BackgroundRecent studies have emphasized the difficulty of early detection of chronic obstructive pulmonary disease (COPD) in symptomatic smokers with normal routine spirometry. This includes post-bronchodilator normal forced expiratory volume in 1 second (FEV1)(L)≥80% predicted, forced vital capacity (FVC)(L)≥80% predicted, and FEV1/FVC ≥70% or greater than age corrected lower limit of normal (LLN). However, in COPD the pathologic site of small airway obstruction and emphysema begins in the small peripheral airways ≤2 mm id which normally contribute <20% of total airway resistance.MethodsExpiratory airflow at high and low lung volumes post-bronchodilator were measured and correlated with lung computed tomography (CT) and lung pathology (6 patients) in 16 symptomatic, treated smokers, and all with normal routine spirometry.ResultsDespite normal routine spirometry, all16 patients had isolated, abnormal forced expiratory flow at 75% of FVC (FEF75) using data from Knudson et al, Hankinson et al NHAMES III, and Quanjer et al and the Global Lung Function Initiative. This reflects isolated detection of small airways obstruction and/or emphysema. Measuring airflow at FEF50 detected only 8 of 16 patients, maximal expiratory flow at 25%-75% of FVC (MEF25-75) only 4 of 16, residual volume (RV) 4 of 16, and RV to total lung capacity ratio only 2 of 16. There was excellent correlation between limited lung pathology and lung CT for absence of emphysema.ConclusionThis study confirms our earlier observations that detection of small airways obstruction and/or emphysema, in symptomatic smokers with normal routine spirometry, requires analysis of expiratory airflow at low lung volumes, including FEF75. Dependence upon normal routine spirometry may result in clinical and physiologic delay in the diagnosis and treatment in symptomatic smokers with emphysema and small airways obstruction.

Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an interstitial lung disease caused by sensitization to an inhaled allergen. Objectives: To identify the molecular determinants associated with progression of fibrosis. Methods: Nine fHP explant lungs and six unused donor lungs (as controls) were systematically sampled (4 samples/lung). According to microcomputed tomography measures, fHP cores were clustered into mild, moderate, and severe fibrosis groups. Gene expression profiles were assessed using weighted gene co-expression network analysis, xCell, gene ontology, and structure enrichment analysis. Gene expression of the prevailing molecular traits was also compared with idiopathic pulmonary fibrosis (IPF). The explant lung findings were evaluated in separate clinical fHP cohorts using tissue, BAL samples, and computed tomography scans. Measurements and Main Results: We found six molecular traits that associated with differential lung involvement. In fHP, extracellular matrix and antigen presentation/sensitization transcriptomic signatures characterized lung zones with only mild structural and histological changes, whereas signatures involved in honeycombing and B cells dominated the transcriptome in the most severely affected lung zones. With increasing disease severity, endothelial function was progressively lost, and progressive disruption in normal cellular homeostatic processes emerged. All six were also found in IPF, with largely similar associations with disease microenvironments. The molecular traits correlated with in vivo disease behavior in a separate clinical fHP cohort. Conclusions: We identified six molecular traits that characterize the morphological progression of fHP and associate with in vivo clinical behavior. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent rather than by diagnosis alone.

Background Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and abnormal inflammatory response in the lungs, mainly caused by cigarette smoking. Animal models exposed to cigarette smoke (CS) are used to mimic human COPD but the use of different CS protocols makes it difficult to compare the immunological and structural consequences of using a nose-only or whole-body CS exposure system. We hypothesized that when using a standardized CS exposure protocol based on particle density and CO (carbon monoxide) levels, the whole-body CS exposure system would generate a more severe inflammatory response than the nose-only system, due to possible sensitization by uptake of CS-components through the skin or via grooming. Methods In this study focusing on early COPD, mice were exposed twice daily 5 days a week to CS either with a nose-only or whole-body exposure system for 14 weeks to assess lung function, remodeling and inflammation. Results At sacrifice, serum cotinine levels were significantly higher in the whole-body (5.3 (2.3–6.9) ng/ml) compared to the nose-only ((2.0 (1.8–2.5) ng/ml) exposure system and controls (1.0 (0.9–1.0) ng/ml). Both CS exposure systems induced a similar degree of lung function impairment, while inflammation was more severe in whole body exposure system. Slightly more bronchial epithelial damage, mucus and airspace enlargement were observed with the nose-only exposure system. More lymphocytes were present in the bronchoalveolar lavage (BAL) and lymph nodes of the whole-body exposure system while enhanced IgA and IgG production was found in BAL and to a lesser extent in serum with the nose-only exposure system. Conclusion The current standardized CS-exposure protocol resulted in a higher internal load of serum cotinine in the whole-body exposure system, which was associated with more inflammation. However, both exposure systems resulted in a similar lung function impairment. Data also highlighted differences between the two models in terms of lung inflammation and remodelling, and potential sensitization to CS. Researchers should be aware of these differences when designing their future studies for an early intervention in COPD.

