[Robot-assisted Thoracic Surgery: Learning Curve and Cost Analysis in a German High-Volume Centre]. / Roboterassistierte Thoraxchirurgie: Ökonomie und Lernkurve an einem High-Volume-Zentrum.

Robot-assisted thoracic surgery (RATS) is a rapidly evolving surgical technique in Europe. The aim of the study was to analyse the learning curve and safety during the establishment of a RATS-program at a high-volume thoracic surgery centre and to quantify the costs of the surgical procedure in Germany. Within a period of 33 months, 255 patients were prospectively enrolled in the study and all perioperative process times and complications were recorded. Mediastinal procedures were performed in 46%, anatomical lung resections in 38%, wedge resections in 7% and diaphragm plications in 6% of patients. The mean operating time was 130 min and the total length of stay was 7 days. The conversion rate was 3.2% and 30-day mortality 1.2%. Mean costs for surgical consumables per intervention amounted to 2,039 €; the average reimbursement was 9,568 €. In summary, RATS can be safely established, performed and trained with low complication rates and acceptable costs for consumables.

Consolidating Lung Volume Reduction Surgery After Endoscopic Lung Volume Reduction Failure.

BACKGROUND: Bronchoscopic valve placement constitutes an effective endoscopic lung volume reduction (ELVR) therapy in patients with severe emphysema and low collateral ventilation. After the most destroyed lobe is occluded with valves, significant target lobe volume reduction leads to improvements in lung function, exercise capacity, and quality of life. The effects are not consistent in some patients, leading to long-term therapy failure. We hypothesized that surgical lung volume reduction (LVRS) would reestablish ELVR short-term clinical improvements after ELVR long-term failure. METHODS: This retrospective single-center analysis included all patients who underwent consolidating LVRS by lobectomy after long-term failure of valve therapy between 2010 and 2015. Changes in forced expiratory volume in 1 second, residual volume, 6-minute walking distance, and Modified Medical Research Council dyspnea score 90 days after ELVR and LVRS were analyzed, and the outcomes of both procedures were compared. RESULTS: LVRS was performed in 20 patients after ELVR failure. A lower lobectomy was performed in 90%. The 30-day mortality of the cohort was 0% and 90-day mortality was 5% (1 of 20). The remaining 19 patients showed a significant increase in forced expiratory volume in 1 second (+27.5% ± 19.4%) and a reduction in residual volume (-21.0% ± 17.4%) and total lung capacity (-11.1% ± 11.1%). This resulted in significant improvements in exercise tolerance (6-minute walking distance: +56 ± 60 m) and relief of dyspnea (ΔModified Medical Research Council: -1.8 ± 1.4 points.). CONCLUSIONS: Consolidating LVRS by lobectomy after failure of a previously successful ELVR is feasible and results in significant symptom relief and improvement of lung function.

[Robot-assisted Mediastinal Mass Resection]. / Roboterassistierte Thoraxchirurgie bei Mediastinaltumoren.

In recent years, robot-assisted thoracic surgery is gaining more and widespread interest in Europe. Due to the narrow space and the complexity of anatomical structures, conventional minimally invasive mediastinal surgery may be challenging for the thoracic surgeon. Robot-assisted mediastinal surgery opens up new possibilities for minimally invasive surgery, as it permits greater dexterity, a three-dimensional view, and tremor adjustment, which allows the surgeon to perform complex procedures in small thoracic spaces. As robotic platforms continue to evolve, more complex mediastinal thoracic surgical interventions will be facilitated, translating to improved outcomes for patients. This article provides an overview of the current status of robot-assisted mediastinal surgery and summarises general aspects of the indication, set-up and steps of robot-assisted thoracoscopic surgery in mediastinal mass resections.

Nationwide effect of high procedure volume in lung cancer surgery on in-house mortality in Germany.

