Koichiro Ishida

Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer

Recently, a subset of IL-17 producing T cells distinct from Th1 or Th2 cells has been described as key players in inflammation and autoimmune diseases as well as cancer development. In this study, we investigated the expression level of IL-17 and T helper 17 (Th17)-related cytokines in gastric cancer tissues and assessed the association of their expression with angiogenesis and their clinicopathological parameters. Tumor and adjacent normal tissues were obtained from 82 patients with gastric cancer. IL-17, IL-21 and IL-23 mRNA expression levels were quantified by real-time RT-PCR. Th17 infiltration, microvessel density and neutrophil infiltration in tumor tissues were examined by immunohistochemistry and double immunofluorescence histochemistry. Expression of IL-17, IL-21 and IL-23 mRNA was found to be significantly up-regulated in tumor tissues compared with adjacent normal tissues. The expression level of IL-17 mRNA strongly and positively correlated with that of IL-21 mRNA in tumor tissue. The number of vascular endothelial cells and infiltrating neutrophils was significantly larger in tumors expressing a high level of IL-17 mRNA than in tumors expressing a low level of IL-17 mRNA. In tumor tissues most CD4+ cells were stained with anti-IL-17 antibody. The expression level of IL-17 mRNA in gastric tumors was associated with the depth of the tumors, lymph-vascular invasion and lymph node involvement, suggesting that IL-17 obviously was related to tumor progression. IL-17 and IL-21, which regulates IL-17, would be potential therapeutic targets for the treatment of gastric cancer.

Surgical management of small gastrointestinal stromal tumors of the stomach.

Small gastrointestinal stromal tumors (GISTs) (<3 cm) occasionally are found in the stomach during endoscopy. There is no consensus about the surgical management of these small tumors, although this clinical issue is crucial because some of the tumors show unexpected malignant behavior. In this study, we evaluated the clinical management of patients with gastric GISTs who underwent surgical resection. Altogether, 31 patients with gastric GISTs were examined retrospectively. Surgical resection was fundamentally indicated for the patients with gastric GISTs suspected to be malignant by endoscopy or endoscopic ultrasonography (EUS). The malignant grade of the GISTs was evaluated by the mitotic rate, tumor size, and MIB-1 index. EUS was useful for differentiating benign from malignant GISTs; but by limiting the study to patients with small tumors (<3 cm), the diagnostic value of EUS was not satisfactory for defining the surgical indication. Tumors that were <50 mm were successfully treated by laparoscopic surgery. Of the 31 patients, 4 had a relapse of the disease, and 1 of those 4 patients had a small tumor (30 mm). All of the recurrences were classified in the high risk category. Surgery is indicated for gastric GISTs that are ≥20 mm or are suspected to be malignant based on EUS findings. Laparoscopic resection is feasible and is recommended as the treatment of choice for patients with tumors < 50 mm. Risk assessment can be most useful for predicting recurrence.

Influence of Overweight on Patients With Gastric Cancer After Undergoing Curative Gastrectomy An Analysis of 689 Consecutive Cases Managed by a Single Center

HYPOTHESIS Overweight (body mass index [calculated as weight in kilograms divided by height in meters squared], > or =25.0) has an effect on surgical results, postoperative complications, and long-term survival in patients with gastric cancer who underwent curative gastrectomy. DESIGN Retrospective study from January 1, 1992, through December 31, 2002. SETTING Wakayama Medical University Hospital. PATIENTS This study included 689 patients who underwent curative gastrectomy (R0). Patients who underwent laparoscopic gastrectomy, gastrectomy with pancreaticoduodenectomy, gastrectomy with another organ resection (liver, colon, or ovary), or gastrectomy with thoracotomy were not included. MAIN OUTCOME MEASURES Duration of operation, amount of blood loss, incidence of postoperative complications, and survival analysis. RESULTS The mean (SD) duration of the operation was longer in the overweight group (315 [75] minutes) than in the normal-weight group (277 [85] minutes) (P < .001). The mean (SD) intraoperative blood loss was larger in the overweight group (882 [764] mL) than in the normal-weight group (536 [410] mL) (P < .001). The rates of postoperative complications (anastomotic leakage, pancreatic fistula, and intra-abdominal abscess) were significantly higher in the overweight group (P < .05). Multivariate logistic regression analysis identified that postoperative complications were significantly associated with being overweight (P = .01) and with undergoing pancreatectomy (P = .03). Disease-specific and overall survival did not show any significant difference between the 2 groups. CONCLUSIONS Being overweight is not a poor risk factor for survival in patients with gastric cancer, although it is independently predictive of postoperative complications.

