Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
INTRODUCTION: Light chain deposition disease is a rare clinical entity characterized by deposition of monoclonal immunoglobulin light chains in organs. The kidneys are almost always affected, while the lung manifestations that have been reported, including nodular or diffuse disease, especially cystic lesions, are unusual. CASE REPORT: We report the case of a 60-year-old man with a diffuse infiltrative lung disease characterized by numerous apical cysts. The diagnosis of light chain deposition cystic lung disease was obtained by surgical lung biopsy. Light chain deposits in the salivary glands were the only extrapulmonary manifestation. Despite 12 chemotherapy cycles, the patient's lung function and radiological appearances worsened. CONCLUSION: This is the fourth case describing a cystic lung disease due to light chain deposition in the literature. It highlights the need for comprehensive investigations so as not to miss this rare cause of cystic lung disease, which appears to be related to a primary pulmonary lymphoproliferative disorder. The only treatment that appears to be effective is lung transplantation.
ISSN: 0761-8425

hal-00873356
https://hal.archives-ouvertes.fr/hal-00873356
https://hal.archives-ouvertes.fr/hal-00873356/document
https://hal.archives-ouvertes.fr/hal-00873356/file/DA_pots_chaines_lA_gA_res_non_amyloides_version_finale.pdf
DOI : 10.1016/j.rmr.2013.02.003

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
The objective of this study is to assess the association of clinical manifestations of systemic sclerosis (SSc) with the absolute count of circulating blood monocyte subpopulations according to their membrane expression of CD16. Forty-eight consecutive patients fulfilling the 2013 ACR/EULAR classification criteria for SSc were included in this cross-sectional study. CD16+ monocyte absolute count was defined by flow cytometry and confronted to the clinical characteristics of SSc patients. Twenty-three healthy donors (HD) were randomly selected for comparison. SSc patients had an increased number of total circulating blood monocytes compared to HD (p < 0.001). The CD16- subpopulation absolute count was increased in SSc patients compared to HD (p < 0.001) but was similar in limited SSc (lSSc) and diffuse SSc (dSSc). On the contrary, the CD16+ population absolute count was increased in dSSc compared to both HD and lSSc patients (dSSc 0.071 Giga/L (+/- 0.034) vs HD 0.039 Giga/L (+/- 0.030), p < 0.01, and dSSc 0.071 Giga/L (+/- 0.034) vs lSSc 0.048 Giga/L (+/- 0.024), p < 0.05). The CD16+ monocyte subpopulation absolute count was significantly correlated with the severity of skin fibrosis evaluated by the modified Rodnan skin score (p < 0.001). The CD16+ monocyte subpopulation was also associated with pulmonary fibrosis (p < 0.05), with the severity of the restrictive ventilatory defect evaluated by total lung capacity (p < 0.05) and with the pulmonary function impairment reflected by diffusing capacity of the lungs for carbon monoxyde measures (p < 0.01). These results suggest that CD16+ monocytes are associated with the main fibrotic manifestations of SSc and their role in the pathogenesis of fibrosis in this autoimmune disorder should therefore be further considered.
ISSN: 0770-3198

hal-01560150
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560150
DOI : 10.1007/s10067-017-3597-6
PUBMED : 28293753

Éditeur(s) : HAL CCSD
Résumé : International audience
INTRODUCTION: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is characterized by imaging features consisting of the association of centrilobular and/or paraseptal emphysema and pulmonary fibrosis. Virtually all patients are smokers and thus at high risk of developing lung cancer. METHODS: This retrospective multicentre study was conducted by the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P). RESULTS: A total of 47 patients presenting with lung cancer and CPFE syndrome were identified. All patients were smokers, with a mean of 47 pack-years. A pathological diagnosis of lung cancer was obtained for 38 (81%) patients. Histological type was squamous cell carcinoma in 17 (36%) patients, adenocarcinoma in 14 (30%), non-small-cell lung cancer not otherwise specified in three (6%), small-cell lung cancer in three (6%), and sarcomatoid carcinoma in one (2%). Overall, 20 of the 47 patients could not receive standard-of-care treatment for lung cancer, as per international recommendations or guidelines; this limitation was considered to be directly related to the CPFE syndrome in eight (40%) cases. CONCLUSION: Lung cancer in patients with CPFE syndrome represents a specific entity with a poor prognosis, that further represents the most characteristic and severe model of tobacco-related disease.
Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer

