Bernard Gasser

Plasma DNA microsatellite panel as sensitive and tumor-specific marker in lung cancer patients

The majority of lung cancer patients have tumor‐derived genetic alterations in circulating plasma DNA that could be exploited as a diagnostic tool. We used fluorescent microsatellite analysis to detect alterations in plasma and tumor DNA in 34 patients who underwent bronchoscopy for lung cancer, including 11 small cell lung cancer (SCLC) and 23 nonsmall cell lung cancer (NSCLC) (12 adenocarcinomas, 11 squamous cell carcinomas) and 20 controls. Allelotyping was performed with a selected panel of 12 microsatellites from 9 chromosomal regions 3p21, 3p24, 5q, 9p, 9q, 13q, 17p, 17q and 20q. Plasma DNA allelic imbalance (AI) was found in 88% (30 of 34 patients), with a similar sensitivity in SCLC and NSCLC. In the 24 paired available tumor tissues, 83% (20 of 24) presented at least 1 AI. Among these patients, 85% (17 of 20) presented also at least 1 AI in paired plasma DNA, but the location of the allelic alterations in paired plasma and tumor DNA could differ, suggesting the presence of heterogeneous tumor clones. None of the 20 controls displayed plasma or bronchial DNA alteration. A reduced panel of six markers (at 3p, 5q, 9p, 9q) showed a sensitivity of 85%. Moreover, a different panel of microsatellites at 3p and 17p13 in SCLC and at 5q, 9p, 9q and 20q in NSCLC patients could be specifically used. Analysis of plasma DNA using this targeted panel could be a valuable noninvasive test and a useful tool to monitor disease progression without assessing the tumor.

Pulmonary Migratory Infiltrates and Pachypleuritis in a Patient with Crohn’s Disease

Crohn’s disease can be associated with several respiratory manifestations. We report here a case of pulmonary migratory infiltrates associated with bilateral pleural thickening and peripheral eosinophilia. The histopathological findings show an association of necrotizing nodules, eosinophilic infiltration in the non-abscessed lung tissue, areas of non-caseating epithelioid granulomas, and an extensive pleural fibrosis. The different histopathological findings are detailed and the responsibility of either Crohn’s disease or treatment by mesalazine is discussed.

Repeated Inhalation of Low Doses of Cat Allergen That Do Not Induce Clinical Symptoms Increases Bronchial Hyperresponsiveness and Eosinophil Cationic Protein Levels

The aim of this study was to investigate whether repeated exposure to subclinical doses of cat allergens, not inducing asthma symptoms, could affect eosinophil cationic protein (ECP) levels in bronchoalveolar lavage (BAL) or in peripheral blood, without the appearance of clinical symptoms. Twelve patients with mild asthma, all sensitized to cats and not exposed to cat allergen at home, underwent a series of inhalations of cat allergen or placebo for 8 days over 2 weeks. A methacholine challenge was performed before and after the allergen and saline exposures, and BAL and blood were sampled for ECP measurements and eosinophil counts. No patients experienced asthma symptoms. However, PD20 methacholine (geometric mean) decreased significantly from 263 μg before to 126 μg after inhalation of allergen. Inhalation of saline did not induce any significant change in PD20. The change in log PD20 before and after cat allergen exposure was statistically different from the change in log PD20 before and after saline. Median ECP levels in BAL and serum increased significantly after allergen exposure, from 0.8 to 3.1 μg/l (p<0.02) and from 15.9 to 31.4 μg/l (p<0.05), respectively. No change was observed after saline inhalations. The change in BAL and serum ECP levels was statistically significant compared to that in the control group. The number of eosinophils did not change, however, nor did IL–5 and RANTES levels in BAL and serum. In conclusion, our results show that (1) exposure of asthma patients to repeated low doses of allergen, which did not provoke any clinical symptoms, is capable of inducing a local eosinophil activation associated with an increase in nonspecific bronchial hyperresponsiveness and (2) the increase in serum ECP levels due to eosinophil activation precedes the occurrence of asthma symptoms and may thus be a marker of allergen exposure in allergic asthma.

Inhibition by glucocorticoids of the interleukin-1β-enhanced expression of the mast cell growth factor SCF

