Laparoscopic sentinel node navigation surgery for early gastric cancer: a prospective multicenter trial.

BACKGROUND: Prospective multicenter trials have shown the feasibility of sentinel node (SN) navigation surgery using a dual tracer of dye and radioisotope for early gastric cancer. However, comparable trials using the indocyanine green (ICG) and the infrared ray laparoscopic system (IRLS) have not been reported. On the basis of our cohort studies, we assumed that the ICG imaging with the IRLS is as effective as the dual tracer in detecting SNs. Therefore, we conducted a prospective multicenter trial to assess the effectiveness and generalizability of the infrared ICG technique in patients with early gastric cancer. PATIENTS AND METHODS: Patients with previously untreated cT1 gastric adenocarcinomas less than 4 cm in gross diameter were eligible for inclusion in this study. SN mapping was performed by using ICG combined with IRLS technique. Following biopsy of the identified SNs, D2 or modified D2 laparoscopic gastrectomy was performed according to the current Japanese Gastric Cancer Association guidelines. RESULTS: Among the 47 patients who gave written informed consent, 44 were eligible from the surgical findings, for whom SN biopsy was performed. The detection rate of the lymphatic basin by the ICG with IRLS was 100% (44/44). The accuracy was also 100% (7/7) for detecting metastatic lymph node, which was verified on the permanent pathologic examination. Following the median follow-up of 114 months (range, 60 to 120 months), no recurrence (0/40) was observed. Although the number of patients was unequally distributed among the hospitals participating in the trial, the detection rates of SNs in low-volume hospitals were comparable to those in high-volume hospitals. Consequently, there was no learning curve in this trial. CONCLUSION: The infrared ICG imaging accurately detected the lymphatic basin and SNs with occult metastasis in SN-navigated gastrectomy for gastric cancer. This method was feasible even for low-volume surgeons and hospitals.

Quantitative assessment of visual estimation of the infrared indocyanine green imaging of lymph nodes retrieved at sentinel node navigation surgery for gastric cancer.

BACKGROUND: Although the infrared indocyanine green (ICG) imaging is an effective method to identify sentinel lymph nodes (SLNs) of gastric cancer, its objectivity has not been verified. METHODS: We studied 563 lymph nodes under infrared light observation from the ICG-positive lymphatic basins of 36 patients who underwent SLN-navigated gastrectomy for clinically node-negative gastric cancer. First, the rate of SLN detection, the number of SLNs and sensitivities were compared between ordinary light observation and infrared light observation. Second, 563 lymph nodes were grouped into ICG-positive and -negative under infrared light observation. The intensities of the region of interest for each lymph node defined as the lymph node on which digital imaging was performed using an imaging-software, and the region of reference defined as its surrounding background, were compared and quantified. RESULTS: In the comparison of ordinary light observation with infrared light observation, the SLN identification rates were 28/36 (78 %) vs. 36/36 (100 %), the mean ± SD (minimum to maximum) number of SLNs was 3.4 ± 3.7 (0-16) vs. 9.2 ± 5.9 (2-25), and the sensitivities were 1/5 (20 %) vs. 5/5 (100 %). The ICG-positive group contained 358 lymph nodes with an intensity of 0.323 ± 1.56 (mean ± SD), and the ICG-negative group contained 205 lymph nodes with an intensity of 0.639 ± 1.93 (mean ± SD), demonstrating a significant difference between these two groups (P < 0.0001). CONCLUSIONS: The significant difference in the intensity as measured by an imaging-software between ICG-positive and ICG-negative lymph nodes would erase the concern about the objectivity of the infrared ICG method for SLN-navigated surgery for early gastric cancer.

The efficiency of micrometastasis by sentinel node navigation surgery using indocyanine green and infrared ray laparoscopy system for gastric cancer.

