Comparison of the prognostic significance between the number of metastatic lymph nodes and nodal stage based on their location in patients with gastric cancer.

PURPOSE: To determine which is the better prognostic determinant in gastric cancer: number of positive metastatic lymph nodes or current nodal stage. PATIENTS AND METHODS: Seven hundred seventy-seven patients who underwent potentially curative resections for gastric cancer were divided into three groups according to the depth of invasion. The influence of the number of positive nodes on their survival rate was analyzed. A multivariate analysis by the Cox proportional hazards model was used to determine independent prognostic factors. RESULTS: A decreased survival rate was associated with an increased number of positive nodes in all of the subjects and in each of the three groups. Patients with one to three positive nodes had as good a prognosis as those without nodal involvement when each of the three groups was analyzed separately. Using a multivariate analysis in the patients with four or more positive nodes, we found that the number of positive nodes was the most important prognostic determinant (P < .0001), followed by the depth of invasion (P < .02), and that the nodal stage was not significantly prognostic. Further multivariate analysis in the patients with one to three positive nodes showed that nodal stage and number of positive nodes were not significantly prognostic. CONCLUSION: The number of metastatic nodes should be adopted for classification of nodal stage in gastric cancer.

Urokinase type plasminogen activator and its receptor regulate the invasive potential of gastric cancer cell lines.

To assess the role of urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) on the invasive potential of cancer cells, in vitro experiments were performed using two human gastric cancer cell lines, NUGC-3 and MKN-28. NUGC-3 cells secreted a higher level of uPA than MKN-28 cells, while the uPAR expression of NUGC-3 cells was lower than that of MKN-28 cells. Both cancer cell lines expressed Met protein and did not express hepatocyte growth factor (HGF). In Matrigel invasion assay, MKN-28 cells demonstrated significantly lower invasion index than NUGC-3 cells. The addition of exogenous uPA significantly increased the invasive activity of MKN-28 cells. The uPA expression in NUGC-3 cells was enhanced by adding conditioned media of fibroblast cells or HGF. These results suggest that uPA promotes the invasive capacity of the uPAR-positive cancer cells, and that stromal cells may play an important role in cancer cell invasion by supplying uPA and/or promoting uPA production.

Thymidylate synthase inhibition by an oral regimen consisting of tegafur-uracil (UFT) and low-dose leucovorin for patients with gastric cancer.

PURPOSE: 5-Fluorouracil (5-FU) remains a standard therapy for patients with advanced gastric cancer. There has been no study using an oral regimen with a combination of tegafur, a masked compound of 5-FU, and leucovorin in gastric cancer. The purpose of this study was to determine whether orally administered low-dose leucovorin enhances thymidylate synthase (TS) inhibition when added to tegafur-uracil (UFT) in patients with gastric cancer. METHODS: A group of 26 patients with resectable gastric cancer were assigned to one of two regimens: UFT alone or UFT plus leucovorin. UFT, equivalent to 400 mg/day tegafur, with or without 30 mg/day leucovorin, was administered orally in divided daily doses every 12 h for 3 consecutive days prior to surgery. Tumor specimens were taken immediately following gastrectomy, and the TS inhibition rate (TSIR) was determined using a ligand-binding assay. RESULTS: The TSIR was significantly higher in the UFT plus leucovorin group than in the UFT alone group (P < 0.01). The TSIR in the patients treated with UFT alone ranged between 14% and 50%, while six of the eight patients treated with UFT plus leucovorin had a TSIR of 55% or higher. The remaining two patients in the group treated with UFT plus leucovorin, with a TSIR of 31% and 44%, had undifferentiated tumors. CONCLUSION: Our results suggest that orally administered low-dose leucovorin can add to the efficacy of UFT in patients with gastric cancer, and provide preliminary data for a randomized clinical trial.

[Telomerase activity during the cell cycle in gastric cancer cell lines].

Telomerase, a ribonucleoprotein that adds telomeric repeats onto chromosome ends, is involved in telomere length maintenance and permits unlimited cell proliferation. We examined the possibility that higher telomerase activity is associated with the replicative phase of the cell cycle using gastric cancer cell lines treated with anticancer drugs. Telomerase activity increased at the time point of S-phase accumulation in NUGC-3 cells (5 x 10(5) cells/ml) incubated with CDDP (0.5 microgram/ml), paclitaxel (0.01 microM), or VP-16 (1 microM) and in MKN-28 cells incubated with CDDP. When these cell lines were incubated with 5-fluorouracil (10 microM) or CPT (0.1 microM), the increase of telomerase activity preceded the S-phase accumulation. Our results suggest that telomerase activity be regulated by the cell cycle.