Annual Trainee Doctors’ Prize Day, Thursday 17th October 2019. Postgraduate Medical Centre, Belfast City Hospital. ORAL PRESENTATION Better The Devil You Know? Comparison Of Decellularised Matrices Against Clinical Alternatives For Defect Closure in a Rabbit Model Of Congenital Diaphragmatic Hernia Mary Patrice Eastwood, Luc Joyeux, Luca Urbani, Koichi Deguchi, Savitree Pranpanus, Rita Rynkevic, Lucie Hympanova, Eric Verbeken , Paolo De Coppi, Jan Deprest Aim: Gore-Tex® is a widely used durable patch for repair of congenital diaphragmatic defects yet results in complications. Early reherniation has been reported in alternative xenografts such as Surgisis®. We wondered whether the matrix or decellularization (decel) process led to failure. We compared diaphragmatic reconstructions using SIS and decel porcine diaphragm (DPD), processed with a comparable decel protocol, to Gore-Tex in a fast-growing rabbit model. Methods: Twenty-three 6-weeks-old rabbits underwent intubation, left subcostal laparotomy and 3*3cm hemidiaphragmatic excision. Defect closure was with a 3,5*3,5cm patch of (a)Gore-Tex® (n=10), (b)Surgisis® (n=6) or (c) DPD (n=7). Rates of herniation or eventration, uniaxial biomechanical testing, and histology were studied at 90days. Results: Eighteen (78%) rabbits survived to 90days. There was mesh failure in all decellularised matrices (p<0.001). Frank reherniation of abdominal contents in 14% of GoreTex group (n=1), 71% in SIS (n=5;fig.1e) and 25% with DPD (n=1). Eventration was observed in SIS (n=2 (29%)) or DPD (n=3 (75%); p<0.05) (fig.1f). Biomechanical testing was only possible with Gore-Tex. Decellularised matrices were replaced by thin fibrous tissue, almost acellular at the mesh centre. Gore-Tex induced a more vigorous inflammatory response. Conclusion: Reconstructions with natural matrices are more likely to fail than Gore-Tex repairs. Outcomes in our fast-growing rabbit model correlate to described clinical outcomes. The “Petechiae in children” (PiC) study: validating clinical decision rules for the management of feverish children with non-blanching rashes Dr Thomas Waterfield, Dr Mark D. Lyttle, Derek Fairley, James Mckenna, Dr Michael Corr , Miss Bethany Patenall, Dr Kerry Woolfall, Dr Julie-Ann Maney, Dr Damian Rolan, Prof Michael D. Shields Introduction: Children commonly present to Emergency Departments (ED) with a non-blanching rash (NBR) in the context of a feverish illness. The approach to assessment of these children is controversial. Aims: Validate clinical practices guidelines (CPGs) for the management of fever and NBR Methods: Prospective multicentre validation study evaluating the performance of available CPGs for feverish children with NBR. The full protocol has been published and is available at https://rdcu.be/bFEtb. Results: 1423 children were recruited from 37 UK sites between the 11th November 2017 to 30th June 2019. This included 77 children with serious bacterial infections (5.4%) and 17 children (1.2%) with confirmed invasive meningococcal disease (MD). Four CPGs (NICE, NBL, London & Nottingham) were prospectively validated. All four demonstrated 100% Sensitivity for identifying children with MD. NICE guidance demonstrated the lowest specificity 10% recommending that 75.3% of children receive parenteral antibiotics and admission to hospital. The NBL, London and Nottingham CPGs all demonstrated a greater specificity ranging from 28% to 41%. Discussion: NICE guidance for the management of NBR performed poorly in this national validation exercise. The alternative CPGs were 100% sensitive and offered greater specificity. Adopting an alternate CPG would reduce painful interventions, parenteral antibiotic use and hospital admissions. Trial registration NCT03378258. Retrospectively registered on December 19, 2017.. Ehler-Danlos; A case of not so simple sciatica Adam Gowdy, Adam Tweedie Introduction: Vascular Ehler-Danlos (vEDS or type IV EDS) is the most dangerous subtype of Ehler-Danlos and is rarer 2 The Ulster Medical Journal UMJ is an open access publication of the Ulster Medical Society (http://www.ums.ac.uk). The Ulster Medical Society grants to all users on the basis of a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Licence the right to alter or build upon the work non-commercially, as long as the author is credited and the new creation is licensed under identical terms. than most EDS subtypes, thought to affect 1-200,000. It is autosomal dominant affecting COL3A1 or COL1A1 genes. Symptoms include those of EDS alongside being easily bruised, visible blood vessels on chest, late miscarriage, unusual facial features and aneurysms/dissections, bowel perforation and uterine perforation. Case: A woman presented with acute onset back pain radiating down her right leg after bending over to pick up a heavy object. History and findings were in keeping with sciatica, she was prescribed analgesia. Discharge was delayed due to a trauma call. On reassessment the patient had deteriorated and was noted to be hypotensive and tachycardia and subsequently transferred to resus. She underwent a CT angiogram revealing a ruptured external-iliac artery. She underwent emergency repair. Discussion: The patient has made a full recovery but had she not remained in the department during the trauma call she may have been sent home. This case serves to highlight the dangers of Ehlers-Danlos syndrome and remind clinicians to be aware of such patients and treat them with caution. This is an example of how younger patients compensate physiologically before acutely deteriorating Standardisation of Immunosuppression review at Renal Transplant clinic Michael Corr, Louise Sloan, Camille Harron, Stephanie Bolton Problem: The Renal Association guidelines for management of kidney transplant patients (KTP) recommend yearly review of immunosuppression (IS). Patient survival improves by addressing IS related mortality risk factors (MRF) and carefully reducing IS. In our unit, baseline data showed IS reviews were carried out every 32 months. Strategy for change: With multidisciplinary team (MDT) input driver diagrams were generated to set out aims and objectives. Plan-Do-Study-Act cycles facilitated change which was analysed continuously using statistical process charts. A transplant clinic template letter and MDT review assessments were created which were refined through subsequent cycles. Measurement of Improvement: 1.) Percentage KTP with documented IS plan and modification of MRF at each clinic 2.) Following adoption-adherence to template Effects of change: Over 3 month period percentage KTP with IS review rose from 9% to 85% enacting 29% more changes to IS compared to pre-intervention weekly. Modifiable risk factors addressed rose from 8% to 56%. Adherence once template adopted reached 93%. Project generated other change ideas e.g. information & dermatology leaflets. Discussion: This project demonstrates that by utilising the MDT and introducing a standardised approach increased frequency of IS review, adaptions to IS and addressing MRF. This could potentially be replicated by other transplant teams. Does High Fidelity Virtual Reality Simulation Have A Role In Foot and Ankle Arthroscopic Training? M. Robinson, R McKenna, D Gibson, J Wong. Background: The traditional method for arthroscopic training relies on appropriate clinical cases, costs particularly with operative time and has implications for patient safety. The Virtamed ArthroS was released in December 2017 and is the world’s first high-fidelity simulator for ankle arthroscopy. The primary aim of this study was to determine the utility of this arthroscopic simulator for training. Methods: Volunteers were recruited from medical students through to consultants. They performed five arthroscopic procedures under control conditions. A 10-minute demonstration on the setup and operation of the simulator was given prior to testing. Performance was evaluated by obtaining predefined metrics for each procedure within the simulator with photo and video acquisition. A questionnaire was administered to evaluate previous arthroscopic and video gaming experience, levels of stress, usefulness and authenticity. Results: Each arm consisted of a minimum of 5 participants from medical students, foundation level, core trainees, orthopaedic registrars and consultants. All groups demonstrated an improvement in time, economy and safety with 20 minutes exposure, reporting high levels of satisfaction and usefulness. Conclusion(s): The Virtamed ArthroS ankle module provides an authentic simulated experience for all levels of training with demonstrable improvements in performance, anatomy knowledge and reductions in adverse events. In the current climate of reduced working times and increased indicative arthroscopy numbers for completion of training the real-world benefits for orthopaedic trainees is promising. Exploiting TP53 mutation in colorectal cancer using a novel cdc7i