Analysis of the prognostic factors and evaluation of surgical treatment for synchronous liver metastases from gastric cancer.

Background and aimsWhether or not a synchronous resection of liver metastases from gastric cancer provides a survival benefit has been a key issue. We identify the significant prognostic factors and clarify the beneficial effect on the survival of liver surgical treatment.Materials and methodsWe reviewed 72 patients who underwent a gastrectomy for gastric cancer with synchronous liver metastases and classified the liver metastases into three grades, such as H1: metastases were limited to one of the lobes, H2: there were a few scattered metastases in both lobes, and H3: there were numerous scattered metastases.ResultsH1, 2 metastases, and an absence of peritoneal dissemination (P0) were significantly independent prognostic factors for liver metastases of gastric cancer. In addition, the cumulative 1 and 5-year survival rates of liver surgical treatment (hepatic resection and/or microwave coagulation therapy) were 80.0% and 60.0%, whereas the survival rates for non-hepatic surgical treatment were 36.4% and 0% in 26 patients with H1, 2, and P0. In those patients, the radical operation, the solitary metastatic liver tumor, and no-distant lymph node metastases were independent prognostic determinants of survival.ConclusionThe radical operation including the surgical treatment for metastatic liver tumors should be performed to improve the prognosis in gastric cancer patients with synchronous H1, 2, and P0.

Dendritic Cells Transduced with Tumor-Associated Antigen Gene Elicit Potent Therapeutic Antitumor Immunity: Comparison with Immunodominant Peptide-Pulsed DCs

Several studies have shown that vaccine therapy using dendritic cells (DCs) pulsed with specific tumor antigen peptides can effectively induce antitumor immunity. Peptide-pulsed DC therapy is reported to be effective against melanoma, while it is still not sufficient to show the antitumor therapeutic effect against epithelial solid tumors such as gastrointestinal malignancies. Recently, it has been reported that vaccine therapy using DCs transduced with a surrogate tumor antigen gene can elicit a potent therapeutic antitumor immunity. In this study, we investigated the efficacy of vaccine therapy using DCs transduced with the natural tumor antigen in comparison with peptide-pulsed DCs. DCs derived from murine bone marrow were adenovirally transduced with murine endogenous tumor antigen gp70 gene, which is expressed in CT26 cells, or DCs were pulsed with the immunodominant peptide AH-1 derived from gp70. We compared these two cancer vaccines in terms of induction of antigen-specific cytotoxic T lymphocyte (CTL) responses, CD4+ T cell response against tumor cells, migratory capacity of DCs and therapeutic immunity in vivo. The cytotoxic activity of splenocytes against CT26 and Meth-A pulsed with AH-1 in mice immunized with gp70 gene-transduced DCs was higher than that with AH-1-pulsed DCs. CD4+ T cells induced from mice immunized with gp70 gene-transduced DCs produced higher levels of IFN-γ by stimulation with CT26 than those from mice immunized with AH-1-pulsed DCs (p < 0.0001), and it was suggested that DCs transduced with tumor-associated antigen (TAA) gene induced tumor-specific CD4+ T cells, and those CD4+ T cells played a critical role in the priming phase of the CD8+ T cell response for the induction of CD8+ CTL. Furthermore, DCs adenovirally transduced with TAA gene showed an enhancement of expression of CC chemokine receptor 7 and improved the migratory capacity to draining lymph nodes. In subcutaneous models, the vaccination using gp70 gene-transduced DCs provided a remarkably higher therapeutic efficacy than that using AH-1-pulsed DCs. These results suggested that vaccine therapy using DCs adenovirally transduced with TAA gene can elicit potent antitumor immunity, and may be useful for clinical application.

