Diagnostic role of serum glypican-3 in differentiating hepatocellular carcinoma from non-malignant chronic liver disease and other liver cancers

Background and Aims:  The role of glypican-3 (GPC3), a novel serum marker, in differentiating hepatocellular carcinoma (HCC) from non-malignant chronic liver disease and other malignant space-occupying lesions in the liver is largely unknown. The aims of this study were to evaluate its diagnostic role and clinical correlations in patients with HCC.
Methods:  Six groups were studied which included 40 healthy subjects, 50 patients with chronic hepatitis (CH), 50 patients with liver cirrhosis (LC), 100 patients with HCC, 50 patients with intrahepatic cholangiocarcinoma (ICC) and 50 patients with metastatic carcinoma (MCA). Serum GPC3 levels were measured by using a sandwich enzyme-linked immunosorbent assay method.
Results:  Fifty-three percent of HCC patients had elevated serum GPC3 levels with values ranging 35.5–7826.6 ng/mL. The serum marker was undetectable in other groups except one patient (2%) with LC and another patient (2%) with MCA. In most cases of HCC, elevated GPC3 values did not correlate with α-fetoprotein (AFP) levels. Detectable GPC3 was significantly correlated with the presence of viral hepatitis markers but was not correlated with tumor size and stage of HCC. Serum GPC3 was superior to AFP in detecting small HCC (56.3% and 31.3%, respectively). A combination of serum GPC3 and AFP yielded an improved sensitivity for detecting small HCC to 75%.
Conclusion:  Serum GPC3 is highly specific for detecting HCC. The combined use of serum GPC3 and AFP provides a potentially promising tool to better differentiate HCC from benign liver disorders, as well as from other liver cancers.     

Incidence and clinical presentation of portal vein thrombosis in cirrhotic patients

BACKGROUND: Portal vein thrombosis (PVT) is due to many risk factors, but its pathogenesis is still not clearly understood. To identify the risk factors for PVT, we analyzed the clinical characteristics and complications associated with PVT in cir-rhotic patients.
METHODS: We studied patients with liver cirrhosis who were admitted to our unit from April 2009 to December 2014. The patients were divided into the PVT and non-PVT groups, and were compared by variables including gender, age, the etiology of cirrhosis, stage of cirrhosis, complications, imaging, and treatment.
RESULTS: PVT was found in 45 (9.8%) of 461 cirrhotic pa-tients admitted to our hospital. Most patients (45.9%) had hepatitis B virus (HBV)-related cirrhosis, with a similar dis-tribution of etiologies between the groups. However, there was no positive relationship between PVT and etiologies of cirrhosis. Most patients (71.5%) were in the stage of hepatic decompensation. No statistically signiifcant differences were found in complications including esophageal varices, ascites, and hepatic encephalopathy between the groups. However, there was a signiifcant positive correlation between hepatocel-lular carcinoma (HCC) and PVT (P<0.01). In 30 patients with PVT, thrombosis occurred in the portal vein and/or portal branches, 37.8% were diagnosed on ultrasound.
CONCLUSIONS: The incidence of PVT was 9.8%, mainly in patients with HBV-related cirrhosis. The development of PVT was associated with the severity of liver disease and HCC.     

Correlation of routinely used coagulation parameters and presence of portal vein thrombosis in patients with liver cirrhosis

