No abstract

Background The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. Methods The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudorandom number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178.

Previous studies have demonstrated symptoms and mediator release occurring as long as 11 h after nasal challenge with antigen in selected allergic subjects. Pretreatment with systemic steroids reduced symptoms and mediators including histamine, TAME-esterase activity, and kinins. The aims of the present study were to characterize the cell influx during the late-phase response to antigen challenge and to determine the effect of pretreatment with systemic steroids on this response. We examined cytospin slides of nasal washings obtained before and hourly for 11 h after nasal antigen challenge in 10 asymptomatic allergic subjects with a history of seasonal rhinitis and 5 normal, nonallergic subjects. Allergic subjects received oral prednisone (20 mg 3 times a day) or placebo in a random, double-blind crossover manner for 2 days before each of 2 challenges 1 month apart. On placebo days, a mixed cell influx occurred in allergic subjects during the late response that was 50-fold greater than the cell influx in the nonallergic control subjects (p less than 0.005). During the first 3 h after antigen challenge, eosinophils (p less than 0.005), but not neutrophils or mononuclear cells, were observed. During the late phase (4 to 11 h), neutrophils, eosinophils, and mononuclear cells were all increased. Oral steroid pretreatment blocked the influx of eosinophils (p less than 0.005), but not that of other cells. These data demonstrate an inflammatory cell influx associated with the nasal late-phase response and suggest an important pathogenetic role for the eosinophil.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

The epithelial cell may contribute to the regulation of pulmonary function during inflammatory diseases of the airways by producing metabolites of arachidonic acid (AA). We have used human tracheal epithelial cells (HTE), grown in serum-free medium, to examine cyclooxygenase metabolism of endogenous AA by these cells. Gas chromatography-negative ion mass spectrometry demonstrated that, regardless of stimulus (buffer, bradykinin, or the calcium ionophore A23187), epithelial cells produce PGE2 and PGF2 alpha but no detectable levels of PGD2, thromboxane B2, 6-keto-PGF1 alpha, or 9 alpha, 11 beta-PGF2. Preincubation of cultures with medium containing 5% human serum led to striking increases in the production of PGE2 and PGF2 alpha, regardless of stimulus. Concomitant with these increases in prostanoids, serum exposure caused a 3.6-fold increase in total cellular arachidonate. Arachidonate levels increased in all phosphoglyceride classes, with the greatest increases in phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol. In serum-pretreated cells, PGE2 production was 1.46 +/- 0.12, 4.74 +/- 0.6, and 6.35 +/- 0.93 ng/10(6) cells (mean +/- SEM; n = 7) upon exposure to buffer, 10(-6) M bradykinin, and 1 micrograms/ml A23187, respectively, whereas PGF2 alpha levels were 1.53 +/- 0.22, 4.44 +/- 0.36, and 5.77 +/- 0.78 ng/10(6) cells, respectively. The response of HTE to bradykinin was dose-dependent (10(-8) to 10(-6) M) and was maximal within 5 min. We conclude that cyclooxygenase metabolism of endogenous arachidonate in HTE results in the specific production of PGE2 and PGF2 alpha. HTE in culture retain receptors for bradykinin and can be used to study lipid metabolism independent of other cell types.

No abstract

With the development of multidetector computed-tomography (MDCT) scanners and ultrathin bronchoscopes, the use of bronchoscopy for diagnosing peripheral lung-cancer nodules is becoming a viable option. The work flow for assessing lung cancer consists of two phases: 1) 3-D MDCT analysis and 2) live bronchoscopy. Unfortunately, the yield rates for peripheral bronchoscopy have been reported to be as low as 14%, and bronchoscopy performance varies considerably between physicians. Recently, proposed image-guided systems have shown promise for assisting with peripheral bronchoscopy. Yet, MDCT-based route planning to target sites has relied on tedious error-prone techniques. In addition, route planning tends not to incorporate known anatomical, device, and procedural constraints that impact a feasible route. Finally, existing systems do not effectively integrate MDCT-derived route information into the live guidance process. We propose a system that incorporates an automatic optimal route-planning method, which integrates known route constraints. Furthermore, our system offers a natural translation of the MDCT-based route plan into the live guidance strategy via MDCT/video data fusion. An image-based study demonstrates the route-planning method’s functionality. Next, we present a prospective lung-cancer patient study in which our system achieved a successful navigation rate of 91% to target sites. Furthermore, when compared to a competing commercial system, our system enabled bronchoscopy over two airways deeper into the airway-tree periphery with a sample time that was nearly 2 min shorter on average. Finally, our system’s ability to almost perfectly predict the depth of a bronchoscope’s navigable route in advance represents a substantial benefit of optimal route planning.

Bronchoscopy is a major step in lung cancer staging. To perform bronchoscopy, the physician uses a procedure plan, derived from a patient’s 3D computed-tomography (CT) chest scan, to navigate the bronchoscope through the lung airways. Unfortunately, physicians vary greatly in their ability to perform bronchoscopy. As a result, image-guided bronchoscopy systems, drawing upon the concept of CT-based virtual bronchoscopy (VB), have been proposed. These systems attempt to register the bronchoscope’s live position within the chest to a CT-based virtual chest space. Recent methods, which register the bronchoscopic video to CT-based endoluminal airway renderings, show promise but do not enable continuous real-time guidance. We present a CT-video registration method inspired by computer-vision innovations in the fields of image alignment and image-based rendering. In particular, motivated by the Lucas–Kanade algorithm, we propose an inverse-compositional framework built around a gradient-based optimization procedure. We next propose an implementation of the framework suitable for image-guided bronchoscopy. Laboratory tests, involving both single frames and continuous video sequences, demonstrate the robustness and accuracy of the method. Benchmark timing tests indicate that the method can run continuously at 300 frames/s, well beyond the real-time bronchoscopic video rate of 30 frames/s. This compares extremely favorably to the ≥1 s/frame speeds of other methods and indicates the method’s potential for real-time continuous registration. A human phantom study confirms the method’s efficacy for real-time guidance in a controlled setting, and, hence, points the way toward the first interactive CT-video registration approach for image-guided bronchoscopy. Along this line, we demonstrate the method’s efficacy in a complete guidance system by presenting a clinical study involving lung cancer patients.