Detection of the mRNA of selected genes by reverse transcriptase-polymerase chain reaction (RT-PCR) is a sensitive and powerful tool for detecting cancer cells in bone-marrow or peripheral-blood samples. In this study, we determined whether carcinoembryonic antigen (CEA) mRNA is detectable in the peripheral blood of patients with gastrointestinal or breast cancer. In addition, we studied selected patients undergoing surgical procedures to assess whether tumor manipulation during operation enhances cancer-cell dissemination. Peripheral blood from 55 patients with gastrointestinal or breast cancer and from 22 control cases was analysed for CEA mRNA using RT-PCR. For 15 selected cases undergoing curative surgery for cancer, samples were also obtained during and after surgery. Breast cancer is conceptually accepted by many investigators as a systemic disease (Brown et al., 1995;Cote et al., 1991). This means that early breast cancer or minimum-sized breast cancer can spread via the blood-stream or lymphatic system to form metastatic foci in distant organs. We have considered that the same situation might exist in gastrointestinal cancers. It was, however, difficult to prove this concept due to the limitcd techniques available. Reccnt dcvelopments in molecular technology now enable us to detect small numbers of circulating cancer cclls in the peripheral blood or bone marrow (Johnson et a/., 1995; Smith et al., 1991).In this study, we detccted the presence of carcinoembryonic antigen ( 1995). If CEA mRNA is detected in blood samples, this implies the presence of ectopic, and hence presumably malignant CEA-expressing cells. One potential problem is that the CEA gene family includes a number of homologous genes partly expressed in granulocytes, which may produce falsepositive results (Stoffel et al., 1993). To overcome this problem, CEA-specific amplification has been developed using welldesigned DNA primers (Gerhard et al., Neumaier el al., 1995). On the basis of the results obtained in our present study, we discuss the significance of the presence of CEA mRNA in the peripheral blood of patients. In addition, to examine the effect of tumor manipulation during operation (Brown et ab, 1995; Nishizaki et aL, 1990), we applied the RT-PCR assay to peripheral blood samples taken from patients before, during and after operation. MATERIAL A N D METHODS PatientsFifty-five patients aged between 31 and 76 years were evaluated; these included 6 with esophageal cancer, 20 with gastric cancer, 20 with colorectal cancer and 9 with breast cancer. Of these, 14 patients including 7 with stage-IV gastric cancer, 6 with Dukes' D colorectal cancer and 1 with stage-IV breast cancer were shown to have distant metastases which were confirmed by chest X-ray, computed tomography, magnetic resonance imaging or ultrasonography. In these 14 advanced cases, a simple resection of the primary lesion was performed in 2 of 7 cases of gastric cancer, 4 of 6 cases of colorcctal cancer and 1 case of breast cancer. The other 7 far advanced cases receive...
Detection of the mRNA of selected genes by reverse transcriptase-polymerase chain reaction (RT-PCR) is a sensitive and powerful tool for detecting cancer cells in bone-marrow or peripheral-blood samples. In this study, we determined whether carcinoembryonic antigen (CEA) mRNA is detectable in the peripheral blood of patients with gastrointestinal or breast cancer. In addition, we studied selected patients undergoing surgical procedures to assess whether tumor manipulation during operation enhances cancer-cell dissemination. Peripheral blood from 55 patients with gastrointestinal or breast cancer and from 22 control cases was analysed for CEA mRNA using RT-PCR. For 15 selected cases undergoing curative surgery for cancer, samples were also obtained during and after surgery. Breast cancer is conceptually accepted by many investigators as a systemic disease (Brown et al., 1995;Cote et al., 1991). This means that early breast cancer or minimum-sized breast cancer can spread via the blood-stream or lymphatic system to form metastatic foci in distant organs. We have considered that the same situation might exist in gastrointestinal cancers. It was, however, difficult to prove this concept due to the limitcd techniques available. Reccnt dcvelopments in molecular technology now enable us to detect small numbers of circulating cancer cclls in the peripheral blood or bone marrow (Johnson et a/., 1995; Smith et al., 1991).In this study, we detccted the presence of carcinoembryonic antigen ( 1995). If CEA mRNA is detected in blood samples, this implies the presence