Introduction: KRAS mutations, the most frequent gain-of function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRASG12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849). Methods: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored. Results: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologicsubtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR)(G12C versus other KRAS) is equal to 1.39 (95% CI: 1.03 to 1.89, p = 0.031) and HRG12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p = 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HRG12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p = 0.030). In addition, among all patients, for relapse-free survival, HRG12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p = 0.017). Conclusions: In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Cardiac surgeries may expose pulmonary arterial tissue to systemic conditions, potentially resulting in failure of that tissue. Our goal was to quantitatively assess pulmonary artery adaptation due to changes in mechanical environment. In 17 sheep, we placed a pulmonary autograft in aortic position, with or without macroporous mesh reinforcement. It was exposed to systemic conditions for 6 months. All sheep underwent 3 ECG-gated MRI’s. Explanted tissue was subjected to mechanical and histological analysis. Results showed progressive dilatation of the unreinforced autograft, while reinforced autografts stabilized after two months. Some unreinforced pulmonary autograft samples displayed more aorta-like mechanical behavior with increased collagen deposition. The mechanical behavior of reinforced autografts was dominated by the mesh. The decrease in media thickness and loss of vascular smooth muscle cells was more pronounced in reinforced than in unreinforced autografts. In conclusion, altering the mechanical environment of a pulmonary artery causes changes in its mechano-biological properties.

