Clinical Stage Progression Research Articles

A new serum tumor marker, CAM 123-6, highly specific to pulmonary adenocarcinoma.

KL‐6, a circulating mucin‐like glycoprotein, is a pulmonary adenocarcinoma‐associated antigen and is also regarded as an indicator of disease activity of interstitial pneumonitis. KL‐6 has extensive heterogeneous antigenic determinants and consists of multiple heterogeneous antigen molecules. We have searched for circulating KL‐6‐associated glycoproteins with superior diagnostic value to KL‐6 as a tumor marker for pulmonary adenocarcinoma. A new murine monoclonal antibody EH‐123 reacting with an asialosugar chain on KL‐6 was established. A new KL‐6‐associated molecule detected by a bimonoclonal bideterminant sandwich assay using the EH‐123 antibody as a catcher and horseradish peroxidase‐labeled KL‐6 as a tracer was designated as CAM 123‐6. In 59% (22 of 37) of patients with pulmonary adenocarcinoma, serum levels of CAM 123‐6 were abnormally elevated and the positive rate increased with the progression of clinical stage. Elevated levels were not detected in normal individuals or in patients with benign lung diseases, other histologic types of lung cancer, gastric cancer, colon cancer or breast cancer. CAM 123‐6 was more specific to pulmonary adenocarcinoma than carcinoembryonic antigen (CEA), but the sensitivity of CAM 123‐6 for pulmonary adenocarcinoma was similar to that of CEA. CAM 123‐6 is a promising candidate as a serum tumor marker for pulmonary adenocarcinoma.

Histologic Grade, DNA Ploidy, and Intraglandular Tumor Extent as Indicators of Tumor Progression of Clinical Stage B Prostatic Carcinoma

Histologic grade, DNA ploidy, and percentage tumor area were assessed in prostatectomy specimens from 73 patients with clinical stage B adenocarcinoma of the prostate and analyzed for their value as predictors of tumor progression. Further, the relationship between percentage tumor area and DNA ploidy was studied. Percentage tumor area was the indicator most strongly associated with the likelihood of tumor extension beyond the capsule of the prostate and of tumor progression as assessed in a logistic regression model. Grade was slightly superior to percentage area in predicting time to progression in a Cox model analysis. Increasing percentage tumor area was associated with an increased likelihood of aneuploidy. Little additional predictive ability was obtained with the concurrent use of two indicators in multivariate analysis, suggesting a high degree of interrelatedness of percentage tumor area, histologic grade, and DNA ploidy. DNA ploidy was not an independent predictive factor, and from a practical standpoint histologic grade and percentage tumor area were more important predictors of tumor progression than DNA ploidy.

Detection of Tumor Associated Antigen, PA8-15, in Sera from Pancreatic and Gastrointestinal Carcinoma Patients

A sandwich enzyme immunoassay was set up to measure tumor associated antigen (antigen PA8-15) detected by monoclonal antibody PA8-15. The cut-off value was set at 55 U/ml. Tests on 437 sera samples from patients with malignant or benign diseases yielded the following positive percentages: esophageal cancer, 9.1%; gastric cancer, 23.1%; colorectal cancer, 44.8%; hepatoma, 32.6%; biliary tract cancer, 47.5%; pancreatic cancer, 84%; lung cancer, 30.8%; breast cancer, 16%; benign diseases, 13.2%. Positive antigen PA8-15 levels in patients with gastric, colorectal and pancreatic cancers, increased with the progression of clinical stage. When antigen PA8-15 was monitored in 11 various cancer cases before and after surgery, a decrease in PA8-15 value was revealed in all resected patients postoperatively, whereas a more than 100% increase in PA8-15 values was noted in non-resected patients. Compared with CEA and CA19-9, the highest positive PA8-15 rate was seen in pancreatic cancer patients. By combining the rates of positive sera obtained with each tumor marker, the overall percentage increased. These results suggest that measuring serum PA8-15 levels will aid in serological cancer diagnoses, particularly pancreatic cancer.

腎細胞癌患者の養子免疫療法に関する研究

The immune responses in patients with renal cell carcinoma were evaluated from the production of interleukin-2 (IL-2), the expression of IL-2 receptors and the activity of lymphokine activated killer (LAK) cells. In addition, the effect of the patient's serum on the expression of IL-2 receptors and LAK activity were investigated. The production of IL-2 by peripheral blood mononuclear cells (PBM) from patients with renal cell carcinoma was not suppressed, when compared with that in controls. However, the expression of IL-2 receptors tended to decrease with the progression of clinical stage. The LAK cells generated by PBM of patients with renal cell carcinoma had significant cytotoxic activity against Daudi cells, ACHN cells and autologous tumor cells, while autologous serum suppressed the expression of IL-2 receptors and the induction of LAK cells in patients with renal cell carcinoma. Furthermore, serum from patients with renal cell carcinoma suppressed the cytotoxic activity of LAK cells generated by PBM from a normal volunteer. These results indicated the presence of immunosuppressive factors in the serum of patients with renal cell carcinoma which impaired the clinical effect of treatment using IL-2 or LAK cells.

