Characterization of three small cell lung cancer cell lines established from one patient during longitudinal follow-up.

Three classic-type, small cell lung cancer cell lines (GLC-14, GLC-16, and GLC-19) have been established from one patient during longitudinal follow-up. During this period the tumor changed from sensitive to completely resistant to (chemo)therapy. A phenotypical and functional characterization of the different cell lines is given in combination with the matching clinical data. (a) The cell lines have been compared with the biopsies from which they were derived. There was a good match between the morphological, biochemical, and immunohistological findings in the cell lines as compared to those obtained in the biopsies. When the biopsy and cell line (GLC-14) obtained before the start of therapy were compared to the biopsies and cell lines (GLC-16 and GLC-19) acquired after the first and second reinduction therapy, respectively, no major changes could be observed. The only clear alteration was the loss of a neuroendocrine antigen (defined by monoclonal antibody MOC-51) in the posttherapy specimens. (b) The doxorubicin, melphalan, and etoposide sensitivity in vitro reflected the clinically observed development of resistance to treatment. The cell line (GLC-14) established before the start of therapy was more sensitive than the lines (GLC-16 and GLC-19) obtained after treatment. It is concluded that the cell lines described in this paper represent a well-characterized in vitro model in which the development of drug resistance in small cell lung cancer can be studied.

Clinical characterization of non-small-cell lung cancer tumors showing neuroendocrine differentiation features.

In most cases of small-cell lung carcinomas (SCLC) phenotypic features compatible with a neuroendocrine differentiation status can be identified by monoclonal (MOC) antibody-based immunohistological procedures. Similar features can be recognized only in a minority of non-SCLC tumors. During a period of 30 months, all diagnostic non-SCLC biopsies (141 cases) were prospectively analysed for the presence of markers indicative for neuroendocrine differentiation. In 31% of all cases, such a presence could be noticed. Neuroendocrine differentiation (50% to 100% positive-staining tumor cells) was recognized more frequently in adenocarcinoma when compared to large-cell and squamous-cell carcinoma (chi 2 = 9.31, 2 degrees of freedom, P less than 0.01). To investigate whether the clinical behavior of these "neuroendocrine" non-SCLC cases mimics SCLC, a multivariate analysis for prognostic factors was performed. Among other prognostic factors, biopsies containing more than 50% positive-staining tumor cells with the MOC antibody-1 (MOC-1) were recognized as negative prognostic factors.

Penetration of VP 16-213 into cerebrospinal fluid after high-dose intravenous administration.

VP 16-213 in standard doses is active against a number of solid tumors. Its penetration into the cerebrospinal fluid (CSF) is very limited at these dose levels. In 10 patients treated with high-dose VP 16-213 (0.9-2.5 g/m2), CSF levels of up to 0.54 microgram/mL were detected. In two patients with central nervous system (CNS) metastases of small cell lung cancer (SCLC) a response was seen after 1.0 and 1.5 g/m2 intravenously. High-dose VP 16-213 can possibly play a role in the treatment of CNS metastases of SCLC. Its application in late intensification regimens as a form of prophylaxis of CNS metastases should be investigated.

The effects of oral slow-release terbutaline on the circadian variation in spirometry and arterial blood gas levels in patients with chronic airflow obstruction.

The circadian variation of spirometry and blood gases was studied in eight male, normoxemic, patients with chronic air flow obstruction and complaints of early morning dyspnea. The patients were selected for a high amplitude in circadian variation of PEFR. They were treated for eight days with placebo and slow-release terbutaline tablets (5 mg at 8 am and 10 mg at 8 pm). Thereafter, arterial blood gas levels were measured at four-hour intervals over 24 hours. Just after blood sampling, FEV1 measurements were performed. The results on placebo therapy were compared with results in eight healthy volunteers matched for age, sex, and smoking habits. The circadian rhythms of FEV1, PaO2, and SaO2 in these patients showed a higher amplitude than in normal subjects. The decrease of FEV1 in the patient group at 8 am coincided with the decrease in PaO2 and SaO2. In normal subjects no significant nocturnal fall in FEV1, PaO2, or SaO2 occurred. Administration of slow-release terbutaline tablets for eight days, providing comparable diurnal and nocturnal serum levels, prevented the nocturnal decrease of FEV1, PaO2, and SaO2. The increase of the FEV1 at all hours of observation showed a significant correlation with the increase of the PaO2.

