Surgery for gastric cancer patients of age 85 and older: Multicenter survey.

AIM: To investigate the surgical therapies for gastric cancer (GC) patients of age 85 or older in a multicenter survey. METHODS: Therapeutic opportunities for elderly GC patients have expanded in conjunction with extended life expectancy. However, the number of cases encountered in a single institution is usually very small and surgical therapies for elderly GC patients have not yet been standardized completely. In the present study, a total of 134 GC patients of age 85 or older who underwent surgery in 9 related facilities were retrospectively investigated. The relationships between surgical therapies and clinicopathological or prognostic features were analyzed. RESULTS: Eighty-nine of the patients (66%) presented with a comorbidity, and 26 (19% overall) presented with more than two comorbidities. Radical lymphadenectomy was performed in 59 patients (44%), and no patient received pre- or post-operative chemotherapy. Forty of the patients (30%) experienced perioperative complications, but no surgical or perioperative mortality occurred. Laparoscopic surgery was performed in only 12 of the patients (9.0%). Univariate and multivariate analyses of the 113 patients who underwent R0 or R1 resection identified the factors of pT3/4 and limited lymphadenectomy as predictive of worse prognosis (HR = 4.68, P = 0.02 and HR =2.19, P = 0.05, respectively). Non-cancer-specific death was more common in cStage I patients than in cStage II or III patients. Limited lymphadenectomy correlated with worse cancer-specific survival (P = 0.01), particularly in cStage II patients (P < 0.01). There were no relationships between limited lymphadenectomy and any comorbidities, except for cerebrovascular disease (P = 0.07). CONCLUSION: Non-cancer-specific death was not negligible, particularly in cStage I, and gastrectomy with radical lymphadenectomy appears to be an effective treatment for cStage II elderly GC patients.

[A Case of Synchronous Multiple Liver Metastases from Ascending Colon Cancer Showing Pathological Complete Response to CapeOX Treatment].

The patient was a 30-year-old man who underwent a medical examination for shortness of breath.An abdominal computed tomography(CT)scan revealed advanced ascending colon cancer with multiple metastases to the liver.We performed a laparoscopic right hemicolectomy first, due to the obstruction.Postoperatively, the patient received capecitabine plus oxaliplatin( CapeOX)chemotherapy.After 10 courses of CapeOX, the multiple liver metastases had reduced remarkably in size. Colectomy of the anastomosis and partial hepatectomy were then performed.Histological examination of the resected tissue revealed no residual cancer cells, suggestive of a pathological complete response.

[A case of complete response (CR) persisting for 2 years from S-1 administered five days a week in a patient with gastric cancer].

We attempted S-1 administered five days a week from March, 2004 for an 84-year-old female harboring Borrmann type 1 gastric cancer because her family did not agree to her gastrectomy. After treatment for 1 month the lesion changed into a shallow ulcer. The lesion was clinically diagnosed with CR about 3 months later. As of October, 2006, 2 years after inducing CR, we have been administering S-1 to the patient, with no regrowth of the tumor.

A new strategy using autologous dendritic cells and lymphokine-activated killer cells for cancer immunotherapy: efficient maturation of DCs by co-culture with LAK cells in vitro.

Among a variety of antigen presenting cells (APCs), accumulating results support that the mature dendritic cell (DC) has the potential to induce efficient cytotoxic T lymphocyte (CTL) responses in the context of peptide-based immunotherapy. DCs have been known to assume the mature form by signaling through the CD40-CD40 ligand (CD40L) interaction, which may be provided by activated CD4+ T cells expressing abundant CD40L molecules on their surfaces. Here, we report that DCs generated from peripheral blood monocytes obtained from patients with advanced cancer exhibit a mature phenotype after co-culturing with autologous lymphokine-activated killer (LAK) cells generated by the stimulation of peripheral blood mononuclear cells with anti-CD3 monoclonal antibody (mAb) and interleukin (IL)-2. Part of this process appeared to be dependent on the expression of CD40L on the surface of LAK cells, although it was also suggested that some other humoral factors produced by LAK cells may be involved in this effect as well. DCs derived from the donors, of which LAK cells demonstrated a higher Th1/Th2 ratio upon activation determined by the intracellular detection of interferon-gamma and IL-4, showed more efficient maturation upon co-culture with LAK cells than DCs from donors with a low Th1/Th2 ratio. Importantly, these matured DCs induced a two-times stronger antigen-presenting capacity measured by an allo-reactive mixed lymphocytes reaction assay as compared to immature DCs. These results imply the use of the combination of DCs and LAK cells for immunotherapy against cancer.

