Liver neoplasm

Abstract: Four thousand eighty inbred rats were maintained from weaning on various different concentrations of N -nitrosodiethylamine (NDEA) or N -nitrosodimethylamine (NDMA). The principal aim was to characterize the dose-response relationship for the effects of these agents on esophageal cancer (NDEA) or on various types of liver cancer (NDEA and NDMA), although NDEA also caused a few tumors of the nasopharynx and NDMA also caused a few tumors of the lung. The numbers of tumors of mesenchymal and Kupffer cells in the liver were too few to allow easy characterization of the dose-response relationships, and although NDMA induced large numbers of bile duct neoplasms, NDEA did not. Thus, the four principal dose-response relationships studied were of NDEA on esophageal or liver cells and of NDMA on bile duct or liver cells. At doses sufficiently high for the median time to death from the disease of interest to be estimated, relationships were observed of the general form (Dose rate) × (median) n = constant where n was about 2.3 for the first three relationships and about 1 for the last one (NDMA on liver cell tumors). By contrast, at doses sufficiently low for longevity to be nearly normal (median survival about 2.5 years), there remained no material dependence on the dose rate of the age distribution of the induced neoplasms. At these low dose rates, the number of liver (but not of esophageal) neoplasms induced by treatment was simply proportional to the dose rate. This finding is not surprising, since the background incidence of liver (but not of esophageal) neoplasms was appreciable. The linear relationship observed at low dose rates (below 1 ppm) suggests that under these experimental conditions, among rats allowed to live their natural life span, a dose of 1 ppm of NDEA or NDMA in the drinking water will cause about 25% to develop a liver neoplasm, a dose of 0.1 ppm will cause about 2.5% to do so, and a dose of 0.01 ppm will cause about 0.25% to do so, etc., with no indication of any “threshold.” (At these low dose rates, the incidence of liver neoplasms appears likely to exceed greatly that of esophageal neoplasms.) In addition, even quite low dose rates of the test agents caused a variety of nonneoplastic liver abnormalities ( e.g. , hyperplastic nodules, or shrinkage of hepatocytes) at a frequency roughly proportional to the dose rate.

Abstract: Aberrant promoter methylation is a fundamental mechanism of inactivation of tumor suppressor genes in cancer. The Ras association domain family 1A gene (RASSF1A) is frequently epigenetically silenced in several types of human solid tumors. In this study, we have investigated the expression and methylation status of the RASSF1A gene in hepatocellular carcinoma (HCC). In two HCC cell lines (HepG2 and Hep3B) RASSF1A was inactivated and treatment of these cell lines with a DNA methylation inhibitor reactivated the transcription of RASSF1A. The methylation status of the RASSF1A promoter region was analysed in 26 primary liver tissues including HCC, hepatocellular adenoma (HCA), liver fibrosis, hepatocirrhosis. Out of 15, 14 (93%) HCC were methylated at the RASSF1A CpG island and hypermethylation was independent of hepatitis virus infection. RASSF1A was also methylated in two out of two fibrosis and in three (75%) out of four cirrhosis; the latter carries an increased risk of developing HCC. Additionally, we analysed the methylation status of p16INK4a and other cancer-related genes in the same liver tumors. Aberrant methylation in the HCC samples was detected in 71% of samples for p16, 25% for TIMP3, 17% for PTEN, 13% for CDH1, and 7% for RARβ2. In conclusion, our results demonstrate that RASSF1A and p16INK4a inactivation by methylation are frequent events in hepatocellular carcinoma, but not in HCA, which is in contrast to HCC without cirrhosis, viral hepatitis, storage diseases, or genetic background. Therefore, this study gives additional evidence against a progression of adenoma to carcinoma in the liver. Thus, RASSF1A hypermethylation could be useful as a marker of malignancy and to distinguish between the distinct forms of highly differentiated liver neoplasm.

Abstract: OBJECTIVE To evaluate whether the histopathological differentiation and the expression of vascular endothelial growth factor (VEGF) of hepatocellular carcinoma (HCC) do show correlation with the apparent diffusion coefficient (ADC) value on diffusion-weighted imaging (DWI). MATERIALS AND METHODS Twenty-seven HCCs from 27 patients who had undergone preoperative liver MRI (1.5T) and surgical resection were retrospectively reviewed. DWI was obtained with a single-shot, echo-planar imaging sequence in the axial plane (b values: 0 and 1,000 sec/mm(2)). On DWIs, the ADC value of the HCCs was measured by one radiologist, who was kept 'blinded' to the histological findings. Histopathologically, the differentiation was classified into well (n = 9), moderate (n = 9) and poor (n = 9). The expression of VEGF was semiquantitatively graded as grade 0 (n = 8), grade 1 (n = 9) and grade 2 (n = 10). We analyzed whether the histopathological differentiation and the expression of VEGF of the HCC showed correlation with the ADC value on DWI. RESULTS The mean ADC value of the poorly-differentiated HCCs (0.9 +/- 0.13x10(-3) mm(2)/s) was lower than those of the well-differentiated HCCs (1.2 +/- 0.22x10(-3) mm(2)/s) (p = 0.031) and moderately-differentiated HCCs (1.1 +/- 0.01x10(-3) mm(2)/s) (p = 0.013). There was a significant correlation between the differentiation and the ADC value of the HCCs (r = -0.51, p = 0.012). The mean ADC of the HCCs with a VEGF expression grade of 0, 1 and 2 was 1.1 +/- 0.17, 1.1 +/- 0.21 and 1.1 +/- 0.18x10(-3) mm(2)/s, respectively. The VEGF expression did not show correlation with the ADC value of the HCCs (r = 0.07, p = 0.74). CONCLUSION The histopathological differentiation of HCC shows inverse correlation with the ADC value. Therefore, DWI with ADC measurement may be a valuable tool for noninvasively predicting the differentiation of HCC.