Circadian rhythm of interleukin-1 production of monocytes and the influence of endogenous and exogenous glucocorticoids in man.

We found a dose-dependent inhibition of spontaneous and LPS-induced IL-1 production of isolated human monocytes by methylprednisolone (MP) in vitro. Kinetic studies of spontaneous and LPS-induced IL-1 production of isolated monocytes of 10 normal individuals showed a synchronous circadian rhythm, with its maximum at 4:00 p.m. and its minimum at 4:00 a.m., which is most probably independent of the physiological circadian rhythm of cortisol levels because the IL-1 production was of the same value at the times of maximum and minimum cortisol levels. In contrast, in a patient with hypercortisolism and a preserved circadian rhythm of cortisol levels, we found the minimum of IL-1 production at 4:00 p.m., 8 hours after the maximum cortisol level was reached. Furthermore, in 7 patients with sarcoidosis both spontaneous and LPS-induced IL-1 production of isolated monocytes were significantly decreased 8 hours after the first injection of MP (1 mg/kg bw i.v.) compared to the values before MP administration. Our findings suggest a physiological circadian rhythm of spontaneous and LPS-induced IL-1 production of monocytes, independent of physiological cortisol levels, whereas unphysiological amounts of endogenous and exogenous glucocorticoids cause a substantial inhibition of IL-1 production with a latency time of 8 hours.

[Initial results of a controlled study of small cell and squamous epithelial bronchial cancer: polychemotherapy and interferons]. / Erste Ergebnisse einer kontrollierten Studie beim kleinzelligen und plattenepithelialen Bronchialkarzinom: PCT versus PCT und Interferone.

We investigated a combination of polychemotherapy with beta- and gamma-interferon in patients with small cell and squamous cell bronchial carcinoma. Immunological monitoring was designed to detect systemic and local immunomodulatory effects of interferon therapy. Small cell carcinoma was treated every three weeks with adriamycin, cyclophosphamide and vincristine, squamous cell carcinoma was treated every three weeks with mitomycin, vindesine and ifosfamide. In one group of patients polychemotherapy was combined with beta- and gamma-interferon. In the event of no change or tumour progression cisplatin and etoposide were administered. In the case of PR and CR the initial schedule was continued. Treatment was stopped on achieving CR after 6 cycles, or in the case of no response. To date, 40 patients have been evaluated. Results indicate a slight increase in the response rate in patients with small cell carcinoma, extensive disease, in the interferon group, and an unchanged response rate in patients with squamous cell carcinoma. Besides the common "flu-like" symptoms there was considerable myelosuppression in patients under additional interferon therapy. In the interferon group we found measurable gamma-interferon serum levels, an increase in the spontaneous production of IL 2 by peripheral lymphocytes, and an increase in the spontaneous production of IL 1 and an in the phagocytic capacity of monocytes. In contrast, alveolar macrophages as part of local immunity show a decrease in the spontaneous and LPS-induced production of IL-1.

Characterization of CA 19-9 bearing mucins as physiological exocrine pancreatic secretion products.

The monoclonal antibody CA 19-9 reacts with a carbohydrate epitope (sialylated lacto-N-fucopentaose II), which was shown to be part of a ganglioside extracted from a colon carcinoma cell line as well as of a mucin isolated from gastrointestinal tract tumor patients' sera. Recently, when we compared CA 19-9 levels in pancreatic juices and corresponding serum samples from a large group of patients, we showed the high serum values to be indicative solely for a malignant disease. In contrast, the overall high CA 19-9 content in pancreatic juices from all diagnostic groups raised the question about the antigenic moieties in these samples. By means of thin layer chromatography of glycolipids with subsequent antibody overlay, gel chromatography, and density gradient analysis, we found only the mucin form in all sources investigated. Thus we conclude that the discrimination potential of the CA 19-9 assay in serum is based on an altered secretion or distribution in pancreatic tumors.

Multiparametric tumor marker (CA 19-9, CEA, AFP, POA) analyses of pancreatic juices and sera in pancreatic diseases.

With respect to their diagnostic utility CA 19-9, CEA, AFP and POA were determined in pancreatic secretions and serum of patients suffering from pancreatic cancer (n = 76/55) or chronic pancreatitis (n = 79/45) and of controls (n = 81/42), respectively. While the determination of AFP and POA both in pancreatic secretions and serum does not permit a differential diagnosis, serum CEA (greater than 10 ng/ml) and CA 19-9 (greater than 50 U/ml) levels were indicative of pancreatic cancer in 30% and 83%, respectively, with a rate of false positive results of 5% and 8.5% confined to the chronic pancreatitis patients. A combination of tumor marker analyses, that is, serum CA 19-9 (greater than 50 U/ml) and pancreatic secretion CEA (greater than 70 ng/ml), proved to be positive in 92.9% of tumor patients with a maximum of 10.5% false positives. Likewise, values of serum CA 19-9 (greater than 50 U/ml) and serum CEA (greater than 10 ng/ml) were found in 85.8% of the pancreatic cancer patients with only 8.8% false positives, which were confined to the chronic pancreatitis patients. These results indicate the superiority of multiparametric tumor marker analyses for the diagnosis of pancreatic cancer, especially when including new monoclonal antibody defined tumor markers.

Monoclonal antibody defines CA 19-9 in pancreatic juices and sera.

In a retrospective study pancreatic juice samples (n = 213) and corresponding serum samples (n = 110) were assayed for their concentration of monoclonal antibody defined CA 19-9/GICA (gastrointestinal cancer associated antigen). Serum CA 19-9 values were found to be good diagnostic and discriminating markers for pancreatic disorders and were raised (greater than 50 u/ml) in more than 80% of the pancreatic cancer patients compared to 8.5% of the pancreatitis group and none of the control group. In contrast pancreatic juice CA 19-9 values showed a considerable overlap between groups. On the basis of recent molecular data on the monoclonal antibody 19-9 defined antigen(s)--that is, monosialoganglioside, mucin--it is proposed that the discrepancies between serum and pancreatic juice findings are due to a specific undirected endocrine release of the mucin into sera in pancreatic tumour patients while in pancreatic juices of all diagnostic groups high CA 19-9 activities are either owing to coexistence of glycolipid and mucin or that the latter is a physiologically exocrine product.

Monoclonal antibody-defined human pancreatic cancer-associated antigens.

Three pancreatic cancer-associated antigens were characterized by use of monoclonal antibodies in immunobinding studies with various cellular and soluble target antigens, in immunoprecipitation, and in immunoperoxidase staining. C54-0 represents a tumor-associated Mr 122,000 antigen, which appears to be widely distributed on various epithelial tumors and to a lower extent on normal tissue. C1-N3 antigen exhibited a more restricted distribution, reacting with pancreatic and various gastrointestinal tract tumors as well as with chronically inflamed pancreatic tissue. The most specific antigen expression was observed for C1-P83 antigen, found on all exocrine tumors of the pancreas, but not on normal or chronically inflamed pancreatic tissue.