Diagnosis and Pharmacotherapy of Stable Chronic Obstructive Pulmonary Disease : The Finnish Guidelines

Peer reviewe

Inhaled corticosteroids for chronic obstructive pulmonary disease-the shifting treatment paradigm

Chronic obstructive pulmonary disease (COPD) guidelines suggest using inhaled corticosteroids (ICS) in patients with severe airflow limitation or those at high risk of exacerbations. This recommendation is based on evidence demonstrating that ICS, especially when prescribed in fixed-dose combinations (FDC) with long-acting β2 agonists (LABA), improve quality of life (QoL), decrease exacerbations and hospitalisations, and have been associated with a trend towards a reduction in all-cause mortality. Audit shows that routine prescribing practice frequently uses inhaler therapies outside current guidelines recommendations; severe to very severe disease constitutes about 20% of all COPD patients, but up to 75% of COPD patients are prescribed an ICS, with significant numbers given ICS/LABA as first-line maintenance therapy. The role of ICS in the treatment paradigm for COPD is changing, driven by the growing evidence of increased risk of pneumonia, and the introduction of a new class of FDC; LABA and long-acting muscarinic antagonists (LAMA), which simplify dual bronchodilation and present a plausible alternative therapy. As the evidence base for dual therapy bronchodilation expands, it is likely that maximal bronchodilation will move up the treatment algorithm and ICS reserved for those with more severe disease who are not controlled on dual therapy. This change has already manifested in local COPD algorithms, such as those at Tayside, and represents a significant change in recommended prescribing practice. This review reassesses the role of ICS in the shifting treatment paradigm, in the context of alternative treatment options that provide maximal bronchodilation

High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease

BACKGROUND: The complexity of chronic diseases is a challenge for investigators conducting randomized trials. The causes for this include the often difficult control for confounding, the selection of outcomes from many potentially important outcomes, the risk of missing data with long follow-up and the detection of heterogeneity of treatment effects. Our aim was to assess such aspects of trial design and analysis for four prevalent chronic diseases. METHODS: We included 161 randomized trials on drug and non-drug treatments for chronic obstructive pulmonary disease, type 2 diabetes mellitus, stroke and heart failure, which were included in current Cochrane reviews. We assessed whether these trials defined a single outcome or several primary outcomes, statistically compared baseline characteristics to assess comparability of treatment groups, reported on between-group comparisons, and we also assessed how they handled missing data and whether appropriate methods for subgroups effects were used. RESULTS: We found that only 21% of all chronic disease trials had a single primary outcome, whereas 33% reported one or more primary outcomes. Two of the fifty-one trials that tested for statistical significance of baseline characteristics adjusted the comparison for a characteristic that was significantly different. Of the 161 trials, 10% reported a within-group comparison only; 17% (n = 28) of trials reported how missing data were handled (50% (n = 14) carried forward last values, 27% (n = 8) performed a complete case analysis, 13% (n = 4) used a fixed value imputation and 10% (n = 3) used more advanced methods); and 27% of trials performed a subgroup analysis but only 23% of them (n = 10) reported an interaction test. Drug trials, trials published after wide adoption of the CONSORT (CONsolidated Standards of Reporting Trials) statement (2001 or later) and trials in journals with higher impact factors were more likely to report on some of these aspects of trial design and analysis. CONCLUSION: Our survey showed that an alarmingly large proportion of chronic disease trials do not define a primary outcome, do not use appropriate methods for subgroup analyses, or use naïve methods to handle missing data, if at all. As a consequence, biases are likely to be introduced in many trials on widely prescribed treatments for patients with chronic disease

Gene expression profiling of liver metastases from colorectal cancer as potential basis for treatment choice

At present no reports on gene expression profiling of liver metastases from colorectal cancer are available. We identified two different signatures using Affymetrix platform: epidermal growth factor receptor pathway was upregulated in metachronous lesions, whereas the pathway mainly related to angiogenesis was in synchronous lesions. Synchronous or metachronous liver metastases could be treated differently on the basis of different molecular pathways

Importance of the Collagen Adhesin Ace in Pathogenesis and Protection against Enterococcus faecalis Experimental Endocarditis

