Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial

BACKGROUND: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS: In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256. FINDINGS: 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0·0001) and non-haematological adverse events (26 events vs 186 events; p<0·0001) occurred in the sequential group than in the combination group. INTERPRETATION: Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer. FUNDING: Sanofi-Aventis France

Genetic polymorphisms and susceptibility to lung disease

Susceptibility to infection by bacterium such as Bacillus anthracis has a genetic basis in mice and may also have a genetic basis in humans. In the limited human cases of inhalation anthrax, studies suggest that not all individuals exposed to anthrax spores were infected, but rather, individuals with underlying lung disease, particularly asthma, sarcoidosis and tuberculosis, might be more susceptible. In this study, we determined if polymorphisms in genes important in innate immunity are associated with increased susceptibility to infectious and non-infectious lung diseases, particularly tuberculosis and sarcoidosis, respectively, and therefore might be a risk factor for inhalation anthrax. Examination of 45 non-synonymous polymorphisms in ten genes: p47phox (NCF1), p67phox (NCF2), p40phox (NCF4), p22phox (CYBA), gp91phox (CYBB), DUOX1, DUOX2, TLR2, TLR9 and alpha 1-antitrypsin (AAT) in a cohort of 95 lung disease individuals and 95 control individuals did not show an association of these polymorphisms with increased susceptibility to lung disease

Mechanisms of the noxious inflammatory cycle in cystic fibrosis

Multiple evidences indicate that inflammation is an event occurring prior to infection in patients with cystic fibrosis. The self-perpetuating inflammatory cycle may play a pathogenic part in this disease. The role of the NF-κB pathway in enhanced production of inflammatory mediators is well documented. The pathophysiologic mechanisms through which the intrinsic inflammatory response develops remain unclear. The unfolded mutated protein cystic fibrosis transmembrane conductance regulator (CFTRΔF508), accounting for this pathology, is retained in the endoplasmic reticulum (ER), induces a stress, and modifies calcium homeostasis. Furthermore, CFTR is implicated in the transport of glutathione, the major antioxidant element in cells. CFTR mutations can alter redox homeostasis and induce an oxidative stress. The disturbance of the redox balance may evoke NF-κB activation and, in addition, promote apoptosis. In this review, we examine the hypotheses of the integrated pathogenic processes leading to the intrinsic inflammatory response in cystic fibrosis

An international randomized study of a home-based self-management program for severe COPD: the COMET

Jean Bourbeau,1 Pere Casan,2 Silvia Tognella,3 Peter Haidl,4 Joëlle B Texereau,5,6 Romain Kessler7 On behalf of the COMET investigators 1Respiratory Epidemiology and Clinical Research Unit, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada; 2Hospital Universitario Central de Asturias, Facultad de Medicina, Oviedo, Spain; 3Lung Department, Ospedale Orlandi, Bussolengo VR, Italy; 4Krankenhaus Kloster Grafschaft, Schmallenberg, Germany; 5Air Liquide Healthcare, Medical Research and Development, Jouy-en-Josas, 6Assistance Publique-Hôpitaux de Paris, Service de Physiologie Clinique, Hôpital Cochin, Paris, 7Department of Pulmonary Medicine, Translational Medicine Federation of Strasbourg, University Hospital of Strasbourg, Strasbourg, France Introduction: Most hospitalizations and costs related to COPD are due to exacerbations and insufficient disease management. The COPD patient Management European Trial (COMET) is investigating a home-based multicomponent COPD self-management program designed to reduce exacerbations and hospital admissions.Design: Multicenter parallel randomized controlled, open-label superiority trial.Setting: Thirty-three hospitals in four European countries.Participants: A total of 345 patients with Global initiative for chronic Obstructive Lung Disease III/IV COPD.Intervention: The program includes extensive patient coaching by health care professionals to improve self-management (eg, develop skills to better manage their disease), an e-health platform for reporting frequent health status updates, rapid intervention when necessary, and oxygen therapy monitoring. Comparator is the usual management as per the center’s routine practice.Main outcome measures: Yearly number of hospital days for acute care, exacerbation number, quality of life, deaths, and costs. Keywords: COPD, disease management, exacerbations, hospitalization, home care, clinical tria

The group B Streptococcus NADH oxidase Nox-2 is involved in fatty acid biosynthesis during aerobic growth and contributes to virulence

Numerous Streptococcaceae produce an H2O-forming NADH oxidase, Nox-2, which has been generally implicated in aerobic survival. We examined the roles of Nox-2 in Group B Streptococcus (GBS), a leading agent of neonatal infections. While nox2 inactivation caused an aerobic growth arrest, no improvement was seen by addition of antioxidants to cultures, suggesting that this defect was not due to accumulation of toxic oxygen species. Using several approaches, we show that the observed inability of the nox2 mutant to grow aerobically is mainly due to an underlying defect in fatty acid (FA) biosynthesis: (i) the nox2 aerobic growth defect is fully and rapidly complemented by adding oleic acid to culture medium, and (ii) direct assimilation of this unsaturated FA in both wild type (WT) and nox2 GBS membranes is demonstrated and correlated with mutant growth rescue. We propose that NAD+ depletion in the nox2 mutant results in reduced acetyl-CoA production, which perturbs FA biosynthesis and hence blocks growth in aerobiosis. The nox2 aerobic growth defect was also complemented when GBS respiration metabolism was activated by exogenous haem and menaquinone. The membrane NADH oxidase activity generated by the functional respiratory chain thus compensates the cytoplasmic NADH oxidase deficiency. The nox2 mutant was attenuated for virulence, as assessed in lung, intraperitoneal and intravenous murine infection models. As the nox2 defect seems only to affect aerobic growth of GBS, its reduced virulence supports the suggestion that aerobic conditions and NADH oxidase activities are relevant to the GBS infection process

Loss of SMARCB1 expression in colon carcinoma

International audienceSMARCB1 is a tumor suppressor gene, which is part of SWI/SNF complex involved in transcriptional regulation. Recently, loss of SMARCB1 expression has been reported in gastrointestinal carcinomas. Our purpose was to evaluate the incidence and prognostic value of SMARCB1 loss in colon carcinoma (CC). Patients with stage III CC (n = 1695), and a second cohort of 23 patients with poorly differentiated CC were analyzed. Immunohistochemistry for SMARCB1 was performed on tissue microarrays, and cases with loss of expression were controlled on whole sections. Loss of SMARCB1 was compared with the clinico-pathological and molecular characteristics, and the prognostic value was evaluated. Loss of SMARCB1 was identified in 12 of 1695 (0.7%) patients with stage III CC. Whole section controls showed a complete loss in only one of these cases, corresponding to a medullary carcinoma. SMARCB1 loss was not associated with histological grade, tumor size nor survival. In the cohort of poorly differentiated CC, we detected 2/23 (8.7%) cases with loss of SMARCB1; one was rhabdoid while the other had medullary and mucinous histology. These 2 cases were deficient for MisMatched Repair (dMMR) and mutated for BRAF. SMARCB1 loss is rare in stage III CC, but appears more frequent in poorly differentiated CC