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Even if the overall number of cancer is increasing, the mortality has started to decrease in the Western World. The role of early detection in this decrease is a matter of debate. To assess its impact on mortality it is important to distinguish between diagnosis of cancer in symptomatic patients, and early detection in asymptomatic individuals who may self-refer or who may be offered ad hoc or systematic screening. The policies for early detection and screening vary greatly between European countries, despite many similarities in their cancer burden, and this partly reflects the uncertainties surrounding asymptomatic testing for cancer. A Task Force of European expert, held in Azzate (VA), Italy, established to address these issues, acknowledged the need for more research in the field of individual risk assessment since general statistics are more and more perceived as inadequate to design personal early detection plans. The group also recognised that combinations of early detection and screening will enforce the effectiveness of new treatments in curbing mortality curves, although policies will vary with different cancers.

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The Research Institute for Diagnosis and Treatment of Early Lung Cancer (RIDTELC) Lung Study was initiated to determine whether lung cancer screening by automated sputum cytometry combined with conventional sputum cytology and auto-fluorescence in addition to white light bronchoscopy could enhance the detection rate of early lung cancer. The present study analyses the initial findings to evaluate the efficiency of automated sputum cytology in predicting the diagnosis of lung cancer. In this study, malignancy grade was used as a predictive parameter for lung cancer. In total, 2,480 heavy smokers (>30 pack-yrs), aged 50-74 yrs, with no previous cancer in the last 5 yrs, received chest radiology, conventional sputum cytology and sputum cytometry screening. In total, twenty-seven lung cancers were diagnosed, representing a prevalence of 1.1%, 25 of which provided sputum samples. Positive automated sputum cytology results were seen in 176 smokers (7.2%), 10 (0.4%) of whom had severe dysplasia or higher lesions (positive results) by conventional sputum cytology examination. Out of 25 tumour cases, 20 had suspicious results using automated sputum cytology, representing 80% sensitivity. One patient out of 24 with tumours had positive results on conventional sputum cytology, representing a sensitivity of 4.2%. For all stages of squamous cell lung cancer and later stage adenocarcinoma the sensitivity of automated sputum cytology was 100%. For adenocarcinoma stage I sensitivity was 25%. In conclusion, DNA analysis of sputum slides by automated sputum cytology may be a suitable tool for the detection of early lung cancer and the characterisation of a high-risk group with pre-invasive lesions for follow-up.

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The correlations between semi-automated sputum cytometry (ASC), conventional cytology and the final diagnosis was investigated in industrially-exposed workers. Slides of sputum samples from 201 former uranium miners with silicosis, 100 patients with asbestosis, 103 workers resected for lung cancer, and 200 controls (50% smokers), were stained using the Papanicolaou (Pap) method and the Feulgen reaction with thionin. Cytometry was performed using the Cyto-Savant automated system. Atypical nuclei were found in 72 of 404 patient samples, 327 samples were normal and five were inadequate for ASC analysis. Thirteen tumours (Pap IV, Pap V) and 11 cases of severe dysplasia were identified by cytology. Lung cancer was confirmed in 20 patients. Compared to the final diagnosis of lung cancer, the sensitivity of ASC was 75% (15 out of 20) and specificity 89.8% (520 out of 579). The results represent a diagnostic efficiency of 89.3%. The combination of ASC with cytology increased sensitivity to 80% (16 out of 20) without significant loss of specificity (89.7% or 523 out of 581). In this investigation of a limited number of patients with occupational radon or asbestos exposure, semi-automated sputum cytometry appears to be sensitive and reliable for the detection of malignant changes in the tracheobronchial mucosa. Together with conventional cytology, it would be reasonable to test the validity of the combined methods in a large-scale feasibility study of early lung cancer detection.

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OBJECTIVES: To determine the advantage of autofluorescent endoscopy for the identification of laryngeal cancer. STUDY DESIGN: This is a prospective, multicenter clinical study. We investigated whether autofluorescent endoscopy using the Lung Imaging Fluorescent Endoscopy (LIFE)-Lung System (Xillix, Olympus) is capable of identifying early cancer of the larynx, especially in comparison with conventional white-light endoscopy and microscopic laryngoscopy. Benign lesions as well as microinvasive and invasive squamous cell carcinoma of the larynx were investigated. For logistic reasons and because of the pilot character of this study, the number of patients was limited. METHODS: Sixteen patients having 24 laryngeal lesions of both benign or malignant character were subsequently examined by autofluorescent endoscopy, white-light endoscopy, and microscopic laryngoscopy. Based on optical appearance, and for each method separately, the lesions were classified as malignant or not. The visual results were documented and histologically verified. RESULTS: The sensitivity of autofluorescent endoscopy for laryngeal cancer detection was more than 90% and therefore higher than that of white-light endoscopy and microscopic laryngoscopy. However, as far as laryngeal cancer is concerned, the specificity of autofluorescent endoscopy was very low. Many of the false-positive results were due to inflammation, hypervascularization, and edema. CONCLUSION: Autofluorescent endoscopy is advantageous only in the hands of an experienced ENT specialist. Although it does not replace the combination of white-light endoscopy and a critical evaluation of the clinical symptoms of the individual disease, it can profitably complement them. Autofluorescent endoscopy can help in determining whether microscopic laryngoscopy performed with general anesthesia should be recommended urgently to the patient. Microscopic laryngoscopy remains the best method for the identification of malignant lesions, if it is combined with obtaining taking multiple biopsy specimens. Confirmation of the results of this pilot study with a larger series of patients is desirable.

