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BACKGROUND Interleukin-18 (IL-18), a recently described cytokine produced mainly by macrophages, stimulates interferon-γ (IFN-γ) production by natural killer cells and T cells. Although it has been reported that serum IL-18 levels are higher in patients with advanced tuberculosis and acute graft-versus-host disease compared with normal controls, the authors found no reports regarding serum IL-18 levels in patients with malignant solid tumors. The purpose of this study was to determine serum IL-18 levels and their clinical significance in patients with gastric carcinoma. METHODS Peripheral blood samples were obtained from 94 patients with gastric carcinoma who underwent curative surgery and from 50 healthy volunteers. The serum IL-18 level, the IFN-γ, level, and the Helicobacter pylori (HP) serology status were determined in each sample with an enzyme-linked immunosorbent assay. RESULTS The mean serum IL-18 level for all patients was significantly higher compared with the mean level in healthy volunteers (P < 0.01). IFN-γ titers were below the level of detection in all samples tested. When the patients were subdivided into groups, it was found that the serum IL-18 level in patients with Stage II and III disease was significantly higher compared with the level found in healthy volunteers (P < 0.01). The serum IL-18 level decreased after patients underwent surgical resection. However, there was no significant difference in the serum IL-18 level between healthy controls and patients with Stage I or IV disease. Patients with IL-18 levels ≥ 310 pg/mL (i.e., equal to or greater than the mean levels ± 1 standard deviation in the healthy volunteers) experienced a significantly lower survival rate compared with patients who had IL-18 levels < 310 pg/mL after undergoing surgery (P < 0.05) despite a lack of any discernible difference in clinicopathologic factors between the two groups. The serum IL-18 level was identified as an independent postoperative prognostic factor in multivariate survival analysis using a Cox proportional hazards model (hazard ratio, 4.89; P = 0.01). There was no significant correlation between HP serology status and serum IL-18 levels. CONCLUSIONS The preoperative serum IL-18 level may represent a significant postoperative prognostic determinant in patients with gastric carcinoma. Its function in the host immune system remains to be elucidated. Cancer 2001;92:2050–5. © 2001 American Cancer Society.

Background and Objectives: Immune status in the peritoneal cavity of patients with gastric cancer remains largely unknown. To clarify the clinical significance of the host immune response within the peritoneal cavity, we examined the levels of interferon-gamma (IFN-γ), a type 1 cytokine, and interleukin-10 (IL-10), a type 2 cytokine, in peritoneal washings obtained from patients with gastric cancer. Methods: Both the concentrations of IFN-γ and of IL-10 in peritoneal washings obtained during surgery from 56 patients with gastric cancer were determined by an enzyme-linked immunosorbent assay. Results: The IFN-γ level was not correlated with the IL-10 level. The IL-10 level increased in a stage-dependent manner. The high IL-10 level correlated with an unfavorable outcome, whereas there was no relationship between the IFN-γ level and survival rate. However, among the stage III–IV cancer patients, the high IFN-γ level correlated with a favorable outcome, while there was no relationship between the IL-10 level and survival rate. Conclusion: Although the IL-10 level increases with tumor progression, the outcome of patients with advanced gastric cancer may be affected by the IFN-γ level, but not by the IL-10 level, in the peritoneal cavity. J. Surg. Oncol. 2001;78:124–130. © 2001 Wiley-Liss, Inc.