[Evaluation of pre-operative administration of TS-1 in patients with advanced gastric or colorectal cancer--estimation of pathological effectiveness for postoperative adjuvant chemotherapy with TS-1].

We performed surgical resections in 6 cases of advanced gastric cancer and 4 cases of colorectal cancer after preoperatively treating them with TS-1 at a daily dose of 80-100 mg/body for 2 weeks, and evaluated whether one can estimate their sensitivity to TS-1 by a pathological examination. Case 1 of type 3 advanced gastric cancer underwent surgery after one week interval following oral administration of TS-1 at a daily dose of 80 mg/body for 2 weeks. Surprisingly, the pathological examination revealed complete disappearance of cancer cells in the resected stomach and no cancer cells in the regional lymphnodes, judged grade 3 in pathological effectiveness. Case 2 of type 2 advanced gastric cancer was treated with TS-1 at a daily dose of 100 mg/body for 2 weeks and underwent surgery after a three-week interval due to the complication of pneumonia. The pathological effectiveness was judged grade 2 in the resected stomach, and no cancer cells were detected in the regional lymphnodes. In both cases, the postoperative course was uneventful, and no adverse effects were detected. In these cases, their high sensitivity to TS-1 was clearly confirmed, and now they have been treated with TS-1 for the postoperative adjuvant chemotherapy, and have undergone regular check-ups at our outpatient clinic in good condition. Recently, we performed the same protocol in 6 cases of advanced gastric cancer including these 2 cases and also in 4 cases of advanced colorectal cancer. This protocol was found useful for evaluating the pathological effect by TS-1. We consider the protocol quite useful and helpful in determining a suitable regimen for postoperative adjuvant chemotherapy.

Recognition of Epstein-Barr virus-associated gastric carcinoma cells by cytotoxic T lymphocytes induced in vitro with autologous lymphoblastoid cell line and LMP2-derived, HLA-A24-restricted 9-mer peptide.

Epstein-Barr virus (EBV) is associated with several types of malignancies including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma, and gastric carcinoma. Previous reports have suggested that EBV-related antigen-targeting immunotherapy is one of the promising approaches for the treatment of these malignancies other than gastric carcinoma. EBV-associated gastric carcinoma (EBVaGC) has been shown to express Epstein-Barr virus nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2). In the present study, DNA and mRNA freshly isolated from tumors of patients with gastric cancer were subjected to polymerase chain reaction (PCR) using EBV-specific primers and reverse transcription (RT)-PCR specific for LMP2 transcripts. EBV-specific region was identified in genomic DNA isolated from cancerous tissues in 22% of gastric cancer patients. LMP2 mRNA was also detected in 3 out of these 5 DNA positive samples tested. To investigate the feasibility of specific immunotherapy for EBVaGC, we induced cytotoxic T lymphocytes (CTLs) from peripheral blood lymphocytes using two kinds of antigen-presenting cells (APCs) such as autologous lymphoblastoid cell line (LCL) and LMP2-derived peptide-pulsed dendritic cells (DCs). The cytotoxicity of these CTLs against peptide-pulsed targets was examined by standard 51Cr release assay and interferon (IFN)-gamma production assay. We further assessed the recognition of tumor cells endogenously expressing LMP2 by these T cells. T cells induced by peptide-loaded DCs and autologous LCL efficiently lysed peptide-pulsed targets. Furthermore, these T cells could recognize not only tumor cells transfected with LMP2, but also LMP2-positive gastric cancer cells which were successfully isolated and cultured from specimens obtained by surgery. Collectively, sensitization of peripheral blood lymphocytes with LMP2-derived peptide was able to induce CTL response against EBVaGC cells. Thus, EBVaGC is susceptible for the LMP2-targeting immunotherapy.

Dendritic cell-based immunotherapy of cancer with carcinoembryonic antigen-derived, HLA-A24-restricted CTL epitope: Clinical outcomes of 18 patients with metastatic gastrointestinal or lung adenocarcinomas.

