Is inconsistency of α-fetoprotein level a good prognosticator for hepatocellular carcinoma recurrence?

AIM: To identify the clinical outcomes of hepato-cellular carcinoma (HCC) patients with inconsistent α-fetoprotein (AFP) levels which were initially high and then low at recurrence.METHODS: We retrospectively included 178 patients who underwent liver resection with high preoperative AFP levels (≥ 200 ng/dL). Sixty-nine HCC patients had recurrence during follow-up and were grouped by their AFP levels at recurrence: group Ⅰ, AFP ≤ 20 ng/dL (n = 16); group Ⅱ, AFP 20-200 ng/dL (n = 24); and group Ⅲ, AFP ≥ 200 n...     

A combination of α-fetoprotein,midkine, thioredoxin and a metabolite for predicting hepatocellular carcinoma

Introduction and objectivesThe heterogenous nature of hepatocellular carcinoma (HCC) motivated this attempt at developing and validating a model based on combined biomarkers for improving early HCC detection.Patients/materials and methodsThis study examined 196 patients for an estimation study (104 patients with HCC, 52 with liver cirrhosis and 40 with liver fibrosis) and 122 patients for the validation study (80 patients with HCC, 42 with liver cirrhosis). All patients were positive for hepatitis C virus. Four markers were measured: Midkine and thioredoxin using ELISA, 1-methyladenosine and 1-methylguanosine using a gas chromatography–mass spectrometry (GC–MS). The results were compared with alpha-fetoprotein (AFP). The performance of the model was estimated in BCLC, CLIP and Okuda staging systems of HCC.ResultsThe model yielded high performance with an area under ROC (AUC) of 0.94 for predicting HCC in patients with liver cirrhosis, compared with AUC of 0.69 for AFP. This model had AUCs of 0.93, 0.94 and 0.94 in patients who had only one single nodule, absent macrovascular invasion and tumor size <2 cm, respectively, compared with AUCs of 0.71, 0.6 and 0.59 for AFP. The model produced AUCs of 0.91 for BCLC (0-A), 0.92 for CLIP (0–1) and 0.94 for Okuda (stage I) compared with AUCs of 0.56, 0.58 and 0.64 for AFP. No significant difference was found between AUC in the estimation and the validation groups.ConclusionThis model may enhance early-stage HCC detection and help to overcome insufficient sensitivity of AFP.     

Is choledocholithiasis a late complication of nonresectional therapies for hepatocellular carcinoma?

We present 3 patients who developed choledocholithiasis 10, 13, and 12 months after percutaneous ethanol injection and/or transcatheter arterial chemoembolization for hepatocellular carcinoma. Since none of these patients had stones in the gallbladder or in the bile ducts before treatment, bile duct stones might have resulted from local injury in the bile ducts by percutaneous ethanol injection and/or transcatheter arterial chemoembolization. Choledocholithiasis may be a late complication of nonresectional and local therapies for hepatocellular carcinoma tumors.     

Highlights for α-fetoprotein in determining prognosis and treatment monitoring for hepatocellular carcinoma

AIM:To explore the prognostic value in the monitoring of treatment efficacy of serial α-fetoprotein(AFP) in hepatocellular carcinoma(HCC) patients.METHODS:We searched MEDLINE,EMBASE and COCHRANE LIBRARY through April 21,2012,to find qualifying articles.Our overall search strategy included terms for HCC,AFP,treatment response,and prognosis.Literature was limited to English-language,human studies.Studies reporting cumulative survival rates were summa-rized qualitatively.For the prognostic meta-analysis,we undertook a series of meta-analyses that summarised the Cox proportional hazard ratios(HRs) by assuming a random effects model.With regards to the correlation of AFP change with radiologic response,the categorical dichotomous variables were assessed using Poisson relative risks(RRs),which were incorporated into the random effects model meta-analysis of accuracy prediction.Between-study heterogeneity was estimated by use of the I2 statistic.Publication bias was evaluated using the Begg funnel plot and Egger plot.Sensitivity analyses were conducted first by separating systemic treatment estimates from locoregional therapy estimates,evaluating different AFP response cut-off point effects,and exploring the impact of different study sizes.RESULTS:Of 142 titles identified in our original search,11 articles(12 clinical studies) met our criteria.Six studies investigated outcome in a total of 464 cases who underwent systemic treatment,and six studies investigated outcome in a total of 510 patients who received locoregional therapy.A random-effects model metaanalysis showed that AFP response was associated with an mortality HR of 0.55(95%CI,0.47-0.65) across HCC in overall survival(OS) and 0.50(95%CI,0.38-0.65) in progression-free survival.Restricting analysis to the six eligible analyses of systemic treatment,the pooled HRs were 0.64(95%CI,0.53-0.77) for OS.Limiting analysis to the six analyses of locoregional therapy,the pooled HRs for OS was 0.39(95%CI,0.29-0.53).We showed a larger pooled HR in the 50% definition studies(HR,0.67,95%CI,0.55-0.83) compared with that from the 20% definition studies(HR,0.41,95%CI,0.32-0.53).Restricting analysis to the four studies including over 100 patients individually,the pooled HR was 0.65(95%CI,0.54-0.79),with a pooled HR for OS of 0.35(95%CI,0.23-0.46) in the studies of less than 100 patients.As to radiological imaging,43.1%(155/360) of the patients in the AFP response group presented with a radiological overall response,while the response rate decreased to 11.5%(36/313) in the patients from theAFP nonresponse group.The RR of having no overall response was significantly lower in the AFP response group than the AFP nonresponse group(RR,0.67;95%CI,0.61-0.75).In terms of disease control rate,86.9%(287/330) in the AFP response group and 51.0%(153/300) in the AFP nonresponse group showed successful disease control,respectively.The RR of disease control failure,similarly,was significantly lower in the AFP response group(RR,0.37;95%CI,0.23-0.58).But these findings could be overestimates because of publication and reporting bias.CONCLUSION:HCC patients presenting with an AFP response are at decreased risk of mortality.In addition,patients with an AFP response also present with a higher overall response rate and disease control rate.     

