Serum Α-fetoprotein Level Research Articles

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

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

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

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

Evaluation of Serum α-Fetoprotein Levels During Different Infection Phases of CHB Patients.

Chronic hepatitis B patients carry a high risk of developing hepatocellular carcinoma (HCC). α-Fetoprotein (AFP) is one of the most commonly used and reliable biomarkers for HCC. However, the AFP level during different phases of CHB is not well understood. We aimed to identify the AFP levels during the different infection phases of CHB patient and explore which phase is at high risk of developing HCC. Three hundred and fifty-five CHB patients were divided into four groups: a. immune tolerant HBeAgpositive phase (IT); b. immune reactive HBeAg-positive phase (IR), c. inactive carrier state (IC), d. HBeAg-negative activation phase (ENA). The risk of development of HCC in different group is assessed by the serum AFP levels. An electrochemiluminescence assay was used to analyze serum AFP levels. Mean AFP levels were different in each phase of CHB (p < 0.001): IT (9.6 ng/mL), IR (33.7 ng/mL), IC (3.2 ng/mL), and ENA (71.6 ng/mL). The ENA phase had the highest AFP level and IC phase has the lowest. There was no correlation between serum AFP level and HBV viral load. A significant correlation between serum ALT levels and HBV viral load was observed (r = 0.272, p < 0.01). These findings suggest that high levels of AFP during HBeAg-negative activation phase (ENA) may be associated with a high risk of developing of HCC. Furthermore, higher burden of HBV viral load is associated with more severe liver damage.

Impact of tumor burden on prognostic prediction for patients with terminal stage hepatocellular carcinoma: A nomogram study.

BackgroundThe recently proposed nomogram of Barcelona Clinic Liver Cancer (BCLC) lacks predictive accuracy for patients with stage D hepatocellular carcinoma (HCC). Tumor burden is crucial in prognostic prediction but is not included in the criteria of stage D HCC. This study aims to develop a nomogram with tumor burden as the core element for BCLC stage D patients.MethodsA total of 386 patients were randomly grouped into derivation and validation sets (1:1 ratio). The multivariate Cox proportional hazards model was used to select factors with significant prognostic effect and generate the nomogram. Concordance indices and calibration plots were used to evaluate the performance of nomogram.ResultsOverall survival of study patients was significantly associated with tumor burden as well as hepatitis B, serum α-fetoprotein level, cirrhosis and performance status in multivariate Cox regression (all p<0.05). Beta-coefficients of these variables in derivation set were used to generate the nomogram. Each patient was assigned with a total nomogram point that predicted individualized 6-month and 1-year survival. The derivation and validation sets had a c-index of 0.759 (95% confidence interval [CI]: 0.552–0.923) and 0.741 (95% CI: 0.529–0.913), respectively. The calibration plots were close to the 45-degree line for 6-month and 1-year survival prediction for all quarters of patients in both derivation and validation sets.ConclusionTumor burden is significantly associated with the outcome for patients with stage D HCC. The tumor burden-incorporated nomogram may serve as a feasible and easy-to-use tool in predicting survival on an individual level.

Short‐term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct‐acting anti‐viral treatment

With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n=152) or without previous HCC (n=1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. During the follow-up period (median: 17months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P<0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0ng/mL and ≥ 9.0ng/mL groups (cut-off value) respectively (log-rank test: P<0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P=0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.

Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by hepatitis C virus genotype 1b infection: Real-world data.

In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan: daclatasvir and asunaprevir in chronic hepatitis C patients with severe fibrosis. Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib-4 index≧3.25 and were included in this study. We investigated antiviral effect and factors associated with sustained viral response 12 (SVR12), and the additional effects on serum α-fetoprotein and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P<0.05 was considered as significant levels. Antiviral effect was lower in patients with severe fibrosis at 8 and 12weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P=0.002 and P=0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P=0.008) was seen in patients with severe fibrosis; however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum α-fetoprotein significantly decreased, and serum albumin levels significantly increased as early as 4weeks after the start of treatment. Although the antiviral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective and well-tolerable treatment in these populations.

