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.

Lower mediastinal lymph node metastasis is an independent survival factor of Siewert type II and III adenocarcinomas in the gastroesophageal junction.

We examined clinicopathological features and surgical outcomes in patients with adenocarcinoma in the gastroesophageal junction (GEJ), while also analyzing the survival factors that have a prognostic impact. Between 1991 and 2009, 61 patients with tumors in the GEJ (Siewert type II and III) underwent primary surgical resection. Thirty of 61 patients had type II tumors (49.2%) and 31 had type III tumors (50.8%). The tumor size was larger in type III tumors than type II tumors (P = 0.0026). The overall 5-year survival rates in patients with type II tumors and type III tumors were 44.2 per cent and 41.4 per cent, respectively, with no significant differences (P = 0.1888). The independent survival factors were lower mediastinal lymph node metastasis (P = 0.0323) and a noncurative resection (P = 0.0442). The independent survival factors for patients who underwent curative resections were the tumor size (P = 0.0422), M category (P = 0.0489), and lower mediastinal lymph node metastasis (P = 0.0482). This study showed lower mediastinal lymph node metastasis to be an independent survival factor, and also suggested that lower mediastinal lymph node metastasis was associated with distant metastasis in patients with adenocarcinoma in the GEJ (Siewert type II and III). Therefore, the preoperative early detection of such metastasis is important to improve patient survival.

The evaluation of surgical treatment for gastric cancer patients with noncurative resection.

PURPOSE: This study aims to analyze the results of treatment in a series of 233 gastric cancer patients who underwent a noncurative resection. METHODS: We performed a retrospective study of patients with noncurative treatment for advanced gastric cancer who were divided into three treatment groups: total gastrectomy (TG, n=150), distal gastrectomy (DG, n=44), and nonresection (NR, bypass procedure or chemotherapy only, n=39). RESULTS: In multivariate analysis, surgical treatment (TG) and an absence of chemotherapy were significant independent prognostic factors for a poor survival. In the late period, the overall survival rate was significantly lower in the TG group than in the DG group (p=0.005) and was marginally lower than in the NR group (p=0.054). The resection group had a poorer compliance for chemotherapy than the NR group, and the TG group had a poorer compliance than the DG group (p<0.01). The morbidity rate was higher in the TG group than in the DG group (p<0.05). CONCLUSIONS: TG is considered to be inappropriate for the treatment of noncurative gastric cancer because of the poor prognosis, high morbidity rates, and poor compliance for chemotherapy associated with the procedure. However, noncurative DG was acceptable and postoperative chemotherapy should be used in selected patients.

[Peptide vaccine therapy with TLR-9 agonist for patients with esophageal squamous cell carcinoma].

Patients with advanced carcinoma are thought to have an impaired immune surveillance system. Therefore, the potent helper action is required for the induction of an antitumor immune response in such patients. We evaluated the efficacy of CpG-ODN, which is TLR-9 agonist, as cancer vaccine adjuvant through in vitro experiments. We also conducted a phase I clinical trial for patients with advanced esophageal squamous cell carcinoma (ESCC) using peptide vaccine in combination with CpG-B. In vitro experiments showed that CpG-ODN caused various immune-modifications, suggesting an efficacy of CpG-ODN as peptide vaccine adjuvant. Moreover, the immune monitoring data in phase I clinical trial suggested that CpG-B augmented the generation of antigen-specific T cell responses and innate immunity. These data indicated that the vaccination with cancer-testis antigen derived peptide in combination with CpG-B may be useful as a new immunotherapy for patients with advanced ESCC.

Endoscopic resection of duodenal bulb neuroendocrine tumor larger than 10 mm in diameter.