hal-01063912
https://hal.archives-ouvertes.fr/hal-01063912
DOI : 10.1097/JTO.0000000000000209
PUBMED : 25157769

Éditeur(s) : HAL CCSD
Résumé : International audience
OBJECTIVES: We investigated the relationship between lung cancer and occupational exposure to welding activity in ICARE, a population-based case-control study. METHODS: Analyses were restricted to men (2276 cases, 2780 controls). Welding exposure was assessed through detailed questionnaires, including lifelong occupational history. ORs were computed using unconditional logistic regression, adjusted for lifelong cigarette smoking and occupational exposure to asbestos. RESULTS: Among the regular welders, welding was associated with a risk of lung cancer (OR=1.7, 95% CI 1.1 to 2.5), which increased with the duration (OR=2.0, 95% CI 1.0 to 3.9 when duration extgreater10 years), and was maximum 10-20 years since last welding. The risk was more pronounced in case of gas welding (OR=2.0, 95% CI 1.2 to 3.3), when the workpiece was covered by paint, grease, or other substances (OR=2.0, 95% CI 1.2 to 3.4) and when it was cleaned with chemical substances before welding. No statistically significant increase in lung cancer risk was observed among occasional welders. CONCLUSIONS: Although these results should be confirmed, we showed that type of welding and mode of workpiece preparation are important determinants of the lung cancer risk in regular welders
Occupational and Environmental Medicine

hal-01274887
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274887
DOI : 10.1136/oemed-2015-102964
PUBMED : 26865654

Éditeur(s) : HAL CCSD BMJ Publishing Group
Résumé : International audience
BACKGROUND: The association between lung cancer and occupational exposure to organic solvents is discussed. Since different solvents are often used simultaneously, it is difficult to assess the role of individual substances. OBJECTIVES: The present study is focused on an in-depth investigation of the potential association between lung cancer risk and occupational exposure to a large group of organic solvents, taking into account the well-known risk factors for lung cancer, tobacco smoking and occupational exposure to asbestos. METHODS: We analysed data from the Investigation of occupational and environmental causes of respiratory cancers (ICARE) study, a large French population-based case-control study, set up between 2001 and 2007. A total of 2276 male cases and 2780 male controls were interviewed, and long-life occupational history was collected. In order to overcome the analytical difficulties created by multiple correlated exposures, we carried out a novel type of analysis based on Bayesian profile regression. RESULTS: After analysis with conventional logistic regression methods, none of the 11 solvents examined were associated with lung cancer risk. Through a profile regression approach, we did not observe any significant association between solvent exposure and lung cancer. However, we identified clusters at high risk that are related to occupations known to be at risk of developing lung cancer, such as painters. CONCLUSIONS: Organic solvents do not appear to be substantial contributors to the occupational risk of lung cancer for the occupations known to be at risk
ISSN: 1351-0711

hal-01282444
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01282444
DOI : 10.1136/oemed-2015-103177
PUBMED : 26911986

