Jean-Louis Corhay

Evaluation of the solitary pulmonary nodule by positron emission tomography imaging

Current noninvasive imaging methods are not sufficiently reliable for accurate detection of malignancy in most solitary pulmonary nodules (SPNs). Positron emission tomography (PET) using 18-fluorodeoxyglucose (FDG), showing increased FDG uptake and retention in malignant cells, has proved useful to differentiate malignant from benign tissue and could, therefore, contribute to the evaluation of the SPN. We performed a prospective study of 50 patients referred to the Pneumology Department with unclear diagnoses of SPN after conventional radiological screening. PET study was performed on each subject before an invasive procedure was proposed. Thirty three patients had a malignant nodule and 17 had a benign nodule. The mean size of malignant nodule was 3 cm (range 1.5-4.5 cm). All showed a marked increase in 18-FDG uptake. The mean size of benign nodule was 1.8 cm (range 0.5-3.5 cm). PET imaging showed the absence of 18-FDG uptake and correctly identified 15 of 17 benign nodules. There was two false-positive cases with a moderate increase in 18-FDG uptake (1 postprimary tuberculosis; and 1 anthracosilicotic nodule with nonspecific inflammation). At present, the sensitivity and specificity of the method are 100 and 88%, respectively. The positive and negative predictive values of PET imaging for SPNs are 94 and 100%, respectively. Our preliminary results demonstrate that PET-FDG imaging is a noninvasive technique, which appears highly accurate in differentiating malignant SPN from benign SPN.

Whole-body 18FDG positron emission tomography in the staging of non-small cell lung cancer

Despite advances in morphological imaging, some patients with lung cancer are found to have nonresectable disease at surgery or die of recurrence within yr of surgery. We performed a prospective study in 109 patients to compare the accuracy of whole-body positron emission tomography (PET) using fluorine-18 deoxyglucose (18FDG) and conventional imaging (CI) methods for the staging of non-small cell lung cancer (NSCLC). When CI or PET study suggested metastatic disease, confirmation was obtained by biopsy or follow-up information. As compared to CI, 18FDG-PET correctly changed the N stage in 22 patients (33%) and the M stage in 15 patients (14%). For the detection of distant metastases, PET study showed five false-positive sites and no false-negative cases. Currently, the accuracy of PET in the detection of M stage is 96%. Our study shows that visual interpretation of whole-body fluorine-18 deoxyglucose-positron emission tomography images can improve the diagnostic accuracy in the staging of non-small cell lung cancer. Further experience is needed to establish if metabolic imaging would be a cost-effective tool in the future management of lung cancer.

Value of FDG-PET in detecting residual or recurrent nonsmall cell lung cancer

In order to evaluate the usefulness of 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the assessment of therapeutic effects, a study was performed before and after therapy in 126 patients with non-small cell lung cancer (NSCLC) codified stage I to stage IIIB. Treatment with an early curative result was given in 58 patients, whereas in 68 cases it was limited to palliation. During the treatment follow-up period (8-40 months), each patient was evaluated every 3 months by clinical examination and < or =6 months by imaging techniques (PET and computed tomography (CT)). A diagnosis of persistent or recurrent tumour was established by means of pathological analysis in 31 patients and by clinical evolution and subsequent imaging progression in 29 other patients. PET showed increased FDG uptake in all cases (n = 60) of persistent or recurrent tumour, whereas CT was nonspecific in 17 cases. Conversely, there were five false positive cases via PET imaging and three via CT. In detecting residual or recurrent NSCLC, PET had a sensitivity of 100% and specificity of 92%, whereas CT had a sensitivity and specificity of 71% and 95% respectively. In conclusion, 18-fluorodeoxyglucose positron emission tomography correctly identified response to therapy in 96% (121 of 126) of patients. Positron emission tomography appears to be more accurate (p = 0.05) than conventional imaging in distinguishing persistent or recurrent tumour from fibrotic scar in patients undergoing treatment for non-small cell lung cancer.

Staging of the mediastinum: value of positron emission tomography imaging in non-small cell lung cancer

Recent studies have shown limitations of morphological imaging in staging mediastinal lymph node involvement in lung cancer. In contrast to computed tomography (CT), which depends primarily on anatomical imaging features, positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) depends mainly on the metabolic characteristics of a tissue for the diagnosis of disease. We have performed a prospective study comparing FDG-PET and CT of the thorax in the presurgical assessment of the mediastinum in 50 patients with newly diagnosed non-small cell lung cancer (NSCLC). CT and PET scans were interpreted separately, and results were compared to pathological staging obtained during thoracotomy. Hilar or mediastinal lymph node involvement was present in 58%. In staging for lymph node involvement, CT had a sensitivity of 72% and specificity of 81%, whereas PET had a sensitivity and specificity of 90% and 86%, respectively. When the PET study was compared to histological results, there were four cases showing more advanced mediastinal involvement with PET and four cases showing less involvement with PET. From our preliminary results, we conclude that positron emission tomography with 18-fluorodeoxyglucose is significantly more accurate than computed tomography in the mediastinal staging of non-small cell lung cancer.