BACKGROUND: The clinical application of sentinel node navigation surgery (SNNS) for patients with gastric cancer requires accurate intraoperative diagnosis of lymph node metastasis. However, the clinical significance of the diagnosis of lymph node micrometastasis for gastric cancer has not been established. In this study, we evaluated lymph nodes dissected during SNNS by immunohistochemistry with anti-cytokeratin antibody (IHC) staining for gastric cancer to investigate the usefulness of SNNS. PATIENTS AND METHODS: The subjects were 130 patients with gastric cancer (3,381 lymph nodes) who underwent SNNS with infrared ray observation and lymph node dissection of D1+α or more. The dissected lymph nodes were stained with IHC (CAM 5.2), and the results were compared with intra- and postoperative diagnoses by hematoxylin and eosin (H&E) staining. In addition, the association of metastatic lymph nodes and ICG-positive lymph nodes was examined. RESULTS: The number of patients (lymph nodes) with lymph node metastasis by HE and IHC staining was 16 (52 nodes) and 31 (91 nodes), respectively. Fifteen patients (27 nodes) diagnosed with pN0 by HE staining were diagnosed to be metastatic by IHC staining. The tumor depth of these patients was pT1 in ten patients (m, 3; sm, 7) and pT2 in five (mp, 4; ss, 1). Regarding the histological type, three patients were classified as well-differentiated type, while six patients each had moderately and poorly differentiated types. The grade of lymphatic invasion was ly0 in 5, ly1 in 6, and ly2 in 4, respectively. Histological assessment of 27 IHC-positive and HE-negative cells indicated 5 single cells, 16 clusters, and 6 micrometastases. These lymph nodes were all included in the sentinel nodes (SN) identified during surgery. All but one patient (0.8%) were recurrence-free at 2-8 years after surgery (median 74.7 months). The one patient developed anastomotic recurrence 4.5 years after the first operation and died. CONCLUSION: Since all 27 lymph nodes in 15 patients with metastasis by IHC staining but not by HE staining were micrometastasis or less and included in the SN, ICG-positive lymphatic basin dissection by SNNS with infrared ray observation seems to be an adequate method of lymph node dissection for gastric cancer.

Preoperative determination of appropriate cutting line for proximal gastrectomy to avoid postoperative jejunal ulcer.

BACKGROUND/AIMS: Although proximal gastrectomy has become a procedure of choice for patients' early cancer in the upper third of stomach, no clinical guide for optimal gastric resection in order to avoid postoperative jejunal ulcer is available. The aim of this study was to investigate whether determining the distribution of parietal and chief cells of the stomach using Congo red test is clinically relevant. METHODOLOGY: The F-line was defined as a boundary line between fundic and intermediate area of the stomach according to the pathological findings in 29 patients who underwent total gastrectomy for early gastric cancer, whereas the f-line was regarded as a boundary line between intermediate and pyloric area. In the additional 6 patients undergoing vagus-preserving proximal gastrectomy with jejunal pouch interposition, endoscopic Congo red test was preoperatively performed to determine the F-f-line. RESULTS: The distances from the pyloric ring to f-line on the lesser and greater curvatures were variable. Long-term outcomes of proximal gastrectomy guided by preoperative endoscopic Congo red test were favorable. CONCLUSIONS: It is suggested that preoperative endoscopic Congo red test is useful to determine the appropriate cutting line in order to avoid postoperative jejunal ulcer after proximal gastrectomy.

Tailoring treatment for early gastric cancer after endoscopic resection using sentinel node navigation with infrared ray electronic endoscopy combined with indocyanine green injection.

BACKGROUND: This study evaluated the efficacy of sentinel node navigation surgery using infrared ray electronic endoscopy (IREE) combined with indocyanine green in patients after endoscopic treatments of early gastric cancer. METHODS: 14 patients with early gastric cancer after endoscopic treatments were included. Each patient underwent sentinel node navigation surgery using IREE. Sentinel node detection rate, accuracy of sentinel node metastases and clinical efficacy including the presence or absence of recurrence were evaluated. RESULTS: The intraoperative sentinel node detection rate was 100% (14/14), and accuracy for sentinel node metastases was 93% (13/14). Based on the results of sentinel node mapping, 2 patients received standard gastrectomy with D2 lymphadenectomy, and the remaining 12 patients underwent limited surgery with lymphatic basin dissection. After median follow-up of 32 months, no patients had tumor recurrence. CONCLUSION: The validity of limited surgery based on sentinel node navigation for early gastric cancer remains unclear because the results of a well-designed multicenter clinical trial of sentinel node mapping for gastric cancer have not yet been reported. However, this study suggests that sentinel node navigation surgery using IREE combined with indocyanine green is useful for early gastric cancer after endoscopic resection.

The possibility of performing a limited resection and a lymphadenectomy for proximal gastric carcinoma based on sentinel node navigation.

