Hannu Halila

Ovarian cancer antigen CA 125 levels in pelvic inflammatory disease and pregnancy.

Circulating CA 125 levels were studied in patients with gynecologic cancer and pelvic inflammatory diseaseand in pregnant women. The CA 125 level was elevated (>;35 U/ml) in 69% (9/13) of patients with active ovarian cancerin 32% (7/22) of patients with active cervical or endometrial cancerin 24% (11/46) of pregnant womenand in 33% (10/30) of patients with acute pelvic inflammatory disease. Sixty‐three other patients with nonmalignant gynecologic disordersincluding 15 patients with ectopic pregnancyhad normal CA 125 levels. The occurrence of elevated CA 125 levels in patients with pelvic inflammatory disease can limit the use of the assay for diagnosis of cancer in young women. Gynecologic tumors may be associated with inflammatory reactions that may contribute to elevated CA 125 levels in some cancer patients.

Tumour-associated trypsin inhibitor (TATI) in ovarian cancer

Tumour-associated trypsin inhibitor (TATI) is a 6 kD peptide isolated from the urine of a patient with ovarian cancer. Increased urinary excretion of TATI has earlier been observed in patients with gynaecological malignancies. The value of TATI in urine and serum as a marker for ovarian cancer was studied in 102 patients. Preoperatively urine TATI was elevated in 55% (18/33) and serum TATI in 27% (12/45) of the patients. In patients with mucinous tumours, elevated preoperative levels of TATI were observed in 6 out of 10 patients, while CA 125 was elevated in 4 and CEA in one of the cases. When assay of TATI was used to predict presence of disease before second-look surgery of 48 patients, the sensitivity and specificity of serum TATI was 19% and 91%, and that of urine TATI 42% and 76%, respectively. Rising TATI levels were observed in progressive disease, whereas regressive disease was not as often associated with falling levels. Serum TATI was elevated in 45% (144/318) and urine TATI in 57% (73/171) of samples from patients with clinical evidence of disease. The TATI assay was found to be of potential value in the management of patients with mucinous ovarian cancer, but in patients with non-mucinous ovarian cancer it did not provide information additional to that obtained from assay of ovarian cancer marker CA 125 alone.

Tumour-associated trypsin inhibitor, TATI, in patients with pancreatic cancer, pancreatitis and benign biliary diseases.

The serum and urine concentrations of a tumour-associated trypsin inhibitor, TATI, were determined by radioimmunoassay in patients with pancreatic cancer and with benign pancreatic and biliary diseases. Elevated serum levels (greater than 20 micrograms l-1) were found in 85% of the patients with pancreatic cancer, and elevated urine levels (greater than 50 micrograms g-1 creatinine) in 96% of the patients. Thus low TATI level, especially in urine, makes the possibility of pancreatic cancer less likely. Serial assay of TATI in serum from three patients with surgically removed pancreatic cancer showed elevation of the TATI level at the time of detection of recurrence. However, high serum and urine levels were also seen in pancreatitis and in benign extrahepatic cholestasis. Thus TATI is a sensitive, although not specific, indicator of pancreatic and biliary disease, but the use of TATI as a tumour marker in the primary diagnosis of pancreatic cancer is limited. Immunohistochemical staining of pancreatic lesions showed that half of the pancreatic tumours expressed TATI, but the pancreatic tissue adjacent to a carcinoma always stained stronger than the carcinoma. It therefore seems that the main source of TATI in serum and urine of patients with pancreatic cancer are the normal acini and not the tumour tissue. In pancreatitis the staining was intense and clearly stronger than in normal pancreas.

Pancreatic secretory trypsin inhibitor-like immunoreactivity in pancreatectomized patients

Pancreatic secretory trypsin inhibitor (PSTI) is a 6000-dalton peptide, that occurs in high concentrations in the pancreas and in pancreatic juice. It is thought to be synthesized by pancreatic acinar cells. We have recently reported the findings of an identical trypsin inhibitor at high concentrations in the urine of patients with gynecological malignancy. Therefore, we have named the inhibitor tumor-associated trypsin inhibitor (TATI). We have now studied patients who have undergone total pancreatoduodenectomy for pancreatic cancer or chronic pancreatitis. By radioimmunoassay (RIA), we found normal levels of this inhibitor in the serum and urine of pancreatectomized patients. The absence of pancreas was confirmed by measuring serum trypsin. By gel filtration and HPLC it was found that PSTI/TATI occurring in pancreatectomized patients was indistinguishable from that found in connection with pancreatitis and ovarian cancer.