According to a survey study of Wijsenbeek and colleagues [1], 76% of respiratory physicians believe fibrotic Hypersensitivity Pneumonitis (fibrotic HP, fHP) should be treated with corticosteroids (CS) as first line treatment. However, data to support such a strategy are limited and confined to acute farmeru0027s lung [2]. Classically, HP patients are classified according to symptom chronicity in acute and chronic HP [3]. Based on new data, however, a stratification according to the (radiological) presence of fibrosis seems more in line with prognosis [4]. In an earlier study [5], we demonstrated that CS treatment was only beneficial in non-fibrotic HP (nfHP) while CS was not effective in fHP, both in terms of survival, FVC% decline and DLCO% decline. In this study, we determined whether the presence of broncho-alveolar lavage lymphocytosis (BAL Lymphocytosis, BALL) or honeycombing (HC) influences the treatment effect of CS in fHP patients. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. De Sadeleer reports non-financial support from Roche, non-financial support from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr. Hermans has nothing to disclose. Conflict of interest: Dr. De Dycker has nothing to disclose. Conflict of interest: Dr. Yserbyt has nothing to disclose. Conflict of interest: Dr. Verschakelen has nothing to disclose. Conflict of interest: Dr. Verbeken has nothing to disclose. Conflict of interest: Dr. Verleden has nothing to disclose. Conflict of interest: Dr. E. Verleden has nothing to disclose. Conflict of interest: Dr. Wuyts reports grants from Roche, grants from Boehringer-Ingelheim, outside the submitted work.

