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Purpose Vascular endothelial growth factor (VEGF)-D and its homolog VEGF-C influence lymphangiogenesis through activation of VEGF receptor 3 (VEGFR-3), and have been implicated in lymphatic tumor spread. Nodal dissemination of gastric adenocarcinomas critically determines clinical outcome and therapeutic options of affected patients. Therefore, we analyzed expression and prognostic significance of VEGF-D along with VEGF-C, and VEGFR-3 in gastric adenocarcinomas. Materials and Methods VEGF-C, VEGF-D, and VEGFR-3 were analyzed in 91 R0-resected primary gastric adenocarcinomas, corresponding noncancerous gastric mucosa, and lymph node metastases employing immunohistochemistry and/or in situ hybridization. Blood and lymph vessel densities were assessed after staining with CD31 and LYVE-1–specific antibodies. Results VEGF-D and VEGF-C were detected in 67.0% and 50.5% of gastric cancers, respectively. Healthy gastric mucosa was negative for VEGF-C and in 12.5% positive for VEGF-D. Presence of VEGF-D (P = .005) or VEGF-C (P = .006) was correlated with lymphatic metastases and decreased survival (VEGF-D, P < .05; VEGF-C, P < .05). VEGFR-3 was correlated with reduced carcinoma-specific survival (P < .05), and Cox multivariate regression analysis qualified VEGF-D and VEGFR-3, but not VEGF-C, as independent prognostic parameters. In lymph node–positive gastric cancers, presence of VEGF-D/VEGFR-3 was associated with poor survival, whereas absence of VEGF-D/VEGFR-3 defined a subgroup of patients with clearly favorable prognosis. Conclusion VEGF-D and VEGFR-3 are novel independent prognostic marker molecules aiding to identify patients with poor prognosis after curative resection of gastric adenocarcinomas. Combined analysis of the VEGF-C/VEGF-D/VEGFR-3 system can be useful to identify patients with unfavorable clinical outcome and thereby may help to refine therapeutic decisions in gastric cancer.

4510 Background: Combined pre- and postoperative chemotherapy improves overall survival in operable gastric cancer, although postoperative treatment is not feasible in half of the patients. We conducted a randomized phase III trial with thorough attention to preoperative staging and to the extent of surgical resection to assess the value of neoadjuvant chemotherapy (CTx). Methods: Patients with locally advanced adenocarcinoma of the stomach and cardia were randomized between primary surgery or two 48-day cycles of weekly folinic acid 500 mg/m2/2h, 5-FU 2,000 mg/m2/24h plus biweekly cisplatin 50 mg/m2/1h followed by surgery. The study was designed to detect an improvement in median survival from 17 months with surgery to 24 months with CTx plus surgery (HR=0.708, power of 80%, type I error of 4% to allow for an interim analysis). It was planned to randomize 360 patients in order to observe the 262 deaths required for the final analysis. Results: From 7/99 to 2/04, 144 patients were randomized (72:72) with comparable baseline characteristics. Median follow-up is 4.4 years. Based on 67 deaths, overall survival between the two arms did not differ (HR=0.84; 95% CI: 0.52 to 1.35; p=0.466). Median survival exceeded 36 months in both arms. Due to low accrual, this trial was stopped early. The unexpected long median survival in the surgery arm would have made the primary objective difficult to reach anyway. Based on 77 events, difference in time to progression was borderline significant (HR=0.66; 95% CI, 0.42–1.03; p=0.065). Response rate to CTx was 35.2% (95% CI: 23.7%-45.7%). The R0-resection rate was 81.9 % after CTx as compared to 66.7% with surgery alone (P=0.036). There were no major differences in intra- or postoperative complications. Conclusions: This prematurely closed trial showed a significantly increased rate of R0 resections after CTx although it could not demonstrate a survival benefit. The outcome after a radical surgical procedure alone with extended lymphadenectomy was better than expected. No significant financial relationships to disclose.