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A sensitive and relatively specific tumoral marker for lung epidermoid carcinomas could be used to identify patients likely to benefit from new therapeutic protocols. The cyfra 21-1 fragment of cytokeratin 19 has raised much hope in this regard amongst both technologists and clinicians. In a study of 195 subjects, we have shown by means of a serum assay that the usual cut-off value for this marker (3.3 ng/ml) can be lowered to 1.5 ng/ml without loss of specificity, and with an increase in sensitivity. There was a good correlation between serum marker level and tumor extension, but though cyfra 21-1 was not predictive of the suitability of a patient for surgery. A decrease of cyfra-21-1 was observed after complete resection of the tumor. There was no relation between serum assay results and immunohistochemical findings.

In head and neck squamous cell carcinoma a reliable serum marker of carcinogenesis should be of predictive value for the development of recurrent disease or a second primary tumour. At the moment, such a tumour marker is not available. Recently, elevated levels of cytokeratin 19-fragments (Cyfra 21-1) have been detected in the serum of patients with lung cancer, in particular with squamous cell carcinoma. Cytokeratin 19 is an intermediate cell filament protein expressed in simple epithelia and their malignant counterparts. Therefore, in this prospective study, a standardized sandwich enzyme-linked immunosorbent assay for soluble cytokeratin 19 fragments was tested in the serum of 20 patients with a previously untreated head and neck squamous cell carcinoma. The results were compared with that of 20 control individuals. Our results showed significantly higher Cyfra 21-1 concentrations in the serum of patients with cancer (10.21 +/- 3.03 ng/ml) than the controls (7.2 +/- 2.63 ng/ml). After radical treatment the marker levels dropped significantly to 1.65 +/- 1.07 ng/ml. Cyfra 21-1 appears to be of value as a circulating tumour marker for head and neck squamous cell carcinoma especially in monitoring disease control.

We evaluated the use of two tumour markers Cyfra 21.1 and tissue polypeptide antigen (TPA) for disease monitoring. Assessment of response to WHO criteria was compared to response assessment according to changes in the tumour marker levels. The criteria defined for marker response were a 65% decrease for a partial response and a 40% increase for progressive disease. When response evaluations with a positive lead time were included, 72% of 115 evaluations for Cyfra 21.1 and 59% of 107 evaluations for TPA yielded the same result. Most discordant evaluations were caused by those evaluations whereby the patient achieved a partial response according to the WHO criteria and had normalisation of the marker. Less cases with a positive lead time, more negative lead times, and more patients with progressive disease without an increase of the marker were seen with TPA compared to Cyfra 21.1. In conclusion, Cyfra 21.1 follows the changes in the tumour load better than TPA. Rising levels of both markers nearly always indicate disease progression, and such knowledge easily obtained may prevent the continuation of ineffective treatment.

CEA, SCC and CYFRA 21-1 were measured in samples of serum coming from 105 'Non small cell lung cancer' (NSCLC) patients. The present study has been carried out to compare these markers, to analyse their prognostic significance and to determine the best combination of tumor markers. The median value and interquartile range were: CYFRA 21-1: 2,3 ng/ml, CEA: 3,7 ng/ml, SCC: 1,2 ng/ml. CEA demonstrated higher values in adenocarcinomas (P = 0.04). SCC and CYFRA 21-1 were comparable in the different histologic groups. CYFRA 21-1 and CEA values were dependant on tumor stage. Advanced tumors (T3 and T4) demonstrated higher serum CYFRA 21-1 level (P = 0.0006). CYFRA 21-1 was higher than 3,3 ng/ml in 36% of patients. CEA was higher than 5 ng/ml in 38% of patients and SCC was higher than 2 ng/ml in 27% of patients. Patients with a high CEA and CYFRA21-1 serum level had a shorter survival than those with a normal serum level. In a Cox regression analysis four variables (TNM stage, age, CYFRA 21-1 and CEA level) were found to be significant in the prediction of survival; CYFRA 21-1 level had the lowest P value (P = 0.0002). The current study suggests the use of a combination of CEA and CYFRA 21-1 in the clinical care of NSCLC.

This study concerns five different tumour marker assays examined in the context of 94 patients with advanced breast cancer treated in a prospectively randomised trial of different doses of medroxyprogesterone acetate (MPA). MPA was administered at doses of 500 or 1000 mg daily and clinical evaluation of patients was carried out according to UICC criteria. Carcinoembryonic antigen (CEA) was selected as a standard marker, with three assays for MUC1 mucins (epithelial mucin core antigens (EMCA), EMCA2 and BR-MA immunoradiometric assay) differing in antibody specificities for different mucin epitopes. An additional novel assay for soluble cytokeratin was also evaluated as an example of an independent marker with a different nature and biology. Sensitivity of individual assays ranged between 44 (EMCA2) and 69% (cytokeratin) and the use of two assays in combination led to sensitivities as high as 84% (cytokeratin+BR-MA). The proportion of patients found to be assessable by each assay ranged between 51 (EMCA2) and 76% (cytokeratin). Of those patients whose marker changes were assessable, those receiving the higher dose of MPA displayed significant falls in marker levels after 12 weeks of treatment. This effect was not observed in patients receiving 500 mg. The change in cytokeratin levels in patients undergoing high dose MPA therapy proved to be most marked. Using the cytokeratin assay, 91% (of 23 patients) of patients with progressive disease showed at least a 25% rise in serum marker levels. Of these, 66% showed increases before disease progression was detected clinically with a mean lead time of 14 weeks. There was very little difference between the responses of the five tumour marker assays in patients with stable or responding disease, the proportion of these patients with stable or falling tumour marker levels ranging between 58% (CEA) and 77% (EMCA). We conclude that the cytokeratin assay has an application in monitoring response to therapy and predicting tumour progression in advanced breast cancer patients with assessable tumour marker profiles, especially if used in combination with a MUC1 mucin assay.

Background: The clinical value of pretreatment serum concentrations of cytokeratin 19 fragments, measured by Cyfra 21-1, was compared with tissue polypeptide antigen (TPA) and squamous cell carcinoma antigen (SCC-Ag) in 78 patients with squamous cell cervical cancer., Methods: Serum levels were compared with tumor stage, size, lymph node status, parametrial involvement, and prognostic data. The clinical performance of the different tests was evaluated by their receiver operating characteristic (ROC) curves., Results: Serum levels of all markers were related significantly to tumor stage and size. Elevated serum levels of these markers were not found to be predictive for the presence of lymph node metastases. In contrast, a positive relation was found between quantitative serum Cyfra 21-1, TPA, and SCC-Ag levels and the presence of either lymph node metastases or parametrial involvement (i.e., extracervical disease). An elevated, i.e. positive, serum Cyfra 21-1 level was related significantly to the presence of extracervical disease (P = 0.020). The clinical performance of each serum marker in predicting lymph node metastases or parametrial involvement appeared to be similar as expressed by their ROC curves. In the univariate analysis, Cyfra 21-1, TPA, and SCC-Ag showed prognostic value with respect to disease free interval and survival. Elevated serum levels were associated with a poor prognosis. However, after adjusting for tumor stage and size, none of these markers remained statistically significant., Conclusions: Cyfra 21-1 may be of additional value in assessing stage of disease, tumor size, and the presence of extracervical disease in patients with cervical cancer. Determining its value during follow-up warrants further study.