Aim:  Portal vein thrombosis (PVT) is a serious complication in patients with liver cirrhosis. In patients with advanced stages of liver cirrhosis plasmatic coagulation and platelet count are often reduced. However, patients with normal coagulation status might carry a high risk for developing PVT. A correlation between coagulation status used in clinical routine and the incidence of PVT in patients with liver cirrhosis has been evaluated in the present retrospective analysis.
Methods:  88 patients with liver cirrhosis were identified by screening a database. Of these patients, 23 suffered from PVT. Patients were classified according to the Child–Pugh classification. Patients were subdivided into early stages (Child A) and advanced stages (Child B/C) of liver cirrhosis.
Results:  In patients with Child–Pugh A cirrhosis, there was no difference in activated partial thromboplastin time (apTT), international normalized ratio (INR), and platelet count between the PVT ( n  = 7) and the control group ( n  = 35). In contrast, the median apTT and INR were significantly lower in patients with Child B/C cirrhosis and PVT ( n  = 16) in comparison with patients without PVT (37 s vs 43 s [ P  = 0.017] and 1.25 vs 1.40 [ P  = 0.022]), respectively. Platelet count did not differ significantly in patients with advanced liver cirrhosis and PVT from those without PVT.
Conclusion:  Patients with advanced liver cirrhosis and PVT displayed lower apTT and INR compared with those without PVT. Therefore, patients with advanced liver cirrhosis and almost normal coagulation parameters might be at particular risk of developing PVT. The results suggest that regular monitoring using Doppler-ultrasound should be carried out in these patients, especially when liver transplantation is intended.     

Surface enhanced laser desorption/ionization profiling: New diagnostic method of HBV-related hepatocellular carcinoma

Background and Aim:  To screen for serum biomarkers of HBV-related hepatocellular carcinoma (HCC) and HBV-related liver cirrhosis (LC) in an attempt to seek a new method for differential diagnosis of HCC and LC using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) techniques.
Methods:  Using SELDI-TOF-MS, serum proteins/peptide profiles on the immobilized metal ion affinity capture (IMAC) protein chips were obtained from 29 HCC patients and 30 LC patients. Discriminant analysis was carried out to establish new diagnostic methods using protein/peptide peaks with or without α-fetoprotein (AFP).
Results:  Forty-five protein/peptide peaks changed much more in the HCC group than they did in the LC group. Discriminant analysis using the Wilcoxon rank-sum test showed high sensitivity and specificity in distinguishing HCC from LC. The most significantly differentiating peak, 3892, offered 69.0% sensitivity, 83.3% specificity and 80% positive predictive value in distinguishing HCC and LC. Interestingly, six HCC patients with negative serum AFP were confirmed by peak 3892. The combination of multi-protein peaks (m/z = 9297, 29 941) with AFP offered an 82.8% sensitivity, 93.3% specificity and 92.3% positive predictive value, which was much better than AFP alone ( P  = 0.013).
Conclusions:  Special proteins/peptides of serum may differentiate HBV-related HCC and HBV-related LC, indicating that SELDI-TOF-MS may be useful to distinguish HCC from LC with the proper discriminant analytical method. SELDI peak 3892 may be a complementary diagnostic marker to positive AFP for HCC and a potential marker for the diagnosis of AFP-negative HCC as well.     

Evaluation of Model for End Stage Liver Disease (MELD)-based systems as prognostic index for hepatocellular carcinoma

Background:  The Cancer of Liver Italian Program (CLIP) and Japan Integrated Scoring System (JIS) used the Child-Turcotte-Pugh (CTP) score to evaluate the liver function.
Aim:  We aimed to evaluate the performance of Model for End Stage Liver Disease (MELD) based CLIP and JIS to predict the prognosis of hepatocellular carcinoma (HCC).
Methods:  Consecutive patients with HCC who presented to our Hepatoma Clinic from January 2003 to April 2005 were studied. MELD-based CLIP and JIS were generated by replacing the original CTP score with MELD score at three categories (<10, 10–14 and >14).
Results:  Among 471 HCC patients (85.1% males; aged 58.8 ± 12.2 years), 73% had chronic hepatitis B, 37.4% had >1 nodule, 84.1% had tumor size >2 cm, 55.0% had Child's B cirrhosis, 12.7% underwent tumor resection and 20.6% received locoregional therapy. The cumulative survival at 3 and 6 months were 67% and 55%, respectively. For 3-month survival, the area under the receiver operating characteristic curves (AUC) of MELD-CLIP (0.69) and MELD-JIS (0.69) were superior to the original systems (0.64, P  = 0.004 and 0.64, P  = 0.0018, respectively). For 6-month survival, AUC of MELD-CLIP (0.64) and MELD-JIS (0.62) were also superior to the original systems (0.54, P  = 0.003 and 0.59, P  = 0.002, respectively). The MELD-based systems performed best among patients who received locoregional therapy to HCC. Advanced cirrhosis (hypoalbuminemia, hyperbilirubinemia, ascites, coagulopathy and elevated creatinine), and cancer (portal vein thrombosis, elevated alpha-fetoprotein, large and multiple tumors) were associated with higher mortality.
Conclusions:  MELD-based systems performed better than Child-Pugh based systems as prognostic indexes for HCC.     

Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis

Objective: The aim of this study was to evaluate the incidence, prognostic factors and clinical significance of delayed clearance of serum HBsAg in compensated cirrhosis B.
Methods: This was a retrospective cohort study of 309 consecutive white patients with biopsy-proved compensated cirrhosis type B.
Results: During a mean follow-up of 68 months, HBsAg loss occurred in 32 patients, including 16 (8%) of 196 untreated patients (mean annual incidence 0.8%), 8 (10%) of 82 interferon (IFN) alpha–treated patients and eight patients who had been treated with other antivirals or steroids. The 5-yr probability of HBsAg loss was 4% and 16% for untreated and IFN-treated patients, respectively (   p = 0.0001  ). Cox's regression analysis identified hepatitis B e antigen–positivity at entry as the sole independent prognostic factor for HBsAg loss. Of the 32 patients who lost HBsAg, one (3%) subsequently developed hepatocellular carcinoma (HCC) and died, whereas, among the patients who remained HBsAg-positive, 11% developed HCC and 20% had died. The probability of HCC appearance was lower (   p = 0.0137  ) and survival was longer (   p = 0.0006  ) in patients who cleared HBsAg compared with patients with HBsAg persistence.
Conclusion: The incidence of HBsAg loss is about 0.8% in cirrhosis type B. Prognostic factors for clearance of HBsAg are initial HBeAg positivity and therapy with alpha interferon. Patients with cirrhosis type B, who lose HBsAg, have a low risk for liver cancer or liver-related death.     

Comparison of outcomes between patients with alcoholic cirrhosis and those with hepatitis C virus-related cirrhosis

Background and Aim:  The natural history of alcoholic cirrhosis, especially in Asian countries, has not been completely understood thus far.
Methods:  We retrospectively compared the outcomes of compensated cirrhosis between Japanese alcoholic and hepatitis C virus (HCV)-infected patients.
Results:  A total of 227 patients (75 alcoholic and 152 HCV-infected patients) with compensated cirrhosis were enrolled. The median follow-up period was 4.9 years. The cumulative rates of hepatocellular carcinoma (HCC) development were significantly lower in the alcoholic patients than in the HCV-infected patients (6.8% vs 50.3% at 10 years, P  = 0.0003), while the cumulative rates of hepatic decompensation (37.4% vs 51.7% at 10 years) and survival (53.8% vs 47.4% at 10 years) did not significantly differ between the two groups (Kaplan-Meir analysis). The main causes of death were hepatic failure and non-hepatic diseases in the alcoholic patients and HCC and hepatic failure in the HCV-infected patients. Multivariate analyses using the Cox proportional hazard model revealed that the risk of HCC was lower in alcoholic cirrhosis than in HCV-related cirrhosis (hazard ratio (HR), 0.46), while the risk of hepatic decompensation and mortality was the same. Predictors of decreased survival were non-abstinence (HR, 2.53) in the alcoholic patients and low serum albumin level (1.58) in the HCV-infected patients.
Conclusions:  Survival of patients with alcoholic cirrhosis was similar to that of patients with HCV-related cirrhosis. The risk of HCC development was lower in alcoholic cirrhosis than in HCV-related cirrhosis. Abstinence from alcohol was important for improving the survival of patients with alcoholic cirrhosis.     

