Hidekazu Sugasawa

Limited Gastrectomy With Dissection of Sentinel Node Stations for Early Gastric Cancer With Negative Sentinel Node Biopsy

Objective:To evaluate the early results of sentinel node (SN)-navigated limited surgery for early gastric cancer. Summary Background Data:False-negative results of SN biopsy cannot be ignored in gastric cancer surgery. Previous studies suggest that dissection of lymph node stations where SNs belong (SN stations) may minimize the possibility of leaving metastasis behind in SN-navigated surgery. Methods:Patients with T1N0M0 gastric cancer <4 cm were informed about the SN-navigated limited surgery from 2003 to 2008. SNs were identified using radioisotope and dye methods. When the SN biopsy by frozen section was negative, limited gastrectomy with dissection of SN stations was performed. Patients with SN stations limited to either the lesser or greater curvature underwent a wedge resection unless it would cause a strong deformity of the stomach. A sleeve gastrectomy was performed in other cases. Results:Six of the 60 enrolled patients chose a standard gastrectomy. Sixteen patients were excluded after laparotomy due to a T2–T3 tumor or tumor location. Three patients with positive SN biopsy underwent D2 gastrectomy, and 35 with negative SN biopsy underwent limited gastrectomy with dissection of SN stations; wedge resection in 8 and sleeve gastrectomy in 27. There were no operative mortalities or morbidities. All patients undergoing the limited surgery had no lymph node metastasis by postoperative pathology, and survived without any recurrence. The average area of the resected stomach for limited surgery was significantly smaller than that for standard procedures (92 ± 50 vs. 189 ± 64 cm2, P < 0.001). Conclusions:SN-navigated limited gastrectomy with dissection of SN stations for T1N0M0 gastric cancer was considered safe and acceptable although long-term follow-up is mandatory.

Helicobacter pylori Augments Growth of Gastric Cancers via the Lipopolysaccharide-Toll-like Receptor 4 Pathway whereas Its Lipopolysaccharide Attenuates Antitumor Activities of Human Mononuclear Cells

Purpose:Helicobacter pylori is reportedly involved in the development of gastric cancer. We investigated the mechanisms by which H. pylori affects gastric cancer growth and antitumor immunities in the host, focusing on H. pylori–derived lipopolysaccharide (LPS). Experimental Design:H. pylori and four gastric cancer cell lines (MKN28, MKN45, NUGC3, and KATOIII) were used. We examined the effect of H. pylori or its LPS stimulation on cancer growth and the involvement of the H. pylori LPS-toll-like receptor 4 (TLR4) pathway. We also examined the cytotoxicities of H. pylori/LPS–stimulated human mononuclear cells (MNC) against gastric cancer cells and the effect of H. pylori LPS stimulation on cytokine production by MNC. Results:H. pylori, as well as its LPS, augmented the growth of gastric cancers, all of which expressed TLR4. Neutralization of TLR4 almost completely abrogated the H. pylori–induced proliferative activity of cancer cells. Escherichia coli LPS also augmented cancer growth via the LPS-TLR4 pathway. However, only H. pylori–derived LPS attenuated the cytotoxicity of MNC against gastric cancer cells. Stimulation with H. pylori/LPS also down-regulated perforin production in cancer cell–cocultured CD56+ natural killer cells. H. pylori LPS induced neither interleukin-12 nor IFN-γ production by MNC, although E. coli LPS did induce production of both significantly. Nevertheless, interleukin-12 stimulation restored the IFN-γ–producing capacity of H. pylori LPS–stimulated MNC. Conclusion:H. pylori augmented the growth of gastric cancers via the LPS-TLR4 pathway, whereas it attenuated the antitumor activity and IFN-γ–mediated cellular immunity of MNC. H. pylori infection might thereby promote proliferation and progression of gastric cancers.

Impact of Postoperative Infection on Long-Term Survival After Potentially Curative Resection for Gastric Cancer