A correct diagnosis of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) is essential both for prognostic and therapeutic reasons. We used discriminant analysis as a method to optimize the discriminant power of serum tumour marker levels for differentiation between SCLC and NSCLC. A panel of serum markers, including neurone specific enolase (NSE), cytokeratin fragment antigen 21.1 (CYFRA-21.1), tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA) was obtained in 50 consecutive NSCLC and 17 SCLC. Data were analysed by the BMDP statistical program after logarithmic transformation of marker levels. The variables selected were NSE and CYFRA-21.1. Considered together, they were able to give a 97% rate of correct classification. The formula generated (canonic variable, CV) was validated on a group of seven SCLC and 22 NSCLC patients. Only two errors occurred. We therefore conclude that the canonic variable tested, based on NSE and CYFRA-21.1, provides a good discrimination between the two types of lung cancer. The method is rapid, relatively inexpensive, and based on simple serum tests.

We investigated the role of tumor markers CEA, NSE, TPS and CYFRA 21.1 in lung cancer diagnosis and staging in 169 patients with histologically confirmed lung cancer (43 SCLC and 126 NSCLC). In SCLC patients NSE and CYFRA 21.1 showed the highest sensitivity and their combination improve significantly the diagnostic sensitivity and accuracy. In NSCLC patients CYFRA 21.1 showed the highest sensitivity and global accuracy and no markers association was as effective as CYFRA 21.1 alone. Based on data from our study it can be concluded that in patients with suspected lung cancer the serum NSE and CYFRA 21.1 assay is a suitable association to confirm the clinical hypothesis. NSE in SCLC and CYFRA 21.1 in NSCLC are useful in the evaluation of disease extent and successive treatment planning.

Background: Cytokeratins are epithelial markers whose expression is not lost during malignant transformation. Cyfra 21-1 is a cytokeratin-19 fragment that is soluble in serum and may be a useful circulating tumor marker., Study Objective: The aims of this study were (1) to confirm sensitivity and specificity of Cyfra 21-1 in detecting non-small cell lung cancer (NSCLC) and especially the squamous cell subtype, (2) to assess the potential relationship between Cyfra 21-1 and disease stage of the disease in NSCLC, and (3) to evaluate prognostic effect of Cyfra 21-1 in NSCLC., Methods: An immunoradiometric assay of serum Cyfra 21-1 was performed in 161 patients with lung cancers and 71 others with benign lung diseases. The ability of Cyfra 21-1 to detect different histologic subtypes of lung cancer vs benign lung diseases was assessed through receiver operating characteristic (ROC) curves and comparisons with other tumor markers such as carcinoembryonic antigen, neuron-specific enolase, and squamous cell carcinoma antigen. Comparisons of Cyfra 21-1 levels according to histologic subtype and disease stage were done using Kruskal-Wallis test. Independent prognostic value of Cyfra 21-1 was studied with a multivariate analysis of survival (Cox's model)., Results: Using a threshold of 3.3 ng/mL for Cyfra 21-1, sensitivity and specificity were, respectively, 0.59 and 0.94 in NSCLC, 0.68 and 0.94 in the subgroup of the squamous cell carcinoma, and 0.19 and 0.94 in small cell lung cancer. Cyfra 21-1 levels were significantly higher in advanced NSCLC than in early-stage disease. All 29 patients with serum concentrations > 32 ng/mL had stage IIIB-IV and only one of 14 patients with stage I-II disease had Cyfra 21-1 level > 18 ng/mL. In the multivariate analysis of survival, Cyfra 21-1 was an independent prognostic factor along with performance status and disease stage in NSCLC., Conclusions: Cyfra 21-1 is a sensitive and specific tumor marker of NSCLC, especially of squamous cell subtype. It also reflects the extent of the disease and has an independent prognostic role along with performance status and disease stage in NSCLC., Implications: A high level of Cyfra 21-1 in apparently early-stage NSCLC should be an indication for more extensive workup before thoracotomy. The independent prognostic role of Cyfra 21-1 level may be useful in stratifying populations with advanced NSCLC or early-stage resected NSCLC as elevated Cyfra 21-1 levels might identify those patients at high risk for treatment failure.

This report represents an attempt to combine the serum levels of more tumor markers together to evaluate the response to chemotherapy in 26 patients affected with small cell lung cancer (SCLC), by means of discriminant analysis. A pilot prospective study was performed on 26 subjects affected with inoperable SCLC (18 extensive diseases, and 8 limited diseases) and treated with chemotherapy (etoposide plus cisplatin regimen). Serum levels of a panel of tumor markers: Carcinoembryonic antigen (CEA), Tissue Polypeptide Antigen (TPA), Neuron Specific Enolase (NSE) and CYFRA -21.1 were determined before starting chemotherapy and at the restaging time (after 3 months). To optimize the classification power of these markers, a discriminant analysis was done, which permitted generating two classification functions, based on Tissue Polypeptide Antigen and Neuron Specific Enolase levels able to correctly classify 25 out of 26 subjects (8 progressions and 18 non progressions). The results obtained, furtherly confirm that tumor markers are useful to evaluate the chemotherapy response and indicate a possible approach to obtain the maximum usefulness of the serum marker levels.

The diagnostic value of the novel tumor marker CYFRA 21-1 in malignant pleural fluid was assessed in comparison to carcinoembryonic antigen (CEA). CYFRA 21-1 and CEA were measured in pleural fluid obtained from patients with 108 malignant and benign diseases. The levels of pleural fluid CYFRA 21-1 in malignant diseases (median: 84.5 ng/ml) were statistically higher than those in benign diseases (median: 13.9 ng/ml; p < 0.01). The CYFRA 21-1 test was able to discriminate significantly between squamous cell lung cancer and pneumonia (p < 0.01), while pleural fluid CEA levels could not. Receiver operating characteristic (ROC) curve analysis showed that the CYFRA 21-1 test has an advantage over CEA because of its higher specificity. These results indicate that measurement of CYFRA 21-1 in pleural fluid is a new tool, in addition to cytologic examination, to discriminate between malignant and benign diseases.

Cytokeratins 8 and 18 are most frequently co-expressed in simple epithelia and carcinomas. Fragments of these cytokeratins are released into the systemic circulation where they can be quantified and utilized as tumour markers. The present paper reports on a solid-phase sandwich monoclonal immunoassay, considered "epithelial tissue-specific", which recognizes fragments of human cytokeratins 8 and 18 of different sizes (10-50 kD). The evaluated ELISA and IRMA assays exhibited a detection limit of 0.1 microgram 1-1 and characteristically demonstrated a within-assay coefficient of variation (CV) of 1-4% and a between-assay CV of 3-5%. The long-term (300 days) repeatability of lyophilized samples tested in the assay was estimated to have a less than 10% CV. Of apparently healthy individuals, 95% were found to have serum concentrations of less than 0.95 micrograms 1-1. A highly significant difference was found between apparently healthy individuals and pancreatic cancer patients. Patients with metastatic disease showed a sensitivity of 93% and those with local disease 83%, at 95% specificity. This TPAcyk assay revealed good correlation (0.98) with the TPS assay detecting the specific M3 epitope of the tissue polypeptide antigen. The correlation with the long established polyclonal assay of tissue polypeptide antigen (TPA) was estimated to be 0.9.

