[Resistance to anti-EGFR through the successive and cumulative acquisition of two new oncogenic addictions: BRAF and ALK]. / Résistance aux anti-EGFR via l'acquisition successive et cumulée de deux nouvelles addictions oncogénique BRAF et ALK.

Targeted therapies are the standard first-line treatment for metastatic lung adenocarcinoma with certain molecular abnormalities. These abnormalities are particularly common in Southeast Asia and French Polynesia. A 51-year-old Tahitian female non-smoker was diagnosed in 2018 with stage IV lung adenocarcinoma harboring a p.L858R EGFR mutation. She received gefitinib as first-line treatment. Due to locoregional progression and the presence of a resistance mutation (p.T790M of EFGR), she received osimertinib as second-line treatment, after which chemotherapy was proposed as 3rd-line treatment. An additional biopsy detected not only the previously known EGFR mutation, but also a BRAF p.V600E mutation. Following disease progression during chemotherapy, the patient received targeted therapies combining dabrafenib, trametinib and osimertinib. Due to a dissociated response after four months of treatment, a 5th line of paclitaxel bevacizumab was initiated. Subsequent to additional progression and given the ALK rearrangement shown on the re-biopsy, 6th-line treatment with alectinib was proposed. As the response was once again dissociated, a final line was proposed before stopping active treatments due to their toxicity and overall deterioration in the patient's state of health. This exceptional case is characterized by resistance to anti-EGFR through the successive and cumulative acquisition of two new oncogene addictions. The authors underline the importance of re-biopsy at each progression, leading (if at all feasible) to yet around round of targeted therapy.

[One-year survival improvement in lung cancer in France. Results of the prospective real life studies KBP-2000-CPHG and KBP-2010-CPHG]. / Amélioration de la survie à 1 an dans le cancer du poumon en France. Résultats des études prospectives en vie réelle, KBP-2000-CPHG et KBP-2010-CPHG.

INTRODUCTION: The French college of general hospital respiratory physicians (CPHG) has conducted 10 years apart two prospective observational studies to assess changes in the primary lung cancer epidemiology and outcomes, including 1-year mortality. METHODS: In 2000 and 2010, all volunteer adult patients followed in the respiratory department of general hospitals participating in the study were consecutively included if their lung cancer was histologically or cytologically diagnosed between 01 January and 31 December (sample date). Their vital status at least 1 year after inclusion and date of death (if applicable) were collected. RESULTS: Respectively, 5667 and 7051 patients were included in the study in 2000 and 2010 and vital status of 5441 (96.0%) and 6981 (99%) patients known. One-year mortality rate was 61.8% in 2000 and 56.4% in 2010 (P<0.0001). Mortality rate significantly decreased from 2000 to 2010 in non-small-cell lung cancer (60.7% vs. 55.2%; P<0.0001) but not in small-cell lung cancer (66.9% vs. 64.2%; P=0.22). The year of diagnosis was an independent risk factor of mortality (OR=0.84; 95% CI: 0.77-0.91; P<0.0001). CONCLUSION: Although it remains low (43.6% in 2010), life expectancy at 1 year for patients with lung cancer has improved in 10 years. Five-year results are expected to show whether this improvement is maintained or not over time.

[Characteristics and management of acute exacerbations of COPD in hospital. EABPCO-CPHG study by the college of general hospital respiratory physicians]. / Caractéristiques et prise en charge des exacerbations aiguës de BPCO hospitalisées. Etude EABPCO-CPHG du Collège des pneumologues des hôpitaux généraux.

INTRODUCTION: A cohort was formed to explore the evolution of COPD patients treated in general hospitals for acute exacerbations (AE). The present article describes and compares patient characteristics according to whether COPD was diagnosed before the AE or not. METHODS: Data were analyzed for 1,824 patients admitted between October 2006 and June 2007 to 68 departments of respiratory medicine. RESULTS: Population characteristics were: male, 77%; mean age, 70.3+/-11.3 years; current smokers, 33%; baseline grade 3-4 dyspnoea, 47%; FEV1

Heparin inhibits neutrophil-induced platelet activation via cathepsin G.