PURPOSE: This study examined the possibility of performing a limited resection and a lymphadenectomy with sentinel node navigation surgery (SNNS) for the treatment of proximal gastric carcinoma. METHODS: Thirty patients with cT1N0 (n = 23) and cT2N0 (n = 7) proximal gastric carcinoma that was located primarily in the U area (the upper third of the stomach) were enrolled. indocyanine green (ICG; 0.5 ml) was injected endoscopically into the submucosa of the four quadrants encompassing the cancer. Twenty minutes after injection, infrared ray electronic endoscopy (IREE) was used to identify the lymph nodes that were stained with ICG (sentinel nodes, SNs) around the serosa and surrounding fat tissue. RESULTS: One hundred percent of the SNs were identified with our SNNS method. The most common location of SNs was No. 3 (T1: 78%, T2: 100%). The main route of lymphatic drainage was from No. 1 or No. 3 to No. 7 (T1: 95%, T2: 100%). In T1 cancer, Indocyanine green was not distributed to the right gastric area, and no patients had SNs in No. 5 or No. 8a. Four cT2 cancer patients had lymph node metastases, all of which were SNs. There were no cases of postoperative metastasis or recurrence. CONCLUSIONS: For the cT1 proximal gastric carcinoma patients, limited dissection of the ICG tracer-positive lymphatic areas alone by SNNS using IREE may be acceptable. The main lymphatic drainage route of proximal gastric carcinoma is the left gastric artery area (Nos. 1, 3, and No. 7) and dissection of this area is important.

Successful preoperative chemotherapy with S-1 plus low-dose cisplatin for advanced gastric cancer with synchronous liver metastases: report of 2 cases.

We report 2 cases of advanced gastric cancer with synchronous liver metastases who were successfully downstaged using S-1 plus low-dose cisplatin chemotherapy followed by surgical resection. S-1 was administered orally (80 mg/m(2)/day) twice daily for 14 consecutive days, and cisplatin (15 mg/m(2)) was infused over 1 h on days 1 and 8. Successful downstaging of the hepatic metastases was confirmed by imaging analyses; however, neither patient showed a complete response of the primary lesion in the stomach. Toxicities, according to the WHO criteria, were mild. The patients underwent surgical resection within 4 weeks after the last chemotherapy. Postoperatively, they were discharged without complications and received adjuvant chemotherapy. Both patients remained alive and well at 17 and 12 months after surgery, respectively, without recurrence. These cases provide further evidence that S-1 plus low-dose cisplatin chemotherapy enables downstaging of advanced gastric cancer and a subsequent potentially curative resection without serious complications.

Where does the first lateral pelvic lymph node receive drainage from?

BACKGROUND: Lateral pelvic lymph node dissection (LPLD) in the treatment of rectal cancer has risks and benefits. Avoidance of unnecessary LPLD is important, however, preoperative and/or intraoperative accurate detection of lateral lymph node metastases have not been established. If the lateral lymph node to which the fluid first spread from the primary lower rectal cancer is detected accurately, it may guide the need for LPLD and may assist in avoiding unnecessary dissection. METHODS: A total of 14 patients with T3 lower rectal cancer were evaluated to locate the lymph nodes through which indocyanine green (ICG) reached the lymphatics. After ICG was injected into the lower rectum via an endoscope preoperatively, total mesorectal excision was first performed, and LPLD was performed with infrared ray electronic endoscopy (IREE) to assess the degree of retention of ICG in each regional lymph node. RESULTS: Drainage of ICG to lateral pelvic lymph nodes was observed in 6 of 14 patients (43%). All ICG-containing lymph nodes were detected by IREE. When present, lateral pelvic wall lymph node drainage was limited exclusively to the peri-internal iliac artery nodes. No obturator nodes were involved. CONCLUSION: The first lateral lymph node that receives lymphatic drainage from lower rectal cancer is located around the internal iliac arteries.

Significance of preserving vagus nerve in ileocolon interposition after total gastrectomy.

BACKGROUND/AIMS: We have performed ileocolon interposition for reconstruction (IR) after total gastrectomy in order to reduce postoperative symptoms such as heartburn, reflux esophagitis and nutritional disturbance. After IR, however, the frequency of diarrhea increased in the postoperative period. We therefore investigated whether post-IR diarrhea could be prevented by preserving the vagus nerve. METHODOLOGY: The vagus nerve was not preserved in 46 (non-PV group) stage I and II gastric cancer patients treated with the IR method, and preserved in 28 for stage IA (PV group). By means of a mailed and interviewed questionnaire, we surveyed the patients at six months postoperatively to examine how diarrhea had occurred in either group. RESULTS: The frequency of diarrhea of the PV group was as low as 26% (7/27) which was significantly lower than 76% (35/46) of the non-PV group. CONCLUSIONS: Preservation of the vagus nerve during reconstruction using ileocolon interposition after total gastrectomy for stage IA is a superior approach for the prevention of postoperative diarrhea.

