The aim of the study was to identify the most effective serum tumor markers for early diagnosis of hepatocellular carcinoma based on the combination of diagnostic characteristics and correlations. Materials and Methods. There were observed 55 patients with chronic hepatitis C in the stage of liver cirrhosis with a verified diagnosis of hepatocellular carcinoma. The control group consisted of 55 patients with chronic hepatitis C at the stage of liver cirrhosis without hepatocellular carcinoma, comparable to the experimental group in terms of basic clinical profile. The following tumor markers were estimated in both groups: alpha-fetoprotein (AFP), alpha-fetoprotein-L3 (AFP-L3), annexin A2 (ANXA2), heparin-binding growth factor Midkine (MDK), glypican-3 (GPC3), des-gamma-carboxyprothrombin (DCP, PIVKA-II), dickkopf-related protein 1 (DKK-1), osteopontin (OPN), and Golgi protein 73 (GP73). There were also evaluated such indices as diagnostic sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio of a positive test, the possible correlation between alpha-fetoprotein and other tumor markers. The area under the ROC curve (AUC) was calculated at the 95% confidence interval. Results. The greatest sensitivity was revealed when using heparin-binding growth factor, annexin A2, osteopontin. Alpha-fetoprotein, alpha-fetoprotein-L3, glypican-3, des-gamma-carboxyprothrombin, dickkopf-related protein 1 had the best specificity. AUC>0.75 was found in annexin A2, heparin-binding growth factor, glypican-3, des-gamma-carboxyprothrombin, osteopontin, Golgi protein 73. The likelihood ratio of a positive test result was the highest for glypican-3. A significant correlation was found between alpha-fetoprotein and alphafetoprotein-L3, annexin A2, des-gamma-carboxyprothrombin. Conclusion. According to the aggregate indicators of diagnostic efficiency, heparin-binding growth factor, glypican-3, and osteopontin are the most promising tumor markers of those studied. When they are used, integral AUC values are above the average, the level of these tumor markers in the blood of patients with hepatocellular cancer does not correlate with alpha-fetoprotein. They are applicable for diagnosing liver cancer in AFP-negative patients. The combined use of AFP + GPC3, AFP + OPN has already shown their advantages. However, the efficacy of the combination of AFP + MDK, GPC3 + OPN has not been determined yet; therefore, significance of the combined use of these tumor markers in the diagnosis of liver cancer should be investigated in the near future.
Hepatocellular carcinoma (HCC) is the second leading cause of death in oncological patients. The prognosis of the disease outcome depends directly on its timely detection. Currently, in the majority of countries, the diagnostic algorithm at the preclinical stage of tumor development includes determination of alpha-fetoprotein in combination with instrumental imaging techniques. This approach allows the detection of about 65-80% of liver tumors at an early stage (A according to the BCLC classification), whereas at a very early stage (0 according to the BCLC classification) only 32-50% of cases, the result which cannot be considered satisfactory. In this regard, the search for effective biomarkers of hepatocellular carcinoma is an important challenge that faces the world healthcare. Advances in proteomics and genomics have led to the discovery of numerous promising markers which are now being clinically tested. Molecules of protein nature proposed as hepatocellular carcinoma tumor markers in different periods of time are described in this review. Comparative data on their effectiveness and specificity are also presented. The possibility of isolated or combined use of these biomarkers for risk assessment and early diagnosis of primary liver cancer is considered.
Background and aim: Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. PI3K/AKT pathway is activated in 50% of HCC. The aim of this study was to assess toxicity and efficacy of a new AKT inhibitor (ARQ 092) compared to sorafenib. Method: In vitro experiments were realized with viability, apoptosis and migration assays in 5 different cell lines to analyze the effects of ARQ 092 and sorafenib on the different mechanisms of carcinogenesis. Furthermore, an in vivo study with a diethylnitrosamine (DEN)-induced rat model of HCC on cirrhosis was performed. After 14 weeks of DEN, rats were randomized in 3 groups: control, sorafenib, or ARQ 092 and treated during 6 weeks. Tumor volume and progression were assessed by MRI before treatment, after 3 and 6 weeks of treatment. After euthanasia, pathological analysis of livers was performed assessing tumor numbers and volumes. Results: ARQ 092 showed a dose-dependent decrease in cell viability, induction of apoptosis, and inhibition of migration. In vivo study on 26 rats showed a significantly lower tumor volume in ARQ 092 group: 45.9% of the control versus 60.4% of the control with sorafenib (p = 0.022). Number of tumors per liver was also significantly lower in ARQ 092 group with a mean of 53.9 tumors versus 96.3 tumors in control group (p = 0.001) and 96.8 tumors in sorafenib group (p = 0.015). MRI analysis showed a lower tumor progression in ARQ 092 group with 57.0% versus 155.3% in control group (p<0.0001), and 80.2% in sorafenib group (p = 0.08). Conclusion: ARQ 092 was more significantly control tumor progression in a DEN-induced cirrhotic rat model with HCC compared to sorafenib. Citation Format: Gael S. Roth, Ayca Zeybek, Zusana Macek-Jilkova, Giovanni Abbadessa, Yi Yu, Patrice Marche, Vincent Leroy, Thomas Decaens. Efficacy of AKT inhibitor ARQ 092 compared with Sorafenib in a cirrhotic rat model with hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B111.
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