Beta-catenin mutations are frequent in hepatocellular carcinomas but absent in adenomas induced by diethylnitrosamine in B6C3F1 mice

Activating mutations in the region of the beta-catenin gene corresponding to the NH2-terminal phosphorylation sites of glycogen synthetase kinase 3beta have been causally implicated in carcinogenesis. In this study, the beta-catenin exon 3 was examined in hepatic lesions induced by diethylnitrosamine in B6C3F1 mice. PCR and DNA sequencing detected seven beta-catenin mutations in 13 samples dissected from hepatocellular carcinoma tissues, but none in 14 hepatic adenomas. All of the mutations were found in codon 41 encoding a threonine residue, one of the possible glycogen synthetase kinase-3beta phosphorylation sites. Although beta-catenin protein was immunohistochemically stained mainly on the cell membrane in preneoplastic hepatocytic foci and most adenomas, as observed in normal hepatocytes, it was detected in the cytoplasm and nuclei in addition to the cell membrane, indicating stabilization of the protein in HCCs. This shift in staining was observed not only in tumors with mutations, but also in examples lacking exon 3 mutations. Our data demonstrate that beta-catenin alterations may be important for malignant progression during multistep hepatic carcinogenesis in mice.     

Vascular endothelial growth factor expression in preoperative biopsy specimens correlates with disease recurrence in patients with early gastric carcinoma.

BACKGROUND: Recently many studies have demonstrated that the degree of tumor angiogenesis is related to the aggressiveness of the tumor and clinical outcome. Vascular endothelial growth factor (VEGF) is a well characterized inducer of angiogenesis. In this study, the authors investigated the prognostic significance of VEGF expression in patients with early gastric carcinoma together with p53 gene abnormality and tumor cell proliferation. METHODS: One hundred ninety-five endoscopically biopsied specimens obtained preoperatively from patients with early gastric carcinoma were studied immunohistochemically. RESULTS: According to conventional clinicopathologic factors, submucosal invasion, lymph node metastases, and tumor size were associated significantly with the incidence of disease recurrence. According to conventional biologic factors, VEGF expression was observed more frequently in patients with disease recurrence compared with those without disease recurrence whereas neither p53 abnormality nor tumor cell proliferation were correlated with prognosis. Moreover, multivariate analysis indicated that VEGF expression (as well as submucosal invasion and lymph node metastases) is an independent predictor of disease recurrence. CONCLUSIONS: The results of the current study show that VEGF expression may be a useful prognostic factor for patients with early gastric carcinoma.     

Reduced expression of p27(Kip1) protein in relation to salivary adenoid cystic carcinoma metastasis.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a malignant tumor of salivary gland origin. It tends to grow slowly but shows frequent recurrence and metastasis, ultimately with a poor outcome. Reduced expression of a cyclin-dependent kinase inhibitor, p27(Kip1), has been reported to correlate with poor survival for patients with various types of carcinoma. However, there has been no previous study reported of p27(Kip1) expression in ACC, to the authors' knowledge. METHODS: To evaluate p27(Kip1) as a prognostic marker, the authors examined the immunohistochemical expression of p27(Kip1) protein in 29 ACCs and correlated its expression with clinicopathologic findings. Eleven pleomorphic adenomas (PAs) were also examined to compare the p27(Kip1) expression in benign and malignant salivary gland tumors. RESULTS: All PAs expressed p27(Kip1) at high levels, whereas 83% of ACCs (24 of 29) showed reduced expression of this protein. Furthermore, the expression levels were significantly lower in ACCs with metastasis than in those without metastasis. The authors also examined the expression of p27(Kip1) in 2 ACC cell lines (ACCh and ACC3) by Northern and Western blot analysis to elucidate the possible mechanism of p27(Kip1) reduction in ACC. Both ACCh and ACC3 expressed p27(Kip1) mRNA, but ACCh did not produce p27(Kip1) protein. In ACCh, the expression of p27(Kip1) protein was induced by treatment with a proteasome inhibitor. CONCLUSIONS: Overall, these findings suggest that reduced expression of p27(Kip1) may correlate with the development and progression of salivary ACC and can be an indicator of its malignant behavior. They also suggest that increased proteasome-mediated degradation may play an important role in this reduction of p27(Kip1) expression.     