This study included 75 cases; 39 with gynecological cancer of different types, stages, and grades (14 ovarian, 11 endometrial, 9 cervical, and 5 vulvovaginal); 23 patients with benign gynecological diseases and 13 normal healthy controls. Serum TPS was estimated using the ELISA kit supplied by Beki Diagnostic AB, Bromma, Sweden. The results of the present study revealed that serum TPS was significantly elevated in cancer patients followed by those with benign diseases. When the cutoff values were adjusted to 137 and 101 U/L, we obtained sensitivities of 56.4% and 82.1% at specifities of 100% and 85%, respectively. The benign diseases group had false positive rates of 13% and 34.8%, respectively. When considering tumor site, vulvo vaginal cancer showed the highest sensitivity (80%) followed by cervical (66.7%), ovarian (50%), and lastly endometrial cancer (45.5%). Serial measurement of TPS was shown to be of important value in the post-surgical follow-up of cancer patients.

Within the past few years, the measurement of serum and tissue markers has had an increasing influence on clinical decisions about initial treatment and follow-up. Lung cancer illustrates the types and importance of these various markers. This review presents data concerning the most studied and interesting markers in non-small cell (NSCLC) and small cell lung cancer (SCLC). CEA, TPA, SCC-Ag, CYFRA 21-1, ferritin, CA19-9, CA50, CA242, H-K-N-ras mutations and p53 mutation seem to be the most prolific in NSCLC, while NSE, BN/GRP, CK-BB, NCAM, IL-2R, IGF-I, transferrin, ANP, mAb (cluster 5), Le-y and c-N-L-myc mutation are markers in SCLC patients. Some of these serum markers might be useful adjuncts for monitoring response to therapy, including early detection of tumour reactivation to allow curative therapy and rapid detection of treatment failure to allow change of the regimen. The study of these markers also may lead to a better understanding of the biological characteristics of lung cancer. The information derived from these biological studies represents the most promising avenue towards new treatment strategies, as well as attempts at secondary prevention.

The purpose of this study was to evaluate the serum tumor markers CYFRA 21-1 and squamous-cell carcinoma antigen (SCC) in the follow-up of squamous-cell cervical cancer patients. One hundred-ninety-three serum samples, which were collected pretherapeutically and during follow-up of 30 patients suffering from squamous-cell cervical cancer FIGO stage III, were analyzed for SCC and CYFRA 21-1. Cutoff values for SCC and CYFRA 21-1 were 3 and 3.3 micrograms/liter, respectively. Fifteen cases were keratinizing and 15 nonkeratinizing squamous-cell carcinomas. Serum tumor marker results were correlated to the results of the clinical and radiologic examinations. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of serum SCC and serum CYFRA 21-1 for the whole study group and separately for the keratinizing and nonkeratinizing squamous-cell carcinoma group. Sensitivity, specificity, PPV, and NPV of serum SCC were 66, 91, 93, and 60%, respectively. Serum CYFRA 21-1 showed a sensitivity of 63%, specificity of 96%, PPV of 96%, and NPV of 59%. The combination of SCC and CYFRA 21-1 increased the sensitivity to 78%, with a specificity, PPV, and NPV of 87, 91, and 69%, respectively. In keratinizing squamous-cell carcinoma serum SCC, CYFRA 21-1 and the combination of both had a sensitivity of 76, 64, and 85%, respectively. In nonkeratinizing squamous-cell carcinoma sensitivity was 58, 61, and 72%, respectively. The detection of cervical cancer recurrences with SCC is improved by the combination with CYFRA 21-1. Especially in nonkeratinizing squamous-cell carcinoma CYFRA 21-1 showed promising results.

Despite extensive research, the role of the commonly employed tumour markers in the diagnosis of lung carcinoma is yet to be clarified. The utility of a new marker, CYFRA 21-1, in the preoperative evaluation of patients with bronchogenic carcinoma was investigated. CYFRA 21-1 was determined with a radiometric assay in serum of 280 patients with lung cancer and 208 patients with various nonmalignant lung diseases. The levels of the marker were significantly higher in lung cancer patients. Among benign lung diseases, elevated CYFRA 21-1 levels were found in pulmonary fibrosis. Using a cut-off of 3.2 ng.ml-1 (95th percentile of levels obtained in benign lung disease), the total sensitivity of the marker was 48%. The best sensitivity was obtained in squamous cell lung cancer (60%). The highest values of CYFRA 21-1 were found in metastatic lung cancer, and the marker sensitivity was more elevated in stage IIIb and IV. On the other hand, 40% of patients with surgically resectable lung cancer had CYFRA 21-1 levels above the cut-off. We conclude that CYFRA 21-1 may be satisfactorily employed in the differential diagnosis between malignant and benign lung diseases in association with other clinical and radiological data.

Objective: Evaluation of Cyfra 21-1 (cytokeratin fraction 21-1) in squamous cell carcinoma of the head and neck., Design: Prospective study., Patients: Serum Cyfra 21-1 concentration was measured in 250 samples from patients with squamous cell carcinoma of head and neck, patients with benign tumors of head and neck, healthy control subjects, and patients in remission from squamous cell carcinoma of head and neck., Results: Cyfra 21-1 concentration was elevated in 60% of the new patients with squamous cell carcinoma but only in 8% of patients with benign tumors and 3.5% of the healthy controls. At a cutoff of 1.3 ng/mL, the sensitivity of the test was 60%, the specificity was 94%, positive predictive value was 75%, and negative predictive value was 89%. The marker levels tended to follow the clinical course of the disease and were useful for therapy monitoring. Cyfra 21-1 levels were in good correlation with the tumor stage expressed by the local (T) and the lymphatic spread (N) and were inversely correlated with histologic grade, eg, higher in poorly differentiated carcinoma than in well-differentiated squamous cell carcinoma., Conclusion: Cyfra 21-1 evaluation in head and neck squamous cell carcinoma is worthwhile for performance of an ample study that will prove and establish its routine use.

