Mucus Release and Airway Constriction by TMEM16A May Worsen Pathology in Inflammatory Lung Disease.

Activation of the Ca2+ activated Cl- channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of activation of TMEM16A was shown in vitro and in studies in sheep, but others reported an increase in mucus production and airway contraction by activation of TMEM16A. We analyzed expression of TMEM16A in healthy and inflamed human and mouse airways and examined the consequences of activation or inhibition of TMEM16A in asthmatic mice. TMEM16A was found to be upregulated in the lungs of patients with asthma or cystic fibrosis, as well as in the airways of asthmatic mice. Activation or potentiation of TMEM16A by the compounds Eact or brevenal, respectively, induced acute mucus release from airway goblet cells and induced bronchoconstriction in mice in vivo. In contrast, niclosamide, an inhibitor of TMEM16A, blocked mucus production and mucus secretion in vivo and in vitro. Treatment of airway epithelial cells with niclosamide strongly inhibited expression of the essential transcription factor of Th2-dependent inflammation and goblet cell differentiation, SAM pointed domain-containing ETS-like factor (SPDEF). Activation of TMEM16A in people with inflammatory airway diseases is likely to induce mucus secretion along with airway constriction. In contrast, inhibitors of TMEM16A may suppress pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction, partially by inhibiting expression of SPDEF.

Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project.

INTRODUCTION: KRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (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 "histologic-subtype" 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.

Enhanced lung inflammatory response in whole-body compared to nose-only cigarette smoke-exposed mice.

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.

Facial nerve palsy in giant-cell arteritis: case-based review.

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.

Multi-modular bone healing assessment in a randomized controlled clinical trial of root-end surgery with the use of leukocyte- and platelet-rich fibrin and an occlusive membrane.

OBJECTIVES: 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. MATERIALS AND METHODS: 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). RESULTS: 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). CONCLUSIONS: 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. CLINICAL RELEVANCE: 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.

Histopathologic and radiologic assessment of nontransplanted donor lungs.

Donor organ shortage results in significant waiting list mortality. Donor lung assessment is currently based on donors' history, gas exchange, chest X-ray, bronchoscopy findings, and ultimately in situ inspection but remains subjective. We correlated histopathology and radiology in nontransplanted donor lungs with the clinical indications to decline the offered organ. Sixty-two donor lungs, not used for transplantation (2010-2019), were procured, air-inflated, frozen, scanned with computed tomography, systematically sampled, and histologically and radiologically assessed. Thirty-nine (63%) lungs were declined for allograft-related reasons. In 13/39 (33%) lungs, histology could not confirm the reason for decline, in an additional 8/39 (21%) lungs, histologic abnormalities were only considered mild. In 16/39 (41%) lungs, radiology could not confirm the reason for decline. Twenty-three (37%) donor lungs were not transplanted due to extrapulmonary causes, of which three (13%) lungs displayed severe histologic abnormalities (pneumonia, n = 2; emphysema, n = 1), in addition to mild emphysema in 9 (39%) lungs and minor bronchopneumonia in 1 (4%). Radiology revealed ground-glass opacities in 8/23 (35%) and emphysema in 4/23 (17%) lungs. Histopathologic and radiologic assessment of nontransplanted donor lungs revealed substantial discrepancy with the clinical reason for decline. Optimization of donor lung assessment is necessary to improve current organ acceptance rates.

Total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation: a single-center experience and review of literature.

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.

Mortality after lung transplantation: a single-centre cohort analysis.

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.

Granulomatous lung disease in two workers making light bulbs.

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.

A retrospective cohort study of PD-L1 prevalence, molecular associations and clinical outcomes in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape Project.

INTRODUCTION: The 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. METHODS: PD-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. RESULTS: PD-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. CONCLUSION: PD-L1 positivity, when adjusted for clinicopathological characteristics, is associated with a better prognosis for non-metastatic adenocarcinoma patients.

Regenerative Endodontic Procedures Posttrauma: Immunohistologic Analysis of a Retrospective Series of Failed Cases.

