[An Elderly Patient with Metastatic Colon Cancer Achieved Long-Term Survival Following Single-Agent Chemotherapy with S-1].

Colorectal cancer is a common malignancy and a major health issue in geriatrics. Systemic chemotherapy should be considered for elderly patients. We report an 85-year-old man with metastatic cecal cancer who has achieved long-term survival following single-agent chemotherapy with S-1. His fecal occult blood test results were positive; he then underwent colonoscopy and was diagnosed with cecal cancer. Chest CT revealed multiple metastases in both lungs. Since radical excision was infeasible, we performed right hemicolectomy to prevent bowel obstruction. Histological examination revealed a T3, N0, M1a (PUL2), Stage IV tumor. After discharge from the hospital, the patient preferred receiving chemotherapy that would have fewer side effects. S-1 monotherapy was administered. Despite increased progression of the pulmonary metastases, he experienced no subjective symptoms, his QOL remained consistent, and he completed 42 cycles of chemotherapy in total. The patient is currently being managed on an outpatient basis. In conclusion, elderly patients with cancer should be carefully evaluated according to both disease control and individual circumstances, such as patient's tolerability, QOL, and preference.

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-gamma production by MNC, although E. coli LPS did induce production of both significantly. Nevertheless, interleukin-12 stimulation restored the IFN-gamma-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-gamma-mediated cellular immunity of MNC. H. pylori infection might thereby promote proliferation and progression of gastric cancers.

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.

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

BACKGROUND AND OBJECTIVES: 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. METHODS: Serum CCL5 levels in patients with gastric cancer were measured by enzyme-linked immunoabsorbent assay. Immunohistochemical staining of three chemokine receptors, CCR1, CCR3, and CCR5, which are known as CCL5 receptors, was performed in gastric cancer tissue. RESULTS: We found that serum CCL5 levels themselves had no impact on survival; however, higher serum CCL5 concentrations were associated with more advanced disease. Eighty-six (41%), 48 (23%), and 60 patients (28%) showed positive expression of CCR1, CCR3, and CCR5, respectively, on gastric cancer cells. Among the patients who underwent curative resection for stages II-IV disease, patients with positive CCR3 expression had significantly lower survival rates compared to those with negative CCR3 expression. Unlike CCR1, positive CCR5 expression was also associated with poorer prognosis. Multivariate analysis revealed that expression of CCR3 and/or CCR5 was an independent prognostic factor. CONCLUSIONS: Tumor expression of CCR3 and/or CCR5 (receptors for CCL5) is associated with a lower survival rate in patients with gastric cancer.

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. METHODS: Peripheral blood samples were taken from patients with gastric carcinoma preoperatively and from healthy volunteers. Serum and tumor tissue granulysin concentrations were measured using a granulysin-specific ELISA kit in order to assess its prognostic value. RESULTS: Both serum and tumor tissue granulysin concentrations were higher in patients with stage II or III gastric cancer and lower in patients with stage IV disease as compared to healthy controls. The low preoperative granulysin levels were associated with more frequent hepatic and peritoneal metastases, and with a poor outcome of the curative gastrectomy. CONCLUSIONS: Preoperative serum granulysin levels reflect the status of cell-mediated immunity in patients with gastric carcinoma. It has significance as a prognostic determinant following a curative resection.

Proposal for a new definition of true cardia carcinoma.

BACKGROUND AND OBJECTIVES: It remains controversial whether cardia carcinoma should be categorized and treated as esophageal cancer or gastric cancer. The purpose of this study was to develop a reasonable definition of cardia carcinoma. METHODS: Patients with Siewert type II carcinomas were divided into two subgroups: 25 patients with a tumor center within 1 cm of the esophagogastric junction (EGJ) (type IIA) and 22 patients with tumor center 1-2 cm aboral of the EGJ (type IIB). Patients with subcardia carcinomas, 40 with invasion to the EGJ (type III) and 110 without (type IIIe-), were used as controls. RESULTS: The patients with type IIB carcinomas showed no different characteristics from those with type III or type IIIe- carcinomas, except for the stage of the disease. On the other hand, those with type IIA carcinomas were associated with a higher male/female ratio, higher incidences of elevated appearance, differentiated histology, and mediastinal node metastasis, and a significantly lower survival rate as compared with patients with subcardia carcinomas. Multivariate survival analysis revealed that type IIA is a significant prognostic determinant, but that type IIB is not. CONCLUSION: Type IIA carcinomas should be treated as true cardia carcinoma; type IIB as subcardia carcinoma. Our results should be confirmed by a prospective study.

Antireflux contrivance in jejunal pouch reconstruction after total and proximal gastrectomies.