We wanted to investigate the diagnostic and prognostic significance of serum CYFRA 21-1, especially in predicting the risk of recurrence in patients with operable squamous cell lung cancer. Serum levels of CYFRA 21-1 were measured using an immunoradiometric assay (CIS bio) in 76 patients with squamous cell lung cancer (64 operable and 12 with unresectable tumours), 22 with other non-small-cell type (12 with adenocarcinoma and 10 with large-cell type) and 45 with nonmalignant lung diseases. Elevated preoperative CYFRA 21-1 levels were identified in 63% of patients with squamous cell type (SqCC), 33% with adenocarcinoma, and 30% with large-cell carcinoma type. The diagnostic specificity of the assay was 96%. Positive CYFRA 21-1 levels were observed in 33% of stage I, 52% of stage II, 76% of stage IIIa and 83% of stage IIIb patients with SqCC type. Statistically significant differences were obtained between stages I and II and between II and IIIa, but not between stages IIIa and IIIb. Recurrence-free survival probability for patients with elevated serum CYFRA 21-1 levels before surgery was 63% (24/38) versus 92% (24/26) for patients with normal serum CYFRA 21-1 levels. However, the difference was not statistically significant when adjusted for the TNM stage (primary tumour, regional lymph node involvement, occurrence of distant metastasis). In 9 of the 10 patients with increased trend for CYFRA 21-1 during follow-up, elevated serum CYFRA 21-1 levels preceded (7) or coincided (2) with the clinical detection of tumour recurrence, providing a predictive value of an increased trend of 90%.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Cyfra 21-1 is a novel marker for non small cell lung cancer. Up to now only few data about the value of Cyfra 21-1 in the diagnosis of malignant and non-malignant pulmonary diseases are available. Further the effect of long-time cigarette consumption on serum concentrations of Cyfra 21-1 has not been described. Aim of this study therefore was the determination of Cyfra 21-1 in different malignant and non-malignant pulmonary diseases and in healthy smokers and nonsmokers., Patients: Sera of healthy individuals (control group, n = 121; 63 smokers and 58 nonsmokers), patients with chronic bronchitis (n = 50), lung fibrosis (n = 38), exogen allergic alveolitis (n = 32), lung tuberculosis (n = 45), sarcoidosis (n = 30), small cell lung cancer (n = 60), squamous cell carcinoma (n = 53), non-small cell carcinoma (n = 29) and adenocarcinoma (n = 52) were analyzed., Results: Within the control group no significant differences of the Cyfra 21-1 serum concentration were observed between smokers and nonsmokers. Serum concentrations of Cyfra 21-1 were similar in the control group, patients with non-malignant pulmonary diseases and patients with small cell lung cancer whereas serum concentrations were significantly increased in patients with non-small cell lung cancer, adenocarcinoma and squamous cell carcinoma., Conclusions: The data confirm the high sensitivity and specific of Cyfra 21-1 for the differential diagnosis between malignant and non-malignant pulmonary diseases as well as small cell and non-small cell lung cancer.

We measured serum cytokeratin fragment 21-1 (CYFRA 21-1) levels by a solid-phase immunoradiometric assay in 102 healthy Japanese women, and set the reference value at 1.9 ng/ml (mean +2 SD of the serum levels based on a linear distribution). Pretreatment serum CYFRA 21-1 levels were also analyzed in 235 women with benign (n = 94) or malignant (n = 141) gynecologic disease, and were compared with the serum levels of CA 125 and SCC. The respective positivity rates for CYFRA 21-1 and CA 125 were 64.0 and 77.2% in ovarian malignancy, while they were 4.2 and 30.8% in benign ovarian masses. CYFRA 21-1 had an accuracy of 61.3% in diagnosing ovarian malignancy, which was higher than that of CA 125 (53.4%). The positive predictive value of CYFRA 21-1 for ovarian malignancy reached 94.1%, which was significantly (p < 0.005) higher than that of CA 125 (68.8%). These findings indicate the potential usefulness of CYFRA 21-1 as a tumor marker for ovarian malignancy. In addition, the positivity rates fo CYFRA 21-1 in cervical cancer (51.2%) and endometrial cancer (52.2%) were also similar to the respective rates for SCC and CA 125, which suggests that CYFRA 21-1 seems to be a general tumor marker for gynecologic malignancy.

Soluble forms of keratins in human sera seem to be useful analytes for the monitoring of cancer patients. CYFRA 21-1 is a new test measuring keratin 19 in human blood. The test was developed as sandwich ELISA based on two monoclonal antibodies, both reacting with keratin 19. The epitopes recognised by the antibodies are located on the rod region of the molecule. In sera from malignant patients CYFRA 21-1 detects immunoreactive compounds which appear to be larger than keratin 19 itself, indicating the presence of oligomers in these sera. In a comparison study the reactivity of other keratin tests (TPA, TPS, TPAcyk) with the keratins 8, 18 and 19 were measured both in solution and on immunoblots. The reactivity pattern was found to be different what may explain the different diagnostic properties of the individual tests.

CYFRA is a new marker which measures a fragment of cytokeratin 19 in the serum by an immune radiometric method. The test is based on the preservation of the cytokeratin expression on the epithelial cells during the course of malignant transformation. In immuno-histochemistry the antibodies which selectively recognise cytokeratin react with all histological types of bronchial cancer. The presence of cytokeratin in the serum of patients suffering from cancer would be linked to their liberation during the course of cellular death. The threshold of specificity for CYFRA 21-1 is 3.3.3.6 ng/ml in a population suffering from benign respiratory diseases. The study performed in bronchial cancer produced the following conclusions: the marker is, above all, useful for epidermoid cancer; it is more discriminating than other markers to separate bronchial cancers and non-malignant respiratory disease. An elevated level of CYFRA 21-1 is predictive of advanced disease but does not permit any prediction as to inoperability. In 65% of cases, variations of CYFRA 21-1 are concordant with the stage of the disease during chemotherapy. Finally, elevated levels of CYFRA 21-1 predict a poor prognosis independent of the state of the disease.

CYFRA 21-1 has proved to be a useful marker for non-small-cell lung cancer (NSCLC), which is the major form of lung cancer. Its most effective application is in monitoring. CYFRA 21-1 provides diagnostic information about the success of primary surgery, the response to chemotherapy and the detection of relapse. It is also an independent prognostic factor. The diagnostic potential may not be fully used because decision-making is currently based on group reference ranges. It seems useful to carry out systematic studies to investigate if the application can be improved and extended by using individual reference ranges for decision-making. In contrast to most of the other tumour markers the comparability of the commercial CYFRA 21-1- assays currently available on the market is good. The high degree of comparability should be maintained by international standardization. The analytical performance of the currently available commercial CYFRA 21-1 tests meets requirements derived from its current clinical applications. However, there are no data available about the analytical performance under field conditions. CYFRA 21-1, an established tumour marker for lung cancer, should be included in external quality assurance schemes.

Cytokeratins, the intermediate filaments, are expressed by many epithelial cells. Immunohistochemistry revealed the presence of cytokeratin-19 both in bronchial epithelium and in lung cancer cells. The aim of our study was to establish the value of serum cytokeratin-19 estimation by immunoenzymatic assay (Enzymun Cyfra 21-1, Boehringer Mannheim) in the patients (pts) with lung cancer (Ic). 153 pts (104 men, 49 women, median age 50 years) entered this study. The group consisted of 37 pts with benign lung diseases (control group), 56 pts with squamous cell Ic, 37 pts with small cell Ic and 23 with adenocarcinoma. Cut off value was determined at 4 ng/ml, with 96% of specificity. Elevated cytokeratin-19 values were found in 41% of pts with lung cancer (45% of squamous cell Ic, 39% of adenocarcinoma and 35% of small cell Ic). Median cytokeratin-19 values were 2.2 ng/ml in the control group, 3.4 ng/ml in squamous cell Ic, 3.3 ng/ml adenocarcinoma and 2.9 in small cell Ic. Cytokeratin-19 elevation was observed more often in non small cell Ic pts with advanced disease, stage III--46%, stage IV--50% than in early stages (I + II)--34%. In small cell Ic pts the frequency of cytokeratin-19 elevation was 20% in limited disease versus 45% in extensive disease. We conclude that cytokeratin estimation is not valuable in the recognition of histologic type of lung cancer, although elevated levels are seen more often in squamous cell Ic. Cytokeratin-19 estimation may be also helpful in lung cancer staging.