INTRODUCTION: Regenerative endodontic procedures (REP) are a novel treatment modality to restore the function of necrotic pulp tissue via stimulation or transplantation of stem cells into the root canal. This study aimed to investigate the immunohistologic outcome of 3 extracted teeth because of sequelae of trauma and unsatisfactory REP outcomes. METHODS: Three immature permanent maxillary central incisors of 3 female patients (6-9 years) were extracted 5.5-22 months after REP. Additionally, 1 sound permanent immature central maxillary incisor of 1 of the included patients was extracted for orthodontic reasons. The teeth were immunohistologically stained with Masson's trichrome, neurofilament (NF), pan cytokeratin, dentin sialophosphoprotein, and Gram+/-. RESULTS: The REP-teeth presented intracanalar vascularized connective/mineralized reparative tissue (RT), which was less organized than the pulp tissue of the sound tooth. Moderate to considerable calcification was observed below the Portland cement used during REP. In 1 case, the RT was NF+; in the 2 other cases, the periodontal ligament and apical granuloma/papilla were NF+. All teeth were Gram+/- negative; nevertheless, inflammatory cells were present in 2 cases. The pan cytokeratin and dentin sialophosphoprotein stainings were not specific enough for 2 cases. CONCLUSIONS: This immunohistologic study of failed REP cases resulted in bacteria-free intracanalar RT and biomaterial-induced calcification. Nevertheless, the presence of inflammatory cells revealed a persistent inflammation. Hence, the clinical and radiographic signs were decisive for tooth survival and multidisciplinary outcome determination.

Combined modality treatment for malignant pleural mesothelioma: a single-centre long-term survival analysis using extrapleural pneumonectomy.

OBJECTIVES: Combined modality treatment (CMT) for malignant pleural mesothelioma (MPM) remains a matter of debate regarding the choice of surgical procedure: extrapleural pneumonectomy (EPP) or pleurectomy/decortication. METHODS: We performed a prospective interventional cohort study between 2003 and 2014. All consecutive patients with any histological MPM subtype, ≤70 years old, World Health Organization performance status ≤1, medically fit for pneumonectomy and stage cT1-2cN0-2cM0 (TNM7) or lower were included. Eligibility for CMT was discussed by the multidisciplinary tumour board. Our local CMT protocol consisted of induction chemotherapy, followed by EPP and hemithoracic radiotherapy. Induction chemotherapy consisted of 3 cycles of cisplatin (75 mg/m2 day 1) and pemetrexed (500 mg/m2 day 1), each administered once every 3 weeks. If non-progressive, EPP was performed followed by hemithoracic radiotherapy (most frequently, intensity-modulated radiotherapy; dose 54 Gy/1.8 Gy ± boost). Feasibility and long-term survival analyses were performed. Overall survival and disease-free survival (DFS) were calculated from histological confirmation of a diagnosis of MPM. RESULTS: Out of 197 patients, 97 started with CMT (79 epithelioid, 15 mixed and 3 sarcomatoid tumours, based on histological analysis). Clinical TNM was IA (n = 9)/IB (n = 8)/II (n = 57)/III (n = 23). A total of 76 patients underwent surgery (EPP: n = 56; exploratory thoracotomy: n = 20). The in-hospital mortality rate was 3.6%. Out of 56 patients who underwent surgery, 47 completed the entire CMT protocol. The intent-to-treat median and 5-year OS were 22.4 [95% confidence interval (CI) = 15.5-27.9] months and 11.2% (95% CI = 6.9-23.4). In patients who completed the CMT protocol (n = 47), these values were 33.2 (95% CI = 23.0-45.0) months and 24.2% (95% CI = 13.4-43.8). The intent-to-treat median and 5-year DFS were 15.6 (95% CI = 14.0-17.3) months and 9.9% (95% CI = 5.1-19.2), 19.8 (95% CI = 16.8-27.7) months and 17.2% (95% CI = 8.6-34.1) in those who had the full CMT. The Cox proportional hazards model showed a significantly lower DFS in positive lymph nodes (HR 2.79, 95% CI=1.35-5.78; P=0.006). In 30 (64%) patients with epithelioid type MPM without positive lymph nodes (pN0) after EPP, the 5-year DFS was 27.0% (95% CI=14.1-51.7). CONCLUSIONS: CMT with EPP for MPM is feasible, with an acceptable surgical mortality rate, and results in a 5-year survival rate of 24%. Careful patient selection (staging and physical performance) is extremely important.

