Outpatient management of cancer-associated pulmonary embolism: A post-hoc analysis from the HOME-PE trial.

INTRODUCTION: Cancer-related pulmonary embolism (PE) is associated with poor prognosis. Some decision rules identifying patients eligible for home treatment categorize cancer patients at high risk of complications, precluding home treatment. We sought to assess the effectiveness and the safety of outpatient management of patients with low-risk cancer-associated PE. METHODS: In the HOME-PE trial, hemodynamically stable patients with symptomatic PE were randomized to either triaging with Hestia criteria or sPESI score. We analyzed 3 groups of low-risk PE patients: 47 with active cancer treated at home (group 1), 691 without active cancer treated at home (group 2), and 33 with active cancer as the only sPESI criterion qualifying them for hospitalization (group 3). The main outcome was the composite of recurrent venous thromboembolism, major bleeding, and all-cause death within 30 days after randomization. RESULTS: Patients treated at home had composite outcome rates of 4.3 % (2/47) for those with cancer vs. 1.0 % (7/691) for those without (odds ratio (OR) 4.98, 95%CI 1.15-21.49). Patients with cancer had rates of complications of 4.3 % when treated at home vs. 3.0 % (1/33) when hospitalized (OR 1.19, 95%CI 0.15-9.47). In multivariable analysis, active cancer was associated with an increased risk of complications for patients treated at home (OR 7.95; 95%CI 1.48-42.82). For patients with active cancer, home treatment was not associated with the primary outcome (OR 1.19, 95%CI 0.15-9.74). CONCLUSIONS: Among patients treated at home, active cancer was a risk factor for complications, but among patients with active cancer, home treatment was not associated with adverse outcomes.

The Adverse Drug Reactions From Patient Reports in Social Media Project: Protocol for an Evaluation Against a Gold Standard.

BACKGROUND: Social media is a potential source of information on postmarketing drug safety surveillance that still remains unexploited nowadays. Information technology solutions aiming at extracting adverse reactions (ADRs) from posts on health forums require a rigorous evaluation methodology if their results are to be used to make decisions. First, a gold standard, consisting of manual annotations of the ADR by human experts from the corpus extracted from social media, must be implemented and its quality must be assessed. Second, as for clinical research protocols, the sample size must rely on statistical arguments. Finally, the extraction methods must target the relation between the drug and the disease (which might be either treated or caused by the drug) rather than simple co-occurrences in the posts. OBJECTIVE: We propose a standardized protocol for the evaluation of a software extracting ADRs from the messages on health forums. The study is conducted as part of the Adverse Drug Reactions from Patient Reports in Social Media project. METHODS: Messages from French health forums were extracted. Entity recognition was based on Racine Pharma lexicon for drugs and Medical Dictionary for Regulatory Activities terminology for potential adverse events (AEs). Natural language processing-based techniques automated the ADR information extraction (relation between the drug and AE entities). The corpus of evaluation was a random sample of the messages containing drugs and/or AE concepts corresponding to recent pharmacovigilance alerts. A total of 2 persons experienced in medical terminology manually annotated the corpus, thus creating the gold standard, according to an annotator guideline. We will evaluate our tool against the gold standard with recall, precision, and f-measure. Interannotator agreement, reflecting gold standard quality, will be evaluated with hierarchical kappa. Granularities in the terminologies will be further explored. RESULTS: Necessary and sufficient sample size was calculated to ensure statistical confidence in the assessed results. As we expected a global recall of 0.5, we needed at least 384 identified ADR concepts to obtain a 95% CI with a total width of 0.10 around 0.5. The automated ADR information extraction in the corpus for evaluation is already finished. The 2 annotators already completed the annotation process. The analysis of the performance of the ADR information extraction module as compared with gold standard is ongoing. CONCLUSIONS: This protocol is based on the standardized statistical methods from clinical research to create the corpus, thus ensuring the necessary statistical power of the assessed results. Such evaluation methodology is required to make the ADR information extraction software useful for postmarketing drug safety surveillance. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/11448.

Heme oxygenase-1 prevents airway mucus hypersecretion induced by cigarette smoke in rodents and humans.