Detection of Soluble Tumor-associated Antigens in Sera and Effusions Using Novel Monoclonal Antibodies, KL-3 and KL-6, against Lung Adenocarcinoma

Two novel monoclonal antibodies, KL-3 (IgM) and KL-6 (IgG1), which can detect soluble antigens in sera and effusions (molecular weights greater than 1,000 K) were produced against human pulmonary adenocarcinoma VMRC-LCR cells. KL-3 and KL-6 antibodies reacted with asialo- and sialo-carbohydrate antigenic determinants, respectively. Both carbohydrate epitopes appear, from competitive inhibition studies, to be different from Lex, Ley, sialyl Lea and sialyl Lexi which were recognized with FH2, AH6, NS19-9 and FH6 antibodies, respectively. Using an enzyme linked immunosorbent assay, elevated KL-6 antigen levels were frequently observed in the sera of patients with lung adenocarcinoma [52% (17/33)], pancreatic cancer [44% (4/9)] and breast cancer [40% (8/20)], but infrequently in the sera of patients with lung squamous cell carcinoma [18% (4/22)], lung small cell carcinoma [8% (1/13)], gastric cancer [0% (0/19)], colorectal cancer [0% (0/8)] and hepatocellular cancer [13% (1/8)]. The levels and positive rates of serum KL-6 antigen increased with the progression of clinical stage of lung adenocarcinoma. In pleural effusions, the prevalences of lung adenocarcinoma cases with elevated levels of KL-3 and KL-6 antigens were 76% (13/17) and 82% (14/17), respectively. These monoclonal antibodies can define novel soluble antigens in sera and effusions which could be useful in tumor diagnoses and for monitoring tumor progression.

Immunohistochemical study on the distribution and significance of mononuclear cells in human breast carcinoma.

Lymphocyte subsets in the tumor nests of breast carcinoma were immunohistochemically investigated and a quantitative analysis was added. The majority of cases showed predominance of T cell and suppressor T cell (T8). A decrease in number of lymphocyte subsets and the helper T (T4)/T8 ratio in the stroma of tumor nests correlated well with the progression of clinical stage and the presence of metastasis. This correlation could not be found in the peripheral region of the tumor nests. Macrophages and NK cells were infrequently observed only in the peripheral region of ductal carcinoma. T cell infiltration was prominent in medullary carcinoma with lymphocyte infiltration (MC), and macrophages, NK cells, and T zone histiocytes were frequently encountered. For the purpose of knowing the activity of T cells, IL-2 receptor (Tac) and transferrin receptor were examined immunohistochemically. The fact that a few activated T cells were found only in the peripheral region of tumor nest suggested the local immune response in ductal carcinoma not to be so active as to reject the tumor cells. Since numerous activated T cells were recognized in the tumor nests of MC, this type of breast carcinoma was thought to have a higher immune reactivity. There was little evidence indicating NK cells to play a role for natural cytotoxicity in breast carcinoma.

Enumeration of absolute numbers of T lymphocyte subsets in B-chronic lymphocytic leukaemia using an immunoperoxidase technique: relation to clinical stage.

An immunoperoxidase technique has been used to identify and enumerate helper and suppressor T-cell subsets, as defined by reactivity with Coulter T4 and OKT8 monoclonal antibodies in 54 patients with B chronic lymphocytic leukaemia (B-CLL) and in the same number of matched controls. The ratio of T4+ to T8+ cells was significantly reduced in the B-CLL group as a whole (P less than 0.001) and in each stage of the three clinical staging systems. There was an increase in the median absolute level of T8+ cells in the whole CLL group (P less than 0.001). However, subdivision of the CLL group by clinical staging systems revealed a large group (28 patients) in which median T8+ cell levels were not raised and median T4+ cell levels were low (P less than 0.01). There was no significant decrease in T4+:T8+ ratio, increase in T8+ cells or decrease in T4+ cells with progression of clinical stage. Absolute numbers of E+ cells were significantly raised in all staging systems as were E+ T4- T8- cells (P less than 0.001). A significant alteration in either of these populations with progression of clinical stage was not present.