Fas ligand (FasL), which induces apoptosis against Fas-expressing cells, has been found to be expressed on various cell types including cancer cells. Membrane-bound FasL is cleaved to release soluble FasL (sFasL). Although serum or plasma sFasL concentration has been reported to increase in various diseases, sFasL concentration in healthy normal persons has not been fully studied. There have been few reports on sFasL concentrations in patients with carcinomas. We measured plasma sFasL concentrations using an enzyme-linked immunosorbent assay in 155 healthy volunteers (70 males and 85 females with an average age of 41.5+/-15.4) and 112 patients with gastric carcinoma (76 males and 36 females with an average age of 62.3+/-11.5). A significant negative correlation existed between age and plasma sFasL concentration in healthy volunteers. sFasL concentrations in males were significantly lower than those in females. Plasma sFasL levels were significantly higher in patients with gastric carcinoma than in healthy volunteers when male subjects aged 50 or older were analyzed, although no significant difference existed between the groups in the age bracket of 35 to 49. Male patients aged 50 or older with stage 1B or 2 tumors showed significantly higher plasma sFasL concentrations than those with stage 1A tumors or those with stage 3 or 4 tumors. In conclusion, age- and gender-matched controls should be used when plasma sFasL concentration is investigated. The origin and physiological or clinical significance of plasma sFasL in healthy volunteers and gastric cancer patients remain to be clarified.

Cytokeratins (CKs) 19 and 20 have been used as targets for detecting cancer cells. We attempted to detect circulating cancer cells in patients with gastric cancer using a high-sensitivity reverse transcriptase-polymerase chain reaction (RT-PCR) assay for CK transcripts.RT-PCR for CK 19 and CK 20 was performed on peripheral blood samples obtained from 52 patients with gastric cancer, from 24 of whom blood samples were collected on three occasions. Fourteen healthy volunteers served as controls.CK 19 and CK 20 were positive in five (9.6%) of 52 patients with gastric cancer. Of these five, four were classified into stage IV and the other stage I, according to the TNM Classification. In gastric cancer patients, three (12.5%) were positive in the 24 cases examined three times and two (7.1%) were positive in 28 cases examined only once. Among the stage IV cancer, positive cases for CK showed significantly lower survival rates than those negative for CK. Between CK 19 and CK 20 in the 24 cases examined three times, CK 19 was found to be more sensitive in detecting cancer cells. CK 20 was detected in one (7.0%) of 14 healthy volunteers, whereas CK 19 was not detected.We conclude that repeated blood sampling may be desirable to detect circulating cancer cells in peripheral blood, even in patients with advanced gastric cancer; CK 19 may be superior to CK 20 in detecting these cells. The clinical significance of detecting occult cancer in peripheral blood remains to be determined.

Afadin is an intracellular binding partner of nectins, cell-cell adhesion molecules, and plays important roles in the formation of cell-cell junctions. Afadin-knockout mice show early embryonic lethality, therefore little is known about the function of afadin during organ development. In this study, we generated mice lacking afadin expression in endothelial cells, and found that the majority of these mice were embryonically lethal as a result of severe subcutaneous edema. Defects in the lymphatic vessels of the skin were observed, although the morphology in the blood vessels was almost normal. Severe disruption of VE-cadherin-mediated cell-cell junctions occurred only in lymphatic endothelial cells, but not in blood endothelial cells. Knockout of afadin did not affect the differentiation and proliferation of lymphatic endothelial cells. Using in vitro assays with blood and lymphatic microvascular endothelial cells (BMVECs and LMVECs, respectively), knockdown of afadin caused elongated cell shapes and disruption of cell-cell junctions among LMVECs, but not BMVECs. In afadin-knockdown LMVECs, enhanced F-actin bundles at the cell periphery and reduced VE-cadherin immunostaining were found, and activation of RhoA was strongly increased compared with that in afadin-knockdown BMVECs. Conversely, inhibition of RhoA activation in afadin-knockdown LMVECs restored the cell morphology. These results indicate that afadin has different effects on blood and lymphatic endothelial cells by controlling the levels of RhoA activation, which may critically regulate the lymphangiogenesis of mouse embryos.

Leukocytes from patients with gastric, colorectal or benign gastrointestinal disease, as well as those from normal control subjects, were tested by the leukocyte migration inhibition test (LMIT), using five different allogeneic 3 M KCl extracts of gastric cancer extracts. In LMIT with a single tumor extract, a pathological MI was found in 48% of 79 gastric cancer patients, a significantly higher figure than in the three other groups of patients (4-21%). In the panel mode of LMIT, that is, testing each blood sample with five different tumor extracts, 62/79 (79%) of patients with gastric cancer showed a positive reaction. Positive reactivity was significantly higher in patients with gastric cancer than in patients in the other groups and the frequency was higher in stage IV cases than in stage I-III cases, although the differences were not significant. In addition, the frequency of the positive reaction was unrelated to the degree of differentiation in adenocarcinoma. Positive reactivity increased in inverse proportion to the degree of nuclear grade (NG) (84% in NG I, 80% in NG II and 64% in NG III), but the correlation was not statistically significant.

