Joint ERS/EACTS/ESTS clinical practice guidelines on adults with spontaneous pneumothorax.

OBJECTIVES: The optimal management for spontaneous pneumothorax (SP) remains contentious, with various proposed approaches. This joint clinical practice guideline from the ERS, EACTS and ESTS societies provides evidence-based recommendations for the management of SP. METHODS: This multidisciplinary Task Force addressed 12 key clinical questions on the management of pneumothorax, using ERS methodology for guideline development. Systematic searches were performed in MEDLINE and Embase. Evidence was synthesised by conducting meta-analyses, if possible, or narratively. Certainty of evidence was rated with GRADE (Grading, Recommendation, Assessment, Development and Evaluation). The Evidence to Decision framework was used to decide on the direction and strength of the recommendations. RESULTS: The panel makes a conditional recommendation for conservative care of minimally symptomatic patients with primary spontaneous pneumothorax (PSP) who are clinically stable. We make a strong recommendation for needle aspiration over chest tube drain for initial PSP treatment. We make a conditional recommendation for ambulatory management for initial PSP treatment. We make a conditional recommendation for early surgical intervention for the initial treatment of PSP in patients who prioritise recurrence prevention. The panel makes a conditional recommendation for autologous blood patch in secondary SP patients with persistent air leak (PAL). The panel could not make recommendations for other interventions, including bronchial valves, suction, pleurodesis in addition to surgical resection or type of surgical pleurodesis. CONCLUSIONS: With this international guideline, the ERS, EACTS and ESTS societies provide clinical practice recommendations for SP management. We highlight evidence gaps for the management of PAL and recurrence prevention, with research recommendations made. SHAREABLE ABSTRACT: This update of an ERS Task Force statement from 2015 provides a concise comprehensive update of the literature base. 24 evidence-based recommendations were made for management of pneumothorax, balancing clinical priorities and patient views.https://bit.ly/3TKGp9e.

Patient-Derived Lung Cancer "Sandwich Cultures" with a Preserved Tumor Microenvironment.

In the past, different spheroid-, organotypic-, and three-dimensional (3D) bioprinting lung cancer models were established for in vitro drug testing and personalized medicine. These tissue models cannot depict the tumor microenvironment (TME) and, therefore, research addressing tumor cell-TME interactions is limited. To overcome this hurdle, we applied patient-derived lung tumor samples to establish new in vitro models. To analyze the tissue model properties, we established two-dimensional (2D) and 3D coculture tissue models exposed to static and dynamic culture conditions that afforded tissue culture for up to 28 days. Our tissue models were characterized by hematoxylin eosin staining, M30 enzyme-linked immunosorbent assay, and immunofluorescence staining against specific lung cancer markers (TTF-1 and p40/p63), cancer-associated fibroblast (CAF) markers (α-SMA and MCT4), and fibronectin (FN). The 3D models were generated with higher success rate than the corresponding 2D model. The cell density of the static 3D model increased from 21 to 28 days, whereas the apoptosis decreased. The dynamic 3D model possessed an even higher cell density than the static 3D model. We identified lung cancer cells, CAFs, and FN. Therefore, a novel in vitro 3D lung cancer model was established, which simulated the TME for 28 days and possessed a structural complexity.

[Risky confirmation of a diagnosis: case series of three female patients with mediastinal mass syndrome]. / Riskante Diagnosesicherung: Fallserie über drei Patientinnen mit Mediastinal-mass-Syndrom.

Mediastinal mass syndrome (MMS) is a life-threatening complication of anesthesia for which prevention and treatment are a complication-prone interdisciplinary task. Clinical symptoms vary from asymptomatic patients up to life-threatening cardiorespiratory impairments, depending on the extent and size of a mediastinal tumor as well as the involvement of corresponding anatomical structures. Especially in the context of sedation or general anesthesia, there is a considerable risk of acute cardiopulmonary or respiratory decompensation related to tumor-induced compression of central blood vessels or even the large airways, which may result in severe complications, including death. In this case series three female patients are presented, who were each referred to this hospital with a mediastinal tumor for interventional or surgical confirmation of the diagnosis. Based on the case histories, characteristic complications are demonstrated and strategies to avoid possible adverse events of MMS are discussed. The specific anesthesiological requirements for MMS, the safety aspects of the choice of surgical and anesthesia procedures, circulatory and airway management for the required single-lung ventilation, and various aspects of the selection of the anesthetic agents are discussed in this case series.

