PIVKA-II Levels Research Articles

Clinical application of alpha fetoprotein combined with abnormal prothrombin in detecting primary liver cancer

Objective To investigate the clinical value of serum alpha fetoprotein(AFP) combined with abnormal prothrombin(PIVKA-Ⅱ) in the detection of primary liver cancer. Methods From May 2017 to October 2017, 80 cases of primary liver cancer in Department of Hepatobiliary Surgery of Deyang People's Hospital, 100 cases of non HCC patients(including chronic liver disease, cirrhosis, metastatic liver cancer) were selected, and another 100 healthy people were selected as control group.The levels of serum AFP and PIVKA-Ⅱ were detected by SIEMENS XP automatic immunoassay analyzer and lumipulseg1200 automatic immune analyzer respectively.All data were analyzed by SPSS17.0 analysis software. Results Comparison between primary liver cancer and non-primary liver cancer: the levels of serum AFP and PIVKA-Ⅱ(F=1.763; F=1.788, sig=0.000, P<0.05). Comparison between non-primary liver cancer and normal group: the levels of serum AFP and PIVKA-Ⅱ(F=0.896; F=0.346, sig=0.000, P<0.05). Serum AFP had a sensitivity of 75.0% and a specificity of 71.5% in the diagnosis of primary liver cancer, while PIVKA-Ⅱ had a sensitivity of 82.0% and a specificity of 78.7%.The diagnosis sensitivity and specificity of AFP combined with PIVKA-Ⅱ reached to 92.0% and 95.0%.The sensitivity of AFP combined with PIVKA-Ⅱ in the diagnosis of primary liver cancer had statistically significant differences compared with AFP and PIVKA-Ⅱ alone(χ2=4.112, P=0.008; χ2=2.991, P=0.010). Conclusion Combined detection of serum AFP and PIVKA-II has important clinical significance in the diagnosis of primary liver cancer. Key words: Liver Neoplasms; Alpha-fetoproteins; Prothrombin

Serum ARCHITECT PIVKA-II reference interval in healthy Chinese adults: Sub-analysis from a prospective multicenter study

BackgroundProtein induced by vitamin K absence or antagonist-II (PIVKA-II) has been widely used as a biomarker for liver cancer diagnosis in Japan for decades. However, the reference intervals for serum ARCHITECT PIVKA-II have not been established in the Chinese population. Thus, this study aimed to measure serum PIVKA-II levels in healthy Chinese subjects. MethodsThis is a sub-analysis from the prospective, cross-sectional and multicenter study (ClinicalTrials.gov Identifier: NCT03047603). A total of 892 healthy participants (777 Han and 115 Uygur) with complete health checkup results were recruited from 7 regional centers in China. Serum PIVKA-II level was measured by ARCHITECT immunoassay. All 95% reference ranges were estimated by nonparametric method. ResultsThe distribution of PIVKA-II values showed significant difference with ethnicity and sex, but not age. The 95% reference range of PIVKA-II was 13.62–40.38 mAU/ml in Han Chinese subjects and 15.16–53.74 mAU/ml in Uygur subjects. PIVKA-II level was significantly higher in males than in females (P < 0.001). The 95% reference range of PIVKA-II was 15.39–42.01 mAU/ml in Han males while 11.96–39.13 mAU/ml in Han females. ConclusionsThe reference interval of serum PIVKA-II on the Architect platform was established in healthy Chinese adults. This will be valuable for future clinical and laboratory studies performed using the Architect analyzer. Different ethnic backgrounds and analytical methods underline the need for redefining the reference interval of analytes such as PIVKA-II, in central laboratories in different countries.

Changes of AFP and PIVKA-II levels during DAA treatment and their predictive value for early diagnosis of HCC in HCV cirrhotic patients with SVR to DAA treatment

Changes of AFP and PIVKA-II levels during DAA treatment and their predictive value for early diagnosis of HCC in HCV cirrhotic patients with SVR to DAA treatment

PIVKA-II as a Potential New Biomarker for Hepatocellular Carcinoma - A Pilot Study.

