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Background: The evaluation of immune response can aid in prediction of cancer behaviour. Here, we assessed the prognostic significance of tumour-infiltrating lymphocytes (TILs) in oropharyngeal squamous cell carcinoma (OPSCC)., Methods: A total of 182 patients treated for OPSCC were included in this study. Assessment of TILs was conducted on tumour sections stained with standard haematoxylin and eosin (HE) staining. We used the scoring criteria proposed by the International Immuno-Oncology Biomarker Working Group., Results: The multivariable analysis showed that TILs associated with disease-specific survival with a hazard ratio (HR) of 2.13 (95% CI 1.14-3.96; P = 0.017). Similarly, TILs associated significantly with overall survival with HR of 1.87 (95% CI 1.11-3.13; P = 0.018). In a sub-analysis of HPV-positive and HPV-negative cases separately, TILs showed a significant prognostic value in both groups (P < 0.05)., Conclusion: The evaluation of TILs as proposed by the International Immuno-Oncology Biomarker Working Group is a simple and promising method in prediction of survival of OPSCC. It is easily applicable and after further validation can be implemented in the routine pathological report as a basic immune parameter., (© 2022. The Author(s).)

Background: An opportunistic oral pathogen, Treponema denticola (Td), has been linked to orodigestive carcinogenesis, but its role in oropharyngeal squamous cell carcinoma (OPSCC) has remained open. We evaluated the presence of Td chymotrypsin-like protease (Td-CTLP) in a series of 201 unselected consecutive OPSCC patients, and the relation of the Td-CTLP to human papillomavirus (HPV) status, to expression of toll-like receptors (TLR) 5, 7, and 9, and to clinical parameters and patient outcome., Methods: Clinicopathological data came from hospital registries. The expression of cell surface-bound Td-CTLP was evaluated by immunohistochemistry. Immunoexpression of TLRs 5, 7, and 9, and HPV status we studied earlier in this patient series., Results: We detected Td-CTLP in 81% of the OPSCC, and especially in HPV-negative tumours (48% of all OPSCCs). Among the HPV-positive tumours (52% of all OPSCCs), low Td-CTLP expression associated with low TLR 5 and high TLR 7 expression. Among those HPV-negative, higher TLR 5 and lower TLR 7 expression associated with high Td-CTLP expression. Strong Td-CTLP expression associated with poor disease-specific survival, but no similar association among HPV-positive and HPV-negative subgroups emerged., Conclusions: Td-CTLP was highly expressed in OPSCC and was associated with the HPV status of tumour tissue.

Background: Periodontal pathogens have been linked to oral and gastrointestinal (orodigestive) carcinogenesis. However, the exact mechanisms remain unknown. Treponema denticola (Td) is associated with severe periodontitis, a chronic inflammatory disease leading to tooth loss. The anaerobic spirochete Td is an invasive bacteria due to its major virulence factor chymotrypsin-like proteinase. Here we aimed to investigate the presence of Td chymotrypsin-like proteinase (Td-CTLP) in major orodigestive tumours and to elucidate potential mechanisms for Td to contribute to carcinogenesis., Methods: The presence of Td-CTLP within orodigestive tumour tissues was examined using immunohistochemistry. Oral, tonsillar, and oesophageal squamous cell carcinomas, alongside gastric, pancreatic, and colon adenocarcinomas were stained with a Td-CTLP-specific antibody. Gingival tissue from periodontitis patients served as positive controls. SDS-PAGE and immunoblot were used to analyse the immumodulatory activity of Td-CTLP in vitro., Results: Td-CTLP was present in majority of orodigestive tumour samples. Td-CTLP was found to convert pro MMP-8 and -9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2, and α-1-antichymotrypsin, as well as complement C1q., Conclusions: Because of its presence within tumours and regulatory activity on proteins critical for the regulation of tumour microenvironment and inflammation, the Td-CTLP may contribute to orodigestive carcinogenesis.