Immunohistochemical staining for the p53 protein and proliferating cell nuclear antigen in familial clustering of gastric cancer.

UNLABELLED: Purpose of this study was to assess the role of p53 gene and tumor proliferating activity in familial clustering of gastric cancer. MATERIALS AND METHODS: Among 344 patients who underwent resections for gastric cancer, 10 patients had two or more gastric cancer-affected, first-degree relatives. We classified them as the group of gastric cancer with family history (FGC). Eighty-seven patients with gastric cancer who had no relatives with any malignant neoplasm were classified as the sporadic group. The paraffin-embedded specimens were stained immuno-histochemically using monoclonal antibodies against the p53 product and proliferating cell nuclear antigen (PCNA). RESULTS: There was no significant difference in any clinicopathologic factor and the PCNA labeling index between the two groups. Staining for the p53 product was positive in 80% of the FGC group and in 38% of the sporadic group (P < 0.05). CONCLUSION: Our study suggests that overexpression of p53 protein is one of the familial factors that correlates with carcinogenesis in the stomach.

Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma.

BACKGROUND: Urokinase-type plasminogen activator (uPA) plays an important role in the destruction of the extracellular matrix and basement membrane around cancer cells. In the current study, the authors investigated uPA expression in cancer cells and stromal cells in patients with gastric carcinoma. METHODS: uPA activity was determined by an enzymatic assay using synthetic substrate (S-2444) in tumor specimens obtained from 71 patients with gastric carcinoma and was compared with the results of immunohistochemical staining for uPA. RESULTS: Higher uPA activity was significantly associated with tumors with peritoneal metastases and tumors with deeper invasion into the gastric wall. Undifferentiated tumors showed significantly higher uPA activities compared with differentiated tumors. The 25 patients with high uPA activity (> or = 60 U/mg protein) had a lower survival rate than the 46 patients with low uPA activity (< 60 U/mg protein) (P < 0.05). uPA activity showed prognostic significance in patients with International Union Against Cancer Stage II and Stage III tumors (P < 0.05, respectively). There was no significant relation between immunohistochemical expression of uPA in cancer cells and uPA enzymatic activity. However, uPA expression in stromal cells significantly correlated with uPA activity in tumor tissues. The uPA expression in stromal cells also correlated with tumor histology and peritoneal metastases. CONCLUSIONS: These results suggest that uPA enzymatic activity is a prognostic factor in gastric carcinoma, and that uPA produced by stromal cells may regulate cancer cell invasion.

Clinical significance of telomerase activity in biopsy specimens of gastric cancer.

Telomerase has been reported to be activated in most immortal cells and human cancers. The purpose of this study was to assess the clinical significance of telomerase activity in biopsy specimens of gastric cancer. Telomerase activity in endoscopic biopsy specimens obtained preoperatively from 31 patients with gastric cancer was determined semiquantitatively using the telomeric repeat amplification protocol assay, a polymerase chain reaction-based assay. Cancer tissues had significantly higher telomerase activity than adjacent normal tissues (13.9 +/-2.0% vs. 7.0 +/- 0.8%; p < 0.05). The ratio of the telomerase activity in cancer tissues to that in normal tissues (telomerase index) was significantly higher in tumors invading the proper muscle layer or deeper or in tumors with moderate or marked lymphatic invasion than in tumors without these invasive factors (4.7 +/- 1.4 vs. 1.1 +/- 0.1 for depth of invasion and 4.4 +/- 1.3 vs. 1.2 +/- 0.2 for lymphatic invasion; p < 0.05 for both). These results suggest that the analysis of telomerase activity in biopsy specimens might contribute to preoperative assessment of the invasive activity or stage of gastric cancer.

Correlation between telomerase activity and DNA ploidy in gastric cancer.

Telomerase has been reported to be activated in most immortal cells and human cancers. In the present study, we assessed the correlation between telomerase activity and cellular DNA ploidy level in gastric cancer. Telomerase activity was determined semiquantitatively using the telomeric repeat amplification protocol assay, a polymerase-chain-reaction-based assay, in surgical specimens of primary tumors obtained from 36 patients with gastric cancer. No correlation was observed between telomerase activity and the proliferating cell nuclear antigen labeling index. In contrast, a positive linear correlation was observed between telomerase activity and the DNA index (r = 0.59; p < 0.01). Tumor cells with aneuploid patterns showed higher telomerase activity than those with diploid patterns (27.6+/-5.8 vs. 5.8+/-1.1%; p < 0.01). Telomerase activity of tumors with liver metastases was significantly higher than activity of those without metastases (34.5+/-16.6 vs. 11.8+/-2.4; p < 0.05). There was a trend toward a lower survival rate in 9 patients with a telomerase activity of 20% or higher compared to 27 patients with telomerase activity lower than 20%. These results suggest that the telomerase activity of gastric cancer tissue may reflect the malignant potential of the tumor.

