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Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity. The host immune response plays a critical role in the immunopathology of SARS-CoV2. Here the authors combine a systems biology approach to implicate monocytes as key drivers of cytokine storm and disturbed neutrophil activation in COVID-19 disease severity.

Probe-based confocal laser endomicroscopy (pCLE) was performed in 15 patients with emphysema and 15 healthy subjects to visualise small airways in a direct and dynamic way. Morphometry shows that the median cross-sectional area of the alveolar openings at the level of the alveolar ducts is significantly larger in emphysema (7.2×104 µm2) as compared with healthy subjects (5.2×104 µm2) (p=0.0002). Normalised autofluorescence intensity histograms show a decrease in median autofluorescence intensity (mAFI) in emphysema (p=0.001). mAFI correlates well with Tiffeneau index (r=0.66, p=0.007, 95% CI 0.21 to 0.88). Autofluorescence intensity in emphysema correlates with corresponding data of CT-based quantification. pCLE-based morphometry and autofluorescence intensity analysis in emphysema is able to detect regional changes inside the ‘quiet zone’.Trial registration numberResults, NCT01204970.

Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients’ molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.

Bronchoscopic lung volume reduction (BLVR) using one-way endobronchial valves (EBV) is a minimally invasive treatment for patients with advanced emphysema and severe hyperinflation. While several randomized controlled trials have demonstrated improvements in lung function, exercise performance, and quality of life, information on long-term outcomes of BLVR outside clinical trial settings are limited. This study provides real-world data with a follow-up of up to two years, incorporating the BODE index (Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index), as part of the follow-up assessments. Data were collected for all patients treated with BLVR at the University Hospitals of Leuven, Belgium, including lung function parameters, 6-minute walking distance, respiratory questionnaires, and the BODE index at intervals of 3, 6, 12, and 24 months. A composite outcome combining FEV1 (forced expiratory volume in 1 second), 6MWD (6-minute walk distance), and SGRQ (St. George's Respiratory Questionnaire) was used to evaluate the overall impact of BLVR. Mixed model analyses were performed. All outcome parameters, including FEV1, residual volume (RV), 6MWD, modified Medical Research Council (mMRC) and SGRQ exhibited significant improvement up to 1 year of treatment. RV and mMRC maintained statistical significance compared to baseline at the 2-year follow-up. The BODE index as well, revealed a significant improvement persisting up to 2 years of treatment. Response rate for the composite outcome was 86% (44/51) at one year and 71% (17/24) at 2 years follow-up. Follow-up data of a real-world setting show maintained benefits of bronchoscopic lung volume reduction with endobronchial valves up to 2 years after treatment, for patients of whom the valves are still in situ. A potential survival benefit of BLVR, based on BODE, and high response rate on the composite outcome was present, in patients who remained in follow-up.

Patients with resectable lung cancer were assigned to neoadjuvant pembrolizumab or placebo plus chemotherapy and adjuvant pembrolizumab or placebo. Two-year event-free survival was 62.4% with pembrolizumab and 40.6% with placebo.

Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4–20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3–7·8] vs 4·5 months [3·0–5·7]; hazard ratio 0·66 [0·51–0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. Amgen.

Pulmonary alveolar (phospholipo)proteinosis (PAP) is a rare lung disease, predominantly autoimmune in nature. This case report describes a patient with insidious dyspnoea since 5 ♣years and a milky appearance of her bronchoalveolar fluid, leading to the diagnosis of PAP. The onset of symptoms coincided with an exchange of her silicone breast implants. Giant cell reaction in axillary adenopathies pointed towards silicone leakage. Adjuvants, such as silicone, might boost pre-existing antigen reactions of the immune system, potentially leading to autoimmune phenomena.

Background About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). Methods This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. Discussion The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. Trial registration ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018–002583-11 ; Clinicaltrials.gov: NCT03705403 ; ISRCTN ID: ISRCTN49817477 ; Date of registration: 03-April-2019.

BackgroundWe recently published clinical results of ASTER, a randomised controlled trial in which endosonography, a strategy of combined endoscopic (EUS) and endobronchial (EBUS) ultrasound (followed by surgical staging if these tests were negative for malignancy), had significantly higher sensitivity and negative predictive value than surgical staging alone for mediastinal staging in NSCLC. Here we present ASTER quality of life (QoL) and cost-effectiveness outcomes.MethodsEuroQoL EQ-5D questionnaire was performed at baseline, end of staging, 2 and 6 months post randomisation. The UK EQ-5D social tariff was applied to calculate utility values. Quality-adjusted survival was estimated using the area under the utility curve. Full resource use information was recorded for all patients and NHS 2008–2009 Reference Costs were applied. Total expected costs over 6 months were estimated by summing the resource use multiplied by its unit cost and taking the sample average for each group.ResultsOf 241 randomised patients, 144 (60%) provided EQ-5D data at baseline; of these 139 (97%) were followed up at the end of staging, 132 (92%) at 2 months and 124 (86%) at 6 months. At the end of staging, those randomised to endosonography had significantly better QoL than those randomised to surgical staging (utility difference=0.11, 95%CI 0.02 to 0.19). At all other time points, there was little difference between the groups, so that quality adjusted survival over the 6 months was similar (4.1 vs 4.0 months respectively). Complete resource use data were available for 172/214 (71%) patients. Other than the number of thoracotomies performed (66% of patients in the surgical staging arm and 53% in the endosonography arm) resource use did not differ between the two groups. The endosonography group had a non-significant cost saving of £746 per patient compared to the surgical staging group.ConclusionsGiven that (a) the sensitivity of endosonography was significantly higher than that of the surgical staging arm; (b) QoL post-staging was higher in the endosonography arm and (c) there is no difference in cost between the two strategies, mediastinal staging should commence with endosonography proceeding to surgical staging if there is no evidence of malignancy.

A 37-year-old woman presented at casualty with a 1-day history of progressive spontaneous left iliac fossa pain. She was having her menstruations for 4 days. She had no respiratory symptoms. Her medical history consisted of laparoscopic surgery for endometriosis and ovarian cysts. A very small right basal pneumothorax with visualisation of a hypervascular nodular lesion on the right diaphragm was incidentally noticed on the right diaphragm. We suspected here a catamenial pneumothorax. During video-assisted thoracoscopy the surgeon observed in the centrum tendineum of the diaphragm a small and a large perforation with partial intrathoracic herniation of the liver, but without visible diaphragmatic or pleural endometriosis. The surgeons converted to a small anterior thoracotomy in order to reinforce the large perforation with interrupted non-absorbable sutures and plication of the smaller perforation, and finally performed a mechanical pleural abrasion with a surgical pad.