Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation

OBJECTIVE: Recognition of hepatocellular carcinoma (HCC) is important in the management of patients awaiting liver transplantation. HCCs >5 cm in diameter are at high risk to recur after transplant. The goal of this study was to assess the sensitivity of the diagnostic tests employed in a pretransplant screening program. METHODS: The study is a retrospective analysis of charts of 106 consecutive adults transplanted over a 1-yr period. All patients had ultrasonography (US), computerized tomography (CT), and serum alpha fetoprotein (AFP) testing within 6 months of transplantation. Radiographic reports were subdivided into low-risk and high-risk groups, based upon level of suspicion for HCC. The results were compared to explant pathology. RESULTS: Pathological analysis of 106 explants revealed HCC in 19 patients. High-risk US exams had a positive predictive value (PPV) of 0.69 and a negative predictive value (NPV) of 0.91 in the diagnosis of HCC. High-risk CT exams had a PPV of 0.67 and an NPV of 0.90. When patients had either a high-risk US or a high-risk CT, there was a PPV of 0.59 and an NPV of 0.83. Of the 19 patients with HCC, three had high-risk US and low-risk CT; two had high-risk CT and low-risk US. Four patients, all with HCC <4 cm, had low-risk US, CT, and serum AFP. CONCLUSIONS: US, CT, and serum AFP, as single tests, are insensitive for detection of HCC in the cirrhotic liver. However, they are highly specific. Sensitivity and specificity for US are comparable to those for CT. Given its lower cost, US is preferable to CT for routine screening of HCC in patients with end-stage liver disease undergoing liver transplantation.     

Diagnostic sensitivity of hepatocellular carcinoma imaging and its application to non-cirrhotic patients

Background and Aims: The American Association for the Study of Liver Disease issued guidelines that proposed that hepatocellular carcinoma (HCC) can be diagnosed if a mass is larger than 2 cm in a cirrhotic liver and shows typical features of HCC at triphasic liver computed tomography (CT) or dynamic magnetic resonance imaging (MRI). In non‐cirrhotic livers, the criteria were not applicable. The aim of the present study was to retrospectively analyze the sensitivity of imaging by samples of definite HCC postoperatively and test their application to diagnose HCC in non‐cirrhotic livers. Methods: From January 2006 to November 2008, a total of 343 pathologically‐diagnosed HCC patients via surgical resection were reviewed. Among the 343 patients, 204 patients had undergone liver CT examination, and 80 patients underwent MRI examination; serum α‐fetoprotein had been checked for all 343 patients prior to operation. The diagnostic sensitivity of HCC by imaging was evaluated and compared in patients with/without cirrhosis by ultrasound and histology. Results: The diagnostic sensitivity of HCC by single imaging was approximately 65–80% (liver CT or MRI). A higher sensitivity of HCC diagnosis was found in patients with ultrasound‐diagnosed cirrhosis than non‐cirrhosis, but the difference in sensitivity disappeared after histologically‐cirrhotic validation. The results indicated that regardless of the presence or absence of cirrhosis (histology), a typical vascular pattern could diagnose HCC with equally high sensitivity. Conclusions: We provide evidence that the sensitivity of HCC diagnosis by imaging is not influenced by the cirrhotic background. Further study is needed to validate the specificity and accuracy.     

Reappraisal of the diagnostic value of alpha‐fetoprotein for surveillance of HBV‐related hepatocellular carcinoma in the era of antiviral therapy

This study was designed to explore if antiviral treatment influences the performance of serum alpha‐fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high‐risk chronic HBV‐infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non‐antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non‐antiviral patients (P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups (P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut‐off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high‐risk population of CHB and LC patients.     

