Preserved Smad4 expression in the transforming growth factor beta signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer.

The signals of the transforming growth factor beta (TGF-beta) superfamily are conveyed through cell surface serine/threonine kinase receptors to the intracellular mediators known as Smads. Activation of Smads causes their translocation from the cytoplasm to the nucleus, where they function to control gene expression. The present study analyzed the expression of Smad4 and TGF-beta1 to determine their prognostic significance in advanced gastric cancer. Of 249 cases of advanced gastric cancer, 41 had invaded the muscular layer, 114 had invaded the subserosal layer, and 94 had invaded the serosa. Anti-Smad4 and TGF-beta1 antibodies were used for immunohistochemical staining. Reduced expression of Smad4 was 75.1%, whereas positive expression of TGF-beta1 was 39.6% in gastric cancer. Smad4 expression was related to the depth of tumor invasion (P < 0.05), and TGF-beta1 expression correlated with tumor gross type (P < 0.05). Postoperative survival analysis indicated that patients who had a tumor with reduced Smad4 expression had a poorer clinical outcome than those with preserved expression (P < 0.05). Furthermore, in patients with TGF-beta1-positive tumors, survival rate was significantly better in patients with preserved Smad4 expression than in those with reduced Smad4 expression (P < 0.05). According to multivariate analysis, Smad4 expression acted as an independent prognostic factor. Smad4 expression, particularly in the TGF-beta pathway, is an effective predictor of outcome for patients with advanced gastric cancer.

Intranodal antitumor immunocyte infiltration in node-negative gastric cancers.

The status and role of immunocytes and dendritic cells in regional lymph nodes in patients with gastric cancer are examined in this study. Forty-nine patients with gastric cancer who underwent curative resection were enrolled in the present study. These patients had no lymph node metastases according to a histological examination. The infiltration of natural killer (NK) cells, dendritic cells, and MIB-1-positive immunocytes was investigated. Based on the Japanese Classification of Gastric Carcinoma, regional lymph nodes were divided into three compartments: (a) compartment 1 (lymph node station numbers 1-6); (b) compartment 2 (lymph node station numbers 7-12); and (c) compartment 3 (lymph node station numbers 14 and 16). Dendritic cells and MIB-1-positive immunocytes infiltrated compartment 1 lymph nodes in increased numbers compared with the lymph nodes of compartments 2 or 3 (P < 0.05). Conversely, intranodal NK cell infiltration did not differ significantly among the three compartments. The incidence of intranodal dendritic and MIB-1-positive cell infiltration in patients with submucosal gastric cancer was significantly higher than in patients with tumors that invaded beyond the muscularis propria. The decreased expression of these immunological markers correlated well with recurrent disease, regardless of tumor depth. The immunocyte level is higher in lymph nodes near the primary tumor (compartment 1) than in those that are distant from the tumor (compartments 2 and 3). This pertains to all three markers, i.e., NK, dendritic, and MIB-1-positive cells. Unlike dendritic and MIB-1-positive cells, intratumoral infiltration of NK cells did not correlate well with either lymph node compartment or the depth of tumor invasion. The degree of NK cell infiltration may be directly associated with antitumor effects, especially in compartment 1. A decrease in all three markers is associated with tumor recurrence.

Expression of p21WAF1/Cip1 in the p53-dependent pathway is related to prognosis in patients with advanced esophageal carcinoma.

The proteins p53 and p21 are important components that regulate G1-S transition through the cell cycle. We immunohistochemically investigated p53 and p21 expression in 111 patients with esophageal squamous cell carcinoma. We also evaluated whether the expression of either of these proteins is a prognostic factor according to the p53-dependent and -independent pathways. The positive rates of p53 and p21 expression were 42.8 and 43.2%, respectively. Clinicopathological findings according to p53 and p21 expression did not differ significantly. The 5-year-survival rates between p21 positive and negative expression did not differ significantly in the p53-positive group. In the p53-negative group, the 5-year-survival rate of patients with p21-positive expression was 22.9%, which was significantly better than that of patients with p21-negative expression (12.7%; P<0.05). Multivariate analysis revealed that p21 expression in the p53-dependent pathway was an independent prognostic factor. Accordingly, the prognostic values of p21 expression between the p53-dependent and -independent pathways differed. Examination of p21-positive expression in the p53-dependent pathway will help to estimate the favorable prognosis of patients with advanced esophageal carcinoma.

p21 expression is a prognostic factor in patients with p53-negative gastric cancer.

