Analysis of the EGFR mutation status in head and neck squamous cell carcinoma before treatment with Gefitinib

BACKGROUND: The efficacy of chemotherapy in metastatic and recurrent squamous cell carcinomas of the head and neck (HNSCC) remains unsatisfactory. Gefitinib offers a new therapeutic option with comparable results and better tolerability than chemotherapy. We conducted this study to see if mutations in the epidermal growth factor receptor (EGFR) might predict the therapeutic benefit in HNSCC patients. PATIENTS AND METHODS: In a pilot trial, 8 patients with metastatic or recurrent HNSCC were treated palliatively with gefitinib (500 mg/day orally). Forceps biopsies were taken to confirm tumor recurrence and to perform an EGFR mutation analysis. RESULTS: The EGFR status could be determined in 6 of the 8 patients. 5 patients had no EGFR gene mutation, and 1 patient showed a silent guanine-to-adenosine mutation in position 2607. Even without any relevant mutation in the EGFR, we observed partial remission in 3 of 6 patients treated with gefitinib. We also observed that an additional 4 patients had stable disease for at least 10 weeks. The median progression-free survival was 6.25 months, and the median overall survival was 7.39 months. CONCLUSION: In HNSCC, there are tumor responses to gefitinib without protein-altering mutations in the EGFR gene

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

Sarcoidosis - a multisystem disease.

Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren's syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways

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

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

Application of microarray technology in pulmonary diseases

Microarrays are a powerful tool that have multiple applications both in clinical and cell biology arenas of common lung diseases. To exemplify how this tool can be useful, in this review, we will provide an overview of the application of microarray technology in research relevant to common lung diseases and present some of the future perspectives

Transcriptome Analysis Describing New Immunity and Defense Genes in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis Patients

Background: Large-scale gene expression profiling of peripheral blood mononuclear cells from Rheumatoid Arthritis (RA) patients could provide a molecular description that reflects the contribution of diverse cellular responses associated with this disease. The aim of our study was to identify peripheral blood gene expression profiles for RA patients, using Illumina technology, to gain insights into RA molecular mechanisms. Methodology/Principal Findings: The Illumina Human-6v2 Expression BeadChips were used for a complete genome-wide transcript profiling of peripheral blood mononuclear cells (PBMCs) from 18 RA patients and 15 controls. Differential analysis per gene was performed with one-way analysis of variance (ANOVA) and P values were adjusted to control the False Discovery Rate (FDR < 5%). Genes differentially expressed at significant level between patients and controls were analyzed using Gene Ontology (GO) in the PANTHER database to identify biological processes. A differentially expression of 339 Reference Sequence genes (238 down-regulated and 101 up-regulated) between the two groups was observed. We identified a remarkably elevated expression of a spectrum of genes involved in Immunity and Defense in PBMCs of RA patients compared to controls. This result is confirmed by GO analysis, suggesting that these genes could be activated systemically in RA. No significant down-regulated ontology groups were found. Microarray data were validated by real time PCR in a set of nine genes showing a high degree of correlation. Conclusions/Significance: Our study highlighted several new genes that could contribute in the identification of innovative clinical biomarkers for diagnostic procedures and therapeutic interventions

Long-term follow-up and survival after Ultraflex stent insertion in the management of complex malignant airway stenoses

BACKGROUND: Despite being commercially available for a few years now, the literature regarding the outcome of Ultraflex stent insertion in complex malignant airway stenoses is sparse. OBJECTIVES: To assess long-term complications and survival in patients with complex malignant airway stenoses treated with insertion of nitinol stents. METHODS: 60 consecutive patients with Ultraflex stent insertion for malignant airway stenoses were included. Follow-up was obtained in all patients. RESULTS: 62 Ultraflex stents (covered = 51, uncovered = 11) were implanted in 60 patients. Diagnoses were bronchial carcinoma (n = 50), esophageal carcinoma (n = 3) and metastases (n = 7). Stents were inserted in the trachea (n = 5), main bronchi/intermediate bronchus (n = 22), from main bronchi/intermediate bronchus to lobar bronchi (n = 28) or in the lobar bronchi themselves (n = 7). Successful reopening of the stenoses and relief were achieved in all patients. There was no procedure-related mortality. Complications included mucous plugging in 8%, stenosing granulation tissue in 5%, tumor ingrowth in 5% and stent migration in 5% of patients. Using Kaplan-Meier estimates, the overall mean survival was 160 days (standard error: 30). Median survival was 91 days. The overall 3- and 6-month survival were 52 and 20%, respectively. Death (n = 59, 98%) was attributed mainly to disease progression with cachexia and metastases, pneumonia (n = 5, 10%), and hemoptysis (n = 1, 2%). CONCLUSION: Ultraflex stents have a low complication rate and can be effectively used in complex malignant airway stenoses with marked asymmetry or irregularity, angulation or changing diameters