Stem cell factor (SCF) is a major mast cell growth factor that promotes differentiation and chemotaxis of mast cells and inhibits their apoptosis. We evaluated the effect of interleukin (IL)‐1β, a major pro‐inflammatory cytokine, on the constitutive expression of SCF and studied the effects of two glucocorticoids, budesonide and dexamethasone, on the IL‐1β‐enhanced SCF expression. Human lung fibroblasts in culture were serum‐starved for 48 h and treated with IL‐1β, budesonide and/or RU486. SCF cDNA was quantified after total RNA reverse transcription by on‐line fluorescent polymerase chain reaction. SCF protein was quantified by ELISA. IL‐1β induced an increase in SCF mRNA (+91% at 2.5 h) and protein production (+32%) by human lung fibroblasts in culture (P<0.001). Budesonide inhibited IL‐1β‐induced SCF mRNA expression (−68%) at 2.5 h and even more so at 10 h (−192%) (P<0.001). The expression of SCF protein also decreased by 3.5‐fold at 10 h. Results were similar with dexamethasone. The glucocorticoid antagonist RU486 cancelled the effects induced by the glucocorticoids. Increased SCF mRNA levels were associated with increased stability of this mRNA as measured after treatment with actinomycin D (1.9‐fold at 2.5 h). Budesonide decreased this IL‐1β‐enhanced stability by about 1.5‐fold (P<0.001). We conclude that in ‘inflammatory’ conditions, mimicked in vitro by IL‐1β, glucocorticoid treatment inhibits expression of the mast cell growth factor SCF. The reduced number and activation of mast cells observed in the bronchi of asthmatic patients treated by glucocorticoids may be due in part to this effect.

Severe Churg-Strauss syndrome with mediastinal lymphadenopathy treated with interferon therapy.

We report a case of severe Churg-Strauss syndrome (CSS) with mediastinal eosinophilic lymphadenopathy, with relapse after standard therapy with steroids and cyclophosphamide, subsequently treated with interferon (IFN) alpha 2b. Our report shows that mediastinal lymph nodes mimicking lymphoma may be one of the clinical manifestations of CSS. We also show that patients with CSS who are resistant to first-line therapy and for whom hypereosinophilia is thought to play an important role may benefit from treatment with IFN.

Thoracic manifestations of primary humoral immunodeficiency: a comprehensive review.

Humoral immunodeficiencies, which are characterized by defective production of antibodies, are the most common types of primary immunodeficiency. Pulmonary changes are present in as many as 60% of patients with humoral immunodeficiency. Chronic changes and recurrent infections in the respiratory airways are the main causes of morbidity and mortality in those affected by a humoral immunodeficiency. Medical imaging, especially computed tomography (CT), plays a crucial role in the initial detection and characterization of changes and in monitoring the response to therapy. The spectrum of abnormalities seen at thoracic imaging includes noninfectious airway disorders, infections, chronic lung diseases, chronic inflammatory conditions (granulomatosis, interstitial pneumonias), and benign and malignant neoplasms. Recognition of characteristic CT and radiographic features, and correlation of those features with clinical and laboratory findings, are necessary to differentiate between the many possible causes of parenchymal and mediastinal disease seen in patients with primary humoral immunodeficiencies.

Migratory pulmonary infiltrates in a patient treated with sotalol

Beta-blockers may induce several types of adverse respiratory reaction such as asthma, interstitial lung disease with or without pleural effusion, systemic lupus erythematosus or hypersensitivity pneumonitis. More recently, bronchiolitis obliterans with organizing pneumonia (BOOP) has been described. We report here on pulmonary migratory infiltrates with combined histopathological features of both BOOP and eosinophilic pneumonia in a woman treated with sotalol long-term. The patient improved only partially with steroids. Tapering off corticosteroid dosage resulted in relapse, and complete recovery was only obtained after sotalol was stopped.

Invasive pulmonary aspergillosis with cerebromeningeal involvement after short-term intravenous corticosteroid therapy in a patient with asthma

The present case report describes a case of invasive pulmonary aspergillosis with cerebromeningeal invasion in an asthmatic non-immunocompromised patient. This fatal complication occurred despite early anti-fungal antibiotherapy after a 2-week course of intravenous corticosteroid therapy for treatment of an exacerbated asthma. Diagnostic and therapeutic procedures are discussed.

Hemodynamic and cardiac anti-hypertrophic actions of clonidine in Goldblatt one-kidney, one-clip rats.

In congestive heart failure, the chronic sympathetic hyperactivity contributes to a poor prognosis. In this respect, clonidine, a centrally acting sympathoinhibitory drug, has previously been tested in clinical trials. The aim of the current study was to evaluate the effects of clonidine on morbidity and mortality in an experimental model of cardiac hypertrophy associated with hypertension, renal failure, and intense sympathetic activation. One-kidney, one-clip Goldblatt hypertensive rats were treated orally with clonidine (200 &mgr;g/kg/d) during 30 days and were compared with untreated rats and with sham-operated animals. Cardiac hemodynamics, left ventricular volume and elasticity, cardiac morphometry and histology, and renal function were evaluated. A survival study was also performed. Clonidine normalized cardiac function, ventricular stiffness, and prevented ventricular structural remodeling. Moreover, despite a marked renal function impairment, survival of the animals was increased in the clonidine group. The centrally acting sympathoinhibitory drug clonidine exhibited marked cardioprotective properties. This study emphasized the interest of evaluating drugs whose aim is to treat congestive heart failure, in an experimental model of cardiac and renal failure.

The role of 5‐HT2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors

Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5‐HT system is associated with VHD. Here, we investigated the contribution of 5‐HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex.