IDNs, in 5, 34, and 72 patients, respectively. We compared these pre-LT radiologic diagnoses and stagings with explant pathology on a per-lesion basis to enable us to identify features of IDNs related to malignancy. Of the 168 nodules seen on MRI, 119 that were classified radiologically as consisting of 1 benign nodule (33.3%), 46 HCCs (93.9%), and 72 IDNs (63.7%) all turned out to be pathological HCCs. Of 32 patients inside Milan and 54 without HCC staged by MRI, 11 progressed beyond the criteria after LT. High serum alpha-fetoprotein level (≥20ng/mL) was the only per-patient factor significantly associated with malignant IDNs. Per-tumor analysis of the MRI signals revealed that arterial hyperintensity, hepatobiliary hypointensity, T2 -weighted mild-to-moderate intensity, and restricted diffusion-weighted images were significantly correlated with malignant IDN. A model combining these 4 MRI factors with alpha-fetoprotein level had the best performance in predicting the identification of IDNs as HCCs in explanted livers. Over 60% of the IDNs seen on dynamic images of cirrhotic livers proved to be HCCs when explanted livers were examined. It may therefore be possible to identify HCCs with reasonable accuracy by means of their hepatocyte-specific MRI features when patients are being assessed for LT.

Diagnostic and prognostic significance of α-fetoprotein in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive tumor with agrowing socioeconomic burden. International guidelines do not predominantly recommend the pretherapeutic determination of the alpha-fetoprotein (AFP) concentration. Regarding the prognostic value of AFP, the European study data are not sufficiently meaningful. This study aimed to demonstrate possible aspects of the AFP level and to investigate the prognostic value of AFP levels as well as to provide impetus for future prospective studies. At the time of data retrieval the prospective liver databank showed 1382 entries. All patients with ahistologically confirmed HCC were included resulting in 92final entries. For these patients, information on T, N, M and G stages, R status as well as sex, age and etiology of the HCC were available. For data analysis the patient population was divided into six groups based on three cut-off values. Furthermore, asurvival analysis was performed using Kaplan-Meier and amultifactorial analysis of the influencing factors regarding outcome. The AFP serum level showed a statistically significant correlation with the tumor diameter (T1/T2 vs. T3/T4) and grading (G1/G2 vs. G3/G4). The survival prognosis was significantly lower in patients with higher AFP values (p < 0.05). The median survival time for patients with AFP levels >8 μg/l was 35months, with AFP levels >200 μg/l or >400 μg/l showed areduced median survival of 15months and 11months, respectively. High AFP levels were a significant influencing factor for the outcome independent of the T stage, age and R status of patients in comparison to low AFP levels. Taking the present results into consideration, the AFP level can have a therapeutic usefulness. Therapeutic consequences could be derived from the height of the measured AFP concentration, with respect to the treatment strategy. Therefore, preoperative and postoperative determination of the AFP serum level is recommended in all HCC patients.

Optimal timing of radiotherapy for incomplete transarterial chemoembolization in BCLC stage B hepatocellular carcinoma.

521 Background: Numerous studies have reported on the efficacy of radiotherapy (RT) after incomplete transarterial chemoembolization (TACE). However, the optimal timing of RT remains unclear. This study investigated the optimal time of initiating RT for incomplete TACE in patients with BCLC stage B hepatocellular carcinoma (BCLC-B HCC). Methods: Between 2001 and 2016, 116 lesions in 104 patients with BCLC-B HCC were treated with RT after TACE. The time interval between the last session of TACE and initiation of RT was obtained from medical records and analyzed retrospectively. The optimal cut-off time-interval that maximized the difference in local failure-free rate (LFFR) was determined using maximally selected rank statistics. Results: The median duration between TACE and RT was 26 (range: 2–165) days. Median number of TACE treatments on the target lesion before RT was 2; median tumor size was 7 cm. At a median follow-up of 18 (range: 3–160) months, the median overall survival was 18 months. The probability of local control increased as the time interval between TACE and RT decreased. The optimal cut-off value of the time interval was 5 weeks. With the cut-off of 5 weeks, 65 and 39 patients were classified into early and late RT groups, respectively. The early RT group had significantly poorer Child-Pugh class and higher alpha-fetoprotein levels. Most characteristics including tumor size (7 cm vs. 6 cm; P = .144) were not significantly different between the groups. One-year LFFR was significantly higher in the early RT group (94.6% vs. 70.8%; P = .005). On multivariate analysis, early RT was an independent predictor of favorable LFFR (hazard ratio: 3.82, 95% confidence interval: 1.64–8.88, P = .002). Conclusions: The optimal time for the administration of RT for incomplete TACE is within 5 weeks following TACE. Early administration of RT within 5 weeks after TACE was associated with better local control.

