Prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma.

BACKGROUND AND OBJECTIVES: Angiogenic factors play a major role in tumor growth and metastasis. The purpose of this study was to clarify the prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma. METHODS: Formalin-fixed and paraffin embedded sections of tumor tissue were obtained from 76 patients who underwent curative gastrectomy for gastric carcinoma. Immunohistochemical staining for VEGF and VEGF-C was performed. RESULTS: VEGF and VEGF-C were positively expressed in 39 and 45% of the patients, respectively. No correlation existed between VEGF and VEGF-C expressions. VEGF expression was significantly correlated with venous invasion. VEGF-C expression was significantly correlated with lymphatic and venous invasion. Patients with positive staining for VEGF showed a significantly lower survival rate than VEGF negative patients. After subdivision, according to the combination of VEGF and VEGF-C expression, VEGF-C expression had a significant unfavorable impact on prognosis among patients with negative staining for VEGF. The expression of VEGF and/or VEGF-C was independent prognostic determinant by the multivariate survival analysis. CONCLUSIONS: The positive expression for VEGF and/or VEGF-C was an important prognostic determinant after curative gastrectomy for gastric carcinoma. VEGF-C may stimulate the tumor progression in the absence of VEGF.

Significant correlation between expression of interleukin-1alpha and liver metastasis in gastric carcinoma.

BACKGROUND: Interleukin (IL)-1 has been reported to augment the hematogeneous metastasis of some cancers by inducing the expression of adhesion molecules on vascular endothelial cells and also increasing the expression of proteases from tumor cells in vitro. The purpose of this study was to determine the clinical significance of the IL-1alpha expression in primary tumors of gastric carcinoma. METHODS: Paraffin embedded sections of the tumors obtained from 109 patients who underwent a gastrectomy for gastric carcinoma with subserosal invasion were stained for IL-1alpha by using the streptavidin biotin method. Staining was considered positive when 10% or more of the malignant cells displayed cytoplasmic staining. RESULTS: Sixty (55.0%) tumors expressed IL-1alpha. Positive staining for IL-1alpha was more likely in patients with differentiated tumors than in those with undifferentiated tumors. The expression of IL-1alpha showed a significant correlation with liver metastasis. Of the 84 patients receiving a curative resection, those with tumors expressing IL-1alpha had a significantly higher incidence of liver recurrence than those without. A logistic regression analysis revealed positive staining for IL-1alpha to be the best predictive factor of patients who develop liver recurrence. CONCLUSIONS: The authors' results suggest that the immunohistochemical expression of IL-1alpha is a useful predictor of liver recurrence in patients undergoing a curative resection for gastric carcinoma with subserosal invasion.

Evaluation of the New American Joint Committee on Cancer/International Union against cancer classification of lymph node metastasis from gastric carcinoma in comparison with the Japanese classification.

BACKGROUND: A new system for the classification of gastric carcinoma, based on the number of metastatic lymph nodes, has been adopted by the current American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) TNM system (1997). The purpose of this study was to evaluate the rationality of this classification in comparison with the Japanese classification, which is based on the location of positive lymph nodes. METHODS: The authors analyzed 587 patients who underwent clinically curative gastrectomy with D2 lymphadenectomy for gastric carcinoma and each had 15 or more lymph nodes histologically examined from 1982 to 1992. Multivariate analysis with the Cox proportional hazards model was carried out to determine which classification was more effective. RESULTS: Within the pN1 or pN2 category of the new AJCC/UICC system, no significant difference in the survival rates existed between n1 patients and n2 patients of the Japanese classification. On the other hand, the survival rates significantly decreased, in the order of pN1, pN2, and pN3 (from greatest to smallest decrease), within the n1 and n2 categories. In multivariate analysis, lymph node involvement by the AJCC/UICC classification was selected as the most significant prognostic determinant, whereas the Japanese lymph node classification was not significantly prognostic. When survival rates were calculated within the pT1, pT2, and pT3-4 categories, no differences existed between pN0 and pN1. There was some discrepancy between the survival rate for each pT and pN category and the corresponding stage. CONCLUSIONS: The new AJCC/UICC classification for lymph node involvement of gastric carcinoma is basically acceptable and considered superior to the Japanese classification. Further analysis involving a greater number of cases may be necessary to confirm the applicability of this staging system.