Value of α-fetoprotein in association with clinicopathological features of hepatocellular carcinoma

AIM:To explore the relationship between α-fetoprotein(AFP) and various clinicopathological variables and different staging system of hepatocellular carcinoma(HCC) thoroughly.METHODS:A retrospective cohort study of consecutive patients diagnosed with HCC between January 2008 and December 2009 in West China Hospital was enrolled in our study.The association of serum AFP values with the HCC clinicopathological features was analysed by univariate and multivariate analysis,such as status of hepatitis B virus(HBV) infection,tumor size,tumor number,vascular invasion and degree of tumor differentiation.Also,patients were divided into four groups at the time of enrollment according to different cutoff values for serum value of AFP(≤ 20 μg/L,21-400 μg/L,401-800 μg/L,and ≥ 801 μg/L),to compare the positive rate of patient among four groups stratified by various clinicopathological variables.And the correlation of different kinds of tumor staging systems,such as TNM,Barcelona Clinic Liver Cancer(BCLC) staging classification and China staging,were compared with the serum concentration of AFP.RESULTS:A total of 2304 HCC patients were enrolled in this study totally;the mean serum level of AFP was 555.3 ± 546.6 μg/L.AFP levels were within the normal range(< 20 μg/L) in 27.4%(n = 631) of all the cases.81.4%(n = 1875) patients were infected with HBV,and those patients had much higher serum AFP level compared with non-HBV infection ones(573.9 ± 547.7 μg/L vs 398.4 ± 522.3 μg/L,P < 0.001).The AFP level in tumors ≥ 10 cm(808.4 ± 529.2 μg/L) was significantly higher(P < 0.001) than those with tumor size 5-10 cm(499.5 ± 536.4 μg/L) and with tumor size ≤ 5 cm(444.9 ± 514.2 μg/L).AFP levels increased significantly in patients with vascular invasion(694.1 ± 546.9 μg/L vs 502.1 ± 543.1 μg/L,P < 0.001).Patients with low tumor cell differentiation(559.2 ± 545.7 μg/L) had the significantly(P = 0.007) highest AFP level compared with high differentiation(207.3 ± 420.8 μg/L) and intermediate differe     

Is surgery for large hepatocellular carcinoma justified?

BACKGROUND/AIMS: Most hepatocellular carcinomas are still discovered at an advanced stage and are left untreated as large hepatocellular carcinomas are contraindications to liver transplantation and percutaneous ethanol injection and are usually considered as poor indications for liver resection. The aim of this study was to reassess the results of surgery in these patients. METHODS: Between 1984 and 1996, 256 patients underwent resection of biopsy-proven, non-fibrolamellar hepatocellular carcinoma. Of these, 121 had a tumour diameter of less than 5 cm (small hepatocellular carcinomas) and 94 a tumour diameter of more than 8 cm (large hepatocellular carcinomas). The short- and long-term outcome of patients with small and large hepatocellular carcinomas were compared. RESULTS: The in-hospital mortality rate following resection of small and large hepatocellular carcinomas was comparable (11.5 vs. 10.6%), even after stratifying for the presence and severity of an underlying liver disease. In patients with a chronic liver disease, large hepatocellular carcinomas were associated with a greater risk of death and recurrence during the first 2 operative years. In the long term, however (3-5 years), survival and disease-free survival following resection of small and large hepatocellular carcinomas were comparable (34 vs. 31% and 25 vs. 21% at 5 years). Similarly, treatment of and survival after the onset of recurrence were not influenced by the size of the initial tumour. CONCLUSIONS: Patients with large hepatocellular carcinomas should not be abandoned and should be considered for liver resection as this treatment may be associated with an in-hospital mortality rate and a long-term survival comparable to that observed after resection of small hepatocellular carcinomas.     