The expression of p21 and p53 proteins was analyzed by immunohistochemistry in 256 patients with advanced gastric cancer. The results showed that strong, weak and negative expression of p21 were detected in 22.2 (57/256), 68.0 (174/256) and 9.8% (25/256) of the patients, respectively. p53 expression was found in 28.9% (74/256). The expression of p21 was not associated with clinicopathological features. In p53 negative tumors, p21 expression was associated with the survival of patients who underwent curative operations (P = 0.007). The 5-year survival rates were 20.1, 36.6 and 59.8% in patients with p21-negative, -weakly positive and -strongly positive tumors, respectively. In contrast, in p53-positive tumors, prognosis did not differ in spite of p21 expression. Multivariate analysis showed that p21 expression was an independent factor in patients with p53-negative tumors. These results indicate that examination of p21 expression in p53 negative tumors will be useful for estimating the prognosis of patients with advanced gastric cancer.

Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer.

Intratumoral natural killer cells (NKC) and dendritic cells (DC) may affect the clinical features of various gastrointestinal cancers. However, the relationship between intratumoral NKC and DC remains unclear. We examined 169 patients with gastric cancer who underwent gastrectomy at Kagoshima University Hospital. Immunohistochemical staining of CD57 and S-100-protein was performed to evaluate NKC and DC infiltration, respectively. A total of 25 areas containing pericancerous tissue were selected for determining the number of NKC and DC under high power microscopy (x400). Patients were classified into two groups according to NKC and DC population. Intratumoral lymphocytic infiltration was also calculated in 15 areas with a high power (x400) objective. The degree of NKC and DC infiltration was gradually decreased according to the progression of nodal involvement. Patients with many NKC infiltration had a lower positivity of lymph node metastasis and lymphatic invasion than patients with little NKC infiltration. DC infiltration was also negatively correlated with depth of invasion, lymph node metastasis and curativity. DC infiltration was positively correlated with lymphocytic infiltration (P=0.01. r=0.6). The 5-year survival rates of patients with many NKC infiltration and patients with DC many infiltration were 75 and 78%, respectively, both of which were significantly better than that of patients with little NKC and DC infiltration (P<0.05). NKC may be activated without DC or intratumoral lymphocytes. Intratumoral NKC may act as an independent immunologic effector against tumor cells, unlike DC.

Essential role for nuclear factor kappaB in ischemic preconditioning for cold ischemia-reperfusion injury of intestinal transplantation.

OBJECTIVE: The present study was designed to examine whether ischemic preconditioning could play a protective role on cold ischemia and reperfusion injury associated with intestinal transplantation in rats. METHODS: The 48 male Sprague Dawley (SD) rats were randomly assigned to 2 groups. Ischemic preconditioning was performed in experimental but not control rats by preserving the self donor small bowel in Ringer lactate solution at 4 degrees C for 3 hours (n = 6), 6 hours (n = 6), 12 hours (n = 6), or 18 hours (n = 6). One hour reperfusion was performed for every rat after orthotopic transplantation of donor small bowel. Small bowel samples were obtained for histological examination and immunohistochemistry analysis of nuclear factor kappaB (NF-kappaB) expression. RESULT: The small intestinal villus was arranged more regularly in experimental compared with control rats. Ischemia preconditioning also decreased edema in the muscule layer and increased Chiu score in experimental rats. Immunohistochemistry analysis revealed that ischemic preconditioning down-regulated the expression of NF-kappaB in the epithelia of experimental rats. CONCLUSION: Ischemic preconditioning improved intestinal transplantation in rats from cold ischemia and reperfusion injury by down-regulating the expression of NF-kappaB.

The cooperative role of p27 with cyclin E in the prognosis of advanced gastric carcinoma.