Tissue specimens from patients with the scirrhous type of gastric carcinoma were stained using the peroxidase-antiperoxidase (PAP) method. Nine out of thirty-seven specimens (24 per cent) showed positive estrogen staining, and here tissues from male or older patients were usually stained. Cumulative survival rate in patients whose tissue showed a positive estrogen staining was higher than that in case of a negative estrogen staining. Four out of thirty-one specimens (13 per cent) stained positively for progesterone, all four patients being male. These results suggest that estrogen and progesterone may relate to the growth of the scirrhous type of gastric cancer.

The present study was undertaken to determine the adenosine deaminase (ADA) activity of peripheral lymphocytes in patients with gastric cancer, with respect to the cancer progression, the effect of surgery and/or immunotherapy. The gastric cancer patients showed lower lymphocyte ADA activity than did the normal control. The lymphocyte ADA activity did not decrease with the cancer progression. There was a significant correlation between lymphocyte ADA activity and blastogenesis of lymphocyte by phytohemaglutinin or concanavalin A. Six months following gastrectomy, the lymphocyte ADA activity was increased, as compared with the preoperative value. The ADA activity of patients on post-operative OK-432 showed a greater increase, as compared to that of patients not given this treatment. In conclusion, decreased lymphocyte ADA activity in gastric cancer patients might be due to either the cancer bearing status or to the immunological suppression.

In this study, the clinical significance of the tumor markers, tissue polypeptide antigen (TPA) and lipid-bound sialic acid (LBSA) in conjunction with carcinoembryonic antigen CEA, was tested in 52 gastric cancer patients. The incidence of elevated serum levels of these 3 markers was as follows: 63% (33/52) for TPA; 40% (21/52) for LBSA; 21% (11/52) for CEA. In a combination assay using all three tumor markers, 37 out of 52 gastric cancer patients (71%) showed a positive combination assay, while 5 out of 20 normal subjects (25%) showed a positive combination assay. In a discriminant analysis of the resulting data, 18 out of 52 gastric cancer patients (35%) were classified correctly based on an analysis of CEA alone. Furthermore, 25 out of 52 gastric cancer patients (48%) and all 20 normal subjects (100%) were classified correctly based on an analysis of all three variables. Our data suggest that TPA and LBSA are more sensitive than CEA as markers of gastric cancer, and that the simultaneous measurement of TPA and LBSA in conjunction with CEA is more useful in cancer detection than the measurement of CEA alone.

This report describes an adrenal myelolipoma occurring in a 39-year-old man first noted incidentally by computed tomography (CT). The radiographic findings of this neoplasm are briefly discussed and magnetic resonance (MR) imaging of myelolipoma is also described. Myelolipomas can be distinguished from nonfunctioning adenomas by differences in signal intensity on T2-weighted images.

Leucocyte migration inhibition test (LMIT) is a useful method to detect tumor associated antigens (TAA) in cancer patients. Carcinoembryonic antigen (CEA) is one of the best tumor markers for gastrointestinal cancer, and especially for colorectal cancer patients, who show high plasma CEA level frequently. In this study, we performed LMIT in 71 colorectal cancer patients with 3 M KCl extracts of cancer tissues and measured concentration of CEA in the plasma and the extracts of cancer tissue simultaneously. Although CEA in colorectal cancer extracts was individually varied from low to high in concentration, the levels of CEA had no relation to LMI reactivity. In addition, the LMI reactivity of colorectal cancer patients did not relate to the plasma CEA level of the corresponding patient. The results suggest that some antigens which induce leucocyte migration inhibition factor (LMIF) to lymphocytes from colorectal cancer patients might be different substances from CEA.