The serum levels of cytokeratin-19 were measured in 116 patients--96 with NSCLC and 20 with non-malignant lung diseases. The reference group consisted of 60 healthy volunteers--30 smokers and 30 non-smokers. Significantly elevated Cyfra 21-1 values were observed in NSCLC. There was not a correlation between of cytokeratin-19 serum levels and histologic types of lung carcinoma. Cyfra 21-1 concentrations generally increased with stage of diseases and the highest were in patients with evidence of distant metastases. In NSCLC, the distribution of Cyfra 21-1 varied significantly according to the performance status of NSCLC patients.

Pretreatment sera of 78 patients with squamous cell cervical cancer were tested for the presence of cytokeratin 19 (CK 19) fragments to determine the relationship among this parameter, tumor stage, various histopathologic characteristics, and prognosis. For the quantitative determination of CK 19 fragments in serum, the enzyme assay Cyfra 21-1 was used. This assay, based on the simultaneous sandwich principle, utilizes two different monoclonal antibodies. The test was considered positive when levels of Cyfra 21-1 were > or = 1.2 micrograms/liter. Cyfra 21-1 was positive in the majority of patients and in all patients with advanced disease (FIGO III or IVa). A highly significant relationship was found between pretreatment Cyfra 21-1 level and FIGO stage (P < 0.0001). Mean Cyfra 21-1 concentration was elevated in the case of macroinvasive disease (FIGO Ib, IIa, IIb, III, IVa). A distinct relationship was found between tumor size (P < 0.001; r = 0.73) and Cyfra 21-1 level. In the univariate Cox analysis Cyfra 21-1 level was significantly related to both disease-free interval (P < 0.0001) and survival (P < 0.0001) of patients. Patients with an increased Cyfra 21-1 level had a significantly worse prognosis. However, in the stepwise Cox regression analysis, these variables had no additional value over known prognostic factors such as FIGO stage and tumor size. It is concluded that Cyfra 21-1 may be of significance as an additional marker in the management of patients with cervical cancer, but further investigation is needed.

Serum levels of cytokeratin subunit 19 (CYFRA 21-1) were measured in 42 healthy volunteers, 104 cases of malignant diseases, 30 patients with chronic renal failure and 13 patients with nonmalignant and infectious diseases. The reliability of the method was demonstrated after dilution of serum samples and intra- and inter-assay reproducibility. Serum CYFRA-21-1 concentrations were less than 2.00 ng/ml in all healthy controls and 86% of the malignant cases had high serum CYFRA 21-1 levels. However slightly elevated values of CYFRA 21-1 were observed in most chronic renal failure patients. High correlation was observed between serum CYFRA 21-1 and Tissue Polypeptide Antigen (TPA) values (r = 0.90, n = 10) but not with serum alpha-feto protein (AFP) concentrations. Furthermore, cross binding tests with the CYFRA 21-1 tracer/CYFRA 21-1 antibody-coated beads and CYFRA 21-1 tracer/TPA antibody-coated beads also gave an almost linear graph. These results indicate that CYFRA 21-1 and TPA share similar type of antigens.

We compared the tumour marker CA 72-4 and the new markers CASA and CYFRA 21-1 with the established marker CA 125II in follow-up care and control of efficacy of treatment in ovarian cancer in order to determine whether there are differences in recognizing ovarian carcinomas of different histological type. The investigation was done retrospectively on serum samples frozen at -80 degrees C obtained from 262 subjects, among them 50 healthy women, 53 sera with benign gynecological diseases and 159 sera with ovarian cancer, 72 of them at the time of primary diagnosis. We used commercially available kits: CA 125 II: Centocor RIA, CASA: Medac EIA, CA 72-4: Centocor RIA and CYFRA 21-1: Boehringer EnzymunR ELISA. Fixing specificity at 95% versus benign gynecological diseases as a clinically relevant reference group, we found cut-off values of 160 U/mL for CA 125II, 6.5 U/mL for CASA, 6.8 U/mL for CA 72-4 and 2.4 ng/ml for CYFRA 21-1. Based on this specificity we can compare the corresponding sensitivities at the time of primary diagnosis (n = 72): CA 125 II 47%, CA 72-4 47%; CASA 31% and CYFRA 21-1 44%. Regarding histological types of ovarian carcinomas, we found a sensitivity of 50% for CA 125 II and CASA, 36% for CA 72-4 and 33% for CYFRA 21-1 in serous ovarian cancer (n = 53), 21% for CA 125 II and CASA, 36% for CYFRA 21-1 and 43% for CA 72-4 for mucinous ovarian cancer (n = 27). Serous ovarian carcinomas were classified by higher FIGO-stages than mucinous ovarian carcinomas. Additional sensitivities were found at the time of primary diagnosis for the combination of CA 125 II and CA 72-4 and in serous ovarian cancer for CA 125 II and CASA. According to our results, at the time of primary diagnosis the combined determination of CA 125 II and CA 72-4 is useful. If both are negative, determination of CASA can be helpful. For follow-up care and control of efficacy of treatment the preoperative positive or leading marker is sufficient.

We evaluated the diagnostic usefulness of measurement of the soluble cytokeratin 19 fragment, a new tumor marker, in 391 patients with lung cancer and in 424 patients with benign lung diseases. Serum concentrations of cytokeratin 19 fragment were measured by a sandwich ELISA (CYFRA). The cut-off value was defined as 3.5 ng/ml, which is associated with a specificity of 85% for benign lung diseases. CYFRA had a high sensitivity (57.5%) in all subjects with lung carcinoma, and had a higher sensitivity for squamous cell carcinoma (73.1%, n = 141) than squamous cell carcinoma-related antigen (61.0%). CYFRA was associated with a relatively high sensitivity (42.1%) in early-stage squamous cell carcinoma (stage I, based on the classification of the Japan Lung Cancer Society), but the CYFRA titer was higher in advanced squamous cell carcinoma than in early-stage squamous cell carcinoma. Our findings suggest that CYFRA is potentially useful for diagnosis and monitoring of lung carcinoma, especially for squamous cell carcinoma.

