High levels of cytokeratin 19 fragments but no evidence of cytokeratins 1, 2, 10/11, 14 or filaggrin in the serum of squamous cell lung carcinoma patients.

The CYFRA 21-1 assay detects circulating fragments of cytokeratin 19, which is a sensitive marker for the diagnosis of lung cancers, particularly squamous cell carcinomas and adenocarcinomas. Epidermis-type proteins, such as cytokeratins 1, 2, 10/11 and 14 or filaggrin, are also expressed in squamous cell carcinomas. These could also be pertinent tumor markers, ideally as sensitive as CYFRA 21-1 and more specific for squamous cell lung cancer. To verify this hypothesis, using monoclonal antibodies produced in our laboratory, we developed immunoassays specific for these proteins. After optimization, the immunoassays were evaluated in sera from 91 controls and 138 patients with squamous cell lung cancer and compared to conventional tumor markers (CEA, SCC Ag and CYFRA 21-1). Less than 14% of the sera were above the lower limit of detection of the cytokeratin- and filaggrin-specific immunoassays. Moreover, part of these positive sera were induced by the presence of interfering heterophilic antibodies in sera. Thus, in patients with squamous cell lung cancer, we confirmed the high diagnostic sensitivity of CYFRA 21-1 (55.6%) but were unable to detect significant levels of epidermis-type cytokeratins or filaggrin.

Evaluation of seven tumour markers in pleural fluid for the diagnosis of malignant effusions.

Carcinoembryonic antigen (CEA), carbohydrate antigens 15-3, 19-9 and 72-4 (CA 15-3, CA 19-9 and CA 72-4), cytokeratin 19 fragments (CYFRA 21-1), neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCC) were evaluated in pleural fluid for the diagnosis of malignant effusions. With a specificity of 99%, determined in a series of 121 benign effusions, the best individual diagnostic sensitivities in the whole series of 215 malignant effusions or in the subgroup of adenocarcinomas were observed with CEA, CA 15-3 and CA 72-4. As expected, a high sensitivity was obtained with SCC in squamous cell carcinomas and with NSE in small-cell lung carcinomas. CYFRA and/or CA 15-3 were frequently increased in mesotheliomas. Discriminant analysis showed that the optimal combination for diagnosis of non-lymphomatous malignant effusions was CEA + CA 15-3 + CYFRA + NSE: sensitivity of 94.4% with an overall specificity of 95%. In malignant effusions with a negative cytology, 83.9% were diagnosed using this association. The association CYFRA + NSE + SCC was able to discriminate adenocarcinomas from small-cell lung cancers. Regarding their sensitivity and their complementarity, CEA, CA 15-3, CYFRA 21-1, NSE and SCC appear to be very useful to improve the diagnosis of malignant pleural effusions.

[Recurrent pneumopathy of the middle lobe...]. / Une pneumopathie récidivante du lobe moyen....

We report a case of a persistent middle-lobar pneumonia, which did not respond to antibiotics. Only a second bronchial endoscopy, with a third thoracic densitometry and histopathological results give the final diagnostic of tracheobronchial foreign body. The choking history happened more than 10 months before. The bronchoscopic extraction restablished the patient.

[Respiratory complications of the vinorelbine-mitomycin combination]. / Complications respiratoires de l'association vinorelbine-mitomycine.

The respiratory toxicity of vinca alkaloids only appears when they are associated with mitomycin. Few reports have been noted with vinorelbine, the last molecule of this class. We report 4 cases of acute dyspnea induced by the association mitomycin-vinorelbin, The 4 patients were treated for lung cancer. At the end of the injection of vinorelbin appeared an acute bronchospasm. In 3 cases, the symptoms disappeared with broncho-dilatators and corticoids. The fourth patient needed an additional respiratory support. After the acute syndrome, a chronic respiratory insufficiency developed in three patients. Two patients required continuous oxygenotherapy. The pulmonary toxicity of the mitomyin-vinca alkaloids association is characterized by an acute dyspnea. The dyspnea appears within 2 hours after the end of the administration of vinorelbine. The frequent existence of airflow obstruction in patients with lung cancer exposes to high risk of severes incidents. These treatments must be stopped at onset of the first pulmonary symptom. The association of mitomycin with vinorelbine (as for all vinca alkaloids) in chemotherapy protocols for treatment of non-small-cell lung cancer should not be indicated because there is an increase of the toxicity without increase of efficiency.

[Bibliographic analysis of the use of laboratory blood parameters for the prognosis of primary lung cancer]. / Analyse critique de la bibliographie sur l'utilisation de paramètres biologiques sanguins pour l'evaluation pronostique de cancer bronchopulmonaire primitif.

In the daily clinical practice, serum calcium, albumin, and cyfra 21-1, are the only laboratory parameters officially recommended for the prognostic evaluation of primary lung cancer patients by the American, European or French respiratory/thoracic societies (and only in non-small cell lung cancer). The present review of the biomedical literature suggests that serum calcium for non operable non-small cell lung cancer, serum orosomucoid (alpha1-acid-glycoprotein) and serum cyfra 21-1 for non-small cell lung cancer, and perhaps plasma prothrombin time, might be the best laboratory parameters for the pre-therapeutic prognostic evaluation of the lung cancer patients, independently from the usual radio-clinical and histological parameters. Further prognostic evaluation studies are necessary in order notably to compare the prognostic values of the aforementioned parameters, not only aimed at evaluating the value of their pre-therapeutic levels, but also aimed at evaluating the value of their post-therapeutic changes. A higher pluridisciplinarity for such future publications also seem necessary.