Suture line recurrence in the jejunal pouch after curative proximal gastrectomy for gastric cancer: report of two cases.

We report two patients with suture line recurrence in the jejunal pouch after curative proximal gastrectomy for gastric cancer. The first patient was a 60-year-old asymptomatic woman with gastric cancer (T2N0M0) after curative proximal gastrectomy with jejunal pouch interposition. She had to undergo a second resection for suture line recurrence in the jejunal pouch 12 months later. On examination of the resected specimen, histological examination revealed a moderately differentiated adenocarcinoma, which was similar to that of the primary tumor. The second patient was a 74-year-old man who was also diagnosed as having locoregional recurrences in the jejunal pouch after a curative proximal gastrectomy with an S-shaped pouch for gastric cancer (T2N0M0). Histological examination of the resected specimen revealed moderately differentiated adenocarcinoma, which had a similar histopathology to that of the primary tumor. During the first procedure, the jejunal pouch was formed using several disposable devices and the end-to-side esophagojejunostomy was performed with another circular stapler to avoid contamination through surgical instruments. Exfoliated cancer cells that may have detached from the primary tumor during the surgical procedures could have contributed to local recurrence along the longitudinal suture line of the pouch.

[S-1 combined with lentinan in patients with unresectable or recurrent gastric cancer].

Lentinan (LNT) is a beta-glucan known to have a life-prolonging effect in combination with chemotherapy for patients with unresectable or recurrent gastric cancer. Thus, a multi-center trial of chemo-immunotherapy using S-1 combined with LNT may benefit patients with unresectable or recurrent gastric cancer with acceptable toxicity. With such a regimen, the median survival time in 32 patients was 559 days. Regardless of change to second-line chemotherapy, the mean period of using S-1+LNT for patients with long NC above 400 days was 725 days. In subset analyses, the survival period of the patients with G/L ratio of equal to or less than 2 was significantly better than that of the higher one (p<0.0001). The incidence of hematological toxicity (grade 3 leukopenia and thrombocytopenia) was 6.3% (2/32), and non-hematological toxicity (grade 2 dysgeusia) was 6.3% (2/32), while no grade 4 toxicity was observed. S-1 and LNT combination immunotherapy was carried out safely with high QOL and allowed a prolonged administration. S-1+LNT regimen may prolong NC periods in patients with unresectable or recurrent gastric cancer.

Prediction of lymph node metastasis and sentinel node navigation surgery for patients with early-stage gastric cancer.

Accurate prediction of lymph node (LN) status is crucially important for appropriate treatment planning in patients with early gastric cancer (EGC). However, consensus on patient and tumor characteristics associated with LN metastasis are yet to be reached. Through systematic search, we identified several independent variables associated with LN metastasis in EGC, which should be included in future research to assess which of these variables remain as significant predictors of LN metastasis. On the other hand, even if we use these promising parameters, we should realize the limitation and the difficulty of predicting LN metastasis accurately. The sentinel LN (SLN) is defined as first possible site to receive cancer cells along the route of lymphatic drainage from the primary tumor. The absence of metastasis in SLN is believed to correlate with the absence of metastasis in downstream LNs. In this review, we have attempted to focus on several independent parameters which have close relationship between tumor and LN metastasis in EGC. In addition, we evaluated the history of sentinel node navigation surgery and the usefulness for EGC.

[Pilot study of TS-1 combined with lentinan in patients with unresectable or recurrent advanced gastric cancer].