Elevation of endoglin (CD105) concentrations in serum of patients with liver cirrhosis and carcinoma

OBJECTIVE: Liver cirrhosis is considered as a premalignant state, as about 80% of hepatocellular carcinoma (HCC) is associated with liver cirrhosis. Although alpha-fetoprotein (AFP) has a high negative predictive value, its sensitivity for detecting HCC is poor. The aim of this study was to evaluate circulating endoglin (CD105) in the serum of patients with liver cirrhosis and at high risk for HCC. METHODS: CD105 and AFP serum concentrations were measured in 70 healthy and 94 nonliver-diseased controls and 130 patients with chronic liver diseases and HCC, respectively. RESULTS: Fifty-seven liver cirrhotic patients, 45 patients with liver cirrhosis plus HCC, 19 liver fibrosis patients and nine patients with HCC only were studied. Serum CD105 is significantly elevated in liver cirrhotic patients compared with healthy (P<0.0001) and nonliver-diseased controls (P<0.0001). Patients with liver cirrhosis and HCC show the highest CD105 concentrations being significantly elevated in comparison to liver cirrhosis (P=0.0006) and HCC only (P=0.0134). A stronger positive correlation exists between CD105 and AFP in the patient group suffering from liver cirrhosis and HCC (r=0.479, P=0.0015) than the obtained correlation between both markers in the group of patients diagnosed with liver cirrhosis alone (r=0.358, P=0.0073). The logistic regression model identified CD105 as an independent marker (P=0.0077, odds ratio 1.3). CONCLUSION: CD105 has the potential to be a novel complementary biomarker that has some important bearing on the risk assessment for development of HCC in cirrhotic patients.     

Fluorine‐18 FDG imaging in hepatocellular carcinoma using positron coincidence detection and single photon emission computed tomography

Abstract: Background/aims: We prospectively evaluated whether fluorine‐18 deoxyglucose (FDG) positron coincidence detection (PCD) or FDG single‐photon emission computed tomography (SPECT) provides additional benefits to our conventional preoperative evaluation of lesion detection in patients suspected to have hepatocellular carcinoma (HCC). Methods: Thirteen consecutive patients with a suspected HCC underwent conventional preoperative evaluation with ultrasonography (US), triple‐phase helical computed tomography (CT), superparamagnetic iron oxides (SPIO) enhanced magnetic resonance imaging (MRI) and serum α‐fetoprotein (AFP) level. All 13 patients had an FDG‐PCD and SPECT. These results were evaluated to assess the value of FDG‐PCD and SPECT in addition to US, SPIO‐enhanced MRI and triple‐phase helical CT. Results: Ten of the 13 (77%) patients had at least one histologically confirmed HCC without extrahepatic abdominal spread. The tumors ranged in size from 1 to 8 cm and the serum AFP ranged from 3 to 30 000 µg/l. Of these 10 patients, two patients had an increased tumor F‐FDG uptake (sensitivity of 20%); one patient with an AFP of 5 µg/l and a tumor size of maximum 4.5 cm and one patient with an AFP of 249 µg/l and a tumor size of maximum 2 cm. In three patients with a benign liver mass, FDG imaging with either PCD or SPECT was negative. There was no false positive finding. Conclusions: We found poor sensitivity of FDG‐PCD and FDG‐SPECT for the detection of HCC. There were no clear relations between AFP or tumor size and FDG uptake. Therefore, we conclude that FDG imaging with PCD or SPECT has no value in the preoperative work‐up for HCC in patients with cirrhosis.     

Diagnostic accuracy of des‐gamma‐carboxy prothrombin for hepatocellular carcinoma in a French cohort using the Lumipulse® G600 analyzer

The increasing incidence of hepatocellular carcinoma (HCC) in Western countries requests reliable tumour markers for preclinical diagnosis. We evaluated the diagnostic accuracy of des‐gamma‐carboxy prothrombin (DCP), in comparison with alpha‐fetoprotein (AFP) in a French cohort using a new analyser. One hundred and sixty‐two patients with virus‐related cirrhosis (46 HCC patients and 116 controls) were recruited in this retrospective proof‐of‐concept study. DCP was measured on new Lumipulse^® G600 analyzer and AFP on usual Cobas e602 analyzer in serum samples that were collected at the time of HCC diagnosis for HCC patients or during follow‐up for controls. DCP and AFP levels were higher in HCC patients. The area under receiver operating characteristic curve was larger for DCP than for AFP (0.89 vs 0.77, P=.03). At the cut‐off value of 128 mAU/mL, sensitivity and specificity for DCP were 74% and 92%. At the cut‐off value of 20 μg/L, sensitivity and specificity for AFP were 63% and 82%. NRI_>0 for the association of “AFP+DCP” were 101%, P<.0001, and 23%, P=.03, compared to “AFP” or “DCP” alone, respectively. We conclude that DCP outperformed AFP for the detection of HCC.     

Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma

Background and Aim: Hepatocellular carcinoma (HCC) is a common complication in patients with chronic viral hepatitis. Detection of HCC at an early stage is critical for a favorable clinical outcome. The study aim was to: (i) compare the levels of des‐γ‐carboxyprothrombin (DCP), α‐fetoprotein (AFP) and AFP‐L3 in HCC patients and in chronic viral hepatitis patients without HCC; (ii) define the level of each tumor marker with the best sensitivity and specificity for HCC diagnosis; and (iii) to correlate the levels of these markers with respect to size and tumor burden. Methods: Two hundred and forty patients with either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection were studied. These included 144 with HCC, 47 with chronic hepatitis (fibrosis stage I–III on liver biopsy) and 49 with cirrhosis. Results: Levels of DCP, AFP and AFP L‐3 were significantly higher in patients with HCC than in those without HCC (P ≤ 0.0001). Receiver–operating curves (ROC) indicated that the cut‐off value with the best sensitivity and specificity for each test was ≥84 mAU/mL for DCP, ≥25 ng/mL for AFP and ≥10% for AFP‐L3. The sensitivity, specificity and positive predictive value (PPV) for DCP was 87%, 85% and 86.8%, for AFP 69%, 87% and 69.8%, and for AFP‐L3 56%, 90% and 56.1%, respectively. DCP levels were below the ROC cut‐off in all patients without HCC. In patients with single lesions, there was a direct correlation of DCP to tumor size. High levels of AFP correlated with diffuse type of HCC. All three markers were significantly elevated in the presence of metastatic HCC. No advantage was observed by combining two or three markers for HCC diagnosis. Conclusion: DCP had the highest sensitivity and PPV for HCC diagnosis, had a direct correlation with tumor size, and was not elevated in any patients without HCC. DCP should be used as the main serum test for HCC detection.     

Cirrhotic Patients With or Without Hepatocellular Carcinoma Harbour AFP-Specific T-Lymphocytes That Can Be Activated in vitro by Human Alpha-Fetoprotein

Background: Alpha-fetoprotein (AFP) is re-expressed in 60%-70% of hepatocellular carcinomas (HCC) and may therefore be a potential target for a prophylactic or therapeutic tumour-specific vaccination. A prerequisite for this approach is the possibility to induce AFP-specific T-lymphocytes in patients with HCC and/or cirrhosis. Methods: Peripheral blood was examined for the presence of AFP-specific T-lymphocytes using a FACS-based interferon- &#110 secretion assay. Results: In a group of healthy volunteers, the presence of AFP-specific CD4- and CD8-lymphocytes was demonstrated. Screening of blood of 14 cirrhotic patients without HCC and 23 cirrhotic patients with HCC showed that patients with liver diseases that represent targets for vaccination also harbour CD4-positive as well as CD8-positive AFP-specific T-lymphocytes. AFP reactivity in patients' lymphocytes was not significantly influenced by soluble serum AFP. The median stimulation factors for CD4-positive T-lymphocytes were significantly higher ( P = 0.0365) in cirrhotic patients without HCC (median 2.08, range 0.50-4.40) compared to cirrhotic patients with HCC (median 1.15, range 0.24-8.50). Conclusion: AFP-specific T-lymphocytes that may be instrumental in HCC vaccination strategies are present in humans. This study suggests that immunopreventive vaccination of cirrhotic patients rather than immunotherapeutic vaccination of HCC patients may be preferable.     

Thyroxine-binding globulin in elderly patients with hepatocellular carcinoma

In order to evaluate the possible relevance of the increased serum levels of thyroxine binding globulin (TBG) in elderly patients with cirrhosis and hepatocellular carcinoma (HCC), TBG and alpha-fetoprotein (AFP) levels were measured in 3 groups: (i) 14 healthy subjects (mean age: 74 +/- 2 years); (ii) 15 patients with cirrhosis of the liver (mean age: 70 +/- 1 years); (iii) 17 patients with cirrhosis and HCC (mean age: 71 +/- 1 years). Both TBG and AFP levels were significantly higher (p < 0.01) in the patients with HCC, as compared to the healthy subjects or to the cirrhotic ones without HCC. The increased plasma TBG levels in cirrhotic patients with HCC is probably due to a derepression of the TBG gene in hepatocytes undergoing neoplastic transformation. The results suggest that TBG together with AFP may be of diagnostic value for the presence of HCC in aging patients with liver cirrhosis.     