BACKGROUND: Endoscopic treatment for duodenal bulb neuroendocrine tumor larger than 10 mm is still controversial. This report presents four cases successfully treated with endosonography (EUS)-assisted endoscopic mucosal resection (EMR) procedure for duodenal bulb neuroendocrine tumor larger than 10 mm in diameter. METHODS: The case series of four patients diagnosed with neuroendocrine tumor from 2003 to 2008 were reviewed. EUS demonstrated well-defined hypoechoic tumors confined to the submucosal hyperechoic layer and the underlying hypoechoic muscularis propria was intact in all four patients. EMR were planned and performed for the duodenal bulb neuroendocrine tumors larger than 10 mm. RESULTS: En bloc resections with tumor free lateral and basal margins were accomplished using an endoscopic diathermic snare with forward-viewing instruments without any complications. Neither residual duodenal neuroendocrine tumors nor metastatic lesions were detected during the observation period ranging 19 to 78 months CONCLUSION: Duodenal bulb neuroendocrine, larger than 10 mm in diameter, can be treated by endoscopic procedure, after confirming that the tumor confined to the submucosal layer in EUS examination, and no lymph node involvement by abdominal CT and US.

Optimal period for the prophylactic administration of neutrophil elastase inhibitor for patients with esophageal cancer undergoing esophagectomy.

BACKGROUND: The present study was designed to determine the optimal period for the prophylactic administration of the neutrophil elastase inhibitor, Sivelestat, in patients undergoing transthoracic esophagectomy. Sivelestat is reported to be effective in patients who undergo esophagectomy by providing an increased oxygenation ability and suppressing the serum inflammatory cytokines in the postoperative period. However, the optimal period for the prophylactic administration of Sivelestat remains to be elucidated. METHODS: The 30 patients who underwent esophagectomy for thoracic esophageal cancer were enrolled in one of two groups. The initial 15 patients were assigned to group A and received intravenous infusion of Sivelestat sodium hydrate until postoperative day (POD) 2, and the subsequent 15 patients were assigned to group B and received Sivelestat until POD 5. Historical controls without Sivelestat administration were used. The postoperative courses and serum inflammatory cytokines were evaluated. RESULTS: Sivelestat improved oxygenation in the postoperative period; however, there were no differences between the two groups in terms of duration of mechanical ventilation, intensive care unit stay, systemic inflammatory response syndrome, and postoperative change of oxygenation. In addition, there were no differences in the postoperative changes in the serum interleukin (IL)-6 and high mobility group box chromosomal protein 1. Although the serum IL-8 on POD 3 was lower in group B than in group A, the neutrophil elastase showed no difference between these groups. None of the patients in either group suffered respiratory complications. CONCLUSIONS: The two-day administration of Sivelestat initiated immediately after intrathoracic manipulation was found to be sufficient for prophylactic use to prevent pulmonary complications by suppressing hypercytokinemia after esophagectomy.

Dendritic cells adenovirally-transduced with full-length mesothelin cDNA elicit mesothelin-specific cytotoxicity against pancreatic cancer cell lines in vitro.

Mesothelin (MSLN) is an attractive candidate as a molecular target for pancreatic cancer immunotherapy. The purpose of this study was to demonstrate that cytotoxic T lymphocytes (CTLs) generated from peripheral blood mononuclear cells (PBMCs) by stimulation with genetically-modified dendritic cells (DCs) expressing MSLN could produce specific anti-tumor immunity against pancreatic cancer cells endogenously expressing MSLN. MSLN-specific CTLs were generated from PBMCs of healthy donors by in vitro stimulation with DCs adenovirally-transduced with the full-length MSLN gene (DC-AxCAMSLN). The cytotoxic activity was tested using a 4-h (51)Cr-release assay. The pancreatic cancer cell lines (PK1, CfPAC1, AsPC1), a lymphoblastoid cell lines (LCL) transduced with the MSLN gene, and LCL pulsed with MSLN-epitope peptides were used as target cells. MSLN-specific CTLs induced by in vitro stimulation with DC-AxCAMSLN killed pancreatic cancer cell lines expressing MSLN in an HLA-restricted fashion. These CTLs also showed cytotoxic activity against autologous LCL pulsed with multiple MSLN-derived epitope peptides. In addition, CD8(+) T cells, as well as CD4(+) T cells, sorted from these CTLs showed significant production of interferon-γ when stimulated with DC-AxCAMSLN. The in vitro stimulation of PBMCs with DCs transduced with the full-length MSLN gene elicited a potent MSLN-specific cytotoxic activity against pancreatic cancer cell lines endogenously expressing MSLN by recognizing multiple MSLN epitopes and activating both CD8(+) T cells and CD4(+) helper T cells. These results therefore suggest the potential of developing future clinical applications of the vaccines using genetically-modified DCs expressing MSLN.

