Teruo Kaiga

Systemic Administration of IL-23 Induces Potent Antitumor Immunity Primarily Mediated through Th1-Type Response in Association with the Endogenously Expressed IL-12

IL-23, a cytokine, which is composed of the p40 subunit shared with IL-12 and the IL-23-specific p19 subunit, has been shown to preferentially act on Th1 effector/memory CD4+ T cells and to induce their proliferation and IFN-γ production. The IL-23 is also reported to act on Th17-CD4+ T cells, which are involved in inducing tissue injury. In this study, we examined the antitumor effects associated with systemic administration of IL-23 and their mechanisms in mouse tumor system. Systemic administration of high-dose IL-23 was achieved using in vivo electroporation of IL-23 plasmid DNA into the pretibial muscles of C57BL/6 mice. The IL-23 treatment was associated with significant suppression of the growth of pre-existing MCA205 fibrosarcoma and prolongation of the survival of treated mice without significant toxicity when compared with those of the mice treated with EGFP. Although the therapeutic outcomes were similar to those with the IL-12 treatment, the IL-23 treatment induced characteristic immune responses distinctive to those of IL-12 treatment. The IL-23 administration even at the therapeutic levels did not induce detectable IFN-γ concentration in the serum. In vivo depletion of CD4+ T cells, CD8+ T cells, or NK cells significantly inhibited the antitumor effects of IL-23. Furthermore, the CD4+ T cells in the lymph nodes in the IL-23-treated mice showed significant IFN-γ and IL-17 response upon anti-CD3 mAb stimulation in vitro. These results and the ones in the IFN-γ or IL-12 gene knockout mice suggest that potent antitumor effects of IL-23 treatment could be achieved when the Th1-type response is fully promoted in the presence of endogenously expressed IL-12.

Evaluation of serum CEA and CA19-9 levels as prognostic factors in patients with gastric cancer

Background. This clinicopathological study evaluated the utility of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 as predictors of locoregional recurrence and long-term disease-free survival in patients with gastric cancer. Methods. During the period January 1989 to December 1994, 485 patients with primary gastric cancer were evaluated. Gastrectomies were performed in 434 patients. Prognostic factors were analyzed by the Kaplan-Meier method and multivariate analysis, using Cox regression. Results. Elevated serum CEA and CA19-9 levels were observed in 92 of the 485 patients (19.0%), and in 95 of the 435 patients (21.8%), respectively, and both markers were elevated in 29 of these 435 patients (6.7%). Elevated serum CEA and CA19-9 levels correlated well with lymph node metastasis, lymphatic invasion, vessel invasion, stage grouping, depth of invasion, and curability. Patients with elevated serum CEA levels were at significantly higher risk of having all recurrence factors than were those with normal serum CEA levels. Patients with elevated serum CA19-9 levels were at significantly higher risk of having peritoneal metastases and distant metastases than were those with normal serum CA19-9 levels. A significant difference in the cumulative survival curves of patients was demonstrated between those with elevated and those with normal serum CEA or CA19-9 levels, even for patients at the same disease stage (stage III). Patients with elevated levels of both markers had a significantly worse prognosis than patients in whom the levels of both markers were normal. In patients who underwent gastrectomy, elevated serum CEA levels either preoperatively or within 3 weeks after gastrectomy were associated with significantly worse prognosis than were normal levels. When the cutoff level of serum CEA was increased to 10 ng/ml, serum CEA, age, lymph node metastasis, and surgical stage grouping were selected as independent prognostic factors by multivariate analysis of 14 prognostic factors, using Cox regression. Conclusion. Serum CEA and CA19-9 levels provide additional prognostic information in patients with primary gastric cancer. In particular, an elevated serum CEA level provides additional prognostic information and is a useful indicator of curability in patients who undergo gastrectomy. Serum CEA level is an independent prognostic factor in patients with primary gastric cancer.

Is there a benefit of pancreaticosplenectomy with gastrectomy for advanced gastric cancer

BACKGROUND In Japan, wide resection with extended lymph node dissection has been performed for advanced cancer with good prognosis. Pancreaticosplenectomy with gastrectomy is performed to facilitate dissection of the lymph nodes around the splenic artery. We attempted to evaluate the effects of pancreaticosplenectomy and splenectomy with gastrectomy for advanced gastric cancer. METHODS Gastric cancer patients underwent splenectomy with gastrectomy (78 cases), pancreaticosplenectomy with gastrectomy (105 cases), or gastrectomy alone (1,755 cases). Survival rates were compared among the three groups for each factor of the depth of invasion, stage, and curability. RESULTS There were no significant differences among the three groups. Pancreaticosplenectomy or splenectomy with gastrectomy to dissect lymph nodes does not improve survival but is associated with severe complications. CONCLUSIONS The spleen should be resected when a patient has clearly positive node metastasis around the splenic hilus and artery, and pancreaticosplenectomy be performed when the cancer lesion invades the pancreas.