Ace is an adhesin to collagen from Enterococcus faecalis expressed conditionally after growth in serum or in the presence of collagen. Here, we generated an ace deletion mutant and showed that it was significantly attenuated versus wild-type OG1RF in a mixed infection rat endocarditis model (P<0.0001), while no differences were observed in a peritonitis model. Complemented OG1RFΔace (pAT392::ace) enhanced early (4 h) heart valve colonization versus OG1RFΔace (pAT392) (P = 0.0418), suggesting that Ace expression is important for early attachment. By flow cytometry using specific anti-recombinant Ace (rAce) immunoglobulins (Igs), we showed in vivo expression of Ace by OG1RF cells obtained directly from infected vegetations, consistent with our previous finding of anti-Ace antibodies in E. faecalis endocarditis patient sera. Finally, rats actively immunized against rAce were less susceptible to infection by OG1RF than non-immunized (P = 0.0004) or sham-immunized (P = 0.0475) by CFU counts. Similarly, animals given specific anti-rAce Igs were less likely to develop E. faecalis endocarditis (P = 0.0001) and showed fewer CFU in vegetations (P = 0.0146). In conclusion, we have shown for the first time that Ace is involved in pathogenesis of, and is useful for protection against, E. faecalis experimental endocarditis

The molecular basis of chemoradiosensitivity in rectal cancer:implications for personalized therapies

Preoperative chemoradiotherapy represents the standard treatment for patients with locally advanced rectal cancer. Unfortunately, the response of individual tumors to multimodal treatment is not uniform and ranges from complete response to complete resistance. This poses a particular problem for patients with a priori resistant tumors because they may be exposed to irradiation and chemotherapy, treatment regimens that are both expensive and at times toxic, without benefit. Accordingly, there is a strong need to establish molecular biomarkers that predict the response of an individual patient's tumor to multimodal treatment and that indicate treatment-associated toxicities prior to therapy. Such biomarkers may guide clinicians in choosing the best possible treatment for each individual patient. In addition, these biomarkers could be used to identify novel molecular targets and thereby assist in implementing novel strategies to sensitize a priori resistant tumors to multimodal treatment regimens. The aim of this review is to summarize recent findings about the molecular basis of treatment resistance and treatment toxicity in patients with rectal cancer. Whole-genome, as well as single-biomarker or multibiomarker, analyses and their potential implications will be highlighted. At the end, we will outline a future vision of rectal cancer treatment in the era of personalized medicine.Deutsche Forschungsgemeinschaft [KFO179

Magnesium nebulization utilization in management of pediatric asthma (MagNUM PA) trial: study protocol for a randomized controlled trial

BACKGROUND: Up to 30 % of children with acute asthma are refractory to initial therapy, and 84 % of this subpopulation needs hospitalization. Finding safe, noninvasive, and effective strategies to treat this high-risk group would substantially decrease hospitalizations, healthcare costs, and the psycho-social burden of the disease. Whereas intravenous magnesium (Mg) is effective in severe refractory asthma, its use is sporadic due to safety concerns, with the main treatment goal being to prevent intensive care unit admission. In contrast, nebulized Mg is noninvasive, allows higher pulmonary drug concentrations, and has a much higher safety potential due to the lower rate of systemic delivery. Previous studies of inhaled Mg show disparate results due to the use of unknown/inefficient delivery methods and other methodological flaws. METHODS/DESIGN: The study is a randomized double-blind controlled trial in seven Canadian pediatric Emergency Departments (two-center pilot 2011 to 2014, Canada-wide November 2014 to December 2017). The trial will include 816 otherwise healthy children who are 2 to 17 years old, having had at least one previous wheezing episode, have received systemic corticosteroids, and have a Pediatric Respiratory Assessment Measure (PRAM) ≥ 5 points after three salbutamol and ipratropium treatments for a current acute asthma exacerbation. Eligible consenting children will receive three experimental treatments of nebulized salbutamol with either 600 mg of Mg sulfate or placebo 20 min apart, using an Aeroneb Go nebulizer, which has been shown to maximize pulmonary delivery while maintaining safety. The primary outcome is hospitalization within 24 h of the start of the experimental therapy for persistent respiratory distress or supplemental oxygen. Secondary outcomes include all-cause hospitalization within 24 h, PRAM, vital signs, number of bronchodilator treatments by 240 min, and the association between the difference in the primary outcome between the groups, age, gender, baseline PRAM, atopy, and “viral induced wheeze” phenotype (Fig. 1). DISCUSSION: If effective, inhaled Mg may represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Unlike previous works, this trial targets nonresponders to optimized initial therapy who are the most likely to benefit from inhaled Mg. Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication. TRIAL REGISTRATION: NCTO1429415, registered 2 September 2011. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-015-1151-x) contains supplementary material, which is available to authorized users