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Purpose The objective of this article was to estimate the social cost of respiratory cancer cases attributable to occupational risk factors in France in 2010. Methods According to the attributable fraction method and based on available epidemiological data from the lit- erature, we estimated the number of respiratory cancer cases due to each identified risk factor. We used the cost- of-illness method with a prevalence-based approach. We took into account the direct and indirect costs. We estimated the cost of production losses due to morbidity (absenteeism and presenteeism) and mortality costs (years of production losses) in the market and nonmarket spheres. Results The social cost of lung, larynx, sinonasal and mesothelioma cancer caused by exposure to asbestos, chromium, diesel engine exhaust, paint, crystalline silica, wood and leather dust in France in 2010 were estimated at between 917 and 2,181 million euros. Between 795 and 2,011 million euros (87-92 %) of total costs were due to lung cancer alone. Asbestos was by far the risk factor representing the greatest cost to French society in 2010 at between 531 and 1,538 million euros (58-71 %), ahead of diesel engine exhaust, representing an estimated social cost of between 233 and 336 million euros, and crystalline silica (119-229 million euros). Indirect costs represented about 66 % of total costs. Conclusion Our assessment shows the magnitude of the economic impact of occupational respiratory cancers. It allows comparisons between countries and provides valu- able information for policy-makers responsible for defining public health priorities.
ISSN: 1618-7598

halshs-00922838
https://halshs.archives-ouvertes.fr/halshs-00922838
DOI : 10.1007/s10198-013-0528-6
PUBMED : 23974964

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
The natural history of pulmonary Langerhans cell histiocytosis (PLCH) has been unclear due to the absence of prospective studies. The rate of patients who experience an early progression of their disease is unknown. Additionally, conflicting effects of smoking cessation on the outcome of PLCH have been reported. In this prospective, multicentre study, 58 consecutive patients with newly diagnosed PLCH were comprehensively evaluated over a two-year period. Our objectives were to estimate the incidence of early progression of the disease and to evaluate the impact of smoking status on lung function outcomes. Lung function deterioration was defined as a decrease of at least 15% in FEV1 and/or FVC and/or DLCO, compared with baseline values. At each visit, smoking status was recorded based on the patients' self-reports and urinary cotinine measurements that were blinded for the patients. The cumulative incidence of lung function outcomes over time was estimated using the non-parametric Kaplan-Meier method. Multivariate Cox models with time-dependent covariates were used to calculate the hazards ratios of the lung function deterioration associated with smoking status with adjustment for potential confounders. The cumulative incidence of lung function deterioration at 24 months was 38% (22% for FEV1 and DLCO, and 9% for FVC). In the multivariate analysis, smoking status and PaO2 at inclusion were the only factors associated with the risk of lung function deterioration. The patients' smoking statuses markedly changed over time. Only 20% of the patients quit using tobacco for the entire study period. Nevertheless, being a non-smoker was associated with a decreased risk of subsequent lung function deterioration, even after adjustment for baseline predictive factors. By serial lung computed tomography, the extent of cystic lesions increased in only 11% of patients. Serial lung function evaluation on a three- to six-month basis is essential for the follow-up of patients with recently diagnosed PLCH to identify those who experience an early progression of their disease. These patients are highly addicted to tobacco, and robust efforts should be undertaken to include them in smoking cessation programs. ClinicalTrials.gov: No: NCT01225601 .
ISSN: 1750-1172

hal-01146047
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146047
PUBMED : 25887097
DOI : 10.1186/s13023-015-0249-2

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
BACKGROUND: Mutations in the telomerase complex (TERT and TR) are associated with pulmonary fibrosis and frequent hematologic manifestations. The aim of this study was to characterize the prognosis of lung transplantation in patients with TERT or TR mutations. METHODS: Patients with documented TERT or TR mutations who received a lung transplant between 2007 and 2013 in France were identified via an exhaustive search of the lung transplantation network, one expert genetic laboratory, and the clinical research network on rare pulmonary diseases. RESULTS: There were 9 patients (7 men) with TERT (n = 6) or TR (n = 3) mutations who received a single (n = 8) or a double (n = 1) lung transplant for pulmonary fibrosis. Median age was 50 years (range, 35-61 years) at diagnosis and 52 years (range, 37-62 years) at the time of lung transplantation. Thrombocytopenia was present in 7 patients before lung transplantation. After lung transplantation, 6 patients developed myelodysplasia and/or bone marrow failure, directly contributing to death in 4 cases. Anemia was observed in 9 patients, and neutropenia was observed in 3 patients. The median survival after lung transplantation was 214 days (range, 59-1,709 days). CONCLUSIONS: Patients with mutations of the telomerase complex are at high risk of severe hematologic complications after lung transplantation, in particular, bone marrow failure. Specific recommendations should be developed for appropriate guidance regarding hematologic risk assessment before transplantation and management of the post-transplantation immunosuppressive regimen.
ISSN: 1053-2498