Acute fibrinous and organising pneumonia (AFOP) after lung transplantation is associated with a rapid decline in pulmonary function. However, the relation with chronic lung allograft dysfunction (CLAD) remains unclear. We investigated the association between detection of AFOP in lung allograft biopsies with clinically important endpoints.We reviewed lung allograft biopsies from 468 patients who underwent lung transplantation at the University Hospitals Leuven (2011–2017). AFOP was categorised as early new-onset (≤90 days post-transplant) or late new-onset (>90 days post-transplant); and associated with CLAD-free survival, graft survival, donor-specific antibodies, airway and blood eosinophilia.Early and late AFOP was detected in 24 (5%) and 30 (6%) patients, respectively. CLAD-free survival was significantly lower in patients with late AFOP (median survival 2.42 years; p<0.0001) compared with patients with early or without AFOP and specifically associated with development of restrictive allograft syndrome (OR 28.57, 95% CI 11.34–67.88; p<0.0001). Similarly, graft survival was significantly lower in patients with late AFOP (median survival 4.39 years; p<0.0001) compared with patients with early AFOP or without AFOP. Late AFOP was furthermore associated with detection of circulating donor-specific antibodies (OR 4.75, 95% CI 2.17–10.60; p=0.0004) compared with patients with early or without AFOP, and elevated airway and blood eosinophilia (p=0.043 and p=0.045, respectively) compared with early AFOP patients.Late new-onset AFOP is associated with a worse prognosis and high risk of CLAD development, specifically restrictive allograft syndrome. Our findings indicate that late new-onset AFOP might play a role in the early pathogenesis of restrictive allograft syndrome.

The aim of this study was to assess in a multi-modular manner the bone healing 1 year post root-end surgery (RES) with leukocyte- and platelet-rich fibrin (LPRF) and Bio-Gide® (BG; Geistlich Pharma North America, Inc., Princeton, USA) as an occlusive membrane. A randomized controlled clinical trial (RCT) of RES +/− LPRF and +/− BG was performed. The follow-up until 1 year post RES was performed by means of ultrasound imaging (UI), periapical radiographs (PR), and cone-beam computed tomography (CBCT). From the 50 included patients, 6 dropped-out during follow-up. For the 44 assessed patients (34 with UI and 42 with PR and CBCT), there was no evidence (p > 0.05) for an effect of LRPF, neither on UI measurements nor on CBCT assessments. On the contrary, there was an indication for a better outcome with BG. UI presented significant shorter healing time for the bony crypt surface (p = 0.014) and cortical opening (p = 0.006) for the groups with BG. The qualitative CBCT assessment for the combined scores of the apical area and cortical plane was significantly higher for BG (p = 0.01 and 0.02). The quantitative CBCT measurement for bone healing after 1 year was lower with BG (p = 0.019), as well as the percentage of non-zero values (p = 0.026), irrespective of the preoperative lesion size and type. Furthermore, UI seemed to be safer for frequent follow-up during the early postoperative stage (0–3 months), whereas CBCT gave more accurate results 1 year post RES. Amongst the assessors, the qualitative PR analysis was inconsistent for a favorable outcome 1 year post RES with LPRF (p = 0.11 and p = 0.023), but consistent for BG (p = 0.024 and p = 0.023). There was no evidence for improvement of bone healing when RES was applied with LPRF in comparison with RES without LPRF. However, RES with BG gave evidence for a better outcome than RES without BG. The addition of an occlusive membrane rather than an autologous platelet concentrate improved bone regeneration 1 year post RES significantly, irrespective of the assessment device applied. The accuracy of PR assessment is questionable.

According to a survey study conducted by Wijsenbeek et al. [1], 76% of respiratory physicians believe fibrotic hypersensitivity pneumonitis (fibrotic HP, fHP) should be treated with corticosteroids (CS) as first line treatment. However, data to support such a strategy are limited and confined to acute farmer's lung [2]. Classically, HP patients are classified according to symptom chronicity in acute and chronic HP [3]. Based on new data, however, a stratification according to the (radiological) presence of fibrosis seems more in line with prognosis [4]. In an earlier study, we demonstrated that CS treatment was only beneficial in non-fibrotic HP while CS was not effective in fHP, both in terms of survival, and decline in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide ( D LCO) [5]. In the present study, we determined whether the presence of bronchoalveolar lavage lymphocytosis (BAL lymphocytosis, BALL) or honeycombing influences the treatment effect of CS in fHP patients. Low BAL lymphocytosis and presence of honeycombing predict poor outcome and absence of corticosteroid treatment effect in fibrotic hypersensitivity pneumonitis We thank the patients who participated in this study.