Prospective Evaluation of Quantitative F-18-FDG-PET/CT for Pre-Operative Thoracic Lymph Node Staging in Patients with Lung Cancer as a Target for Computer-Aided Diagnosis.

PURPOSE: Pre-operative assessment of thoracic lymphonodal (LN) involvement in patients with lung cancer (LC) is crucial when choosing the treatment modality. Visual assessment of F-18-FDG-PET/CT (PET/CT) is well established, however, there is still a need for prospective quantitative data to differentiate benign from malignant lesions which would simplify staging and guide the further implementation of computer-aided diagnosis (CAD). METHODS: In this prospective study, 37 patients with confirmed lung cancer (m/f = 24/13; age: 70 [52-83] years) were analyzed. All patients underwent PET/CT and quantitative data (standardized uptake values) were obtained. Histological results were available for 101 thoracic lymph nodes. Quantitative data were matched to determine cut-off values for delineation between benign vs. malignant lymph nodes. Furthermore, a scoring system derived from these cut-off values was established. Statistical analyses were performed through ROC analysis. RESULTS: Quantitative analysis revealed the optimal cut-off values (p < 0.01) for the differentiation between benign and malignant thoracic lymph nodes in patients suffering from lung cancer. The respective areas under the curve (AUC) ranged from 0.86 to 0.94. The highest AUC for a ratio of lymph node to healthy lung tissue was 0.94. The resulting accuracy ranged from 78.2% to 89.1%. A dedicated scoring system led to an AUC of 0.93 with a negative predictive value of 95.4%. CONCLUSION: Quantitative analysis of F-18-FDG-PET/CT data provides reliable results for delineation between benign and malignant thoracic lymph nodes. Thus, quantitative parameters can improve diagnostic accuracy and reliability and can also facilitate the handling of the steadily increasing number of clinical examinations.

[Treatment of Persistent Parenchymal Lung Injuries in Thoracic Trauma: Lung Laceration, Pleural Fistula and Pneumothorax]. / Behandlung von persistierenden Lungenparenchymverletzungen beim Thoraxtrauma: Lungenlazeration, pleurale Fistel und Pneumothorax.

Thoracic trauma is a frequent injury pattern with high patient morbidity and mortality. Preclinical and clinical emergency treatment is consented in a national S3-guideline. Following emergency therapy one third of patients may develop lung lacerations, pleural fistulation and persisting pneumothorax. An interdisciplinary working group of the German Society for Thoracic Surgery and the German Society for Traumatology reviewed the published medical literature on treatment of those injuries and assessed the existing evidence according to consensus recommendations. An inconsistent classification of those subsequent lung injuries was found. Evidence for diagnostic and therapeutic recommendations is small.

Optimization of Primary Human Bronchial Epithelial 3D Cell Culture with Donor-Matched Fibroblasts and Comparison of Two Different Culture Media.

In vitro airway models are increasingly important for pathomechanistic analyses of respiratory diseases. Existing models are limited in their validity by their incomplete cellular complexity. We therefore aimed to generate a more complex and meaningful three-dimensional (3D) airway model. Primary human bronchial epithelial cells (hbEC) were propagated in airway epithelial cell growth (AECG) or PneumaCult ExPlus medium. Generating 3D models, hbEC were airlifted and cultured on a collagen matrix with donor-matched bronchial fibroblasts for 21 days comparing two media (AECG or PneumaCult ALI (PC ALI)). 3D models were characterized by histology and immunofluorescence staining. The epithelial barrier function was quantified by transepithelial electrical resistance (TEER) measurements. The presence and function of ciliated epithelium were determined by Western blot and microscopy with high-speed camera. In 2D cultures, an increased number of cytokeratin 14-positive hbEC was present with AECG medium. In 3D models, AECG medium accounted for high proliferation, resulting in hypertrophic epithelium and fluctuating TEER values. Models cultured with PC ALI medium developed a functional ciliated epithelium with a stable epithelial barrier. Here, we established a 3D model with high in vivo-in vitro correlation, which has the potential to close the translational gap for investigations of the human respiratory epithelium in pharmacological, infectiological, and inflammatory research.

[Development of Academic Thoracic Surgery in Germany]. / Entwicklung der akademischen Thoraxchirurgie in Deutschland.