hal-01146848
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146848
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146848/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146848/file/Severe%20hematological%20complications%20after%20lung%20transplantation_accepted.pdf
DOI : 10.1016/j.healun.2014.11.010

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: The effects of pressure-controlled (PC) ventilation on the ventilatory and haemodynamic parameters during laparoscopy procedures had not been carefully assessed. This prospective cross-over study was undertaken to compare how volume-controlled (VC) and PC modes could affect pulmonary mechanics, gas exchange, and cardiac function in patients undergoing laparoscopy. METHODS: Twenty-one patients undergoing laparoscopic urological procedures had their lungs ventilated at the beginning with VC ventilation. PC ventilation was instituted at the end of the VC sequence. Ventilator settings were adjusted to keep tidal volume, respiratory rate, and Fi(o(2)) constant in every mode. A complete set of ventilatory, haemodynamic, and gas exchange parameters was obtained under VC after 40 min of pneumoperitoneum and 20 min after switching for PC. Transoesophageal echocardiography was performed in order to evaluate systolic and diastolic function of the heart. RESULTS: When VC was switched to PC, peak airway pressure decreased [mean (sd) 32 (6) vs 27 (6) cm H(2)O; P < 0.0001], peak inspiratory flow increased [17 (3) vs 48 (8) litre min(-1); P < 0.0001), and dynamic compliance improved [+15 (8)%]. No difference was noted for static airway pressure, static compliance, and arterial oxygenation. No significant change could be demonstrated in the systolic [left ventricular end-systolic wall stress 66 (16) vs 63 (14) x 10(3) dyn cm(-2) m(-2)] or diastolic function [early diastolic velocity 10.3 (2.5) vs 10.5 (2.7) cm s(-1)]. CONCLUSIONS: In this study, no short-term beneficial effect of PC ventilation could be demonstrated over conventional VC ventilation in patients with pneumoperitoneum.
BJA

hal-00689758
https://hal.archives-ouvertes.fr/hal-00689758
DOI : 10.1093/bja/aem166
PUBMED : 17626027

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Smoking only partly explains the higher lung cancer incidence observed among socially deprived people. Occupational exposures may account for part of these inequalities, but this issue has been little investigated. We investigated the extent to which smoking and occupational exposures to asbestos, silica and diesel motor exhaust mediated the association between education and lung cancer incidence in men. We analyzed data from a large French population-based case–control study (1976 lung cancers, 2648 controls). Detailed information on lifelong tobacco consumption and occupational exposures to various carcinogens was collected. We conducted inverse probability-weighted marginal structural models. A strong association was observed between education and lung cancer. The indirect effect through smoking varied by educational level, with the strongest indirect effect observed for those with the lowest education (OR = 1.34 (1.14–1.57)). The indirect effect through occupational exposures was substantial among men with primary (OR = 1.22 (1.15–1.30) for asbestos and silica) or vocational secondary education (OR = 1.18 (1.12–1.25)). The contribution of smoking to educational differences in lung cancer incidence ranged from 22 % (10–34) for men with primary education to 31 % (−3 to 84) for men with a high school degree. The contribution of occupational exposures to asbestos and silica ranged from 15 % (10–20) for men with a high school degree to 20 % (13–28) for men with vocational secondary education. Our results highlight the urgent need for public health policies that aim at decreasing exposure to carcinogens at work, in addition to tobacco control policies, if we want to reduce socioeconomic inequalities in the cancer field.
ISSN: 0393-2990

hal-01360240
http://hal.upmc.fr/hal-01360240
http://hal.upmc.fr/hal-01360240/document
http://hal.upmc.fr/hal-01360240/file/Menvielle_2016_Quantifying_the.pdf
PUBMED : 27417979

