Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade.

RATIONALE: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. OBJECTIVES: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. METHODS: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with non-small cell lung cancer and patients with melanoma. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. CONCLUSIONS: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Pulmonary Surfactant Proteins Are Inhibited by Immunoglobulin A Autoantibodies in Severe COVID-19.

Rationale: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. Objectives: To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity. Methods: We collected 147 blood, 9 lung tissue, and 36 BAL fluid samples from three tertiary hospitals in Switzerland and one in Germany. Severe COVID-19 was defined by the need to administer oxygen. We investigated the presence of IgA autoantibodies and their effects on pulmonary surfactant in COVID-19 using the following methods: immunofluorescence on tissue samples, immunoprecipitations followed by mass spectrometry on BAL fluid samples, enzyme-linked immunosorbent assays on blood samples, and surface tension measurements with medical surfactant. Measurements and Main Results: IgA autoantibodies targeting pulmonary surfactant proteins B and C were elevated in patients with severe COVID-19 but not in patients with influenza or bacterial pneumonia. Notably, pulmonary surfactant failed to reduce surface tension after incubation with either plasma or purified IgA from patients with severe COVID-19. Conclusions: Our data suggest that patients with severe COVID-19 harbor IgA autoantibodies against pulmonary surfactant proteins B and C and that these autoantibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation.

CCL19-producing fibroblastic stromal cells restrain lung carcinoma growth by promoting local antitumor T-cell responses.

BACKGROUND: A particular characteristic of non-small cell lung cancer is the composition of the tumor microenvironment with a very high proportion of fibroblastic stromal cells (FSCs). OBJECTIVE: Lapses in our basic knowledge of fibroblast phenotype and function in the tumor microenvironment make it difficult to define whether FSC subsets exist that exhibit either tumor-promoting or tumor-suppressive properties. METHODS: We used gene expression profiling of lung versus tumor FSCs from patients with non-small cell lung cancer. Moreover, CCL19-expressing FSCs were studied in transgenic mouse models by using a lung cancer metastasis model. RESULTS: CCL19 mRNA expression in human tumor FSCs correlates with immune cell infiltration and intratumoral accumulation of CD8+ T cells. Mechanistic dissection in murine lung carcinoma models revealed that CCL19-expressing FSCs form perivascular niches to promote accumulation of CD8+ T cells in the tumor. Targeted ablation of CCL19-expressing tumor FSCs reduced immune cell recruitment and resulted in unleashed tumor growth. CONCLUSION: These data suggest that a distinct population of CCL19-producing FSCs fosters the development of an immune-stimulating intratumoral niche for immune cells to control cancer growth.

Treatment of COPD Exacerbation in Switzerland: Results and Recommendations of the European COPD Audit.

BACKGROUND: The European COPD Audit initiated by the European Respiratory Society (ERS) evaluated the management of hospital admissions due to exacerbation of chronic obstructive pulmonary disease (COPD) in several European countries. Data on the treatment of severe acute exacerbations of COPD (AECOPDs) in Switzerland are scarce. OBJECTIVES: In light of the GOLD 2010 guidelines, this work aims to examine the quality of care for AECOPD and to provide specific recommendations for the management of severe AECOPD in Switzerland. METHODS: A total of 295 patients requiring hospital admission to 19 Swiss hospitals due to exacerbation of COPD during a predefined 60 days in 2011 were included in the study. We compared the Swiss data to the official GOLD 2010 recommendations and to the results of the other European countries. RESULTS: Approximately 43% of the Swiss patients with severe AECOPD were current smokers at hospital admission, compared to 33% of the patients in other European countries (p < 0.001). In Switzerland and in Europe, spirometry data were not available for most patients at hospital admission (65 and 60%, respectively; p = 0.08). In comparison to other European countries, antibiotics were prescribed 14% less often in Switzerland (p < 0.001). Only 79% of the patients in the Swiss cohort received treatment with a short-acting bronchodilator at admission. CONCLUSIONS: Considering the overall high standard of health care in Switzerland, in light of the GOLD 2010 guidelines we are able to make 7 recommendations to improve and standardize the management of severe AECOPD for patients treated in Switzerland.

Interference with the CXCL12/CXCR4 axis as potential antitumor strategy: superiority of a sulfated galactofucan from the brown alga Saccharina latissima and fucoidan over heparins.

