796 research outputs found

    Radiolabeled albumin through S<sub>N</sub>Ar of cysteines as a potential pretargeting theranostic agent

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    Human serum albumin (HSA) has been shown to be a promising tumor targeting vector and target for generating theranostics by bioconjugation. Unstable chemical conjugation to HSA via a cysteine (Cys34) by reversible Michael additions is most commonly applied for this purpose. Herein, we describe utilization of our recently developed site-selective irreversible S(N)Ar conjugation to Cys34 using perfluorobenzene sulfonyl derivatives to introduce a trans-cyclooctene (TCO) handle. The TCO could then be bioorthogonally ligated within minutes through an inverse-electron demand Diels–Alder reaction (IEDDA) to tetrazines (Tzs) containing a radionuclide. The methodology opens up a wide range of chemistries including pretargeting, ‘click-to-release’ tumor selective drug delivery or ultra-fast and complete conjugation of any drug. The proof-of-principle study demonstrated that the conjugation chemistry is feasible, robust and easy to carry out, being promising for pretargeted imaging and therapy studies as well as selective drug delivery using HSA

    Bronchial Thermoplasty Global Registry (BTGR): 2-year results

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    Asma; Broncoscòpia; Termoplàstia bronquialAsma; Broncoscopia; Termoplastia bronquialAsthma; Bronchoscopy; Bronchial ThermoplastyObjectives: Bronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected real-world data on subjects undergoing this procedure. Design: The BTGR is an all-comer, prospective, open-label, multicentre study enrolling adult subjects indicated for and treated with BT. Setting: Eighteen centres in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa and Australia PARTICIPANTS: One hundred fifty-seven subjects aged 18 years and older who were scheduled to undergo BT treatment for asthma. Subjects diagnosed with other medical conditions which, in the investigator's opinion, made them inappropriate for BT treatment were excluded. Primary and secondary outcome measures: Baseline characteristics collected included demographics, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, comorbidities and 12-month baseline recall data (severe exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 years post-BT. Results: Subjects' baseline characteristics were representative of persons with severe asthma. A comparison of the proportion of subjects experiencing events during the 12 months prior to BT to the 2-year follow-up showed a reduction in SE (90.3% vs 56.1%, p<0.0001), emergency room visits (53.8% vs 25.5%, p<0.0001) and hospitalisations (42.9% vs 23.5 %, p=0.0019). Reductions in asthma maintenance medication dosage were also observed. AQLQ and ACT scores improved from 3.26 and 11.18 at baseline to 4.39 and 15.54 at 2 years, respectively (p<0.0001 for both AQLQ and ACT). Conclusions: The BTGR demonstrates sustained improvement in clinical outcomes and reduction in asthma medication usage 2 years after BT in a real-world population. This is consistent with results from other BT randomised controlled trials and registries and further supports improvement in asthma control after BT.This study was sponsored by Boston Scientific Corporation, Marlborough, MA, USA

    Influence of airway‐occluding instruments on airway pressure during jet ventilation for rigid bronchoscopy

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    We measured changes in airway pressure (Paw) caused by microsurgical instruments introduced into a rigid bronchoscope during high frequency jet ventilation (HFJV). With approval of the institutional Ethics Committee, 10 adults undergoing elective tracheobronchial endoscopy and endosonography during general anaesthesia were investigated. Inflation of an endosonography probe balloon in the left main stem bronchus caused airway obstruction. Pressure measurements proximal and distal to the obstruction were compared after three degrees of obstruction (0%, 50% and 90%) and with two different driving pressure settings. Airway obstruction increased the mean (sd) peak inspiratory pressure (PIP) from 7.5 (2.6) to 9.5 (3.5) mm Hg for 2 atm (P=0.0008) and from 9.7 (3.7) to 13.0 (5.1) mm Hg for 3 atm (P=0.0001). Airway obstruction did not alter peripheral PIP (7.2 (4.1) to 7.1 (3.7) mm Hg for 2 atm and 8.8 (4.3) to 9.4 (5.2) mm for 3 atm), but resulted in an end‐expiratory pressure (EEP) beyond the narrowing being significantly greater than in the unobstructed airway (2.5 (3.4) to 5.5 (3.7) mm Hg for 2 atm; P=0.0005) and 3.2 (3.6) to 8.0 (4.3) mm for 3 atm; P<0.0001). Severe airway narrowing increases inspiratory pressure proximal and expiratory pressure distal to the obstruction in relation to the applied driving pressure. Since the distal EEP never exceeded PIP, even near‐total airway obstruction should not cause severe lung distension or barotrauma in subjects with normal lungs. Br J Anaesth 2000; 85: 463-

    Pretargeted Theranostics

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    Personalized medicine is becoming an integral part of our healthcare system, in which theranostics play a fundamental role. Nanomedicines such as monoclonal antibodies are a commonly used targeting vector in such approaches due to their outstanding targeting abilities as well as their capabilities to function as drug delivery vehicles. However, the application of nanomedicines in a clinical setting is connected with several challenges. For example, nanomedicines typically possess slow pharmacokinetics in respect to target accumulation and excretion. For targeted radionuclide therapy, this results in high radiation burden to healthy tissue. For drug delivery systems, long circulation and excretion times of the nanomedicine complicate site-specific release approaches and limit as such the usability of these strategies. One way to circumvent these challenges is the use of pretargeting strategies, which allow to separate the accumulation and excretion of nanomedicines from the actual diagnostic or therapeutic application. As such, pretargeting allows to use theranostic concepts utilizing the same nanomedicine and determine the success chances with diagnostic measures before initiating therapy. This chapter will explain the concept of pretargeted theranostics, which pretargeting systems have thus far been developed and compare how these systems performed