Fetal gut–like differentiation in gallbladder cancer

Adenocarcinomas showing fetal gut-like (enteroblastic) differentiation can arise in a variety of organs and are frequently accompanied by an elevated serum α-fetoprotein (AFP) level. However, no study has investigated fetal gut-like differentiation in gallbladder cancer in detail. Herein, we performed morphological and immunohistochemical analyses of fetal gut-like differentiation in 49 consecutive gallbladder cancer cases. The expression of Sal-like protein 4 (SALL4), an embryonic stem cell marker reported to represent fetal gut-like differentiation, as well as other oncofetal proteins, including glypican-3 (GPC3) and AFP, was assessed. We found 1 case of fetal gut-like adenocarcinoma that coexisted with conventional-type adenocarcinoma. The fetal gut-like adenocarcinoma component revealed diffuse immunoreactivity for SALL4 and partial positivity for AFP, whereas the conventional-type adenocarcinoma component was negative. We also found 2 poorly differentiated adenocarcinomas with hepatoid morphology and 1 clear cell carcinoma, none of which showed SALL4 positivity. In other conventional-type adenocarcinomas, focal immunoreactivity for SALL4 and GPC3 was occasionally observed. The overall positivity rates for SALL4 and GPC3 were 12.2% (6/49) and 16.3% (8/49), respectively. SALL4 and GPC3 expression was not associated with clinicopathological factors, including T category, lymphovascular invasion, and lymph node metastases. In conclusion, fetal gut-like adenocarcinoma was found in 2% of our gallbladder cancer series. We conclude that fetal gut-like adenocarcinoma is a distinct histological subtype of gallbladder cancer, characterized by SALL4 expression.

Validated preoperative computed tomography risk estimation for postoperative hepatocellular carcinoma recurrence.

AIMTo develop and validate a risk estimation of tumor recurrence following curative resection of operable hepatocellular carcinoma (HCC).METHODSData for 128 patients with operable HCC (according to Barcelona Clinic Liver Cancer imaging criteria) who underwent preoperative computed tomography (CT) evaluation at our hospital from May 1, 2013 through May 30, 2014 were included in this study. Follow-up data were obtained from hospital medical records. Follow-up data through May 30, 2016 were used to retrospectively analyze preoperative multiphasic CT findings, surgical histopathology results, and serum α-fetoprotein and thymidine kinase-1 levels. The χ2 test, independent t-test, and Mann-Whitney U test were used to analyze data. A P-value of < 0.05 was considered statistically significant.RESULTSDuring the follow-up period, 38 of 128 patients (29.7%) had a postoperative HCC recurrence. Microvascular invasion (MVI) was associated with HCC recurrence (χ2 = 13.253, P < 0.001). Despite postoperative antiviral therapy and chemotherapy, 22 of 44 patients with MVI experienced recurrence after surgical resection. The presence of MVI was 57.9% sensitive, 75.6% specific and 70.3% accurate in predicting postoperative recurrence. Of 84 tumors without MVI, univariate analysis confirmed that tumor margins, tumor margin grade, and tumor capsule detection on multiphasic CT were associated with HCC recurrence (P < 0.05). Univariate analyses showed no difference between groups with respect to hepatic capsular invasion, Ki-67 proliferation marker value, Edmondson-Steiner grade, largest tumor diameter, necrosis, arterial phase enhanced ratio, portovenous phase enhanced ratio, peritumoral enhancement, or serum α-fetoprotein level.CONCLUSIONNon-smooth tumor margins, incomplete tumor capsules and missing tumor capsules correlated with postoperative HCC recurrence. HCC recurrence following curative resection may be predicted using CT.

Vaginal Yolk Sac Tumors: Our Experiences and Results.

