Serum Des-gamma-carboxy Prothrombin Levels Research Articles

Association of Serum Levels and Immunohistochemical Labelling of Des-Gamma-Carboxy-Prothrombin in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma.

Hepatocellular cancer (HCC) is one of the main reasons for liver transplantation (LT). Biomarkers, such as alpha-foetoprotein (AFP) and Des-gamma-carboxy-prothrombin (DCP), can be helpful in defining the recurrence risk post LT. This study aims to evaluate the association between the intensity of DCP immunohistochemical labelling and serum DCP levels in patients undergoing LT for HCC. We carried out a prospective monocentric study including patients who all underwent LT for cirrhosis between 2016 and 2018 and all fell under the Milan criteria. The accepted diagnostic criteria for HCC were contrast-enhanced imaging and histology. Thirty-nine patients were followed for a median of 21 months, with HCC lesions categorized into negative, focally positive, and diffusely positive groups based on DCP immunohistochemistry. The serum DCP levels were significantly higher in the positive groups (258 mAU/mL for the focally and 257 mAU/mL for the diffusely positive) than in the negative group (48 mAU/mL) (p = 0.005) at diagnosis and at the time of liver transplantation (220 mAU/mL for the diffuse positive group). Microvascular invasion (58.8% vs. 19.0% for the diffusely positive and negative groups, respectively, p < 0.001) and lesion size (20 mm in the diffusely labelled group versus 12 mm in the other groups, p = 0.002) were significantly correlated with DCP labelling. Late recurrence occurred only in the positive groups; in the negative group, it occurred within the first 3 months after transplantation. DCP labelling in liver lesions correlates with serum levels and a more aggressive tumour profile. Further investigation is needed to determine if highly DCP-labelled tumours allow for the better selection of high-risk patients before LT.

Correlation Between Serum ESPL1 and Hepatitis B Virus-related Hepatocellular Carcinoma Histological Grade: A Chinese Single-center Case-control Study.

Serum markers to determine the histological grade of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) are still limited. This study aimed to investigate if serum extra spindle pole bodies-like 1 (ESPL1) protein could reflect the histological grade of HBV-related HCC. A total of 154 patients with HBV-related HCC were enrolled in the experimental group and 41 non-HBV-related patients in the control. Enzyme-linked immunosorbent assay was used to detect serum ESPL1 levels. The differences in serological ESPL1, alpha-fetoprotein (AFP), and des-gamma-carboxy prothrombin (DCP) were compared between the two groups. HCC tumor diameter was measured, and pathological examination was performed to compare the relationship between ESPL1, AFP, and DCP and tumor size and histological grade. Serum AFP and DCP levels showed no significant difference between experimental group and control group, and increased when the tumor diameter increased but were not related to HCC histological grade. Serological ESPL1 levels were higher in the experimental group than those in the control group, and positively correlated with the histological grade. In the experimental group, tumor size and histological grade were almost independent (Kappa=0.000); patients with medium size tumors had the highest serum ESPL1 levels and the highest proportion of poorly differentiated carcinomas, whereas 75.6% of patients with small size tumors had moderately differentiated carcinomas and only 20% well differentiated carcinomas. Serum ESPL1 can reflect the malignant degree of HBV-related HCC and is helpful in identifying small size HCC tumors.

Characteristics of TP53 and CTNNB1 mutation according to the serum tumor markers in hepatocellular carcinoma