Serum midkine is a more sensitive predictor for hepatocellular carcinoma than Dickkopf-1 and alpha-L-fucosidase in cirrhotic HCV patients

Alpha fetoprotein (AFP) level is the gold standard diagnostic tool for detection and monitoring hepatocellular carcinoma (HCC) but with low sensitivity. Thus, the identification of alternative or combined serum markers of HCC is highly needed. Therefore, the aim of this work was to verify the value of serum midkine (MDK), Dickkopf-related protein 1 (DKK1), and alpha-L-fucosidase (AFU) in detection of HCC.We recruited 244 subjects to the present study; 89 with liver cirrhosis, 86 cirrhotic hepatitis C virus (HCV) induced HCC, and 69 apparently healthy volunteers as controls. Serum AFP, MDK, DKK1, and AFU were measured by ELISA.Patients with HCC showed significantly higher serum MDK, DKK1, and AFU levels compared with those patients with liver cirrhosis and healthy controls (X² = 179.56, 153.94, and 90.07 respectively) (P < .001 in all). In HCC cases, neither of MDK, DKK1, or AFU was correlated with tumor number. On the other hand, only serum DKK1 was significantly higher in lesions >5 cm, those with portal vein thrombosis and advanced HCC stage. Receiver operator characteristic (ROC) curve analysis showed that serum MDK levels discriminated between cirrhosis and HCC at a sensitivity of 100%, a specificity of 90% at cut-off value of >5.1 ng/mL.Although our results showed that serum MDK, DKK-1, and AFU are increased in HCC cases only MDK may be considered as the most promising serological marker for the prediction of the development of HCC in cirrhotic HCV patients.     

Angiopoietin-2 serum levels are elevated in patients with liver cirrhosis and hepatocellular carcinoma

OBJECTIVES: Liver cirrhosis is characterized by remodeling leading to nodules that are difficult to discern from hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) serum levels are used for the screening for HCC, with limited success. We evaluated angiopoietin-2 as a serum marker in patients with cirrhosis and with HCC. METHODS: In a retrospective study, we measured angiopoietin-2 serum levels in 131 patients with HCC, 180 patients with cirrhosis, and 40 healthy controls. We also determined AFP serum levels in patients with HCC and compared the test characteristics of both serum markers. The expression patterns of angiopoietin-2 were determined by in situ hybridization in healthy and cirrhotic livers as well as in HCC. RESULTS: Angiopoietin-2 serum levels were elevated in patients with liver cirrhosis (P < 0.0001) compared with healthy controls. Levels were further elevated in patients with HCC compared with healthy controls (P < 0.0001) and cirrhotic patients (P < 0.0001). The combination with AFP measurements led to improved discrimination between HCC and cirrhosis. Angiopoietin-2 message was present in tumor cells of HCCs but was absent from hepatocytes of cirrhotic and healthy livers. In cirrhosis, message was detected within the strands of fibrous tissue. CONCLUSIONS: Serum angiopoietin-2 levels are elevated in patients with cirrhosis, implicating a possible role of the angiopoietin-Tie-2 system for neoangiogenesis in cirrhosis. Serum levels are further elevated in patients with HCC, suggesting the potential use of angiopoietin-2 as a marker for the detection of cirrhosis and HCC.     