Generation of mature dendritic cells fully capable of T helper type 1 polarization using OK-432 combined with prostaglandin E2

Dendritic cell (DC) administration appears to be a very promising approach for the immunotherapy of cancer. The results of clinical studies have suggested that the nature and the magnitude of antitumor immune responses are critically affected by DC functions, including production of T helper type 1 (Th1)‐inducing cytokines, activation of T cell subsets and natural killer (NK) cells, and migration from peripheral tissues to the T cell area of the draining lymph nodes. Administration of immature DCs could fail to fully stimulate antigen‐specific immune responses and might induce tolerance under some conditions. In this study, we developed a method to obtain fully mature DCs, and we compared in detail the DCs thus obtained with those obtained using a maturation stimulus termed monocyte‐derived medium (MCM)‐mimic, which is a mixture of recombinant cytokines and prostaglandin E2 (PGE2) mimicking the components of monocyte‐conditioned medium. Using DCs derived from monocytes of advanced cancer patients in this study, we found that DCs stimulated with OK‐432 alone showed phenotypes similar to those of mature DCs induced using MCM‐mimic, though with better secretion of IL‐6 and IL‐12. However, these DCs were found to have poor migratory capacity associated with the marginal expression of CCR7. When OK‐432 was combined with PGE2, the CCR7 expression and migratory capacity of DCs were significantly improved without impairing other immuno‐stimulatory functions. These results suggest that stimulation with the combination of OK‐432 and PGE2 could be applicable as an alternative to MCM‐mimic in clinical trials which require fully matured DCs to induce Th1‐type immune responses against tumor cells even in patients with advanced cancer.

FLEP Chemotherapy for α-Fetoprotein-Producing Gastric Cancer

Objective: This study aimed at comparing the efficacy of FLEP chemotherapy in the treatment of stage IV AFP-producing gastric cancer and stage IV non-AFP-producing gastric cancer. Methods: Between 1989 and 2002, 57 patients with stage IV inoperable gastric cancer were given a combination of chemotherapy with 5-fluorouracil (5-FU), leucovorin (LV), etoposide (VP-16) and cis-diamminedichloroplatinum (CDDP) (designated as FLEP). In the two groups classified histologically according to AFP positivity, the rate of response and conversion to surgery, disease-free and overall survival were compared. The disease-free and overall survival in the two groups was compared by a log-rank test. Results: Patients of the AFP-producing group had a significantly better response rate (70 vs. 31.9%, p = 0.03) and a better conversion rate (40 vs. 12.8%, p = 0.04) than those of the non-AFP-producing group. Patients of the AFP-producing group also had a significantly better disease-free and overall survival (p = 0.02) than those of the non-AFP-producing group. AFP-producing gastric cancer was identified as an independent prognostic factor. Conclusion: FLEP chemotherapy was more effective for stage IV AFP-producing gastric cancer than in stage IV non-AFP-producing gastric cancer. Preoperative FLEP chemotherapy improved the prognosis of AFP-producing gastric cancer because of downstaging.

D2 gastrectomy with versus without bursectomy for gastric cancer.

Objectives:The purpose of this study was to determine the survival benefit of bursectomy by retrospectively comparing the prognosis in patients undergoing D2 lymphadenectomy and gastrectomy (D2 gastrectomy) with bursectomy for gastric cancer with that in patients undergoing D2 gastrectomy alone. Methods:A total of 254 consecutive stage IA to IIIC gastric cancer patients undergoing curative intent surgery between 2004 and 2009 were enrolled. The patients were divided into 2 groups: a bursectomy group, which included patients undergoing curative D2 gastrectomy with bursectomy by one surgeon, and a nonbursectomy group, which included those undergoing curative D2 gastrectomy alone by other surgeons. Results:No statistically significant difference was observed in the number of metastatic nodes or penetration of the serosa between the 2 groups. The overall incidence of surgery-related complications was 24.0% in the bursectomy group (29 of 121 patients) and 25.6% in the nonbursectomy group (34 of 133 patients). The 5-year overall survival rate was 85.8% in the bursectomy group and 80.8% in the nonbursectomy group (hazard ratio 0.82; 95% confidence interval, 0.37-1.74; P=0.60). Conclusions:The results of this retrospective study indicate no survival benefit for bursectomy plus D2 gastrectomy over D2 gastrectomy alone.

Partially MHC-Matched Donor CD8+ T Cells are Indispensable for Switching to Splenocytic Chimerism

BACKGROUND We have shown that partially major histocompatibility complex (MHC)-matched splenocytes can replace bone marrow (BM) and maintain skin grafts by establishing splenocytic chimeras. Our aim was to identify the population of splenocytes that are indispensible for switching from BM to splenocytic chimerism. METHODS C3H/B6D2F1 mixed BM chimeras were established in lethally irradiated C3H mice. Skin grafts from C57BL/6 mice were transplanted 30 d later. After an additional 30 d, splenocytes from B6C3F1 mice were transplanted to establish splenocytic BM chimeras using total splenocytes (group A), CD90(+)-depleted splenocytes (group B), CD4(+)-depleted splenocytes (group C), or CD8(+)-depleted splenocytes (group D). RESULTS In group A, the BM switched to splenocyte-derived BM chimeras. Total B6C3F1 splenocytes created stable splenocyte BM chimeras that permitted long-term retention of skin grafts, without rejection. In groups B and D, the splenocytes failed to replace the recipient BM, and there was no decrease in the number of recipient-derived BM cells compared with group A from d 14 to 28 after splenocyte injection, as was the case for CD8(+) T cells. In group C mice, the recipient BM was slowly and incompletely replaced. CONCLUSIONS Partially MHC-matched donor CD8(+) T cells are indispensable for generating splenocyte chimeras in BM and maintaining allogeneic skin grafts.