Serum alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). However, associations among molecular characteristics and serum biomarkers are unclear. We analyzed RNA expression and DNA variant data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) to examine their associations with serum biomarker levels and clinical data. From 371 TCGA-LIHC patients, we selected 91 seen at 3 institutions in Korea and the United States and measured AFP, AFP-L3, and DCP from preoperatively obtained serum. We conducted an integrative clinical and molecular analysis, focusing on biomarkers, and validated the findings with the remaining 280 patients in the TCGA-LIHC cohort. Patients were categorized into 4 subgroups: elevated AFP or AFP-L3 alone (↑AFP&L3), elevated DCP alone (↑DCP), elevation of all 3 biomarkers (↑All), and reference range values for all biomarkers (RR). CTNNB1 variants were frequently observed in ↑DCP patients (n = 7 [53.8%]) and RR patients (n = 10 [38.5%]), but ↑DCP patients with a CTNNB1 variant had worse survival than RR patients. TP53 sequence variants were associated with ↑AFP (n = 8 [30.8%]) and ↑DCP (n = 4 [30.8%]). The Wnt signaling pathway was activated in the ↑AFP&L3, whereas liver-related Wnt signaling was activated in the RR. TGF and VEGF signaling are activated in high AFP&L3, while dysregulated bile acid and fatty acid metabolism were dominant in ↑DCP. We validated these finding using the remainder of the TCGA-LIHC cohort and showed similar results to the test cohort. Serum AFP, AFP-L3, and DCP levels can help predict variants in the genetic profile.

Identification of the Response-Related Biomarker of Bimonthly Hepatic Arterial Infusion Chemotherapy.

Despite the availability of molecularly targeted agents for advanced hepatocellular carcinoma (aHCC), these are limited to compensated cirrhotic patients, and concerns about decreased hepatic functional reserve (HFR) and unknown adverse events, which may affect long-term survival, remain unaddressed. In this study, we enrolled 96 aHCC patients treated with bimonthly hepatic arterial infusion chemotherapy (B-HAIC) with cisplatin or sorafenib monotherapy (oral sorafenib 400 mg twice daily) not only to demonstrate its efficacy and significance but also to indicate preferable candidates by setting a response-related biomarker. Differences in treatment had no significant effect on overall survival (OS). The response rate in patients treated with B-HAIC was relatively higher than those treated with sorafenib. HFR was well maintained over the treatment course with B-HAIC, while it was significantly impaired with sorafenib. By employing multivariate analysis, we found negative trends between progression-free survival (PFS) periods and serum levels of alpha fetoprotein as well as des-gamma-carboxy prothrombin (DCP). In addition, a logistic regression analysis of the relationship between serum DCP levels and PFS periods over 420 days (14 months) showed that the PFS periods of patients with higher DCP was significantly shorter than those of patients with lower DCP (p = 0.02). Subsequently, the present study demonstrated the efficacy and safety of B-HAIC and identified a predictor of unpreferable patients. Based on these results, B-HAIC might be an alternative treatment after the implementation of new molecularly targeted therapies.

Evaluation of serum AFP and DCP levels in the diagnosis of early-stage HBV-related HCC under different backgrounds.

ObjectiveThis study compared the diagnostic performance of alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) in early-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) under different backgrounds.MethodsPatients were enrolled and divided in four groups: chronic HBV infection (CHB), liver cirrhosis (LC), early-stage CHB-HCC, and early-stage LC-HCC. Serum AFP and DCP levels were measured. Receiver-operating characteristic (ROC) curve and area under the curve (AUC) analyses were applied to compare the diagnostic performance of DCP and AFP for HCC.ResultsIn total, 200 patients were enrolled, including 48, 64, 33, and 55 patients with CHB, LC, CHB-HCC, and LC-HCC, respectively. ROC curve analysis revealed that the AUCs of AFP, DCP, and their combination in differentiating early-stage LC-HCC from LC were 0.776, 0.758, and 0.786, respectively. The values of these markers in discriminating early-stage CHB-HCC from CHB were 0.828, 0.731, and 0.862, respectively.ConclusionsDCP was inferior to AFP in differentiating early-stage CHB-HCC from CHB. However, AFP and DCP displayed similar performance in distinguishing early-stage LC-HCC and LC.

Des-gamma-carboxy prothrombin affects the survival of HCC patients with marginal liver function and curative treatment: ACRoS1402.