Screening for hepatocellular carcinoma in patients with advanced cirrhosis

OBJECTIVE: Most available data on screening for hepatocellular carcinoma (HCC) in patients with cirrhosis originate from Asia and Europe. These data may not be applicable to patients from the United States because of geographic variation in the underlying etiology and other factors. Our aim was to assess the risk of HCC in U.S. patients with cirrhosis undergoing standardized screening. METHODS: All cirrhotic patients evaluated for liver transplantation at our institution from January 1, 1994-December 31, 1997 were included in this study. The screening strategy included initial screening, which was offered to all patients and consisted of alpha-fetoprotein (AFP), abdominal ultrasound, and computed tomography (CT) scan, and extended screening, which was performed only on transplant-eligible patients and consisted of semiannual AFP and ultrasound. RESULTS: During the study period, 285 patients with cirrhosis were evaluated for transplantation and underwent initial screening. Of these, 166 were eligible for transplantation and underwent extended screening during a median follow-up of 15 months (range 6-42 months). Twenty-seven HCC were found, 22 during initial screening and five during extended screening. The cancer-free proportions of the cohort who underwent extended screening at 1, 2, and 3.5 yr were 98.6% +/- 1.4%, 96.4 +/- 1.8%, and 77.1% +/- 1.7%, respectively (mean +/- SE). Hepatitis C, either alone or in part, was the etiology in 63% of patients with HCC. The sensitivity of CT scan (88%) was significantly higher than AFP >20 ng/ml (62%) and ultrasound (59%) for detecting HCC (p < 0.001). CONCLUSIONS: In patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening (7%). Hepatitis C was the most common etiology for cirrhosis in study. In U.S. patients with established cirrhosis, CT scan exhibited higher sensitivity for detecting HCC than ultrasound or AFP.     

Hepatocarcinoma in cirrhosis

It has been reported that hepatoma (HCC) cells produce abnormal proteins such as erytropietin, fibrinogen, prothrombin, and recently, antithrombin III (AT III). In a preliminary report, we reported increased AT III levels in patients bearing HCC independent of their clinical liver status. The present study was performed to assess antithrombin III levels and other serological data present in patients with cirrhosis and in patients with cirrhosis and clinical findings of neoplastic disease. In 70 well-matched patients (47 with cirrhosis and 23 with cirrhosis and proven HCC) serum total cholesterol, albumin, prothrombin, alkaline phosphatase, AFP, aminotransferases, and AT III were determined. Together with AFP and alkaline phosphatase, patients with HCC had higher values of AT III (88±7%) and total cholesterol (184±17 mg/100 ml), as compared with cirrhotic patients (AT III 56±3.6%; total cholesterol 113±5 mg/100 ml) (P<0.001). No difference was observed between these two groups for albumin, prothrombin, and aminotransferases. In HCC patients, AT III levels were related to the total cholesterol level (R ²=0.317), whereas in the cirrhotic patients it correlated with the prothrombin level (R ²=0.274). These data suggest that in HCC patients a greater rate of synthesis of AT III occurs, whereas in cirrhotic patients lower levels of AT III occur due to impaired synthesis or increased catabolism of the protein. The serial determination of AT III in cirrhotic patients as a means of detecting neoplastic transformation is suggested.Presented at the Proceeding of the International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Differential vascular endothelial growth factor A protein expression between small hepatocellular carcinoma and cirrhosis correlates with serum vascular endothelial growth factor A and α‐fetoprotein

Background/Aims: Drugs with antivascular endothelial growth factor A (anti‐VEGF‐A) action are under clinical evaluation with encouraging results in advanced hepatocellular carcinoma (HCC). The relative VEGF‐A protein expression in non‐advanced HCC and in the cirrhotic non‐tumoral tissue in the same patient, a variable that could be important for treatment efficacy, has been investigated with conflicting results, only using the cirrhotic tissue surrounding the neoplasm (CS). Methods: We measured, for the first time, VEGF‐A expression in non‐advanced HCC and in the respective CS and cirrhotic tissue at a distance from the tumour (CD), in 24 patients who underwent liver transplantation. Results: VEGF‐A protein was more expressed (P<0.05) in HCC than in CD, while no difference was found between HCC and CS. In HCC patients with a serum α‐fetoprotein (AFP) higher than 20 ng/ml, VEGF‐A protein expression in HCC was higher than in the corresponding CD in 83% of cases and AFP and serum VEGF‐A corrected for the platelet count positively correlated with the differential VEGF‐A protein expression between HCC and CD. Conclusion: Our data provide a rationale for clinical trials involving anti‐VEGF‐A treatments in patients with non‐advanced HCC, and suggest that serum AFP and VEGF‐A are variables to be taken into account in these studies.     

