Efficacy of non-invasive intelligent volume assured pressure support (iVAPS) and pressure support ventilation (PSV) in clinical practice

Aims of the study: Noninvasive ventilation (NIV) is a well-established treatment option for hypercapnic respiratory failure; however, the best mode of ventilation remains unknown. The aim of this retrospective study was to compare patients’ adherence to NIV using either pressure support ventilation (PSV) or intelligent volume-assured pressure support (iVAPS). Patients and methods: In this retrospective cohort study, we assessed in- and outpatients suffering from hypercapnic respiratory failure of various aetiologies (chronic obstructive pulmonary disease [COPD], obese COPD [body mass index >30 kg/m2], obesity hypoventilation syndrome and other diseases such as amyotrophic lateral sclerosis or interstitial lung disease) after NIV initiation with PSV or iVAPS. Adherence to treatment was compared between these modes using the Wilcoxon test. Within-group differences were tested using linear regression models. Mortality and emergency hospital readmission rates were modelled using Kaplan-Meier estimates and Cox proportional hazards models. Results: Adherence to treatment was similar in both groups throughout the observation period – after 6 weeks: PSV 363 min/night (interquartile range [IQR] 200–448), iVAPS 369 min/night (IQR 310–468) (p = 0.619); after 1 year: PSV 423 (323–500), iVAPS 429 (298–475) (p = 0.901); at the last follow up: PSV 481 (395–586), iVAPS 426 (391–565) (p = 0.284). NIV reduced PaCO2 significantly compared with baseline at all follow-ups: PSV −1.29/−1.49/−1.49 kPa, iVAPS −1.47/−1.23/−1.24 kPa, p <0.001 each, PSV vs iVAPS: p = 0.250, 0.756 and 0.352, respectively. Median survival time (PSV 5.06 years, iVAPS median not reached; p = 0.800) and time to first readmission (PSV 3.6 years, iVAPS 7.33 years, p = 0.200) did not differ between groups. Obese COPD patients had a longer time to hospital readmission than lean COPD patients (3.8 vs 1.5 years, hazard ratio (HR) 0.39, 95% confidence interval [CI] 0.16–0. 74; p = 0.007). Good adherence (>4 h/night and >80% nightly usage) was associated with a lower mortality rate (HR 0.34, 95% CI 0.15–0.77; p = 0.010). Conclusion: In a real-world setting of a mixed population with hypercapnic respiratory failure, iVAPS and PSV seem to be similarly effective in improving gas exchange and demonstrate excellent adherence to treatment. A longer survival was noted in NIV-adherent patients. Randomised controlled studies are necessary to identify patients who might benefit more from hybrid ventilation modes

24h-gene variation effect of combined bevacizumab/erlotinib in advanced non-squamous non-small cell lung cancer using exon array blood profiling

Abstract Background The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy. Methods Blood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix’ exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset. Results Significant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on “Pathways in cancer”, by significantly down-regulating genes involved in cytokine–cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti-angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients’ response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE. Conclusions The 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole-genome exon arrays. Putative predictive markers at 24h could reflect patients’ response to BE after adjusting for their mutational status. Trial registration ClinicalTrials.gov: NCT0035454

Non-pharmaceutical interventions to optimize cancer immunotherapy

The traditional picture of cancer patients as weak individuals requiring maximum rest and protection is beginning to dissolve. Too much focus on the medical side and one’s own vulnerability and mortality might be counterproductive and not doing justice to the complexity of human nature. Unlike cytotoxic and lympho-depleting treatments, immune-engaging therapies strengthen the immune system and are typically less harmful for patients. Thus, cancer patients receiving checkpoint inhibitors are not viewed as being vulnerable per se, at least not in immunological and physical terms. This perspective article advocates a holistic approach to cancer immunotherapy, with an empowered patient in the center, focusing on personal resources and receiving domain-specific support from healthcare professionals. It summarizes recent evidence on non-pharmaceutical interventions to enhance the efficacy of immune checkpoint blockade and improve quality of life. These interventions target behavioral factors such as diet, physical activity, stress management, circadian timing of checkpoint inhibitor infusion, and waiving unnecessary co-medication curtailing immunotherapy efficacy. Non-pharmaceutical interventions are universally accessible, broadly applicable, instantly actionable, scalable, and economically sustainable, creating value for all stakeholders involved. Most importantly, this holistic framework re-emphasizes the patient as a whole and harnesses the full potential of anticancer immunity and checkpoint blockade, potentially leading to survival benefits. Digital therapeutics are proposed to accompany the patients on their mission toward change in lifestyle-related behaviors for creating optimal conditions for treatment efficacy and personal growth

Impact of laughter on air trapping in severe chronic obstructive lung disease

Static and dynamic hyperinflation is an important factor of exertional dyspnea in patients with severe COPD. This proof-of-concept intervention trial sought to study whether laughter can reduce hyperinflation through repetitive expiratory efforts in patients with severe COPD. For small groups of patients with severe COPD (n = 19) and healthy controls (n = 10) Pello the clown performed a humor intervention triggering regular laughter. Plethysmography was done before and up to 24 hours after intervention. Laughing and smiling were quantified with video-analysis. Real-time breathing pattern was assessed with the LifeShirt™, and the psychological impact of the intervention was monitored with self-administered questionnaires. The intervention led to a reduction of TLC in COPD (p = 0.04), but not in controls (p = 0.9). TLC reduction was due to a decline of the residual volume. Four (22 [CI 95% 7 to 46] %) patients were ≥10% responders. The frequency of smiling and TLC at baseline were independent predictors of TLC response. The humor intervention improved cheerfulness, but not seriousness nor bad mood. In conclusion, smiling induced by a humor intervention was able to reduce hyperinflation in patients with severe COPD. A smiling-derived breathing technique might complement pursed-lips breathing in patients with symptomatic obstruction

Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study

Objective To study the association between wheezy symptoms in young children and the presence of bacteria in the airways

Therapeutic bronchoscopy for malignant airway stenoses: Choice of modality and survival

Background: There are no data regarding the factors influencing the choice of therapeutic bronchoscopic modality in the management of malignant airway stenoses. Objectives: To assess the choice of therapeutic bronchoscopy modality and analyze factors influencing survival in patients with malignant central airway obstruction. Materials and Methods: We performed 167 procedures in 130 consecutive patients, for malignant central airway obstruction, over six years. Results: Laser was used either alone or in combination with stent insertion in 76% procedures. Laser only was used in 53% procedures for lesions below the main bronchi. Stents alone were used for extrinsic compression or stump insufficiency. Combined laser and stent insertion was most frequently used for lesions involving the trachea plus both main bronchi or only the main bronchi. The Dumon stent was preferred in lesions of the trachea and the right bronchial tree, the Ultraflex stent for lesions on the left side and stenoses below the main bronchi. Survival was better in patients with lung cancer, lesions restricted to one lung and when laser alone was used compared to esophageal cancer, metastases and tracheal involvement. Conclusion: The choice of different airway stents can be made based on the nature and site of the lesion. Dumon stents are suited for lesions in trachea and right main bronchus and the Ultraflex stents on the left side and stenoses beyond the main bronchi. Survival can be estimated based on the diagnosis, site of the lesion and treatment modality used

Stability of gene contributions and identification of outliers in multivariate analysis of microarray data

BACKGROUND: Multivariate ordination methods are powerful tools for the exploration of complex data structures present in microarray data. These methods have several advantages compared to common gene-by-gene approaches. However, due to their exploratory nature, multivariate ordination methods do not allow direct statistical testing of the stability of genes. RESULTS: In this study, we developed a computationally efficient algorithm for: i) the assessment of the significance of gene contributions and ii) the identification of sample outliers in multivariate analysis of microarray data. The approach is based on the use of resampling methods including bootstrapping and jackknifing. A statistical package of R functions was developed. This package includes tools for both inferring the statistical significance of gene contributions and identifying outliers among samples. CONCLUSION: The methodology was successfully applied to three published data sets with varying levels of signal intensities. Its relevance was compared with alternative methods. Overall, it proved to be particularly effective for the evaluation of the stability of microarray data

Effect of a 14-day course of systemic corticosteroids on the hypothalamic-pituitary-adrenal-axis in patients with acute exacerbation of chronic obstructive pulmonary disease

<p/> <p>Background</p> <p>As supra-physiological intake of corticosteroids is a well known risk factor for the development of adrenal insufficiency, we investigated the function of the hypothalamic-pituitary-adrenal (HPA) axis during a 14-day course of systemic corticosteroids in patients with acute exacerbation of chronic obstructive pulmonary disease using clinical and laboratory measures.</p> <p>Methods</p> <p>A systematic clinical and laboratory assessment including measurement of basal cortisol levels and the response to low dose (1 μg) ACTH stimulation was performed in nine patients before, on the first and the last day of treatment, as well as 2, 7 and 21 days after corticosteroid withdrawal.</p> <p>Results</p> <p>At baseline, all nine patients had normal responses to 1 μg ACTH. On the first day of steroid treatment, 78% had a blunted peak cortisol response. This percentage increased to 89% after 14 days of steroid treatment. 78%, 33% and 33% of the patients had a blunted cortisol response to ACTH 2, 7, and 21 days after corticosteroid withdrawal, respectively. ROC curve analysis revealed that only basal cortisol concentrations (AUC 0.89), but not ACTH concentrations (AUC 0.49) or clinical signs (AUC 0.47) were predictive of an impaired function of the HPA axis. Basal cortisol levels of > 400 and < 150 nmol/l were 96% and 100% sensitive for a normal or pathological response to the ACTH stimulation test, respectively.</p> <p>Conclusion</p> <p>Immediate and prolonged suppression of the HPA axis is a common finding in otherwise asymptomatic patients undergoing systemic steroid treatment for acute exacerbation of chronic obstructive pulmonary disease and can reliably be assessed with the low-dose ACTH test.</p

Analysis with respect to instrumental variables for the exploration of microarray data structures

BACKGROUND: Evaluating the importance of the different sources of variations is essential in microarray data experiments. Complex experimental designs generally include various factors structuring the data which should be taken into account. The objective of these experiments is the exploration of some given factors while controlling other factors. RESULTS: We present here a family of methods, the analyses with respect to instrumental variables, which can be easily applied to the particular case of microarray data. An illustrative example of analysis with instrumental variables is given in the case of microarray data investigating the effect of beverage intake on peripheral blood gene expression. This approach is compared to an ANOVA-based gene-by-gene statistical method. CONCLUSION: Instrumental variables analyses provide a simple way to control several sources of variation in a multivariate analysis of microarray data. Due to their flexibility, these methods can be associated with a large range of ordination techniques combined with one or several qualitative and/or quantitative descriptive variables