Activated human polymorphonuclear neutrophils (PMNs) induce platelet stimulation via cathepsin G (cat G), a platelet-activating cationic serine proteinase released from the azurophilic granules. Heparin inhibited up to 100% of aggregation and serotonin release triggered by 180 nmol/L of purified cat G in a concentration-dependent manner between 10 and 70 mU/ml. When tested against the enzymatic activity of 180 nmol/L cat G (hydrolysis of N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide), inhibition by heparin never exceeded 60% (up to 100 U/ml). Inhibition was most probably related to electrostatic interactions between the cationic cat G and the anionic heparin, because addition of 180 mU/ml of protamine sulfate restored platelet activation. Low molecular weight heparin, CY 216, used between 5 and 50 mU/ml, also inhibited cat G-induced platelet activation. When purified PMNs and washed platelets were mixed together and challenged with a PMN agonist (FMLP at 1 mumol/L), platelet activation was observed. Pretreatment of the mixed cell population with 300 mU/ml heparin prevented platelet activation. This was illustrated by electron microscopy studies. The present data, apart from confirming a participation of cat G in the PMN-platelet interaction, bring evidence that heparin has potent antiproteinase effect in a biologic model.

Activation of human platelets by C5a-stimulated neutrophils: a role for cathepsin G.

Human platelets can be stimulated by recombinant human fifth component of complement (rhC5a) in the presence of human neutrophils. After challenge with N-formyl-Met-Leu-Phe or rhC5a, concentrated neutrophils release cathepsin G into the supernatant. The concentrations of cathepsin G recovered by titration of the enzymatic activity correlate with the capability of these supernatants to induce platelet stimulation as measured by serotonin release. Cathepsin G purified from neutrophil granules triggered platelet aggregation and serotonin release independent of arachidonic acid metabolites and platelet-activating factor formation. A concentration of 100 nM of cathepsin G, which was reached in the surrounding space of activated neutrophils, induced a 50% platelet stimulation. Three distinct antiproteinases were tested against cathepsin G-induced platelet activation. Z-Gly-Leu-Phe-CH2Cl, a specific inhibitor of cathepsin G enzymatic activity, proved to be nonspecific in our biological system. By contrast, alpha 1-antichymotrypsin and alpha 1-antitrypsin displayed specific activities. The physiological specific inhibitor of cathepsin G, alpha 1-antichymotrypsin, was the most potent and was used in the rhC5a-induced neutrophils-mediated platelet activation. A complete inhibition was achieved, showing that release of cathepsin G from neutrophils accounts for platelet activation. Such a chain of events involving C5a, neutrophils, cathepsin G, and platelets may be of relevance in certain inflammatory states, particularly the adult respiratory distress syndrome.

Interference of recombinant eglin C, a proteinase inhibitor extracted from leeches, with neutrophil-mediated platelet activation.

Eglin C is an inhibitor of two serine proteinase-derived polymorphonuclear leucocytes (PMN) i.e., elastase and cathepsin G. Since the latter has recently been shown to be involved in the activation of platelets by stimulated PMN, the effects of recombinant eglin C in the PMN-platelet cooperation model were studied. First, the inhibitory capacity of eglin C against purified cathepsin G was measured spectrophotometrically by following hydrolysis of a specific synthetic substrate, N-succinyl-ala-ala-pro-phe-para-nitroanilide. The inhibition of the enzymatic activity of 180 nM (5 micrograms/ml) cathepsin G was directly proportional to eglin C concentration and reached 100% with 2 micrograms/ml (240 nM). Platelet activation generated by a submaximal concentration of cathepsin G (200 nM) was also totally suppressed by 2 micrograms/ml of eglin C. Inhibition was specific (a 100 times higher concentration of eglin C did not alter platelet activation induced by thrombin), and surmountable (an increase of cathepsin G concentration reduced the eglin C effect). Thus, the mechanism of inhibition by eglin C of cathepsin G-induced platelet activation could be explained by a stoichiometric relation between eglin C and cathepsin G as previously described. Investigations were then performed with the PMN-platelet cooperation model, using two distinct stimuli, N-formylmethionylleucylphenylalanine (FMLP) or recombinant human C5a, at submaximal concentrations, 2.10(-7) M and 10(-7) M, respectively. A concentration-dependent inhibition of platelet activation aggregation and serotonin release-lambda was observed. Eglin C used at 10 micrograms/ml and 25 micrograms/ml totally blocked the platelet responses induced by recombinant human C5a and FMLP, respectively. Leucotriene B4, but also thromboxane B2 production measured by radioimmunoassays, were observed under FMLP activation. In the presence of eglin C, thromboxane B2 formation was totally suppressed, whereas leucotriene B4 synthesis was still effective. In fact, the mechanism of inhibition of eglin C is located neither on PMN (leucotriene B4 formation by FMLP-activated PMN was not affected), nor on platelets (response to thrombin was unchanged). The target is most probably cathepsin G since eglin C suppressed thromboxane B2 formation by platelets challenged by this serine proteinase. These results constitute an argument in favor of the implication of cathepsin G in the PMN-mediated platelet activation. Moreover, they reinforce the hypothesis that this mechanism could be operating under in vivo pathologic conditions, since eglin C is capable of preventing or ameliorating some experimental pulmonary diseases.