Successful cancer vaccine therapy for carcinoembryonic antigen (CEA)-expressing colon cancer using genetically modified dendritic cells that express CEA and T helper-type 1 cytokines in CEA transgenic mice

This study was designed to determine whether the vaccination of genetically modified dendritic cells (DCs) simultaneously expressing carcinoembryonic antigen (CEA), granulocyte macrophage colony‐stimulating factor (GM‐CSF) and interleukin 12 (IL‐12) can overcome the peripheral T‐cell tolerance to CEA and thereby elicit a therapeutic response in CEA transgenic mice. CEA transgenic mice were immunized once by subcutaneous injection with DCs adenovirally transduced with CEA and T helper‐type 1 cytokine genes. The cytotoxic activity of spleen cells against CEA‐expressing tumors, MC38‐CEA, in the mice immunized with DCs expressing CEA (DC‐AxCACEA) was higher than that in those immunized with DCs‐AxCALacZ (p < 0.0001), and was augmented by the cotransduction with the GM‐CSF/IL‐12 gene (p < 0.05). The vaccination with DC‐AxCACEA/GM‐CSF/IL‐12 could elicit a more potent therapeutic immunity than the vaccination with DC‐AxCACEA in subcutaneous tumor models (p < 0.0001), and 4 of 5 mice showed a complete eradication of the subcutaneous tumors in these vaccination groups. Even in a large tumor model, this vaccination therapy completely eliminated the subcutaneous tumors in all mice. This antitumor activity mostly vanished with the depletion of CD8+ T cells and NK cells in vivo and was completely abrogated with the depletion of CD4+ T cells. A histopathological examination showed no evidence of an autoimmune reaction. No other adverse effects were observed. This vaccination strategy resulted in the generation of highly efficient therapeutic immune responses against MC38‐CEA in the absence of autoimmune responses and demonstrated no adverse effects, and may therefore be useful for future clinical applications as a cancer vaccine therapy.

Optimal Dose of Preoperative Enteral Immunonutrition for Patients with Esophageal Cancer

PurposeA preoperative immunonutrition pharmaceutics diet (IMPACT) significantly reduced the incidence of postoperative infectious complications, but the optimal regimen still remains unclear. We evaluated the optimal dose of a preoperative IMPACT for patients with esophageal carcinoma and the incidence of postoperative complications based on the dose of IMPACT.MethodsThis study design was a prospective nonrandomized study. Twenty patients with thoracic esophageal carcinoma who underwent a right transthoracic subtotal esophagectomy were divided into two groups. These patients were administered immunonutrition of 500 ml/day (IMP500) or 1000 ml/day (IMP1000) for 7 days before the operation.ResultsThe incidence of postoperative mortality and morbidity was not different between the IMP500 group and the IMP1000 group. No difference was observed in the perioperative changes in inflammatory, immunological and nutritional variables between the two groups. There were no adverse effects in the IMP500 group, but four patients (40%) had diarrhea and four patients (40%) had appetite loss in the IMP1000 group. In the IMP1000 group, only four patients (40%) could take 1000 ml, but others reduced the quantity of IMPACT because of diarrhea and discomfort.ConclusionThis study suggests that 500 ml of IMPACT is recommended as an optimal dose for patients with esophageal cancer.