Limited results about treatment with total lymphoid irradiation (TLI) in lung transplant (LTx) recipients suffering from progressive bronchiolitis obliterans syndrome (BOS) have been reported. We performed a retrospective analysis of all LTx recipients undergoing TLI for progressive BOS in our center, focusing on long-term outcomes regarding overall survival and lung allograft function. Treatment with TLI (2004-2017, n = 20, 1 BOS stage 1, 6 BOS stage 2, and 13 BOS stage 3) resulted in significant attenuation of the FEV1 -decline in the majority of patients, mainly in those with a rapid decline (P = 0.0005). This allowed bridging to redo-transplantation in five patients. However, three patients progressed from BOS to RAS following prior TLI. Overall patient survival was 44% at 2 years post-TLI and 38% after 17 years. Generally, TLI was well tolerated, with limited side effects and no serious adverse events. TLI may attenuate the decline in FEV1 of LTx recipients with rapid progressive BOS and could thus help to bridge selected patients to redo-transplantation.

Acute peripheral facial nerve palsy is most frequently idiopathic (Bell's palsy) or virally induced, but can also be due to several other conditions. A rare cause is underlying systemic or autoimmune disease. A 79-year-old man presented with peripheral facial nerve palsy, malaise, and fever. Physical examination revealed tenderness of the left temporal artery and reduced pulsatility. 18F-FDG-PET/CT and biopsy of the temporal artery confirmed the diagnosis of giant cell arteritis (GCA). Prompt institution of corticosteroid therapy produced rapid decrease in inflammatory markers and gradual improvement of the facial nerve palsy. We searched the MEDLINE, Embase, and Scopus databases to identify previous reports of peripheral nerve palsy in GCA, other vasculitides, and autoimmune diseases. Facial nerve palsy as the presenting symptom of GCA has very rarely been reported. Although temporal artery biopsy is the gold standard for diagnosis, it may be negative in up to one-third of cases. In doubtful cases, imaging can help establish the diagnosis. Ultrasound, 3 T MRI, and 18F-FDG-PET/CT have all been previously reported to be useful. Peripheral facial nerve palsy may very rarely be the presenting symptom of GCA. Early correct diagnosis is essential for starting appropriate therapy. In patients with atypical features, 18F-FDG-PET/CT may be useful for establishing the diagnosis.

Gold et al 1 Gold W.M. Kaufman H.S. Nadel J.A. Elastic recoil of the lungs in chronic asthmatic patients before and after therapy. J Appl Physiol. 1967; 23: 433-438 Crossref PubMed Scopus (75) Google Scholar reported the reversible loss of lung elastic recoil during an acute exacerbation among nonsmoking patients with asthma, followed by a return of normal spirometry. Subsequently, from 2000 to 2004, we documented long-term loss of lung elastic recoil in nonsmoking patients with asthma with persistent expiratory airflow limitation despite therapeutic intervention. 2 Gelb A.F. Schein A. Nussbaum E. et al. Risk factors for near-fatal asthma. Chest. 2004; 126: 1138-1146 Abstract Full Text Full Text PDF PubMed Google Scholar However, lung computed tomography (CT) did not reveal significant lung tissue breakdown, and diffusing capacity remained normal. 2 Gelb A.F. Schein A. Nussbaum E. et al. Risk factors for near-fatal asthma. Chest. 2004; 126: 1138-1146 Abstract Full Text Full Text PDF PubMed Google Scholar These observations created a radiographic-physiological dilemma that needed to be addressed pathologically to reach a meaningful understanding.

Detailed data on postoperative death in lung transplant (LTx) recipients are lacking. Therefore, we investigated all deaths after LTx in a large, single-centre, 25-year follow-up cohort. Prevalence, time, place and cause of death (COD) were retrospectively analysed for all patients undergoing primary LTx between July 1991 and December 2015 in our centre. Over subsequent years, postoperative survival significantly improved, with proportionally more patients surviving to 1-year post-LTx (P < 0.0001). A total of 347 (38.9%) LTx recipients died, of which 53.6% expired within 3 years post-LTx [median time to death 910 (236-2447) days]. Autopsy was performed in 34.8% of deaths. COD included CLAD in 27.1% (BOS 63.8% vs. RAS 36.2%); infection (26.5%); malignancy (15.6%); postoperative complication (11.2%); cardiovascular disease (4.6%) or other causes (6.9%). In 8.1%, no clear COD could be determined. COD significantly differed between the various LTx indications (P = 0.047). With longer follow-up, infection becomes a less prevalent COD, but CLAD and malignancies a more important COD. The majority of patients died on the intensive care unit (40.6%) or hospital ward (29.1%), but place of death varied depending on the underlying COD. The current study provides insights into the postoperative deaths of LTx recipients.