Non‐virological factors are drivers of hepatocellular carcinoma in virosuppressed hepatitis B cirrhosis: Results of ANRS CO12 CirVir cohort

Worldwide, hepatocellular carcinoma (HCC) occurs mainly in Asian patients with hepatitis B virus (HBV) infection. This study aimed to decipher the environmental and virological factors associated with HCC occurrence and validate risk scoring systems in a French multicentre prospective cohort of HBV cirrhotic patients. Patients with biopsy‐proven Child‐Pugh A viral cirrhosis included in the ANRS CO12 CirVir cohort who were HBsAg(+) without hepatitis C coinfection were selected for: (a) interview through a standardized questionnaire reporting coffee consumption and HCC familial history; (b) HBsAg quantification using baseline and sequential 2‐year frozen sera; (c) baseline HBV genotype determination; and (d) assessment of risk factors and applicability of HCC risk scores (Kaplan‐Meier analysis, Cox models). Among 317 patients studied (261 men, median age 53 years, past or ongoing antiviral treatment 93.3% and baseline detectable HBV DNA in 88 patients), the baseline and 2‐year median HBsAg levels were 810 and 463 IU/mL, respectively. After a median follow‐up of 65.2 months, 27 HCC cases were diagnosed (annual incidence: 1.6%). Three factors were independently associated with HCC occurrence: age > 50 years, platelets ≤ 150 × 10³/mm³ and body mass index ≥ 30 kg/m². Two out of five risk scores were validated, and the most accurate was PAGE‐B at 1 year. Moreover, HCC in patients without maintained virological suppression seems more aggressive and less accessible to curative treatment. In conclusion, in French patients with HBV cirrhosis mostly virally suppressed, independent HCC risk factors were host‐related (age, obesity) or linked to the severity of cirrhosis (thrombopenia), and the European PAGE‐B score was the most accurate risk score.     

Preoperative Alpha-Fetoprotein Has No Prognostic Role in Small Hepatocellular Carcinoma in Non-Cirrhotic Patients After Surgical Resection

Background: Alpha-fetoprotein (AFP) has been widely used as a tumor marker in the treatment of hepatocellular carcinoma (HCC) in patients with cirrhosis. However, a large number of HCC patients are diagnosed without cirrhosis, and the prognostic capability of AFP was unclear in HCC patients without cirrhosis. Our purpose was to investigate the prognostic efficiency of AFP in patients with non-cirrhosis, single, and small HCC who were treated with surgical resection.Methods: Among the 111 374 liver cancer patients included in the Surveillance, Epidemiology, and End Results database, we selected 224 patients without cirrhosis with a single HCC ≤3 cm in diameter who were identified at diagnosis and treated with surgical resection. The AFP test results were recorded as AFP-positive and AFP-negative levels.Results: Kaplan–Meier method showed that there was no significant survival difference between the AFP-positive and AFP-negative groups (P = .566). The same results were found in the subgroups of patients with tumor size ≤2 cm and 2-3 cm (P = .710 and .687, respectively). Receiver operating characteristic (ROC) curve analysis showed that AFP had inadequate accuracy to discriminate survivors and deceased patients in subgroups of patients with tumor size ≤3 cm, 2-3 cm, or ≤2 cm (area under the ROC curve = 0.449, 0.458, 0.443; 95% confidence interval = 0.366-0.533, 0.346-0.571, 0.317-0.569, respectively).Conclusion: AFP levels have no predictive value in well-compensated non-cirrhosis patients with single, small HCC (≤3 cm) treated with surgical resection for curative intent.     