N6-methyladenosine (m6A) RNA methylation regulators are associated with clinical prognosis in hepatocellular carcinoma.

BackgroundN6-methyladenosine (m6A) methylation is a common class of RNA modification. Similar to DNA methylation, m6A methylation regulates most mRNA expressions. At present, most research has found that m6A methylation is related to tumorigenesis and development; however, there are few studies about hepatocellular carcinoma (HCC). This study aimed to analyze the expression level of m6A methylation regulators and their correlation on the clinical features in HCC.MethodsA total of 13 m6A methylation regulators were evaluated. mRNA data and clinical information were obtained from the Cancer Genome Atlas (TCGA). The Wilcoxon test was utilized to analyze the differences between m6A RNA methylation regulators, and Pearson’s test was used to test the correlation between them. We constructed a tumor subgroup model based on the 13 molecules used for the analysis of the correlations with the clinical features. Two genes (ZC3H13 and YTHDF2) screened by Cox and LASSO regression were used to construct a tumor risk model for analyzing the correlations with clinical features. Finally, we verified the expression of the two molecules in liver cancer and adjacent tissues by Western blot and real-time polymerase chain reaction (PCR) (n=6). P<0.05 was considered statistically significant.ResultsEleven of the 13 molecules were higher in the liver cancer tissues than the adjacent tissues (P<0.05), and most were significantly positively related. Two subgroup models were constructed. Subgroup 2 patients had higher levels of alpha-fetoprotein (AFP), while grade and the three-year survival were lower than subgroup 1 (49% vs. 77%) with significant differences (P<0.05). The risk model suggested that patients in the high-risk group showed high AFP levels, and the 3- and 5-year survival rates were lower than the low-risk group (3-year survival rate: 19% vs. 31%, 5-year survival rate: 12% vs. 17%). The Western blot test showed that the expression of YTHDF2 in the liver cancer tissues was greater than that in the precancerous tissues (P<0.05), while the expression of ZC3H13 was not significant. Real-time PCR showed that the expression of YTHDF2 mRNA in liver cancer tissues were higher than that in adjacent tissues (7.64±0.44 vs. 4.99±0.61, P=0.006), while the expression of ZC3H13 mRNA had no statistical difference (5.56±0.18 vs. 5.42±0.33, P>0.05). The results of the in vitro experiment were consistent with bioinformatic analysis.ConclusionsThe abnormal expression of m6A methylation regulators in the liver tissues suggest that m6A may play an important role in the development of HCC. Tumor models we constructed that could effectively predict the prognosis of patients, and the clinical correlation results were consistent with clinical practices. Our research is expected to provide a reference for the prognostic stratification and treatment strategy development of HCC.

Aberrant AFP expression characterizes a subset of hepatocellular carcinoma with distinct gene expression patterns and inferior prognosis.

Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored.Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied.Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues (r = 0.72, p = 1.6e-45). Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster (Chi-square: 16.86, P = 0.0002). Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024).Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue.

Hepatocellular Carcinoma with Increased AFP Levels and Extrahepatic Manifestation after Liver Transplantation: A Case of Late-Onset Recurrence

Liver transplantation is the best treatment modality in patients with hepatocellular carcinoma. The major concern after liver transplantation for hepatocellular carcinoma treatment is recurrence, because it’s the most important factor for the long term survival. There are two forms of recurrence; early-onset (within 2 years of liver transplantation) and late-onset (after 2 years of liver transplantation). A lot of factors have been reported in the literature to foresee recurrence after liver transplantation and one of them is alpha-fetoprotein. Many studies have shown that high levels of pre-transplant alpha-fetoprotein is related to early-onset recurrence and worse outcomes in the long term. In this case report, we report a case of late-onset recurrence, despite having high levels of pre-transplant alpha-fetoprotein in contrary to the literature, and still survive with a high quality of life 6 years after transplantation.