OBJECTIVES:The purpose of this study was to investigate whether propagation velocities of naturally occurring shear waves (SWs) at mitral valve closure (MVC) increase with the degree of diffuse myocardial injury (DMI) and with invasively determined LV filling pressures as a reflection of an increase in myocardial stiffness in heart transplantation (HTx) recipients. BACKGROUND:After orthotopic HTx, allografts undergo DMI that contributes to functional impairment, especially to increased passive myocardial stiffness, which is an important pathophysiological determinant of left ventricular (LV) diastolic dysfunction. Echocardiographic SW elastography is an emerging approach for measuring myocardial stiffness in vivo. Natural SWs occur after mechanical excitation of the myocardium, for example, after MVC, and their propagation velocity is directly related to myocardial stiffness, thus providing an opportunity to assess myocardial stiffness at end-diastole. METHODS:A total of 52 HTx recipients who underwent right heart catheterization (all) and cardiac magnetic resonance (CMR) (n = 23) during their annual check-up were prospectively enrolled. Echocardiographic SW elastography was performed in parasternal long axis views of the LV using an experimental scanner at 1,135 ± 270 frames per second. The degree of DMI was quantified with T1 mapping. RESULTS:SW velocity at MVC correlated best with native myocardial T1 values (r = 0.75; p < 0.0001) and was the best noninvasive parameter that correlated with pulmonary capillary wedge pressures (PCWP) (r = 0.54; p < 0.001). Standard echocardiographic parameters of LV diastolic function correlated poorly with both native T1 and PCWP values. CONCLUSIONS:End-diastolic SW propagation velocities, as measure of myocardial stiffness, showed a good correlation with CMR-defined diffuse myocardial injury and with invasively determined LV filling pressures in patients with HTx. Thus, these findings suggest that SW elastography has the potential to become a valuable noninvasive method for the assessment of diastolic myocardial properties in HTx recipients.

Background: Familial pulmonary fibrosis (FPF) is a rare condition defined by the presence of at least two first line-relatives with interstitial lung disease (ILD) in one family. The aim of this study was to compare transplant-free survival outcomes from familial IPF (f-IPF) and sporadic IPF (s-IPF) patients. Methods: Clinical characteristics of all IPF patients referred for multidisciplinary expert discussion between 2005 and 2018 were retrospectively collected. Patients were stratified according to a family history of a first-line relative with ILD. Survival in patients with f-IPF was contrasted to s-IPF patients. Results: Within the 750 included IPF patients, 104 f-IPF patients (13.9%) were identified. Compared to s-IPF patients, f-IPF patients were significantly younger (68.7y vs 71.1y; p=0.0046), more frequent females (32.7 vs 20.6%; p=0.0086) and had a significantly more preserved diffusion capacity (DLCO 52.5 vs 48.2%; p=0.0024) at time of diagnosis. Both groups showed no difference in forced vital capacity (FVC) and treatment with antifibrotics. A family history of ILD was a significant risk factor for a worse transplant-free survival (p=0.0209; hazard ratio 1.51) in multivariate analysis by cox-proportional hazard model adjusted for GAP parameters (gender, age, FVC and DLCO) and treatment with antifibrotics. Conclusion: f-IPF patients have a worse transplant-free survival compared to s-IPF patients.