BACKGROUND/AIM: In the reconstruction after gastrectomy, a jejunal pouch may be inferior as a gastric substitute to an isoperistaltic jejunum in terms of preventing reflux. We have developed an antireflux contrivance. METHODS: A jejunal pouch was made by side-to-side anastomosis of both limbs of the jejunum folded into an inverted U, leaving a bridge of the jejunum 15 cm long at the top of the jejunal pouch (apical bridge). The apical bridge is cut near its oral end, and esophagojejunostomy is done, leaving the isoperistaltic jejunum 6-8 cm long positioned between esophagus and jejunal pouch. RESULTS: This antireflux contrivance was performed in 37 patients undergoing total gastrectomy and in 22 patients undergoing proximal gastrectomy. There were no operative deaths in this series. Neither anastomotic bleeding nor anastomotic leakage were observed. In a questionnaire survey, 5 patients answered that they had had heartburn twice a week or more often, but the answer was not repeated by any patient. On endoscopic examination, all patients but 1 had normal findings for the esophagus. Mild esophagitis was observed in 1 patient. CONCLUSION: The antireflux contrivance reported here can be easily, safely, and uniformly done, and it is a useful technique.

Preoperative chemoradiotherapy for esophageal cancer enhances the postoperative systemic inflammatory response.

BACKGROUND: Chemoradiotherapy (CRT) has been established to improve the long-term survival in patients with esophageal carcinoma. However, little is known about whether preoperative CRT may affect the postoperative systemic response. METHODS: We investigated the postoperative clinical course in terms of the systemic inflammatory response syndrome (SIRS) in patients with preoperative CRT (CRT group) and surgery alone (SA group). RESULTS: Both the postoperative heart and respiratory rate in the CRT group were significantly higher than in the SA group. The duration and incidence of SIRS, as well as the number of positive criteria for SIRS, were significantly greater than those in the SA group. There was no difference in the postoperative morbidity and mortality between the two groups. CONCLUSIONS: Preoperative CRT was found to significantly enhance the postoperative SIRS, thus suggesting its potentially higher risk of complications.

Individualized surgery for early gastric cancer guided by sentinel node biopsy.

BACKGROUND: We have reported that lymphatic mapping using indocyanine green (ICG) solution can be a good tool for identifying sentinel nodes (SNs) in gastric cancer. The purpose of this study was to evaluate individualized operations for gastric cancer guided by SN biopsy and to explore the possibility for more limited operative procedures using SN technology. METHODS: SNs were identified by using (99m)Tc-labeled tin colloid and ICG solution in patients with clinically T1N0M0 gastric cancer. When pathologic examination by frozen section revealed metastasis in SNs, we performed a standard D2 gastrectomy. Less extensive lymphadenectomy preserving vagus and pylorus was applied when the SN biopsy was negative. Then, postoperative pathology was analyzed. RESULTS: Among the 80 enrolled patients, 7 patients with apparent node metastasis or T2-3 neoplasms and 10 patients with positive metastasis in SNs underwent D2 gastrectomy. Sixty-one patients with negative metastasis in SNs underwent a less extensive, function-preserving gastrectomy. The false-negative rate in sentinel node biopsy was 23% (3/13) for frozen section and 7% (1/14) for postoperative pathology. In 3 patients with a false-negative result, metastasis was found in lymph nodes located at the station where the tracers were distributed. Of the 7 patients in whom metastasis was detected in 2 or more SNs by frozen section, postoperative pathology revealed that 3 patients (43%) belonged to the N2 category. CONCLUSIONS: SN biopsy is a useful tool for individualizing the operative procedure for early gastric cancer. Dissecting the lymph node stations only where the tracers are distributed may be a promising procedure for patients with no metastatic SNs.

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 kappaB activation. When IL-18-pretreated gastric cancer cells were cultured with cytokine-activated peripheral blood killer lymphocytes, the antitumor machineries, perforin or interferon-gamma 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.

Modified radical lymphadenectomy (D1.5) for T2-3 gastric cancer.

BACKGROUND: The operative mortality in gastric cancer surgery has been reported to be higher with D2 lymphadenectomy than with D1 in the West. The modified radical lymphadenectomy (D1.5) may be safer than D2 under these circumstances. This study was aimed to determine whether D1.5 would deteriorate long-term survival as compared with D2. METHOD: Since the concept of the extent of lymphadenectomy varied among the surgeons, 461 patients who underwent curative gastrectomy for T2-4 gastric adenocarcinoma were retrospectively categorized into three groups according to the surgeon: D1 with dissection along the left gastric and common hepatic arteries (D1.5); lymphadenectomy between D1.5 and D2; D2 or more extended dissection. RESULTS: No differences were found in the survival rates among the three groups within each of the T2a, T2b, and T3 categories. According to a multivariate analysis using Cox's proportional hazard model, the classification according to the surgeons had no survival impact (p>0.8). CONCLUSION: D1.5 lymphadenectomy resulted in a survival rate that was almost equal to that of D2. The use of D1.5 instead of D2 can be an attractive option to be compared with D1 in future trials.