    Treatment of Advanced Emphysema with Emphysematous Lung Sealant (AeriSeal (R))

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    Background: This report summarizes initial tests of an emphysematous lung synthetic polymer sealant (ELS) designed to reduce lung volume in patients with advanced emphysema. Objectives: The primary study objective was to define a therapeutic strategy to optimize treatment safety and effectiveness. Methods: ELS therapy was administered bronchoscopically to 25 patients with heterogeneous emphysema in an open-label, noncontrolled study at 6 centers in Germany. Treatment was performed initially at 2-4 subsegments. After 12 weeks, patients were eligible for repeat therapy to a total of 6 sites. Safety and efficacy were assessed after 6 months. Responses were evaluated in terms of changes from baseline in lung physiology, functional capacity, and health-related quality of life. Follow-up is available for 21 of 25 patients. Results: Treatment was well tolerated. There were no treatment-related deaths (i.e. within 90 days of treatment), and an acceptable short-and long-term safety profile. Physiological and clinical benefits were observed at 24 weeks. Efficacy responses were better among Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III patients {[}n = 14; change in residual volume/total lung capacity (Delta RV/TLC) = -7.4 +/- 10.3%; Delta forced expiratory volume in 1 s (Delta FEV(1)) = +15.9 +/- 22.6%; change in forced vital capacity (Delta FVC) = +24.1 +/- 22.7%; change in carbon monoxide lung diffusion capacity (Delta DLCO) = +19.3 +/- 34.8%; change in 6-min walk test (Delta 6MWD) = +28.7 +/- 59.6 m; change in Medical Research Council Dyspnea (Delta MRCD) score = -1.0 +/- 1.04 units; change in St. George's Respiratory Questionnaire (Delta SGRQ) score = -9.9 +/- 15.3 units] than for GOLD stage IV patients (n = 7; Delta RV/TLC = -0.5 +/- 6.4%; Delta FEV 1 = +2.3 +/- 12.3%; Delta FVC = +2.6 +/- 21.1%; Delta DLCO = -2.8 +/- 17.2%; Delta 6MWD = +28.3 +/- 58.4 m; Delta MRCD = 0.3 +/- 0.81 units; Delta SGRQ = -6.7 +/- 7.0 units). Conclusions: ELS therapy shows promise for treating patients with advanced heterogeneous emphysema. Additional studies to assess responses in a larger cohort with a longer follow-up are warranted. Copyright (C) 2011 S. Karger AG, Base

    Geriatrische Assessments und Diagnostik beim älteren Patienten

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    As is the case with younger patients, the treatment decisions for elderly patients with thoracic tumours are primarily based on the results of the usual routine diagnostics. Standardised assessments of existing comorbidities and geriatric assessments may provide information which are of particular relevance for intensive and/or complex therapy modalities and which may require early corresponding intervention or measures for support

    Germline genetic variants of the renin-angiotensin system, hypoxia and angiogenesis in non-small cell lung cancer progression: Discovery and validation studies

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    Introduction: The renin–angiotensin system (RAS) is involved in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. Our aim was to study the association of putatively functional genetic polymorphisms in genes coding for proteins involved in RAS, hypoxia and angiogenesis with non-small cell lung cancer (NSCLC) prognosis. Methods: Genotyping of 52 germline variants from genes of the RAS and hypoxic/angiogenic factors/receptors was performed using MassARRAY iPLEX Gold in a retrospective cohort (n = 167) of advanced NSCLC patients. Validation of the resulting genetic markers was conducted in an independent group (n = 190), matched by clinicopathological characteristics. Results: Multivariate analysis on the discovery set revealed that MME rs701109 C carriers were protected from disease progression in comparison with homozygous T (hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.2–0.8, p = 0.010). Homozygous A and T genotypes for KDR rs1870377 were at increased risk for disease progression and death compared to heterozygous (HR = 1.7, 95% CI = 1.2–2.5, p = 0.005 and HR = 2.1, 95% CI = 1.2–3.4, p = 0.006, respectively). Carriers of homozygous genotypes for ACE2 rs908004 presented increased risk for disease progression, only in the subgroup of patients without tumour actionable driver mutations (HR = 2.9, 95% CI = 1.3–6.3, p = 0.010). Importantly, the association of homozygous genotypes in MME rs701109 with risk for disease progression was confirmed after multivariate analysis in the validation set. Conclusion: This study provides evidence that MME polymorphism, which encodes neprilysin, may modulate progression-free survival in advanced NSCLC. Present genetic variation findings will foster basic, translational, and clinical research on their role in NSCLC.M.J.C. was supported by the Associação de Estudos Respiratórios and the Portuguese Pulmonology Society
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