We investigated the role of heme oxygenase-1 (HO-1), a powerful anti-inflammatory and anti-oxidant enzyme, in modulating cigarette smoke (CS)-induced mucus secretion. In both rats and mice, 5-day CS exposure increased HO-1 expression and activity, mucus secretion, MUCIN 5AC (MUC5AC) gene and protein expression, and local inflammation, along with up-regulation of dual oxidase 1 gene expression and both the activity and phosphorylation of the epidermal growth factor receptor, which is involved in MUC5AC induction. Pharmacological induction of HO-1 prevented these actions and inhibition of HO-1 expression by a specific siRNA potentiated them. In French participants to the European Community Respiratory Health Survey II (n = 210, 30 to 53 years of age, 50% males) exposed to CS, a significant increase in the percentage of participants with chronic sputum was observed in those harboring at least one allele with a long (GT)(n) in the HO-1 promoter gene (>33 repeats), which is associated with a low level of HO-1 protein expression, compared with those with a short number of (GT)n repeats (21.7% versus 8.6%, P = 0.047). No such results were observed in those who had never smoked (n = 297). We conclude that HO-1 has a significant protective effect against airway mucus hypersecretion in animals and humans exposed to CS.

Interaction between a heme oxygenase-1 gene promoter polymorphism and serum beta-carotene levels on 8-year lung function decline in a general population: the European Community Respiratory Health Survey (France).

Oxidative stress is thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease, characterized by impaired lung function. A large number (> or =33) of GT repeats (L-allele) in the gene of the powerful antioxidant enzyme heme oxygenase-1 has been associated with susceptibility to accelerated lung function decline. In contrast, beta-carotene may help to protect against accelerated decline. To determine whether high serum levels of beta-carotene might counterbalance the greater susceptibility of L-allele carriers, the authors analyzed the annual decline in forced expiratory volume in 1 second (FEV1) in a general population sample of 523 French subjects (20-44 years, 50% men) examined in 1992 and 2000 as part of the European Community Respiratory Health Survey. Analysis of covariance, adjusted for sex as well as baseline age, body mass index, smoking, and FEV1, showed that, among subjects with low beta-carotene levels, L-allele carriers experienced a steeper mean FEV1 decline than did noncarriers (mean = -58.8, 95% confidence interval: -73.2, -44.5 vs. mean = -34.7, 95% confidence interval: -38.9, -29.8 ml/year) (p = 0.009), whereas among subjects with high beta-carotene levels, the FEV1 decline was not different in L-allele carriers and noncarriers (two-sided p = 0.9). The results suggest that high levels of beta-carotene might counterbalance the effects on FEV1 decline of a genetically determined deficiency in antioxidant response.

ETB receptor polymorphism is associated with airway obstruction.

BACKGROUND: Endothelin-1 (EDN1) has been involved in the development of airway obstruction and inflammation in asthma. Several polymorphisms have been identified among the genes encoding for preproET1, an inactive precursor of ET-1, and for ETA (EDNRA) and ETB (EDNRB), the two receptors for EDN1. In the present work, we hypothesised that molecular variation in these genes could be a major determinant of the degree of bronchial obstruction. The purpose of this study was to investigate whether the genetic polymorphisms of preproET-1, EDNRA and EDNRB genes were associated with the degree of airway obstruction, assessed by FEV1. METHODS: Polymorphisms of preproET-1, EDNRA and EDNRB were first studied in a population of adult asthmatic patients. Results were confirmed in a large population of adults from the general population from the ECRHS II study. RESULTS: In our population of adult asthmatic patients, the EDNRB-30G>A (Leu277Leu) polymorphism (GG genotype) is strongly associated with a low FEV1 and with a higher percentage of patients with FEV1 < 80% of predicted value. No relationship was found between pulmonary function and EDNRA-1363C>T (His323His) or preproET-1-595G>T (Lys198Asp) polymorphism. In the adult population from the ECRHS II, we found a similar association between GG genotype and a low FEV1 or a higher percentage of subjects with FEV1 < 80% predicted, especially in the subgroups of asthmatics subjects (OR = 4.31 (95%CI 1.03 - 18.04)) and smokers (OR = 7.42 (95%CI 1.69 - 32.6)). CONCLUSION: the EDNRB-30G>A polymorphism could be a determinant of airway obstruction in humans with predisposing factors such as tobacco smoke exposure or asthma.

Association between farm exposure and atopy, according to the CD14 C-159T polymorphism.