The increase of CD57+ T cells in the peripheral blood and their impaired immune functions in patients with advanced gastric cancer.

In addition to natural killer (NK) cells, T cells expressing natural killer cell markers, CD56 or CD57 (NK type T cells), have been considered to play an important role in antitumor immunity. We examined the proportion of NK cell and NK type T cell subsets in the peripheral blood from patients with gastric cancer. The IFN-gamma production capacity and population of cytoplasmic perforin positive cells in peripheral blood mononuclear cells (PBMC) were evaluated. Peripheral blood samples were obtained from 56 patients with gastric cancer and 21 healthy volunteers. The proportion of CD56- CD57+ T cells (CD57+ T cells) was significantly higher in advanced gastric cancer patients than those in healthy volunteers and patients with early stage gastric cancer, whereas no correlation was observed between the proportion of CD56+ T cells or NK cells and tumor progression. Furthermore, a significant decrease of CD8+ CD57+ T cells was found in patients with advanced gastric cancer. The proportion of CD57+ T cells did not correlate with interferon-gamma (IFN-gamma) production from PBMC in gastric cancer patients, although a significant correlation was found between them in healthy volunteers. The proportion of perforin positive CD57+ T cells, especially CD8+ CD57+ T cells, in patients with gastric cancer was markedly lower than that in healthy volunteers. Collectively, although the proportion of CD57+ T cells in PBMC was found to increase with tumor progression, their function in antitumor immunity is impaired in patients with gastric cancer.

Minimum number of lymph nodes that should be examined for the International Union Against Cancer/American Joint Committee on Cancer TNM classification of gastric carcinoma.

The classification of lymph node metastasis based on the number of positive nodes has been adopted in the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM classification of gastric carcinoma. However, the N classification (for condition of the regional lymph nodes) would be underestimated when the number of examined nodes were too small. To determine the minimum number of lymph nodes to examine for a correct classification, we analyzed 926 patients undergoing curative resection for gastric carcinoma. The number of metastatic lymph nodes correlated significantly with the number of examined lymph nodes. The pN0 patients with 10 to 14 examined nodes showed a significantly higher survival rate than did those with 5 to 9 examined nodes, and they had as good a prognosis as those with 15 or more examined nodes. In the pN1 and pN2 categories, patients with 29 or fewer examined nodes tended toward lower survival rates than did patients with 30 or more examined nodes. Among the patients who were classified as stage IA, the survival rate for those with 5 to 9 examined nodes was significantly lower than that for patients with 30 or more examined nodes. Among the patients classified as stage III, those with 10 to 19 examined nodes and those with 20 to 29 examined nodes had lower survival rates than did patients with 30 or more examined nodes. In conclusion, the minimum number of lymph nodes examined for a correct pN0 classification can be reduced from 15 to 10. For pN1-3 classifications, 20 or more nodes should be examined, and examining 30 or more lymph nodes may be desirable.

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.

The influence of interleukin-10 and interleukin-18 on interferon-gamma production by peritoneal exudate cells in patients with gastric carcinoma.

Although the peritoneal cavity (PC) is the most common site of metastasis in gastric carcinoma, its immune status in patients with advanced cancer remains largely unknown. We investigated the relationship between clinical parameters and cytokine levels in the PC and also evaluated IFN-y production by peritoneal exudate cells (PEC), obtained during surgery from patients with stage III-IV gastric carcinoma. Although the IFN-gamma and IL-12 levels in the PC did not differ between stage III and stage IV cancer patients, the latter had higher levels of IL-10 and IL-18. Those patients with higher IFN-gamma levels experienced a significantly better survival-rate than those with lower IFN-gamma levels, whereas IL-18 (but not IL-10) levels were inversely-correlated with survivaL IFN-gamma levels increased in parallel with IL-18 levels in patients who survived more than two years, but this correlation did not apply to patients who died of disease within two years. In addition, anti-CD3-Ab or cytokine- stimulated PEC from patients with low IL-10 levels in their PC produced a significantly greater amount of IFN-gamma than PEC from patients with high PC IL-10 levels. In conclusion, a high level of IFN-y in the PC is an indicator of favorable outcome. Both IL-10 and IL-18 levels in the PC increased with tumor progression. Although the number of PEC capable of producing IFN-gamma increases with tumor progression, their ability to secrete IFN-gamma in response to IL-18 may be influenced by local IL-10 levels in the PC.