Serum samples from 137 lung cancer patients were examined by RIA to evaluate the clinical efficacy of the new tumor marker, CYFRA 21-1, which could identify the soluble fragment of cytokeratin 19. The cut-off value was determined to be 2.2 ng/ml according to the receiver operating characteristic curve. The sensitivity, specificity and accuracy of the RIA for CYFRA 21-1 were 57.7, 91.9 and 64.9%, respectively. The serum concentration of CYFRA 21-1 and the sensitivity of the assay increased as the disease progressed. Histologically, the sensitivity was highest for squamous cell carcinomas (SQ) (76.5%) in comparison with adenocarcinomas (47.8%) and small cell lung cancers (42.1%) (P < 0.01, P < 0.05, respectively). The sensitivities for SQ were 60.0, 83.3, 80.0 and 100% at stages I, II, III and IV, respectively. When compared with CEA (45.3%) and squamous cell carcinoma related antigen (SCC) (22.6%) in all lung carcinomas, CYFRA 21-1 showed the highest sensitivity (57.7%), (P < 0.05, P < 0.01, respectively). In SQ, the sensitivity of the CYFRA 21-1 RIA was significantly higher than that of the assay for SCC (47.1%) (P < 0.05). In patients with adenocarcinomas, the sensitivity of the CYFRA 21-1 assay was almost the same as that for CEA (49.3%). In a combination of CYFRA 21-1 and CEA for non-small cell lung cancers (NSCLC), the sensitivity and accuracy increased to 75.4 and 78.1%, respectively, although the specificity decreased to 86.5%. It is concluded that CYFRA 21-1 could replace SCC, a less satisfactory tumor marker, for SQ of the lung. The potentiality of the combination of CYFRA 21-1 and CEA for NSCLC should be estimated using larger samples in the near future.

We evaluated the newly developed tumor marker assay kit, "Centocor CYFRA 21-1", an immunoradiometric assay (IRMA) kit for determining the serum cytokeratin 19 fragment using the sera of healthy subjects, patients with benign lung diseases and patients with lung cancer. The assay procedure is simple and based on the one-step IRMA system. There were no problems in reproducibility, dilution test and recovery test. The minimum detectable dose was 0.3 ng/ml. The antigen measured by this kit was immunologically cross-reactive with tissue polypeptide antigen (TPA) and CYFRA 21-1 concentration was closely correlated with TPA concentration in the patient's serum (r = 0.86, p < 0.01). The cut-off value of serum CYFRA 21-1 based on the assay results of this kit was calculated to be 1.6 ng/ml from the receiver operating characteristic curve. Three of 47 healthy subjects (6.4%) and 9 of 30 patients with benign lung diseases (30.0%) showed a concentration over the cut-off value. By contrast, serum CYFRA 21-1 concentration was elevated in 31 of 50 patients with lung cancer (62.0%), 11 of 13 squamous cell carcinoma patients (84.6%), 8 of 12 small cell carcinoma patients (66.7%), 4 of 7 large cell carcinoma patients (57.1%) and 8 of 18 adenocarcinoma patients (44.4%). In addition, the positive rate of serum CYFRA 21-1 in patients with lung cancer gradually increased with staging of the disease: 50.0% in stage I, 50.0% in stage II, 61.9% in stage III, and 76.9% in stage IV. Thus, our results suggested that the Centocor CYFRA 21-1 kit is a useful assay system for serum cytokeratin 19 fragment as a tumor marker in patients with lung cancer.

The serological results from apparently healthy individuals and prostate cancer patients were evaluated with a new assay called TPAcyk ELISA. This assay has a biochemical specificity for fragments of cytokeratins 8 and 18, and exhibits a low within- and between-assay imprecision. The data indicate a significant difference between the results of males and females, but no significant age-dependent relation was found. The cut-off value (95% specificity) for healthy individuals was estimated to be 1.27 ng/mL (n = 190) for males and 0.95 ng/mL (n = 81) for females. When using a cut-off value of 1.27 ng/mL, we found a sensitivity for prostate cancer patients with T2-3 N0M0 of about 20%. For patients with metastatic disease, a sensitivity of 75% was found. A higher sensitivity was obtained with patient sera analyzed with PSA than with TPAcyk, particularly in patients with early stages of the disease. We conclude that the results from this new TPAcyk assay were significantly elevated in patients initially diagnosed with poorly differentiated tumors, that patients with localized tumors exhibited low concentrations, and that patients with metastatic disease showed, on average, 8 times higher concentrations than patients with localized disease. The combination of the TPAcyk and PSA results increased the sensitivity for prostate cancer, particularly in patients with metastatic disease.

Enzyme immunoassay CYFRA 21-1, a novel lung tumor marker presented in serum (upper limit of normal values: 3.5 ng/ml) was measured in 84 patients with lung cancer and 141 patients with benign respiratory diseases. The positive rate for CYFRA 21-1 in primary lung cancer was 70.3% and the false positive rate in respiratory diseases was 24.1%. In respect to the histological types of lung cancer, CYFRA 21-1 was elevated in 85.0% of squamous cell carcinoma and in 64.8% of other cell types of primary lung cancer. Elevated CYFRA 21-1 levels were found in 40% of Stage I-II, in 80.0% of Stage IIIA-B, and in 73.5% of Stage IV. The overall diagnostic efficiency was 53.4% for CYFRA 21-1 and 44.5% for CEA, respectively. Receiver operating characteristic (ROC) curve analysis suggested that CYFRA 21-1 test has an advantage over CEA. From the results of this study, CYFRA 21-1 was more efficient than CEA as primary diagnostic marker in lung cancer.

Tissue polypeptide antigen (TPA), TPS, Cyfra 21-1, Cytokeratins 8-18 (CTKRS 8-18), SCC and CA 125 were measured in blood samples drawn at diagnosis from 43 patients with endometrial cancer, 47 with cervical cancer, 11 with cervical intraepithelial neoplasia (CIN), and 236 with benign uterine disease as controls. The cut-off values for all antigens were chosen at the 95th percentile of the standard Gaussian variate of controls; these limits were 98 U/L for TPA, 127 U/L for TPS, 1.6 ng/mL for Cyfra 21-1, 1.2 ng/mL for CTKRS 8-18, 48 U/mL for CA 125, and 2.8 ng/mL for SCC. TPA had the same sensitivity as SCC for squamous cell carcinoma of the cervix (42%) and a higher sensitivity than CA 125 for endometrial cancer (40% vs 12% respectively). TPA was more sensitive than TPS for both cervical (40% vs 13%) and endometrial cancer (40% vs 21%). TPA and SCC had a higher sensitivity than Cyfra 21-1 (34%) and CTKRS 8-18 (27%) for squamous cell carcinoma of the cervix. In conclusion, as for soluble cytokeratin fragments, the serum TPA seems to be the most reliable marker for the management of cervical and endometrial cancer.

From a panel of 4 murine monoclonal antibodies directed against keratin 19 various antibody combinations were evaluated in solid-phase enzyme-linked sandwich immunoassays for detection of soluble keratin 19 fragments in patient sera. One of these antibody combinations, comprised of the monoclonal antibodies Ks 19.1 and BM 19.21, was selected for further development to a routine test (Enzymun-Test CYFRA 21-1) because of its high diagnostic sensitivity and specificity for non-small cell lung carcinoma (NSCLC). Both antibodies are specific for keratin 19, no reactivity could be observed with cytokeratin 8 or 18. The epitopes of the two antibodies were determined to be within helix 2B of the rod romain. The epitope sequences lie within the sequence 311-335 for the catcher antibody Ks 19.1 and 346-367 for the detector antibody BM 19.21. These sequences are unique, as could be confirmed from sequence databases. The standard material for the assay was prepared from a cytoskeleton fraction of cultivated MCF-7 cells. Subsequent digestion of this fraction with chymotrypsin yielded a soluble and stable standard material. Both the standard material and the serum analyte appeared as oligomers when analysed on gel chromatography: the serum analyte appeared exclusively at a M(r) of 100 +/- 10 kD, whereas the standard material eluted in fractions corresponding to 100 +/- 10 kD and 450 kD. Due to the precise definition of the antigen and the localisation of the antibody binding sequences, Enzymun-Test CYFRA 21-1 is one of the best characterised tumor markers so far.

