DNA hypermethylation of zygote arrest 1 (ZAR1) in hepatitis C virus positive related hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common human malignancies in the world, and its prognosis is generally poor. Epigenetic alteration such as DNA methylation has been shown to be important in the development of human cancers including HCC. Here, we analyzed the methylation status of ZAR1, which has been reported to be aberrantly methylated in a few human cancers. METHODS: We investigated the methylation status of ZAR1 in 88 HCV-positive HCC and matched nontumorous liver tissue samples and 4 normal liver tissue samples used as a control using MassARRAY EpiTYPER. Further statistical analysis was performed to determine the relationship between methylation level and patient clinicopathological features and prognosis. RESULTS: CpG islands in ZAR1 exon 1 showed a higher methylation level in all 88 HCC than in nontumorous tissues. The hypermethylation group, whose cancer tissues showed a twofold or higher methylation level compared with nontumorous tissues, showed a significantly higher serum AFP (p = 0.018) and lower serum albumin (p = 0.001) and single rather than multiple tumors (p = 0.031) compared with the hypomethylation group. Multivariate regression analyses were performed to identify which of the following factors were the predictors of the hypermethylation group: serum albumin, AFP, and tumor multiplicity. This study showed that patients who had Zar1 hypermethylation in the HCC tissues had a significantly lower serum albumin level than those in the hypomethylation group (p = 0.007). CONCLUSION: Although it is still unknown how ZAR1 hypermethylation affects HCC development, it could be a potential marker to detect HCV-related HCC.

Reduced transforming growth factor-beta receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis.

Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-beta (TGF-beta) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-beta signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-beta signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-beta receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-beta. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (P<0.001), poor differentiation (P<0.001), portal vein invasion (P=0.002), intrahepatic metastasis (IM) (P<0.001), and shorter recurrence-free survival (P=0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC.

[Case report of transarterial chemoembolization to lymph node metastasis of hepatocellular carcinoma].

We performed transarterial chemoembolization (TACE) on the 67-year-old man who had hepatectomy for hepatocellular carcinoma with hepatitis C, recurrence in the liver and lymph nodes.The metastasis in lymph node did not show a clear increase until dying, and TACE showed the possibility of one treatment method to the metastasis in lymph node of the hepatocellular carcinoma.

Two cases of primary malignant fibrous histiocytoma of the liver: immunohistochemical expression of ezrin and its relationship with prognosis.

Malignant fibrous histiocytoma (MFH) as soft tissue sarcoma would not be especially noteworthy, but primary hepatic MFH reports are extremely rare. Herein, we report ezrin expression in tumor tissues from two primary hepatic MFH cases with different prognoses. Cases 1 and 2 were both women, ages 45 and 70 years, respectively. Case 1 had an 11 x 10 cm liver tumor in segment (S) 3, and case 2 had two liver tumors, 12 x 8 cm in S5 and 10 x 7 cm in S8. Neither had any other systemic tumors. Cases 1 and 2 survived for two year and ten months and for eight and a half months, respectively, after the initial tumor resection. Microscopically, the tumors of these two cases were similar and showed proliferation of atypical cells, including spindle, pleomorphic and multi-nucleated giant cells arranged in storiform, sheet and/or fascicle patterns, with scattered foci of inflammatory cells, indicating MFH. Ezrin expression in tumor tissue from case 1 was sparse, whereas that of case 2 showed strong ezrin expression in many tumor cells. The present results indicate ezrin immunoreactivity in primary hepatic MFH to correlate possible with prognosis, which is consistent with reports on some other types of malignancies.

[Elderly patient with metastatic gallbladder cancer treated by cisplatin, epirubicin and continuous infusion 5-fluorouracil].

An 80-year-old woman, who was followed as an A-bomb victim, was diagnosed to have advanced gallbladder cancer with liver metastasis on December, 2005. Due to her advanced age, her previous doctor recommended the best supportive care. Therefore, her general condition was good, so we decided to treat her with cisplatin, epirubicin and continuous infusion of 5-fluorouracil(CEF therapy). She was given 5-fluorouracil 500 mg/body per day via continuous infusion on days 1 to 5, cisplatin 50mg body and epirubicin 20mg body on day 1 every 28 days, and these dosages have been reduced. CEF therapy was started from February, 2007. Primary lesion and liver metastasis decreased remarkably after completion of 2 cycles, and we judged it as a complete response. After 10 cycles, lung metastasis was found by CT scan in August, 2007. We tried chemotherapy with gemcitabine as a second-line treatment. The result of gemcitabine was again a progressive disease, so we switched her regimen to S-1 as a third-line treatment on January, 2008. Chemotherapy is continued by the outpatient care now, 25 months after the medical treatment started. The present result suggests that CEF therapy may be useful for metastatic gallbladder cancer.

[A case of advanced sigmoid colon cancer with peritoneal dissemination responding to FOLFOX4 therapy].

A 62-year-old woman complained of thin feces, lower blood and abdominal pain, and she was diagnosed as having bowel obstruction due to sigmoid colon cancer. Abdominal CT showed peritoneal dissemination and ascites on the surface of liver. The serum CEA levels were 663.7 ng/mL. We established a diagnosis of unresectable sigmoid colon cancer accompanied by severe peritoneal dissemination and therefore performed only transverse colostomy in April, 2006. Pathological examination of omental dissemination demonstrated moderately-differentiated adenocarcinoma. FOLFOX4 therapy was started on April, 2006. Primary lesion decrease and release from bowel obstruction after 4 cycles was judged as a partial response. The partial response continued, and the serum CEA decreased 18.5 ng/mL after completion of 16 cycles, but grade 3 neuropathy occurred. We started S-1 as second-line chemotherapy in May, 2007. There was primary lesion re-growth after 4 cycles, so we changed to S-1+CPT-11 therapy. The adverse events were grade 3 neuropathy and leucopenia throughout the course. Chemotherapy is now continued on an outpatient basis, 24 months after the medical treatment started. FOLFOX4 therapy is useful for patients with advanced colon cancer accompanied by peritoneal dissemination.