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC.
ISSN: 0300-483X

hal-00682486
https://hal.archives-ouvertes.fr/hal-00682486
DOI : 10.1016/j.tox.2011.11.011
PUBMED : 22138297

Éditeur(s) : HAL CCSD Impact journals
Résumé : International audience
Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine. We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients. Frequencies of ROS1 and RET rearrangements were 2.1% and 2.52%, respectively. Contrary to common belief, both ROS1 and RET rearrangements were detected in patients with a history of smoking, and the RET-positive patients were not younger than the negative patients. Moreover, RET but not ROS1 rearrangement was associated with the female gender. Nearly half of the ROS1-rearranged patients were successfully treated with ROS1 TKIs. In contrast, only 5/18 RET-positive patients received off-label RET TKIs. Two patients had stable disease, and three experienced disease progression. In addition to the 18 RET-positive cases, 10 showed isolated 5' signals. The clinical relevance is unknown but if the frequency is confirmed by other groups, the question whether these patients are eligible to TKIs will arise. More potent RET TKIs are under development and may improve the response rate in RET-positive patients. Therefore, we recommend the routine implementation of RET testing in non-squamous NSCLC patients, including those with a history of smoking.
ISSN: 1949-2553

hal-01578586
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578586
DOI : 10.18632/oncotarget.18408
PUBMED : 28881815

Éditeur(s) : HAL CCSD
Résumé : International audience
Occupational exposure constitutes a common risk factor for lung cancer. We observed molecular alterations in 73% of never-smokers, 35% of men and 8% of women were exposed to at least one occupational carcinogen. We report herein associations between molecular patterns and occupational exposure.BioCAST was a cohort study of lung cancer in never-smokers that reported risk factor exposure and molecular patterns. Occupational exposure was assessed via a validated 71-item questionnaire. Patients were categorised into groups that were unexposed and exposed to polycyclic aromatic hydrocarbons (PAH), asbestos, silica, diesel exhaust fumes (DEF), chrome and paints. Test results were recorded for EGFR, KRAS, HER2, BRAF and PIK3 mutations, and ALK alterations.Overall, 313 out of 384 patients included in BioCAST were analysed. Asbestos-exposed patients displayed a significantly lower rate of EGFR mutations (20% versus 44%, p=0.033), and a higher rate of HER2 mutations (18% versus 4%, p=0.084). ALK alterations were not associated with any occupational carcinogens. The DEF-exposed patients were diagnosed with a BRAF mutation in 25% of all cases. Chrome-exposed patients exhibited enhanced HER2 and PIK3 mutation frequency.Given its minimal effects in the subgroups, we conclude that occupational exposure slightly affects the molecular pattern of lung cancers in never-smokers. In particular, asbestos-exposed patients have a lower chance of EGFR mutations.
European Respiratory Journal

hal-01647080
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01647080
DOI : 10.1183/13993003.00716-2017
PUBMED : 29074543