The aim of this study was to evaluate the clinical contribution of protein induced by vitamin K absence (PIVKA-II) for hepatocellular carcinoma (HCC) diagnostics and compare it with alpha-foetoprotein (AFP), a routinely used tumour marker. A total of 332 participants were enrolled in this study: 64 with HCC, 48 with liver metastases of colorectal cancer origin, 42 with liver cirrhosis and 178 healthy individuals. Serum levels of PIVKA-II were measured using the chemiluminescent assay of the Architect 1000i System (Abbott, USA) and AFP levels using the chemiluminescent assay by DxI 800 (Beckman Coulter, USA). PIVKA-II achieved better clinical sensitivity than AFP and the difference in this sensitivity was statistically significant. PIVKA-II achieved the best sensitivity (96.9%) in distinguishing between the HCC and control groups with the proposed cut-off value of 60 mAU/ml. Our recommendation is for addition of PIVKA-II to the routine panel of HCC tumour markers.

Coagulopathy in Zellweger spectrum disorders: a role for vitamin K

IntroductionZellweger spectrum disorders (ZSDs) are caused by an impairment of peroxisome biogenesis, resulting in multiple metabolic abnormalities. This leads to a range of symptoms, including hepatic dysfunction and coagulopathy. This study evaluated the incidence and severity of coagulopathy and the effect of vitamin K supplementation orally and IV in ZSD.MethodsData were retrospectively retrieved from the medical records of 30 ZSD patients to study coagulopathy and the effect of vitamin K orally on proteins induced by vitamin K absence (PIVKA-II) levels. Five patients from the cohort with a prolonged prothrombin time, low factor VII, and elevated PIVKA-II levels received 10 mg of vitamin K IV. Laboratory results, including thrombin generation, at baseline and 72 h after vitamin K administration were examined.ResultsIn the retrospective cohort, four patients (13.3%) experienced intracranial bleedings and 14 (46.7%) reported minor bleeding. No thrombotic events occurred. PIVKA-II levels decreased 38% after start of vitamin K therapy orally. In the five patients with a coagulopathy, despite treatment with oral administration of vitamin K, vitamin K IV caused an additional decrease (23%) of PIVKA-II levels and increased thrombin generation.ConclusionBleeding complications frequently occur in ZSD patients due to liver disease and vitamin K deficiency. Vitamin K deficiency is partly corrected by vitamin K supplementation orally, and vitamin K administered IV additionally improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation.

Efficacy of Proton Beam Therapy for Hepatocellular Carcinoma With Portal Vein or Inferior Vena Cava Tumor Thrombosis

Vascular invasion, such as portal vein tumor thrombosis (PVTT) and inferior vena cava tumor thrombosis (IVCTT), is a common condition in advanced hepatocellular carcinoma (HCC). HCC patients with PVTT or IVCTT have an extremely poor prognosis. In order to clarify the clinical outcome of proton beam therapy (PBT) for HCC with PVTT or IVCTT, this prospective study was performed. This was a clinical study for HCC with PVTT or IVCTT using PBT based on protocols determined at Nagoya Proton Therapy Center. The primary and secondary endpoints were overall survival (OS) and complication rates, respectively. The number of patients required for this study was estimated to be 31 using the chi-square test (type 1 error=0.05, power=0.8, P0=0.3, P1=0.6). Response after PBT was evaluated using modified RECIST. OS rates were calculated using the Kaplan-Meier method and were compared using the log-rank test. Toxicities were graded according to the common terminology criteria for adverse events (v4.03). Between September 2013 and January 2017, 34 patients (27 males and 7 females) were enrolled, assuming dropout of a few patients. The median follow-up period was 8.4 months (interquartile range (IQR), 4.7-19.1). Median patient age was 68 years (IQR, 61-73). Twenty patients had Child-Pugh A liver function, 12 had Child-Pugh B, and 2 had Child-Pugh C. Etiology of HCC was hepatitis B (7), hepatitis C (18), alcoholism (5), autoimmune hepatitis (1), and nonalcoholic steatohepatitis (1). Median alpha-fetoprotein and PIVKA-II levels were 171.2 ng/mL (IQR, 28.9-5241.3) and 2620 mAU/ml (IQR, 135-12800), respectively. Median gross tumor volume was 220.0 ml (IQR, 87.6-620.6). The median biologically effective dose 10 (BED10) was 81.3 GyE (IQR, 75-96.6). Twenty-one (62%) lesions achieved a complete (15%) or partial response (47%). Stable and progressive diseases were observed in 12 (35%) and 1 (3%), respectively. Tumor thrombosis was present in the portal vein trunk (15), portal vein branch (18), or inferior vena cava (8). The 1-year OS rate was 55%. Eighteen patients in whom all tumors could be included in the irradiation field had good prognoses (P<0.05). The prognoses of 16 patients whose tumor thrombosis shrank after irradiation were good (P<0.05). One patient had grade 3 acute dermatitis. Grade 3 liver enzyme elevation was observed in 2 patients at 3 months after radiotherapy. However, no severe radiation-induced liver disease was observed. No late gastrointestinal symptoms with grade 3 or higher toxicity, such as ulceration, bleeding, perforation, and ileus were recorded. PBT for advanced HCC with PVTT or IVCTT is a safe and effective treatment without severe complications. When all the tumors can be included in the irradiation field, PBT may be effective even for large HCC.

