Tumor volume and tumor marker index based on CYFRA 21-1 and CEA are strong prognostic factors in operated early stage NSCLC.

The aim of the study was to analyze the relation between tumor volume (V(path)), tumor marker index (TMI) and prognosis in 261 completely resected (R0) stages I and II non-small cell lung cancer (NSCLC) patients by univariate and multivariate analyses. V(path) was calculated as an ellipsoid body. TMI represents the geometric mean of normalized CYFRA 21-1 and CEA values. Patients with a V(path)< or =13.7cm(3) had a significantly better 5-year-survival rate than patients with a V(path)>13.7cm(3) (78.1% vs. 47.9%; p<0.001). Patients with a TMI< or=0.54 had a 5-year-survival rate of 79.1% compared to only 47.2% in patients with a TMI>0.54 (p<0.001). Besides age (>70 years), performance status and gender, both V(path) (>13.7 cm(3)) and TMI (>0.54) bore significance in the multivariate Cox model with a hazard ratio (HR) of 1.9 (95% CI: 1.1-3.3, p=0.016) and 2.3 (95% CI: 1.3-4.2, p=0.006), respectively. Based on a combination of V(path) and TMI, a low risk group (17% of the patients) with both parameters in the normal range could be identified. Patients with elevated V(path) or TMI (31%) had an intermediate HR of 3.4 (95% CI: 1.3-9.2). When both factors were elevated (52% of patients) the HR increased to 5.95 (95% CI: 2.4-14.9). The elevation of V(path) and TMI was found in 46.2% of stage I and in 59.1% of stage II. The 5-year-survival rates were found to be 89.1, 62.2 and 43.0%, respectively. In conclusion, elevated levels of TMI and V(path) have a strong negative prognostic impact on survival in operated early stage of NSCLC. These patients might be considered for adjuvant chemotherapy.

Cystatins in non-small cell lung cancer: tissue levels, localization and relation to prognosis.

Cystatins regulate tumour-associated cysteine proteases, however, their role in tumour progression is not clear yet. To assess their relevance in the progression of non-small cell lung cancer (NSCLC) the protein level, cysteine protease activity (CPI) and localization of type I (stefins A and B) and type II (C, E/M and F) cystatins were defined in tumours and control lung counterparts from 165 patients. The medians of CPI activity, stefins A and B were significantly greater in tumour than in lung tissue (2.1-fold, 1.7-fold, 1.2-fold, respectively, all p<0.001). The median levels of cystatin C and cystatin E/M were lower in tumour tissue (0.9-fold, p=0.06; 0.6-fold, p<0.01). In all the samples the levels of cystatin F were below the detection limit. Immunohistochemical analysis revealed the presence of all cystatins in tumour cells and infiltrated inflammatory cells such as macrophages and neutrophils. In univariate survival analysis patients with high levels of stefin A, stefin B and CPI activity exhibited a better survival probability (p=0.05, p=0.05, p<0.01, respectively). In contrast, cystatins C and E/M provided no prognostic information. In multivariate analysis the most powerful predictor of survival was the pTNM stage (p<0.0001; RR 3.5), followed by stefin A, stefin B and CPI activity (all p=0.03; RR 1.5). Our results suggest that only stefins A and B, i.e. type I cystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity. As biological markers they may add independent prognostic information for better assessment of low- and high-risk patients with NSCLC.

CYFRA 21-1 and CEA are independent prognostic factors in 153 operated stage I NSCLC patients.