Histamine-induced inhibition of neutrophil chemotaxis and T-lymphocyte proliferation in man

Histamine inhibits in vitro human neutrophil chemotaxis and T‐lymphocyte proliferation via H2 receptors. The aim of this study was to verify these inhibitory effects of histamine in man in vivo. Healthy volunteers were challenged with histamine by intravenous (1 mg), subcutaneous (1 mg) and inhalatory (2.4 mg) routes. Venous blood was taken before and at different times after challenge. Neutrophil chemotaxis was studied by the Boyden assay and T‐lymphocyte proliferation by counting H3‐thymidine incorporation in cultured mononuclear cells. Plasma histamine was measured by radioimmunoassay. Histamine infusion caused transient systemic symptoms as well as a significant decrease of neutrophil chemotaxis (x̄−26%± 6) and of PHA‐pulsed T‐lymphocyte proliferation (x̄−16%± 6) 4 h after histamine challenge. Subcutaneous injection of histamine caused only a significant decrease of neutrophil chemotaxis (x̄−24%± 15) 4 h after injection. Histamine inhalation was well tolerated and caused a significant depression of neutrophil chemotaxis (x̄−40%± 15) and of T‐lymphocyte proliferation (x̄−27%± 6) 2 and 4 h after the challenge. Histamine challenges were always accompanied by a rapid and transient rise in plasma histamine. Inhalation of an H3 agonist (impromidine) but not of an H2 agonist (betahistine) caused a decrease of neutrophil chemotaxis and of T‐lymphocyte proliferation. Oral pretreatment with an H1 antagonist (cimetidine) before histamine inhalation prevented histamine‐induced decrease of neutrophil chemotaxis and T‐lymphocyte proliferation, whereas astemizole, an H3 antagonist, had no effect. In conclusion, during the few hours following administration, exogenous histamine in man causes a depression of neutrophil chemotaxis and T‐lymphocyte proliferation via H2 receptors. These observations are consistent with the concept that endogenous histamine may exert some modulatory effects on inflammatory and immune cells in man.

Increased IL-6 and TGF-β1 concentrations in bronchoalveolar lavage fluid associated with thoracic radiotherapy☆

PURPOSE To assess, in lung cancer patients, the effects of thoracic radiotherapy (RT) on the concentrations of transforming growth factor-beta(1) (TGF-beta(1)) and interleukin-6 (IL-6) in the bronchoalveolar lavage (BAL) fluid. METHODS AND MATERIALS Eleven patients with lung cancer requiring RT as part of their treatment were studied. BAL was performed bilaterally before, during, and 1, 3, and 6 months after RT. Before each BAL session, the patients status was assessed clinically using pulmonary function tests and an adapted late effects on normal tissue-subjective, objective, management, analytic (LENT-SOMA) scale, including subjective and objective alterations. The National Cancer Institute Common Toxicity Criteria were used to grade pneumonitis. The TGF-beta(1) and IL-6 levels in the BAL fluid were determined using the Easia kit. RESULTS The TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated areas were significantly increased by thoracic RT. The increase in TGF-beta(1) levels tended to be greater in the group of patients who developed severe pneumonitis. In the BAL fluid from the nonirradiated areas, the TGF-beta(1) and IL-6 concentrations remained unchanged. CONCLUSION The observed increase in TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated lung areas demonstrated that these cytokines may contribute to the process leading to a radiation response in human lung tissue.

Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also features systemic inflammation. The purpose of our study was to compare airway and systemic inflammation in COPD to that seen in healthy subjects and to relate the inflammation with the disease severity. METHODS Ninety-five COPD patients, encompassing the whole severity spectrum of the disease, were recruited from our outpatient clinic and rehabilitation center and compared to 33 healthy subjects. Induced sputum and blood samples were obtained for measurement of inflammatory cell count. Interleukin (IL)-4, IL-6, IL-10, TNF-α and IFN-γ produced by 24h sputum and blood cell cultures were measured. RESULTS Compared to healthy subjects, COPD exhibited a prominent airway neutrophilic inflammation associated with a marked IL-10, IL-6 and TNF-α release deficiency that contrasted with a raised IFN-γ production. Neutrophilic inflammation was also prominent at blood level together with raised production of IFN-γ, IL-10 and TNF-α. Furthermore, sputum neutrophilia correlated with disease severity assessed by GOLD stages. Likewise the extent of TNF-α release from blood cells also positively correlated with the disease severity but negatively with that of sputum cell culture. Blood release of TNF-α and IL-6 negatively correlated with body mass index. Altogether, our results showed a significant relationship between cellular marker in blood and sputum but poor relationship between local and systemic release of cytokines. CONCLUSIONS COPD is characterized by prominent neutrophilic inflammation and raised IFN-γ production at both bronchial and systemic level. Overproduction of TNF-α at systemic level correlates with disease severity and inversely with body mass index.