Risk factors of early recurrence after curative hepatectomy in hepatocellular carcinoma.

Early recurrence is common after curative hepatectomy for hepatocellular carcinoma and is associated with poor prognosis. This study aimed to identify risk factors of early recurrence after curative hepatectomy in hepatocellular carcinoma. Overall, 63 patients who underwent curative hepatectomy for hepatocellular carcinoma were enrolled. Patients were divided into the early recurrence group, who developed recurrence within 12 months after hepatectomy (n = 10), and the non-early recurrence group (n = 53). Clinicopathological factors of early recurrence were retrospectively analyzed. Among the 63 patients, 10 (15.9%) patients experienced early recurrence. Univariate analysis showed tumor necrosis (p = 0.012), level of PIVKA-II (prothrombin induced by vitamin K absence or antagonist-II; p = 0.002), and microvascular invasion (p = 0.029) to be associated with early recurrence. By multivariate analysis, there were significant differences in high PIVKA-II (p < 0.001) and tumor necrosis (p = 0.012) in patients with early recurrence. The optimal cutoff values of PIVKA-II and tumor necrosis were 46 mAU/mL and 3% of total tumor volume, respectively. Patients with a high preoperative PIVKA-II level and extent of tumor necrosis, which are independent risk factors for early recurrence, should be actively treated and monitored closely after hepatectomy.

Effectiveness of PIVKA-II in the detection of hepatocellular carcinoma based on real-world clinical data

BackgroundProtein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) is an efficient biomarker specific for hepatocellular carcinoma (HCC). Some researchers have proved that levels of PIVKA-II reflect HCC oncogenesis and progression. However, the effectiveness of PIVKA-II based on real-world clnical data has barely been studied.MethodsA total of 14,861 samples were tested in Southwest Hospital in over 2 years’ time. Among them, 4073 samples were PIVKA-II positive. Finally, a total of 2070 patients with at least two image examinations were enrolled in this study. Levels of AFP and PIVKA-II were measured by chemiluminescence enzyme immunoassay (CLEIA) and chemiluminescent microparticle Immunoassay (CMIA), respectively.ResultsA total of 1016 patients with HCC were detected by PIVKA-II in a real-world application. In all these cases, 88.7% cases primarily occurred and patients with advanced HCC covered 61.3%. Levels of PIVKA-II were significantly higher in advanced group (4650.0 mAU/ml, 667.0–33,438.0 mAU/ml) than early-stage group (104.5 mAU/ml, 61.0–348.8 mAU/ml; P < 0.001). Levels of PIVKA-II elevated significantly in recurrence and residual group than recovery group (P < 0.001). A total of 1054 PIVKA-II positive patients were non-HCC cases. Among them, cirrhosis took the largest part (46.3%), followed by hepatitis (20.6%) and benign nodules (15.3%). High-levels of PIVKA-II in at-risk patients is an indicator of HCC development in two-year time.ConclusionsOur data showed that PIVKA-II effectively increases the detection rate of HCC was a valid complement to AFP and image examination in HCC surveillance.