BACKGROUND: The literature reports that hospital caseload volume is associated with survival for lung cancer resection. The aim of this study is to explore this association in a nationwide setting according to individual hospital caseload volume of every inpatient case in Germany. METHODS: This retrospective analysis of nationwide hospital discharge data in Germany between 2014 and 2017 comprises 121,837 patients of whom 36,051 (29.6 %) underwent surgical anatomic resection. Hospital volumes were defined according to the number of patient resections for lung cancer in each hospital, and patients were categorized into 5 quintiles based on hospital caseload volume. A logistic regression model accounting for death according to sex, age, comorbidity, and resection volume was calculated, and effect modification was evaluated using the Mantel-Haenszel method. RESULTS: In-house mortality ranged from 2.1 % in very high-volume centers to 4.0 % in very low-volume hospitals (p < 0.01). In multivariable logistic regression analysis, lower in-house mortality in very high-volume centers performing > 140 anatomic lung resections per year was observed compared with very low-volume centers performing < 27 resections (OR, 0.58; CI, 0.46 to 0.72; p < 0.01). This relationship also held for failure to rescue rates (12.9 vs 16.7 %, p = 0.01), although a greater number of extended resections were performed (23.1 vs. 14.8 %, p < 0.01). CONCLUSIONS: Hospitals with high volumes of lung cancer resections performed surgery with a higher ratio of complex procedures and achieved reduced in-house mortality, fewer complications, and lower failure to rescue rates.

Frequent Molecular Subtype Switching and Gene Expression Alterations in Lung and Pleural Metastasis From Luminal A-Type Breast Cancer.

PURPOSE: Conversion of tumor subtype frequently occurs in the course of metastatic breast cancer but is a poorly understood phenomenon. This study aims to compare molecular subtypes with subsequent lung or pleural metastasis. PATIENTS AND METHODS: In a cohort of 57 patients with breast cancer and lung or pleural metastasis (BCLPM), we investigated paired primary and metastatic tissues for differential gene expression of 269 breast cancer genes. The PAM50 classifier was applied to identify intrinsic subtypes, and differential gene expression and cluster analysis were used to further characterize subtypes and tumors with subtype conversion. RESULTS: In primary breast cancer, the most frequent molecular subtype was luminal A (lumA; 49.1%); it was luminal B (lumB) in BCLPM (38.6%). Subtype conversion occurred predominantly in lumA breast cancers compared with other molecular subtypes (57.1% v 27.6%). In lumA cancers, 62 genes were identified with differential expression in metastatic versus primary disease, compared with only 10 differentially expressed genes in lumB, human epidermal growth factor receptor 2 (HER2)-enriched, and basal subtypes combined. Gene expression changes in lumA cancers affected not only the repression of the estrogen receptor pathway and cell cycle-related genes but also the WNT pathway, proteinases (MME, MMP11), and motility-associated cytoskeletal proteins (CK5, CK14, CK17). Subtype-switched lumA cancers were further characterized by cell proliferation and cell cycle checkpoint gene upregulation and dysregulation of the p53 pathway. This involved 83 notable gene expression changes. CONCLUSION: Our results indicate that gene expression changes and subsequent subtype conversion occur on a large scale in metastatic luminal A-type breast cancer compared with other molecular subtypes. This underlines the significance of molecular changes in metastatic disease, especially in tumors of initially low aggressive potential.

[Surgical Therapy of Pulmonal Echinococcosis]. / Die chirurgische Therapie der pulmonalen Echinokokkose.

Human echinococcosis is a rare zoonotic infection caused by larvae of the tapeworm species Echinococcus. The most relevant two species to humans are Echinococcus multilocularis and the dog tapeworm Echinococcus granulosus. The latter causes cystic echinococcosis, which plays a dominant role in thoracic surgery due to its pulmonal involvement. The parasite develops characteristic hydatic cysts mostly in liver and lung. In 2016 a rise in cases of cystic echinococcosis in Germany was recorded, a probable cause could have been the refugee wave. The infection and advanced stages of the disease does not always cause symptoms and stays asymptomatic. Dry cough, thoracic pain and hemoptysis are uncharacteristic symptoms. Cysts may rupture and void into the bronchial system or thoracic cavity, which can result in empyema. Surgery remains the main therapeutic approach for pulmonary cystic echinococcosis. Surgical therapy includes peri- or endocystectomy, wedge and anatomic resections. Depending on size and localization of hydatid cysts the appropriate surgical technique should be chosen aiming on minimal loss of lung parenchyma. The treatment strategies need to be discussed in an interdisciplinary setting including infectiologists and thoracic or general surgeons. The respective treatment should be carried out in specialized centers due to the low incidence of the disease.

Publisher Correction: Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats.

This corrects the article DOI: 10.1038/ncomms4562.