Serum alpha-fetoprotein levels and liver histology in patients with chronic hepatitis C

Objective: The clinical and morphological significance of a raised alpha-fetoprotein (AFP) level in patients with chronic hepatitis C is undefined. We sought to determine the relation between serum AFP level and liver histology in this population.
Methods: We reviewed the clinical and histological records of 200 consecutively evaluated patients with chronic hepatitis C whose serum AFP levels were recorded. Two groups were studied: group I = 125/200 (62%) patients with normal AFP, < 10 ng/ml; and group II = 75/200 (38%) patients with raised AFP, > 10 ng/ml. The groups were compared according to age, gender, duration of disease, histology, and history of alcohol abuse.
Results: There was no significant difference in serum AFP based on age, gender, alcohol consumption, or disease duration. Significant histological differences were observed: cirrhosis was present in 57 (45%) patients in group I versus 51 (68%) in group II (   p < 0.001  ). Hepatocellular carcinoma was more frequent in group II (14/75 [19%]) than in group I (1/125 [1%]) (   p < 0.001  ). Ten of 77 (13%) noncirrhotic patients and 51/108 (47%) cirrhotic patients had a raised AFP (   p < 0.002  ; relative risk, 3.262; confidence interval [C.I.], 1.912–5.564). A derived AFP level of 17.8 ng/ml maximized specificity for predicting histological outcome: one of 76 (1.3%), 29/108 (26.8%), and 14/15 (93.3%) patients were noncirrhotic, cirrhotic, or had HCC, respectively. This derived AFP value is 35% sensitive and 98.6% specific for cirrhosis, with a positive predictive value of 97.7%.
Conclusions: A serum AFP level >17.8 ng/ml strongly suggests the diagnosis of cirrhosis in a population of patients with chronic hepatitis C.     

Low alpha‐fetoprotein hepatocellular carcinoma

Background and Aim: A large proportion of hepatocellular carcinoma (HCC) patients do not secrete elevated levels of the tumor marker alpha‐fetoprotein (AFP). There is little published guide to prognostic features of this patient subset. Methods: We interrogated a large HCC database in which all patients had been followed until death, to examine which features might be prognostically useful. Results: We found 413 biopsy‐proven unresectable HCC patients with low serum AFP values. Serum gamma glutamyl transpeptidase (GGTP) levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels < 110 U/100 mL and small tumors had longest survival > 795 days. Patients with GGTP ≥ 110 U/mL and large tumors with the presence of portal vein thrombosis had the shortest survival range of 300–560 days. Conclusions: Serum levels of the onco‐fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.     

Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C

Background and Aim:  Ethnic differences in non-alcoholic steatohepatitis (NASH) are well-documented, but there has been no study on the prognosis of Japanese NASH patients with cirrhosis. Accordingly, we compared cirrhotic NASH with liver cirrhosis caused by chronic hepatitis C (LC-C) to clarify its clinical features and define the risk factors for death.
Methods:  A prospective evaluation of the outcomes of NASH patients with severe fibrosis was started in 1990. Data on age- and sex-matched patients with biopsy-proven LC-C were collected retrospectively and used as the control.
Results:  There were 68 patients with cirrhotic NASH and 69 with LC-C. The Child–Turcotte–Pugh (CTP) class was similar in these two groups. Although the outcome of the NASH group was better than that of the LC-C group, cirrhotic NASH followed a similar course to that of LC-C; that is, complications of cirrhosis developed, including hepatocellular carcinoma (HCC; the 5-year HCC rate was 11.3% for NASH and 30.5% for HCV) and death (the 5-year survival rates were 75.2% and 73.8%, respectively). HCC was the leading cause of death in both groups (NASH, 47%; HCV, 68%). The occurrence of HCC and the CTP class were significant risk factors for mortality in NASH patients according to a multivariate analysis (HCC: hazard ratio [HR] 7.96, 95% confidence interval [CI] 2.45–25.88, CTP class A: HR 0.17, 95% CI 0.06–0.50).
Conclusion:  In conclusion, the present study confirmed that cirrhotic NASH has a similar course to LC-C. The occurrence of HCC was the strongest predictor of mortality in the NASH groups. These findings may be helpful when deciding on therapeutic interventions for NASH and also for the daily management of these patients.     