Currently, no further therapy in addition to surgery is recommended in completely resected NSCLC stage I patients. However, the 5-year survival rate at this stage has been reported to be approximately 60%, i.e. 40% of patients had a lower survival rate. The aim of the study was to identify those patients at increased risk by using the tumor markers CYFRA21-1 and CEA as prognostic factors. One hundred and fifty-three stage I NSCLC patients, who were treated exclusively by surgery between 1996 and 1998, entered this retrospective study. It was shown, by multivariate analysis, that elevated CYFRA 21-1 (>3.3ng/ml) and CEA (>9.8ng/ml) levels were associated with a worse outcome in 21.3% and 13.1% of the patients under study, respectively. The corresponding 3-year survival rates were found to be 60.2% for increased CYFRA 21-1 levels (p=0.029) and approximately 40% for increased CEA levels (p=0.022), compared to a rate of 78.4% and 79.0% in case of normal marker levels, respectively. The relative risk (95% confidence interval) was found to be 2.156 (1.08-4.29) for elevated CYFRA 21-1 and 2.707 (1.15-6.36) for elevated CEA. The detection rate for the identification of patients with worse outcome increased when a combination of both markers was used. Thereby, it was possible to identify 32% of patients where one or both markers were elevated. The 3-year survival rate was 55.7% in this group compared to that of 82.5% in those patients where both markers were in the normal range (p=0.0014). In order to consider the degree of marker elevation that is thought to reflect tumor burden, we introduced a tumor marker index (TMI) corresponding to the geometric mean of normalized CYFRA21-1 and CEA levels (marker value divided by diagnostic cut-off). Thereby, we were able to identify 3 groups of patients at different risk levels: the first group (22.7%) had a 3-year survival rate of 96.7%, the second group (42.6%) had one of 77.2% and the third group (34.7%) had one of only 55.7%. In conclusion, elevated CYFRA 21-1 and CEA levels were able to identify a group of curatively operated NSCLC patients who were at high risk of early death. Those patients may benefit from more aggressive treatment approaches. The group of patients with a 3-year survival rate of 96.7% probably does not need further treatment.

Increased CYFRA 21-1 and CEA levels are negative predictors of outcome in p-stage I NSCLC.

Besides established factors, we assessed the prognostic impact of tumor markers CYFRA 21-1, CEA and NSE on survival probability in a series of 515 NSCLC patients who were treated by surgery. In addition, we studied the prognostic significance of CYFRA 21-1 and CEA with reference to the individual postoperative (p-) stages. It was found that p-stages correlated inversely with survival probability. Complete resection had a favourable impact on prognosis (R0 versus R1/R2: p < 0.0001). Among patient characteristics, we found that age (> 70 years) was an unfavourable prognostic factor (p = 0.0014). Performance status (PS, ECOG) also pointed to an adverse prognosis for PS 1-2 versus PS 0 (p = 0.014), whereas gender was not prognostically important. Elevated LDH levels (> 240 U/l), although non-specific, had adverse prognostic significance (p = 0.0034). Patients with CYFRA 21-1 levels above 3.3 ng/ml had a median survival of 24.2 months compared to 55.0 months for patients with marker levels below that cut-off point (p < 0.0001). CEA levels above 9.8 ng/ml were also associated with shorter survival. Median survival was 19.2 months versus 49.9 months in patients with CEA levels below 9.8 ng/ml (p < 0.0001). NSE was of no prognostic value. However, increased NSE levels (> 14.5 ng/ml) in a subgroup of patients with advanced stages IIIa up to IV were found to be associated with shortened survival (p = 0.024). In p-stage I, 3-year survival was shorter for patients with abnormal CYFRA 21-1 levels compared to patients with normal marker expression (60.2% versus 78.4%, p = 0.015). CEA was also of prognostic value in this stage (p = 0.013). In p-stage II, patients with normal CYFRA 21-1 and CEA levels tended to have a better outcome (p = 0.064 and 0.09, respectively). Combined use of both markers showed that stage I patients in whom both markers were normal had a 3-year survival rate of 82.5% compared to those where at least one marker was abnormal (3-year survival: 55.7%, p = 0.0014). It is concluded that tumor markers CYFRA 21-1 and CEA proved to be important adjuncts to the staging system and may help to better assess prognosis. A subgroup of p-stage I patients at high risk was identified by elevated marker levels. These patients may benefit from adjuvant chemotherapy.

Cystatins C, E/M and F in human pleural fluids of patients with neoplastic and inflammatory lung disorders.

Secretory type 2 cystatins, like cystatins C, E/M and F, are thought to be involved in many pathobiological processes, including vascular amyloidosis, rheumatoid arthritis, Alzheimer's disease, osteoporosis, viral and bacterial infections, inflammatory disorders and tumour invasion and metastasis. In order to define the levels of cystatins C, E/M, and F in pleural effusions and to investigate whether these cystatins correlate with diagnostic parameters of pleural and lung diseases, we determined their concentrations in 160 pleural effusions. The median concentration of cystatin C in pleural effusions was 1437 microg/l (95.8 nM), ranging between 18-3967 microg/l. Cystatin C did neither correlate with malignant nor with benign diseases. The concentration of cystatin E/M was significantly higher in effusions of primary pleural tumours (mesotheliomas) compared to secondary pleural tumours and benign diseases. Furthermore, there was a significant correlation between the concentration of cystatin E/M of mesotheliomas and the pleural fluid tumour cell count and of cystatin C. The median values of cystatin F were significantly increased in parapneumonic/empyema thoracis pleural effusions and tuberculous pleurisy compared to malignant pleural effusions, respectively. The concentration of cystatin F in benign effusions correlated significantly with diagnostic parameters and inflammation (total protein; lactate dehydrogenase; C-reactive protein). Finally, only in the group of parapneumonic/empyema thotatin F and the neutrophil count. In conclusion, pleural effusions of different origin contain high levels of cystatin C, perhaps constituting the major part of an inhibitor reservoir. The level of cystatin E/M appears to be significantly associated with primary pleural tumours and cystatin F correlates with inflammatory processes of lung disorders.