Background: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein expressed in several solid cancers. Our purpose was to study its role in serous ovarian cancer patients, and the association to clinicopathological variables and molecular markers., Methods: We collected retrospectively 562 consecutive serous ovarian cancer patients treated at the Helsinki University Central Hospital. We stained tumour tissue microarrays for CIP2A by immunohistochemistry and constructed survival curves according to the Kaplan-Meier method. Associations to clinicopathological and molecular markers were assessed by the χ(2)-test., Results: We found strong cytoplasmic CIP2A immunoreactivity in 212 (40.4%) specimens, weak positivity in 222 (42.4%) specimens, and negative in 90 (17.2%). Immunopositive CIP2A expression was associated with high grade (P<0.0001), advanced stage (P=0.0005), and aneuploidy (P=0.001, χ(2)-test). Cancerous inhibitor of protein phosphatase 2A overexpression was also associated with EGFR protein expression (P=0.006) and EGFR amplification (P=0.043). Strong cytoplasmic CIP2A immunopositivity predicted poor outcome in ovarian cancer patients (P<0.0001, log-rank test)., Conclusion: Our results show that CIP2A associates with reduced survival and parameters associated with high grade in ovarian cancer patients, and may thus be one of the factors that identify aggressive subtype (type II) of this disease.

Background: No reliable prognostic markers exist for squamous cell carcinoma of the tongue, and its prognosis can even in early stages be unpredictable and survival poor despite treatment. A potential marker is oncoprotein cancerous inhibitor of PP2A (CIP2A), which acts as a prognostic marker in gastric and non-small cell lung cancers., Methods: We collected specimens of 73 stage T1N0M0 and T2N0M0 oral squamous cell carcinomas of the tongue, as well as samples from normal oral mucosa, dysplastic lesions, and invasive carcinomas (n=39). All samples were stained for CIP2A by immunohistochemistry. Survival curves were constructed according to the Kaplan-Meier method. The Cox proportional hazard model served for univariate and multivariate survival analysis., Results: High CIP2A immunoreactivity predicted poor survival in tongue cancer patients (P=0.027, logrank test). In multivariate survival analysis, CIP2A was an independent prognostic factor (HR 2.02, 95% confidence interval 1.07-3.82, P=0.030). Cytoplasmic CIP2A expression was higher in severe dysplasia than in mild dysplasia., Conclusion: Our results suggest that high CIP2A expression characterises aggressive disease. Acting as a prognostic marker it might be of help when choosing patients for adjuvant treatment in tongue cancer patients.

Background: The prognosis of squamous cell carcinoma of the oral tongue is poor and it would be beneficial to find prognostic markers to better adjust treatment. Bmi-1 controls cell cycle and self-renewal of tissue stem cells, transcription factor c-myc affects cell proliferation and apoptosis, and Snail regulates epithelial-mesenchymal transition. The expression of these markers has been connected to prognosis in many cancer types., Methods: Bmi-1, c-myc, and Snail expressions were studied in our material consisting of 73 primarily T1N0M0 oral tongue carcinoma patients. We compared the immunoexpressions of Bmi-1, c-myc, and Snail with clinical parameters including the degree of histological differentiation, tumour size, TNM classification, depth of invasion, and resection margins. In addition, survival analyses were performed, comparing disease-free survival time with the registered protein expression of the markers mentioned above., Results: A significant correlation between Bmi-1 protein expression and recurrence (log-rank test, P=0.005) was detected. Snail and c-myc expression did not correlate with prognosis. Snail expression correlated with histopathological grade (Fisher's exact test, P=0.007) and with the invasion depth of tumours (chi(2)-test, P=0.037)., Conclusion: Negative Bmi-1 immunoexpression might serve as a marker of poor prognosis in oral tongue carcinoma patients.

Proteolysis mediated by matrix metalloproteinases (MMPs) and serine proteinases is associated with cancer invasion and metastasis. Activation of latent proMMPs, and especially the proforms of the type IV collagen degrading gelatinases A and B (proMMP-2 and proMMP-9), is thought to be a critical step in this process. We have recently found that human tumour-associated trypsin-2 is a potent activator of proMMP-9 and it also activates proMMP-2 in vitro. Trypsinogen, MMP-2, and MMP-9 are expressed in ovarian cancer. To elucidate the function of trypsin in vivo, we studied whether high concentrations of trypsinogen-1, trypsinogen-2, their alpha(1)-proteinase inhibitor (API) complexes, and tumour-associated trypsin inhibitor (TATI) are associated with proMMP-2 and proMMP-9 activation in ovarian tumour cyst fluids. Zymography and immunofluorometric analysis of 61 cyst fluids showed a significant association between high trypsin concentrations and the activation of MMP-9 (P = 0.003-0.05). In contrast, the trypsin concentrations were inversely associated with the activation of MMP-2 (P = 0.01-0.02). Immunohistochemical analysis of ovarian tumour tissue demonstrated expression of trypsinogen-2 and TATI in the secretory epithelium. MMP-2 was detected both in stromal and epithelial cells whereas MMP-9 was detected in neutrophils and macrophage-like cells in stromal and epithelial areas. These results suggest that trypsin may play a role in the regulation of the MMP-dependent proteolysis associated with invasion and metastasis of ovarian cancer., (Copyright 2001 Cancer Research Campaign.)