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INTRODUCTION: Automated image cytometry represents a new method for the quantitative analysis of nuclear structure and DNA-content of exfoliative airway epithelial cells. In the present investigation, we examined the correlation between automated cytometry, conventional cytology and histopathology with the final diagnosis as the "gold standard". METHODS: In 142 patients (100 males and 42 females) with suspected lung cancer and 50 controls (COPD, asthma), bronchial washings (5-10 ml) were obtained during bronchoscopy before taking biopsies for cytological and/or histological examinations. The washings were collected in 20 ml Saccomanno's fixative and centrifuged (500 g, 15 min). The cell pellet was resuspended in Saccomanno's solution. Two specimens were stained according to Papanicolaou and another two using the Feulgen reaction with thionine. Image cytometry was performed by means of a special, trainable classifier for exfoliative cells of the respiratory tract, using the Cyto-Sacant (Oncometrics, Vancouver). RESULTS: In the patients with suspected lung cancer we found numerous abnormal nuclei in 97 samples, 36 samples contained normal cells only, and 9 samples were insufficient. In our control group there was no sample with abnormal nuclei, and all washings were evaluable. Compared to the final diagnosis of lung cancer, we found a sensitivity of 90% (92/102) and a specificity of 84% (26/31). For histology sensitivity was 91% (73/80) and specificity 100%, while we found a sensitivity of 92% (92/100) and specificity of 100% for cytology. For automated cytometry the positive predicted value was 95%, the negative predicted value 71%. CONCLUSIONS: In the investigation of patients with suspected lung cancer, automated image cytometry of bronchial washings is a sensitive and reliable method for the detection of malignant changes in the tracheobronchial mucosa. The automated procedure seems well suited not only for analysing bronchial washings, but also for a screening procedure.

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BACKGROUND: Conventional bronchoscopy in the identification of preneoplasias and carcinoma in situ (CIS) has been inadequate to date. Tissue autofluorescence was found to differentiate normal mucosa from dysplastic or carcinomatous bronchial mucosa. This principle resulted in the development of the LIFE System (Light Imaging Fluorescence Endoscope, Xillix Techn., Vancouver, BC), now in routine use worldwide at 35 centres. In a prospective multicentric study in North America the relative sensitivity for diagnosing intraepithelial neoplasias of combined white light (WLB) and LIFE bronchoscopy in 173 at-risk patients was 6.3 as compared to WLB alone. A similar European multicentric study will be completed by spring of 1998. PATIENTS AND RESULTS: We report on our experience with the routine use of the LIFE System over 23 months. 194 examinations (165 patients) were performed. Moderate to severe dysplasias and in situ carcinomas were diagnosed with a relative sensitivity of 2.7 by the combined WLB-LIFE examination as compared to WLB alone. CONCLUSION: Autofluorescence bronchoscopy as a routine investigation without need of photosensitizers in patients with a high risk for lung cancer can lead to a substantial increase in the detection rate of CIS and moderate to severe dysplasias compared to white light bronchoscopy alone.

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BACKGROUND: Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and the existence of naturally occurring cytokine antagonists has added to this complexity. Upregulation of both interleukin 1 beta (IL-1 beta) and its naturally occurring receptor antagonist, interleukin 1 receptor antagonist (IL-1ra), has previously been observed on asthmatic bronchial epithelium compared with normal airways. METHODS: The effect of inhaled beclomethasone dipropionate (BDP) on asthmatic bronchial epithelial expression of IL-1 beta and IL-1ra was studied. Frozen bronchial biopsy specimens from nine asthmatic subjects receiving 1000 micrograms BDP daily for eight weeks and from six asthmatic subjects receiving matching placebo were stained with anti-IL-1 beta and anti-IL-1ra antibodies. Hue-saturation-intensity (HSI) colour image analysis was used to quantify the brown immunoperoxidase reaction colour present on the bronchial epithelium. RESULTS: There was a significant twofold decrease in the epithelial expression of IL-1 beta after treatment with BDP but no significant change was seen in IL-1ra (P = 0.175). CONCLUSION: The selective inhibition of IL-1 beta, without effect on IL-1ra, provides a novel mechanism for the anti-inflammatory action of glucocorticosteroids.