Vaginal yolk sac tumors (YSTs) are rare malignant germ cell tumors largely affecting children younger than 3 years. Because of their low incidence, there is no consensus regarding diagnosis and treatment. In this article, we describe the presentation, diagnosis, treatment, and outcomes of 16 patients with vaginal YSTs diagnosed and managed at our center. Diagnoses of YST of the vagina were confirmed by 2 experienced pathologists. All patients were treated with bleomycin, etoposide, and cisplatin (PEB) combination chemotherapy alone. Complete remission (CR) was defined by a normal serum α-fetoprotein (AFP) level, no tumor detected on computed tomography, and negative pathology results. Biochemical CR (bCR) was defined by a normal serum AFP level. Long-term follow-up was completed according to our regulations. The median age of patients at diagnosis was 10 months (range, 5-44 months), and all patients presented with abnormal vaginal bleeding and/or vaginal discharge. Serum αAFP is a sensitive tumor marker, and it was markedly elevated in all patients (median 4848 ng/mL; baseline at our hospital is <20 ng/mL). Thirteen patients completed a chemotherapy regimen consisting of PEB alone without surgery. Importantly, all patients achieved CR. Patients received additional cycles of consolidation chemotherapy after bCR and there are no cases of recurrence to date. We propose a contemporary treatment strategy in line with current practice. First, all suspected cases of vaginal YST should be diagnosed by histopathological examination and serum AFP levels. Second, nonsurgical treatment with PEB chemotherapy should be initiated until patients achieve bCR, followed by an additional 2 cycles of consolidation therapy to optimize results and reduce the risk of remission.

High expression of GP73 in primary hepatocellular carcinoma and its function in the assessment of transcatheter arterial chemoembolization.

Golgi glycoprotein 73 (GP73) is a type II Golgi transmembrane protein and a potential novel marker for the diagnosis of primary hepatocellular carcinoma (PHC). However, its reliability as a serum marker for the diagnosis of PHC following transcatheter arterial chemoembolization (TACE) remains unknown. The aim of the present study was to evaluate the diagnostic value of serum GP73 levels in patients with PHC, to determine its diagnostic accuracy in patients with PHC following TACE. Reverse transcription-quantitative polymerase chain reaction analysis was used to measure GP73 expression in PHC and adjacent para-carcinomatous liver tissue in 40 patients with PHC, and 15 normal liver samples from benign hepatic tumors. The associations between GP73 expression levels with clinicopathological characteristics of the patients were also analyzed. Serum GP73 levels were detected by ELISA in 68 patients with PHC following TACE and 29 healthy individuals. The levels of serum GP73 were tested 2 days prior to intervention, and 7 and 30 days following TACE. GP73 mRNA expression levels in PHC were significantly higher than in the corresponding para-carcinomatous liver and normal liver samples. High expression levels of GP73 mRNA were associated with tumor size, vascular invasion and tumor differentiation, suggesting augmented tumor invasion and metastasis. The expression levels of serum GP73 were markedly higher in the patients with PHC compared with healthy individuals. Serum GP73 levels in the 68 patients with PHC were higher compared with the 29 normal controls [152.5 (76.4-284.5) compared with 49.3 (12.6-26.7) µg/l], and the difference was statistically significant (P<0.01). High levels of serum GP73 were associated with tumor differentiation. The levels of Barcelona clinic liver cancer stage A, B and C were 92.12 (38.9-135.2), 122.9 (55.2-178.5), and 162.55 (110.8-232.9) µg/l, respectively (P<0.05). The serum GP73 levels 7 days following TACE [99.2 (66.7-150.8)] were significantly lower than prior to TACE, and the difference was statistically significant (P<0.05). In the group of 49 patients with serum α-fetoprotein (AFP) levels <400 µg/l, the serum GP73 levels were >132 µg/l. Serum GP73 levels may serve as a potential independent diagnostic marker for PHC, and the combined evaluation of serum GP73 and AFP may increase the diagnostic efficiency of PHC. Significant overexpression of GP73 mRNA was associated with aggressive PHC. However, further research is required to confirm the potential of GP73 as a diagnostic marker.