Usefulness of PIVKA-II After Living-donor Liver Transplantation for Hepatocellular Carcinoma

ObjectiveProthrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) is a useful tumor marker for hepatocellular carcinoma (HCC). However, the usefulness of post-transplantation surveillance with PIVKA-II is not clear. We evaluated the clinical value of PIVKA-II in monitoring HCC recurrence after living-donor liver transplantation (LDLT). MethodsOne hundred twenty patients who had undergone LDLT for HCC from February 1999 to December 2010 and whose serum alpha-fetoprotein (AFP) and PIVKA-II had been measured sequentially before and after LDLT were included in this study. Patients were classified into four groups according to the preoperative level of AFP and PIVKA-II (group I, normal AFP and PIVKA-II; group II, elevated AFP; group III, elevated PIVKA-II; and group IV, elevated both AFP and PIVKA-II). ResultsPreoperative PIVKA-II level tended to increase with increasing tumor size, number of nodules, presence of microvascular invasion, and poor differentiation. In 27 patients developing recurrent HCC after LDLT, the sensitivity of AFP and PIVKA-II was 59.2% and 88.8%, respectively. When the two markers were combined, the sensitivity increased to 92.5%. Especially, the sensitivity for PIVKA-II was high at groups I and III (100.0% for both, respectively). In patients in groups I, III, and IV, an elevated PIVKA-II level was the most common first sign of HCC recurrence after LDLT. An elevated PIVKA-II level was the most common first sign of recurrence, regardless of recurrence site. ConclusionsPIVKA-II might be a useful tumor marker in the monitoring of recurrence after LDLT, complementary to AFP.

PIVKA-II correlates with INR but not protein C or protein S concentrations in cord blood among newborns.

Protein induced by vitamin K absence (PIVKA)-II, inactive precursor of prothrombin, is elevated in vitamin K (VK) deficiency. Our aims were to find the prevalence of VK deficiency in neonates, assess the utility of international normalized ratio (INR) as a screening tool, and explore the relationship between PIVKA-II, activated partial thromboplastin time (aPTT) and VK dependent anticoagulants. INR, aPTT, PIVKA-II, and proteins C and S activities were measured in neonatal cord blood prior to VK administration. We found 45% of neonates had subclinical VK deficiency based on PIVKA-II levels and 7% based on INR. Receiver operating characteristic (ROC) analysis assessed the utility of INR in detecting >4 ng/mL of PIVKA-II and ROC of the area under the curve was 0.70 (95% CI 0.46-0.92, p = 0.07). Proteins C and S activities were normal for age and did not correlate with PIVKA-II [(r = 0.40, p = 0.14) and (r = 0.29, p = 0.29), respectively]. There was no association between aPTT and PIVKA-II (p = 0.83). PIVKA-II seems to be a sensitive indicator of mild VK deficiency. Further studies are needed to investigate the lack of relationship between PIVKA-II and functional protein C or S levels.

Diagnostic Performance of Alpha-Fetoprotein, Protein Induced by Vitamin K Absence, Osteopontin, Dickkopf-1 and Its Combinations for Hepatocellular Carcinoma.