Computer-Based Intensity Measurement Assists Pathologists in Scoring Phosphatase and Tensin Homolog Immunohistochemistry - Clinical Associations in NSCLC Patients of the European Thoracic Oncology Platform Lungscape Cohort.

INTRODUCTION: Phosphatase and tensin homolog (PTEN) loss is frequently observed in NSCLC and associated with both phosphoinositide 3-kinase activation and tumoral immunosuppression. PTEN immunohistochemistry is a valuable readout, but lacks standardized staining protocol and cutoff value. METHODS: After an external quality assessment using SP218, 138G6 and 6H2.1 anti-PTEN antibodies, scored on webbook and tissue microarray, the European Thoracic Oncology Platform cohort samples (n = 2245 NSCLC patients, 8980 tissue microarray cores) were stained with SP218. All cores were H-scored by pathologists and by computerized pixel-based intensity measurements calibrated by pathologists. RESULTS: All three antibodies differentiated six PTEN+ versus six PTEN- cases on external quality assessment. For 138G6 and SP218, high sensitivity and specificity was found for all H-score threshold values including prospectively defined 0, calculated 8 (pathologists), and calculated 5 (computer). High concordance among pathologists in setting computer-based intensities and between pathologists and computer in H-scoring was observed. Because of over-integration of the human eye, pixel-based computer H-scores were overall 54% lower. For all cutoff values, PTEN- was associated with smoking history, squamous cell histology, and higher tumor stage (p < 0.001). In adenocarcinomas, PTEN- was associated with poor survival. CONCLUSION: Calibration of immunoreactivity intensities by pathologists following computerized H-score measurements has the potential to improve reproducibility and homogeneity of biomarker detection regarding epitope validation in multicenter studies.

A Randomized Clinical Trial of Flex 19G Needles versus 22G Needles for Endobronchial Ultrasonography in Suspected Lung Cancer.

BACKGROUND: A flexible 19-gauge (Flex 19G) needle has been developed for endobronchial ultrasonography. OBJECTIVES: We aimed to evaluate quantitative and qualitative specimen characteristics of Flex 19G in a randomized controlled setting for patients with suspected lung cancer. METHODS: We undertook a single-center, randomized, controlled trial. A computer-generated randomization assigned all enrolled patients 1: 1 to undergo endobronchial ultrasonography using a Flex 19G or a 22-gauge (22G) needle for lymph node tissue sampling. Pathologists were blinded to the group assignment. The primary end point was histological tissue core procurement. The secondary end points were diagnostic yield, specimen bloodiness and overall quality, tissue surface area and performance for next-generation sequencing (NGS), and procedure-related complications. RESULTS: Between June 2016 and February 2017, we randomly allocated a total of 78 patients: 39 patients to Flex 19G and 39 patients to 22G. No superiority in tissue core procurement was observed for Flex 19G compared to 22G (67 vs. 72%, p = 0.81). No significant difference was observed in diagnostic yield and overall specimen quality, but transbronchial needle aspiration specimens by Flex 19G were bloodier and had a larger tissue surface area. NGS was successful for clinically relevant genes in 96% and for all 26 genes tested in 81% of the samples. There was no difference in clinically relevant complications. CONCLUSIONS: No superiority is observed for Flex 19G in histological tissue core procurement rate. The Flex 19G needle could be considered when a larger tissue surface is of special interest.

Reinforcing the pulmonary artery autograft in the aortic position with a textile mesh: a histological evaluation.