Technical performance and diagnostic utility of the new Elecsys neuron-specific enolase enzyme immunoassay.

This international multicenter study was designed to evaluate the technical performance of the new double-monoclonal, single-step Elecsys neuron-specific enolase (NSE) enzyme immunoassay (EIA) and to assess its utility as a sensitive and specific test for the diagnosis of small-cell lung cancer (SCLC). Intra- and interassay coefficients of variation, determined in five control or serum specimens in six laboratories, ranged from 0.7 to 5.3 (inter-laboratory median: 1.3%) and from 1.3 to 8.5 (inter-laboratory median: 3.4%), respectively. Laboratory-to-laboratory comparability was excellent with respect to recovery and inter-assay coefficients of variation. The test was linear between 0.0 and 320 ng/ml (highest measured concentration). There was a significant correlation between NSE concentrations measured using the Elecsys NSE and the established Cobas Core NSE EIA II in all subjects (n = 723) and in patients with lung cancer (n = 333). However, NSE concentrations were systematically lower (approximately 9%) with the Elecsys NSE than with the comparison test. Based on a specificity of 95% in comparison with the group suffering from benign lung diseases (n = 183), the cut-off value for the discrimination between malignant and benign conditions was set at 21.6 ng/ml. NSE was raised in 73.4% of SCLC patients (n = 188) and was significantly higher (p < 0.01) in extensive (87.8%) as opposed to limited disease (56.7%). NSE was also elevated in 16.0% of the cases with non-small cell lung cancer (NSCLC, n = 374). It is concluded that the Elecsys NSE EIA is a reliable and accurate diagnostic procedure for the measurement of NSE in serum samples. The special merits of this new assay are the wide measuring range (according to manufacturer's declaration up to 370 ng/ml) and a short incubation time of 18 min.

Comparison of changes in the NSE levels with clinical assessment in the therapy monitoring of patients with SCLC.

In a series of 130 consecutive patients suffering from small cell lung cancer (SCLC), we compared response evaluations according to standard criteria of the WHO with response evaluations according to changes in the neuron-specific enolase (NSE) levels during systemic therapy. For assessment by changes in the marker levels, the difference between two consecutive levels must exceed 30%. This value is based on the formula: Dc = 2(square root 2) x CV (CV: inter-assay coefficient of variation of the NSE test, set at 10 %). Of the 130 patients who entered this study, 18 patients received best supportive care and were excluded from the therapy monitoring. In the remaining 112 patients, 502 evaluations for response to therapy by both methods were performed, ie. 4.5 observations per patient. We found a concordance between the response evaluations according to the marker criteria and the clinical assessment in 69.7 % of the observations when including cases with positive lead-time and those with a temporary drop in the NSE levels due to a short-term response to therapy. The latter cases met the criteria consistent with the clinical evaluations at the next observation. The concordance with the clinical response evaluation increased to 84.2% when considering only those changes in the NSE levels where at least one of the consecutive marker levels was in the pathological range (> 14.5 ng/ml). Most discordant results were due to insufficient changes in the NSE levels at clinical remission or progression. A further limitation to the general use of NSE for therapy monitoring was founded on the marker negativity throughout the follow-up period, despite tumor progression or relapse. Changes in the levels between pretreatment NSE and after the first cycle of chemotherapy were shown to provide prognostic information. Patients with a drop in the NSE levels proved to have a significantly better survival probability than those with unchanging or rising marker values (p = 0.004). It is concluded that in the majority of evaluations, changes in the NSE levels are consistent with clinical findings based on imaging techniques but remain of doubtful utility in an individualpatient. NSE measurement can only be recommended as an adjunct to the clinical assessment in the follow-up of SCLC patients.