Serum and tissue PIVKA-II expression reflect the biological malignant potential of small hepatocellular carcinoma

Tamano, Masaya; Sugaya, Hitoshi; Oguma, Motoo; Iijima, Makoto; Yoneda, Masashi; Murohisa, Toshimitsu; Kojima, Kensuke; Kuniyoshi, Toru; Majima, Yuichi; Hashimoto, Takashi; Terano, Akira

doi:10.1016/s1386-6346(01)00150-4

Cited by 27 publications

(25 citation statements)

References 17 publications

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“…Together, these findings suggest that the PIVKA-II levels are independently related to extrahepatic metastases regardless of serum AFP level and tumor staging; additionally, they showed a strong association with early stages with low AFP. This is consistent with prior clinical studies showing that the pre-operative PIVKA-II level is an independent predictor of microvessel invasion in post-surgical histology or after liver transplantation [15-17]. This finding may also be explained by an in vitro study showing that PIVKA-II stimulates cell proliferation and cell migration of vascular endothelial cells by binding to the kinase insert domain receptor, alternatively referred to as the vascular endothelial growth factor receptor-2 [18].…”

Section: Discussionsupporting

confidence: 92%

Protein induced by vitamin K absence or antagonist-II production is a strong predictive marker for extrahepatic metastases in early hepatocellular carcinoma: a prospective evaluation

et al. 2011

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BackgroundClinicians often experience extrahepatic metastases associated with hepatocellular carcinoma (HCC), even if no evidence of intrahepatic recurrence after treatment is observed. We investigated the pretreatment predictors of extrahepatic metastases in HCC patients.MethodsPatients diagnosed with HCC without evidence of extrahepatic metastases were prospectively enrolled. We evaluated the correlation between extrahepatic metastases and pretreatment clinical variables, including serum tumor markers.ResultsA total of 354 patients were included. Seventy-six patients (21%) had extrahepatic metastases during the observation period (median, 25.3 months; range, 0.6-51.3 months). Cox regression multivariate analysis showed that serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) production levels, the intrahepatic tumor stage, platelet count, and portal vein thrombosis were independent risk factors for extrahepatic metastases. Patients with a PIVKA-II production ≥ 300 mAU/mL had a 2.7-fold (95% confidence interval; 1.5-4.8; P < 0.001) and 3.7-fold (95% confidence interval; 2.0-6.6; P < 0.001) increased risk for extrahepatic metastases after adjustment for stage, platelet count, alpha-fetoprotein ≥ 400 ng/mL, and portal vein thrombosis according to the AJCC and BCLC staging systems, respectively.ConclusionPIVKA-II production levels might be a good candidate predictive marker for extrahepatic HCC metastases, especially in patients with smaller and/or fewer tumors in the liver with in stages regardless of serum alpha-fetoprotein.

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Section: Discussionsupporting

confidence: 92%

Protein induced by vitamin K absence or antagonist-II production is a strong predictive marker for extrahepatic metastases in early hepatocellular carcinoma: a prospective evaluation

et al. 2011

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“…Specific HCC markers, such as PIVKA-II or AFP L3 fraction, in combination with AFP level, are commonly used in Japan for the diagnosis of HCC or evaluation of tumor aggressiveness (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)17,18,20,21). High values of these markers reflect patient prognosis after any treatment (13-15, 17, 18, 22).…”

Section: Discussionmentioning

confidence: 99%

“…(6) Protein induced by vitamin K absence or antagonist II (PIVKA-II; des-gamma-carboxy prothrombin) was proposed as specific markers for the diagnosis of HCC, evaluation of tumor aggressiveness and prognosis. (7,8) PIVKA-II has been commonly used for the diagnosis in HCC in Japan and has been also adopted worldwide since 2000 (9,10).…”