[Pulmonary embolism in patients using estrogen-progestagen contraceptives]. / Embolies pulmonaires sous contraception estro-progestative.

OBJECTIVES: The risk of thromboembolism in patients taking estrogen-progestagen oral contraceptive drugs has apparently increased since the introduction of third-generation progestagens (desogestrel, gestodene). We examined the clinical features, risk factors and outcome of pulmonary embolism in this context. PATIENTS AND METHODS: We reviewed 11 cases of thromboembolism in patients on oral contraception and hospitalized in emergency situations in 1995 and 1996 for pulmonary embolism in order to determine the gravity of the thromboembolic event, risk factors and type of drug used. RESULTS: Early clinical signs had preceded the onset of embolism by 2 to 164 days. PaO2 was below 70 mmHg in 4 patients. Diagnosis was achieved with pulmonary scintigraphy (11 cases), spiral CT (3 cases) and angiopneumography (2 cases). Duplex Doppler visualized the phlebitis in 7 patients. Given heparin (with fibrinolysis in 3 cases) then anti-vitamin K, and after withdrawal of the oral contraceptive, outcome was favorable in all cases. There were no recurrences. The nature of the oral contraceptive varied. Five patients were taking third-generation progestagens. In two cases, embolism had occurred following a change from a second-generation to a third-generation progestagen. Family history of phlebitis and/or abnormal laboratory findings were observed in 6 patients: resistance to activated protein C (2 patients), protein C deficiency (2 patients), anticardiolipin (2 patients) and low-titre antinuclear antibodies (2 patients). CONCLUSION: Pulmonary embolism in patients on oral contraceptives persists despite changes in the hormone content of the drugs. Diagnosis is often delayed. Family history of thrombosis or biological risk factors are often found.

Evaluation of pleural CYFRA 21-1 and carcinoembryonic antigen in the diagnosis of malignant pleural effusions.

CYFRA 21-1 assay, measuring cytokeratin 19 fragments, was compared with carcinoembryonic antigen (CEA) assay, as an addition to cytological analysis for the diagnosis of malignant effusions. Both markers were determined with commercial enzyme immunoassays in pleural fluid from 196 patients. Cytological analysis and/or pleural biopsy confirmed the malignant origin of the effusion in 99 patients (76 carcinomas, nine pleural mesotheliomas and 14 non-epithelial malignancies). Effusions were confirmed as benign in 97 patients (33 cardiac failures, 39 infectious diseases--including 12 tuberculosis-- and 25 miscellaneous effusions). Both markers were significantly higher in malignant than in benign effusions. All the patients with non-epithelial malignancies presented CYFRA and CEA values lower than the 95% diagnostic specificity thresholds (100 and 6 ng ml(-1) respectively). The diagnostic sensitivity in the group of carcinomas and mesotheliomas was similar for CYFRA (58.8%) and CEA (64.7%). However, CEA had a significantly higher sensitivity in carcinomas (72.4% vs 55.3%), while CYFRA had a clearly higher sensitivity in mesotheliomas (89.9% vs 0%). Interestingly, 12 out of the 16 malignant effusions with a negative cytology were CEA and/or CYFRA positive. Regarding their high diagnostic sensitivity and their complementarity, CEA and CYFRA appear to be very useful for the diagnosis of malignant pleural effusions when cytology is negative.

Relation between unbound plasma concentrations and toxicity in a prolonged oral etoposide schedule.

OBJECTIVE: This study was undertaken in order to evaluate the impact of pharmacokinetics on the toxicity of oral etoposide administered daily for 21 days. METHODS: The daily dose was 50 mg/m2. Thirty-two patients 24 males and eight females, 36 76 years old, treated for various tumour types), were evaluated. Blood samples were obtained on day 1 for all patients, and on day 21 for 16 patients. Plasma etoposide concentrations were determined by high-performance liquid chromatography, and etoposide plasma protein binding by equilibrium dialysis. RESULTS: On day 1, the mean value (with coefficient of variation for interindividual variability) for the unbound fraction (fu), area under the concentration versus time curve (AUC), and unbound AUC was 9.8% (59%), 34 mg x h/l (39%), and 3.5 mg x h/l (92%), respectively. The ratio between AUC on day 1 and day 21 ranged between 0.5 and 1.8 (mean 0.9, with CV 33%). The plasma trough unbound concentrations and the unbound AUCs both corresponding to the first administration were significantly higher in the 11 patients who had a severe neutropenia than in the 21 patients who had no or moderate toxicity. However, total etoposide concentrations did not differ between these two groups. A limited sampling strategy using the NONMEM program and a database of 89 patients previously studied was performed. The optimal sampling schedule (i.e. 1, 4, and 24 h after oral etoposide administration) allowed to obtain the AUC accurately on day 1. CONCLUSION: Individual adjustment of oral etoposide based on unbound pharmacokinetics after the first administration appears relevant and feasible.