Background & AimsAlpha-fetoprotein (AFP) is the most widely used serum biomarker for hepatocellular carcinoma (HCC), despite its limitations. As complementary biomarkers, protein induced by vitamin K absence (PIVKA-II), osteopontin (OPN), and Dickkopf-1 (DKK-1) have been proposed. This study aimed to perform a head-to-head comparison of the diagnostic performance of AFP, PIVKA-II, OPN and DKK-1 as single or in combination to seek the best biomarker or panel, and to investigate the clinical factors affecting their performance.MethodsUsing 401 stored plasma samples obtained from 208 HCC patients and 193 liver cirrhosis control patients, plasma AFP, PIVKA-II, OPN and DKK-1 levels were measured by ELISA, and receiver operating characteristic curve analyses were performed for each biomarker and for every combination of two to four markers.ResultsOf the four biomarkers, AFP showed the highest area under the curve (0.786). The sensitivity and specificity for each single biomarker was 62% and 90.2% (AFP>20 ng/mL), 51.0% and 91.2% (PIVKA-II>10 ng/mL), 46.2% and 80.3% (OPN>100 ng/mL), and 50.0% and 80.8% (DKK-1>500 pg/mL), respectively. Among the combinations of two biomarkers, AFP>20 ng/mL or DKK-1>500 pg/mL showed the best diagnostic performance (sensitivity 78.4%, specificity 72.5%). Triple or quadruple combination did not improve the diagnostic performance further. The patient’s age, etiology and tumor invasiveness of HCC affected the performance of each marker.ConclusionsAFP was the most useful single biomarker for HCC diagnosis, and the combined measurement of AFP and DKK-1 could maximize the diagnostic yield. Clinical decision should be based on the consideration of various factors affecting the diagnostic performance of each biomarker. Efforts to seek novel HCC biomarkers should be continued.

Development and evaluation of analytical performance of a fully automated chemiluminescent immunoassay for protein induced by vitamin K absence or antagonist II

ObjectivesProtein induced by vitamin K absence or antagonist II (PIVKA-II), an abnormal form of prothrombin, has been used as an aid in the diagnosis of hepatocellular cancer (HCC) as a tumor marker. We developed a fully automated quantitative immunoassay for PIVKA-II on the ARCHITECT® i systems. The aim of this study was to evaluate the analytical performance of this assay. Design and MethodAssay imprecision, sensitivity, dilution linearity, high dose hook effect, sample type equivalency, assay interferences of potential interfering materials and correlation with Picolumi PIVKA-II (Eidia, Tokyo, Japan) were evaluated. ResultsThe percentage coefficient of variation (%CV) of total imprecision ranged from 2.8% to 5.4% with 10 levels of samples. The limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) were less than 0.63mAU/mL, 1.62mAU/mL, and 8.25mAU/mL, respectively. Linearity up to 30,000mAU/mL, no high dose hook effect, no difference among sample types and no interference of common drugs and endogenous substances were observed. Correlation study with the Picolumi PIVKA-II gave a correlation coefficient of 0.93 and a regression slope of 1.07. ConclusionsThe results demonstrate that the fully automated prototype ARCHITECT PIVKA-II assay is an accurate, highly sensitive and precise assay for the measurement of PIVKA-II levels in human sera and plasmas.

The influence of alcoholic liver disease on serum PIVKA-II levels in patients without hepatocellular carcinoma.

Background/AimsProthrombin induced by vitamin K deficiency or antagonist II (PIVKA-II) is a widely used diagnostic marker for hepatocellular carcinoma (HCC). We evaluated the correlation between alcoholic liver disease (ALD) and serum PIVKA-II levels in chronic liver disease (CLD) patients.MethodsWe retrospectively reviewed the medical records of 2,528 CLD patients without HCC. Among these patients, 76 exhibited serum high PIVKA-II levels of >125 mAU/mL (group 1). We categorized 76 control patients matched by age, sex, and the presence of liver cirrhosis from the remaining patients who were negative for serum PIVKA-II (group 2).ResultsGroup 1 revealed increased antibiotic usage (23.7% vs 2.6%, p<0.001) and incidence of ALD (60.5% vs 14.5%, p<0.001) as well as elevated aspartate aminotransferase (52.5 IU/L vs 30.5 IU/L, p=0.025) and γ glutamyl transpeptidase (67.5 IU/L vs 36.5 IU/L, p=0.005) levels compared with group 2. Further, group 1 was significantly associated with a worse Child-Pugh class than group 2. In the multivariate analysis, ALD (odds ratio [OR], 7.151; p<0.001) and antibiotic usage (OR, 5.846; p<0.001) were significantly associated with positive PIVKA-II levels.ConclusionsOur study suggests that ALD and antibiotics usage may be confounding factors when interpreting high serum PIVKA-II levels in patients without HCC. Therefore, serum PIVKA-II levels in patients with ALD or in patients administered antibiotics should be interpreted with caution.