Considering the initial treatment of hepatocellular carcinoma (HCC), the best prognostic index for Child-Pugh classes B and C (CP-BC) patients has not been yet established. This study aimed to elucidate the risk factors for disease-free survival (DFS) and overall survival (OS) in multicenter patients with a poor liver functional reserve after curative treatment. Between April 2000 and April 2014, 212 CP-BC patients who received treatment in five high-volume centers in Japan were included in this study. CP-B and C patients were 206 and 6, respectively. Cox proportional hazard regression analyses for DFS and OS were performed to estimate the risk factors. The mean observation time was 1132days. Mean Child-Pugh score and indocyanine green retention rate at 15min were 7.5 and 31.5%, respectively. Histological chronic hepatitis and liver cirrhosis were observed in 20% and 74% patients, respectively. In the multivariate analysis, the risk factors for DFS were des-gamma-carboxy prothrombin (DCP) [hazard ratio (HR), 1.6; P = 0.012] and treatment without liver transplantation. Moreover, DCP was identified as an independent risk factor for OS (HR, 1.7; P = 0.01). Tumor size, number, tumor thrombus, Milan criteria, liver cirrhosis, and treatment without liver transplantation were not identified as risk factors for OS. The 5-year OS in patients with high serum DCP levels (< 90mAU/mL) was significantly better than that in those with low serum DCP levels (P = 0.003). Serum DCP value before treatment predicted both DFS and OS in CP-BC patients with HCC.

Diagnostic Value of Serum Biomarkers in Combined Hepatocelluar-Cholangiocarcinoma.

To explore the value of des-gamma-carboxyprothrombin (DCP), alpha-fetoprotein (AFP) and carbohydrate antigen-199 (CA-199) for diagnosis of combined hepatocellular-cholangiocarcinoma (cHCC-CC). Observational correlational study design. The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, from June 2016 to June 2019. Patients with cHCC-CC (n = 26) diagnosed by histological examination and immunohistochemical staining were matched as 1:2 to controls (n = 52) based on age (±2 years), gender (male or female), liver texture (cirrhosis or not) and ethnicity. Serum DCP, AFP and CA-199 levels were determined and Youden indices were calculated. Receiver operating characteristic (ROC) curves were generated and areas under the receiver operating characteristic curve (AUC) were calculated. The levels of DCP, AFP and CA-199 were clearly elevated in the cHCC-CC group relative to controls with p-values of <0.001, <0.001 and 0.001, respectively. Youden index values for DCP, AFP, CA-199, and their combination (DCP+AFP+CA-199) were 0.5, 0.423, 0.173 and 0.673, respectively. The AUC curve values for DCP, AFP, CA-199 and their combination (DCP+AFP+CA-199) were 0.759 (95% CI: 0.624 - 0.894), 0.826 (95% CI: 0.720 - 0.933), 0.727 (95% CI: 0.613 - 0.841) and 0.862 (95% CI: 0.755 - 0.968), respectively. DCP, AFP and CA-199 have diagnostic value for cHCC-CC, and the combination of DCP, AFP and CA-199 is useful for assisting diagnosis before histological examination. Clinicians should be alert for cHCC-CC when DCP, AFP, or CA-199 levels are abnormal.

Diagnostic value of alpha-fetoprotein, Lens culinaris agglutinin-reactive alpha-fetoprotein, and des-gamma-carboxyprothrombin in hepatitis B virus-related hepatocellular carcinoma.

ObjectiveThis study aimed to explore the use of different combinations of alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP) for the early diagnosis of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-associated liver cirrhosis (LC).MethodsThere were 167 subjects, including 100 with HCC and 67 with LC, who were enrolled into this study. Serum AFP, AFP-L3, and DCP levels were detected by chemiluminescent enzyme immunoassay and analyzed using the receiver operating characteristics (ROC) method.ResultsThe sensitivity and specificity of AFP and DCP for differentiating between early HCC and HBV-associated LC were 51.5% and 92.5%, and 60.0% and 84.7%, respectively. Comparative analysis of ROC curves showed no significant difference in the area under the curve (AUC) for AFP and DCP. Moreover, the combination of AFP and DCP showed the largest AUC value with a diagnostic sensitivity and specificity of 67% and 83.1%, respectively.ConclusionThese results suggest that AFP is the best single biomarker for distinguishing between HBV-associated LC and early HCC induced by HBV. However, the combination of AFP and DCP can enhance the diagnostic value of AFP for differentiating between these diseases.