Cirrhotic patients with or without hepatocellular carcinoma harbour AFP-specific T-lymphocytes that can be activated in vitro by human alpha-fetoprotein

BACKGROUND: Alpha-fetoprotein (AFP) is re-expressed in 60%-70% of hepatocellular carcinomas (HCC) and may therefore be a potential target for a prophylactic or therapeutic tumour-specific vaccination. A prerequisite for this approach is the possibility to induce AFP-specific T-lymphocytes in patients with HCC and/or cirrhosis. METHODS: Peripheral blood was examined for the presence of AFP-specific T-lymphocytes using a FACS-based interferon-gamma secretion assay. RESULTS: In a group of healthy volunteers, the presence of AFP-specific CD4- and CD8-lymphocytes was demonstrated. Screening of blood of 14 cirrhotic patients without HCC and 23 cirrhotic patients with HCC showed that patients with liver diseases that represent targets for vaccination also harbour CD4-positive as well as CD8-positive AFP-specific Tlymphocytes. AFP reactivity in patients' lymphocytes was not significantly influenced by soluble serum AFP. The median stimulation factors for CD4-positive T-lymphocytes were significantly higher (P = 0.0365) in cirrhotic patients without HCC (median 2.08, range 0.50-4.40) compared to cirrhotic patients with HCC (median 1.15, range 0.24-8.50). CONCLUSION: AFP-specific T-lymphocytes that may be instrumental in HCC vaccination strategies are present in humans. This study suggests that immunopreventive vaccination of cirrhotic patients rather than immunotherapeutic vaccination of HCC patients may be preferable.     

Hepatitis B viral load and risk for liver cirrhosis and hepatocellular carcinoma in The Gambia,West Africa

Summary. The main objectives of this study were to define the occurrence and levels of hepatitis B virus (HBV) DNA in asymptomatic HBV carriers, cirrhosis patients and hepatocellular carcinoma (HCC) cases from The Gambia, and to evaluate the risk for cirrhosis or HCC associated with HBV viremia. We used sensitive real‐time quantitative PCR assays to measure HBV DNA in samples from a case–control study consisting of 60 asymptomatic HBV carriers, 53 cirrhotic patients and 129 HCC cases. Logistic regression was used to estimate the risks of cirrhosis and HCC associated with HBV‐DNA levels and HBV e antigenemia (HBeAg) detection (a surrogate marker for viral replication). Detectable HBV viremia and HBeAg positivity were both significantly associated with cirrhosis (increasing risk by fourfold and 11‐fold respectively) and with HCC (increasing risk by sixfold and threefold respectively). HBV‐DNA levels were significantly higher in both HCC cases and cirrhotic patients compared to asymptomatic carriers (P < 0.01 for both). High‐level HBV DNA (>10 000 copies/mL) was strongly associated with both HCC and cirrhosis (17‐ and 39‐fold increased risk). Lower level HBV viremia (200–10 000 copies/mL) conferred a significant risk of HCC, although the association with cirrhosis was not significant. In conclusion, we find that high HBV‐DNA levels are strongly associated with the serious sequelae of HBV infection, independent of HBeAg status. While risk for cirrhosis and for HCC notably increases at HBV‐DNA levels ≥10 000 copies/mL, low‐level viremia was also associated with significant risk for HCC.     

A prospective study of blood alpha-fetoprotein messenger RNA as a predictor of hepatocellular carcinoma in patients with cirrhosis

Summary. Blood alpha-fetoprotein messenger RNA (AFP mRNA) is thought to be a marker of hepatocellular carcinoma (HCC). Its value as a predictor of HCC in patients at risk is not known. A series of 201 patients with compensated cirrhosis (114 men, mean age 58 years) underwent surveillance with semi-annual ultrasound and serum alpha-fetoprotein measurements. Total RNA was extracted from peripheral blood mononuclear cells collected at different intervals and AFP mRNA was retrotranscribed and amplified by nested polymerase chain reaction. Ten patients with HCC and 30 blood donors were used as controls. Three patients with HCC, 39 with cirrhosis under surveillance and four blood donors circulated AFP mRNA (30, 20 and 13%, NS). During 50 months of surveillance, 27 patients with cirrhosis developed HCC: the tumour was detected more often in patients with higher than normal baseline serum AFP (≥7 IU/L) than in those with normal AFP levels (21% vs 9%, P  = 0.02). The incidence of HCC was the same in patients with and without AFP mRNA at baseline (15% vs 14%). In 53 patients, AFP mRNA was re-tested after 6–25 months of surveillance. HCC developed in two of 11 (18%) who were initially AFP mRNA positive and later became negative, in none of those who were initially negative and later became positive and in two of 39 (5%) who remained persistently negative. In conclusion, blood AFP mRNA is not a sensitive predictor of HCC in patients with compensated cirrhosis.