BACKGROUND: A higher exposure to bacterial compounds is purported to explain the lower prevalence of allergy in farm children, but responsiveness to bacterial compounds is modulated by genetic factors. OBJECTIVE: To assess whether the protective effect of farm exposure on atopy is influenced by a CD14 promoter functional polymorphism. METHODS: We administered a detailed questionnaire on farm exposure in childhood and genotyped the CD14 C-159T polymorphism in 2 French centers participating in the European Community Respiratory Health Survey (ECRHS)-II. RESULTS: Six hundred randomly selected young adults provided blood samples for IgE measurements and had CD14 C-159T genotyped. Exposure to a farming environment in early life was associated with a reduced risk of nasal allergies (odds ratio [OR], 0.54; 95% CI, 0.29-1.00) and atopic sensitization (OR, 0.47; 95% CI, 0.24-0.93) in adulthood. A lower risk of allergic rhinitis and atopy was also observed in carriers of the CD14-159TT genotype compared with -159CC subjects (OR, 0.52; 95% CI, 0.30-0.88; and OR, 0.54; 95% CI, 0.31-0.92, respectively). When farm exposure and CD14 C-159T were considered together, the risk of nasal allergies and atopy was the most reduced in the subjects who combined both an early-life exposure to a farming environment and the -159TT genotype (OR, 0.26; 95% CI, 0.07-0.94; and OR, 0.21; 95% CI, 0.05-0.93, respectively, vs nonexposed -159CC+CT subjects). The results were consistent in the 2 centers, supporting the validity of the results. CONCLUSION: A gene-by-environment interaction between CD14 C-159T and environmental exposure in childhood may modify the development of atopy. CLINICAL IMPLICATIONS: This polymorphism should be considered in interventions studies that use microbial stimuli to reduce sensitization.

[Association of lung function decline with the microsatellite polymorphism in the heme oxygenase-1 gene promoter, in a general population sample. Results from the Longitudinal European Community Respiratory Health Survey (ECRHS-France)]. / Association entre la diminution de la fonction pulmonaire et le polymorphisme du promoteur du gène de l'hème oxygénase chez des adultes jeunes issus de la population générale. Etude longitudinale européenne sur la santé respiratoire (ECRHS-France).

Heme oxygenase (HO1) acts against oxidants which are thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD). A (GT)n repeat polymorphism in the HO1 gene promoter can modulate the transcription of this gene in response to oxidative stress. We postulated that this polymorphism might be associated with the degree and decline of lung function in subjects exposed to oxidative stress (smokers). We genotyped 749 French subjects (20-44 years, 50% men, 40% never-smokers) who were examined in both 1992 and 2000 as part of the ECRHS. Lung function was assessed by measuring FEV1 (Forced Expiratory Volume in 1 second) and the FEV1/FVC (Forced Ventilatory Capacity) ratio. We compared long (L)-allele carriers ((GT)n > or = 33 repeats for one or two alleles) to non-carriers. During the 8-year study period, the mean annual FEV1 and FEV1/FVC declines were -30.9 +/- 31.1 ml/year and -1.8 +/- 6.1 units/year, respectively. The FEV1/FVC decline was steeper in L-allele carriers than in non-carriers (-2.6 +/- 5.5 vs -1.5 +/- 6.4, p = 0.07). There was a strong interaction between allele L and smoking. In 2000, allele L was associated with lower FEV1 and FEV1/FVC values in heavy smokers (J20 cig/day) only (p for the interactions, 0.07 and 0.002 respectively). Baseline heavy smokers carrying allele L showed the steepest FEV1 decline (-62.0 +/- 29.5 ml/year) and the steepest FEV1/FVC decline (-8.8 +/- 5.4 units/year) (p for the interactions, 0.009 and 0.0006). These results suggest that a long (L) HO1 gene promoter increases the risk of airway obstruction in heavy smokers.

Association between asthma and rhinitis according to atopic sensitization in a population-based study.

BACKGROUND: Although asthma and rhinitis often occur together, the reason for this common comorbidity is still a matter of debate. OBJECTIVE: We sought to assess whether the coexistence of asthma and rhinitis could be explained by common risk factors. METHODS: International cross-sectional study of representative samples of young adults, who completed a detailed questionnaire and underwent lung function tests, bronchoprovocation challenge, IgE measurements, and skin prick tests. RESULTS: In all countries, asthma and bronchial hyperreactivity were more frequent in subjects with rhinitis than in those without (odds ratio [OR], 6.63; 95% CI, 5.44-8.08; and OR, 3.02 95% CI, 2.66-3.43, respectively). Seventy-four percent to 81% of subjects with asthma reported rhinitis, depending on sensitization to specific allergens. Conversely, the risk of asthma increased from 2.0% in subjects without rhinitis to 6.7% in subjects with rhinitis only when exposed to pollen, 11.9% in subjects with rhinitis when exposed to animals, and 18.8% in subjects with rhinitis either when exposed to pollen or to animals. The association between rhinitis and asthma remained significant after adjustment for total IgE, parental history of asthma, and allergen sensitization (OR, 3.41; 95% CI, 2.75-4.2 suggesting that the coexistence of asthma and rhinitis is not solely due to atopic predisposition to these 2 diseases. CONCLUSIONS: Although there were some variations in the association between asthma and rhinitis according to sensitization to individual allergens, the strong association between asthma and rhinitis was not fully explained by shared risk factors, including atopy. Our findings are consistent with the hypothesis that rhinitis might increase the risk of asthma.