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Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and recent findings have suggested that naturally occurring cytokine antagonists may also be involved. In this study we looked at the expression of interleukin-1 beta (IL-1beta) and its naturally occurring receptor antagonist, IL-1ra, in the normal and asthmatic bronchial wall. Frozen bronchial biopsies from 12 normal and 18 asthmatic individuals were double stained with EBM11 (a CD68 macrophage marker) and either a rabbit anti-IL-1beta or a rabbit anti-IL-1ra. Hue-saturation-intensity color image analysis (HSI) was used to quantify the brown immunoperoxidase reaction product present on the bronchial epithelium. There was an increased expression of both IL-1beta and IL-1ra in the asthmatic bronchial epithelium, p < 0.0002 and p < 0.0001, respectively. Additionally, the numbers of macrophages, of IL-1beta producing cells, and the percentage of macrophages producing IL-1beta were significantly increased in the asthmatic submucosa (p < 0.004, p < 0.002, and p < 0.008, respectively).

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Pulmonary lymphangioleiomyomatosis was diagnosed in a 26-year-old woman with recurrent pneumothorax by histological evaluation of a lung biopsy obtained during video-thoracoscopy. A tumour of the right kidney had been removed 2 years previously; the histological picture was that of an angiomyolipoma. Immunohistochemical staining for anti-smooth muscle actin gave a strongly positive reaction in the tissue of the renal angiomyolipoma and in the pathologic lung tissue. Additional investigations showed an asymptomatic intracerebral tumour 5 cm in diameter in the left frontal lobe (brain scan). This multilocal renal, pulmonary and cerebral manifestation of benign mesenchymal proliferating tumours supports the classification of this case in the tuberous sclerosis complex.

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The expression of the monocyte chemoattractant protein (MCP-1), a member of the chemokine family of low molecular weight cytokines, was assessed by immunohistochemistry in bronchial biopsies from 12 asthmatic and 12 normal subjects. Both a monoclonal antibody (F9) and a polyclonal antibody were employed to detect MCP-1, while the mouse myeloma protein (MOPC21) was used as a negative control. Strong positive reactions for MCP-1 were seen in the bronchial epithelium. Subepithelial macrophages, blood vessels, and bronchial smooth muscle were also stained. Hue-saturation-intensity color image analysis was used to quantify reactions of the monoclonal antibody in the epithelial and subepithelial layers. With the monoclonal antibody, asthmatic biopsies showed 51.8 +/- 3.7% (mean +/- SEM) of the epithelium staining positively, whereas normal subjects reacted much less, with 6.4 +/- 1.9% of the epithelium staining (P < 0.0001); there was no overlap between the two groups. Likewise, staining was increased in the subepithelium of asthmatic airway biopsies, with 11.5 +/- 3.1% and 2.0 +/- 1.0% staining positively in asthmatic and normal subepithelium, respectively, (P < 0.002). There was a significant correlation between staining of the epithelium and subepithelium (r = 0.77, P < 0.001). The polyclonal anti-MCP-1 antibody also gave strong reactions in the epithelium and subepithelium, with 34.0 +/- 7.8% of the asthmatic and 1.6 +/- 1.0% of the normal bronchial epithelium staining positively (P < 0.0001). These increased levels of MCP-1 in the asthmatic airways suggest that they may play a role in macrophage recruitment and activation and thereby contribute to the inflammatory pathology of bronchial asthma.

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The presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) in airway epithelial cells in vivo was assessed in 15 asthmatic and 9 normal subjects. GM-CSF was analyzed using immunohistochemistry with a polyclonal and a monoclonal antibody. Hue saturation intensity color image analysis was used to quantify staining. Asthmatic airway epithelial cells stained significantly more with anti-GM-CSF than those from normal subjects (p = 0.0013 and p = 0.0003 for the polyclonal and monoclonal antibodies, respectively). Additionally, 8 asthmatic individuals inhaled 1,000 micrograms beclomethasone diproprionate per day for 8 wk and 6 asthmatic patients inhaled matching placebo. There was a significant reduction of GM-CSF in the epithelium in the patients who were given corticosteroids (p = 0.014), whereas the group of subjects who were given placebo showed no significant change in GM-CSF staining. There was a correlation between the percentage suppression of GM-CSF staining by inhaled corticosteroids and the percentage increase in FEV1 (r = 0.61, p < 0.05) and percentage decrease in carbachol responsiveness (r = 0.80, p < 0.01). These findings suggest that GM-CSF may play a role in the inflammatory processes of bronchial asthma and that the epithelial cell may be a target cell for drug action.