Chimeric acceleration by donor CD4+CD25+T-reg depleted fraction in splenocyte transplantation

BACKGROUND We have established a splenocytic chimera model that can induce donor-specific tolerance and reconstitute the recipient immune system by donor splenocytes. AIM To accelerate such reconstitution, we investigated the role of donor-derived CD4(+)CD25(+) regulatory T-cells (T-reg). METHODS We established C3H/B6D2F1 mixed bone marrow chimeras in lethally irradiated C3H mice. We transplanted skin grafts from C57BL/6 mice 30 d later. After an additional 30 d, we transplanted the following types of splenocytes from B6C3F1 mice: total splenocytes (group A), CD4(+)CD25(+) T-reg depleted splenocytes (group B), CD8(+)-depleted splenocytes (group C), and CD4(+)-depleted splenocytes (group D). We assessed class I major histocompatibility complex, percentage of chimeric cells in peripheral blood, and survival of skin grafts in each group. RESULTS Group A and B mice switched to splenocytic chimeras, permitting the long-term survival of skin grafts. The proportions of H-2K(b+)H-2K(k-) cells in group B were significantly lower than those in group A on day 14 (0.47% ± 0.68% versus 9.49% ± 8.30%; P = .01) and day 21 (0.16% ± 0.25% versus 3.35% ± 2.78%; P = .01). The initial increase in the proportion of H-2K(b+)H-2K(k+) double-positive cells in group B was faster than that in group A (from 0.33% ± 0.10% versus. 0.39% ± 0.14% before splenocyte injection to 39.03% ± 30.50% versus 10.73% ± 11.54% on day 7; P = .02). The initial increase in the proportion of CD8(+) T-cells was faster in group B than in group A (from 2.72% ± 0.52% versus 2.49% ± 1.07% before splenocyte injection to 29.61% ± 26.72% versus 4.92% ± 1.56% on day 7; P = .04). CONCLUSIONS The depletion of CD4(+)CD25(+) T-reg fraction in donor splenocytes can accelerate switching to splenocytic chimera.

Dual primary gastric and colorectal cancer: is the prognosis better for synchronous or metachronous?

ObjectivesThe purpose of this study was to investigate the prognosis and clinicopathologic features of synchronous and metachronous dual primary gastric and colorectal cancer (DPGCC). MethodsWe reviewed clinical data of 96 patients with DPGCC, comprising 63 men and 33 women, from among 4523 patients with gastric or colorectal cancer who underwent surgical treatment or chemotherapy, but no endoscopic resection, for colorectal cancer between 1990 and 2009. The selected patients were classified into 2 groups according to the time of gastric or colorectal cancer detection as follows: synchronous group (n= 42) and metachronous group (n = 54). ResultsAmong 4523 patients treated for gastric and colorectal cancer, DPGCC was diagnosed in 96 (2.1%). In terms of clinicopathologic features, the proportion of early-stage gastric and colorectal cancer was higher in the metachronous DPGCC group, with P values of 0.02 and 0.01, respectively. Overall survival in the metachronous DPGCC group was significantly longer than in the synchronous DPGCC group (P = 0.02). Metachronous DPGCC was identified as an independent predictor of survival by both univariate and multivariate analyses, with a P value of 0.02 and 0.006, respectively. ConclusionMetachronous DPGCC had a better prognosis than synchronous DPGCC due to the tendency for metachronous DPGCC to occur in patients with early-stage cancer.

Pharmacokinetics of oxaliplatin in gastrointestinal cancer patients with malignant ascites.

Abstract The pharmacokinetics of oxaliplatin in plasma and ascitic fluid was investigated in 5 gastrointestinal cancer patients with malignant ascites. Oxaliplatin was administered at 85 mg/m2 by 2-hour infusion in the FOLFOX4 regimen, and the concentrations of total and free platinum were measured. There was a trend of lower plasma Cmax values of total platinum in patients with a larger volume of ascetic fluid. The AUC0-t values of mean concentration curves of total plasma platinum, total ascites platinum, free plasma platinum, and free ascites platinum were 31.15, 7.96, 4.93 and 2.93 μg·h/ml, respectively. The concentrations of free ascites platinum were similar to those of free plasma platinum at the last sampling time of 26 h in each patient. The decrease or disappearance of ascitic fluid was observed in 4 patients. These results suggest that oxaliplatin exerted a beneficial effect in gastrointestinal cancer patients with malignant ascites, even when administered intravenously.