OBJECTIVES: The Ross procedure involves replacing a patient's diseased aortic valve with their own pulmonary valve. The most common failure mode is dilatation of the autograft. Various strategies to reinforce the autograft have been proposed. Personalized external aortic root support has been shown to be effective in stabilizing the aortic root in Marfan patients. In this study, the use of a similar external mesh to support a pulmonary artery autograft was evaluated. METHODS: The pulmonary artery was translocated as an interposition autograft in the descending thoracic aortas of 10 sheep. The autograft was reinforced with a polyethylene terephthalate mesh (n = 7) or left unreinforced (n = 3). After 6 months, a computed tomography scan was taken, and the descending aorta was excised and histologically examined using the haematoxylin-eosin and Elastica van Gieson stains. RESULTS: The autograft/aortic diameter ratio was 1.59 in the unreinforced group but much less in the reinforced group (1.11) (P < 0.05). A fibrotic sheet, variable in thickness and containing fibroblasts, neovessels and foreign body giant cells, was incorporated in the mesh. Histological examination of the reinforced autograft and the adjacent aorta revealed thinning of the vessel wall due to atrophy of the smooth muscle cells. Potential spaces between the vessel wall and the mesh were filled with oedema. CONCLUSIONS: Reinforcing an interposition pulmonary autograft in the descending aorta with a macroporous mesh showed promising results in limiting autograft dilatation in this sheep model. Histological evaluation revealed atrophy of the smooth muscle cell and consequently thinning of the vessel wall within the mesh support.

Clinical behaviour of patients exposed to organic dust and diagnosed with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Although idiopathic pulmonary fibrosis (IPF) patients experience a worse survival compared with chronic hypersensitivity pneumonitis (CHP), organic dust exposure is a known risk factor for both IPF and CHP. METHODS: We divided patients diagnosed with IPF, based on their exposure to moulds/birds (absent: group A; present: group B). We retrospectively compared pulmonary function and survival between groups A and B, and a separate CHP cohort (group C). RESULTS: A total of 293 patients were included (group A: n = 171, group B: n = 73, group C: n = 49). Demographics and baseline pulmonary function did not differ between groups A and B, but significant differences were seen between groups B and C. Median survival of group B was 84 months, which was longer than group A (43 months, P = 0.002), but lower than group C (157 months, P = 0.04), in both univariate and multivariate analyses. Antifibrotic treatment resulted in a better outcome in group A (hazard ratio (HR): 0.44) and group B (HR: 0.12) without interaction between exposure and antifibrotic use (P = 0.20). Forced vital capacity (FVC) decline was not associated with mould/bird exposure in this cohort. CONCLUSION: Group B patients experienced a better outcome compared with (non-exposed) IPF patients, although worse compared with CHP patients. Antifibrotic treatment in group B resulted in a similar beneficial effect compared with group A. Further research is needed to ascertain the diagnostic designation in this exposed usual interstitial pneumonia (UIP) patient group without other CHP features.

Creation of Abdominal Aortic Aneurysms in Sheep by Extrapolation of Rodent Models: Is It Feasible?

BACKGROUND: Abdominal aortic aneurysms (AAAs) are a potentially deathly disease, needing surgical or endovascular treatment. To evaluate potentially new diagnostic tools and treatments, a large animal model, which resembles not only the morphological characteristics but also the pathophysiological background, would be useful. METHODS: Rodent animal aneurysm models were extrapolated to sheep. Four groups were created: intraluminal infusion with an elastase-collagenase solution (n = 4), infusion with elastase-collagenase solution combined with proximal stenosis (n = 7), aortic xenograft (n = 3), and elastase-collagenase-treated xenograft (n = 4). At fixed time intervals (6, 12, and 24 weeks), computer tomography and autopsy with histological evaluation were performed. RESULTS: The described models had a high perioperative mortality (45%), due to acute aortic thrombosis or fatale hemorrhage. A maximum aortic diameter increase of 30% was obtained in the protease-stenosis group. In the protease-treated groups, some histological features of human AAAs, such as inflammation, thinning of the media, and loss of elastin could be reproduced. In the xenotransplant groups, a pronounced inflammatory reaction was visible at the start. In all models, inflammation decreased and fibrosis occurred at long follow-up, 24 weeks postoperatively. CONCLUSIONS: None of the extrapolated small animal aneurysm models could produce an AAA in sheep with similar morphological features as the human disease. Some histological findings of human surgical specimens could be reproduced in the elastase-collagenase-treated groups. Long-term histological evaluation indicated stabilization and healing of the aortic wall months after the initial stimulus.