In Germany, thoracic surgery is mainly represented at non-university thoracic surgery clinics. It is only established clinically as an independent department or clinic and scientifically as a W2 or W3 professorship at relatively few university hospitals. As a result, it is significantly more difficult to recruit junior specialists and to generate academically active thoracic surgeons as contact persons for researchers from the various fields of life and engineering sciences and for the further development of the field of thoracic surgery, than it is for other surgical specialities. In medical faculties, teaching, research and patient care are on an equal footing. For thoracic surgeons to take on these tasks, concepts are needed to expand and promote academic thoracic surgery in German university medicine. A structured curriculum for academic thoracic surgery can support an academic career in thoracic surgery in addition to mentoring programs, funding opportunities and additional freedom for research or teaching.

[Occult and Retained Haemothorax - Recommendations of the Interdisciplinary Thoracic Trauma Task Group of the German Trauma Society (DGU - Section NIS) and the German Society for Thoracic Surgery (DGT)]. / Okkulter und residueller Hämatothorax nach Thoraxtrauma ­ Empfehlungen der interdisziplinären Arbeitsgruppe Thoraxtrauma der Sektion NIS der Deutschen Gesellschaft für Unfallchirurgie (DGU) und der Deutschen Gesellschaft für Thoraxchirurgie (DGT).

The management of occult and retained haemothorax is challenging for all involved in the care of polytrauma patients in terms of diagnosis and treatment. The focus of decision making is preventing sequelae such as pleural empyema and avoiding a trapped lung. An interdisciplinary task force of the German Society for Thoracic Surgery (DGT) and the German Trauma Society (DGU) on thoracic trauma offers recommendations for post-trauma care of patients with occult and/or retained haemothorax, as based on a comprehensive literature review.

Human 3D Airway Tissue Models for Real-Time Microscopy: Visualizing Respiratory Virus Spreading.

Our knowledge about respiratory virus spreading is mostly based on monolayer cultures that hardly reflect the complex organization of the airway epithelium. Thus, there is a strong demand for biologically relevant models. One possibility to study virus spreading at the cellular level is real-time imaging. In an attempt to visualize virus spreading under somewhat more physiological conditions, Calu-3 cells and human primary fibroblasts were co-cultured submerged or as air-liquid interface (ALI). An influenza A virus (IAV) replicating well in cell culture, and carrying a red fluorescent protein (RFP) reporter gene was used for real-time imaging. Our three-dimensional (3D) models exhibited important characteristics of native airway epithelium including a basement membrane, tight junctions and, in ALI models, strong mucus production. In submerged models, first fluorescence signals appeared between 9 and 12 h post infection (hpi) with a low multiplicity of infection of 0.01. Virus spreading further proceeded in the immediate vicinity of infected cells. In ALI models, RFP was found at 22 hpi and later. Consequently, the progression of infection was delayed, in contrast to the submerged model. With these features, we believe that our 3D airway models can deliver new insights in the spreading of IAV and other respiratory viruses.

Fatal course of a benign mediastinal lipoblastoma in a 20-year-old woman.

Lipoblastoma is a rare benign, but highly proliferative tumor most commonly seen in early childhood. Recurrence rates are high when complete resection is unfeasible and systemic therapy is necessary. We report the case of a large, aggressive thoracic and mediastinal lipoblastoma in a 20-year-old woman, which was surgically not resectable. The tumor has been characterized extensively including molecular pathology, molecular karyotyping, conventional chromosomal analysis and in vitro-chemosensitivity testing in search for alternative therapies. Nevertheless, this did not reveal treatable targets and systemic therapies, which were based on chemosensitivity testing proved ineffective. Despite all treatment attempts, the disease showed a progressive fatal course.

[Anesthesia for thoracic surgery in a female patient with Ullrich congenital muscular dystrophy]. / Anästhesie bei einer thoraxchirurgischen Patientin mit kongenitaler Muskeldystrophie Typ Ullrich.

Ullrich congenital muscular dystrophy (UCMD) is a rare disease caused by mutations in the COL6A1, COL6A2 or COL6A3 genes leading to deficiency of collagen VI in extracellular matrices (ECM). Patients present with generalized muscle weakness, predominantly in the trunk and proximal limbs, hyperlaxity of distal joints, spinal rigidity, scoliosis and various proximal joint contractures, loss of ambulation by 9-11 years of age and progressive respiratory dysfunction. About 50% of the patients require noninvasive ventilation (NIV) by the age of 11-12 years. We report about a female patient (age 21 years) with severe UCMD. After decompression of spontaneous pneumothorax, a major subpleural hematoma of the left lower lobe emerged necessitating video-assisted thoracoscopic surgery (VATS). Anesthesiological aspects, including underlying disease, comorbidities, airway management for one-lung ventilation and choice of anesthetics for patients with muscular dystrophy are discussed. The clinical course during anesthesia, surgery and postoperatively was uneventful and the patient was discharged 7 days after VATS.