Role of des-gamma-carboxy prothrombin in assessment of liver function and prognosis of patients with liver cirrhosis

Objective To investigate the role of des-gamma-carboxy prothrombin (DCP) in assessment of liver function and prognosis of patients with liver cirrhosis. Methods From January 2013 to August 2016, a total of 137 patients with liver cirrhosis in Shanghai Changzheng Hospital were enrolled. The serum DCP level was measured, the clinical data was collected and the complication and survival situation was followed up. The 137 patients were divided into DCP negative group (DCP≤40 mAU/mL, 118 cases) and DCP positive group (DCP>40 mAU/mL, 19 cases). Forty-five patients with compensated liver cirrhosis were divided into high-level DCP group (DCP>16.5 mAU/mL, 32 cases) and low-level DCP group (DCP≤16.5 mAU/mL, 13 cases). Chi square test was used to analyze the difference in the positive rate of DCP in patients with different Child-Pugh classification. Spearman correlation test was performed to analyze the correlation between DCP and model for end-stage liver disease (MELD) scores. Kaplan-Meier survival curve was used to analyze the correlation between DCP and liver disease related mortality. Results Compared to that of DCP negative group, albumin level of patients in DCP positive group decreased (35 g/L, 20 to 57 g/L vs. 29 g/L, 17 to 42 g/L), however, total bilirubin (TBil), prothrombin time (PT), and international normalized ratio all increased (12.9 mg/L, 1.80 to 83.0 mg/L vs.22.2 mg/L, 6.4 to 169.0 mg/L; 15.5 s, 11.7 to 35.7 s vs.17.5 s, 13.9 to 33.4 s; 1.24, 0.96 to 3.72 vs.1.44, 1.09 to 3.22), and the differences were statistically significant (Z=-2.785, -2.891, -2.945 and -2.879, all P 40 mAU/mL) rates of Child-Pugh A, B and C patients were 1.8% (1/55), 21.2% (11/52) and 23.3% (7/30), respectively, and the difference was statistically significant (χ2=11.246, P=0.003). The DCP levels of patients with Child-Pugh class B and C cirrhosis were significantly correlated with MELD scores (r=0.259, P=0.021). There were 16 and three patients with ascites and spontaneous bacterial peritonitis (SBP) of DCP positive group, and the incidence was higher than that of DCP negative group (55.1%, 65/118 and 1.7%, 2/118), and the differences were statistically significant (χ2=5.744 and 97.636, both P<0.05). Patients in high-level DCP group had a higher proportion of clinical decompensation than low-level DCP group (53.1% (17/32) and two cases), the difference was statistically significant (χ2=5.397, P=0.024). The overall survival rate of DCP positive group (nine survival cases) were lower than that of DCP negative group (87.9%, 87/99), and the difference was statistically significant (χ2=5.442, P=0.020). Conclusions Serum DCP level is closely related to liver function, ascites and SBP in patients with liver cirrhosis. Furthermore, it is associated with occurrence of decompensation in compensated patients and liver-related mortality in patients with liver cirrhosis. DCP may be a useful serum marker for evaluation of disease severity and prognosis in patients with liver cirrhosis in clinical practice. Key words: Liver cirrhosis; Des-gamma-carboxy prothrombin; Liver fuction; Prognosis

Differences in the impact of prognostic factors for hepatocellular carcinoma over time.

