A phase II study of induction therapy with carboplatin and gemcitabine among patients with locally advanced non-small cell lung cancer.

INTRODUCTION: The objectives of this trial were to evaluate the activity and safety of gemcitabine carboplatin as induction therapy in patients with locally advanced non-small cell lung cancer METHODS: Patients received two cycles of gemcitabine (1250 mg/m on day 1 and 8), plus carboplatin (area under the curve = 5 on day 1), after which response was established. Patients received a third course only in the case of an objective response (OR). Non-responding patients were directly irradiated. Toxicity was assessed according to the NCI-CTC version 2, radiation toxicity was assessed according to RTOG criteria. Response evaluation was performed according to RECIST criteria. RESULTS: We identified 42 patients, of whom 37 were eligible. Of these, 51% (95% CI, 34%-68%) achieved an OR, all partial responses. No disease progression on therapy was established. Toxicity was mostly hematological: 35% trombocytopenia grade 3 and 4, and 40% neutropenia grade 3 and 4. No severe bleeding or hospitalization because of febrile neutropenia occurred. CONCLUSIONS: Gemcitabine and carboplatin administered according to a 3-week schedule is an active and safe induction regimen. Pending the results of a phase III study, we believe that it is a reasonable alternative among patients for whom cisplatin-based chemotherapy is contraindicated.

A high prevalence of culture-positive extrapulmonary tuberculosis in a large Dutch teaching hospital.

BACKGROUND: In the Netherlands the incidence of tuberculosis (TB) has increased during the last decade. Growing immigration and international travel were important determining factors. To determine if this has resulted in altered clinical manifestations of the disease, we assessed the clinical spectrum of all TB cases diagnosed at our hospital in the period 1994 to 2000. METHODS: All culture-proven TB cases during the study period were retrospectively reviewed for clinical and demographic data. RESULTS: Sixty-five patients were identified. Solitary pulmonary TB was diagnosed in 33.9%, extrapulmonary TB in 51.8% and combined pulmonary and extrapulmonary TB in 14.3% of all cases. Patients were of foreign descent in 78.6% of all cases. Incidence peaked between 15 to 45 years. Decreased immunity was an important determining factor in the older patients. Presenting symptoms were mostly aspecific causing an important doctor's delay in establishing the diagnosis in 25%. Mortality was 3.6% and isoniazid resistance 3.6% CONCLUSIONS: Our data suggest an increase in the percentage of extrapulmonary TB concomitantly with an increasing percentage of patients of foreign descent. Because of aspecific presenting symptoms, TB was often diagnosed late. Treatment is mainly hindered by non-compliance and a high index of suspicion is necessary in making the diagnosis.

Effects of fluticasone propionate in COPD patients with bronchial hyperresponsiveness.

BACKGROUND: Treatment of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma. It seems that only certain subgroups of patients with COPD benefit from steroid treatment. A study was undertaken to examine whether inhaled fluticasone propionate (FP) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness (BHR). METHODS: Twenty three patients with COPD were studied. Patients had to be persistent current smokers between 40 and 70 years of age. Non-specific BHR was defined as a PC(20) for histamine of

Effects of fluticasone propionate inhalation on levels of arachidonic acid metabolites in patients with chronic obstructive pulmonary disease.

BACKGROUND: In smoking COPD patients the bronchoalveolar lavage (BAL) fluid contains high numbers of inflammatory cells. These cells might produce arachidonic acid (AA) metabolites, which contribute to inflammation and an increased bronchomotor tone. AIMS: To investigate levels of AA metabolites in BAL fluid, before and after inhaled glucocorticoid therapy: fluticasone propionate (FP) 1 mg per day, or placebo. METHODS: A double-blind placebo controlled trial lasting six months. COPD patients were selected by clinical criteria and the presence of bronchial hyper-responsiveness (BHR). Lung function was recorded and in BAL fluid we counted cell numbers and measured LTB4, LTC4/D4/E4, PGE2, 6kPGF1alpha, PGF2alpha and TxB2. A control group consisted of asymptomatic smokers (n=6). RESULTS: Paired data were obtained from 9 FP treated and 11 placebo patients. BAL cells were almost exclusively alveolar macrophages. In patients and controls both cellularity and levels of AA metabolites were equal Cell numbers did not change after treatment. Statistically significant decreases after FP therapy were noticed for PGE2 (30%), 6kPGF1alpha (41%) and PGF2alpha (54%). CONCLUSIONS: In COPD, the capability of inflammatory cells to produce certain AA metabolites was decreased after inhaled FP treatment. This result is discussed in its relation to clinical effects, the influence of smoking, and the results of an earlier, similar study in asthma patients.

