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Extracellula r matri x (ECM)-derived hydrogels are in demand for use in lung tissue engineering to mimic the native microenvironment of cells in vitro. Decellularization of native tissues has been pursued for preser v i n g organotypic ECM while eliminating cellular content and reconstitution into scaffolds which allows re-cellularization for modeling homeostasis, regeneration, or diseases. Achieving mechanical stabi l i t y and understanding the effects of the decellularization process on mechanical parameters of the reconstituted ECM hydrogels present a challenge in the field. Stiffness and viscoelasticity are important characteristics of tissue mechanics that regulate crucial cellular processes and their in vitro representation in engineered models is a current aspiration. The effect of decellulariza-tion on viscoelastic properties of resulting ECM hydrogels has not yet been addressed. The aim of this study was to establish bovine lung tissue decellularization for the first time via pursuing four different protocols and characterization of reconstituted decellularized lung ECM hydrogels for biochemical and mechanical properties. Our data reveal that bovine lungs provide a reproducible alternative to human lungs for disease modeling with optimal retention of ECM components upon decellularization. We demonstrate that the decellularization method significa n t l y affects ECM content, stiffness, and viscoelastic properties of resulting hydrogels. Lastly, we examined the impact of these aspects on viabi l i t y , morphology, and growth of lung cancer cells, healthy bronchial epithelial cells, and patient-derived lung organoids., This work was funded by the International Fellowship for Outstanding Researchers Program of Scientific and Technological Research Council of Turkey (TÜBİTAK) (grant no. 118C238) and Marie Sklodowska-Curie Individual Fellowship (MiTuMi, grant no. 101032602).

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRAS(G12D) in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRAS(G12D) lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration., European Union (EU); Horizon 2020; European Research Council 2010 Starting Independent Investigator; ERC Proof of Concept 2015 (ERC-PoC-2015); German Research Society; ALTERNATIVE; German Ministry for Education and Research; German Center for Lung Research Translational Research Grant; Greek State Scholarship Foundation Program; European Union (EU); European Union Social Fund; Greek National Fund; Reinforcement of Postdoctoral Researchers-1 stand 2nd cycles; General Secretariat for Research and Innovation; Hellenic Foundation for Research and Innovation; REPSIRE European Respiratory Society Fellowship; Institut National de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche en Sante Respiratoire des Pays de la Loire; National Research Agency Programme d' Investissements d' Avenir; Pays de la Loire Region Research Program; Ligue Contrele Cancer; Chancellerie des Universites de Paris; Projekt DEAL

Background: we aimed to assess the feasibility and short-term clinical outcomes of surgical procedures for cancer at an institution using a coronavirus disease 2019 (COVID-19)-free surgical pathway during the peak phase of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Materials and methods: this was a single-center study, including cancer patients from all surgical departments, who underwent elective surgical procedures during the first peak phase between March 10 and June 30, 2020. The primary outcomes were the rate of postoperative SARS-CoV-2 infection and 30-day pulmonary or non-pulmonary related morbidity and mortality associated with SARS-CoV-2 disease. Results: four hundred and four cancer patients fulfilling inclusion criteria were analyzed. The rate of patients who underwent open and minimally invasive procedures was 61.9% and 38.1%, respectively. Only one (0.2%) patient died during the study period due to postoperative SARS-CoV2 infection because of acute respiratory distress syndrome. The overall non-SARS-CoV2 related 30-day morbidity and mortality rates were 19.3% and 1.7%, respectively; whereas the overall SARS-CoV2 related 30-day morbidity and mortality rates were 0.2% and 0.2%, respectively. Conclusions: under strict institutional policies and measures to establish a COVID-19-free surgical pathway, elective and emergency cancer operations can be performed with acceptable perioperative and postoperative morbidity and mortality., NA

Background/aim: programmed death ligand-1 (PD-L1) is a predictive marker for immunotherapeutic agents. However, heterogeneous staining of PD-L1 can cause false-negative results. The aim of this study is to evaluate the importance of histological patterns on PD-L1 staining heterogeneity in lung adenocarcinomas (LAC). Materials and methods: PD-L1 immunohistochemistry (IHC) stain was performed to two different tissue cores of 128 LAC cases, and cut-off values are given for grouping the cases according to the percentage of staining (1%-10%, 11%-49%, 50%-100%). Staining rates between cores were compared and analyzed by their histological patterns. Also, the relation of the PD-L1 expression with the clinicopathological characteristics of the cases was analyzed. Results: overall, PD-L1 expression was observed in 53 of 128 cases (41.4%, 1% cut-off), 23.5% of them were positive at 10% cut-off and 14.1% at 50% cut-off. PD-L1 expression was significantly related to the high grade micropapillary and solid patterns of adenocarcinomas (p:0.01). Staining cut-offs were mostly similar between cores (43/50, 86%) (k:0.843). However, 14% of them were positive only in one core (7 of 50). This false negativity was mostly related to the histological patterns. Conclusion: our data reveal the heterogeneous staining of PD-L1 expression, also micropapillary and solid patterns show higher rates of PDL expression. Therewithal, these findings also highlight the importance of taking into consideration of histological patterns, when choosing a paraffin block for the PDL1., NA