Ruptured hepatocellular carcinoma in a patient with chronic hepatitis C and a sustained viral response

Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease in the world (1). The goal of chronic hepatitis C therapy is to prevent cirrhosis of the liver and hepatocellular carcinoma (HCC) by achieving a sustained virologic response (SVR). It has been reported that telaprevir-based triple therapy enabled 60%–70% SVR in genotype 1 (G1) patients (2,3). The 74-year-old male patient was diagnosed with chronic hepatitis C 6 years ago, and peginterferon (P) + ribavirin (R) therapy was initiated. As HCV-RNA positivity continued in the 24th week of treatment, the patient was considered unresponsive, and his treatment was concluded. With the introduction of telaprevir into the therapy approximately one year later, the G1b patient was started on a triple therapy (telaprevir, PR) for 12 weeks followed by a 36-week course of double therapy (PR); thereby, his treatment was completed in a total of 48 weeks. The patient, who now had SVR, has been followed up in the 4 years since the completion of his therapy by carrying out tests on his HCV-RNA and alpha-fetoprotein (AFP) levels, alongside abdominal ultrasonography (ABD USG) performed every 6 months. The patient, who presented to the emergency department with a complaint of severe abdominal pain reflecting on his right shoulder about 4 months after his latest follow-up, had a heterogeneous solid mass about 6 cm in size in his eighth liver segment alongside free fluid in the perihepatic and pelvic areas, as revealed by ABD USG. The results of testing showed that the patient had a high AFP level of 36 ng/mL (0–8.1). The results of all abdominal computed tomography scans carried out in view of these findings showed that the patient’s liver was of a normal size with no pronounced undulation of the contours. A heterogeneous solid mass lesion about 67 × 73 × 68 mm in size growing toward the subdiaphragmatic space in liver segment 8 was observed to reveal a hyperdense, possibly arterial contrasting image; the presence of high-density fluid around the mass in the subdiaphragmatic space was also visualized. Consequently, the rapidly contrasting arterial mass on the hepatic dome was diagnosed as HCC (?), hepatic adenoma (?), and a ruptured mass, and it was recommended that the patient undergo dynamic magnetic resonance (MR). A T1A hypointense, T2A mildly hyperintense heterogeneous solid mass, 63 × 70 mm in size with fine borders and irregular contours, was visualized on the dome level of the eighth segment of the right lobe (Figure 1). As a result, the patient was diagnosed with spontaneous rupture of the mass because of his high AFP levels, the presence of a solid mass concordant with HCC, contour irregularity neighboring the superior, and signs of hemoperitoneum observed in the perihepatic area. The patient was taken into surgery and died in the perioperative period. The risk of HCC development in patients with SVR through direct-acting antiviral (DAA) has proven to be a controversial issue (4,5). Patients with SVR through DAA administration should be followed up every 6 months with regards to ABD USG results and AFP levels.

Evaluation of HCV-associated Hepatocellular Carcinoma based on Alpha-fetoprotein levels

Background and study aim: Alpha-fetoprotein (AFP) cannot be relied on alone for diagnosis of hepatocellular carcinoma (HCC). However, it may have a prognostic value and can be used for monitoring response to different modalities of treatment for HCC. This study aimed to differentiate the clinical and pathological features of HCCs according to AFP levels. Subjects and Methods: This retrospective study included 60 patients with HCC secondary to chronic hepatitis C (HCV). They were divided based on serum AFP into two groups; group I; included 30 patients with AFP lower than 302.5ng/ml. and group II; included 30 patients with AFP higher than 302.5ng/ml. clinical, laboratory and pathological differences between both groups were compared. Results: Regarding the pathological features, patients with higher AFP secreting tumors have larger tumor size compared to lower AFP secreting tumors; (5.8 cm Vs. 4.5 cm, P value; 0.001). Number of lesions and tumor location were similar between the two groups. Conclusion: HCC-secreting high levels of AFP are larger and aggressive tumors when compared to low secreting AFP-HCC.