Artificial neural network models for early diagnosis of hepatocellular carcinoma using serum levels of α-fetoprotein, α-fetoprotein-L3, des-γ-carboxy prothrombin, and Golgi protein 73.

More than 70% of hepatocellular carcinoma (HCC) cases develop as a consequence of liver cirrhosis (LC). Here we have evaluated the diagnostic potential of four serum biomarkers, and developed models for HCC diagnosis and differentiation from LC patients. Serum levels of α-fetoprotein (AFP), AFP-L3, des-γ-carboxy prothrombin (DCP), and Golgi protein 73 (GP73) were analyzed in 114 advanced HCC patients, 81 early stage HCC patients, and 152 LC patients. Multilayer perceptron (MLP) and radial basis function (RBF) neural networks were used to construct the diagnostic models. Using all stages, HCC diagnostic models had a higher sensitivity (>70%) than the individual serum biomarkers, whereas only early stage HCC diagnostic models had a higher specificity (>80%). The early stage HCC diagnostic models could not be used as HCC screening tools due to their low sensitivity (about 40%). These results suggest that a combination of the two models might be used as a screening tool to distinguish early stage HCC patients from LC patients, thus improving prevention and treatment of HCC.

Prognostic role of noninvasive liver reserve markers in patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BackgroundVarious noninvasive liver reserve markers were proposed to indicate the severity of liver damage. However, the role and feasibility of these markers to predict the prognosis of patients with hepatocellular carcinoma (HCC) are unknown. We aimed to identify the prognostic role of the 8 currently used hepatic reserve markers in patients with HCC undergoing transarterial chemoembolization (TACE).MethodsBetween 2002 and 2013, a total of 881 patients with HCC undergoing TACE were prospectively identified and retrospectively analyzed. The baseline characteristics, tumor status and noninvasive markers were collected. Homogeneity and corrected Akaike information criteria (AICc) were compared between these markers. The Cox proportional hazards model was used to identify independent predictors of survival.ResultsSignificant differences in survival distribution were found for albumin-bilirubin (ALBI) grade, Child-Turcotte-Pugh (CTP) class, Lok index, fibrosis index based on 4 factors (FIB-4), Göteborg University cirrhosis index (GUCI), cirrhosis discriminant index (CDI) and model for end-stage liver disease (MELD) score (all p values <0.05). Among these markers, the ALBI grade showed the highest homogeneity and lowest AICc value, indicating a better prognostic performance. Cox multivariate analysis confirmed that ALBI grade 2, ascites, serum alkaline phosphatase and α-fetoprotein level, tumor diameter, vascular invasion and performance status were significant independent prognostic predictors. The distribution of the ALBI score well correlated with baseline CTP and MLED scores.ConclusionsOur data suggest that among the currently used liver reserve markers, ALBI grade may serve as an objective and feasible surrogate to predict the prognosis of HCC patients undergoing TACE.

Safety and Efficacy of Irreversible Electroporation for the Treatment of Hepatocellular Carcinoma Not Amenable to Thermal Ablation Techniques: A Retrospective Single-Center Case Series.