[Robotic-assisted Thoracic Surgery]. / Roboterassistierte Thoraxchirurgie.

In the last decade robotic-assisted thoracoscopic surgery (RATS) emerged as a new minimally invasive surgical modality to operate pulmonary, mediastinal and esophageal diseases. Superior to video-assisted thoracoscopic surgery (VATS), RATS affords accurate surgical manipulation in spatially confined anatomical regions. Numerous surgical case studies demonstrated technical reliability and oncological equivalence of RATS compared to open surgery and VATS. Consequently, the number of RATS operations for oncological and non-oncological resections is rising rapidly. The lacking evidence of therapy improvement in the context of significantly increased treatment costs slows the development. Currently, various new companies introduce new robotic surgical platforms into the market and it is expected that market competition will change the costs of these modern therapies. This article summarizes the technical features of RATS and its anesthesiologic implications for patient management.

EMT, Stemness, and Drug Resistance in Biological Context: A 3D Tumor Tissue/In Silico Platform for Analysis of Combinatorial Treatment in NSCLC with Aggressive KRAS-Biomarker Signatures.

Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRASG12C or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-ß. To investigate further determinants of drug response, we tested several drugs in combination with a KRASG12C inhibitor in KRASG12C mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.

Surgical stabilization of serial rib fractures is advantageous in patients with relevant traumatic brain injury.

PURPOSE: To evaluate the clinical benefit of surgical stabilization of rib fractures (SSRF) in polytrauma patients with serial rib fractures. METHODS: Retrospective single-center cohort analysis in trauma patients. Serial rib fracture was defined as three consecutive ribs confirmed by chest computer tomography (CT). Study cohort includes 243 patients that were treated conservatively and 34 patients that underwent SSRF. Demographic patient data, trauma mechanism, injury pattern, Injury Severity Score (ISS), Glasgow Coma Scale (GCS) and hospital course were analyzed. Two matched pair analyses stratified for ISS (32 pairs) and GCS (25 pairs) were performed. RESULTS: The majority of patients was male (74%) and aged 55 ± 20 years. Serial rib fractures were associated with more than 6 broken ribs in average (6.3 ± 3.7). Other thoracic bone injury included sternum (18%), scapula (16%) and clavicula (13%). Visceral injury consisted of pneumothorax (51%), lung contusion (33%) and diaphragmatic rupture (2%). Average ISS was 22 ± 7.3. Overall hospital stay was 15.9 and ICU stay 7.4 days. In hospital, mortality was 13%. SSRF did not improve hospital course or postoperative complications in the complete study cohort. However, patients with a significantly reduced GCS (7.6 ± 5.3 vs 11.22 ± 4.8; p = 0.006) benefitted from SSRF. Matched pair analysis stratified for GCS showed shorter ICU stays (9 vs 15 days; p = 0.005) including shorter respirator time (143 vs 305 h; p = 0.003). CONCLUSION: Patients with serial rib fractures and simultaneous moderate or severe traumatic brain injury benefit from surgical stabilization of rib fractures.

How to prepare for academic leadership: scientific training curriculum.

Thoracic surgery has evolved into an independent discipline out of general surgery practice over the past decades. The development of the field of thoracic surgery was generated from surgeons being motivated to move this field forward by constant analysis and critical appraisal and review of current practice, as well as identification of new research approaches as the pool and generator of innovation. For this purpose, scientific skills are needed that are currently not covered during the surgical training. In the present overview, we will try to summarize important factors for an academic career, although none of these recommendations are validated and also not realistic to be uniquely applied to every geographical setting. Several key factors will be described being necessary for pursuing basic science, translational, and clinical research as a surgeon scientist introducing "from bench to bedside" research ideas into clinic and "from bedside to bench" bringing important clinical problems back to the lab.

Susceptibility of primary human airway epithelial cells to Bordetella pertussis adenylate cyclase toxin in two- and three-dimensional culture conditions.