Performance of serum α-fetoprotein levels in the diagnosis of hepatocellular carcinoma in patients with a hepatic mass

Objectives

The role of serum α-fetoprotein (AFP) measurements in the diagnosis of hepatocellular carcinoma (HCC) remains controversial. Some guidelines have advised against the use of AFP in the diagnosis of HCC. This study was conducted to evaluate the performance of AFP in the diagnosis of HCC, and to identify the optimal cut-off value of serum AFP in the diagnosis of HCC in patients with a hepatic mass.

Methods

Patients who presented during the period from May 1997 to March 2003 with hepatic lesions, for whom paired data on serum AFP values at baseline and lesion histology were available, were reviewed. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis.

Results

Data for a total of 805 patients were evaluated. The mean AFP value was 26 900 ng/ml (range: 0–1 965 461 ng/ml). The histological diagnosis was HCC in 557 patients. The optimal AFP cut-off value was 10 ng/ml (for sensitivity of 82.6% and specificity of 70.4%). At a cut-off level of 200 ng/ml, sensitivity, specificity, and positive and negative predictive values were 47.7%, 97.1%, 97.5% and 44.4%, respectively. The diagnostic performance of AFP remains similar in patients with chronic hepatitis B virus infection, despite a lower negative predictive value. Common aetiologies of liver lesions associated with elevated AFP include cholangiocarcinoma and neuroendocrine tumours.

Conclusions

In Asian patients with suspicious liver lesions, the cut-off AFP level of 200 ng/ml is useful to achieve a diagnosis of HCC with high specificity and reasonable sensitivity. The measurement of serum AFP should not be excluded from guidelines for the diagnosis of HCC.     

Liver transplantation for hepatocellular carcinoma: is zero recurrence theoretically possible?

BACKGROUND: Hepatocellular carcinoma(HCC) recurrence remains a key issue after liver transplantation. This study aimed to determine a subgroup of HCC patients within the Milan criteria who could achieve a theoretical goal of zero recurrence rates after liver transplantation.METHODS: Between 1999 and 2009, 179 patients who received liver transplantation for HCC within the Milan criteria were retrospectively included. Analysis of the factors associated with HCC recurrence was performed to determine the subgroup of patients at the lowest risk of recurrence.RESULTS: Seventy-two percent of the patients received a bridging therapy, including 54 liver resections. Eleven(6.1%) patients recurred within a delay of 19±22 months and ultimately died. Factors associated with recurrence were serum alpha-fetoprotein level 400 ng/m L, satellite nodules, poor differentiation, microvascular invasion and cholangiocarcinoma component. Recurrence rates decreased from 6.1% to 3.1% in patients without any of these factors.CONCLUSIONS: Among HCC patients within the Milan criteria, selecting patients with factors based on histology would allow tending towards zero recurrence, and prior histological assessment by liver biopsy or resection may be essential to rule out poorly differentiated tumors, microvascular invasion,and cholangiocarcinoma component.     

Is the American Association for the Study of Liver Diseases recommendation for hepatocellular carcinoma screening a cul-de-sac?

The American Association for the Study of Liver Diseases just confirmed a grade Ⅰ recommendation for hepatocellular carcinoma (HCC) screening despite growing controversy. Why should HCC be an exception in the long list of other cancers where the feasibility and the efficacy of screening were investigated by randomized trials? Only 12.0% of United States patients are screened, a fact that precludes efficacy, and there are no relevant figures on the benefit-risk ratio. The ethics of belief is a treacherous reef. Screening is not just performing a test, but is a public health issue: a national program is needed to ensure minimal participation, quality controls and evaluation of the results to improve the process. There are also serious concerns regarding undisclosed potential conflicts of interest.     

Relationship between expression of α-fetoprotein messenger RNA and some clinical parameters of human hepatocellular carcinoma

AIM To certify the relationship between AFP mRNA and some pathological parameters of he-patocellular carcinoma (HCC).METHOD We detected the expression of AFP in mRNA level in tissue samples from 52 patients suffering from HCC by RT-PCR method.RESULTS The positive rate of AFP mRNA was 76.9% in the HCC tumor tissues, and 69.4% in the paratumor tissues from the HCC patients with severe cirrhosis. However, in HCC patients without cirrhosis, the positive rate reached 50% in tumor tissues, but no AFP mRNA expression was found in the related paratumor tissues.CONCLUSION The AFP protein was specially expressed by HCC cells and mutated hepatocytes. The AFP mRNA was positively related with cirrhosis, but no significant relationship was found between AFP mRNA and tumor size, capsule status and tumor metastasis.     

