Phase II Multicenter Clinical Trial of Pulmonary Metastasectomy and Isolated Lung Perfusion with Melphalan in Patients with Resectable Lung Metastases

IntroductionThe 5-year overall survival rate of patients undergoing complete surgical resection of pulmonary metastases (PM) from colorectal cancer (CRC) and sarcoma remains low (20–50%). Local recurrence rate is high (48–66%). Isolated lung perfusion (ILuP) allows the delivery of high-dose locoregional chemotherapy with minimal systemic leakage to improve local control.MethodsFrom 2006 to 2011, 50 patients, 28 male, median age 57 years (15–76), with PM from CRC (n = 30) or sarcoma (n = 20) were included in a phase II clinical trial conducted in four cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, with 45 mg of melphalan at 37°C, followed by resection of all palpable PM. Survival was calculated according to the Kaplan–Meier method.ResultsOperative mortality was 0%, and 90-day morbidity was mainly respiratory (grade 3: 42%, grade 4: 2%). After a median follow-up of 24 months (3–63 mo), 18 patients died, two without recurrence. Thirty patients had recurrent disease. Median time to local pulmonary progression was not reached. The 3-year overall survival and disease-free survival were 57% ± 9% and 36% ± 8%, respectively. Lung function data showed a decrease in forced expiratory volume in 1 second and diffusing capacity of the alveolocapillary membrane of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 months, compared with preoperative values.ConclusionCompared with historical series of PM resection without ILuP, favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in patients with resectable PM from CRC or sarcoma

Curriculum vitae of the LOTOS-EUROS (v2.0) chemistry transport model

The development and application of chemistry transport models has a long tradition. Within the Netherlands the LOTOS–EUROS model has been developed by a consortium of institutes, after combining its independently developed predecessors in 2005. Recently, version 2.0 of the model was released as an open-source version. This paper presents the curriculum vitae of the model system, describing the model's history, model philosophy, basic features and a validation with EMEP stations for the new benchmark year 2012, and presents cases with the model's most recent and key developments. By setting the model developments in context and providing an outlook for directions for further development, the paper goes beyond the common model description. With an origin in ozone and sulfur modelling for the models LOTOS and EUROS, the application areas were gradually extended with persistent organic pollutants, reactive nitrogen, and primary and secondary particulate matter. After the combination of the models to LOTOS–EUROS in 2005, the model was further developed to include new source parametrizations (e.g. road resuspension, desert dust, wildfires), applied for operational smog forecasts in the Netherlands and Europe, and has been used for emission scenarios, source apportionment, and long-term hindcast and climate change scenarios. LOTOS–EUROS has been a front-runner in data assimilation of ground-based and satellite observations and has participated in many model intercomparison studies. The model is no longer confined to applications over Europe but is also applied to other regions of the world, e.g. China. The increasing interaction with emission experts has also contributed to the improvement of the model's performance. The philosophy for model development has always been to use knowledge that is state of the art and proven, to keep a good balance in the level of detail of process description and accuracy of input and output, and to keep a good record on the effect of model changes using benchmarking and validation. The performance of v2.0 with respect to EMEP observations is good, with spatial correlations around 0.8 or higher for concentrations and wet deposition. Temporal correlations are around 0.5 or higher. Recent innovative applications include source apportionment and data assimilation, particle number modelling, and energy transition scenarios including corresponding land use changes as well as Saharan dust forecasting. Future developments would enable more flexibility with respect to model horizontal and vertical resolution and further detailing of model input data. This includes the use of different sources of land use characterization (roughness length and vegetation), detailing of emissions in space and time, and efficient coupling to meteorology from different meteorological models

Comparison of Outcome After Percutaneous Mitral Valve Repair With the MitraClip in Patients With Versus Without Atrial Fibrillation