Improved physical condition by limiting lymphadenectomy around the coeliac artery after distal gastrectomy for gastric cancer.

OBJECTIVE: To find out whether a less extensive lymphadenectomy could relieve the postoperative symptoms associated with D2 resection of gastric cancer. DESIGN: Retrospective study. SETTING: Teaching hospital, Japan. SUBJECTS: 142 patients who had dissection along the left gastric and common hepatic arteries and dissection of the perigastric nodes during curative distal gastrectomy without splenectomy or pancreatectomy between 1990 and 1994. 79 who had no dissection around the coeliac artery were compared with 63 who had. INTERVENTIONS: Questionnaires sent out in February 1996. MAIN OUTCOME MEASURES: Short term and long term morbidity. RESULTS: The patients who had had coeliac dissection were significantly more likely to prefer digestible and light food (p = 0.006); and were significantly more likely to complain of diarrhoea (p = 0.001), abdominal pain (p = 0.02), and late dumping (p = 0.03) than those who did not. Patients who had had coeliac dissection tended to eat more digestible foods in smaller volumes/meal during the early postoperative years, and had more abdominal pain, fullness, and oesophageal reflux during the later years. CONCLUSION: Limiting coeliac dissection during curative distal gastrectomy can improve the patients' physical condition postoperatively.

Surgical strategy for patients with gastric carcinoma with submucosal invasion. A multivariate analysis.

BACKGROUND: Early gastric cancer can be treated by endoscopic excision or simple wedge surgical resection. Standard gastrectomy often is advised if submucosal invasion is found, even though only 15-25% of these patients have lymph node metastases. In this study, the risk of lymph node involvement was examined by multivariate analysis to develop a simple discriminant function for surgical decision making in this setting. METHODS: The authors determined factors significantly correlated with lymph node involvement in a retrospective review of 196 patients with gastric adenocarcinoma invading into, but not beyond, the submucosa. Depth and horizontal spread of cancer in the submucosa were evaluated in addition to ordinary pathologic factors. Discriminant analysis for lymph node involvement was performed using explanatory variables chosen from the results of the univariate analyses. RESULTS: Lymph node involvement correlated significantly with larger tumor size; greater dimension of submucosal invasion; deeper submucosal invasion; gross appearance of Type I, IIc + III or IIa + IIc; and severity of vessel invasion. Of the variables, the amount of lymphatic invasion, macroscopic appearance, and maximum dimension of submucosal infiltration were selected as effective predictors of lymph node involvement according to discriminant analysis. A correct discrimination of 74.8% was obtained with a linear discriminant function using these variables. Lymph node involvement was observed in 50% of the cases with a discriminant score less than -1 and in 25% of those with a score between -1 and 0, whereas no lymph node involvement was observed in those with a score greater than 2. CONCLUSIONS: Discriminant function as used in this study provided a useful criterion for additional surgery for patients with gastric carcinoma invading the submucosa who were treated initially by localized excision. Prophylactic lymph node dissection may not be necessary for a discriminant score greater than 2, whereas extended lymphadenectomy would be recommended for a score less than -1.

Relationship between nodal stage and the number of dissected perigastric nodes in gastric cancer.

To evaluate the rationality of the current nodal staging system in gastric cancer, we retrospectively analyzed 152 patients with perigastric node involvement localized to a single station, in whom the route of metastasis to distant nodes was limited. No significant differences in pathology or survival were observed between patients with stage n1 and those with stage n2-3 nodal involvement, but the mean (standard deviation) number of perigastric nodes dissected was 22.6 (12.6) in those with stage nl involvement and 18.5 (9.5) in those with stage n2-3 involvement (P = 0.04). When perigastric node involvement was localized to station 3, the mean number of dissected station 3 nodes was 7.7 (4.2) in nl patients and 5.3 (2.8) in n2-3 patients (P = 0.04). This tendency was also observed in patients with perigastric node involvement limited to either station 1 (P = 0.08) or station 6 (P = 0.11). Thus, patients with fewer perigastric nodes may have more lymphatics that bypass perigastric nodes and empty directly into distant nodes, increasing the likelihood of skip metastases. The number of positive nodes, affected to a lesser degree by lymphatic distribution than the location of positive nodes, should be incorporated into the staging criteria.