BACKGROUND: Cyclin E and p27 play opposing roles in the cell cycle. This study investigated the protein expression of p27 with cyclin E in the progression and prognosis of gastric carcinoma. METHODS: Of 241 patients with advanced gastric carcinoma, 38 had muscular layer invasion, 113 had subserosal layer invasion, and 90 had serosal invasion. Anti-p27 and cyclin E antibodies were used for immunohistochemical staining. RESULTS: Positive expression of p27 and cyclin E was 32.4% and 38.2%, respectively. Both p27 and cyclin E expression were related to histology of tumors but not to depth of invasion, lymph node metastasis, or stage grouping. A positive correlation was observed between p27 and cyclin E expression (P < 0. 05). Tumors were divided into two groups according to the expression of cyclin E. Within the cyclin E positive tumors, the five-year survival rate was higher in patients with a p27 positive tumor than in those with a p27 negative tumor (P < 0.05). Patients with cyclin E positive tumors showing low expression of p27 had a poor prognosis. In cyclin E negative group tumors, no significant differences were observed irrespective of p27 expression. CONCLUSIONS: Reduced p27 expression is a negative prognostic factor for patients with cyclin E positive tumors.

Angiogenesis as an unfavorable factor related to lymph node metastasis in early gastric cancer.

BACKGROUND: Recent studies suggest that angiogenesis enhances tumor growth and metastasis. Lymph node metastasis influences the prognosis and selection of treatment modalities in cancers. In this study, the authors investigated the correlation between angiogenesis and clinicopathologic features to determine whether angiogenesis correlated with lymph node metastasis in early-stage gastric cancer. METHODS: A total of 97 specimens from patients with early gastric cancer were studied by immunohistochemical methods using anti-Factor VIII-related antigen antibody. RESULTS: Tumor size was significantly correlated with microvessel count, which increased as tumor size increased. Microvessel counts from tumors with lymphatic vessel invasion, lymph node metastasis, and submucosal invasion were significantly higher than those without. Furthermore, microvessel count was an independent factor that influenced lymph node metastasis (P = .0016) by multivariate logistic regression analysis. CONCLUSION: In the early stage of gastric carcinoma, angiogenesis is an independent factor that impacts on lymph node metastasis.

The expression of cadherin-catenin complex in association with the clinicopathologic features of early gastric cancer.

Although impaired expression of E-cadherin (E-cad) is frequently observed in tumors with aggressive histopathologic characteristics, the correlation between alpha-catenin (alpha-cat) expression and the clinicopathologic features of early gastric cancer have not been fully examined. In this study, we evaluated the expression of E-cad and alpha-cat by early gastric carcinomas, and examined the relationships between this expression and various clinicopathologic characteristics. A total of 69 specimens obtained from surgery were studied by immunohistochemistry. Reduced expression of E-cad and alpha-cat were found in 53.6% and 65.2% of the tumors, respectively, and a significant correlation was observed between the decreased expression of E-cad or alpha-cat and tumor histology, the quantity of stroma, and the infiltration pattern of the tumor. The reduced expression of alpha-cat correlated more strongly with these features than E-cadherin expression. Furthermore, alpha-cat expression was also related to the lymph node metastasis of tumors. The expression of E-cad or alpha-cat in the primary tumor was consistent with the expression of tumor cells that invaded the lymphatic vessels, but discordant with staining in the metastasized lymph nodes. In some cases, as the tumor invaded deeper, the expression of E-cad or alpha-cat changed from preserved to reduced. Our observations suggest that the reduced expression of E-cad or alpha-cat may be involved in the initial steps leading to the invasion and metastasis of early gastric cancer.

Cooccurrence of reduced expression of alpha-catenin and overexpression of p53 is a predictor of lymph node metastasis in early gastric cancer.

BACKGROUND AND OBJECTIVES: Even though the pathological background contributes to lymph node metastasis, the biological characteristics of tumors have also gained wide attention. In this study, the expression of the cadherin-catenin complex and p53 was studied in early gastric cancer. Their correlation with lymph node metastasis and the predictability of lymph node metastases, by combining these factors, were also discussed. METHODS: One hundred and one specimens obtained from surgery were studied by immunohistochemistry using monoclonal anti-E-cadherin, anti-alpha-catenin and anti-p53 antibodies. RESULTS: Expression of E-cadherin and alpha-catenin was reduced in 50.5 and 64.4%, respectively. p53 protein staining was positive in 29.7%. There was a significant correlation between E-cadherin and alpha-catenin expression, but no correlation was found between p53 expression and E-cadherin or alpha-catenin expression. A reduction in alpha-catenin expression and p53 overexpression correlated to lymph node metastases, respectively. Multivariate analysis showed that cooccurrence of reduced expression of alpha-catenin and overexpression of p53 was an independent factor indicating lymph node metastases. CONCLUSION: A study of both alpha-catenin and p53 expression may be helpful to predict lymph node metastases in early gastric cancer.