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61 patients suffering from intrinsic (idiotypic) or extrinsic (allergic) asthma were investigated for signs of complement activation and for C3 phenotype distribution. Activation of both the classical and alternative pathway of the complement system and generation of the membrane attack complex could be assessed by ELISAs for the activation-specific protein-protein complexes C1rsC1 inhibitor, C3b(Bb)P and SC5b-9, respectively. A possible deficiency of the complement regulatory proteins C1 inhibitor, factor H and factor I was excluded. In contrast to earlier studies, C3 allele frequencies did not differ from those found in the healthy population. Our results support the role of complement activation during bronchial asthma and, thereby, provide further evidence for the inflammatory nature of the disease.

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Bronchoalveolar lavage (BAL) was performed on 11 atopic patients with mild asymptomatic bronchial asthma and 11 healthy nonasthmatic volunteers. All asthmatic subjects had evidence of bronchial hyperresponsiveness to inhaled carbachol. The concentrations of leukotriene (LT) C4, LTD4, LTE4, LTB4, prostaglandin D2 (PGD2), platelet-activating factor (PAF) and histamine in BAL fluid measured. The leukotrienes were measured by radioimmunoassay following reverse phase high performance liquid chromatography. PGD2 concentrations were determined by radio immunoassay after Amprep C2 extraction. PAF was quantitated by means of in vitro aggregation of rabbit platelets and histamine content was measured using a single isotope radio-enzymatic assay. There was an increase in the levels of PGD2 and a decrease in the concentration of LTB4 in asthmatic lavage samples. There were no significant differences in the lavage concentrations of LTC4/D4/E4 and histamine between the two groups of individuals. PAF was undetectable.

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Relatively little has been reported about destruction through brachytherapy of mucosa-perforating and extraluminary tumors with probable large vessel involvement causing major hemorrhagic or fistular complications. We report 12 patients subjected to laser and brachytherapy for centrally occluding lung cancer, whom we have periodically followed up from June 1986 until they died. Although all laser procedures were free from complications, necrotic cavitation in five cases, two of which were accompanied by large bronchoesophageal fistulas, and massive fatal hemoptysis occurred in six. Minor complications included radiation mucositis (two), noncritical mucosal scarring (two), and cough (four). Characteristics that will identify patients at risk of developing fatal hemoptysis and fistulas should be better defined by imaging and endoscopic techniques. In such cases, modifying the protocol or using alternative procedures should be considered. Minor complications, such as cough, can be avoided by using topical steroid therapy (eg, beclomethasone dipropionate).

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To establish whether a general dysfunction, i.e., an increase in permeability, had occurred in 16 trauma patients (6 with adult respiratory distress syndrome [ARDS]), we measured beta 2-microglobulin (beta 2MG), myoglobin (MG), immunoglobulin G (IgG), and transferrin (TF) concentrations in bronchoalveolar lavage fluid (BAL), serum, and urine as well as extravascular lung water content (EVLW) over a period of 14 days. Our results show a positive correlation (p = 0.03) between increases of EVLW, reflecting lung edema, and beta 2MG concentrations in urine of all patients with ARDS, indicating systemically increased permeability. Generalized increase of permeability can also explain the elevation of MG urine concentrations (p = 0.03) together with an EVLW increase, and an increase of BAL protein concentrations (IgG, TF, p less than 0.01) in the early post-trauma phase during the first 48 h after admission. In contrast, commonly used kidney function tests remained unchanged over the time course of 14 days.

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On the basis of comprehensive clinicopathological evidence 6 patients presenting with unilateral left-sided hyperlucent lungs are evaluated for pathogenesis, function and postoperative (n = 5) course. The common denominator in all proves to be moderate to severe hypoperfusion and overinflation of the respective lungs. Pulmonary function is characterized by a combined restrictive-obstructive pattern. In 4 patients overinflation is due to a central check-valve mechanism (tumor: n = 3; central airways collapse: n = 1), whereas in 2 increased translucency results from some sort of peripheral obstruction (Swyer-James syndrome: n = 1; congenital cystic bronchiectasis: n = 1). We consider the origin of hypoperfusion to be alveolar distension and hypoxic precapillary vasoconstriction, both participating in diminished blood flow to the check-valve obstructed lung. In Swyer-James syndrome reduced vascularity is an additional feature. Preoperative and long-term postoperative lung function data of 5 pneumonectomized patients are compared. On the whole, FEV1 and IVC remain unchanged, whereas the obstructive profile (RV, RV/TLC, sRAW) improves. From these data it is concluded that the affected hyperlucent lung is 'amputated' even before operation - irrespective of the nature of tissue damage. On the other hand postoperative relief of airways obstruction is supposed to be due to both antiobstructive medication and the removal of a diseased lung.

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