Purpose To assess the safety and efficacy of irreversible electroporation (IRE) in the treatment of patients with inoperable hepatocellular carcinoma (HCC) who are ineligible for thermal ablative techniques. Materials and Methods This retrospective study was approved by an ethics review board, and the requirement to obtain informed written consent was waived. From March 2012 to June 2015, 58 patients (median age, 65.4 years; range 41.6-90 years) with cirrhosis received IRE for the treatment of 75 HCC tumors. The median tumor diameter was 24 mm (range, 6-90 mm). IRE was selected because of tumor location (48 patients) or the patient's poor general condition (10 patients). Treatment response was assessed with magnetic resonance (MR) imaging 1 month after treatment and every 3 months thereafter. Overall local tumor progression-free survival (PFS) per nodule (including initial treatment failures) was assessed by using the Kaplan-Meier method. The marginal Cox proportional hazards model was used to assess the factors associated with overall local tumor PFS. Complications were recorded and graded according to the Clavien-Dindo classification. Results Of 75 tumors, 58 (77.3%), 67 (89.3%), and 69 (92%) were completely ablated after one, two, and three IRE procedures, respectively. After a median follow-up of 9 months (range, 3 days to 31 months), the 6- and 12-month overall local tumor PFS rates for the 75 treated nodules were 87% (95% confidence interval [CI]: 77%, 93%) and 70% (95% CI: 56%, 81%), respectively. A preablative serum α-fetoprotein level higher than 200 ng/mL (hazard ratio: 9.94 [95% CI: 2.82, 35.06], P = .0004) was the only factor linked with overall local tumor PFS. Complications occurred in 11 of the 58 patients (19%) and were classified as grade I in three patients, grade II in five patients, grade IV in two patients, and grade V in one patient. The three (5.2%) complications classified as grade III or higher were liver failures occurring in patients with Child-Pugh class B disease; one led to death. Conclusion IRE offers safe, complete ablation of HCC tumors in patients with contraindications to other commonly used ablative techniques. © RSNA, 2017 Online supplemental material is available for this article.

Changes in serum α-fetoprotein level predicts treatment response and survival in hepatocellular carcinoma patients and literature review.

Oxaliplatin-based chemotherapy is an alternative systemic treatment for patients with metastatic hepatocellular carcinoma (HCC) who were refractory or intolerant to sorafenib. To date, there have been no biomarkers reported to monitor the therapeutic efficacy and to predict the outcomes of HCC patients receiving oxaliplatin-based chemotherapy. Eighty-one HCC patients with elevated baseline α-fetoprotein (AFP) levels and extrahepatic spreading who received oxaliplatin-based chemotherapy between 2012 and 2014 were retrospectively enrolled in this study. Two AFP tests were performed, at baseline and 2-4 weeks after the initiation of chemotherapy. The change in AFP levels was calculated for survival analysis. In the AFP decline group (decreased compared to baseline), the median progression-free survival (PFS) and overall survival (OS) were 7.0 months and 12.3 months, respectively. In the AFP nondecline group, the median PFS and OS were 2.3 months and 3.0 months, respectively. The difference in OS between the two groups was significant (p<0.005). In the multivariate analysis for disease progression, the best response to chemotherapy and AFP decline were independent factors, with p values of 0.004 and 0.009, respectively. In the multivariate analysis for OS, the baseline Child-Pugh score, best response to chemotherapy, and AFP decline were independent prognostic factors, with p values of 0.01, 0.001, and 0.008, respectively. Additionally, the unit change in AFP level was predictive of PFS and OS with p values of 0.007 and 0.001, respectively. The change in AFP levels 2-4 weeks after initiating oxaliplatin-based chemotherapy is useful to predict treatment response and survival.

PLCE1 polymorphisms and expression combined with serum AFP level predicts survival of HBV-related hepatocellular carcinoma patients after hepatectomy.