Glucocorticoids hamper the ex vivo maturation of lung dendritic cells from their low autofluorescent precursors in the human bronchoalveolar lavage: decreases in allostimulatory capacity and expression of CD80 and CD86.

Dendritic cells (DCs) were prepared from human bronchoalveolar lavage (BAL) cells. We previously reported that, in particular, the CD1a fraction of the low autofluorescent (LAF) cells contains the precursors for DCs: after overnight culture, 40% of the LAF cells change into functionally and phenotypically prototypic dendritic/veiled cells. There are, as yet, no data on the modulatory effects of glucocorticoids (GC) on the maturation and function of such DCs isolated from the human lung. Functional tests (allogeneic mixed lymphocyte reaction: allo-MLR) were therefore performed with CD1a+ LAF cells at different stimulator-to-T-cell ratios and after preincubation with different dexamethasone (DEX) concentrations. DEX caused suppression of the T-cell stimulatory capacity of CD1a+ LAF cells, which was dose-dependent, and more evident at the higher stimulator-to-T-cell ratios. Here, we also show that CD80 and CD86 are normally expressed at low levels on CD1a+ LAF cell-derived DCs compared to other DC populations. This low-level expression of costimulatory molecules is discussed here in relation to the previously reported low-level expression of CD80 (and CD86) on lung DCs in experimental animals. This appears to play a role in a predominant Th2 cell stimulating potential of DC from the lung environment. DEX exposure of CD1a+ LAF cells prevented the upregulation of even this low-level expression of CD80 and CD86. The veiled/dendritic morphology and the expression of other relevant cell surface markers and adhesion molecules was not affected by DEX exposure. It is concluded that DEX hampers the maturation of CD1a+ LAF cells into active lung DCs.

Effect of an inhaled glucocorticoid on reactive oxygen species production by bronchoalveolar lavage cells from smoking COPD patients.

Oxidative stress in the lung is important in the pathogenesis of COPD. Published data indicate that glucocorticoids inhibit blood cells in their capacity to produce reactive oxygen species (ROS). We investigated the effect of Fluticasone propionate (FP) on the ROS production capabilities of pulmonary cells. Bronchoalveolar lavage (BAL) was performed in smoking COPD patients, before and after a six month, placebo-controlled treatment with FP. BAL cells were stimulated with phorbol myristrate acetate (PMA) alone, and together with superoxide dismutase (SOD). From kinetic plots of ferricytochrome-c conversion we calculated the maximal rate of superoxide production: V(max). We also examined BAL cell subsets and performed correlation analyses on ROS production and relevant clinical determinants. Paired results were obtained from 6 FP- and 9 placebo-treated patients. No significant change of V(max) was found in both patient groups. Also BAL cellularity was unchanged. Correlation analyses showed a significant (inverse) association of V(max) with the number of cigarettes smoked per day. We concluded that a potent inhaled glucocorticoid had no effect on the ROS production capability of BAL cells from smoking COPD patients. Apparently, heavy smoking impaired the ability of alveolar macrophages to produce ROS, which was not further decreased by FP.

Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients.

STUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the augmented mechanical behavior of the lung. Therefore, we studied the interrelationships between indexes of BHR, on the one hand, and markers of lung parenchymal destruction, on the other. PATIENTS AND METHODS: COPD patients were selected by clinical symptoms, evidence of chronic, nonreversible airways obstruction, and BHR, which was defined as a provocative dose of a substance (histamine) causing a 20% fall in FEV(1) (PC(20)) of

Airway inflammation in asthma and chronic obstructive pulmonary disease with special emphasis on the antigen-presenting dendritic cell: influence of treatment with fluticasone propionate.

Asthma is a chronic inflammatory disorder of the airways characterized by variable airflow limitation and airway hyperresponsiveness. The type of inflammatory response in asthma is compatible with a major contribution of professional antigen-presenting cells. The airways in chronic obstructive pulmonary disease (COPD) are also markedly inflamed; however, the predominant types of inflammatory cells and the main anatomical site of the lesion appear to differ from those in asthma. COPD is characterized by reduced maximum expiratory flow and slow forced emptying of the lungs. Steroids are the most prominent medication used in the treatment of asthma and COPD; however, the beneficial effect of steroid treatment in COPD is subject of debate. We investigated the efficacy of fluticasone propionate (FP) treatment in atopic asthmatics and in COPD patients with bronchial hyperreactivity who smoke. The effect of the treatment on bronchial hyperreactivity and indices of the methacholine dose-response curve were analysed, as well as indices of inflammation of the airway mucosa with special emphasis on the antigen presenting dendritic cell. Treatment of allergic asthmatic patients resulted in improvement of lung function (FEV1), a decrease in bronchial hyperresponsiveness and a decrease of maximal airway narrowing. During the FP-treatment of COPD patients, FEV1 remained stable, while FEV1 deteriorated significantly in the placebo group. Therefore, steroid treatment may have a beneficial effect in COPD patients with bronchial hyperresponsiveness (BHR). Since immunohistochemical analysis of bronchial biopsy specimens from asthma and COPD patients show disease-specific aspects of inflammation, the anti-inflammatory effect of FP is obtained through modulation of different cell populations in asthma and COPD.