Alpha-Fetoprotein (AFP) and AFP-L3 Is Most Useful in Detection of Recurrence of Hepatocellular Carcinoma in Patients after Tumor Ablation and with Low AFP Level

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is a leading cause of mortality worldwide. While there are many risk factors for HCC including alcohol, obesity, and diabetes, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection still account for the majority of HCC worldwide. Globally, HBV is the leading risk factor for HCC. Patients with chronic hepatitis B (CHB) and advanced liver disease are at high risk for HCC. Screening for HCC is done routinely with ultrasound with or without alpha-fetoprotein (AFP) at six-month intervals. The combination of ultrasound and AFP has been shown to provide some additional detection of 6–8% of cases compared to ultrasound alone; however, this also increases false-positive results. This is because AFP can be elevated not only in the setting of HCC, but also in chronic hepatitis, liver cirrhosis, or ALT flare in CHB, which limits the specificity of AFP. AFP-L3 is a subfraction of AFP that is produced by malignant hepatocytes. The ratio of AFP-L3 to total AFP is reported as a percentage, and over 10% AFP-L3 is consistent with a diagnosis of HCC. Here, we review five cases of patients with CHB, cirrhosis, and HCC, and their levels of AFP and the AFP-L3% at various stages of disease including ALT flare, cirrhosis, initial diagnosis of HCC, and recurrence of HCC. These cases emphasize the utility of AFP-L3% in identifying early, new or recurrent HCC prior to the presence of imaging findings.     

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.     

Clinical application of an enzyme-linked immunosorbent assay detecting hepatoma-specific γ-glutamyltransferase

Aim:  To develop a sandwich enzyme-linked immunosorbent assay (ELISA) measuring hepatoma-specific datura stramonium agglutinin–tightly bounding γ -glutamyltransferase (DSA-GGT) and evaluate its clinical application for hepatocellular carcinoma (HCC) diagnosis.
Methods:  Serum DSA-GGT concentrations were measured with the sandwich ELISA system in 96 patients with HCC, 240 patients with chronic liver diseases and 119 healthy subjects. The diagnostic performance of DSA-GGT for HCC was assessed using receiver operating characteristic (ROC) curves. The diagnostic accuracy of DSA-GGT was compared with serum α-fetoprotein (AFP).
Results:  The area under the ROC curve of DSA-GGT in discriminating patients with HCC from non-HCC was 0.865 (95% confidence interval: 0.818–0.915, P  < 0.001). Serum DSA-GGT was positive in 67 out of 96 patients with HCC and 23 out of 240 patients with non-HCC diseases. The sensitivity and specificity of DSA-GGT and AFP for the diagnosis of HCC were 69.8% and 90.5%, and 72.9% and 89.1%, respectively. A higher sensitivity (93.8%) in the identification of HCC was observed by combining DSA-GGT and AFP.
Conclusion:  The sandwich ELISA system showed good reliability and reproducibility, and using the measurement, we found that serum DSA-GGT was a valuable marker of HCC, as a usable complementary to AFP. The sensitivity for identifying HCC could be significantly improved by combining DSA-GGT and AFP, and the combination could be used in large-scale screening for HCC in susceptible individuals.     

The preoperative positivity for serum hepatitis B e antigen did not affect overall survival after curative resection of hepatitis B virus-related hepatocellular carcinoma