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Bronchoalveolar lavage (BAL) is a major diagnostic tool in lung diseases, including viral respiratory infections. We aimed to better define the situations where viral tests should be performed on BAL fluid (BALF). We retrospectively studied all cases where viral tests [immunofluorescence, immunocytochemistry, viral culture, and/or polymerase chain reaction (PCR)] were performed on BALF during a period of 1 year (2008) in our institution. We compared the characteristics of patients with virus-positive versus virus-negative BALF. Of the 636 BALF samples sent to the microbiology laboratory, 232 underwent viral tests. Of these, 70 (30 %) were positive and identified 85 viruses: herpes simplex virus (HSV)-1 (n = 27), cytomegalovirus (CMV, n = 23), Epstein-Barr virus (EBV, n = 18), human herpesvirus (HHV)-6 (n = 12), respiratory syncytial virus (RSV, n = 3), rhinovirus (n = 1), and adenovirus (n = 1). The variables associated with positive viral tests on univariate analysis were immunosuppression [human immunodeficiency virus (HIV), corticosteroids >10 mg/day for ≥3 weeks, or other immunosuppressive therapy], ground-glass attenuations on computed tomography (CT) scanning, late-onset ventilator-associated pneumonia (VAP), and durations of (i) hospital stay, (ii) intensive care unit (ICU) stay, and (iii) mechanical ventilation before BAL (p < 0.01 for each comparison). On multivariate analysis, only immunosuppression [odds ratio (OR) 6.4, 95 % confidence interval (CI) [2.8-14.3], p < 0.0001] and ground-glass attenuations (OR 3.7, 95 % CI [1.8-7.7], p = 0.0004) remained associated with virus-positive BAL. None of the viral tests performed on BALF for the initial assessment of diffuse infiltrative lung disease (n = 15) was positive. PCR improved the diagnostic yield of viral tests on BALF by 50 %. Testing for viruses on BALF should be mostly restricted to immunocompromised patients with acute respiratory diseases and/or patients with unexplained ground-glass attenuations on CT scanning.
ISSN: 0934-9723

hal-00873158
https://hal.archives-ouvertes.fr/hal-00873158
DOI : 10.1007/s10096-012-1791-7
PUBMED : 23238685

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Socioeconomic inequalities in cancer mortality have been observed in different European countries and the US until the end of the 1990s, with changes over time in the magnitude of these inequalities and contrasted situations between countries. The aim of this study is to estimate relative and absolute educational differences in cancer mortality in France between 1999 and 2007, and to compare these inequalities with those reported during the 1990s. METHODS: Data from a representative sample including 1% of the French population were analysed. Educational differences among people aged 30--74 were quantified with hazard ratios and relative indices of inequality (RII) computed using Cox regression models as well as mortality rate difference and population attributable fraction. RESULTS: In the period 1999--2007, large relative inequalities were found among men for total cancer and smoking and/or alcohol related cancers mortality (lung, head and neck, oesophagus). Among women, educational differences were reported for total cancer, head and neck and uterus cancer mortality. No association was found between education and breast cancer mortality. Slight educational differences in colorectal cancer mortality were observed in men and women. For most frequent cancers, no change was observed in the magnitude of relative inequalities in mortality between the 1990s and the 2000s, although the RII for lung cancer increased both in men and women. Among women, a large increase in absolute inequalities in mortality was observed for all cancers combined, lung, head and neck and colorectal cancer. In contrast, among men, absolute inequalities in mortality decreased for all smoking and/or alcohol related cancers. CONCLUSION: Although social inequalities in cancer mortality are still high among men, an encouraging trend is observed. Among women though, the situation regarding social inequalities is less favourable, mainly due to a health improvement limited to higher educated women. These inequalities may be expected to further increase in future years.
ISSN: 1471-2458

inserm-00868759
http://www.hal.inserm.fr/inserm-00868759
http://www.hal.inserm.fr/inserm-00868759/document
http://www.hal.inserm.fr/inserm-00868759/file/1471-2458-13-823.pdf
DOI : 10.1186/1471-2458-13-823