Prognostic roles of preoperative α-fetoprotein and des-γ-carboxy prothrombin in hepatocellular carcinoma patients

AIM:To clarify the utility of using des-γ-carboxy prothrombin(DCP)andα-fetoprotein(AFP)levels to predict the prognosis of hepatocellular carcinoma(HCC)in patients with hepatitis B virus(HBV)and the hepatitis C virus(HCV)infections.METHODS:A total of 205 patients with HCC(105patients with HBV infection 100 patients with HCV infection)who underwent primary hepatectomy between January 2004 and May 2012 were enrolled retrospectively.Preoperative AFP and DCP levels were used to create interactive dot diagrams to predict recurrence within 2 years after hepatectomy,and cutoff levels were calculated.Patients in the HBV and HCV groups were classified into three groups:a group with low AFP and DCP levels(LL group),a group in which one of the two parameters was high and the other was low(HL group),and a group with high AFP and DCP levels(HH group).Liver function parameters,the postoperative recurrence-free survival rate,and postoperative overall survival were compared between groups.The survival curves were compared by logrank test using the Kaplan-Meier method.Multivariate analysis using a Cox forward stepwise logistic regression model was conducted for a prognosis.RESULTS:The preoperative AFP cutoff levels for recurrence within 2 years after hepatectomy in the HBV and HCV groups were 529.8 ng/m L and 60 m AU/m L,respectively;for preoperative DCP levels,the cutoff levels were 21.0 ng/m L in the HBV group and 67 m AU/m L in the HCV group.The HBV group was significantly different from the other groups in terms of vascular invasion,major hepatectomy,volume of intraoperative blood loss,and surgical duration.Significant differences were found between the LL group,the HL group,and the HH group in terms of both mean disease-free survival time(MDFST)and mean overall survival time(MOST):64.81±7.47 vs 36.63±7.62 vs 18.98±6.17mo(P=0.001)and 85.30±6.55 vs 59.44±7.87 vs46.57±11.20 mo(P=0.018).In contrast,the HCV group exhibited a significant difference in tumor size,vascular invasion,volume of intraoperative blood loss,and surgical duration;however,no significant difference was observed between the three groups in liver function parameters except for albumin levels.In the LL group,the HL group,and the HH group,the MDFST was 50.09±5.90,31.01±7.21,and 14.81±3.08 mo(log-rank test,P0.001),respectively,and the MOST was 79.45±8.30,58.82±7.56,and 32.87±6.31 mo(log-rank test,P0.001),respectively.CONCLUSION:In the HBV group,the prognosis was poor when either AFP or DCP levels were high.In the HCV group,the prognosis was good when either or both levels were low;however,the prognosis was poor when both levels were high.High levels of both AFP and DCP were an independent risk factor associated with tumor recurrence in the HBV and HCV groups.The relationship between tumor marker levels and prognosis was characteristic to the type of viral hepatitis.     

Diagnostic accuracy of α-fetoprotein and des-γ-carboxy prothrombin in screening for hepatocellular carcinoma in liver transplant candidates

Aim: Although hepatocellular carcinoma (HCC)‐specific serum tumor markers, α‐fetoprotein (AFP) and des‐γ‐carboxy prothrombin (DCP), are used in the screening for HCC, their utility in pre‐transplantation evaluation is not well established. This study aimed to evaluate the accuracy of AFP and DCP measurement for the diagnosis of HCC in liver transplant candidates. Methods: A total of 315 consecutive adult patients (174 men and 141 women, mean age 52 years), who were to receive liver transplantation for end‐stage liver diseases, were enrolled. The pre‐transplant levels of AFP and DCP were compared with the histopathology of explanted liver. Results: Hepatocellular carcinoma was present in the explanted liver of 106 recipients (median number of nodules 2, mean diameter 2.5 cm). The area under receiver operating characteristic curve for the diagnosis of HCC was 0.83 (95% confidence interval, 0.78–0.88) for AFP and 0.47 (0.41–0.54) for DCP. With the cut‐off value of 100 mAU/mL, 20/106 (18.9%) patients with HCC and 54/194 (27.8%) patients without HCC were positive for DCP. DCP positivity was associated with vascular invasion, tumor differentiation and size among patients with HCC, which was associated with albumin level among patients without HCC. Vitamin K was administered prior to transplantation to 20 patients who were positive for DCP (two with and 18 without HCC), resulting in a decrease in DCP levels in 19 of them. Conclusions: Serum DCP levels may be raised in end‐stage liver disease patients without HCC, and cannot be used as a reliable marker for HCC among liver transplant candidates.