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Tumor-associated trypsin inhibitor (TATI) [also called serine peptidase inhibitor Kazal type1, SPINK1 and, in the pancreas, pancreatic secretory trypsin inhibitor (PSTI)] inhibits trypsin and other serine proteinases and is expressed in several tissues. In addition to being a protease inhibitor, it also acts as an acute phase reactant and a growth factor. Furthermore, it may modulate apoptosis, play a role in reproduction, and be essential for normal tissue differentiation and repair. Serum TATI is elevated in many cancers and can thus be used as a diagnostic marker. Over-expression of TATI predicts an unfavorable outcome in several cancers and serum TATI can be used to identify patients at increased risk of aggressive disease. Serum TATI also increases in acute pancreatitis. Some TATI mutations predict susceptibility to recurrent or chronic pancreatitis. Recent developments in assay technologies may help in identifying mutation carriers conveniently without DNA testing. As TATI acts as a growth factor in some cancers, it has also been suggested as a therapeutic target. Taken together, assessment of TATI has several potentially important clinical applications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Tumor-associated trypsin inhibitor (TATI) is mainly proposed as a tumor marker for ovarian cancer. However, recent discoveries of TATI in cancer and inflammatory diseases show that assay of TATI in biological samples is of increasing interest., Methods: We validated a previously described TR-IFMA and a newly developed dual-monoclonal sandwich ELISA for TATI. These methods were compared with a commercial radioimmunoassay (RIA). We studied preanalytical factors affecting serum TATI concentrations and established age- and gender specific reference intervals using serum samples from 195 healthy volunteers., Results: The assay range and precision were 0.8-45 μg/L and <9.1% for the ELISA, and 0.13 μg/L-150 μg/L and <12.5% for the TR-IFMA, respectively. Both assays correlated well with a RIA. Type of blood sample and nutritional status were not critical and TATI was stable in serum samples when stored at +4°C and -20°C for 4 weeks and at -80°C for 8 weeks. The 95% reference limits for serum TATI in adults were 5.2-15.3 μg/L in the age group 18-70 years and 7.5-21.3 μg/L in the age group >70 years., Conclusions: Significantly higher concentrations of serum TATI were observed in elderly women and in men. Both ELISA and TR-IFMA technologies can be employed to develop sensitive and robust immunoassays for TATI using monoclonal antibodies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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.

The clinical usefulness of serum pancreatic secretory trypsin inhibitor (PSTI) in pancreatic diseases was evaluated. The mean serum PSTI level of 41 healthy normal persons was 9.4 ng/ml (ranging from 5.2 to 16.7 ng/ml). Serum PSTI levels were abnormally raised in all patients with acute pancreatitis ranging from 35.0 to 4500 ng/ml, but were almost within normal range in patients with chronic pancreatitis, pancreatic cyst, acute abdominal emergencies such as perforated ulcer and intestinal obstruction, and macroamylasemia. There was no correlation between serum PSTI levels and total or pancreatic-type isoamylase activity. Patients with acute pancreatitis in whom the elevation of serum PSTI was transient and occurred after that of serum amylase activity had relatively mild symptoms and recovered along with normalization of serum PSTI levels. On the other hand, patients whose serum PSTI values became increased coincidentally with serum amylase activity and remained elevated, had severe clinical symptoms and unfavorable clinical outcome. Of 2 patients who underwent partial pancreatectomy, the serum PSTI level increased markedly in one who developed postoperative pancreatitis but not in the other without pancreatitis. In contrast to patients with acute pancreatitis, the serum response to the secretin stimulation in patients with chronic pancreatitis, was only small and transient, reaching the maximum at 10 min after administration of secretin. These results suggest that measurement of serum PSTI concentration may be useful in the diagnosis of acute pancreatitis and that the degree of rise and the duration of the elevated levels of serum PSTI are closely related to the severity of acute pancreatitis.

The levels and physicochemical properties of the pancreatic secretory trypsin inhibitor, also known as Kazal type trypsin inhibitor, were studied in human amniotic fluid. In the second trimester, the median concentration was 160 ng/ml, which exceeds the maternal serum levels 20-fold. Towards term, the amniotic fluid levels declined about 5-fold, whereas the maternal serum values remained constant. In fetal urine, the concentration of the trypsin inhibitor was similar to that in amniotic fluid in early gestation, whereas in newborn urine, the median level was 4-to 5-fold higher than in term amniotic fluid. The physiochemical characteristics of the trypsin inhibitor in amniotic fluid, neonatal urine and cancer urine from an ovarian cancer patient were similar, as studied by gel filtration, high performance reverse phase liquid chromatography, and complete immunological identity in immunodiffusion. The physicochemical similarity and levels in various compartments suggest fetal contribution to amniotic fluid levels of the trypsin inhibitor.

A reliable radioimmunoassay (RIA) for human pancreatic secretory trypsin inhibitor (PSTI) has been developed. The method is highly sensitive (0.4 ng/ml), reproducible and specific. A good parallel relationship was observed between the standard curve and dilution curves for serum and urine. The PSTI bound to trypsin-alpha 2-macroglobulin complexes was found not to be immunoreactive, whereas a part of the psti-trypsin complex was immuno-reactive. In healthy individuals, serum PSTI level ranged from 5.4 ng/ml to 16.0 ng/ml, the average being 11.3 ng/ml (S.D. +/- 2.7). Elevated values were observed in patients with acute pancreatitis (highest value 3200 ng/ml), and in some patients with chronic relapsing pancreatitis.

The concentration of the pancreatic secretory trypsin inhibitor (PSTI) was measured in serum from 360 patients with acute abdominal diseases. Elevated levels were found in acute pancreatitis, cholangitis, choledocholithiasis, acute cholecystitis, pancreatic pseudocyst, malignancy, renal failure and in several different inflammatory conditions not connected with the pancreas. The results suggest the possibility of an extra-pancreatic production of PSTI, especially since the changes seen over time do not favour leakage or reabsorption as the cause of the high PSTI levels seen in acute pancreatitis. PSTI rather behaves as an acute phase reactant, as judged from the parallelism in the reaction pattern with antichymotrypsin.