The present study demonstrates that fucose-containing sulfated polysaccharides (FCSP) from brown algae interfere with the CXCL12/CXCR4 axis in human Burkitt's lymphoma cells by binding CXCL12 and thereby blocking both CXCL12-induced CXCR4 receptor activation and downstream effects like migration and secretion of matrix metalloproteinase-9. This mode of action is currently considered as promising strategy for tumor therapy and may contribute to the known in vivo antitumor, antimetastatic and antiangiogenic activity of FCSP. In terms of the inhibition of the CXCR4 activation, FCSP from Saccharina latissima (S.l.-FCSP) proved to be more active than a commercial "Fucoidan" from Fucus vesiculosus, and both FCSP were superior to heparins by more than one order of magnitude. Fractionation of S.l.-FCSP revealed that its main fraction is composed of a homogeneous, higher sulfated galactofucan (S.l.-SGF) which consistently exhibited stronger activities and can therefore be considered as the active ingredient of S.l.-FCSP. By subjecting Fucoidan to the same fractionation procedure, the inhibitory activity of the obtained purified Fucoidan on the CXCL12/CXCR4 axis tended to be weaker and its antioxidant and antiproliferative effects were lost. This was probably due to the separation of contaminants including phenolic compounds, whose content additionally showed marked batch-to-batch variability. Regarding the need of standardized, well-characterized FCSP preparations for any potential medical application, our results indicate that S.l.-SGF is a promising candidate for further investigations and that S. latissima may be a more appropriate source of FCSP than F. vesiculosus or other algae species with high contents of co-extractable compounds.

Endobronchial ultrasound-guided transbronchial needle aspiration of an intravascular sarcoma metastasis.

The role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of endovascular lesions has rarely been described. We report a case of EBUS-TBNA of a solid mass in the left pulmonary artery in a patient with synovial sarcoma of the kidney, which was performed without complications and led to the diagnosis of metastatic disease. EBUS-TBNA seems to be a rapid, minimally invasive, safe and effective diagnostic procedure in selected cases of endovascular lesions.

Individualised PPI prescription in patients on combination antiplatelet therapy and upper gastrointestinal events after percutaneous coronary intervention: a cohort study.

BACKGROUND: We investigated the effect of individualised proton pump inhibitors (PPI) prescription on upper gastrointestinal adverse events in a cohort of patients who received combination antiplatelet therapy (aspirin and clopidogrel) after percutaneous coronary intervention (PCI). METHODS: Upper gastrointestinal risk factors and other parameters were extracted from a dedicated electronic database. Patients were contacted with a standardised questionnaire. A structured phone interview was performed in all patients with upper gastrointestinal adverse events. RESULTS: A cohort of 718 patients on combination therapy yielded 87 (12.1%) patients with prophylactic PPI treatment. Upper gastrointestinal adverse events occurred in 18.4% patients with and in 11.1% patients without prophylactic PPI (OR 1.80, P = 0.054). Co-treatment with corticosteroids was the main identifiable risk factor for upper gastrointestinal adverse events (adjusted OR 5.45, P = 0.014). CONCLUSIONS: Individualised prescription of PPI-prophylaxis after PCI in patients on combined antiplatelet therapy based on risk assessment for upper gastrointestinal bleeding seems to represent an effective measure to minimise upper gastrointestinal adverse events after PCI.

[A Rare Differential Diagnosis of Chronic Cough]. / Eine seltene Differenzialdiagnose von chronischem Husten.

History and admission findings We report on a 62-year-old male patient with dry cough for 3 months, constitutional symptoms and elevated inflammatory markers. Investigations Despite extensive diagnostics no infectious, malignant or rheumatologic disease could be found. Bronchoscopy with bronchoalveolar lavage showed lymphocytosis. 18-FDG-PET/CT demonstrated increased metabolic activity of the aorta and its primary branches. Diagnosis, treatment and course We diagnosed large vessel vasculitis consistent to a subtype of giant cell arteritis (GCA) without cranial manifestation. Immunosuppressive therapy resulted in prompt resolution of symptoms and normalizing of inflammatory markers. Conclusions Elderly patients with unexplained fever, cough and constitutional symptoms should be investigated for GCA, even when classic symptoms are absent. Respiratory symptoms occur in about 4 % as initial and only presenting manifestation of GCA and in about 9 % along with classical symptoms.In cases with unclear focus of inflammation 18-FDG-PET/CT is becoming more and more important as a diagnostic tool.

A chest wall mass after breast carcinoma surgery: a simple diagnosis?