We have recently demonstrated an association between distant metastasis and the expression of the extracellular matrix glycoprotein tenascin-C (Tn-C) in the invasion border of small axillary node-negative breast carcinomas. Our purpose was to assess the relationship between the expression of Tn-C in the tumour invasion border and several histopathological and biological variables and to compare their usefulness in predicting local and distant disease recurrences. The original patient group consisted of 143 women with axillary node-negative breast cancer (one bilateral) treated with breast-conserving surgery and post-operative radiotherapy, and followed for a median of 8 years. Because of the small number of recurrences an additional group of 15 similarly treated women with recurrent breast cancer was also studied. The size of the tumour, its histology, including a possible intraductal component, and grade were re-evaluated. The expression of erbB-2, p53, Ki-67 and Tn-C was evaluated by immunohistochemistry. Ploidy and S-phase fraction (SPF) were assessed by flow cytometry. The only statistically significant prognostic factor for local recurrence was Tn-C expression in the invasion border. For metastasis Ki-67 positivity, tumour size and Tn-C expression in the invasion border were statistically significant, but Ki-67 positivity was the only independent prognostic factor. Tn-C expression in the invasion border was associated with a higher proliferation rate measured by Ki-67 and SPF, which is consistent with the suggested growth-promoting activity of Tn-C. Tn-C may be a useful marker in selecting patients for adjuvant therapies to reduce the rate of both local and distant cancer recurrences.

EDAcFN enzyme immunoassay (EIA) is a new tumour marker assay measuring the extra domain A-containing isoform of cellular fibronectin (cFN), a component mainly found in extracellular matrices. The concentration cFN was measured in plasma and serum from 468 patients with malignant and benign diseases. The concentrations of cFN were higher in plasma than in serum. Using receiver operating characteristic (ROC) curve analysis, determination from plasma was superior to serum at specificity levels higher than 78% and was chosen for further analysis. The highest frequencies of elevated cFN values were seen in patients with hepato-pancreato-biliary malignancies (50-67%). In pancreatic and bile duct cancers, cFN provided little further information to that obtained by CA 19-9. The greatest advantage over CA 19-9 and CEA was seen in patients with local colorectal cancer and in hepatocellular carcinomas. Four out of nine patients with Dukes' stage B colorectal cancer had an elevated cFn level, but only one had an abnormal CEA level. In hepatocellular carcinomas, cFN was also compared with alpha-fetoprotein. The sensitivity of cFN (72%) was superior to that of AFP (61%), and concomitant use of cFN and AFP raised the sensitivity to 83%. The highest frequencies of elevated values in patients with benign diseases were observed in those with severe liver disease (32%) and biliary (17%) and pancreatic (24%) diseases. A combination of cFN and CA 19-9 showed the highest overall sensitivity of 47%, compared with 31% for cFN and 33% for CA 19-9. The corresponding specificities were 76% for cFN +/- CA 19-9, 85% for cFN and 83% for CA 19-9. The accuracy of a combination of cFN and CA 19-9 or CEA (60% respectively) was higher than that of cFN (55%), CA 19-9 (55%) or CEA (45%) alone. In conclusion, the results of the new cFN test are encouraging and further studies on larger patient materials have been started.

The prognostic value of preoperative serum concentrations of carcinoembryonic antigen (CEA), CA 242, tissue polypeptide antigen (TPA), specific tissue polypeptide antigen (TPS) and human chorionic gonadotrophin beta (hCG beta) in 251 patients with colorectal cancer (39 Dukes' A, 98 Dukes' B, 56 Dukes' C and 58 Dukes' D) was investigated. When using the cut-off levels recommended for diagnostic purposes, there was a significantly longer overall survival in patients with low tumour marker levels compared with patients with elevated serum levels for all the investigated markers. In Dukes' stage B, C and D CA 242 emerged as a significant predictor of survival, whereas TPA, TPS and hCG beta showed a value only in Dukes' D. Unfortunately, no marker provided prognostic information in Dukes' A. In multivariate analysis, entering the tumour markers as continuous variables, Dukes' stage was the strongest prognostic factor, followed by CA 242. TPS, hCG beta and localisation of the tumour were also independent prognostic factors, whereas age, gender, CEA and TPA were not.