The human pathogen Bordetella pertussis targets the respiratory epithelium and causes whooping cough. Its virulence factor adenylate cyclase toxin (CyaA) plays an important role in the course of infection. Previous studies on the impact of CyaA on human epithelial cells have been carried out using cell lines derived from the airways or the intestinal tract. Here, we investigated the interaction of CyaA and its enzymatically inactive but fully pore-forming toxoid CyaA-AC- with primary human airway epithelial cells (hAEC) derived from different anatomical sites (nose and tracheo-bronchial region) in two-dimensional culture conditions. To assess possible differences between the response of primary hAEC and respiratory cell lines directly, we included HBEC3-KT in our studies. In comparative analyses, we studied the impact of both the toxin and the toxoid on cell viability, intracellular cAMP concentration and IL-6 secretion. We found that the selected hAEC, which lack CD11b, were differentially susceptible to both CyaA and CyaA-AC-. HBEC3-KT appeared not to be suitable for subsequent analyses. Since the nasal epithelium first gets in contact with airborne pathogens, we further studied the effect of CyaA and its toxoid on the innate immunity of three-dimensional tissue models of the human nasal mucosa. The present study reveals first insights in toxin-cell interaction using primary hAEC.

Redistribution of pulmonary ventilation after lung surgery detected with electrical impedance tomography.

BACKGROUND: Regional ventilation of the lung can be visualized by pulmonary electrical impedance tomography (EIT). The aim of this study was to examine the post-operative redistribution of regional ventilation after lung surgery dependent on the side of surgery and its association with forced vital capacity. METHODS: In this prospective, observational cohort study 13 patients undergoing right and 13 patients undergoing left-sided open or video-thoracoscopic procedures have been investigated. Pre-operative measurements with EIT and spirometry were compared with data obtained 3 days post-operation. The center of ventilation (COV) within a 32 × 32 pixel matrix was calculated from EIT data. The transverse axis coordinate of COV, COVx (left/right), was modified to COVx' (ipsilateral/contralateral). Thus, COVx' shows a negative change if ventilation shifts contralateral independent of the side of surgery. This enabled testing with two-way ANOVA for repeated measurements (side, time). RESULTS: The perioperative shift of COVx' was dependent on the side of surgery (P = .007). Ventilation shifted away from the side of surgery after the right-sided surgery (COVx'-1.97 pixel matrix points, P < .001), but not after the left-sided surgery (COVx'-0.61, P = .425). The forced vital capacity (%predicted) decreased from 94 (83-109)% (median [quartiles]; [left-sided]) and 89 (80-97)% (right-sided surgery) to 61 (59-66)% and 62 (40-72)% (P < .05), respectively. The perioperative changes in forced vital capacity (%predicted) were weakly associated with the shift of COVx'. CONCLUSION: Only after right-sided lung surgery, EIT showed reduced ventilation on the side of surgery while vital capacity was markedly reduced in both groups.

Activated clotting factor X mediates mitochondrial alterations and inflammatory responses via protease-activated receptor signaling in alveolar epithelial cells.

There is growing evidence for the contribution of the activated coagulation factor X (FXa) in the development of chronic inflammatory lung diseases. Therefore, we aimed to investigate effects of exogenous FXa on mitochondrial and metabolic function as well as the induction of inflammatory molecules in type II alveolar epithelial cells. Effects of FXa on epithelial cells were investigated in A549 cell line. Activation of extracellular signal-regulated kinase (ERK) and induction of inflammatory molecules were examined by immunoblot and gene expression analysis. Mitochondrial function was assessed by the measurement of oxygen consumption during maximal oxidative phosphorylation and quantitative determination of cardiolipin oxidation. Apoptosis was tested using a caspase 3 antibody. Metabolic activity and lactate dehydrogenase assay were applied for the detection of cellular viability. FXa activated ERK1/2 and induced an increase in the expression of pro-inflammatory cytokines, which was prevented by an inhibitor of FXa, edoxaban, or an inhibitor of protease-activated receptor 1, vorapaxar. Exposure to FXa caused mitochondrial alteration with restricted capacity for ATP generation, which was effectively prevented by edoxaban, vorapaxar and GB83 (inhibitor of protease-activated receptor 2). Of note, exposure to FXa did not initiate apoptosis in epithelial cells. FXa-dependent pro-inflammatory state and impairment of mitochondria did not reach the level of significance in lung epithelial cells. However, these effects might limit regenerative potency of lung epithelial cells, particular under clinical circumstances where lung injury causes exposure to clotting factors.