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Lung diseases are aggravated by exposure to diesel exhaust particles (DEPs) found in air pollution. Macrophages are thought to play a crucial role in lung immune response to these pollutants, even if the mechanisms involved remain incompletely characterized. In the present study, we demonstrated that classically and alternative human macrophages (MΦ) exhibited increased secretion of PDGF-B in response to DEP extract (DEPe). This occurred via aryl hydrocarbon receptor (AhR)-activation because DEPe-induced PDGF-B overexpression was abrogated after AhR expression knock-down by RNA interference, in both M1 and M2 polarizing MΦ. In addition, TCDD and benzo(a)pyrene, two potent AhR ligands, also significantly increased mRNA expression of PDGF-B in M1 MΦ, whereas some weak ligands of AhR did not. We next evaluated the impact of conditioned media (CM) from MΦ culture exposed to DEPe or of recombinant PDGF-B onto lung fibroblast proliferation. The tyrosine kinase inhibitor, AG1295, prevents phosphorylations of PDGF-Rβ, AKT and ERK1/2 and the proliferation of MRC5 fibroblasts induced by recombinant PDGF-B and by CM from M1 polarizing MΦ, strongly suggesting that the PDGF-BB secreted by DEPe-exposed MΦ is sufficient to activate the PDGF-Rβ pathway of human lung fibroblasts. In conclusion, we demonstrated that human MΦ, whatever their polarization status, secrete PDGF-B in response to DEPe and that PDGF-B is a target gene of AhR. Therefore, induction of PDGF-B by DEP may participate in the deleterious effects towards human health triggered by such environmental urban contaminants.
ISSN: 0041-008X

hal-01146840
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146840
DOI : 10.1016/j.taap.2015.04.007
PUBMED : 25896968

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
Alveolar proteinosis (AP) is a rare disease characterized by alveolar accumulation of surfactant components, which impairs gas exchange. AP is classified into three groups: auto-immune AP defined by the presence of plasma autoantibodies anti-GM-CSF, the most frequent form (90 % of all AP); secondary AP, mainly occurring as a consequence of haematological diseases, or following on from toxic inhalation or infections, and genetic AP, which affects almost exclusively children. AP diagnosis is suspected where chest CT-scan demonstrates interstitial lung disease with a crazy paving aspect; and confirmed by bronchoalveolar lavage, which has a milky appearance and contains periodic acid Schiff positive proteinaceous alveolar deposits. The use of surgical lung biopsy to confirm AP is less frequent nowadays. In this context, positive antibodies against GM-CSF indicates an auto-immune etiology of the AP. Concerning management, whole lung lavage is the gold standard therapy. In refractory AP, new treatments are available such as subcutaneous or inhaled GM-CSF supplementation, or rituximab infusions. The clinical course is unpredictable. Spontaneous improvement or even cure can occur, and the 5-year actuarial survival is 95 %. The most frequent complications are infectious etiology.
La protéinose alvéolaire pulmonaire (PAP) est une maladie rare caractérisée par l’accumulation alvéolaire de composants du surfactant qui gêne les échanges gazeux. Les PAP sont séparées en trois groupes : les PAP auto-immunes caractérisées par la présence d’anticorps sériques anti-GM-CSF qui sont les plus fréquentes ; les PAP secondaires à une maladie sous-jacente, le plus souvent hématologique, mais aussi à l’inhalation de toxiques et à des infections ; enfin, les PAP d’origine génétique. Le diagnostic de PAP est évoqué sur le scanner thoracique avec une pneumopathie infiltrante diffuse ayant un aspect classique de crazy paving, puis confirmé par l’aspect laiteux du lavage bronchoalvéolaire, et la présence de matériel lipoprotéinacé PAS positif. La confirmation du diagnostic de PAP par biopsie pulmonaire chirurgicale est désormais rarement nécessaire. La positivité des anticorps sériques anti-GM-CSF signe le caractère auto-immun de la maladie. Le traitement de référence des PAP auto-immunes est le « grand lavage pulmonaire thérapeutique ». En cas de maladie réfractaire, d’autres traitements sont disponibles, tels que le GM-CSF en injection sous-cutanée ou en aérosol et le rituximab. L’évolution de la maladie est imprévisible. Une évolution spontanément favorable ou même une guérison spontanée peuvent survenir et la survie actuarielle à 5 ans est de 95 %. Les principales complications sont infectieuses.
ISSN: 0761-8425

hal-01085907
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01085907
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01085907/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01085907/file/Prot%C3%A9inose%20alv%C3%A9olaire%20pulmonaire_accepted.pdf
DOI : 10.1016/j.rmr.2014.08.009