Clinical significance and function of RDH16 as a tumor-suppressing gene in hepatocellular carcinoma.

Our previous transcriptome sequencing analysis detected that retinol dehydrogenase16 (RDH16) was dramatically downregulated in hepatocellular carcinoma (HCC). RDH16 belongs to the short-chain dehydrogenases/reductases super family, and its role in HCC remains unknown. This study aimed to investigate the expression and function of RDH16 in HCC. The mRNA and protein level of RDH16 in HCC samples were detected by quantitative real-time polymerase chain reaction and immunohistochemistry analyses, respectively. The role of RDH16 in HCC was determined by invitro and invivo functional studies. Downregulation of RDH16 has been detected in approximately 90% of primary HCCs, which was significantly associated with high serum alpha-fetoprotein level, tumor size, microsatellite formation, thrombus, and poor overall survival of HCC patients. Compared with non-tumor tissues, higher density of methylation was identified in HCC samples. In addition, RDH16 increases the level of retinoic acid and blocks the de novo synthesis of fatty acid in HCC cells. Functional study shows that ectopic expression of RDH16 in HCC cells suppresses cell growth, clonogenicity, and cell motility. RDH16 might be a prognostic biomarker and intervention point for new therapeutic strategies in HCC.

The Correlation between Alpha-fetoprotein and Liver Function Tests

Background Serum alpha-fetoprotein (AFP) level is a good indicator of important pathological stages in patients with chronic liver diseases. This study aims to investigate the alpha-fetoprotein level in male and female patients and to correlate it with other liver functions tests (LFTs), such as ALT, AST, total albumin and total protein. Methods A total of 100 patients within the age range 20-85 years who visited Shaukat Khanum Laboratory in Lahore were recruited for this study. Automated chemiluminicence microparticle immuno assay and immulite 2000 (CMIA, siemens USA) were used to measure serum AFP level. To measure serum ALT and AST, Architect 8200 kit (Abbott, USA) was used with a reference range of 0-50 U/L, according to the manufacturer’s protocols. Results Out of the total 100 samples (55 males, 45 females), 47 samples (47%) had normal AFP level (&lt;5IU/l) and 53 samples (53%) had high AFP level (&gt;5IU/l). A higher frequency of elevated AFP was observed in men at 60.38%. There was no significant correlation of AFP level with ALT (p= 0.38, r2= 0.002), T.P. (P. value= 0.7635 r2= 0.002) and albumin levels (p= 0.07, r2 =0.041). However, a significant correlation was found between AFP and AST levels (p= 0.02, r2= 0.15). Conclusion Our study found a higher AFP level in older population (&gt;60) as compared to the younger people (20-40) and a higher frequency among males (60.38%) as compared to females (39.63%). It also found that AFP level significantly correlates with AST level but does not show any association with ALT and albumin levels.

Targeted agents for second-line treatment of advanced hepatocellular carcinoma.

Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.

Prenatal Biochemical Screening and a Woman’s Long-Term Risk of Cancer: A Population-Based Cohort Study

BackgroundSome hormones measured in pregnancy are linked to certain hormone-sensitive cancers. We investigated whether routine serum screening in pregnancy is associated with a woman’s subsequent risk of hormone-sensitive cancer.MethodsThis population-based cohort study included women aged 12–55 years who underwent prenatal screening between 11 weeks + 0 days of gestation to 20 weeks + 6 days of gestation in Ontario, Canada, 1993–2011, where universal health care is available. The hazard ratio of newly diagnosed breast, ovarian, endometrial, and thyroid cancer—arising at 21 weeks + 0 days of gestation or thereafter—was estimated in association with an abnormally low (≤5th) or high (>95th) percentile multiple of the median (MoM) for alpha-fetoprotein (AFP), total human chorionic gonadotropin (hCG), unconjugated estriol, pregnancy-associated plasma protein A, and dimeric inhibin A.ResultsAmong 677 247 pregnant women followed for a median of 11.0 years (interquartile range = 7.5–16.1), 7231 (1.07%) developed breast cancer, 515 (0.08%) ovarian cancer, 508 (0.08%) endometrial cancer, and 4105 (0.61%) thyroid cancer. In multivariable adjusted models, abnormally high hCG greater than the 95th percentile MoM was associated with a doubling in the risk of endometrial cancer (adjusted hazard ratio [aHR] = 1.98, 95% confidence interval [CI] = 1.33 to 2.95), and abnormally low AFP at the fifth percentile or less MoM conferred a moderately greater risk of thyroid cancer (aHR = 1.21, 95% CI = 1.07 to 1.38). Abnormally low pregnancy-associated plasma protein A at the fifth percentile or less MoM was not statistically significantly associated with breast cancer after multivariable adjustment (aHR = 1.19, 95% CI = 0.98 to 1.36).ConclusionsWomen with abnormally high levels of serum hCG or low AFP in early pregnancy may be at a greater future risk of certain types of hormone-sensitive cancers.