Cytokeratins (CKs), which are biochemically related to intermediate filaments (IFs), form an intracellular network of filaments that is believed to participate in maintaining the structural integrity of cells. Twenty individual polypeptides, divided into two groups, constitute the cytokeratin family. Each type of epithelial cell can be characterized by its content of cytokeratin polypeptides since the expression pattern varies with the type of epithelium. During transformation of normal epithelial cells into malignant cells, the cytokeratin patterns are usually maintained. This property has enabled the use of cytokerations as histological tumor markers, especially for tumors that are not easily classified. Cytokeratins 8, 18 and 19 are the most abundant cytokeratins in carcinomas. They are released into necrotic areas and can be found intratumorally and in blood, circulating as partially degraded complexes, and can as such be used as tumor markers. Cytokeratin deposits in tumors make these structures potential targets for radioimmunodetection and immunotherapy. The usefulness of tissue polypeptide antigen (TPA) as a serological tumor marker has been known for a long time. TPA is a molecular complex containing CK 8, 18 and 19 and determinations of TPA in serum samples can be used in the follow-up of patients with many types of cancer.

CYFRA 21-1, CEA, CA 125, SCC and NSE serum levels were determined in 50 healthy subjects and in 189 patients with primary lung cancer (101 with locoregional disease, 68 with recurrence and 20 patients with no evidence of residual disease (NED). Abnormal CYFRA 21-1 serum levels were found in 53.6% (90/168) of the patients with active cancer. Neither healthy subjects nor NED patients had abnormal serum levels. CYFR alpha 21-1 serum concentrations were significantly higher in patients with active cancer than in healthy subjects or in NED patients (p < 0.0001). CYFRA 21-1 sensitivity was related to tumor histology with abnormal levels in 64.7% of patients with NSCLC and in 30% of patients with SCLC (P < 0.0001). In NSCLC, serum CYFRA 21-1 concentrations were also related to histological type, the highest values being found in squamous cell carcinomas and LCLC and the lowest in adenocarcinomas (p < 0.04). There was also a clear relationship between CYFRA 21-1 and tumor extension, with significantly higher values in patients with metastases than in those without metastases (p < 0.0001). Abnormal CEA values were found in 49.1%, CA 125 in 39%, SCC in 27.8% and NSE in 21.3% of the patients with active cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

The commercially available tumor marker tests TPA, TPS, TPACYK and CYFRA 21-1 react with simple epithelium keratins. From clinical studies it can be deduced that the pattern of keratin recognition must be different for each of these tests. We therefore studied the reactivity of the keratin fragment combinations K8/K18 and K8/K19 in the different tests and determined the reactivity of the corresponding soluble antibodies with purified keratin 8, 18 and 19 in immunoblots. TPS and CYFRA 21-1 were found to distinguish clearly between the keratin fragment combinations K8/K18 (TPS) and K8/K19 (CYFRA 21-1). TPA and TPACYK reacted with both combinations, however, with different intensities. On immunoblots the CYFRA 21-1 antibodies reacted exclusively with K19, whereas the antibodies of the other assays reacted with at least 2 of the keratins investigated.

Recently CYFRA 21-1, a new tumor marker measuring a fragment of cytokeratin 19, was introduced and proved to be suitable for therapy monitoring and follow-up of non-small cell lung carcinomas (NSCLC), in particular squamous cell carcinomas. Besides CYFRA 21-1 there are two other tumor markers, tissue polypeptide antigen (TPA) and tissue polypeptide-specific antigen (TPS), which also measure various cytokeratins in serum. In a retrospective study we investigated the clinical significance of these three cytokeratin markers in lung cancer and in carcinoma of the urinary bladder. For this purpose we investigated the sera of 50 healthy persons, 273 patients with various benign diseases, 218 patients with histologically proven lung cancer and 88 patients with carcinoma of the urinary bladder. In a first step the specificity was established for the different reference groups and the cutoff values were fixed at a specificity of 95%. In lung cancer the single and combined sensitivities were calculated versus benign lung diseases (n = 58) as reference group. With single determinations CYFRA 21-1 proved to have the highest sensitivity in lung cancer in general (61%), in non-small cell lung carcinomas (64%), in squamous cell carcinomas (79%), in adenocarcinomas (54%) and in large cell carcinomas (65%). In small cell lung carcinomas (SCLC) NSE was confirmed to be the marker of choice (55%). With combined determinations a clear increase in sensitivity could only be reached in large cell carcinomas (CYFRA 21-1 + TPA: 77%) and in small cell carcinomas (CYFRA 21-1 + NSE: 62%).(ABSTRACT TRUNCATED AT 250 WORDS)

Recently, a new immunometric assay (Cyfra 21-1) was developed to measure serum concentrations of a soluble fragment of cytokeratin subunit 19. With this method, supplied by Boehringer Mannheim (EIA Test Cyfra 21-1), an Italian multicenter trial was performed in patients with lung cancer. Cyfra 21-1 serum levels were determined in 568 normal subjects (blood donors), 607 patients with non-malignant diseases (491 respiratory diseases) and 730 patients with malignancies. In the latter group 584 had lung cancer. All these 584 patients had pathologically confirmed disease; 314 were epidermoid tumors, 166 adenocarcinomas, 88 small cell cancers and 16 large cell cancers. In the 568 healthy blood donors the mean Cyfra 21-1 value was 0.91 ng/ml (SD 0.47 ng/ml; range 0.05-2.90 ng/ml). A threshold of 1.9 ng/ml was chosen as the upper limit of normality. High levels of Cyfra 21-1 were observed in patients with chronic hepatitis (positivity rate: 17/51-33.3%) and with pancreatitis (positivity rate 5/16-31.3%). In 114 out of 491 (23.2%) patients with respiratory diseases Cyfra 21-1 showed values greater than 1.9 ng/ml. The overall sensitivity (all stages) of Cyfra 21-1 in lung cancer was 65.6% (383/584). When the histology was considered the highest positivity rates were found in patients with squamous cell tumors (226/314; 72%) followed by adenocarcinomas (105/166; 63%). In patients with SCLC the global sensitivity was 52.3% (46/88). Higher sensitivity of Cyfra 21-1 was observed from stage I to stage IV (53.9% vs 85.7%; Chi square: p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The levels of the new tumour marker CYFRA 21-1 were assessed in 115 patients with non-small cell lung cancer (NSCLC) and in 45 patients with non-malignant lung disease. Increased levels of CYFRA 21-1 were observed in 47.8%, mostly in patients with squamous cell carcinoma (SCC; 69.1%). Serum CYFRA 21-1 levels were correlated with the stage of SCC type. Positive CYFRA 21-1 levels in patients with SCC were present in 40% of stage I, 61.1% of stage II, and 85.2% of stage III. In addition, SCC patients who presented mediastinal lymph nodes (N2) demonstrated higher serum CYFRA 21-1 levels, compared with patients without mediastinal lymph nodes metastases (N0 or N1). With regard to tumour size, significant difference was observed between T1, T2 and T3. The study also showed that the percentage of patients who survived 18 months with normal preoperative level of CYFRA 21-1 was higher compared with those patients with elevated preoperative levels of this marker, but the differences were not statistically significant.