Anesthesia for endobronchial laser surgery: a modified technique.

UNLABELLED: We describe a technique for endobronchial surgery with the neodynium:yttium-aluminum-garnet laser, in which an insufflation catheter with side holes placed into the contralateral mainstem bronchus is used for high-frequency positive pressure ventilation. Thirty-five patients (45 procedures) were treated during general anesthesia using a rigid bronchoscope in combination with a fiberoptic bronchoscope. Perioperatively, oxygen saturation (SaO2), mean arterial pressure, and heart rate were recorded. SaO2 during the recovery period was comparable to that during the intraoperative period but was significantly (P < 0.05) higher than that before the induction of anesthesia. There was a considerable (> or = 5%) increase in SaO2 at the end of the treatment in six patients, which indicates that the recanalization of the treated airway was successful. Our data support the assumption that, during endobronchial resection, selective ventilation of the nonaffected lung was adequate; in addition, subcarinal placement of the insufflation catheter with side holes was advantageous. We conclude that this technique contributes to the prevention of lung complications during endobronchial laser surgery. IMPLICATIONS: We describe a technique in which an insufflation catheter with side holes placed into the contralateral mainstem bronchus largely prevented inhalation of laser smoke and aspiration of blood and debris.

CD1a+ and CD1a- accessory cells from human bronchoalveolar lavage differ in allostimulatory potential and cytokine production.

Recently, we described the isolation through fluorescent-activated cell sorting (FACS) of low autofluorescent (LAF) cells from human bronchoalveolar lavage (BAL). These LAF cells displayed an immunophenotype comparable with that of dendritic cells (DC), and showed a high potency to stimulate naive T cells. In the study reported here we investigated the capability of LAF cells to produce interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-alpha), and the role of these cytokines in allogeneic T-cell stimulation by LAF cells. Lipopolysaccharide (LPS)-stimulated LAF cells released biologically active IL-1, IL-6, and TNF, and also showed intracellular immunoreactivity for IL-1, IL-6, and TNF-alpha. A neutralizing antibody against IL-1 slightly but statistically significantly (P < 0.05, Wilcoxon's test) inhibited the ability of the LAF cells to stimulate allogeneic T-cell proliferation (89% of stimulation in the absence of the antibody). Neutralizing antibodies against IL-6 and TNF-alpha had no effect. An antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF) also interfered with the accessory function of the LAF cells (79% of stimulation in the absence of the antibody, P < 0.05). We also investigated whether subsets of LAF cells (i.e., positive or negative for CD1a and purified by FACS sorting) differed in T-cell stimulatory capacity and in the ability to produce IL-1, IL-6, TNF-alpha, and S100. CD1a+ LAF cells were positive for and produced S100, CD1a- LAF cells were negative in this respect. The CD1a+ subset exhibited a clearly higher and very strong accessory capability as compared with the CD1a- subset. Despite this, CD1a+ LAF cells were poor producers of IL-1, IL-6, and TNF-alpha. The neutralizing antibody to IL-1, however, inhibited the ability of CD1a+ cells to stimulate allogeneic T-cell proliferation (43% of stimulation in the absence of the antibody, P < 0.01). Anti-IL-6 and alpha-GM-CSF had no effects. CD1a- LAF cells were potent producers of IL-1, IL-6, and TNF-alpha, and antibodies to IL-1, IL-6, and GM-CSF strongly interfered with their weaker accessory capability. In conclusion, two different subsets of LAF cells could be identified on the basis of accessory capability and cytokine profile. CD1a+ LAF cells (S100+; very potent T-cell stimulators, poor cytokine producers) are the "Langerhans cells" of the lung. CD1a- LAF cells (S100-; lower T-cell stimulatory capability, potent producers of IL-1, IL-6, and TNF-alpha) displayed a marker pattern intermediate between that of monocytes and monocyte-derived DC.

Suggestive evidence for bromocriptine-induced pleurisy.