Background and Aim:  Previous studies have reported different risk factors for early and late intrahepatic recurrence after resection of hepatocellular carcinoma (HCC). However, the prognostic significance of the risk factors for early and late recurrence has not been clarified.
Methods:  A total of 190 Hepatitis B surface antigen-positive patients who received curative resection for HCC were reviewed. We investigated prognostic factors for disease-free and overall survival after resection, and further analyzed the relationship between significant prognostic factors and risk factors for early (≤14 months) and late (>14 months) intrahepatic recurrence.
Results:  The 5-year disease-free and overall survival rates were 43.9% and 71.5%, respectively. In multivariate analysis, adverse prognostic factors for disease-free survival were presence of serum HBeAg, perioperative transfusion, and the presence of portal vein invasion (PVI) and/or intrahepatic metastasis (IM). Multivariate analysis revealed that overall survival was associated with ICG R15, serum albumin, Edmondson–Steiner grade, and the presence of PVI and/or IM. Independent risk factors for early intrahepatic recurrence were perioperative transfusion and PVI and/or IM, whereas positivity for HBeAg was the only risk factor for late recurrence. In addition, post-recurrence survival in patients with late intrahepatic recurrence was completely comparable to that of patients who never experienced recurrence.
Conclusions:  The presence of serum HBeAg, the risk factor for late intrahepatic recurrence did not affect overall survival after resection because late recurrence was relatively well controlled by current available treatments. To further improve long-term surgical outcomes, effective treatment and preventive methods for early intrahepatic recurrence should be investigated.     

Fine-needle aspiration cytology to distinguish dysplasia from hepatocellular carcinoma with different grades

Background:  Distinguishing dysplasia from hepatocellular carcinoma (HCC) by fine-needle aspiration (FNA) cytology is difficult. The aim of this study was to diagnose HCC and the distinction of liver cell dysplasia from HCC with different grades by interpreting and scoring the cyto-morphological features.
Methods:  Eighty-three cirrhotic patients undertook a sonography-guided FNA and subsequent needle biopsy for the tumor. HCC was confirmed in 68 cases and cirrhosis with dysplasia in 15 cases by pathology and follow-up for longer than 2 years. Eighteen cytological features were scored as degree of one, two or three according to their presence or prominence.
Results:  Two cases of well-differentiated HCC were diagnosed as negative for HCC initially. The sensitivity, specificity, false positive, false negative and accuracy were 97%, 100%, 0%, 3% and 97.6% for FNA cytology in the diagnosis of HCC, respectively. The score of dysplasia was 20.8 ± 1.3 (mean ± SD) and lower than 26.2 ± 3.4 in Edmondson's grade I HCC ( P  < 0.01), 28.9 ± 2.9 in grade II HCC ( P  < 0.01), and 34.9 ± 4.3 in grade III/IV HCC ( P  < 0.01). The score was also significantly lower in grade II HCC than in grade III/IV HCC ( P  < 0.01).
Conclusions:  FNA yielded a high accuracy in the distinction of dysplasia from HCC with different grades. There is a good correlation in cyto-morphological scores of liver cell dysplasia and HCC with different grades. Dysplasia displayed the lowest score and the score increased in order from dysplasia to grade III/IV HCC.     

Endoscopic thermal ablation therapies for hepatocellular carcinoma: a multi-center study

Aim:  The differing efficacies of radiofrequency ablation and microwave coagulation for hepatocellular carcinoma (HCC) are unknown. Therefore, we performed a multi-center study to assess the factors contributing to survival and local recurrences of HCC among patients with solitary tumors who underwent endoscopic thermal ablation as their primary treatment.
Methods:  From six institutions, 391 patients with solitary HCC who were first treated by endoscopic thermal ablation were enrolled in this study and assessed retrospectively. We investigated age, gender, location of tumor, longest diameter of tumor, method of anesthesia, type of endoscope, method of thermal ablation, Child–Pugh classification, the Japan Integrated Staging score and the Cancer of the Liver Italian Program score. Statistical analyses were performed using univariate analysis with log–rank test and multivariate analysis with the Cox proportional hazards model.
Results:  On univariate analysis, advanced Child–Pugh score, advanced Italian Program score and local recurrences were significant predictors of poor survival. Young age (≤70), large tumor (>30 mm) and the use of the thoracoscopic approach were significant predictors for the development of local recurrence. On multivariate analysis, local anesthesia and advanced Child–Pugh score were independent predictors of poor survival. Young age, large tumor, local anesthesia and the use of the thoracoscopic approach were independent predictors for the development of local recurrence. The method of thermal ablation did not influence survival or local recurrence.
Conclusions:  Differences in the effect on survival and local recurrence between microwave and radiofrequency were not observed in this retrospective, multi-center study of endoscopic thermal ablation for HCC.     

Hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis in Denmark: A nationwide cohort study

Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC ), and surveillance with ultrasound (US ) and alpha‐fetoprotein (AFP ) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR ) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C, and data from national health registries and patient charts were obtained. Tumour stage was based on Barcelona‐Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stages 0‐3. We included 1075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4988 person years (PY ), 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI 95% 0.4‐1.5] in 2002‐2003 to 2.9/100 PY [2.4‐3.4] in 2012‐2013. One‐year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP  ≥ 20 ng mL^?1 was 17%. Twenty‐three (21%) patients were diagnosed with early‐stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early‐stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal, and most patients were diagnosed with advanced HCC with a poor prognosis.     

Identification of osteopontin as a novel marker for early hepatocellular carcinoma

The aim of this study was to identify a biomarker that could improve alpha-fetoprotein (AFP) performance in hepatocellular carcinoma (HCC) surveillance among patients with cirrhosis. We performed proteomic profiling of plasma from patients with cirrhosis or HCC and validated selected candidate HCC biomarkers in two geographically distinct cohorts to include HCC of different etiologies. Mass spectrometry profiling of highly fractionated plasma from 18 cirrhosis and 17 HCC patients identified osteopontin (OPN) as significantly up-regulated in HCC cases, compared to cirrhosis controls. OPN levels were subsequently measured in 312 plasma samples collected from 131 HCC patients, 76 cirrhosis patients, 52 chronic hepatitis C (CHC) and B (CHB) patients, and 53 healthy controls in two independent cohorts. OPN plasma levels were significantly elevated in HCC patients, compared to cirrhosis, CHC, CHB, or healthy controls, in both cohorts. OPN alone or in combination with AFP had significantly better area under the receiver operating characteristic curve, compared to AFP, in comparing cirrhosis and HCC in both cohorts. OPN overall performance remained higher than AFP in comparing cirrhosis and the following HCC groups: HCV-related HCC, HBV-associated HCC, and early HCC. OPN also had a good sensitivity in AFP-negative HCC. In a pilot prospective study including 22 patients who developed HCC during follow-up, OPN was already elevated 1 year before diagnosis. CONCLUSION: OPN was more sensitive than AFP for the diagnosis of HCC in all studied HCC groups. In addition, OPN performance remained intact in samples collected 1 year before diagnosis.     

Role of serum C-reactive protein as a marker of hepatocellular carcinoma in patients with cirrhosis

BACKGROUND: The usefulness of C-reactive protein (CRP) as a tumour marker in patients with hepatocellular carcinoma (HCC) is controversial. The purpose of this study was to determine whether CRP estimation could be used to identify patients with HCC among those with cirrhosis. METHODS: Serum levels of CRP and alpha-fetoprotein (AFP) were investigated in 122 previously untreated patients with cirrhosis and HCC. Another 76 patients with cirrhosis alone were also investigated as controls. RESULTS: Of the subjects tested, 47.5% of patients with HCC and 39.5% of controls had elevated CRP values (> 6 microg/mL). Although using elevated CRP and/or AFP (> 20 ng/mL) as a criterion showed a significant difference between controls and patients with multiple nodular, massive, or diffuse type HCC (all P < 0.005), the clinical application of this criterion was limited because of low specificity (58%) and accuracy (all < 73%). By using receiver-operating characteristic curves no valuable threshold value of CRP was found to discriminate various types of HCC, except for distinguishing the diffuse type from controls. The CRP value of 12 microg/mL could be used as the cut-off value to differentiate diffuse-type HCC from controls (sensitivity 82.4%, specificity 82%, accuracy 82.1%, P<0.005). CONCLUSIONS: Serum CRP is not a good marker for HCC. However, very high values of CRP in patients with cirrhosis may suggest the presence of a diffuse-type HCC.