Treatment of haemothorax

SummaryHaemothorax is a problem commonly encountered in medical practice and is most frequently related to open or closed chest trauma or to invasive procedures of the chest. Spontaneous haemothorax is less common and can have various causes, such as the use of anticoagulants, neoplasia, and rupture of pleural adhesions. Identification by radiography and thoracentesis is indicated and treatment of the underlying trauma should start immediately. After insertion of a large chest tube, antibiotic prophylaxis in trauma patients should be administered for 24 h.Further treatment depends on the haemodynamic stability of the patient, the volume of evacuated blood and the occurrence of persistent blood loss. Surgical exploration by VATS or thoracotomy is necessary if >1.500 ml of blood has accumulated and/or an ongoing production of >200 ml of blood per hour is observed. If the haemorrhage is less severe, careful investigation into the underlying cause must be performed and blood should be evacuated by tube thoracostomy. If clotted blood retained in spite of tube thoracostomy, intrapleural fibrinolytic therapy can be applied to breakdown clots and adhesions. If conservative treatment is insufficient, a surgical approach with VATS or thoracotomy is indicated to prevent subsequent complications

A bispecific inhibitor of the EGFR/ADAM17 axis decreases cell proliferation and migration of EGFR-dependent cancer cells

Dysregulated epidermal growth factor receptor (EGFR) is an oncogenic driver of many human cancers, promoting aberrant cell proliferation, migration, and survival. Pharmacological targeting of EGFR is often challenged by acquired mechanisms of resistance. Ligand-dependent mechanisms in EGFR wild-type cells rely on ligand or receptor overexpression, allowing cells to outcompete inhibitors and perpetuate signaling in an autocrine manner. Importantly, EGFR ligands are synthesized as membrane-bound precursors that must be solubilized to enable receptor-ligand interactions. The A disintegrin and metalloproteinase 17 (ADAM17) is considered the main sheddase of several EGFR ligands, and a potential pharmacological target. However, its broad substrate range and ubiquitous expression complicate its therapeutic targeting. Here, we present a novel bispecific fusion protein construct consisting of the inhibitory prodomain of ADAM17 (TPD), fused to an EGFR-targeting designed ankyrin repeat protein (DARPin). TPD is a natural inhibitor of ADAM17, maintaining the protease in a zymogen-like form. Meanwhile, the high affinity anti-EGFR DARPin E01 binds to EGFR and inhibits ligand binding. The resulting fusion protein E01-GS-TPD retained binding ability to both molecular targets EGFR and ADAM17. The large difference in affinity for each target resulted in enrichment of the fusion protein in EGFR-positive cells compared to EGFR-negative cells, suggesting a possible application in autocrine signaling inhibition. Accordingly, E01-GS-TPD decreased migration and proliferation of EGFR-dependent cell lines with no significant increase in apoptotic cell death. Finally, inhibition of proliferation was observed through EGFR ligand-dependent mechanisms as growth inhibition was not observed in EGFR mutant or KRAS mutant cell lines. The use of bispecific proteins targeting the EGFR/ADAM17 axis could be an innovative strategy for the treatment of EGFR-dependent cancers

Treatment with inhaled antibiotics in bronchiectasis, side effects, and evaluation of the tolerance test; analysis from the BATTLE randomized controlled trial

INTRODUCTION: Tobramycin inhalation solution (TIS) is a treatment option for patients with frequent exacerbations of bronchiectasis. A possible side effect of TIS is the development of chronic cough and bronchospasm, whereby the guidelines suggest a (in hospital) tolerance test with the first dose of TIS. However, data on respiratory adverse events are not consistent. In the present analysis from the BATTLE study (NCT02657473), we evaluated the added value of the tolerance test and aimed to observe the development of inhaled treatment related bronchial hyperreactivity. METHODS: Fifty-seven patients from the BATTLE study were analyzed. Patients were randomized to receive TIS or placebo OD for 1 year. A tolerance test was performed with spirometry measurements before and after the first dose and with a bronchodilator in advance. Adverse events were strictly monitored. RESULTS: Fifty-seven patients (100%) passed the tolerance test with no decrease in spirometry measurements or development of local intolerability. During the study treatment, a total of five TIS-treated patients (17.8%) withdrew due to airway hyperresponsiveness after a mean of 9.2 (SD13.9) weeks and one placebo-treated patient (3.5%) after 2 weeks (TIS vs. placebo; p = 0.66). The other TIS-related adverse events were not clinically significant. CONCLUSION: The use of inhaled medication is well tolerated in the heterogenous bronchiectasis population, without signs of airway hyperresponsiveness after the first dose of inhaled medication. From this observation, it can be concluded that there is no additional value for this advised tolerance test. However, closely monitoring on adverse effects during the first weeks after starting TIS is recommended