IntroductionThe PD-L1 biomarker is an important factor in selecting patients with non-small cell lung cancer for immunotherapy. While several reports suggest that PD-L1 positivity is linked to a poor prognosis, others suggest that PD-L1 positive status portends a good prognosis.MethodsPD-L1 positivity prevalence, assessed via immunohistochemistry (IHC) on tissue microarrays (TMAs), and its association with clinicopathological characteristics, molecular profiles and patient outcome- Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS)- is explored in the ETOP Lungscape cohort of stage I-III non-small cell lung cancer (NSCLC). Tumors are considered positive if they have ≥1/5/25/50% neoplastic cell membrane staining.ResultsPD-L1 expression was assessed in 2182 NSCLC cases (2008 evaluable, median follow-up 4.8 years, 54.6% still alive), from 15 ETOP centers. Adenocarcinomas represent 50.9% of the cohort (squamous cell: 42.4%). Former smokers are 53.7% (current: 31.6%, never: 10.5%). PD-L1 positivity prevalence is present in more than one third of the Lungscape cohort (1%/5% cut-offs). It doesn’t differ between adenocarcinomas and squamous cell histologies, but is more frequently detected in higher stages, never smokers, larger tumors (1/5/25% cut-offs). With ≥1% cut-off it is significantly associated with IHC MET overexpression, expression of PTEN, EGFR and KRAS mutation (only for adenocarcinoma). Results for 5%, 25% and 50% cut-offs were similar, with MET being significantly associated with PD-L1 positivity both for AC (p < 0.001, 5%/25%/50% cut-offs) and SCC (p < 0.001, 5% & 50% cut-offs and p = 0.0017 for 25%). When adjusting for clinicopathological characteristics, a significant prognostic effect was identified in adenocarcinomas (adjusted p-values: 0.024/0.064/0.063 for RFS/TTR/OS 1% cut-off, analogous for 5%/25%, but not for 50%). Similar results obtained for the model including all histologies, but no effect was found for the squamous cell carcinomas.ConclusionPD-L1 positivity, when adjusted for clinicopathological characteristics, is associated with a better prognosis for non-metastatic adenocarcinoma patients.

BACKGROUND:Associations between sarcoidosis or sarcoid-like granulomatous lung disease and exposure to silica and other inorganic agents have been suggested in several studies.CASES:We describe granulomatous lung disease in two workers of a small production unit making metal-halide lamps. Initially, both were diagnosed with sarcoidosis. However, in both men, birefringent particles were observed in the lung or mediastinal lymph node biopsies. Clipping of glass tubes led to moderate exposure to dust, consisting mainly of amorphous fused silica, with some cristobalite. After removal from exposure, both subjects improved clinically, radiologically, and functionally.CONCLUSION:The present cases support the hypothesis that silica might be a trigger for sarcoid-like granulomatous lung disease. Sarcoidosis should be considered a diagnosis of exclusion and clinicians should carefully collect occupational and environmental exposure histories to identify workplace triggers.

BACKGROUND:Although the third most frequent interstitial lung disease, hypersensitivity pneumonitis (HP) remains an enigmatic disease without clear diagnostic and therapeutic guidelines. We assessed the effect of the commonly used therapeutic interventions (i.e. exposure avoidance and corticosteroid treatment) in an HP cohort.METHODS:We collected clinical data of all HP patients followed at our centre between January 1, 2005, and December 31, 2016. HP patients were stratified according to the presence of fibrosis on chest CT. Survival was analysed using the multivariate Cox proportional hazards model. Forced vital capacity (percent predicted, FVC%) and diffusing capacity of the lung for carbon monoxide (percent predicted, DLCO%) evolution were analysed using linear mixed-effect models.RESULTS:Two hundred and two HP patients were identified: 93 non-fibrotic HP (nfHP) and 109 fibrotic HP (fHP), experiencing a monthly FVC% decline before treatment of 0.93% and 0.56%, respectively. While nfHP had an excellent survival, fHP patients experienced a median survival of 9.2 years. Corticosteroid treatment and exposure avoidance did not result in survival differences. Although nfHP patients showed FVC% and DLCO% increase after corticosteroid initiation, no therapeutic effect was seen in fHP patients. FVC% and DLCO% increased in nfHP patients after exposure avoidance, while a positive numerical trend was seen for FVC% after exposure avoidance in fHP patients (p = 0.15).CONCLUSIONS:nfHP patients experienced an excellent survival with good therapeutic effect on pulmonary function tests with both corticosteroid initiation as well as antigen avoidance. In contrast, fHP patients experienced a dismal prognosis (median survival of 9.2 years) without any therapeutic effect of corticosteroid treatment. Whether antigen avoidance is useful in fHP patients is still unclear.