Tuberculosis affects pulmonary and extra-pulmonary sites with a multitude of differing presentations. The involvement of thoracic wall is a rare entity. We report the case of a patient who had a tumefaction on the right chest wall 6 months after a right breast mastectomy. After an initial radiological suspicion of malignancy, we detected intraoperatively an abscess in which histologic examination revealed granulomas with multinucleated giant cells.

Handheld single photon emission computed tomography (handheld SPECT) navigated video-assisted thoracoscopic surgery of computer tomography-guided radioactively marked pulmonary lesions.

OBJECTIVES: Radioactive marking can be a valuable extension to minimally invasive surgery. The technique has been clinically applied in procedures involving sentinel lymph nodes, parathyroidectomy as well as interventions in thoracic surgery. Improvements in equipment and techniques allow one to improve the limits. Pulmonary nodules are frequently surgically removed for diagnostic or therapeutic reasons; here video-assisted thoracoscopic surgery (VATS) is the preferred technique. VATS might be impossible with nodules that are small or located deep in the lung. In this study, we examined the clinical application and safety of employing the newly developed handheld single photon emission tomography (handheld SPECT) device in combination with CT-guided radioactive marking of pulmonary nodules. METHODS: In this pilot study, 10 subjects requiring surgical resection of a pulmonary nodule were included. The technique involved CT-guided marking of the target nodule with a 20-G needle, with subsequent injection of 25-30 MBq (effective: 7-14 MBq) Tc-99m MAA (Macro Albumin Aggregate). Quality control was made with conventional SPECT-CT to confirm the correct localization and exclude possible complications related to the puncture procedure. VATS was subsequently carried out using the handheld SPECT to localize the radioactivity intraoperatively and therefore the target nodule. A 3D virtual image was superimposed on the intraoperative visual image for surgical guidance. RESULTS: In 9 of the 10 subjects, the radioactive application was successfully placed directly in or in the immediate vicinity of the target nodule. The average size of the involved nodules was 9 mm (range 4-15). All successfully marked nodules were subsequently completely excised (R0) using VATS. The procedure was well tolerated. An asymptomatic clinically insignificant pneumothorax occurred in 5 subjects. Two subjects were found to have non-significant discrete haemorrhage in the infiltration canal of the needle. In a single subject, the radioactive marking was unsuccessful because the radioactivity spread into the pleural space. CONCLUSIONS: In our series of 10 patients, it was demonstrated that using handheld SPECT in conjunction with VATS to remove radioactively marked pulmonary nodules is feasible. The combination of proven surgical techniques with a novel localization device (handheld SPECT) allowed successful VATS excision of pulmonary nodules which, due to their localization and small size, would typically have required thoracotomy. REGISTRATION: ClinicalTrials.gov, NCT02050724, Public 01/29/214, Joachim Müller.

Epidermal growth factor receptor mutation in a patient with squamous cell carcinoma of the lung: who should be tested?

We report the case of a 64-year-old ex-smoker with metastatic poorly differentiated squamous cell carcinoma (SCC) of the lung and an epidermal growth factor receptor (EGFR) mutation in exon 21 (p.L858R) who achieved prolonged clinical benefit from treatment with an EGFR tyrosine kinase inhibitor (TKI). The initial diagnosis of SCC of the lung obtained by bronchoscopic biopsy was based on immunohistochemical staining only with positivity for cytokeratin (CK) 5/6 and p63 because morphological diagnosis was not possible. Patients with non-small cell lung cancer (NSCLC), not otherwise specified (NOS) favouring SCC are usually not tested for the presence of EGFR mutations, and therefore may not receive EGFR TKI therapy. A bronchoscopic rebiopsy showed small nests of undifferentiated tumour cells with weak immunoreactivity of some tumour cells for CK5/6, p63 and no positivity of some tumour cells for thyroid transcription factor-1. These findings suggested a mixed squamous/glandular immunophenotype that has been missed at the initial biopsy. Our clinical case illustrates the problem of tumour heterogeneity encountered in small bronchoscopic biopsies and the difficulties of evaluating the histological subtype in poorly differentiated carcinomas. Initial bronchoscopy should be performed by an experienced pulmonologist who attempts to obtain sufficient material from different areas of the tumour. In the era of targeted therapy, a remote smoking history in a patient with NOS favouring SCC should also lead to EGFR mutation testing to allow highly effective therapy to be offered to mutation-positive patients.