Percutaneous mitral valve repair with the MitraClip is an established treatment for patients with mitral regurgitation (MR) who are inoperable or at high risk for surgery. Atrial Fibrillation (AF) frequently coincides with MR, but only scarce data of the influence of AF on outcome after MitraClip is available. The aim of the current study was to compare the clinical outcome after MitraClip treatment in patients with versus without atrial fibrillation. Between January 2009 and January 2016, all consecutive patients treated with a MitraClip in 5 Dutch centers were included. Outcome measures were survival, symptoms, MR grade, and stroke incidence. In total, 618 patients were treated with a MitraClip. Patients with AF were older, had higher N-terminal B-type natriuretic peptide levels, more tricuspid regurgitation, less often coronary artery disease and a better left ventricular function. Survival of patients treated with the MitraClip was similar for patients with AF (82%) and without AF (non-AF; 85%) after 1 year (p = 0.30), but significantly different after 5-year follow-up (AF 34%; non-AF 47%; p = 0.006). After 1 month, 64% of the patients with AF were in New York Heart Association class I or II, in contrast to 77% of the patients without AF (p = 0.001). The stroke incidence appeared not to be significantly different (AF 1.8%; non-AF 1.0%; p = 0.40). In conclusion, patients with AF had similar 1-year survival, MR reduction, and stroke incidence compared with non-AF patients. However, MitraClip patients with AF had reduced long-term survival and remained more symptomatic compared with those without AF.</p

Evaluation of Staphylococcus aureus Nasal Carriage Screening before Vascular Surgery

INTRODUCTION: Staphylococcus aureus is the most important pathogen in the development of surgical site infections (SSI). Patients who carry S. aureus in the nose are at increased risk for the development of SSI in cardiothoracic and orthopedic surgery. In these populations it has been shown that the risk for SSI can be substantially reduced by eradicating S. aureus carriage. For vascular surgery the relation between nasal carriage and surgical site infections has not been clearly investigated. For this reason we performed this study to analyze the relation between S. aureus nasal carriage and SSI in our vascular surgery population. METHODS: A prospective cohort study was undertaken, including all patients undergoing vascular surgery between January first 2010 and December 31th 2010. Before surgery patients were screened for S. aureus nasal carriage using a PCR technique. The presence of SSI was recorded based on criteria of the CDC. RESULTS: Screening was performed in 224. Of those, 55 (24.5%) were positive, 159 (71.0%) were negative and 10 (4.5%) were inconclusive. In the screened vascular population 4 S. aureus SSI occurred in the 55 carriers compared with 6 in 159 non-carriers (p=0.24). A stratified analysis revealed a 10-fold increased risk in nasal carriers undergoing central reconstruction surgery (3 S. aureus SSI in 20 procedures versus 1 in 65 procedures in non-carriers, p=0.039). DISCUSSION: In patients undergoing central reconstruction surgery nasals carriers are at increased risk for the development of S. aureus SSI. These patients will probably benefit from perioperative treatment to eradicate nasal carriage

Mobile app-based symptom-rhythm correlation assessment in patients with persistent atrial fibrillation

Background: The assessment of symptom-rhythm correlation (SRC) in patients with persistent atrial fibrillation (AF) is challenging. Therefore, we performed a novel mobile app-based approach to assess SRC in persistent AF.Methods: Consecutive persistent AF patients planned for electrical cardioversion (ECV) used a mobile app to record a 60-s photoplethysmogram (PPG) and report symptoms once daily and in case of symptoms for four weeks prior and three weeks after ECV. Within each patient, SRC was quantified by the SRC-index defined as the sum of symptomatic AF recordings and asymptomatic non-AF recordings divided by the sum of all recordings.Results: Of 88 patients (33% women, age 68 +/- 9 years) included, 78% reported any symptoms during recordings. The overall SRC-index was 0.61 (0.44-0.79). The study population was divided into SRC-index tertiles: low (= 0.73). Patients within the low (vs high) SRC-index tertile had more often heart failure and diabetes mellitus (both 24.1% vs 6.9%). Extrasystoles occurred in 19% of all symptomatic non-AF PPG recordings. Within each patient, PPG recordings with the highest (vs lowest) tertile of pulse rates conferred an increased risk for symptomatic AF recordings (odds ratio [OR] 1.26, 95% coincidence interval [CI] 1.04-1.52) and symptomatic non-AF recordings (OR 2.93, 95% CI 2.16-3.97). Pulse variability was not associated with reported symptoms.Conclusions: In patients with persistent AF, SRC is relatively low. Pulse rate is the main determinant of reported symptoms. Further studies are required to verify whether integrating mobile app-based SRC assessment in current workflows can improve AF management

Microglia regulate myelin growth and integrity in the central nervous system

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health(1), it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease(2,3)

Effects of Dual Targeting of Tumor Cells and Stroma in Human Glioblastoma Xenografts with a Tyrosine Kinase Inhibitor against c-MET and VEGFR2

Contains fulltext : 118357.pdf (publisher's version ) (Open Access)Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited . Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from experiments, blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be needed for full activity

Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema

Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an