Polymorphisms in the phospholipase C epsilon (PLCE) 1 gene play a crucial role in the development and progression of several types of cancer. The present study investigated the prognostic significance of PLCE1 gene polymorphisms and expression combined with serum α-fetoprotein (AFP) level in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Single nucleotide polymorphisms were genotyped by sequencing DNA isolated from surgically resected tumor samples of 421 HBV-related HCC patients, and expression profiles were generated based on the GSE14520 dataset. A joint-effects analysis of PLCE1 haplotypes (Ars2274223Crs3765524; Grs2274223Trs3765524) with AFP level stratified at 20 ng/ml showed a significant association with overall survival(OS) of HBV-related HCC patients(log-rank P=0.0003). Patients with AC and GT haplotypes with AFP level ≥ 20 ng/ml had an increased risk of death as compared to those with the AC haplotype and AFP level < 20 ng/ml (adjusted P=0.029 and 0.041, respectively). Patients with the GT haplotype and AFP level < 20 ng/ml also had an increased risk of death, although with a non-significant P value (adjusted P=0.092). Joint-effects analysis of PLCE1 mRNA expression with serum AFP level stratified at 300 ng/ml was significantly associated with HBV-related HCC recurrence and OS. Our results demonstrate that PLCE1 haplotypes (including rs2274223 and rs3765524) and expression combined with serum AFP level may predict postoperative outcome of HBV-related HCC patients.

Prognostic significance of combined albumin-bilirubin and tumor-node-metastasis staging system in patients who underwent hepatic resection for hepatocellular carcinoma.

In recent years, the establishment of new staging systems for hepatocellular carcinoma (HCC) has been reported worldwide. The system combining albumin-bilirubin (ALBI) with tumor-node-metastasis stage, developed by the Liver Cancer Study Group of Japan, was called the ALBI-T score. Patient data were retrospectively collected for 357 consecutive patients who had undergone hepatic resection for HCC with curative intent between January 2004 and December 2015. The overall survival and recurrence-free survival were compared by the Kaplan-Meier method, using different staging systems: the Japan integrated staging (JIS), modified JIS, and ALBI-T. Multivariate analysis identified five poor prognostic factors (higher age, poor differentiation, the presence of microvascular invasion, the presence of intrahepatic metastasis, and blood transfusion) that influenced overall survival, and four poor prognostic factors (the presence of intrahepatic metastasis, serum α-fetoprotein level, blood transfusion, and each staging system (JIS, modified JIS, and ALBI-T score)) that influenced recurrence-free survival. Patients for each these three staging system had a significantly worse prognosis regarding recurrence-free survival, but not with overall survival. The modified JIS score showed the lowest Akaike information criteria statistic value, indicating it had the best ability to predict overall survival compared with the other staging systems. This retrospective analysis showed that, in post-hepatectomy patients with HCC, the ALBI-T score is predictive of worse recurrence-free survival, even when adjustments are made for other known predictors. However, modified JIS is better than ALBI-T in predicting overall survival.

Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee.

The identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma. Patients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level <100 ng/mL were eligible. Patients received 2 cycles of V at a dose of 1.5 mg/m2 /day intravenously on days 1 and 8 and I at a dose of 50 mg/m2 /day intravenously on days 1 to 5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to Response Evaluation Criteria In Solid Tumors (RECIST) or a 90% (>1 log10 ) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone. A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively. The VI combination appears to have substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR hepatoblastoma remains to be determined. Cancer 2017;123:2360-2367. © 2017 American Cancer Society.

Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma.

Forkhead Box M1 (FoxM1) is a proliferation-specific transcription factor. In this study, we aimed to elucidate the clinicopathological and prognostic values of FoxM1 expression in human hepatocellular carcinoma (HCC) and correlate FoxM1 expression with various etiologies of liver diseases. We also investigated its therapeutic value in HCC. We investigated the expression of FoxM1 in tumor tissues and adjacent non-tumor tissues of 79 Japanese HCC patients by quantitative real-time reverse transcription-polymerase chain reaction analysis. Depletion by siRNA or specific inhibition by siomycin A were also used to investigate the effect of FoxM1 inhibition on stem-like features of human HCC cells. Quantitative real-time reverse transcription-polymerase chain reaction analysis showed that tumor tissues displayed an approximately 14-fold increase in FoxM1 expression compared with adjacent non-tumor tissues. Interestingly, the expression levels of FoxM1in tumor tissues did not depend on the etiology of liver disease. The expression of FoxM1 in tumor tissues was associated with serum α-fetoprotein level, maximum tumor size, histological grade, TNM staging, and portal involvement. Kaplan-Meier analysis indicated that the high FoxM1 expression (≥median) group had a poor prognosis compared with the low FoxM1 expression (<median) group. Using multivariate analysis, the expression of FoxM1 in tumor tissues was shown to be an independent prognostic factor that affected overall survival and disease-free survival. Furthermore, FoxM1 inhibition by siRNA or siomycin A reduced spheroid colony formation of HCC cells in vitro. Our data suggest that FoxM1 might be a prognostic biomarker and a promising therapeutic target for HCC.