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.

Isolation of (-)-14-O-Malonylindolactam-V as a Possible Precursor of (-)-Indolactam-V and (-)-14-O-Acetylindolactam-V from Streptomyces blastmyceticum.

(-)-Indolactam-V (1) has the fundamental structure of potent tumor-promoting teleocidins. A new teleocidin-related metabolite, (-)-14-O-malonylindolactam-V (2), was isolated from the culture broth of Streptomyces blastmyceticum NA34-17 which produced a large quantity of 1 along with a small amount of (-)-14-O-acetylindolactam-V (3). Heat treatment of 2 in methanol readily produced 1 and 3, suggesting that S. blastmyceticum NA34-17 excreted 1 as a malonic acid conjugate to accumulate 1 and 3 in the culture broth during cultivation.

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.

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.

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.

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.

Proposal of a risk score for recurrence in patients with curatively resected gastric cancer.

In this study, 168 patients who underwent curative resection for gastric cancer with prognostic serosal invasion [ps(+)] and 150 without prognostic serosal invasion [ps(-)] were analyzed separately to determine the prognostic importance of clinicopathological factors, and identify which patients were at high risk of recurrence. A multivariate analysis of survival time using Cox's proportional hazard model revealed the important prognostic factors to be: Lymph node involvement, the classification of gross appearance, macroscopic serosal invasion, and interstitial connective tissue in the ps(+) group; and lymph node involvement, macroscopic serosal invasion, and venous invasion in the ps(-) group. We proposed a risk score of recurrence based on the results of a further multivariate analysis called Hayashi's Quantification Analysis II, in which recurrence was chosen as an objective variable and the above prognostic factors were chosen as explanatory variables. Eighty-four percent of the patients with a score of 0 or higher in the ps(+) group and 83% of those with a score of +6 or higher in the ps(-) group showed recurrence. Thus, we believe that this score is useful for identifying those patients at high risk of recurrence, who should receive intensive chemotherapy even after curative resection.

[Effects of syngeneic preserved blood cells on metastatic growth of the Lewis lung carcinoma].

Each of B6C3HF1 mice was infused with stored syngeneic blood cells, fresh syngeneic blood cells, or saline, and then was injected intravenously with 1 x 10(6) Lewis lung carcinoma cells. Survival rate of each group declined in order of the saline group, the fresh-cell group, and the stored-cell group with a significant difference between all paired groups (p less than 0.001). When the number of metastases and 125I-Iododeoxyuridine uptake in the lungs and livers were compared between these groups, there were significant differences with greater number and uptake in the stored-cell group than the fresh-cell group or the saline group on day 15 through 17, and greater in the fresh-cell group than the saline group on day 23 and 24. In the second experiment, each mouse was inoculated subcutaneously with 1 x 10(5) tumor cells. Twenty-one days later, the subcutaneous tumors were removed, and the mice were infused with blood cells or saline immediately. The number of lung metastases of the stored-cell group was significantly larger than that of the fresh-cell group or the saline group on 9 and 11 days following tumor removal. In conclusion, the transfusion of the preserved syngeneic blood cells was considered to enhance both artificial and spontaneous metastasis of the Lewis lung carcinoma.

A case of leiomyosarcoma associated with humoral hypercalcemia of malignancy: demonstration of biological and immunological activities of parathyroid hormone-related protein in the tumor extract.

Hypercalcemia occurred in a patient with leiomyosarcoma when multiple lung metastases developed. Despite normal plasma parathyroid hormone (PTH) levels and low 1,25-dihydroxyvitamin D, this hypercalcemic patient had a marked hypercalciuria and phosphaturia associated with an increased excretion of nephrogenous cyclic AMP (NcAMP). Administration of cisplatin ameliorated both the hypercalcemia and hypercalciuria without any reduction in tumor size of NcAMP excretion. Terminally, acute pancreatitis occurred producing a profound hypocalcemia. In the extract of tumor tissue obtained post mortem, bioactivity stimulating the generation of cyclic AMP in osteogenic cells was demonstrated along with the immunoreactive PTH-related protein (PTH-rP). the first report of a solid non-epithelial malignancy producing PTH-rP and associated with humoral hypercalcemia of malignancy. The hypercalcemia in this case caused acute pancreatitis, which led to a profound hypocalcemia.