We focused on the impact of postoperative infection on long-term survival after potentially curative resection for gastric cancer. Postoperative surgical and medical complications have been implicated as a negative predictor of long-term outcome in various malignancies. However, there have been no published reports assessing the impact of complications arising from postoperative infection on survival in gastric cancer. We studied a population of 1,332 patients who underwent curative resection for gastric cancer. These patients were divided into two groups based on the occurrence (141 patients, 10.6%) or absence (1,191 patients, 89.4%) of postoperative complications due to infection. We investigated the demographic and clinicopathological features of each patient with and without postoperative complications from infection, and thereby the impact of postoperative infection on long-term survival. Patients with postoperative infection had significantly higher frequency of males, upper side tumor location, and total gastrectomy as a surgical procedure, more advanced stage of gastric cancer, and greater age compared with those without postoperative infection. Patients with complications due to postoperative infection had significantly more unfavorable outcome compared with those patients without postoperative infection. Multivariate analysis demonstrated that age, preoperative comorbidity, blood transfusion, tumor depth, nodal involvement, and postoperative infection correlated with overall survival. We conclude that postoperative complications from infection are a predictor of adverse clinical outcome in patients with gastric cancer. However, further immunological study and prospective trials are necessary to confirm the biological significance of these findings.

Prognostic significance of expression of CCL5/RANTES receptors in patients with gastric cancer.

The clinical significance of CCL5 has been reported in several malignancies. In this study, we examined the prognostic impact of serum CCL5 levels and the expression of CCL5 receptors on tumor cells in patients with gastric cancer.

Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination.

The level of serum CCL5, a C‐C chemokine, is reportedly correlated with tumor progression in several cancers. We herein investigated the mechanisms by which CCL5 might contribute to tumor progression in gastric cancer. Serum CCL5 levels significantly correlated with tumor progression and prognosis in patients with gastric cancer. Immunohistochemistry showed that tumor‐infiltrating lymphocytes expressed CCL5, while the tumor cells expressed the CCL5 receptors. Fluorescent double staining showed that tumor‐infiltrating CD4+ cells rather than CD8+ cells preferentially expressed CCL5. Using gastric cancer cell lines (MKN45, KATO III), we examined CCL5 production by coculturing whole peripheral blood mononuclear cells (PBMCs), CD4+ cells, or CD8+ cells, with tumor cells. CD4+ cells cocultured with tumor cells remarkably enhanced CCL5 production in a direct cell–cell contact manner over other cocultured PBMCs, including CD8+ cells. Gastric cancer cell lines expressed CCL5 receptors and augmented their proliferation in response to CCL5 stimulation. Furthermore, we examined the effect of CCL5‐treated cancer cells on the cocultured PBMCs, focusing on the CD4+/CD8+ proportion and apoptosis. Coculture of CCL5‐treated gastric cancer cells with PBMCs resulted in a significant decrease in the proportion of CD8+ cells but not CD4+ cells, suggesting Fas‐FasL‐mediated apoptosis in CD8+ cells. In immunodeficient mice coinjected with KATO III and PBMCs, neutralization of CCL5 significantly suppressed tumor progression, resulting in a favorable outcome. In conclusion, gastric cancer cells might thus induce CD4+ T cells to secrete CCL5 and exploit it for their progression, as well as to aid in the prevention of CD8+ T cell‐involved tumor elimination.

Is Adenocarcinoma of the Gastric Cardia a Distinct Entity Independent of Subcardial Carcinoma

Cardia carcinoma has been defined diversely. The purpose of this study was to determine whether cardia carcinoma should be categorized as a distinct entity independent of subcardial carcinoma. We retrospectively analyzed 65 patients undergoing resection for adenocarcinoma involving the esophagogastric junction (EGJ) with the tumor center within 5 cm of the EGJ. Adenocarcinomas of the EGJ were classified into Type I, Type II, and Type III according to Siewert’s criteria. There was only one Type I adenocarcinoma, and it was associated with Barrett’s esophagus. No tumors had their center between 1 cm and 2 cm proximal to the EGJ. Clinicopathologic features and prognosis were compared among patients with Type II adenocarcinomas (n = 31), patients with Type III adenocarcinomas (n = 33), and patients with adenocarcinomas in the upper third of the stomach not invading the EGJ (n = 153). Siewert’s Type II adenocarcinoma was associated with a higher male/female ratio and with higher incidences of well-demarcated appearance and differentiated histology than carcinoma of the upper third of the stomach without esophageal invasion. Lymph nodes along the greater curvature and parapyloric nodes were rarely involved in Type II tumors. Within the pT2 category, patients with Siewert’s Type II tumors showed a higher incidence of lymph node metastasis and a significantly lower survival rate than did patients with tumors of the upper third of the stomach without esophageal invasion. In conclusion, cardia carcinoma, appropriately defined as adenocarcinoma with its epicenter between 1 cm proximal and 2 cm distal to the EGJ, should be categorized as a distinct entity.

Has the Accuracy of Preoperative Diagnosis Improved in Cases of Early-stage Gastric Cancer?