The Use of Mathematical Modelling for Improving the Tissue Engineering of Organs and Stem Cell Therapy.

Regenerative medicine is a multidisciplinary field where continued progress relies on the incorporation of a diverse set of technologies from a wide range of disciplines within medicine, science and engineering. This review describes how one such technique, mathematical modelling, can be utilised to improve the tissue engineering of organs and stem cell therapy. Several case studies, taken from research carried out by our group, ACTREM, demonstrate the utility of mechanistic mathematical models to help aid the design and optimisation of protocols in regenerative medicine.

Autologous Peripheral Blood Mononuclear Cells as Treatment in Refractory Acute Respiratory Distress Syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating disorder. Despite enormous efforts in clinical research, effective treatment options are lacking, and mortality rates remain unacceptably high. OBJECTIVES: A male patient with severe ARDS showed no clinical improvement with conventional therapies. Hence, an emergent experimental intervention was performed. METHODS: We performed intratracheal administration of autologous peripheral blood-derived mononuclear cells (PBMCs) and erythropoietin (EPO). RESULTS: We found that after 2 days of initial PBMC/EPO application, lung function improved and extracorporeal membrane oxygenation (ECMO) support was reduced. Bronchoscopy and serum inflammatory markers revealed reduced inflammation. Additionally, serum concentration of miR-449a, b, c and miR-34a, a transient upregulation of E-cadherin and associated chromatin marks in PBMCs indicated airway epithelial differentiation. Extracellular vesicles from PBMCs demonstrated anti-inflammatory capacity in a TNF-α-mediated nuclear factor-x03BA;B in vitro assay. Despite improving respiratory function, the patient died of multisystem organ failure on day 38 of ECMO treatment. CONCLUSIONS: This case report provides initial encouraging evidence to use locally instilled PBMC/EPO for treatment of severe refractory ARDS. The observed clinical improvement may partially be due to the anti-inflammatory effects of PBMC/EPO to promote tissue regeneration. Further studies are needed for more in-depth understanding of the underlying mechanisms of in vivo regeneration.

Characterization of stem-like cells in mucoepidermoid tracheal paediatric tumor.

Stem cells contribute to regeneration of tissues and organs. Cells with stem cell-like properties have been identified in tumors from a variety of origins, but to our knowledge there are yet no reports on tumor-related stem cells in the human upper respiratory tract. In the present study, we show that a tracheal mucoepidermoid tumor biopsy obtained from a 6 year-old patient contained a subpopulation of cells with morphology, clonogenicity and surface markers that overlapped with bone marrow mesenchymal stromal cells (BM-MSCs). These cells, designated as MEi (mesenchymal stem cell-like mucoepidermoid tumor) cells, could be differentiated towards mesenchymal lineages both with and without induction, and formed spheroids in vitro. The MEi cells shared several multipotent characteristics with BM-MSCs. However, they displayed differences to BM-MSCs in growth kinectics and gene expression profiles relating to cancer pathways and tube development. Despite this, the MEi cells did not possess in vivo tumor-initiating capacity, as proven by the absence of growth in situ after localized injection in immunocompromised mice. Our results provide an initial characterization of benign tracheal cancer-derived niche cells. We believe that this report could be of importance to further understand tracheal cancer initiation and progression as well as therapeutic development.

Tracheal tissue engineering in rats.

Tissue-engineered tracheal transplants have been successfully performed clinically. However, before becoming a routine clinical procedure, further preclinical studies are necessary to determine the underlying mechanisms of in situ tissue regeneration. Here we describe a protocol using a tissue engineering strategy and orthotopic transplantation of either natural decellularized donor tracheae or artificial electrospun nanofiber scaffolds into a rat model. The protocol includes details regarding how to assess the scaffolds' biomechanical properties and cell viability before implantation. It is a reliable and reproducible model that can be used to investigate the crucial aspects and pathways of in situ tracheal tissue restoration and regeneration. The model can be established in <6 months, and it may also provide a means to investigate cell-surface interactions, cell differentiation and stem cell fate.

Biomechanical and biocompatibility characteristics of electrospun polymeric tracheal scaffolds.