Assessment of the effect of esterified propoxylated glycerol (EPG) on the status of fat-soluble vitamins and select water-soluble nutrients following dietary administration to humans for 8 weeks

This double-blind, randomized, controlled study assessed the effect of esterified propoxylated glycerol (EPG) on fat-soluble vitamins and select nutrients in human subjects. For 8weeks, 139 healthy volunteers consumed a core diet providing adequate caloric and nutrient intakes. The diet included items (spread, muffins, cookies, and biscuits) providing EPG (10, 25, and 40g/day) vs. margarine alone (control). EPG did not significantly affect circulating retinol, α-tocopherol, or 25-OH D2, but circulating β-carotene and phylloquinone were lower in the EPG groups, and PIVKA-II levels were higher; 25-OH D3 increased but to a lesser extent than the control. The effect might be related to EPG acting as a lipid “sink” during gastrointestinal transit. No effects were seen in secondary endpoint measures (physical exam, clinical pathology, serum folate, RBC folate, vitamin B12, zinc, iron, calcium, phosphorus, osteocalcin, RBP, intact PTH, PT, PTT, cholesterol, HDL-C, LDL-C, triglycerides). Gastrointestinal adverse events (gas with discharge; diarrhea; oily spotting; oily evacuation; oily stool; liquid stool; soft stool) were reported more frequently by subjects receiving 25 or 40g/day of EPG. In general, the incidence and duration of these symptoms correlated directly with EPG dietary concentration. The results suggest 10g/day of EPG was reasonably well tolerated.

Clinicopathological factors and long-term outcome comparing between lung and peritoneal metastasectomy after hepatectomy for hepatocellular carcinoma in a tertiary institution

Recurrence after liver resection for hepatocellular carcinoma (HCC) is common. Resection of extrahepatic recurrences such as lung metastasectomy (LM) has been well documented. Conversely, reports on the long-term outcomes of peritoneal metastasectomy (PM) are lacking. In this study, we compared the outcome of lung and peritoneal metastasectomy after hepatectomies for HCC in a tertiary institution. We reviewed retrospectively the data of 1,222 patients who underwent hepatectomies for HCC in Samsung Medical Center in Korea from January 2006 to August 2010. We studied the clinicopathologic factors between resected lung metastasis (LM) and peritoneal metastases (PM) and the long-term outcome of patient survival. Kaplan-Meier analysis was used to study the survival outcome. The recurrence rate of resected HCC in this cohort was 41.6% (n = 508). Thirty-two patients with lung metastasis (23% of all lung metastasis) underwent LM whereas 13 patients (36% of all peritoneal metastasis) with peritoneal metastasis underwent PM. Two patients underwent PM and LM sequentially. Demographic and clinical data between the LM and PM groups were comparable. The mean prehepatectomy PIVKA-II level was greater in the LM group compared with the PM group (P = .029). On univariate analysis of pathologic factors, the median tumor size (P = .005), proportion of patients with tumor >75 mm (P = .005) and rate of microvascular invasion (P = .047) were greater in the LM group. The median time-to-recurrence in the LM group was 12 (4-45) months compared with 18 (1-102) months in the PM group (P = .896). The 1-year, 3-year, and 5-year overall survival of patients in the LM group was 92%, 55%, 55% (4-year) whereas that in the PM group was 90%, 75%, and 75%, respectively. The mean overall survival in the LM was comparable with that in the PM group (P = .578). Twenty-three percent of patients with lung metastasis and 36.1% of patients with peritoneal metastasis could be considered for metastasectomy. The long-term survival of patients with PM and LM was comparable in this study. Although resection of LM improves survival in patients with resected HCC, we demonstrated favorable outcomes for PM as well, which in the past would have been considered palliative.