Blood Flow and Metabolism of Oligodendrogliomas: A Positron Emission Tomography Study with Kinetic Analysis of 18F-fluorodeoxyglucose

To accurately characterize the pathophysiology and proliferating activity of oligodendrogliomas, we studied cerebral blood flow and metabolism using positron emission tomography (PET) in five patients with this tumor. Regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), oxygen extraction fraction (rOEF), and cerebral metabolic rates of oxygen (rCMRO₂) and of glucose (rCMRGl) were quantitatively measured in tumor lesions and the contralateral gray matter. rCMRGl was analyzed based on both kinetic and autoradiographic methods. Tumor rCBF and rCBV were lower than in the contralateral gray matter in all preoperatively examined patients. Oxygen metabolism, determined by rCMRO₂ and rOEF, was consistently reduced in the tumor (rCMRO₂, P<0.05 vs. gray matter, determined by the Student's t-test). Tumor rCMRGl was significantly lower than the gray matter rCMRGl in both kinetic (P<0.01) and autoradiographic (P<0.05) analyses. Kinetic tumor rCMRGl varied between 1.22 and 4.13mg/100ml/min, but was lower than the gray matter value in all patients. Autoradiographic tumor rCMRGl, which ranged from 1.02 to 5.79mg/100ml/min, was also reduced in all tumors but one; the remaining tumor, which had a relatively high value of autoradiographic rCMRGl (comparable to gray matter rCMRGl), infiltrated the contralateral hemisphere through the corpus callosum, and was characterized by high cellular density. In one patient who suffered from tumor recurrence 8 years and 10 months after initial treatment, phosphorylation constant (K3) and kinetic rCMRGl of the recurring tumor were higher than those of the original tumor. No other tumors have regrown or recurred during the postoperative follow-up periods, which ranged from 22 to 130 months (median=101 months). Circulation and metabolism measured by PET provide in vivo biological characteristics, including proliferating activity, in oligodendrogliomas.     

Increased serum soluble Fas ligand associated with recurrent B-cell non-Hodgkin's lymphoma after autologous peripheral blood stem cell transplantation.

Fas-ligand (FasL) is a member of the tumor necrosis factor family and transmits apoptotic cell death signal by binding to its receptor, Fas. FasL is expressed on the cell surface of activated T-cell and natural killer (NK) cell. It has been shown that the FasL can be released from the cell surface by metalloproteinase. The serum soluble FasL (sFasL) is increased in some patients with NK cell lymphoma/large granular lymphocytic leukemia. We have recently seen a patient with recurrent B-cell lymphoma accompanied with an increased serum sFasL level after autologous peripheral blood stem cell transplantation. The sFasL was markedly decreased with the tumor regression induced by the chemotherapy. We present here the first case of an elevated serum sFasL level associated with B-cell lineage malignancy and discuss the possible clinical value of sFasL.     

Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas.

Recently, we demonstrated that elevated expression of cyclooxygenase 2 (COX-2) is frequently seen in a specific type of lung cancer, i.e., adenocarcinoma, and is possibly associated with its invasion and metastasis. Here, the prognostic significance of elevated COX-2 expression was evaluated in a cohort of 130 adenocarcinoma patients who had consecutively undergone potentially curative resections. Immunohistological examination showed the presence of tumor cells with markedly increased COX-2 immunoreactivity in 93 of 130 (72%) cases. No relationship was found between the increase in COX-2 expression and clinical outcomes when the entire cohort was considered (P = 0.099). Reasoning that the influence of the increase in COX-2 expression may have been obscured by the clinical and molecular pathogenetic complexities in cases with an advanced disease, we also separately analyzed the prognostic significance of increased COX-2 expression after stratification according to the disease stage. A significant relationship between elevated COX-2 expression and shortened patient survival was observed only in a cohort of patients with stage I disease (P = 0.034). These findings suggest that an increase in COX-2 expression may be clinically significant for the prognosis of patients undergoing surgical resection of early-stage adenocarcinomas and, thus, warrant further conclusive studies involving a larger cohort.     

Estrogen receptor status is the most important prognostic factor in breast cancer with ten or more positive lymph nodes

Background. In breast cancer, the prognosis worsens with increasing lymph node involvement, and aggressive therapies may prolong survival in patients with advanced breast cancer. However, there are sub-populations of patients with advanced breast cancer with ten or more diseased nodes who have long survival. Implementing appropriate treatment depends on having a realistic and well-founded view of the prognosis. Methods. Sixty-nine patients (mean follow-up, 46 months) were enrolled. All patients underwent adjuvant therapy following radical mastectomy. Thirty-seven patients relapsed after curative surgery and 40 died of their cancer. Clinicopathologic factors, tumor estrogen receptor (ER) status, progesterone receptor status, and p53 protein expression were analyzed for prognostic significance. Results. Lower lymph node stage and positive ER status reflected longer relapse-free survival (P = 0.001 and P = 0.0001, respectively). Lower tumor stage (P = 0.039), lower lymph node stage (P = 0.006), absence of distant metastasis (P = 0.006), positive ER status (P = 0.0002), and negative p53 status (P = 0.02) reflected longer overall survival. ER status was the only independent significant prognostic factor for both relapse-free and overall survival. Conclusion. ER status, an indicator of response to endocrine therapy, was the most significant factor predicting prognosis in patients with breast cancer with ten or more positive lymph nodes. Received: February 25, 1998 / Accepted: December 24, 1998