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells
ISSN: 2045-2322

hal-01165439
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439/file/TP53%20transcription%20factor.pdf
DOI : 10.1038/srep10356

Éditeur(s) : HAL CCSD BMJ Publishing Group
Résumé : International audience
OBJECTIVE: To investigate the role of occupational exposure to chlorinated solvents in lung cancer aetiology. METHODS: ICARE (Investigation of occupational and environmental CAuses of REspiratory cancers) is a French, multicentre, population-based, case-control study. Information on the lifelong work history of 2926 cases and 3555 controls was collected using standardised questionnaires. Occupational exposures were assessed using job-exposure matrices for five chlorinated solvents. Solvents were studied separately and in combinations. ORs were computed using unconditional logistic regression models adjusted for classic risk factors, including a history of cigarette smoking and exposure to asbestos. Adjustment for socioeconomic status (SES) was also made. RESULTS: After adjustment for exposure to asbestos, we observed a positive, statistically significant association with lung cancer for men and women exposed to a combination of perchloroethylene (PCE), trichloroethylene and dichloromethane (DCM). Further adjustment for SES slightly decreased this association. In contrast, no statistically significant associations were found for other solvent combinations. CONCLUSIONS: These results suggest that exposure to PCE may constitute a risk factor for lung cancer, especially among women, who seem to have a higher prevalence of exposure than men.
ISSN: 1351-0711

hal-01063908
https://hal.archives-ouvertes.fr/hal-01063908
DOI : 10.1136/oemed-2014-102182
PUBMED : 25015929

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The heterodimeric L-type amino acid transporter (LAT) 1/ CD98hc is overexpressed in lung cancers with a poor prognosis factor. Factors that contribute to LAT1/CD98hc overexpression in lung cells remain however to be determined, but the implication of atmospheric pollution can be suspected. The present study was therefore designed to analyze the effects of diesel exhaust particle (DEP) extract (DEPe) on LAT1/CD98hc expression in bronchial epithelial BEAS-2B cells. Exposure to DEPe up-regulated LAT1 and CD98hc mRNA levels in a concentration-dependent manner, with DEPe EC50 values (around 0.2 μg/mL) relevant to environmental situations. DEPe concomitantly induced LAT1/CD98hc protein expression and LAT1-mediated leucine accumulation in BEAS-2B cells. Inhibition of the aryl hydrocarbon receptor (AhR) pathway through the use of a chemical AhR antagonist or the siRNA-mediated silencing of AhR expression was next found to prevent DEPe-mediated induction of LAT1/CD98hc, indicating that this regulation depends on AhR, known to be activated by major chemical DEP components like polycyclic aromatic hydrocarbons. DEPe exposure was finally shown to induce mRNA expression and activity of matrix metalloproteinase (MMP)-2 in BEAS-2B cells, in a CD98hc/focal adhesion kinase (FAK)/extracellular regulated kinase (ERK) manner, thus suggesting that DEPe-mediated induction of CD98hc triggers activation of the integrin/FAK/ERK signaling pathway known to be involved in MMP-2 regulation. Taken together, these data demonstrate that exposure to DEPe induces functional overexpression of the amino acid transporter LAT1/CD98h in lung cells. Such a regulation may participate to pulmonary carcinogenic effects of DEPs, owing to the well-documented contribution of LAT1 and CD98hc to cancer development.
ISSN: 0041-008X

hal-01237095
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237095
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237095/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237095/file/Aryl%20hydrocarbon%20receptor-dependent%20up-regulation_accepted.pdf
DOI : 10.1016/j.taap.2015.11.014