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.

Vaccination with peptides derived from cancer-testis antigens in combination with CpG-7909 elicits strong specific CD8+ T cell response in patients with metastatic esophageal squamous cell carcinoma.

Potent helper action is necessary for peptide-based vaccines to efficiently induce antitumor immune responses against advanced cancer. A phase I trial for advanced esophageal squamous cell carcinoma was carried out for patients with HLA-A*2402 using epitope peptides derived from novel cancer-testis antigens, LY6K and TTK, in combination with CpG-7909 (NCT00669292). This study investigated the feasibility and the toxicity as well as induction of tumor antigen-specific immune responses. Nine patients were vaccinated on days 1, 8, 15, and 22 of each 28-day treatment cycle with peptide LY6K-177, peptide TTK-567, and CpG-7909 (level-1; 0, level-2; 0.02, level-3; 0.1 mg/kg) and all were tolerated by this treatment. LY6K-specific T cell responses in PBMCs were detected in two of the three patients in each level. In particular, two patients in level-2/3 showed potent LY6K-specific T cell responses. In contrast, only two patients in level-2/3 showed TTK-567-specific T cell responses. The frequency of LY6K-177 or TTK-567-specific CD8+ T cells increased in patients in level-2/3 (with CpG). The vaccination with peptides and CpG-7909 increased and activated both plasmacytoid dendritic cells and natural killer cells, and increased the serum level of α-interferon. There were no complete response (CR) and partial response (PR), however, one of three patients in level-1, and four of six patients in level-2/3 showed stable disease (SD). In conclusion, vaccination with LY6K-177 and TTK-567 in combination with CpG-7909 successfully elicited antigen-specific CD8+ T cell responses and enhanced the innate immunity of patients with advanced esophageal squamous cell carcinoma. This vaccine protocol is therefore recommended to undergo further phase II trials.

Clinicopathological characteristics of remnant gastric cancer after a distal gastrectomy.

INTRODUCTION: The survival rate of patients with remnant gastric cancer (RGC) is unfavorable in comparison to that of cancer in the nonresected stomach. However, when RGC is curatively resected, no significant differences have been reported between both groups in regard to survival. The aim of this study is to analyze the clinicopathological factors influencing a curative resection of RGC. METHODS: Thirty-eight consecutive patients with RGC from January 1, 1994 through March 31, 2009 were enrolled in this retrospective study. RESULTS: Their primary diseases were gastric cancers (21; 55.3%) and benign diseases (17; 44.7%). The type of the reconstruction methods of first gastrectomy were Billroth I (28; 73.7%) and Billroth II (10; 26.3%). A total of 31 patients underwent a laparotomy. Twenty patients underwent a curative resection, four patients underwent a palliative resection, and seven underwent a nonresective operation. A total of seven patients underwent an endoscopic resection for early gastric cancer, and all patients received a curative resection. Univariate and multivariate logistic regression analyses were performed to identify the clinicopathological and background factors influencing a curative resection of RGC. A multivariate analysis revealed only an annual follow-up endoscopic examination after the initial gastrectomy to be an independent factor for a curative resection (p=0.016; odds ratio, 35.3). CONCLUSIONS: An annual follow-up endoscopic examination an after initial gastrectomy may be related to improving the prognosis of patients with RGC.

Optimal dose of preoperative enteral immunonutrition for patients with esophageal cancer.

PURPOSE: A 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. METHODS: This 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. RESULTS: The 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. CONCLUSION: This study suggests that 500 ml of IMPACT is recommended as an optimal dose for patients with esophageal cancer.

Association of allogeneic blood transfusions and long-term survival of patients with gastric cancer after curative gastrectomy.