Objectives: Whether acute phase and immune responses are minimally affected following minimally invasive lung surgery needs further investigation. We performed a pilot study to evaluate the immune profile of patients who underwent video-assisted thoracoscopic surgery or robot-assisted thoracic surgery lobectomies for the treatment of suspicious or known stage I non-small-cell lung cancer. Methods: blood samples were taken preoperatively and 3 and 24 h postoperatively were analysed for C-reactive protein, glucose, cortisol, tumour necrosis factor alpha (TNF-α), interleukin 8 (IL-8) and interleukin 10 (IL-10) levels. TNF-α, IL-8 and IL-10 were also measured in lung tissues. T (CD4, CD8), B (CD19) and natural killer (CD56, CD16) cell counts and natural killer cell functions were analysed using a flow cytometry-based assay before and after surgery. Results: minimally invasive surgery (robot-assisted thoracic surgery + video-assisted thoracoscopic surgery) significantly decreased IL-10 (P = 0.016) levels after surgery. No significant differences were detected in TNF-α (P = 0.48) and IL-8 (P = 0.15) levels before and after surgery. C-reactive protein (P < 0.001), cortisol (P < 0.001) and glucose levels (P < 0.001) increased significantly after surgery. Lymphocyte, total T cell, CD3+CD4+ and CD3+CD8+ CD16+CD56+ cell counts were significantly lower on postoperative day 1. Conclusion: there seems to be a dynamic balance between pro- and anti-inflammatory cytokines and immune cells following minimally invasive lobectomy.

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Purpose: One of the key immune cells involved in the pathogenesis of lung cancer is natural killer (NK) cells and these cells are novel targets for therapeutic applications in lung cancer. The purpose of this review is to summarize the current literature on lung cancer pathogenesis with a focus on the interaction between NK cells and smoking, how these factors are related to the pathogenesis of lung cancer and how NK cell-based immunotherapy effect lung cancer survival. Methods: The relevant literature from PubMed and Medline databases is reviewed in this article. Results: The cytolytic potential of NK cells are reduced in lung cancer and increasing evidence suggests that improving NK cell functioning may induce tumor regression. Recent clinical trials on NK cell-based novel therapies such as cytokines including interleukin (IL)-15, IL-12 and IL-2, NK-92 cell lines and allogenic NK cell immunotherapy showed promising results with less adverse effects on the lung cancer survival. Conclusions: The NK cell targeting strategy has not yet been approved for lung cancer treatment. More clinical studies focusing on the role of NK cells in lung cancer pathogenesis are warranted to develop novel NK cell-based therapeutic approaches for the treatment of lung cancer., NA

Background: The aim of this case report is to discuss diagnostic workup and clinical management of cytomegalovirus reactivation in a critically ill immunocompetent pediatric patient. Case presentation: A 2-year-old white boy who had no medical history presented with respiratory distress and fever. His Pediatric Risk of Mortality and Pediatric Logistic Organ Dysfunction scores were 20 and 11, respectively. Our preliminary diagnosis was multiple organ dysfunction secondary to sepsis. Antibiotic treatment was started; he was intubated and artificially ventilated. Norepinephrine infusion was started. Hemophagocytic lymphohistiocytosis was diagnosed because our patient had elevated levels of serum ferritin, bicytopenia, splenomegaly, fever (> 38.5 °C), and hemophagocytosis shown in a bone marrow sample. Therapeutic plasma exchange and intravenously administered high-dose corticosteroid for hemophagocytic lymphohistiocytosis and continuous renal replacement treatment for acute renal failure were initiated. Following 5-day high-dose corticosteroid administration, therapeutic plasma exchange, and continuous renal replacement treatment, his clinical status and kidney and liver functions improved, and vasoactive requirement and ferritin levels decreased. He was extubated on the seventh day. On the tenth day of hospitalization he had a seizure and was diagnosed as having septic encephalopathy. His immune functions were found to be normal. Although his medical condition improved continuously, he had left spontaneous pneumothorax on the 21st day of admission as a complication of necrotizing pneumonia. Since pneumothorax persisted, left upper lobectomy surgery was performed on the 30th day of hospitalization. In the pathological examination of the excised lung tissue, features of cytomegalovirus infection were observed. Ganciclovir treatment was started. Serological tests indicated that our patient had cytomegalovirus reactivation. Antiviral treatment was stopped after 17 days, w, NA