3232 Metastatic Adenocarcinoma of the Stomach With Elevated AFP but Normal CEA in a White American Patient

INTRODUCTION: Globally, gastric cancers are the fourth most common cancer and second most common cause of cancer-related mortality. Alpha-fetoprotein (AFP) is a glycoprotein that is typically found during the process of fetal development. It has a very short half-life and is cleared from the body rapidly after birth. Increasing concentration of this glycoprotein in adult life is associated with malignancy of the liver, yolk sac tumor of testis, mediastinum and other conditions like hepatitis and cirrhosis of the liver. Alpha-fetoprotein (AFP) producing gastric adenocarcinoma is very rare. Its incidence is reported to be only 2.7 to 8% amongst all gastric cancers. Most of the cases of gastric adenocarcinoma producing AFP reported in the literature are from Asia. It is a very aggressive tumor with an estimated survival time of less than one year because of its rapid spread to lymph nodes and liver. CASE DESCRIPTION/METHODS: In this case report, we present a unique case of AFP producing gastric adenocarcinoma in a white American patient. AFP producing gastric adenocarcinoma have elevated levels of both AFP and carcinoembryonic antigen (CEA). Our case had closer to normal levels of CEA despite very high levels of AFP. The levels of AFP in our patient did not correlate with the size, stage or prognosis of the tumor. Despite the presence of liver metastasis, our case had a very good prognosis so far and had received up to six cycles of chemotherapy without any complications. DISCUSSION: In this case report, we have discussed the histological subtypes of AFP producing gastric adenocarcinomas. We have emphasized the use of immunohistochemical markers in the differentiation of primary hepatocellular carcinoma from AFP producing gastric adenocarcinoma. We have also discussed up to date treatment options, prerequisites for treatment, monitoring of treatment response and prognosis of AFP producing gastric adenocarcinomas in detail in this case report.

757P - Efficacy and safety of ramucirumab (RAM) for advanced hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) following first-line sorafenib across age subgroups in two global phase III trials (REACH and REACH-2)

757P - Efficacy and safety of ramucirumab (RAM) for advanced hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) following first-line sorafenib across age subgroups in two global phase III trials (REACH and REACH-2)

1278 Often a Favorable Prognostic Factor: Unusually Elevated Alpha-Fetoprotein (AFP) in a Case of Hepatitis B Virus (HBV) Associated Intrahepatic Cholangiocarcinoma (ICC)