of ectopic, and hence presumably malignant CEA-expressing cells. One potential problem is that the CEA gene family includes a number of homologous genes partly expressed in granulocytes, which may produce falsepositive results (Stoffel et al., 1993). To overcome this problem, CEA-specific amplification has been developed using welldesigned DNA primers (Gerhard et al., Neumaier el al., 1995). On the basis of the results obtained in our present study, we discuss the significance of the presence of CEA mRNA in the peripheral blood of patients. In addition, to examine the effect of tumor manipulation during operation (Brown et ab, 1995; Nishizaki et aL, 1990), we applied the RT-PCR assay to peripheral blood samples taken from patients before, during and after operation. MATERIAL A N D METHODS PatientsFifty-five patients aged between 31 and 76 years were evaluated; these included 6 with esophageal cancer, 20 with gastric cancer, 20 with colorectal cancer and 9 with breast cancer. Of these, 14 patients including 7 with stage-IV gastric cancer, 6 with Dukes' D colorectal cancer and 1 with stage-IV breast cancer were shown to have distant metastases which were confirmed by chest X-ray, computed tomography, magnetic resonance imaging or ultrasonography. In these 14 advanced cases, a simple resection of the primary lesion was performed in 2 of 7 cases of gastric cancer, 4 of 6 cases of colorcctal cancer and 1 case of breast cancer. The other 7 far advanced cases receive...
Lymphokine-activated killer (LAK) cell activity of peripheral blood mononuclear cells (PBM), spleen cells (SPC), regional lymph node cells (LNC), and tumor-infiltrating lymphocytes (TIL), induced by activation with interleukin 2 (IL 2) for 4 days, was evaluated in patients with gastric carcinoma. TIL exhibited the lowest LAK activity and the cytotoxicity of LNC was significantly lower than that of either PBM or SPC. There was no difference between PBM and SPC. Then, there were significant correlations of LAK activity among PBM, SPC, and LNC, whereas poor correlations were observed in the cytotoxicity between TIL and PBM, SPC, or LNC. Phenotypic analysis of each cell population was performed before and after activation with IL 2. Before culture, the cells mediating natural killer (NK) activity such as CD16+, CD56+, and CD57+ cells were few in LNC and TIL. However, CD56+ and CD57+ cells in TIL were increased after culture. Then, CD4+Leu8+ and CD8+CD11+ cells, which identify suppressor cell function, were not elevated in LNC or TIL, as compared to that in PBM or SPC. Further, the proportions of OKIa1+ and CD25+ cells expressing T-cell activation and IL 2 receptor were uniformly increased in all cell populations after culture. These results indicate the differential reactivity of each lymphocyte population to IL 2 and fundamental dysfunction of LNC and, especially TIL, suggesting the specific influence of the local tumor environment on the lymphocyte function in the area in patients with gastric carcinoma.
On the basis of our clinical findings that the ability of cancer patients to generate lymphokine-activated killer cells became markedly augmented after mitomycin C administration, we designed a treatment regimen comprising mitomycin C 12 mg/m2, i.v. on day 1 and recombinant interleukin-2 700 U/m2 (8000 IU/kg), i.v. every 12 h from day 4 through day 8. The treatment course was repeated at almost 7-day intervals. Altogether 33 patients with advanced carcinoma, including mainly gastrointestinal carcinoma, were treated with this regimen. Of these, 10 had a partial response (PR) and 4 had a minor response (MR). Since eosinophil counts peaked 1 day after either the first or second course of the therapy, the posttreatment values were compared to each pretreatment level, with regard to the clinical antitumor response to this treatment. When patients who showed PR were defined as responders, absolute eosinophil counts and the percentage of eosinophils in responders after both the first and second courses of the therapy were significantly greater than each pretreatment value or the posttreatment level in nonresponders. Further, these findings were almost identical, when both PR and MR were considered to be a true remission and therefore patients who exhibited PR or MR were defined as responders, although the difference between posttreatment levels of eosinophils in responders and nonresponders was not significant at the second course. These results indicate that eosinophilia induced by this treatment correlates with the clinical response to this therapy.
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