The aim of the present study was to evaluate the prognostic significance of serum markers that reflect tumor progression, liver function, or liver fibrosis in patients with hepatocellular carcinoma (HCC), focusing on how their impact changes over time after diagnosis. Alpha‐fetoprotein (AFP), des‐gamma‐carboxy prothrombin (DCP), albumin‐bilirubin (ALBI) score, aspartate aminotransferase to platelet ratio index (APRI), and FIB‐4 index were measured at the time of initial non‐recurrent HCC diagnosis in 1669 patients between 1997 and 2016. Survival rates after diagnosis were compared after stratifying patients by these markers. Time‐dependent receiver‐operating characteristics (ROC) analysis was carried out to assess how these markers predict patient survival or death. Serum AFP and DCP levels, ALBI score, and APRI and FIB‐4 index were strongly correlated with HCC progression, liver function, and degree of liver fibrosis, respectively. Survival rates after diagnosis were significantly different when patients were stratified by these markers. In the time‐dependent ROC analysis, AFP and DCP had a high prognostic impact within 3 years of diagnosis but the impact decreased thereafter. In contrast, APRI and FIB‐4 index had higher prognostic impact 10 years after diagnosis. ALBI score had a high prognostic impact throughout the study period. Time‐dependent ROC analysis clearly showed changes in the prognostic importance of serum markers based on the duration after diagnosis. Whereas the prognostic impact of tumor progression markers was strong in the short term, liver fibrosis markers had higher prognostic impact long after diagnosis. Liver function had constant prognostic impact on patient survival after diagnosis.

Diagnosis value of combined detection of serum golgi protein 73, desgamma carboxy prothrombin and α-fetoprotein in primary hepatic carcinoma

To analyze the clinical value of the detection of serum desgamma carboxy prothrombin (DCP), golgi glycoprotein 73 (GP73), heat-shock protein 70 (HSP70) in primary hepatic carcinoma (PHC) diagnosis. Enzyme-1inked immunosorbent assay and electrochemiluminescence immunoassay were used to detect the serum DCP, GP73, HSP70 and α-fetoprotein (AFP) levels in 35 PHC patients and 35 healthy controls. AFP, DCP and GP73 levels in PHC patients were 13.780 (1.140-8 487.000)µg/L, 3 213.953 (2.510-53 994.602)pg/ml and 76.838 (24.500-232.875)ng/ml respectively, significantly higher than those in healthy controls (1.240 (0.605-5.310)µg/L, 104.610 (0.000-4 138.770)pg/ml and 30.770 (16.343-87.453)ng/ml, U value were 134.50, 258.00 and 168.00, all P < 0.01); HSP70 could not be detected in any objects. The area under the ROC curve of DCP or GP73 was 0.789, 0.863 respectively. The sensitivity and specificity to PHC diagnosis were 54.3% and 97.1% by DCP (2 939.4 pg/ml as cut-off value), 85.7% and 74.3% by GP73 (41.3 ng/ml as cut-off value), 45.7% and 100% by AFP (20 µg/L as cut-off value). In combined detection the sensitivity, specificity and accuracy were 88.6%, 74.3%, 81.4% by GP73/AFP and 91.4%, 71.4%, 81.4% by GP73/DCP/AFP. GP73, DCP are new effective markers in the diagnosis of PHC, and the combined detection of GP73, DCP and AFP can improve the diagnosis value of PHC.

New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma

The microvascular invasion of cancer cells (mvi) is a good prognostic factor after hepatic resection (HR) and liver transplantation for hepatocellular carcinoma (HCC). This study aimed to predict mvi in patients with HCC. We studied 63 hepatectomized patients with HCC who had HCC without any extrahepatic metastases and vascular invasion, which were detected during preoperative evaluation. The preoperative clinicopathological data of these patients were analysed to predict presence of mvi. A scoring system was designed using significant risk factors. This system was applied to another series of 34 patients with HCC who underwent HR, and was evaluated for validation. Tumour size, serum des-gamma-carboxy prothrombin (DCP) levels and the maximum standardized uptake value (SUVmax) on 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography were independent clinical predictors for mvi after multivariate analyses. Tumour size, serum DCP levels, and values of SUVmax were used to plot a receiver operating characteristic curve for predicting mvi. Areas under the curve of tumour size, serum DCP levels and SUV max values, were 0.8652, 0.8027 and 0.7848 respectively. Maximal sensitivity and specificity were obtained when the tumour size was 3.6cm, SUVmax was 4.2, and the serum DCP level was 101mAU/ml. A scoring system was designed using these three variables. The sensitivity and specificity of our scoring system were 100% and 90.9%, respectively, in the validation test. Our scoring system for mvi, consisting of tumour size, serum DCP levels, and SUV max, provides a precise prediction of mvi.