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC), often an incidental finding is a rare tumor of the epithelial cells of the biliary ducts that originate in the liver and extrahepatic bile ducts. Serum alpha-fetoprotein (AFP), as a tumor marker of hepatocellular carcinoma (HCC), and carbohydrate antigen 19-9 (CA 19-9), as a tumor marker of ICC, have been widely used in clinical practice. Although, a subset of patient with ICC (20-25%) present with elevated AFP levels, usually &gt;100 ng/mL and very rarely &gt;1000 ng/mL, its role remains significant in prognosis of ICC. Herein, we discuss a case of Hepatitis B virus (HBV) associated ICC in a young individual with exceptionally high serum AFP levels. CASE DESCRIPTION/METHODS: A 45-year-old male with no apparent past medical history was seen for complaints of fatigue, nausea, anorexia, and associated 34-lb weight loss of 6-weeks duration. Initial labs revealed a chronic HBV infection and an obstructive pattern on liver function tests. Computerized tomography (CT) scan of the abdomen showed a large heterogeneous mass originating from porta hepatis and invading the left lobe of the liver with multiple liver metastases and metastatic lymphadenopathy of the porta hepatis. CT also revealed a mass in the gallbladder along with thrombosed portal vein and intrahepatic biliary dilation (Figures 1 and 2). Magnetic resonance cholangiopancreatography (MRCP) confirmed initial CT findings. Labs revealed an AFP level of 9,715 ng/mL and CA 19-9 level of 554 units/mL. Percutaneous transhepatic cholangiography (PTC) and tissue biopsy revealed liver parenchymal poorly differentiated adenocarcinoma. Attempted internalization of a biliary stent by interventional radiology (IR) was unsuccessful. Management options were discussed with the patient and family who opted for a palliative approach without chemotherapy. DISCUSSION: Intrahepatic cholangiocarcinoma (ICC) is a rare tumor of the epithelial cells of the biliary ducts originating in the liver and extrahepatic bile ducts. ICC tends to be aggressive due to lymph node involvement at diagnosis with intrahepatic, and peritoneal dissemination. Several factors have been implicated in the pathogenesis of ICC including hepatitis B and C viral infections. Role of AFP, often a marker of HCC, is a significant one in prognostication of ICC. Elevated AFP levels, especially with HBV-associated ICC carries a favorable prognosis. Unfortunately, in the case of our patient, due to the advanced nature of his condition, his prognosis remained poor.

Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway

Sestrin 3 (Sesn3) belongs to a small protein family that has been implicated in multiple biological processes including anti-oxidative stress, anti-aging, cell signaling, and metabolic homeostasis. However, the role of Sesn3 in hepatocellular carcinoma (HCC) remains unclear. Here we generated a Sesn3 knockout mouse model and induced HCC development by a combination of a single dose of diethylnitrosamine and chronic feeding of a choline deficient-high fat diet. After 6 months of the dietary treatment, Sesn3 knockout mice developed more severe HCC with higher levels of alpha-fetoprotein, arginase 1, and cytokeratin 19, but also higher metastatic rates than wild-type mice. Histological analysis revealed elevated extracellular matrix and cancer stem cell markers including Acta2, Cd44, and Cd133. Signaling analysis showed activated IL6-Stat3 and Akt pathways. Biochemical and microscopic analyses uncovered a novel inhibitory regulation of Gli2, a downstream transcription factor of the hedgehog signaling, by Sesn3. Two of the Gli2-regulated genes – Pdgfrb and Cd44 were upregulated in the Sesn3-deficient liver tissue. In conclusion, our data suggest that Sesn3 plays a critical tumor suppressor role in the liver partly through the inhibition of the hedgehog signaling.

Identification of hedgehog signaling as a potential oncogenic driver in an aggressive subclass of human hepatocellular carcinoma: A reanalysis of the TCGA cohort.

Hepatocellular carcinoma (HCC) is a heterogeneous disease and the second most common cause of cancer-related death worldwide. Marked developments in genomic technologies helped scientists to understand the heterogeneity of HCC and identified multiple HCC-related molecular subclasses. An integrative analysis of genomic datasets including 196 patients from The Cancer Genome Atlas (TCGA) group has recently reported a new HCC subclass, which contains three subgroups (iCluster1, iCluster2, and iCluster3). However, the transcriptional molecular characteristics underlying the iClusters have not been thoroughly investigated. Herein, we identified a more aggressive subset of HCC patients in the iCluster1, and re-clustered the TCGA samples into novel HCC subclasses referred to as aggressive (Ag), moderate-aggressive (M-Ag), and less-aggressive (L-Ag) subclasses. The Ag subclass had a greater predictive power than the TCGA iCluster1, and a higher level of alpha fetoprotein, microscopic vascular invasion, immune infiltration, isocitrate dehydrogenase 1/2 mutation status, and a worse survival than M-Ag and L-Ag subclasses. Global transcriptomic analysis showed that activation of hedgehog signaling in the Ag subclass may play key roles in tumor development of aggressive HCC. GLI1, a key transcriptional regulator of hedgehog signaling upregulated in the Ag subclass, was correlated with poor prognosis of HCC, and may be a potential prognostic biomarker and therapeutic target for Ag subclass HCC patients.