Section: Introductionmentioning

confidence: 99%

Tumor Marker Levels Before and After Curative Treatment of Hepatocellular Carcinoma as Predictors of Patient Survival

et al. 2011

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Abstract-fetoprotein (AFP) is used as a marker for hepatocellular carcinoma (HCC), which is influenced by hepatitis. Protein induced vitamin K absence or antagonist II (PIVKA-II) is a sensitive diagnostic marker. Changes in these markers after treatment may reflect curability and predict outcome. We conducted an analysis of prognosis in 470 HCC patients who received curative treatments, and examined relationship between changes in AFP and PIVKA-II levels after 1-month of treatment in 156 patients. Subjects were divided into three groups according to changes in both levels: 1) normal (L) group before treatment, 2) normalization (N) or 3) decreased but still above normal level or unchanged (ANU) group after treatment. High AFP and PIVKA-II levels were significantly associated with poor tumor-free and overall survival. Presence of large size and advanced stage were significantly associated with prevalence of DU group. Overall survival in the AFP-L group was significantly better than those of other groups and overall survival in PIVKA-II-L and N groups were significantly better than those of PIVKA-II-ANU groups. Combination of changes in AFP-ANU and PIVKA-II-ANU group showed the worst tumor-free and overall survivals. Multivariate analysis identified high pre-treatment levels of AFP and PIVKA-II and combination of AFP-ANU and PIVKA-II-ANU as significant determinants of poor tumor-free and overall survival, particularly in patients who underwent hepatectomy. We conclude that high levels of AFP or PIVKA-II after treatment for HCC did not sufficiently reflect curative efficacy of treatment and reflected a poor predictor of prognosis in HCC patients. Nanashima et al., Page 3

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“…So far, the precise mechanism underlying DCP production is still controversial. Prothrombin is synthesized in the liver depending on the presence of vitamin K-dependent ␥ -glutamyl carboxylase in the posttranslational process [4][5][6]20] . The prothrombin precursor has 10 Glu residues in the N-terminus that are converted into ␥ -carboxy-glutamic acid (Gla) residues by ␥ -glutamyl carboxylase in the presence of vitamin K [21] .…”

Section: Discussionmentioning

confidence: 99%

“…A large tumor size has been associated with high levels of DCP in serum. DCP was found to bind to cell surface receptor Met causing stimulation of HCC growth [6][7][8] . Therefore, inhibition of DCP production is considered to be an effective strategy in HCC treatment.…”

Section: Introductionmentioning

confidence: 99%

Vitamin K<sub>2</sub> Inhibits the Growth of Hepatocellular Carcinoma via Decrease of Des-Gamma-Carboxy Prothrombin

et al. 2008

Chemotherapy

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Background: Des-γ-carboxy prothrombin (DCP) is a serum protein produced by hepatocellular carcinoma (HCC) cells in the absence of vitamin K. Serum and tissue DCP expressions are thought to reflect the biological malignant potential of HCC. Hence, we aimed to examine the efficacy of vitamin K₂ on the production of DCP as well as tumor cell growth and invasion. Methods: Cell growth and viability were evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. The in vivo efficacy of vitamin K₂ was examined in nude mice bearing HCC cells. A 24-well transwell chamber was used to evaluate the motility and invasive ability of HCC cells. Levels of DCP in supernatant of cultures and in serum of mice were measured using an electrochemiluminescence immunoassay method. Western blot and immunohistochemical analysis were employed to evaluate the expression of DCP in HCC. Results: Vitamin K₂ (2–40 μM) significantly decreased the levels of DCP production in supernatant of PLC/PRF/5 and HepG2 cells and in serum of nude mice bearing HCC xenografts. The inhibition of DCP was also observed using the assays of Western blot analysis in HCC cultures and immunohistochemical analysis in HCC xenografts in mice. As a result of administration of vitamin K₂, the capacity of HCC growth was inhibited and the invasion and migration of tumor cells were decreased. Furthermore, the inhibitory effects of HCC growth were also observed in vivo and the sensitivitywas well correlated with the decrease of DCP in the serum of mice. Conclusion: Vitamin K₂ might suppress the growth and invasion of HCC cells via decrease of DCP.

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Serum and tissue PIVKA-II expression reflect the biological malignant potential of small hepatocellular carcinoma

Cited by 27 publications

References 17 publications

Protein induced by vitamin K absence or antagonist-II production is a strong predictive marker for extrahepatic metastases in early hepatocellular carcinoma: a prospective evaluation

Protein induced by vitamin K absence or antagonist-II production is a strong predictive marker for extrahepatic metastases in early hepatocellular carcinoma: a prospective evaluation

Tumor Marker Levels Before and After Curative Treatment of Hepatocellular Carcinoma as Predictors of Patient Survival

Vitamin K<sub>2</sub> Inhibits the Growth of Hepatocellular Carcinoma via Decrease of Des-Gamma-Carboxy Prothrombin

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