Expression and Significances of G-Protein-Coupled Receptor Kinase 3 in Hepatocellular Carcinoma.

Objective: To investigate expression, clinical, pathologic and prognostic significances of G-protein-coupled receptor kinase 3 (GRK3) in hepatocellular carcinoma (HCC).Materials and Methods: Expression of GRK3 was detected using Western blotting and tissue microarray-based immunohistochemical staining in 8 and 395 patients (training set: n=164; validation set: n=231) with HCC underwent hepatectomy, respectively. GRK3 expression and its associations with cliniopathologic variables and tumor-specific survival were evaluated.Results: Expression of GRK3 was lower in tumor than in non-tumor tissues from 4 out of 8 patients. In the training set, the H-score of tumoral GRK3 staining was much lower than that in adjacent non-tumor liver tissues. In addition, GRK3 was associated with tumor-node-metastasis (TNM) stage and serum α-fetoprotein (AFP) level. Patients with high GRK3 tumors were found to carry significantly better tumor-specific survival, compared with those with low GRK3 ones. Furthermore, GRK3 was identified as one of independent predictors of favorable prognosis, adjusted for clinicopathologic parameters. Importantly, these results were further validated in the independent validation set. In all patients and 7 out of 10 subgroups, GRK3 was also revealed to be prognostic.Conclusions: GRK3 is down-regulated and predicts good prognosis in HCC. Therefore, GRK3 might function as a tumor suppressor gene in HCC.

Clinical correspondence to hepatocellular carcinoma-related lesions with atypical radiological pattern.

In patients at risk of hepatocarcinogenesis, tumors are frequently detected with atypical radiological patterns related to hepatocellular carcinoma (HCC) on imaging studies. Despite their high potential for malignancy, whether to resect such lesions immediately is controversial. Based on histological findings, patients with non-enhanced tumors or enhanced tumors without washout were divided into two groups: those with tumors that should be treated containing well, moderately, and poorly differentiated HCC (Group 1), and those that can be observed containing early HCC, hepatocellular adenoma, focal nodular hyperplasia, dysplastic nodules, and regenerative nodules (Group 2), and we elucidated the clinical correspondence to these tumors. Seventy-two patients had a single tumor with atypical radiological pattern: 39 patients had HCC (Group 1), while 33 patients had benign tumors or early HCC (Group 2). Among nine baseline variables, serum α-fetoprotein (AFP) level in Group 1 (median, 13.2 ng/mL; range, 0.6-5881.6) was significantly higher than that in Group 2 (5.6 ng/mL; 0.8-86.3, P = 0.003). The cut-off value of AFP was 36.4 ng/mL for prediction of Group 1, and the median overall and recurrence-free survival periods of 23 patients in the high-AFP (≥ 36.4 ng/mL) group (5.3 years; 95%CI, 2.1 - N.A. and 1.6 years; 0.5-2.2) were significantly shorter than those of the 49 patients in the low-AFP (< 36.4) group (7.5 years; 7.5 - N.A., P = 0.047, and 2.8 years; 1.9-3.3, P = 0.001). Taken together, HCC-related tumors with an atypical radiological pattern could be observed unless serum AFP level is elevated.