TS-1, an anticancer, antimetabolis agent, has shown clinically superior antitumor activity against unresectable advanced or recurrent gastric cancer (UARG). A biological response modifier, lentinan (LNT) prolonged the survival period of patients with UARG when combined with tegafur (FT). To assess the efficacy, the safety and prognostic factors of chemo-immunotherapy using TS-1, a FT derivative, and LNT, we conducted a multi-institutional pilot study in patients with UARG. Patients were treated with TS-1 at 80 mg/m2/day (bid) for 4-weeks, and LNT was given at 2 mg/body (i.v.) in a week, followed by a 2-week rest for 4 cycles. Twenty-two patients were entered from 4 institutes and 19 patients were eligible. The median survival time in eligible patients was 400 days. The incidence of hematological toxicity (grade 2 leukopenia), and non-hematological toxicity (grade 3 nausea or fatigue) was 5.3% (1/19) and no grade 4 toxicity was observed. The response ratio was 37.5% in 8 patients who had been administered the planned dose of TS-1. In subset analyses, the survival period of the patients with normal (< 500 micrograms/ml) serum immunosuppressive acidic protein level was significantly (p < 0.0001) better than that of the higher one. The survival period for those patients whose granulocytes/lymphocytes ratio was not more than 2 tended to be better. From the prolonged survival periods, chemo-immunotherapy using TS-1 combined with LNT would seem to have a benefit against UARG, and reduced toxicity. Future clinical trials are warranted to confirm its potency.

Sentinel lymph node navigation surgery for early stage gastric cancer.

We attempted to evaluate the history of sentinel node navigation surgery (SNNS), technical aspects, tracers, and clinical applications of SNNS using Infrared Ray Electronic Endoscopes (IREE) combined with Indocyanine Green (ICG). The sentinel lymph node (SLN) is defined as a first lymph node (LN) which receives cancer cells from a primary tumor. Reports on clinical application of SNNS for gastric cancers started to appear since early 2000s. Two prospective multicenter trials of SNNS for gastric cancer have also been accomplished in Japan. Kitagawa et al reported that the endoscopic dual (dye and radioisotope) tracer method for SN biopsy was confirmed acceptable and effective when applied to the early-stage gastric cancer (EGC). We have previously reported the usefulness of SNNS in gastrointestinal cancer using ICG as a tracer, combined with IREE (Olympus Optical, Tokyo, Japan) to detect SLN. LN metastasis rate of EGC is low. Hence, clinical application of SNNS for EGC might lead us to avoid unnecessary LN dissection, which could preserve the patient's quality of life after operation. The most ideal method of SNNS should allow secure and accurate detection of SLN, and real time observation of lymphatic flow during operation.

Validity of modified gastrectomy combined with sentinel node navigation surgery for early gastric cancer.

BACKGROUND: The present study examined the clinical validity of modified gastrectomy for early gastric cancer, in terms of the results of sentinel node navigation surgery (SNNS), using infrared ray electronic endoscopy (IREE) plus indocyanine green (ICG) staining. METHODS: One-hundred and sixty-one patients with fT1N0 gastric cancer were enrolled in the study. ICG (0.5 ml, 5 mg/ml) was injected endoscopically into four quadrants of the submucosa surrounding the cancer. Twenty minutes after the injection, sentinel lymph nodes (SNs) stained with ICG were observed intraperitoneally around the serosa and surrounding fat tissue. IREE was used to illuminate regional lymph nodes from the serosal side. RESULTS: Group 2 lymph nodes were judged as SNs in 52 patients (32%). The most common locations of the SNs were stations No. 7 in each of the upper-, middle-, and lower-thirds of the stomach. In two patients, lymph node metastasis was positive. One of these patients, with cancer in the middle one-third of the stomach, had SNs in stations No. 3, 4sb, 4d, 7, and No. 11p, and had metastatic lymph nodes in No. 3 and No. 7 (all SNs). The other patient, with cancer in the lower one-third of the stomach, had SNs in No. 1, 3, 4d, and 6, and had a metastatic lymph node in No. 4d (SN). Skip metastasis was not observed in this study, and metastatic lymph nodes were judged to have been dissected by the D1+a procedure. CONCLUSION: For T1N0 gastric cancer, modified gastrectomy (D1+a dissection) combined with SNNS is suitable; however, for those whose Group 2 lymph nodes are judged to be SNs, additional dissection of lymphatic basins detected by SNNS should be performed to confirm the absence of lymph node metastasis.

Detection of sentinel nodes by a novel red-fluorescent dye, ATX-S10Na (II), in an orthotopic xenograft rat model of human gastric carcinoma.