Preoperative serum levels of CEA and CA 242 were determined in 260 patients with colorectal cancer and in 92 patients with benign colorectal diseases. The overall sensitivity of the CEA test was 43% and of the CA 242 test 39%. The corresponding specificities were 90% and 87% respectively, using 5 ng ml-1 as cut-off level for CEA and 20 U ml-1 for CA 242. The sensitivity of CEA was 26%, 32%, 38% and 77% for Dukes A, B, C and D colorectal cancer, and the sensitivity of CA 242 was 26%, 26%, 40% and 67%, respectively. The correlation between CEA and CA 242 was low. Concomitant elevation of both markers was seen in 5%, 12%, 18% and 59% of patients with Dukes A, B, C and D colorectal cancer, respectively. Of all the patients, 23% showed elevation of both the CEA and the CA 242 level, whereas CEA alone was elevated in 20% and CA 242 alone in 15% of the patients with colorectal cancer. Combined use of both markers raised the overall sensitivity from 43% to 58%, but reduced the specificity from 90% to 80%. The increase in sensitivity by combining the two markers was most marked in Dukes A, B and C colorectal cancer. Either or both of the markers were elevated in 46%, 46% and 60% of the patients respectively. The clinical value of combining CEA and CA 242 seems very promising and should be further investigated in prospective studies.

The concentration of cellular fibronectin (cFN) containing the extra domain A (EDA) was measured in 479 plasma and 300 serum samples from healthy blood donors by a competitive enzyme immunoassay (EIA). Serum and plasma samples contained low concentrations of EDAcFN. The mean concentration of EDAcFN was higher in plasma (2.46 mg l-1) than in serum (0.30 mg l-1). No significant differences between sexes or age groups were found. The EDAcFN concentrations were also measured in 120 patients with various malignancies. The mean values in serum were 4.28 mg l-1, 2.01 mg l-1 and 5.18 mg l-1 in patients with digestive tract malignancies, breast cancer and a group of miscellaneous cancers respectively. In plasma, the corresponding values were 12.26 mg l-1, 4.38 mg l-1 and 11.12 mg l-1 respectively. The serum EDAcFN concentration was higher than the 97.5th percentile level of healthy blood donors in 86% of patients with digestive tract and in 76% with miscellaneous malignancies. In patients with breast cancer 60% had elevated levels of EDAcFN. The corresponding figures for plasma samples in patients with digestive tract and miscellaneous malignancies were 79% and 71% respectively. In patients with breast cancer only 30% had elevated plasma levels of EDAcFN. The mean values in serum and plasma of 20 patients with benign diseases were below the cut-off levels. Consistent with the EIA results, Western blotting revealed increased amounts of EDAcFN in blood samples from cancer patients. Pregnancy did not affect the EDAcFN concentration. The mean values in 20 pregnant women were below the cut-off levels.

The serum expression of a novel tumour marker, CA 242, defined by monoclonal antibody C 242, was studied in 179 patients with pancreatic cancer. The results were compared with CA 19-9, CA 50 and CEA. CA 242 is a carbohydrate closely related, but not identical, to CA 19-9 and CA 50. The overall sensitivity of the CA 242 assay was 74%: 55% in stage I, 83% in stage II-III and 78% in stage IV disease. The specificity calculated from 112 patients with benign diseases was 91%. CA 19-9 had a higher sensitivity of 83%, but the specificity was only 81%. When comparing the markers by receiver operating characteristic analysis, the sensitivities were almost identical at all specificity levels. The CA 242 level was elevated in 7%, 15% and 7% of patients with benign pancreatic, biliary and liver disease respectively. The corresponding figures for CA 19-9 were 19%, 28% and 15% respectively. The sensitivity of CA 242 was higher than that of CA 50 and CEA at all specificity levels. In conclusion, tumour marker CA 242 seems to be a useful diagnostic tool for the diagnosis of pancreatic cancer, and is an alternative to CA 19-9. The advantage of CA 242 over CA 19-9 is its higher specificity when using the recommended cut-off levels of the assays.