Leukotriene B4 Contributes to Exhaled Breath Condensate and Sputum Neutrophil Chemotaxis in COPD

BACKGROUND Neutrophils have been implicated in the pathogenesis of COPD. Several chemoattractants for neutrophils have been measured in samples of exhaled breath condensate (EBC) and induced sputum (IS) from patients with COPD. The aims of this study were to compare EBC and IS supernatant neutrophil chemotactic activity (NCA) from ex-smoking subjects with COPD and healthy ex-smokers, and to assess the contribution of leukotriene B(4) (LTB(4)) to this activity. METHODS Thirty-four subjects with COPD were compared to 24 control subjects. EBC and IS chemotactic activity for neutrophils was assessed by using Boyden microchambers. The chemotactic index was used to evaluate cell migration. LTB(4) was measured by a specific enzyme immunoassay. The contribution of LTB(4) to EBC and sputum neutrophil chemotaxis was assessed by an LTB(4) receptor antagonist (U-75302; Cayman Chemical Company; Ann Arbor, MI). RESULTS EBC and IS samples from both COPD patients and healthy subjects displayed significant NCA, but this activity was raised in COPD patients compared to healthy subjects. The chemotactic activity contained in sputum, however, failed to correlate with that in EBC. In COPD patients, there was a significant correlation between EBC NCA and sputum neutrophil counts. LTB(4) levels were raised in EBC samples, but not in sputum samples, from COPD subjects compared to those from healthy subjects. LTB(4) receptor antagonist concentrations (2.5 x 10(-4) mol/L) reduced by 44.6% and by 44.4%, respectively, the chemotactic activity contained in the EBC and sputum samples. CONCLUSIONS EBC and IS from COPD patients have a raised NCA to which LTB(4) contributes.

18F-FDG PET imaging in assessing exudative pleural effusions.

Background This study evaluates the accuracy of [18F]fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging with semi-quantitative analysis for differentiating benign from malignant pleural exudates and for guiding the search for the primary tumour of pleural metastases. Methods Whole-body 18F-FDG PET was performed in 79 patients with exudative pleurisy. Standard uptake values were normalized for body weight, body surface area, lean body mass (SUVbw, SUVbsa, SUVlbm) with and without correction for blood glucose levels. Thoracoscopy was systematically performed to reveal pathological diagnosis. Results All SUVs were significantly higher in all malignant pleural diseases (n=51) than in benign (n=28) (P<0.001). Moreover SUVs were greater in the pleural metastases from pulmonary primaries (n=25) and in mesotheliomas (n=8) than in extrathoracic primaries (n=18) (P<0.01) with no significant difference between lung cancers and mesotheliomas. Receiver operating curve (ROC) analysis between benign and malignant lesions showed areas under the curves that ranged from 0.803 (SUVbsa g−1) to 0.863 (SUVbw). The cut-off value for SUVbw which gave the best accuracy (82.3%) was 2.2. When comparing thoracic with extrathoracic primaries the highest accuracy (80.4%) was found for a cut-off value of 2.6. Conclusion Semi-quantitative analysis of 18F-FDG PET imaging helps to differentiate malignant from benign pleural exudates and to distinguish between thoracic or extrathoracic primaries.

Diagnostic value of interleukine-6, transforming growth factor-beta 1 and vascular endothelial growth factor in malignant pleural effusions.

STUDY OBJECTIVES We evaluate the accuracy of pleural interleukine-6 (IL-6), transforming growth factor-beta 1 (TGF-beta1), and vascular endothelial growth factor (VEGF) levels for differentiating benign from malignant pleural exudates. PATIENTS AND METHODS Levels of IL-6, TGF-beta1, and VEGF were measured by ELISA in 103 patients with non neutrophilic (<50%) exudative pleurisy including both benign and malignant effusions. Pleurisies were split into benign and malignant according to the pathological diagnosis. RESULTS Thirty-nine benign (seven infections; 32 inflammatory diseases) and 64 malignant (34 extrathoracic tumors; 25 lung cancers; five mesotheliomas) pleural exudates were diagnosed by thoracoscopy. Pleural reticulo-monocyte count, protein Lights ratio and lactic dehydrogenase Lights ratio were significantly higher in malignant than in benign effusions (p<0.05, p<0.001 and p<0.001, respectively). The median (range) level of VEGF was significantly higher in malignant than in benign effusions (664.50 pg/ml [10-40,143] vs 349 pg/ml [10-8888]) (p<0.05). VEGF levels correlated with pleural LDH (r=0.41, p<0.0001), glucose (r=-0.30, p<0.01) and red cell count (r=0.57, p<0.0001). No significant difference was found between malignant and benign effusions with respect to IL-6 (26.8 ng/ml [1.8-421] vs 18.4 ng/ml [0.45-400], respectively) and TGF-beta1 (1079 pg/ml [18-6206] vs 1123 pg/ml [34-5447]) levels. ROC analysis between benign and malignant pleurisies for VEGF showed an area under the curve of 619 (p=0.03) with a value of 382 pg/ml as the best threshold for distinguishing benign from malignant effusions. CONCLUSIONS Malignant effusions may enhance the release of VEGF in pleural space and its measurement may help in the diagnosis of malignant effusion.