To clarify the significance of immunoreactive carcinoembryonic antigen in gastric juice (gastric CEA) from gastric cancer patients, we studied the gastric CEA in comparison with cancer progress, histologic types of tumors, staining, for CEA and extent of intestinal metaplasia. The gastric CEA levels from patients with other gastric diseases, i.e., gastric ulcer, duodenal ulcer and chronic gastritis were also investigated. The mean gastric CEA level from gastric cancer patients was significantly higher than from gastric or duodenal ulcer patients, but there was no significant difference between levels in patients with gastric cancer and in those with chronic gastritis. The gastric CEA levels from cancer patients increased with progression of the cancer. The differentiated carcinomas showed significantly higher gastric CEA levels than the poorly differentiated carcinomas. Positive CEA tumors showed significantly higher gastric CEA levels than did the negative CEA tumors. The tumors with diffuse intestinal metaplasia revealed high gastric CEA levels. Determination of gastric CEA levels is considered to be useful for screening of gastric cancer.

The aim of this paper is to determine whether the incidence of estrogen-, progesterone-, CEA-, and ferritin- positive staining of primary tumors, by using the PAP method, is related to the prognosis of breast cancer status. A significantly higher incidence (71 per cent) of CEA-positive tumors was observed in patients who had a recurrence of breast cancer within 2 years after radical operation. Patients, whose tumors were positive in estrogen or negative in CEA, showed a relatively good prognosis, even after a recurrence of the disease. Distant metastases were seen in most of the patients positive in CEA (78 per cent). Before the recurrence of breast cancer, those patients positive in progesterone had a good prognosis. After the recurrence, however, there was no relationship between the prognosis of recurrent disease and the progesterone-staining of primary tumors. Our data suggest that the immunohistological staining of estrogen, progesterone and CEA might offer the effective prognostic indices in breast cancer patients.

Expression of CEA was studied in tissue sections from 140 cases of gastric and 54 cases of colorectal carcinoma by the immunoperoxidase technique. In some cases of gastric cancer, the intensity of CEA staining was compared with the CEA concentration by radioimmunoassay, and the intensity of the CEA staining was related to CEA concentration. CEA was more strongly positive in colorectal carcinomas than in gastric carcinomas. The intensity of the CEA staining was stronger in differentiated gastric and colorectal carcinomas than in anaplastic ones. No relationship was seen between the expression of CEA and the extent of disease in gastric or colorectal carcinoma. The CEA expression was related to the location of tumors in colorectal carcinomas, but not in gastric carcinomas.

Wolfe has reported that his classification of xerographic parenchymal patterns of the breast was of value in screening programs. However, there has been no attempt to confirm his work in Japan. Therefore, we investigated the relationship of breast parenchymal patterns to breast carcinoma prevalence in Japanese females. In the cancer patients, the P2 pattern was the most dominant pattern (49.4%), followed by the DY pattern (23.6%), the P1 pattern (14.0%), and the N pattern (13.0%). In the group without carcinoma, the dominant pattern was the N pattern (45.2%), followed by the P1 pattern (26.9%), the P2 pattern (21.3%), and the DY pattern (6.7%). The DY pattern was associated with 31% of breast carcinomas that occurred in women under 50 years of age, whereas it was associated with only 13% of breast carcinomas in women older than 50 years. Conversely, the P2 pattern was associated with 58% of the breast carcinomas occurring in women over age 50 years compared to 41% of those occurring in women younger than age 50. More than 70% of the patients with breast carcinoma who were between 30 and 59 years of age demonstrated the P2 and DY patterns. In the patients with breast carcinoma who were over 60 years of age, the incidence of these patterns was somewhat lower (55.6%).

The pulsed power generation from the inductive energy storage system, which is extremely compact and light, is investigated by the two-staged opening switches of fuses and a plasma erosion opening switch. The current rise time decreases from about 1 µs to about 200 ns by the fuses, and then to about 100 ns by the plasma erosion opening switch.