The prognostic value of preoperative serum levels of CA 19-9 and CEA was evaluated in 160 patients with pancreatic cancer. The survival of patients whose tumour marker value was below a certain cut-off level was compared with the survival of those with a higher value using the log-rank test. The lowest cut-off level dividing patients into groups with significant difference in survival (P < 0.05) was determined by graphical analysis of chi-square values at different cut-off levels. If stage of disease was not taken into account, there was a significant difference in survival between patients with low vs high preoperative CA 19-9 and CEA levels. When patients were classified according to stage, a difference was found for CA 19-9 in stage II-III patients. Patients with preoperative CA 19-9 below 370 U ml-1 had a significantly better prognosis than those with a higher level (P < 0.05). In stage I and stage IV patients, no significant difference was found between the groups at any cut-off level. The analysis of CEA showed a significant difference in survival only in stage IV patients, with CEA above 15 ng ml-1 being associated with shorter survival. In conclusion, in patients with stage II-III disease, particularly in patients with a non-resectable tumour, in whom the exact spread of the disease may be difficult to evaluate even at operation, the preoperative CA 19-9 level seems to have a prognostic value.

The levels of CA 242, a new tumour marker of carbohydrate nature, were measured in sera of 185 patients with malignancies of the digestive tract and of 123 patients with benign digestive tract diseases. High percentages of elevated CA 242 levels (greater than 20 U ml-1) were recorded in patients with pancreatic and biliary cancers (68%). The sensitivity was somewhat lower than that of CA 19-9 (76%) and CA 50 (73%). On the other hand, in benign pancreatic and biliary tract diseases the CA 242 level was less frequently elevated than the CA 19-9 and CA 50 levels. The serum CA 242 concentration was increased in 55% of patients with colorectal cancer. CA 242 detected more Dukes A-B carcinomas (47%) than CEA (32%), whereas CEA was more often elevated (71% vs 59%) in Dukes C-D carcinomas. CA 242 was slightly elevated (ad 41 U ml-1) in 10% of patients with benign colorectal diseases. CA 50 and CA 19-9 had lower sensitivities than CA 242 using the recommended cut-off values. When cut-off levels based on relevant benign colorectal diseases were used, the sensitivities of these markers were similar and somewhat higher than that of CEA. Less than half of patients with gastric cancer (44%) had an elevated CA 242 serum level. CA 242 is a promising new tumour marker, that may be of additional value in the diagnosis of pancreatic and biliary, as well as colorectal cancer, and may be useful in monitoring cancer patients after radical surgery.

The expression of tumour markers CA 19-9 and CA 50, defined by the monoclonal antibodies 1116 NS 19-9 (19-9 antibody) and C 50, was studied by the immunoperoxidase technique in formalin-fixed, paraffin-embedded tissue sections from 11 hepatocellular carcinomas and 10 cholangiocarcinomas of the liver, and from specimens of normal liver and liver cirrhosis. The 19-9 and C 50 antibodies react with sialosylfucosyllactotetraose, corresponding to sialylated blood group antigen Lewis, and the C 50 antibody also with another sugar moiety, sialosyllactotetraose. Neither marker was cancer specific. The CA 19-9 and CA 50 antigens are normal constituents of bile ducts. Nine out of 10 cholangiocarcinomas stained for CA 50, and eight out of 10 for CA 19-9. There was no apparent difference between the staining pattern of CA 19-9 and CA 50. Hepatocellular carcinomas were consistently negative for both markers. Thus, hepatocellular carcinomas and cholangiocarcinomas showed a clear difference in the reactivity for tumour marker antigens CA 19-9 and CA 50. This difference might be of clinical importance in the differential diagnosis between hepatocellular carcinoma and cholangiocarcinoma.

CA125 is a tumour marker test based on a monoclonal antibody against an antigen from an ovarian carcinoma cell line. Serum concentrations of CA125 were determined in 95 patients with pancreatic cancer and in 106 patients with benign pancreatic, biliary and hepatocellular diseases. The CA125 concentrations were compared with the CA19-9 and CEA levels. Almost half (45%) of the patients with pancreatic cancer had an elevated CA125 level (greater than 35 U ml-1). Elevated values were also found in benign diseases (24%), especially in patients with pancreatitis and benign hepatocellular diseases, but more seldom in extrahepatic cholestasis. It seems that CA125 is of limited value in the diagnosis of pancreatic cancer. Combination of the CA125 with the CA19-9 test increases the sensitivity only 6% as compared to the CA19-9 assay alone. There may, however, be a use for CA125 in differentiating between obstructive jaundice of benign and malignant origin.