The use of AFP and DCP as serum biomarkers to differentiate between hepatocellular carcinoma and intrahepatic cholangiocarcinoma in non-cirrhotic livers.

e15162 Background: Differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) can be challenging in patients without evidence of liver cirrhosis. Definitive diagnosis is based on tissue biopsy. We investigated if the use of serum biomarkers could help differentiate between these two types of malignancies, thereby avoiding the risks associated with biopsy. Methods: Patients with cholangiocarcinoma and HCC were recruited from Queen Elizabeth Hospital, Birmingham, UK; blood samples were collected at time of diagnosis. Two biomarkers, alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were measured in the serum samples from 56 patients with cholangiocarcinoma and 35 patients with HCC without evidence of liver cirrhosis. Of the 56 patients with cholangiocarcinoma, 17 were intrahepatic and 39 were extrahepatic. Results: 17 ICC and 35 HCC were included in the analysis. The levels of AFP and DCP were much higher in HCC as compared to ICC. The median AFP was 64.6 (IQR 10.9, 3564.2) in HCC as compared to 3 (IQR 2.4, 3.9) in ICC. Similarly, the median DCP was 215.41 (IQR 22.46, 692.53) in HCC as compared to 0.33 (IQR 0.16, 1.08) in ICC. Stepwise logistic regression was performed using both biomarkers. Log- DCP remained significant at 95% level in predicting HCC from ICC, giving an AUC of 0.96. Conclusions: In patients with a non-cirrhotic liver and radiological evidence of cancer, measurement of serum AFP and DCP level may help differentiate between HCC and ICC. In this study, DCP is the most useful discriminator between HCC and ICC. Further prospective studies should be done with larger sample sizes to validate the use of AFP and DCP as diagnostic biomarkers in this clinical setting.

Increased activity of serum mitochondrial isoenzyme of creatine kinase in hepatocellular carcinoma patients predominantly with recurrence

Mitochondrial isoenzyme of creatine kinase (MtCK) is reportedly highly expressed in hepatocellular carcinoma (HCC). Clinical relevance of serum MtCK activity in patients with HCC was assessed using a novel immuno-inhibition method. Among patients with cirrhosis caused by hepatitis B or C virus, 147 patients with HCC (12 with the first occurrence and 135 with recurrence) and 92 patients without HCC were enrolled. Serum MtCK activity was higher in cirrhotic patients with HCC than in those without HCC or healthy subjects. Elevated serum MtCK activity in HCC patients decreased after radiofrequency ablation. In case of prediction of HCC, MtCK had a sensitivity of 62.6% and a specificity of 70.7% at a cut-off point of 8.0 U/L, with an area under the receiver operating curve of 0.722 vs. 0.713 for alpha-fetoprotein (AFP) and 0.764 for des-gamma-carboxy prothrombin (DCP). Among the HCC patients, serum MtCK activity was elevated in 52.9% individuals with serum AFP level < 20 ng/ml and 63.2% individuals with serum DCP level < 40 mAu/ml. Even in patients with a single HCC ≤ 2 cm, the sensitivity of serum MtCK activity for the prediction of HCC was 64.4%, which was comparable to the overall sensitivity. This increased activity was due to an increase in ubiquitous MtCK, not sarcomeric MtCK, and the enhanced mRNA expression of ubiquitous MtCK was observed in cell lines originating from HCCs in contrast to healthy liver tissues. Serum MtCK activity merits consideration as a novel marker for HCC to be further tested as for its diagnostic and prognostic power.

