AFP-negative Patients Research Articles

Evaluation of seven different staging systems for alpha-fetoprotein expression in hepatocellular carcinoma after hepatectomy

Alpha-fetoprotein (AFP) represents the most important biomarker for hepatocellular carcinoma (HCC). The aim of this study was to identify the optimal staging system to predict the survival of AFP-negative and AFP-positive patients. This study analyzed the data of 431 AFP-negative HCC patients who had previously undergone surgery and 471 AFP-positive HCC candidates. Kaplan-Meier (K-M) survival estimates were plotted, and the P values were assessed using log-rank tests. The Akaike information criterion (AIC) was calculated using the results of a Cox's regression to compare the overall assessment of the seven different staging systems. The AFP-positive group displayed characteristics of poor tumor biological behavior (tumor multiplicity [P = 0.032], low grade differentiation [P = 0.000] and carcinoma cell embolus [P = 0.031]), poor liver function (Child-Pugh B classification [P = 0.003], abnormal prothrombin time activity [P = 0.037] and moderate/severe cirrhosis [P = 0.000]) and increased operative difficulties (transfusion; P = 0.001). TNM7th staging showed the lowest AIC value (1,279.528) for the AFP-negative group, while the Barcelona Clinic Liver Cancer (BCLC) staging system revealed the lowest AIC value (1,991.233) for the AFP-positive group. In conclusion, among the seven favorable staging systems, BCLC staging was superior for the AFP-positive group, while the TNM7th was a more appropriate staging model for the AFP-negative group.

Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma

To date, the useful markers of hepatocellular carcinoma (HCC) remains incompletely developed. Here, we show that annexin A2 complement alpha-fetoprotein (AFP), a widely used liver cancer marker, in the serologically surveillance and early detection of HCC. First, differentially expressed proteins in HCC were identified using a subcellular proteomic approach. Annexin A2 was then selected for further verification. It was found to be overexpressed in HCC tissues (60.7%, 136/224). Using a self-estabished sandwich enzyme-linked immunosorbent assay, we found that annexin A2 significantly increased in the sera of HCC (n = 175, median, 24.75ng/µl) compared with the healthy (n = 49, median, 16.69ng/µl), benign tumors (n = 19, median, 19.92ng/µl), hepatitis (n = 23, median, 6.48ng/µl) and cirrhosis (n = 51, median, 7.39ng/µl) controls and other malignant tumors (n = 87). Importantly, raised concentrations of annexin A2 were observed in 83.2% (79/95) of early stage (median, 24.32ng/µl) and 78.4% (58/74) of AFP-negative (median, 24.09ng/µl) patients. Annexin A2 alone had a better area under the receiver-operating characteristic curve (AUC = 0.79, 95% confidence interval: 0.73–0.85) in comparison with AFP (AUC = 0.73, 95% confidence interval: 0.66–0.80) in detecting of early stage HCC. Combining both markers notably improved the diagnostic efficiency of early HCC with an achieved sensitivity of 87.4%. Additionally, the expression characteristics of annexin A2 during hepatocarcinogenesis were detected in p21-HBx gene knockin transgenic mice model. The results showed that annexin A2 expression was substantially elevated in HCC-bearing mice, in accordance with the finding in human samples. In conclusion, annexin A2 may be an independent serological candidate for hepatitis B virus–related HCC, especially in the early stage cases with normal serum AFP.

Prognostic Significance of Alpha-fetoprotein Status in the Outcome of Hepatocellular Carcinoma after Treatment of Transarterial Chemoembolization

Alpha-fetoprotein (AFP) has been used as a diagnostic biomarker for hepatocellular carcinoma (HCC), but its prognostic significance is not well defined. This study was performed to classify the prognostic significance of AFP status in HCC patients after transarterial chemoembolization (TACE). Four hundred forty-one HCC patients from a prospective maintained database with pathologic confirmation including 139 with normal AFP levels and 302 with elevated AFP levels were retrospectively studied for prognostic significance of AFP in treatment response and survival after TACE. Univariate and multivariate analyses were used to identify the prognostic factors. There were significant differences in overall survival (OS) after TACE between AFP-negative and AFP-positive HCC patients when the AFP cutoff value was defined as 20 ng/ml (P < 0.0001). Among the AFP-positive patients, different AFP levels had no significantly prognostic effects on OS after TACE (P = 0.093). Multivariate analysis revealed that AFP status for AFP-negative or positive was an independent prognostic factor for HCC patients after TACE (P = 0.001), along with γ-glutamyltransferase (GGT) level (P = 0.004) and tumor diameter (P < 0.0001). In addition, there were significant differences in clinicopathologic features between AFP-positive and AFP-negative patients with regard to age, gender, alanine transferase level, GGT level, tumor diameter, and Barcelona Clinic Liver Cancer stage. Compared with AFP-positive HCC patients, patients with AFP-negative status have a better treatment response and prognosis after TACE.