Pleurisy of initially unknown origin was found in a patient who was treated with bromocriptine for Parkinson's disease for 6 years. At presentation, bilateral pleural thickening existed that caused severe restriction of pulmonary function. There were an elevated erythrocyte sedimentation rate, polyclonal hypergammaglobulinaemia, increased levels of acute phase proteins and anaemia. After withdrawal of the bromocriptine the patient's complaints as well as the laboratory parameters markedly improved. Further loss of pulmonary function did not occur. However, the pleural thickening did not resolve, not even upon subsequent corticosteroid treatment, probably due to fibrosis. Together, these findings strongly suggest a causative role of bromocriptine. The results of the laboratory studies suggested an immunopathogenetic mechanism, but in vitro lymphocyte-proliferation studies and skin patch tests with bromocriptine were negative. Bromocriptine should be considered as a cause of pleurisy. The drug must be stopped immediately upon the occurrence of pleural thickening in order to prevent impairment of pulmonary function. In addition, periodic laboratory and X-ray studies in patients on long-term bromocriptine treatment should be considered.

Dopamine-producing paraganglioma not visualized by iodine-123-MIBG scintigraphy.

A patient with an aorticopulmonary paraganglioma was found to have normal plasma norepinephrine and epinephrine levels and elevated dopamine levels. Iodine-123-MIBG scintigraphy did not visualize this tumor. The same finding on a negative MIBG scan in two patients with exclusively dopamine-secreting chemodectomas has been previously reported. In our patient, [111In-DTPA-D-Phe1]-octreotide scintigraphy proved to be an effective imaging technique.

Dendritic cells and their precursors isolated from human bronchoalveolar lavage: immunocytologic and functional properties.

Human bronchoalveolar lavage (BAL) has been described to contain, besides a large number of alveolar macrophages (AM) (approximately 95%), small numbers of monocyte-like cells (approximately 2%) and dendritic cells (DC) (approximately 0.4%). To separate AM (high autofluorescence) from DC, we used a fluorescence activated cell sorter (FACS) to separate BAL cells into a low autofluorescent (LAF) fraction and a high autofluorescent (HAF) fraction. Immunocytologic and functional properties of these fractions were investigated. The LAF fraction was composed of acid phosphatase (APh)- and RFD9-negative cells, which were strongly positive for HLA-DR, L25, RFD1, and CD68. A portion of these cells expressed CD1a (22%) and My4 (60%). The marker pattern of these cells is reminiscent to that of intraepithelial bronchial DC and to that of blood DC. The majority of the LAF cells had a monocyte-like morphology, but after overnight culture the percentage of LAF cells with long cytoplasmic extensions (DC morphology) was strongly augmented (from 18 to 51%). The HAF fraction contained 100% AM, strongly positive for APh, HLA-DR, CD68, RFD7, and RFD9. In culture, the LAF cells formed clusters with T cells and vigorously stimulated the proliferation of allogeneic T cells and naive (CD45RO-negative) T cells. BAL and LAF cells produced higher responses in nonsmokers than in smokers. In contrast, HAF cells did not form clusters with T cells and did not stimulate allogeneic T cell proliferation. HAF cells even suppressed mitogen-driven T cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Planar cobalt-57 bleomycin scintigraphy compared with CT-scan in the diagnosis and staging of lung cancer.

OBJECTIVES: Cobalt-57 bleomycin accumulates in tumour cells and is a diagnostic aid for discriminating malignant and benign lesions. Published data indicate that planar cobalt-57 bleomycin scintigraphy (bleo-scan) is a sensitive and specific test in the diagnosis and staging of lung cancer. CT-scan was however not used in these studies. We tested the value of bleo-scan and compared the results with those of computed tomography (CT-scan). METHODS: Bleo-scan and CT-scan were obtained from patients who were consecutively investigated because of a suspicious lesion on their chest X-ray. RESULTS: In 59 patients carcinoma of the lung was diagnosed 49 times (83%). The sensitivity of bleo-scan was 90%, specificity was 30% and positive predictive value (PPV) 86%. CT-scan could not discriminate between malignant and benign lesions. Thirty-two of the 41 patients with non-small-cell lung cancer had pathological examination of mediastinal lymph nodes, revealing metastases in 47% of the patients. Bleo-scan and CT-scan, respectively, had a sensitivity of 53 and 87%, a specificity of 77 and 82%, and negative predictive values (NPV) of 65 and 87%. In the 49 lung cancer patients distant metastases were detected at 11 sites in 10 patients. Bleo-scan gave false-negative and false-positive results. CONCLUSIONS: Bleo-scan in (suspected) lung cancer adds too little to the diagnostic procedure to make it a routine procedure. CT-scan gives indispensable information about possible mediastinal involvement.