Prognostic significance of IL-17 mRNA expression in peritoneal lavage in gastric cancer patients who underwent curative resection

Peritoneal dissemination is frequently detected in patients with advanced gastric cancer. The peritoneal cavity is a compartment in which an immunologic host-tumor interaction can occur. There are no reports on the relationship between IL-17 expression in peritoneal lavage and prognosis in gastric cancer patients. Therefore, we investigated the expression of IL-17 mRNA in peritoneal lavage from gastric cancer patients and assessed the association of its expression with clinicopathological parameters and prognosis. Peritoneal lavage was obtained from 114 patients with gastric cancer at initial surgery. Seventy-nine patients underwent curative resection. Among these 79 patients, IL-17 mRNA expression was associated with the depth of tumor invasion (p<0.05). Twelve of the 79 patients who underwent curative resection died, and 9 of those 12 developed peritoneal metastasis. Notably, among the 79 patients who underwent curative resection, those with high expression of IL-17 mRNA in peritoneal lavage had significantly prolonged survival when compared to these patients with low expression of IL-17 mRNA in peritoneal lavage (p<0.05) as evidence by the survival curves. In a multivariate analysis, low expression of IL-17 mRNA in peritoneal lavage and tumor size were found to be independent significant predictive factors for prognosis (HR, 7.91; 95% CI, 1.65-38.03) in the patients who underwent curative resection. IL-17 mRNA expression in peritoneal lavage is a reliable prognostic factor for patients undergoing curative resection for gastric cancer. Low IL-17 expression in the peritoneal cavity may correlate with cancer development in the peritoneal cavity in patients with gastric cancer.

Tumor vaccine therapy against recrudescent tumor using dendritic cells simultaneously transfected with tumor RNA and granulocyte macrophage colony-stimulating factor RNA

Recently, dendritic cells (DC) transfected with tumor RNA have been used as a cancer vaccine. The efficacy of a cancer vaccine using DC transfected tumor RNA was examined. Of particular interest was whether a vaccine using DC transfected with recrudescent tumor RNA is effective for the treatment of a regrowing tumor after prior immunotherapy. In addition, the usefulness of co‐transfection of granulocyte macrophage colony‐stimulating factor (GM‐CSF) mRNA to augment the DC vaccine was examined. CT26 tumor‐bearing mice were immunized by s.c. injection with DC transfected with CT26 mRNA (DC‐CT26). The cytotoxic activity against CT26 in mice immunized with DC‐CT26 was significantly higher than that in the control group (P < 0.001) and was augmented by GM‐CSF mRNA co‐transfection (P < 0.05), resulting in remarkable therapeutic efficacy in CT26 s.c. tumor models. Cytotoxic T lymphocytes induced by the vaccination using DC transfected with mRNA from the recrudescent tumor showed a potent cytotoxicity against the recrudescent CT26 tumor cells, which was significantly higher than the cytotoxicity induced by the vaccination using DC‐CT26 (P < 0.05). In addition, in a recrudescent tumor model, this vaccination suppressed the regrowing s.c. tumors, and was augmented by GM‐CSF mRNA co‐transfection (P < 0.05). These results suggested that vaccination therapy using DC simultaneously transfected with whole tumor RNA and GM‐CSF mRNA could generate therapeutic immune responses even against recrudescent tumor after prior vaccination. (Cancer Sci 2008; 99: 407–413)

Skeletal muscle metastasis from esophageal cancer: a report of two cases and a review of the literature

Skeletal muscle metastases from carcinoma are very rare. This report describes two cases of skeletal muscle metastasis from esophageal cancer as the first distant metastasis. Case 1, a 58-year-old man with stage IVa upper thoracic esophageal squamous cell carcinoma (SqCC), underwent chemoradiotherapy (CRT) and a subtotal esophagectomy with a three-field lymph node dissection. After the operation, he complained of a painful mass in his forearm, which was diagnosed to be metastatic SqCC by a biopsy. Local radiation therapy and systemic chemotherapy were performed, but he died 7 months after the first CRT. Case 2, a 61-year-old woman with stage IVa middle thoracic SqCC, underwent CRT. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) after the CRT showed a hot spot in the right gluteus maximus muscle, and it was diagnosed to be metastatic SqCC by a biopsy. Although additional treatment was performed, she died 6 months after the first visit. A short review of the literature concerning skeletal muscle metastasis from esophageal cancer was conducted.