Tumour-associated trypsin inhibitor (TATI) in human ovarian cyst fluid. Comparison with CA 125 and CEA

The levels of tumour-associated trypsin inhibitor (TATI), CA 125 and CEA were measured in ovarian cyst fluids from 21 patients. TATI in cyst fluid was immunologically and physicochemically similar to the peptide originally isolated from the urine of a patient with ovarian cancer. Mucinous cysts contained significantly higher levels of TATI than did serous cysts. Immunohistochemically TATI was localized in the apical parts of cells of mucinous ovarian cysts. These results suggest that this tumour-associated peptide is actually produced by a tumour. Like TATI, CEA occurred at higher concentrations in mucinous than in serous cyst fluids, whereas CA 125 was found in higher concentrations in serous than in mucinous cyst fluids. The concentrations of these tumours markers in cyst fluids did not correlate with circulating levels of the same markers. In spite of the very high levels of all these tumour markers in benign cyst fluids, serum levels were normal or only slightly elevated. Clearly elevated serum levels occurred only in patients with malignant tumours. Cyst fluid levels of these tumour markers could not be used to distinguish between benign and malignant tumours.

Ca 125 in the Follow–Up of Patients with Ovarian Cancer

The value of CA 125 measurement in the diagnosis and follow–up of ovarian cancer was studied in 102 patients. The CA 125 levels were elevated in 88% (3221365) of samples from 82 patients with clinical evidence of disease and in 14% (561403) of samples from 58 patients without clinical evidence. Preoperative levels were elevated in 84% (44152) of the patients, and in 100% of those with stage III and IV disease. In patients with non–mucinous tumors the preoperative levels were elevated in 95% of cases (38140). CA 125 levels were significantly correlated with the course of disease in 88% (36141) of patients whose tumor regressed, and in 87% 120123) of those whose tumor progressed. Before second–look surgery of 48 patients, the sensitivity of the CA 125 test was 35% and the specificity was 86%. The results suggest that, although far from infallible, CA 125 is a useful marker for ovarian cancer. It is useful for monitoring the course of chemotherapy, but normal levels do not rule out the possibility of persistent or recurrent disease.

The Effect of Hysterectomy on Serum CA-125 Levels in Patients with Adenomyosis and Uterine Fibroids

The human endometrium has been reported to release CA 125 in tissue culture, and elevated levels have been found in patients with endometriosis and adenomyosis. The serum levels of CA 125 were measured in 22 women undergoing hysterectomy for adenomyosis (n = 11) or fibroids (n = 11) of the uterus. In 20 patients (91%) the pre-operative CA 125 level was normal (less than 35 U/ml). All patients with adenomyosis had a normal pre-operative serum CA 125 concentration. Five weeks after the operation the CA 125 levels did not differ from the pre-operative levels. Our results show that the uterine contribution to the serum CA 125 level is minimal, and do not confirm the initial enthusiasm concerning the possible use of levels as an aid in the diagnosis of adenomyosis.

Characterization of a tumour-associated serine protease

We have earlier identified and characterized a tumor-associated trypsin inhibitor (TATI) in the urine of patients with gynecological cancer. Elevated levels of TATI occur in urine and serum of cancer patients (Stenman, U. H., Huhtala, M. L., Koistinen, R. & Seppälä, M. (1982) Int. J. Cancer 30, 53-57). To explain the elevation of TATI in cancer, we have postulated the existence of a tumor-associated protease reacting with TATI. Such a protease, tentatively called protease T, was found in cyst fluid from mucinous ovarian tumors. The protease occurs in complex with TATI, and its protease activity can be measured only after dissociation of the complex. This is achieved by reversed phase chromatography at low pH and elution with an isopropyl alcohol gradient. Protease T is inhibited by phenylmethanesulphonyl fluoride indicating that it is a serine protease. Its optimum activity at pH 9.1 and molecular mass of 24 kDa in gel chromatography are similar to those of trypsin but the substrate specificity is not identical and its isoelectric point (pI) is about 4.0, which is lower than the corresponding values of both cationic (pI 9) and anionic trypsin (pI 5). Protease T could be associated with the elevation of TATI seen in certain tumor patients.