Distinctions Between Clinicopathological Factors and Prognosis of Alpha-fetoprotein Negative and Positive Hepatocelluar Carcinoma Patients

Serum alpha-fetoprotein (AFP) is a significant marker for clinical diagnosis and prognosis evaluation in hepatocellular carcinoma (HCC) patients. However, some proportion of liver cancer patients are AFP-negative (AFP ≤20 ng/ml). In order to study the differences between clinicopathological factors and prognosis of alpha-fetoprotein negative and positive patients, a total of 114 cases (41 AFP-negative and 73 AFP-positive) were selected for our research. By systematically statistical analysis, the results demonstrated that compared with AFP-negative patients, AFP-positive examples were more likely to feature cirrhosis nodules, non-complete neoplasm capsules, and a poor Edmondson-steiner grade. Furthermore, AFP-negative patients demonstrated a favorable long-term prognosis. By univariate analysis and multivariate analysis with Cox's proportional hazards model, multiple tumors were found to be independent risk factors for worse survival of AFP negative patients; however, less tumor-free margins, multiple tumors and Edmondson-steiner grades III/IV, proved to be independent risk factors leading to a poor prognosis of AFP positive cases. Finally, we can infer that high levels of AFP signify a highly malignant tumor and unfavorable prognosis.

A Case-Control Study of Correlation between Preoperative Serum AFP and Recurrence of Hepatocellular Carcinoma after Curative Hepatectomy

The prognostic impact of serum alpha-fetoprotein (AFP) on patients with hepatocellular carcinoma (HCC) undergoing curative resection remains unclear. We conducted a case-control study to investigate it. A total of 196 HCC patients with negative preoperative AFP were admitted and treated by curative liver resection. During the same period, 196 patients with positive preoperative AFP were enrolled to match the TN M stages, Child-Pugh score and HBs-Ag status of the AFP-negative patients. Time to recurrence (TTR) and overall survival (OS) were prospectively studied. Through a median follow-up duration of 5.25 years, we found that the median TTR of patients with negative preoperative AFP was significantly longer than those with positive AFP (17.3 vs. 12.8 months, p=0.001). The median TTRs of AFP-negative and positive patients were 22.1 and 21.0 months (p=0.266), 145 and 7.4 months (p=0.005) and 3.7 and 2.9 months (p=0.197) in TNM stages I, II and IIIa, respectively. The median TTRs of TNM stage II patients with :≤20, 20-400, 400-1000 and >1000 ng/mL preoperative AFP concentration were 14.5, 13.7, 10.7 and 9.6 months (p=0.092), respectively. Preoperative AFP level is an independent prognostic factor affecting postoperative recurrence in HCC patients and correlated with the TTR of TNM II.

Evaluation of nitric oxide as a novel diagnostic marker for hepatocellular carcinoma

IntroductionLiver cancer is the sixth most common cancer worldwide. HCC is the most common primary tumor of the liver. The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for treatment of hepatobiliary cancers propose surveillance for the early detection of HCC by liver ultrasonography every 3–6months and evaluation of AFP. AFP >200ng/ml is considered diagnostic for HCC, although fewer than half of patients of HCC may generate levels that are high, so that the specificity of AFP is close to 100% but the sensitivity is 45%. Nitrite/Nitrate is a stable end product of nitric oxide increase in patients with HCC. AimIt was to evaluate nitric oxide as a novel diagnostic marker for hepatocellular carcinoma. MethodsEighty patients and 15 normal individuals enrolled in the study: Group (1) 15 normal individuals. Group (2) 30 patients with chronic liver disease without HCC. Group (3) 50 patients with HCC. History taking, clinical examination, (detection of liver masses, ascites, spleen size, and grade of encepathalopathy), and Child-pugh scoring. Laboratory investigation: (AlT, AST, bilirubin, albumin, prothrombin, GGT, platelet count, AFP, nitric oxide, HBs-Ag, and HCV-Ab). Abdominal ultrasonography and spiral CT. ResultsThe median level of nitric oxide was significantly higher in Group (3) (170μmol/l) than in Group (2) (56μmol/l) than in Group (1) (22μmol/l), with a sensitivity of (68%) and specificity of (90%) at a cutoff level of 110μmol/l and area under the curve of (0.810).While AFP, at a cutoff level of 200ng/ml had a sensitivity of (52%), specificity of (100%) and area under the curve (0.855). Indeed nitric oxide was high in 42% of AFP-negative HCC patients. ConclusionNitric oxide is a novel diagnostic marker for hepatocellular carcinoma, the simultaneous determination of serum nitric oxide and AFP gave significant improvement in detection of HCC patients compared to that of AFP alone.