Des‐gamma‐carboxyprothrombin in patients with hepatocellular carcinoma and liver cirrhosis

To ascertain serum and tissue expression of des-gamma-carboxyprothrombin (DCP) in patients with hepatocellular carcinoma (HCC) and liver cirrhosis and clarify the relationship between DCP expression and prognosis. Expression of DCP in tissues was evaluated with immunohistochemical staining using anti-DCP antibody in 74 patients with a single primary HCC nodule and liver cirrhosis. Their serum DCP levels were determined using an enzyme immunoassay with a double antibody sandwich system. Positive DCP expression in cancerous and non-cancerous tissues was related to a worse prognosis for patients with HCC and liver cirrhosis. The combined evaluation of tissue DCP expression and serum DCP level showed that prognosis was the worst for patients with positive tissue DCP expression and a high serum DCP level. Univariate analysis indicated that a lower 5-year survival rate was significantly correlated with positive tissue DCP expression, a high serum DCP level and the combined factor of positive tissue DCP expression and a high serum DCP level. Multivariate analysis indicated that the combined factor of positive tissue DCP expression and a high serum DCP level was a significant prognostic factor. The combined evaluation of tissue DCP expression and serum DCP level is more useful than either factor alone in predicting prognosis for patients with HCC and liver cirrhosis.

Outcome and survival analysis of pulmonary metastasectomy for hepatocellular carcinoma

The lung is the most common site for extrahepatic metastasis from hepatocellular carcinoma (HCC). We previously reported in a series of 20 patients that pulmonary metastasectomy for HCC is feasible in selected patients. The objective of this study was to re-evaluate the long-term outcomes and prognostic factors with an additional 25 patients. We retrospectively analyzed the records of 45 consecutive patients who underwent pulmonary metastasectomy due to HCC at our institution between 1990 and 2010. Thirty-nine patients underwent hepatectomy or liver transplantation, whereas six patients underwent locoregional therapy for primary liver lesions. Twenty-seven patients died during a median 17.6-month follow-up period. The 2-year disease-free survival (DFS) was 19.5%. The 5-year overall survival (OS) was 40.9%. History of recurrence and serum des-gamma-carboxy prothrombin (DCP) level >40 mAU ml(-1) at initial pulmonary resection were unfavorably associated with OS in univariate analysis. Pulmonary metastasectomy for HCC in selected patients resulted in relatively good outcomes with regard to OS. History of recurrence and serum DCP levels were shown to be candidates of prognostic factors for OS.

Impact of the preoperative des-gamma-carboxy prothrombin level on prognosis after hepatectomy for hepatocellular carcinoma meeting the Milan criteria

Hepatectomy is feasible for patients with hepatocellular carcinoma (HCC) who are eligible for liver transplantation according to the Milan criteria if they have good hepatic function. This retrospective study investigates the prognostic factors of hepatectomy in HCC patients meeting the Milan criteria. Between 1991 and 2005, 175 patients underwent hepatectomy for HCC at our institute; 111 met and 64 exceeded the Milan criteria. The prognostic factors for hepatectomy were investigated using a Cox regression model. Operative mortality and morbidity were significantly lower in the patients who met the criteria than in those who exceeded the criteria. After a median follow-up of 51.5 months, the 5-year survival rate was significantly better for the patients who met the criteria than for those who exceeded the criteria (77.8% vs 35.7%; P < 0.0001). The factors predictive of poor prognosis were poor differentiation, microscopic vasculobiliary invasion, and a high serum des-gamma-carboxy prothrombin (DCP) level (>100 mAU/ml) for the patients who met the Milan criteria; and only the presence of a microsatellite lesion for the patients who did not meet the Milan criteria. Hepatectomy is safe and beneficial for HCC patients who meet the Milan criteria, but a high preoperative serum DCP level may be predictive of a poor prognosis.

