Mikihito Nakamori

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.

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.

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)