Diagnostic Ability of a Dynamic Multidisciplinary Discussion in Interstitial Lung Diseases: A Retrospective Observational Study of 938 Cases.

BACKGROUND: The advice of a dynamic multidisciplinary discussion (MDD) is believed to be important in the diagnosis of interstitial lung diseases (ILDs). However, to what extent MDD diagnoses differ from the preliminary diagnoses before formal workup and MDD (preMDD diagnoses) is still insufficiently studied. METHODS: We compared preMDD and MDD diagnoses in patients discussed at the Leuven University Hospitals MDDs between January 2005 and December 2015. RESULTS: Of 938 consecutive patients discussed in an MDD, 755 (80.5%) received a specific diagnosis. From the 183 patients with unclassifiable ILD, 150 patients (16.0%) received suggestions concerning further investigations to establish a definite diagnosis. In 191 patients (41.9% of patients with a preMDD diagnosis), the MDD changed the diagnosis. In 384 patients (79.5% of patients without preMDD diagnosis), MDD provided a diagnosis when the referring physician did not. MDD diagnosis showed a trend toward better prognostic discrimination between idiopathic pulmonary fibrosis and other ILDs compared with preMDD diagnosis (Harrell C-index, 0.666 vs 0.631; P = .08), which was particularly clear in patients with discordant MDD and preMDD diagnoses (hazard ratio, 2.68 vs 0.84; P = .012 vs .768). CONCLUSIONS: The MDD provided a definite diagnosis in 80.5% of presented cases, suggesting further investigations in almost all others. Given the high number of patients without preMDD diagnosis, the rate of change in preMDD diagnoses (41.9% of patients with a preMDD diagnosis) probably is an underestimation. The better prognostic discrimination among ILDs by using MDD indicates the added value of MDD in ILD.

Is central lung tumour location really predictive for occult mediastinal nodal disease in (suspected) non-small-cell lung cancer staged cN0 on 18F-fluorodeoxyglucose positron emission tomography-computed tomography?

OBJECTIVES: Current guidelines recommend preoperative invasive mediastinal staging in centrally located tumours with negative mediastinum on positron emission tomography-computed tomography, based on a 20-30% prevalence of occult mediastinal disease (pN2-3). However, a uniform definition of central tumour location is lacking. Our objective was to determine the best definition in predicting occult pN2-3. METHODS: A single-institution database was queried for patients with (suspected) non-small-cell lung cancer staged cN0 after positron emission tomography-computed tomography and referred to invasive staging and/or primary surgery. We evaluated 5 definitions: inner 1/3, inner 2/3, contact with bronchovascular structures, ≤2 cm from bronchus or endobronchial visualization. RESULTS: Between 2005 and 2015, 813 patients were eligible (cT1: 42%, cT2: 28%, cT3: 17% and cT4: 11%). Invasive mediastinal staging and resection were performed in 30% and 97% of patients, respectively. Any nodal upstaging (pN+) was found in 21% of patients, of whom pN2-3 was found in 8%. Central tumour location demonstrated 4 times higher odds for any pN+ [for inner 1/3 vs outer 2/3, odds ratio 3.90 (95% confidence interval 2.24-6.77), P < 0.001], whereas no significantly different odds was observed for pN2-3. The discriminative ability for pN+ was not significantly different between the several definitions. CONCLUSIONS: The prevalence of occult pN2-3 was only 8% when modern fusion positron emission tomography-computed tomography imaging pointed at clinical N0 non-small-cell lung cancer. None of the 5 verified definitions of centrality was predictive for occult pN2-3. However, each definition of centrality was related to any pN+ at a prevalence of 21%, without significant differences in discriminative ability between definitions. These data question whether indication for preoperative invasive mediastinal staging should be based on centrality alone.