BACKGROUND AND OBJECTIVE: We developed a new imaging system to detect sentinel nodes (SNs) using a novel fluorescent tracer, ATX-S10Na(II), and investigated its usefulness in an animal model. STUDY DESIGN/MATERIALS AND METHODS: Human gastric carcinoma cells were implanted orthotopically into nude rats. ATX-S10Na(II) was injected subserosally into the primary tumor lesion, and visualized by a fluorescence spectro-laparoscope. Presence of tumor cells in lymph nodes (LNs) was determined by RT-PCR specific for human beta-actin. RESULTS: Injection of ATX-S10Na(II) was successful in 27 tumor-bearing rats. A red fluorescence was incorporated into the left gastric and hepatic LNs in 25 and 2 rats, respectively. Of note, human beta-actin was detected in most of these LNs. Fluorescence was not detected in LNs that did not contain cancer. CONCLUSION: ATX-S10Na(II) is useful for the detection of cancer-containing SNs in an animal model of gastric carcinoma, and may serve as a novel tracer in SN navigation surgery.

Recurrent gastrointestinal stromal tumor (GIST) of the stomach associated with a novel c-kit mutation after imatinib treatment.

A 57-year-old man with gastrointestinal stromal tumor (GIST) of the stomach with peritoneal dissemination underwent gastrectomy. After surgery, he was treated with 400 mg/day of imatinib, without recurrence, for 26 months. At 26 months, the imatinib dose was reduced because of nausea, and 4 months after the dose reduction, recurrence of GIST was detected, for which surgical resection was performed again. The first surgical specimen had a mutation of exon 11 in the c-kit receptor gene. Intriguingly, the second surgical specimen had a novel mutation of exon 17, in addition to the above-mentioned mutation, in the c-kit receptor gene. Based on the result of molecular analysis, the novel mutation of exon 17, induced by longterm chemotherapy, was judged to have been responsible for the recurrence, which perhaps was triggered by the dose reduction of imatinib.

Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma.

BACKGROUND: Both vascular endothelial growth factor (VEGF)-C and (VEGF)-D are ligands of VEGF receptor (VEGFR)-3 (Flt-4) and VEGFR-2 (KDR/FLK-1) and are supposed to participate in lymphangiogenesis. The purpose of this study was to clarify the clinical significance of the expression of these factors and to evaluate their relationship with prognosis in patients with gastric carcinoma. METHODS: Fifty pairs of normal mucosa and cancer specimens were obtained from patients who had undergone gastrectomy for primary gastric carcinoma and subjected to reverse transcriptase-polymerase chain reaction for VEGF-C, VEGF-D, and VEGFR-3. RESULTS: Both VEGF-C and VEGF-D mRNA expression significantly correlated with lymphatic invasion (P < 0.05). Although VEGF-C and -D were concomitantly expressed in most cases, only VEGF-C expression was related to lymph node metastasis. VEGFR-3 expression was associated both with VEGF-C and VEGF-D expression, but not with lymph node metastasis. Tumors expressing these mRNAs tended to correlate with poorer prognosis, but the relationships were not statistically significant. CONCLUSION: Our study suggests that both VEGF-C and VEGF-D are involved in lymphatic spreading of gastric cancer cells, which is clinically useful for the evaluation of lymphatic invasion in patients with gastric carcinoma.

Prognostic significance of vascular endothelial growth factor D in gastric carcinoma.

The angiogenic factor called vascular endothelial growth factor (VEGF)-D is a ligand for VEGF receptor-2 (VEGFR-2/KDR) and receptor-3 (VEGFR-3/Flt-4). It is implicated in the development of lymphatic vessels and promotion of lymphatic metastasis. The purpose of this study was to investigate the prognostic significance of VEGF-D expression in patients with gastric carcinoma. We assessed the expression of VEGF-D in gastric carcinoma by immunohistochemistry on 143 consecutive patients' stored sections and evaluated the lymphatic vessel count (LVC) in tumors using the novel selective lymphatic endothelium marker D2-40. VEGF-D expression was observed in 55 (39%) tumor sections. The expression of VEGF-D correlated significantly with tumor size, T of the TNM classification, lymphatic and venous system invasion, LVC, lymph node metastasis, M of TNM, and pTNM stage. Multivariate analysis indicated that VEGF-D expression was an independent prognostic factor for both relapse-free survival (RFS) and overall survival (OS). Our data indicate the involvement of VEGF-D in tumor progression via lymphoangiogenic pathways. Practically, VEGF-D expression can be useful for predicting RFS and OS in patients with gastric carcinoma.