BackgroundAdequate preoperative evaluation for gastric cancer staging is essential to develop an individualized treatment strategy involving surgery with reduced lymphadenectomy and laparoscopic gastrectomy.MethodsA total of 509 gastric cancer patients with clinical Stage IA or IB disease were divided into two groups: 304 patients were admitted in 2000 or earlier (Group A), and 205 patients were admitted in 2001, when multidetector computed tomography (MD-CT) was available, or later (Group B). We evaluated the accuracy of the preoperative diagnoses of tumor depth, lymph node involvement, and tumor stage.ResultsWith respect to tumor depth, 94.5 and 52.8% of patients were staged correctly in cT1 and cT2 patients, respectively. Among both cT1 and cT2 patients, the underestimated rates were lower in Group B than in Group A. For nodal metastasis, 83.2 and 30.0% of patients were staged correctly in cN0 and cN1 patients, respectively. Among the cN0 patients, 82.1 and 84.7% of Group A and Group B patients, respectively, were staged correctly. Among the cN1 patients, none of the patients in Group B was underestimated, while 9.7% of Group A patients were underestimated. There was a significant increase in the percentage of correctly staged patients and a decrease in the percentage of underestimated patients in Group B in comparison to Group A in both cStage IA and cStage IB patients.ConclusionsRemarkable advances have been observed in the accuracy of preoperative staging in the early stage of gastric cancer. However, it is necessary to continue to develop accurate preoperative and intraoperative diagnostic systems.

Serum granulysin level as a novel prognostic marker in patients with gastric carcinoma

Background:  Granulysin is a cytolytic molecule present in human cytotoxic T cells and natural killer cell granules, and plays a key role in the cell‐mediated immunity against tumor and infection. However, few studies have estimated serum granulysin concentrations in patients with solid or hematological malignancies.

Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity

Interleukin‐18 (IL‐18) is a pleiotropic cytokine that enhances Th1 or Th2 immune response. We show a novel mechanism of gastric cancer cells that allows their immune escape utilizing IL‐18. All 4 gastric cancer cell lines, but not colon lines, constitutively expressed IL‐18 receptors and IL‐18 dose‐dependently enhanced their in vitro proliferation accompanied by nuclear factor κB activation. When IL‐18‐pretreated gastric cancer cells were cultured with cytokine‐activated peripheral blood killer lymphocytes, the antitumor machineries, perforin or interferon‐γ production of killer lymphocytes decreased, resulting in a decreased susceptibility of cancer cells to killer lymphocytes. Furthermore, gastric cancer cells cultured with IL‐18 showed an increased expression of a granzyme B inhibitor, protease inhibitor 9. IL‐18 injections into severe combined immuno‐deficient mice intraperitoneally inoculated with gastric cancer cells consistently decreased the mouse survival time. Our results indicate that gastric cancers exploit IL‐18 to grow/invade and evade immunosurveillance in the hosts.

How should tracers be injected to detect for sentinel nodes in gastric cancer--submucosally from inside or subserosally from outside of the stomach?

BackgroundIn sentinel node (SN) detection for cases of early gastric cancer, the submucosal dye injection method appears to be more reasonable than the subserosal injection. To compare the two injection methods, we have focused on the rate of concordance between hot nodes (HNs) obtained from the radioisotope (RI) method and green nodes (GNs) obtained from the dye-guided method in addition to the number and distribution of GNs detected, and the sensitivity of metastatic detection.MethodsThe subjects of this study were 63 consecutive patients with gastric cancer (sT1–T2, sN0, tumor diameter ≦ 4 cm) in whom we attempted SN detection using a combination of RI and dye methods. 99mTc-tin colloid was injected a day before the surgery, and indocyanine green was injected either submucosally (n = 43) with endoscopes or subserosally (n = 20) by direct vision.ResultsAn average of hot and green nodes (H&G: 4 ± 3 vs. 4 ± 3), hot and non-green nodes (H&NG: 2 ± 3 vs. 1 ± 2), cold and green nodes (C&G: 2 ± 2 vs. 3 ± 4), and the rate of concordance (H&G/H&G + H&NG + C&G: 45 + 27% vs. 48 ± 30%) were not significantly different between the submucosal and subserosal injection methods. The spread of GNs to tier 2 stations (24% vs. 30%) and metastatic detection sensitivity (86% vs. 100%) were also not different between the submucosal and subserosal injection methods.ConclusionThe tracer injection sites do not have to be limited to the submucosa.