P2-12-1 - A Case of Alpha-Fetoprotein(Afp)- Producing Pancreatic Ductal Carcinoma Responding to Gemcitabine and Erlotinib Therapy

Although it has been reported that alpha-fetoprotein (AFP)-producing pancreatic cancer is derived from acinar cells, carcinoma from ductal cells is relatively rare. Here we report a case of AFP-producing pancreatic ductal adenocarcinoma that showed response to gemcitabine and erlotinib.Case: A 53-year-old woman presented with body weight loss and epigastralgia. MRI and CT scan revealed multiple tumors in the liver and a mass in the head of the pancreas. The origin was obscure because AFP and PIVKA-II serum levels were significantly elevated (34748 ng/ml, 474 mAU/ml, respectively), whereas CEA and CA19-9 were not. Finally, we diagnosed pancreatic ductal carcinoma (stage IVb) by liver biopsy. Gemcitabine (1000 mg/m2 on day 1, 8, and 15, every 4 weeks) and erlotinib (100 mg/body, day 1–28) were administrated as first-line chemotherapy. A partial response of the primary lesion and of the liver metastases was achieved, and serum levels of AFP and PIVKA-II significantly decreased. Although we switched to second-line chemotherapy (gemcitabine and S-1), 8 months later the patient died of liver failure due to the progression of the tumor. The tumor was classified as a poor/middle differentiated ductal adenocarcinoma by pathologic analysis, and it strongly expressed AFP detected by immunohistochemistry.

Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation.

Background/AimsThe most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated.MethodsNinety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 ± 1.3 ng/mL (mean ± SD).ResultsThe 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive 18fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05).ConclusionsInduction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients.

Single hepatocellular carcinoma ≤ 3 cm in left lateral segment: Liver resection or radiofrequency ablation

To evaluate the long-term results of radiofrequency ablation (RFA) compared to left lateral sectionectomy (LLS) in patients with Child-Pugh class A disease for the treatment of single and small hepatocellular carcinoma (HCC) in the left lateral segments. We retrospectively reviewed the data of 133 patients with single HCC (≤ 3 cm) in their left lateral segments who underwent curative LLS (n = 66) or RFA (n = 67) between 2006 and 2010. The median follow-up period was 33.5 mo in the LLS group and 29 mo in the RFA group (P = 0.060). Most patients had hepatitis B virus-related HCC. The hospital stay was longer in the LLS group than in the RFA group (8 d vs 2 d, P < 0.001). The 1-, 2-, and 3-year disease-free survival and overall survival rates were 80.0%, 68.2%, and 60.0%, and 95.4%, 92.3%, and 92.3%, respectively, for the LLS group; and 80.8%, 59.9%, and 39.6%, and 98.2%, 92.0%, and 74.4%, respectively, for the RFA group. The disease-free survival curve and overall survival curve were higher in the LLS group than in the RFA group (P = 0.012 and P = 0.013, respectively). Increased PIVKA-II levels and small tumor size were associated with HCC recurrence in multivariate analysis. Liver resection is suitable for single HCC ≤ 3 cm in the left lateral segments.

TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis

Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD14+CD16+TIE2+ cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD34+ vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro-vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC. TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.

Necrotic Hepatocellular Carcinoma Occurring within an Inflammatory Pseudotumor-like Nodule

Hepatocellular carcinoma (HCC) and inflammatory pseudotumor of the liver (IPL) are often difficult to differentiate before surgery. To date, colocalization of IPL and HCC has not been reported. We experienced a case of necrotic HCC surrounded by IPL-like tissue. The raised levels of alpha-fetoprotein and PIVKA-II declined to within the normal ranges after resection of the tumor. The IPL-like nodule most likely developed as a process of an inflammatory reaction such as abscess formation after the spontaneous destruction of the HCC. Our case is a warning that the presence of a 'pseudotumor' does not rule out the possible simultaneous presence of carcinoma.