Construction and Validation of a Novel Risk Index for Hepatocellular Carcinoma in Central European In-Patients

Introduction: Screening for hepatocellular carcinoma (HCC) is recommended for cirrhotic patients. Unfortunately, current screening tests have less than optimal sensitivity and specificity. Lack of resources precludes the use of more sensitive procedures such as magnetic resonance imaging in all patients. In this study, we develop and validate a screening index to discriminate patients with HCC from patients with cirrhosis but without HCC. Patients and methods: 409 consecutive in-patients with either liver cirrhosis or HCC were included in this study. Following univariate analysis to define differences between the patients with HCC and cirrhotic patients, stepwise logistic regression was performed to construct an index to differentiate between HCC patients and cirrhotics. This index was then validated using another unrelated cohort of 558 consecutive in-patients. 237 patients with HCC from the German national registry of HCC served as a further independent control group. Results: The screening index includes age, sex, ALT, the presence of ascites, portal vein thrombosis, markers of hepatitis B or C, and performance status. This index detected HCC patients (n=111) among the total validation cohort of 558 patients with a sensitivity of 96% (95%-confidence interval (CI): 91–99%). The negative predictive value was 98% (CI 94–99%) while the positive predictive value was 28%. Testing the score on yet another 237 HCC patients from the German National registry of HCC yielded a sensitivity of HCC detection of 94% (CI 89–96%). Similar results were obtained in the subgroup of AFP-negative patients. Conclusions: A simple score derived from seven readily available variables distinguishes between in-patients with HCC or cirrhosis. The index could be used to identify patients with a high likelihood for HCC who could then be further evaluated. Conversely, low risk individuals in whom costly procedures may not be indicated could be identified.

Plasma nitrite/nitrate concentrations as a tumor marker for hepatocellular carcinoma

Since plasma concentrations of nitrite/nitrate, the stable end-products of nitric oxide, increase in patients with hepatocellular carcinoma (HCC) correlatively to tumor volume, we examined the ability of plasma nitrite/nitrate to discriminate between those patients with HCC and those without and compared the diagnostic performance of the parameter with that of serum α-fetoprotein (AFP) concentrations. Plasma nitrite/nitrate and serum AFP concentrations were measured using a Griess reaction and a solid phase enzyme immunoassay, respectively. Eighty-nine patients with chronic liver diseases (CLD) with ( n=39) or without HCC ( n=50) and 50 healthy control subjects participated in the study. A receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value and accuracy. The areas under ROC curves for nitrite/nitrate and AFP were calculated to be 0.758 and 0.812, respectively, which were not significantly different. There was no correlation between the concentrations of plasma nitrite/nitrate and serum AFP. The sensitivity, the specificity, and diagnostic efficiency were 79.5, 72.0, and 75.3%, respectively, for nitrite/nitrate, and 74.4, 76.0, and 75.3%, respectively, for AFP. Based on a partial ROC curve, the clinical utility of plasma nitrite/nitrate as a tumor marker approximated that of serum AFP, but exceeded in AFP-negative patients. Indeed, nitrite/nitrate was positive in 70% of AFP-negative HCC patients. The simultaneous determinations of serum AFP and plasma nitrite/nitrate concentrations gave significant improvement in detection of HCC in CLD patients compared with that of serum AFP alone.

Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: Experience with cis-platinum-based chemoradiotherapy in 76 patients

Internationally, hepatoma is a common cause of cancer death. Although the only curative therapy is surgical, most tumors are unresectable and cause death. The value of nonsurgical, antineoplastic therapy for such tumors is controversial. This study was undertaken to extend and confirm promising, but preliminary, treatment observations in the unresectable context. From 1988 to 1993, 76 patients with unresectable, biopsy proven, hepatoma underwent uniform pretreatment assessment followed by induction therapy with external beam radiotherapy (21 Gy/7 fractions/10 days) and intravenous Cisplatinum, 50 mg/m2. One month later patients began monthly intrahepatic artery Cisplatinum, 50 mg/m2. Clinical course and treatment outcomes were correlated with previously published prognostic factors and groupings (Nomura et al., Okuda et al., Stillwagon, et al.). The toxicity of this therapy was modest and nonlimiting. Twenty-four patients (32%) progressed during induction and prior to receiving two cycles of intrahepatic artery Cisplatinum without evidence of benefit. Patients showing this early progression were more likely to be Stillwagon unfavorable than favorable (p = 0.013), Okuda Stage II than Stage I (p = 0.024), and slightly but not statistically more likely to be alpha-fetoprotein positive than alpha-fetoprotein negative (p = 0.098). The overall objective response rate was 43% (38% among AFP positive and 62% among AFP negative patients) (p = 0.15). Although 21 patients had evidence of extra hepatic metastases, survival for these patients did not differ from patients without metastases (p = 0.09) and patients with extra hepatic metastases were just as likely to show intrahepatic response (p = 0.84). The chemoradiotherapy program utilized produced objective response and minimal toxicity. One-third of patients progressed rapidly in spite of treatment. Among the remaining patients, response occurred frequently. This treatment appears to represent an important therapeutic option for many, but not all, patients with unresectable hepatoma.

4 Tumour markers in diagnosis and management

The 20-year period since the discovery of AFP by Abelev has seen the introduction of a wide range of new tumour markers and it is now clear that PLC is biologically heterogeneous. Hepatoblastomas, fibrolamellar carcinomas, hepatocellular carcinomas and cholangiocarcinomas may secrete a variety of distinctive markers which are predominantly glycoproteins, and may resemble those found in placenta or fetal liver. Diagnostically, AFP remains the best marker for HCC, both in sensitivity and specificity; it is known to consist of isoforms. In patients with elevated serum AFP and filling defects on liver scan, Con A reactive AFP may differentiate PLC from hepatic metastases, whilst fucosylated AFP may distinguish PLC from benign disorders when AFP is non-diagnostically elevated. With this recognition of tumour heterogeneity the value of a multiplemarker approach has become apparent. The measurement of vitamin B 12 binding protein and neurotensin should lead to the detection of most patients with the fibrolamellar variant of HCC and many of these should be resectable. In patients with normal serum AFP levels, HCC-associated GGTP is of major value whilst in low-incidence areas for HCC, patients should also be screened for H-ALP; using a multiple marker approach in high-risk groups, 90% of clinically diagnosed hepatocellular carcinomas are serologically positive. The Chinese and Alaskan studies, in which small, potentially resectable tumours were detected, suggest that it is now possible to achieve 5-year survival figures of up to 60% in HCC patients detected by screening. The value of such a strategy in low-incidence countries is currently under study. In patient monitoring, as in diagnosis, AFP remains the outstanding marker. In AFP-negative patients, other markers including vitamin B 12binding protein, neurotensin, HCC-specific isoenzymes, des-γ-carboxy-prothrombin and α-fucosidase, are of undoubted diagnostic value, but their value as indicants of disease progression remains to be established. In monitoring the response of hepatic metastases, CEA remains the least unsatisfactory marker but should always be used in conjunction with serial ultrasound scans. Tumour markers now play an important role in the diagnosis and monitoring of PLC but a role is also emerging in tumour imaging and drug targeting. The next 20 years should see the introduction of tumour markers of high sensitivity and specificity which make a fundamental contribution not only to detection and monitoring, but also to the effective treatment of liver cancer.

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One hundred and fourteen Chinese patients with hepatocellular carcinomas (HCC) were studied for alpha-fetoprotein (AFP), hepatitis B surface antigen (HBsAg), anti-HBsAg, and HLA markers. Younger patients with HCC (less than 60 yr old) were more significantly associated with elevated serum AFP (P less than 0.0001) and serum HBsAg (P less than 0.0001) than were older (greater than or equal to 60 yr old) patients. A strong correlation existed between serum AFP and HBsAg among the patients (P less than 0.0001). Of 27 AFP-negative patients, 15 (55.6%) had HLA-B15 compared to 53 of 238 (22.3%) healthy controls (corrected P less than 0.003, relative risk = 4.4). The frequency of HLA-B15 was even higher in the AFP-negative plus HBsAg-negative subgroup (61%). AFP-negative patients also had a significant lack of blood group A.