Hypoxia-induced des-γ-carboxy prothrombin production in hepatocellular carcinoma

Des-gamma-carboxy prothrombin (DCP) is an established HCC tumor marker, but the precise mechanism of its production is still unclear. Recently, we demonstrated that cytoskeletal changes during epithelial-to-fibroblastoid conversion (EFC) or epithelial mesenchymal transition (EMT) induced by chemicals plays a critical mechanistic role in DCP production via impairment in vitamin K uptake. Our proposed mechanism of DCP production is consistent with substantial clinical evidence. Supplementary vitamin K2 analogues reduced serum DCP levels in hepatocellular carcinoma (HCC) patients. HCC patients with high serum DCP are associated with vascular invasion, metastasis and tumor recurrence. On the other hand, hypoxia has been reported to induce EMT or cytoskeletal changes. Therefore, we examined whether hypoxia induced DCP production during EFC or EMT in HCC cells. Indeed, hypoxic stimulation induced hepatoma cell lines (HepG2 or PLC/PRF/5 cells) to undergo EFC or EMT and these cells produced DCP. Immunofluorescence study demonstrated that hypoxic stimulation impaired labeled low-density lipoprotein uptake, which was a surrogate for vitamin K uptake. In addition, fine filamentous actin network, which has crucial role for clathrin-mediated endocytosis of vitamin K, was disrupted in DCP producing cells by hypoxic stimulation. Thus, hypoxic stimulation induced HCC cells to produce DCP in the same mechanism as chemicals. Furthermore, immunohistochemical study using surgically resected HCC samples showed that a positive staining of nuclear hypoxia inducible factor (HIF)-1alpha was more frequently observed in HCC cells with stronger staining intensity of DCP. Importantly, clinical observations that DCP as an HCC tumor marker was more useful in larger tumors, which is likely to be exposed with hypoxia during tumor development, support our results.

Intrahepatic distant recurrence after radiofrequency ablation for a single small hepatocellular carcinoma: Risk factors and patterns

The pathogenesis of frequent intrahepatic recurrence of hepatocellular carcinoma (HCC) after surgical resection or local ablation therapy remains uncertain. Risks and patterns of intrahepatic distant recurrence (IDR) of a single, primary HCC lesion after radiofrequency (RF) ablation were examined. Ninety patients with a single primary HCC lesion of less than 3 cm who had complete RF ablation were enrolled in the study. Risk factors for IDR and the patterns of IDR after RF ablation were analyzed. The median follow-up was 37.4 months. IDR was observed in 44 (48.9%) patients. The cumulative rate of IDR was 10.4%, 52.5%, and 77.0% at 1, 3, and 5 years, respectively. Univariate analysis revealed that a pretreatment serum alpha-fetoprotein (AFP) level of > or =50 ng/ml (P = 0.0324), a des-gamma-carboxy prothrombin (DCP) level of > or =40 mAu/ml (P = 0.006), an ablative margin of <5 mm of the ablation zone (P = 0.0306), and a prothrombin time of <70% (P = 0.0188) were related to IDR. A multivariate stepwise Cox proportional hazards regression model revealed that pretreatment serum AFP and DCP level and the ablative margin were independent risk factors for IDR pretreatment. Serum DCP level > or = 40 mAu/ml (P = 0.025), local tumor progression (P = 0.011), and ablative margin < 5 mm (P = 0.024) were related to multiple IDR. HCC patients with high serum AFP or DCP before RF ablation should be carefully followed up to monitor any IDR. A sufficient ablative margin in RF ablation for HCC is required to prevent IDR.

The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma—with special reference to the serum levels of des‐gamma‐carboxy prothrombin

The microvascular invasion of cancer cells (mvi) is a good prognostic factor after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The aim of this study is to predict mvi in patients with HCC who were candidates for OLT. We studied 218 patients with HCC resections who had HCC without any extrahepatic metastases and vascular invasion detected during preoperative evaluation. We analyzed the clinico-pathological data of these patients to predict the mvi presence. The mvi prediction scoring system was made and the accuracy of this system was examined using independent clinico-pathologic factors. The size and histological grade of the tumor were significantly correlated with the mvi. The des-gamma-carboxy prothrombin (DCP) is a mvi predictor. The sensitivity of our mvi prediction system was 75% and the specificity was 85% in 32 patients who underwent living-donor liver transplantations for HCC. Our study shows that besides the tumor size and histological grade, a measurement of the serum DCP levels could be a good predictor for mvi. A tumor biopsy and a preoperative measurement of DCP could improve the selection of patients with HCC for OLT. Our scoring system for mvi provides us a precise prediction of the presence of mvi.