INTRODUCTION: The relationship between perioperative allogeneic blood transfusions and poor prognosis in patients with gastric cancer remains controversial. The aim of this study is to examine the effect of perioperative blood transfusions on long-term survival of patients undergoing curative gastric resection for gastric cancer. METHODS: Eight hundred fifty-six consecutive patients with gastric cancer who underwent curative gastrectomy (R0) from January 1, 1991 through December 31, 2002 were enrolled in this retrospective study. RESULTS: A multivariate overall survival analysis using Cox proportional hazard regression model revealed macroscopically infiltrative tumor, tumor infiltration of serosa, lymph node metastasis, blood transfusions (hazard ratio, 2.69), pulmonary disease, and liver dysfunction as prognostic factors for long-term survival. Blood transfusion was an independent prognostic factor at all stages of disease. Disease-specific and overall survival showed significant differences between the transfused and nontransfused groups (log-rank, P < 0.0001). Based on multivariate logistic regression analysis, the need for blood transfusion was significantly associated with advanced age (>or=65 years), long duration of operation (>or=300 min), massive blood loss (>or=1,000 ml), and anemia (Hb < 10 g/dl). CONCLUSIONS: Allogeneic blood transfusion is an independent prognostic factor for long-term survival in gastric cancer patients.

Evaluation of double tract reconstruction after total gastrectomy in patients with gastric cancer: prospective randomized controlled trial.

BACKGROUND: The double tract (DT) method was compared with the Roux-en-Y (R-Y) method to identify the optimal reconstruction procedure after total gastrectomy for patients with gastric cancer. The DT reconstruction is as simple as the R-Y, and it can be safely performed even after total gastrectomy. However, these have been no studies evaluating the usefulness of DT reconstruction in comparison to R-Y reconstruction. METHODS: A group of 44 patients with gastric cancer were intraoperatively randomized for R-Y (n = 23) or DT reconstruction (n = 21) after total gastrectomy (TG). Body weight, food intake, nutritional conditions, and quality of life (QOL) were determined at 3 and 12 months after the operation. This study is registered with ClinicalTrials.gov, no. NCT00746161. RESULTS: Food intake significantly decreased soon after the operation. No differences were observed between the DT and R-Y groups. The body weight decreased throughout the ensuing period (P < 0.05) and thereafter gradually recovered. However, no differences were observed between the two groups. Among the nutritional laboratory parameters, serum prealbumin, retinol-binding protein, total cholesterol, and triglyceride were decreased soon after the operation. The changes of those parameters were not substantially different between the two groups. The postoperative QOL was evaluated, and no differences were observed between those groups. CONCLUSIONS: There were no particular advantages in the DT method after TG in comparison to the simple R-Y method in terms of body weight, QOL, and nutritional conditions, suggesting that the DT method might not be recommended after TG for patients with gastric cancer.

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.

High CCR7 mRNA expression of cancer cells is associated with lymph node involvement in patients with esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (SCC) is one of the biological malignant tumors. Once a tumor invades the submucosa, an incidence of lymph node (LN) metastases is very high, thus resulting in poor survival. Recently, chemokines have been reported to play an important role in organ-specific metastases in several malignancies. In particular, CCR7 has been reported to be associated with LN metastases by immunohistochemistry. However, there have been no studies of quantitative analyses of CCR7 mRNA expression on cancer cells. In this study, we investigated the clinical significance of the expression of CCR7 in the establishment of LN metastases of esophageal SCC. A series of 78 patients with esophageal SCC who underwent esophagectomy were consecutively selected. The expression of CCR7 mRNA from tumor tissue samples was analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), and that from cancer cell samples collected using laser microdissection system was analyzed by qRT-PCR. Immunohistochemical staining of CCR7 was also performed. Although CCR7 mRNA expression in tumor tissues demonstrated no association with the LN metastases, that in cancer cells correlated with LN metastases (p<0.05) due to the fact that not only cancer cells but also infiltrating lymphocytes expressed CCR7 in tumor tissue. Multivariate logistic regression analysis revealed a high CCR7 expression in cancer cells to be an independent predictive factor for LN metastases. These results suggested that CCR7 expression might play an important role in establishing LN metastases in patients with esophageal SCC.

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

BACKGROUND AND AIMS: Whether 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 METHODS: We 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. RESULTS: H1, 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. CONCLUSION: The 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.