Pulmonary function after recovery from the adult respiratory distress syndrome.

Eight adult patients with acute respiratory distress syndrome were treated with positive end-expiratory pressure (PEEP) ventilation. The results of detailed examinations of pulmonary function in these eight patients obtained after different periods of time following discharge from the respiratory care unit were analyzed to determine the degree of disturbances in pulmonary function. For comparison, examinations of pulmonary function were also performed on two patients who were treated with zero end-expiratory pressure ventilation. This follow-up study showed remarkably few abnormalities. Whe present, restrictive disturbances in pulmonary function, especially decreased static compliance and diffusing capacity, were found. No correlation was found between the pulmonary-function results of the eight patients and the duration of the PEEP treatment, nor between the results and the time interval between treatment at the respiratory care unit and the moment of the pulmonary function studies.

Changes in pulmonary function during and after bleomycin treatment in patients with testicular carcinoma.

Pulmonary function tests, including spirometry, transfer factor of the lungs for carbon monoxide (TlCO), and the two components of TlCO, the diffusing capacity of the alveolocapillary membrane (Dm) and pulmonary capillary blood volume (Vc), were carried out in a group of patients with testicular carcinoma during and after treatment with the Einhorn regimen. The lung function parameters of patients who developed bleomycin-induced pneumonitis were compared with those recorded in a group of patients who did not develop this syndrome. We suggest that bleomycin-induced damage to the pulmonary capillary vasculature can be monitored by measuring Vc and that ensuing fibrosis can be measured by recording Dm. The decrease in Dm is probably compensated for by an increase in Vc, leading to a smaller change in TlCO.

Clinical signs in severe Guillain-Barré syndrome: analysis of 63 patients.

Clinical data are presented of 63 artificially ventilated Guillain-Barré patients. About half of them had an antecedent event. In 57% the disease was heralded by sensory symptoms. The mean progressive phase lasted 12 days, the plateau 12 days and the recovery phase 568 days. In all patients one or more cranial nerves were involved, most often leading to facial palsy or difficulties in swallowing. Three-quarters of the patients had sensory signs, proprioceptive more often than superficial. Autonomic disturbances were common, especially hypertension and tachycardia. Twenty-two percent of the patients were severely confused in the first weeks of the disease. Laboratory examination showed atypical lymphocytes in the blood of 37% of patients and disturbed hepatic function tests in 79%. CSF protein level was elevated in all patients, with a mean value of 1.5 g/l.

Effect of beta-adrenergic stimulation on the circulatory lymphocyte count: studies in normals and in patients with chronic airflow obstruction.

In eight non-allergic patients with chronic airflow obstruction (CAO) and eight age and sex matched, healthy control subjects the circadian variation in circulatory lymphocyte count was studied in relation to serum cortisol and urinary epinephrine levels. In addition, we investigated the effect of the beta-adrenergic agent terbutaline on the lymphocyte count in two ways: as a long-term effect after 8 days of oral slow-release terbutaline with constant diurnal and nocturnal serum levels in patients, and as a short-term effect by a constant rate infusion of 0.2 micrograms/min over 4 hr in normals. Both patients and controls showed similar circadian patterns of urinary epinephrine excretion and lymphocyte counts. Patients with CAO, however, had significantly lower epinephrine levels and significantly higher lymphocyte counts at all hours of observation (every 4 hr from 0800 to 0800 hr the next day), as compared with normal controls. After 8 days of slow-release terbutaline the lymphocyte count in the patient group decreased to levels not significantly different from that of normals. The circadian rhythm of the lymphocytes, however, persisted under terbutaline therapy. No correlation existed between the lymphocyte count modulating factor, serum cortisol and the lymphocyte count over 24 hr. On placebo infusion in the control persons an increase of lymphocytes over 4 hr occurred, as a consequence of circadian rhythmicity. On terbutaline infusion a significant increase of lymphocytes after 1 hr was followed by a decrease to levels significantly below those on the placebo day. The same pattern was found in the leucocyte count. From this study it is concluded that beta-adrenergic stimulation corrects the relative lymphocytosis to counts comparable with normals. Other coinciding factors must regulate, however, the circadian rhythmicity.