We conducted a clinical study of cancer vaccine therapy with dendritic cells (DCs) and HLA-A24-restricted carcinoembryonic antigen (CEA)-derived peptide to assess the feasibility and efficacy of such therapy. Eighteen patients with CEA-expressing metastatic gastrointestinal or lung adenocarcinomas who were positive for human leukocyte antigen (HLA)-A24 were enrolled. DCs were generated from the patients' autologous monocyte-enriched fractions of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. The generated DCs were pulsed with CEA-derived, HLA-A24-restricted 9-mer peptide (CEA652) and injected into the patients intradermally and subcutaneously every 2 weeks. Toxicity and clinical and immunological responses were closely monitored in each patient. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. Although no definite tumor shrinkage occurred in any patient, long-term stable disease or marked decreases in the serum CEA level were observed in some patients after therapy. Most of the patients in whom treatment was clinically effective showed a positive skin response to CEA652-pulsed DCs (delayed-type hypersensitivity skin test) and a positive in vitro CTL response to CEA652 peptide after therapy. We conclude that active specific immunotherapy using DCs pulsed with CEA652 is a safe and feasible treatment that is clinically effective in some patients with metastatic gastrointestinal or lung adenocarcinomas. Our results will hopefully encourage further refinement and development of DC-based immunotherapy with HLA-A24-restricted CEA-derived peptide for refractory solid cancers that express CEA.

Streptococcal preparation OK432 promotes functional maturation of human monocyte-derived dendritic cells.

Streptococcal preparation OK432 is an immunomodulatory agent extensively used as adjuvant therapy for gastric cancer in Japan. OK432 augments the cytotoxic activity of various effector cells such as lymphocytes, macrophages and (natural killer) NK cells and induces the production of multiple cytokines. Dendritic cells (DC) are professional antigen-presenting cells (APC) that can be used for cancer vaccine therapy. In the present study, we investigated the effect of OK432 on the activation of DC. Here we report that OK432 induced phenotypic and functional maturation of human monocyte-derived DC. In vitro culture of immature DC generated from adherent peripheral blood mononuclear cells (PBMC) using granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) with OK432 at various doses (0.01 to 0.1 KE/ml) for 2 days resulted in increased cell surface expression of CD80, CD83, CD86 and ICAM-1 in a dose-dependent manner. The expression of CD83, a selective marker of mature DC, on DC activated by OK432 (OK-DC) was maximally enhanced after 3 days of incubation. Assay of cytokine production in OK-DC after 2 days in culture revealed that OK432 was a strong inducer of IL-12 and interferon-gamma (IFN-gamma). OK432 efficiently augmented the primary allogeneic T-cell responses by DC. This distinct phenotypic profile and allostimulatory capacity of OK-DC was stable for at least 48 h of additional culture in the absence of any cytokines. Moreover, the antiviral cytotoxic T lymphocytes (CTL) response in vitro was also enhanced by the addition of OK432 to the cultures. These findings suggest that OK432 is a potent stimulator of DC, and that stimulated DC are strong inducers of the T helper 1 (Th1)-type response. We conclude that OK-DC are likely candidates for use as an adjuvant for DC-based cancer immunotherapy.

Immunotherapy of solid cancer using dendritic cells pulsed with the HLA-A24-restricted peptide of carcinoembryonic antigen.

Carcinoembryonic antigen (CEA), an oncofetal glycoprotein overexpressed in most gastrointestinal and lung cancers, is a candidate molecule for cancer immunotherapy. Recently, a CEA-derived 9-mer peptide, CEA652 (TYACFVSNL), has been identified as the epitope of cytotoxic T lymphocytes restricted with human leukocyte antigen (HLA)-A24, which is present in 60% of the Japanese population and in some Caucasians. The authors performed a clinical study of a vaccine using autologous dendritic cells (DCs) pulsed with CEA652 and adjuvant cytokines, natural human interferon alpha (nhuIFN-alpha), and natural human tumor necrosis factor alpha (nhuTNF-alpha), for the treatment of patients with CEA-expressing advanced metastatic malignancies. Ten HLA-A24 patients with advanced digestive tract or lung cancer were enrolled in the study to assess toxicity, tolerability and immune responses to the vaccine. DCs were generated from plastic adherent monocytes of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMCs) in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). Generated DCs showing an immature phenotype were loaded with CEA652 and injected into patients intradermally and subcutaneously with 50% of the dose administered by each route every 2 weeks for a total of ten vaccinations. The total dose of administered DCs ranged from 2.7x10(7)cells to 1.6x10(8)cells. Adjuvant cytokines, i.e., 1x10(6) U/body of nhuIFN-alpha and nhuTNF-alpha, were administered to patients twice a week during the vaccination period. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. In the delayed-type hypersensitivity (DTH) skin test, two patients showed a positive skin response to peptide-pulsed DCs after vaccination, although none of the patients tested positive prior to vaccination. In the two patients who showed a positive skin response disease remained stable for 6 and 9 months respectively. These results suggest that active immunization using DCs pulsed with CEA652 peptide in combination with the administration of adjuvant cytokines is a safe and feasible treatment procedure.