Multiple early gastric cancer with gastritis cystica profunda showing various histological types.

We report a case of multiple early gastric cancer showing varied histological types associated with gastritis cystica profunda (GCP). A 61-year-old man who had early gastric cancer associated with GCP underwent a distal gastrectomy with lymphadenectomy. Histological examination showed various histological types of cancer -well differentiated, moderately differentiated, poorly differentiated adenocarcinoma, mucinous adenocarcinoma and signet ring cell carcinoma- that had developed independently in the mucosal and submucosal layers of the resected specimen. Furthermore, multiple cysts with a single layer of columnar epithelium were present in the submucosa around the cancerous lesions. However, no neoplastic changes were found in those epithelial cells. Helicobacter pylori was detected in the residual stomach 3 months after surgery. Although the mechanism of the relationship between gastric carcinoma and GCPs is obscure, we speculate that repeated erosion and regeneration induced by chronic inflammation causes multicentric carcinogenesis as well as an aberration of the gastric glands. GCPs may be a risk factor for multiple 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.

Streptococcal preparation OK-432 promotes the capacity of dendritic cells (DCs) to prime carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte responses induced with genetically modified DCs that express CEA.

Cancer immunotherapy using dendritic cells (DCs) adenovirally transduced with the whole tumor-associated antigen (TAA) gene is an effective approach. Streptococcal preparation OK-432 is useful for stimulating DCs in terms of maturation. In this study, we established carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes (CTLs) using in vitro stimulation with adenovirally modified human DCs that express CEA. We investigated whether OK-432 stimulation could be more effective in inducing CEA-specific CTLs compared with other typical stimuli. DCs adenovirally transduced with the CEA gene were cultured under various conditions with tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), or OK-432. A cytotoxicity assay using peripheral blood mononuclear cell (PBMC)-derived CTLs was performed in a 4 h-51Cr release assay. OK-432 stimulated immature DCs to acquire a mature phenotype and to produce significant amounts of T-helper 1 cytokines. In all groups (immature DCs, TNF-alpha/DCs, LPS/DCs, OK-432/DCs), CEA-specific CTLs were generated. OK-432-stimulated DCs (HLA-A24) induced the most potent cytotoxic activity against CEA-expressing targets (A24) but not against controls. OK-432/DCs were able to induce markedly potent CTLs specific to target cells pulsed with CEA652 peptide (HLA-A24-restricted peptide), although others failed to induce potent CTLs. In conclusion, the CTL induction protocol using adenovirally modified DCs that express CEA after maturation with OK-432 showed a potent antitumor activity against CEA-expressing target cells, and is therefore promising for clinical applications as a cancer vaccine therapy.

An analysis of the factors contributing to a reduction in the incidence of pulmonary complications following an esophagectomy for esophageal cancer.

BACKGROUND: Pulmonary complications occur most frequently following a transthoracic esophagectomy for esophageal cancer and would get to be lethal occasionally. In this study, we sought to determine the effect of respiratory physiotherapy, corticosteroid administration, and the use of the video-assisted thoracoscopic (VATS) esophagectomy with a small thoracotomy incision, on the incidence of pulmonary complications following a transthoracic subtotal esophagectomy. MATERIALS AND METHODS: Approximately 184 patients who had undergone a right transthoracic subtotal esophagectomy for squamous cell carcinoma of the thoracic esophagus were studied. To reduce the incidence of pulmonary complications, we performed clinical trials using respiratory physiotherapy, corticosteroid administration, and the VATS-esophagectomy surgical technique. RESULTS: The independent risk factors for pulmonary complications in the multivariate logistic regression analysis were not administering corticosteroids, blood loss greater than 630 ml, and not providing respiratory physiotherapy. In addition, the use of a small surgical incision, less than 10 cm, for the thoracotomy had no effect on the prevention of pulmonary complications. CONCLUSIONS: We concluded that patients with thoracic esophageal cancer could undergo a three-field dissection in comparative safety if the patients were provided with corticosteroid medication in the perioperative period, if the patients received sufficient respiratory physiotherapy, and if surgical blood loss was reduced.