c-erb-2 amplification and overexpression are currently attracting a great deal of attention because a new adjuvant therapy using an antibody against the c-erbB-2 gene product, trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), has proved effective in treating breast cancer with amplification and/or overexpression of c-erbB-2. Aberrations of c-erbB-2 have also been detected in ovarian, endometrial and gastric carcinomas at varied frequencies. Amplification of the c-erbB-2 locus (17q12-q21.32), overexpression of c-erbB-2 protein (p185) and serum levels of soluble c-erbB-2 protein fragments (p105) were examined in gastric cancer patients using fluorescence in situ hybridization (FISH), immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Overexpression of c-erbB-2 protein was found in 29 (8.2%) of the 352 gastric carcinomas analyzed. In FISH analysis, all tumors with 3؉ immunostaining and 1 of 5 tumors with 2؉ staining showed high-level amplification of c-erbB-2. Pre-operative serum p105 was quantified in serum specimens from 129 patients with gastric cancer and 28 patients with benign diseases. There were no significant differences in the serum p105 levels among 11 patients with c-erbB-2-overexpressing carcinomas, 118 patients with c-erbB-2 non-overexpressing carcinomas and 28 controls, although a single case of gastric carcinoma overexpressing c-erbB-2 with extensive liver metastasis had a higher level than the cut-off value. The mechanisms of overexpression of p185 and highlevel amplification of c-erbB-2 in gastric adenocarcinomas seem similar to those well-established in breast cancers. Patients having gastric adenocarcinoma with c-erbB-2 amplification are potential candidates for a new adjuvant therapy using humanized monoclonal antibody.
Background: Patients with gastric cancers producing alpha-fetoprotein (AFP) were reported to have a poor prognosis with high rates of liver metastasis. The purpose of the present study was to clarify the clinicopathological features of AFP-producing gastric cancers, in particular characteristics of liver metastasis, and to evaluate treatment of these cancers. Methods: In 27 of the 29 cases with elevated preoperative serum AFP levels among a total of 974 primary gastric cancers, AFP production was confirmed in gastric cancer cells by immunohistochemistry. These cases were included in the AFP-positive gastric cancer group (AFP(+), 2.7%). The remaining 945 cases with normal serum AFP levels were designated the AFP-negative gastric cancer group (AFP(–)). Results: There was a higher incidence of lymph node metastasis, a deeper invasion of the gastric wall, a higher frequency of advanced stage, a more marked lymphatic invasion and a higher rate of liver metastasis in the AFP(+) group than in the AFP(–) group. The patients received curative resection in AFP(+) group had a significantly worse survival rates in comparison to that in AFP(–) group. With respect to liver metastasis (n = 17) in AFP(+) group, of 3 cases who received curative hepatic resection, 1 patient survived more than 3 years, while the remaining 2 died in less than 3 years due to multiple liver recurrence. The patients (n = 5) who received palliative resection for liver metastasis followed by transarterial continuous infusion chemotherapy all died in less than 1 year. Conclusion: AFP-producing gastric cancers had aggressive behavior and their clinical or biological features were quite different from the common AFP-negative gastric cancers. Surgical resection of liver metastasis from AFP-producing gastric cancers was unsatisfactory. The development of a novel multimodal therapy against AFP-producing gastric cancers is needed.
Liver metastasis is one of the poor prognostic factors for gastric cancer. Hepatocyte growth factor (HGF) and its receptor, c-Met, have been reported to be related to the proliferation of carcinoma cells. We examined c-Met and HGF expression in stage IV gastric cancers (n = 121) and compared the results in groups with liver metastasis (n = 47, LM group) and without liver metastasis (n = 74, no-LM group). The survival rate for the LM group was significantly poorer than for the no-LM group (p < 0.01). We found a high frequency of c-Met expression in the LM group compared with the no-LM group at protein level detected by immunohistochemistry (p = 0.0005) and at mRNA level detected by semiquantitative reverse transcriptase-polymerase chain reaction (p = 0.0386) in primary gastric tumors. Furthermore, we evaluated HGF expression in both carcinoma cells and stromal cells in gastric cancers. There was no significant difference in the HGF expression between the LM and no-LM groups. The labeling index of proliferating cell nuclear antigen for the carcinomas in the LM group was higher than that in the no-LM group (47.1 ± 24.5 vs. 26.2 ± 24.5%, p < 0.0001). Thus, the high frequency of c-Met overexpression in carcinoma cells may be involved in the mechanism of liver metastasis in gastric cancers. Moreover, the evaluation of c-Met expression might be a useful indicator of liver metastasis in patients with gastric cancer.
To investigate the prognostic factors of pancreatic cancer, a retrospective analysis of 193 patients who underwent curative resection was conducted. Of the 193 patients, 38 (20%) survived for more than 5 years, the 5-year survival rates for stages I, II, II, and IV disease being 41%, 17%, 11%, and 6%, respectively. According to a multivariate analysis, lymph node metastasis, intrapancreatic perineural invasion, and portal vein invasion were significant prognostic factors. Subsequently, a subgroup analysis concerning nodal metastasis and intrapancreatic perineural invasion was performed in 126 patients with records of these histological findings. In the group of patients without nodal metastasis, the 5-year survival rate for those without perineural invasion was 75%, whereas that for those with perineural invasion was 29%, the difference in survival of these subgroups being significant (P < 0.02). In the group of patients with nodal metastasis, the 5-year survival rate for those without perineural invasion was 17%, while that for those with perineural invasion was 10%. The most favorable 5-year survival of 89% was observed in the subgroup of patients with stage I disease without perineural invasion. Thus, pancreatic adenocarcinoma categorized by the combination of these independent types of biological behavior showed 5-year survival rates ranging from very high to low, indicating that these two factors play an important role in the prognosis of this disease.
We investigated the effects of gadolinium chloride (GdCl3.6H2O), which blocks phagocytosis by liver macrophages, on the mortality, blood tumor necrosis factor (TNF) levels, and hepatotoxicity in a lethal endotoxic shock rat model system [10 mg/kg body weight lipopolysaccharide (LPS) intravenously]. With administration of GdCl3, twice at 0.5 or 5 mg/kg, the survival rate 24 h after LPS injection was 56% and 100%, respectively, whereas the level of TNF in blood was not affected. Microscopic investigation of the liver revealed that the focal necrosis of hepatocytes under endotoxemia was completely protected by the administration of GdCl3 at 5 mg/kg. We then investigated the effects of GdCl3 on superoxide (O2-) production by isolated liver macrophages in vitro. The O2- production by liver macrophages isolated from control rats was suppressed by GdCl3 in a dose-dependent manner. GdCl3 also had a cytotoxic effect on these macrophages. The enhanced O2- production by liver macrophages isolated from sublethal endotoxemic (1 mg/kg) rats was suppressed by pretreatment with GdCl3 (5 mg/kg). It was suggested that lethality in endotoxemia cannot be explained only by the degree of increase in blood TNF levels and that the mechanism by which GdCl3 reduces mortality and hepatotoxicity in endotoxemia possibly includes suppression of superoxide production by liver macrophages.
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