The development of tracheal scaffolds fabricated based on electrospinning technique by applying different ratios of polyethylene terephthalate (PET) and polyurethane (PU) is introduced here. Prior to clinical implantation, evaluations of biomechanical and morphological properties, as well as biocompatibility and cell adhesion verifications are required and extensively performed on each scaffold type. However, the need for bioreactors and large cell numbers may delay the verification process during the early assessment phase. Hence, we investigated the feasibility of performing biocompatibility verification using static instead of dynamic culture. We performed bioreactor seeding on 3-dimensional (3-D) tracheal scaffolds (PET/PU and PET) and correlated the quantitative and qualitative results with 2-dimensional (2-D) sheets seeded under static conditions. We found that an 8-fold reduction for 2-D static seeding density can essentially provide validation on the qualitative and quantitative evaluations for 3-D scaffolds. In vitro studies revealed that there was notably better cell attachment on PET sheets/scaffolds than with the polyblend. However, the in vivo outcomes of cell seeded PET/PU and PET scaffolds in an orthotopic transplantation model in rodents were similar. They showed that both the scaffold types satisfied biocompatibility requirements and integrated well with the adjacent tissue without any observation of necrosis within 30 days of implantation.

Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats.

A tissue-engineered oesophageal scaffold could be very useful for the treatment of pediatric and adult patients with benign or malignant diseases such as carcinomas, trauma or congenital malformations. Here we decellularize rat oesophagi inside a perfusion bioreactor to create biocompatible biological rat scaffolds that mimic native architecture, resist mechanical stress and induce angiogenesis. Seeded allogeneic mesenchymal stromal cells spontaneously differentiate (proven by gene-, protein and functional evaluations) into epithelial- and muscle-like cells. The reseeded scaffolds are used to orthotopically replace the entire cervical oesophagus in immunocompetent rats. All animals survive the 14-day study period, with patent and functional grafts, and gain significantly more weight than sham-operated animals. Explanted grafts show regeneration of all the major cell and tissue components of the oesophagus including functional epithelium, muscle fibres, nerves and vasculature. We consider the presented tissue-engineered oesophageal scaffolds a significant step towards the clinical application of bioengineered oesophagi.

Modelling biological cell attachment and growth on adherent surfaces.

A mathematical model, in the form of an integro-partial differential equation, is presented to describe the dynamics of cells being deposited, attaching and growing in the form of a monolayer across an adherent surface. The model takes into account that the cells suspended in the media used for the seeding have a distribution of sizes, and that the attachment of cells restricts further deposition by fragmenting the parts of the domain unoccupied by cells. Once attached the cells are assumed to be able to grow and proliferate over the domain by a process of infilling of the interstitial gaps; it is shown that without cell proliferation there is a slow build up of the monolayer but if the surface is conducive to cell spreading and proliferation then complete coverage of the domain by the monolayer can be achieved more rapidly. Analytical solutions of the model equations are obtained for special cases, and numerical solutions are presented for parameter values derived from experiments of rat mesenchymal stromal cells seeded onto thin layers of collagen-coated polyethylene terephthalate electrospun fibers. The model represents a new approach to describing the deposition, attachment and growth of cells over adherent surfaces, and should prove useful for studying the dynamics of the seeding of biomaterials.

Preservation of aortic root architecture and properties using a detergent-enzymatic perfusion protocol.

Aortic valve degeneration and dysfunction is one of the leading causes for morbidity and mortality. The conventional heart-valve prostheses have significant limitations with either life-long anticoagulation therapeutic associated bleeding complications (mechanical valves) or limited durability (biological valves). Tissue engineered valve replacement recently showed encouraging results, but the unpredictable outcome of tissue degeneration is likely associated to the extensive tissue processing methods. We believe that optimized decellularization procedures may provide aortic valve/root grafts improved durability. We present an improved/innovative decellularization approach using a detergent-enzymatic perfusion method, which is both quicker and has less exposure of matrix degenerating detergents, compared to previous protocols. The obtained graft was characterized for its architecture, extracellular matrix proteins, mechanical and immunological properties. We further analyzed the engineered aortic root for biocompatibility by cell adhesion and viability in vitro and heterotopic implantation in vivo. The developed decellularization protocol was substantially reduced in processing time whilst maintaining tissue integrity. Furthermore, the decellularized aortic root remained bioactive without eliciting any adverse immunological reaction. Cell adhesion and viability demonstrated the scaffold's biocompatibility. Our optimized decellularization protocol may be useful to develop the next generation of clinical valve prosthesis with a focus on improved mechanical properties and durability.