Identifying a nasal gene expression signature associated with hyperinflation and treatment response in severe COPD

Hyperinflation contributes to dyspnea intensity in COPD. Little is known about the molecular mechanisms underlying hyperinflation and how inhaled corticosteroids (ICS) affect this important aspect of COPD pathophysiology. To investigate the effect of ICS/long-acting β2-agonist (LABA) treatment on both lung function measures of hyperinflation, and the nasal epithelial gene-expression profile in severe COPD. 117 patients were screened and 60 COPD patients entered a 1-month run-in period on low-dose ICS/LABA budesonide/formoterol (BUD/F) 200/6 one inhalation b.i.d. Patients were then randomly assigned to 3-month treatment with either a high dose BDP/F 100/6 two inhalations b.i.d. (n = 31) or BUD/F 200/6 two inhalations b.i.d. (n = 29). Lung function measurements and nasal epithelial gene-expression were assessed before and after 3-month treatment and validated in independent datasets. After 3-month ICS/LABA treatment, residual volume (RV)/total lung capacity (TLC)% predicted was reduced compared to baseline (p < 0.05). We identified a nasal gene-expression signature at screening that associated with higher RV/TLC% predicted values. This signature, decreased by ICS/LABA treatment was enriched for genes associated with increased p53 mediated apoptosis was replicated in bronchial biopsies of COPD patients. Finally, this signature was increased in COPD patients compared to controls in nasal, bronchial and small airways brushings. Short-term ICS/LABA treatment improves RV/TLC% predicted in severe COPD. Furthermore, it decreases the expression of genes involved in the signal transduction by the p53 class mediator, which is a replicable COPD gene expression signature in the upper and lower airways.Trial registration: ClinicalTrials.gov registration number NCT01351792 (registration date May 11, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 20, 2009), ClinicalTrials.gov registration number NCT00158847 (registration date September 12, 2005)

Current inpatient treatment options for COVID-19:an update

In dit overzichtsartikel geven wij een update van de adviezen voor de medicamenteuze behandeling van covid-19 in de tweede lijn.Deze adviezen zijn opgesteld door de Stichting Werkgroep Antibioticabeleid (SWAB) in samenwerking met onder andere de Federatie Medisch Specialisten (FMS).Zowel opties voor behandeling in het ziekenhuis als opties voor behandeling in de ambulante setting worden besproken.De behandeling omvat zowel anti-inflammatoire als antivirale therapie.In this article we provide an overview of the current treatment recommendations for COVID-19. These recommendations are made by the SWAB (StichtingWerkgroepAntibioticabeleid), in cooperation with the FMS (FederatieMedischSpecialisten (online: swab.nl/nl/covid-19.). Treatment options for patients in both ambulatory care and admitted to the hospital are listed. These treatment options include both antiinflammatory and antiviral therapy.</p

Biomarker guided antibiotic stewardship in community acquired pneumonia: A randomized controlled trial

Background In community-acquired pneumonia (CAP), the role of biomarkers to shorten duration of antibiotic treatment has not been firmly established. We assessed the effectiveness of active feedback of treatment algorithms based on procalcitonin (PCT) and C-reactive protein (CRP), compared to standard care, on the duration of antibiotic treatment in patients hospitalized with community-acquired pneumonia (CAP) in non-ICU wards. Methods and findings We performed a randomised, open label, parallel group, multi-centre trial in 3 Dutch teaching hospitals. Treatment was guided by a PCT algorithm, CRP algorithm or standard care. Participants were recruited by a member of the study team and randomised at day 2–3 of admission in a 1:1:1 ratio. Treatment was discontinued upon predefined thresholds of biomarkers that were assessed on admission, day 4 and days 5–7 if indicated. The primary outcome was total days on antibiotic treatment until day 30. In total 468 participants were included in this study. The median days on antibiotics (IQR) was 7 (IQR 7–10) in the control group, 4 (IQR 3–7) in the CRP group (rate ratio (RR) of 0.70, 95% CI 0.61–0.82 compared to standard care; p <0.001), and 5.5 (IQR 3–9) in the PCT group (RR of 0.78, 95% CI 0.68–0.89 compared to standard care; p <0.001). New antibiotics within the first 30 days were prescribed to 24, 23 and 35 patients in standard care, CRP and PCT groups, respectively. The hazard ratio for a new prescription in patients in the PCT group compared to standard care 1.63 (CI 0.97–2.75; p = 0.06). No difference in time to clinical stability or length of stay was found. Conclusions A strategy of feedback of CRP-guided and PCT-guided treatment algorithms reduced the number of days on antibiotic in the first 30 days after hospital admission in non-ICU wards for CAP. The study was not powered to determine safety of shortening duration of antibiotic treatment. (NCT01964495)