The expression of a novel tumour associated antigen CA 242, defined by the monoclonal antibody C 242, was studied by immunoperoxidase staining in formalin-fixed, paraffin-embedded tissue sections from normal pancreata, pancreata with pancreatitis and benign and malignant pancreatic neoplasms. The antigenic determinant of the C 242 antibody is a sialylated carbohydrate structure, related but chemically different from tumour marker antigens CA 19-9 and CA 50. Thirty-eight of 41 (93%) well to moderately differentiated ductal adenocarcinomas of the pancreas and all cystadenocarcinomas were positive for CA 242. The staining was most intense in the apical border of the cells, and in the intraluminal mucus. Only two out of seven poorly differentiated adenocarcinomas stained, and the number of positive cells was smaller than in well differentiated carcinomas. Only occasional cells were stained in one out of five anaplastic carcinomas. Part of large ducts were positive in 91% (21/23) specimens of chronic pancreatitis. In acute pancreatitis small terminal ducts, centro-acinar cells and some large ducts stained for CA 242. In normal pancreas only a few small terminal ducts were CA 242 positive. Carcinomas always stained more strongly for CA 242 than normal pancreatic tissue adjacent to the carcinoma. The results of CA 242 are compared with those of tumour marker antigens CA 50 and CA 19-9. Serum CA 242 levels were determined in 23 of the patients with pancreatic cancer using a fluoroimmunoassay. Fifteen (65%) patients had an elevated value. There was no clear-cut correlation between the serum levels and the immunohistochemical expression of the CA 242 antigen. The expression of CA 242 in pancreatic tissue resembles that of CA 50 and is similar to CA 19-9. The antigen is expressed in serum of many patients with pancreatic cancer and, therefore, is a potential candidate for a serum tumour marker.

Serum levels were determined in 434 patients with benign and malignant gastrointestinal diseases and compared with the serum concentrations of carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP). The highest proportion of elevated CA-50 levels (greater than 17 U ml-1) was found in patients with pancreatic cancer (73%). High levels were mainly associated with advanced cancer, but also half of the patients with a resectable pancreatic tumour had an increased CA-50 concentration. The CA-50 level was elevated in 37-58% of patients with colorectal, gastric, hepatocellular and biliary tract cancers. In all gastrointestinal cancers, CA-50 gave additional information compared with CEA and AFP, except in hepatocellular carcinoma where AFP was the best marker.

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.

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.

The expression of the gastrointestinal cancer associated antigen CA 19-9, defined by the monoclonal antibody 1116 NS 19-9, was studied by immunoperoxidase staining in routine formalin-fixed, paraffin-embedded tissue sections from normal pancreata, pancreata with pancreatitis and from benign and malignant pancreatic neoplasms. The formalin-fixed specimens were treated with pepsin, which enhanced the staining intensity. Eighty-five per cent of well to moderately differentiated adenocarcinomas were positive. The staining was most intense in the apical border of cells lining the lumina of malignant glands, and in mucus inside the lumina, but cytoplasmic staining was also seen. In poorly differentiated adenocarcinomas the number of positive cells was smaller and in anaplastic carcinomas only occasional cells were stained. All mucinous cystadenomas and cystadenocarcinomas stained intensely, whereas serous cystadenomas, and all benign and malignant islet cell tumours were negative. Ducts in chronic pancreatitis and in normal pancreata were positive in 96% and 79%, respectively, but the staining was focal and usually weaker than in carcinomas. In acute pancreatitis (92% positive) the staining was more intense, and the CA 19-9 expression was seen predominantly in small terminal ducts and in centroacinar cells. There was an apparent correlation between the degree of differentiation of the ductal adenocarcinomas and the expression of CA 19-9, whereas the correlation between tissue expression and serum levels of CA 19-9 was poor.

Serum concentrations of the CA 19-9 antigen were determined in 91 patients with pancreatic cancer and in 111 patients with benign pancreatic, biliary and hepatocellular diseases. The CA 19-9 concentration was above the cut-off limit (37 U ml-1) in 78% of the patients with pancreatic cancer and high levels (greater than 500 U ml-1) were seen in 56% of these patients. Elevated levels were also seen in benign diseases (22%), especially in patients with extrahepatic cholestasis (up to 440 U ml-1). Hepatocellular jaundice and pancreatitis were associated with normal values (84% of the patients), or with only slightly elevated CA 19-9 levels (up to 88 U ml-1). The CA 19-9 test can be useful as an additional diagnostic tool for the detection of pancreatic cancer. Preliminary results suggest that the CA 19-9 assay can be used in the monitoring of surgically treated patients.