The Cyfra 21.1 assay is a newly developed test which measures in serum a fragment of cytokeratin 19. We evaluated this marker in 212 patients with non-small-cell lung cancer (NSCLC), predominantly stage 3a-b and 4, and compared it with three other markers: carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and tissue polypeptide antigen (TPA). Sensitivities for Cyfra 21.1, TPA, CEA and SCC (using cut-off levels corresponding to a 95% specificity for benign lung diseases) were 40%, 40%, 42% and 19% respectively. The sensitivity of CEA was significantly higher in patients with adenocarcinomas compared with the other three markers, while the sensitivity of Cyfra 21.1 and TPA was significantly higher in patients with squamous cell carcinomas. The value of Cyfra 21.1 for monitoring disease during chemotherapy could be evaluated in 23 patients with squamous cell carcinomas. When the cases of lead time were included a concordance between clinical evaluations according to WHO response criteria and evaluations according to changes in the marker levels of 74% was found. The criteria defined for marker response were a 65% decrease in the marker level for a partial response and a 40% increase for progressive disease. In particular, increasing levels of this marker indicated usually disease progression. In conclusion, Cyfra 21.1 is a useful serum marker for patients with NSCLC, especially for disease monitoring of patients with squamous cell carcinoma during and after chemotherapy.

We evaluated the newly produced tumor marker assay kit, "Ball ELSA CYFRA21-1", which detects cytokeratin 19 fragment in the sera of patients with malignancies, especially lung cancers. The assay procedure is simple based on the one-step radioimmunometric assay method. The measured values depend somewhat on incubation temperature and time. Reproducibility and recovery were good. The minimum measurable level was 1 ng/ml. The dilution test was satisfactory. The CYFRA21-1 levels were gradually decreased by repeated freezing and thawing and after seven such exercises its activity dropped to about 70% of that of first assay. The presence of CYFRA21-1 antigen was strongly correlated with TPA antigen and, although some discrepancies could be observed in clinical samples, CYFRA21-1 activity was completely absorbed by anti-TPA antibody-coated beads in one sample. CYFRA21-1 levels of 44 normal controls were below 1.0 ng/ml. Assuming a cut-off value of 2.0 mg/ml, 32.7% of all cases with benign disease had values greater than 2.0 ng/ml. This fell to 21.4% on exclusion of cases of interstitial pulmonary disease. Those with malignant diseases had high CYFRA21-1 levels whether associated with lung cancer or not. The most high positive ratios were observed in squamous cell lung cancer, small cell lung cancer, and uterine cervical cancer. In conclusion, CYFRA21-1 may be a good tumor marker comparable to TPA not only for lung cancer but also other malignancies as well. High false positives for lung cancer, however, were observed in other pulmonary diseases.

An important role in differentiation and proliferation has been demonstrated for the 20 cytokeratin (CK) polypeptides. The serum of 24 patients with biopsy-proven non-small cell lung cancer (NSCLC) and a similar number of controls was examined for evidence of CK8 and CK18. Using enzyme-linked immunosorbent assay (ELISA), all the control sera were negative, but 9 of the 24 patients were positive (mean 2.62 ng/ml; range 1.4-5.8; P = 0.0036). Western blotting confirmed the results of the ELISA in all cases, and indicated full size CK polypeptides. Advanced stage disease patients were more likely to be seropositive (P = 0.00024). Biopsy specimens showed CK8 expression in all 24 cases by immunochemistry and CK18 in 22 cases. This is the first study to demonstrate that a subgroup of NSCLC patients have intact CK8 and CK18 peptides in their serum, and their detection may correlate with advanced disease.

The present study was designed to determine whether CYFRA 21-1, measuring cytokeratin 19, could be a specific and sensitive tumour marker for non-small cell lung cancer (NSCLC). Serum measurements were made at diagnosis in 2250 patient samples by an immunoradiometric "sandwich type" assay, using two cytokeratin 19 specific monoclonal antibodies. Among healthy individuals (n = 711) and patients with benign lung disease (n = 546), 95 percentiles were 1.2 and 2.95 ng/ml, respectively. Cumulative distribution analysis curves were established. From these data, 3.3 ng/ml gave 96% specificity. Using this cutoff, the sensitivity for small cell lung cancer was 16% (n = 74) compared to 41% for NSCLC (n = 547). In histological sub-groups, sensitivity was 57% for squamous cell lung cancer, 34% for undifferentiated large cell carcinoma and 27% for adenocarcinoma, the level of CYFRA 21-1 was correlated with tumour size and UICC stage. In squamous cell lung cancer, the sensitivity of the squamous cell carcinoma marker was 30%, 25% for carcinoembryonic antigen and 46% for tissue polypeptide antigen, using the same series of samples and cutoffs defined at 96% specificity. In conclusion, CYFRA 21-1 is a sensitive tumour marker for NSCLC, especially squamous cell lung cancer.

We evaluated "BALL ELSA CYFRA21-1" kit, an immunoradiometric assay kit for cytokeratin 19. Monoclonal antibodies KS19-1 and BM19-21 are used for immunoadsorbent and indicator, respectively. There was no problems in reproducibility, dilution test and recovery test. Minimum detectable concentration was 0.42 ng/ml. The antigen measured by this kit was immunologically cross-reactive with tissue polypeptide antigen (TPA) and CYFRA21-1 concentration was closely correlated with TPA concentration in patient's serum. One of twenty-six healthy subjects showed serum concentration over a cut-off value of 2.0 ng/ml. Serum CYFRA21-1 concentration elevated in 5 of 10 esophageal cancer patients, 5 of 10 gastric cancer patients, 7 of 10 colorectal cancer patients and 6 of 10 pancreatic cancer patients. Positive rate in patients with benign disease including hepatopathy was low. BALL ELSA CYFRA21-1 kit is reliable and CYFRA21-1 could be a useful tumor marker in gastrointestinal cancer.

Serum level of cytokeratin 19 fragment which is a tumor associated antigen of lung cancer was detected by the radioimmunometric assay. Effect of smoking and of aging on serum reference value was analyzed over 331 normal individuals. Serum cytokeratin 19 fragment level of smokers, mean 0.89ng/ml, was higher than that of non-smokers, mean 0.70ng/ml although there was no statistical meaning over the difference. And there was tendency to increase of cytokeratin 19 fragment level with aging. Mean + 2SD of cytokeratin 19 fragment of normal was 2.17ng/ml. Clinico-epidemiological specificity of cytokeratin 19 fragment on normal individuals was discussed.