Advanced lung cancer patient benefits from minimally invasive costal resection and reconstruction: an effective palliative approach for costal metastasis.

We hereby describe the resection and reconstruction of a rib infiltrated by a lung cancer metastasis. Despite prior radiation therapy aimed at mitigating pain from rib infiltration in a stage IV non-small cell lung cancer patient, results were unsatisfactory. Employing a minimally invasive palliative strategy, we executed a successful operation to address this issue. This technique presents a viable alternative for patients experiencing recurrent pain post radiation therapy.

Transcriptomic comparison of primary human lung cells with lung tissue samples and the human A549 lung cell line highlights cell type specific responses during infections with influenza A virus.

Influenza A virus (IAV) causes pandemics and annual epidemics of severe respiratory infections. A better understanding of the molecular regulation in tissue and cells upon IAV infection is needed to thoroughly understand pathogenesis. We analyzed IAV replication and gene expression induced by IAV strain H3N2 Panama in isolated primary human alveolar epithelial type II cells (AECIIs), the permanent A549 adenocarcinoma cell line, alveolar macrophages (AMs) and explanted human lung tissue by bulk RNA sequencing. Primary AECII exhibit in comparison to AM a broad set of strongly induced genes related to RIG-I and interferon (IFN) signaling. The response of AECII was partly mirrored in A549 cells. In human lung tissue, we observed induction of genes unlike in isolated cells. Viral RNA was used to correlate host cell gene expression changes with viral burden. While relative induction of key genes was similar, gene abundance was highest in AECII cells and AM, while weaker in the human lung (due to less IAV replication) and A549 cells (pointing to their limited suitability as a model). Correlation of host gene induction with viral burden allows a better understanding of the cell-type specific induction of pathways and a possible role of cellular crosstalk requiring intact tissue.

Human alveolar progenitors generate dual lineage bronchioalveolar organoids.

Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280+/EpCAM+ population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3ß inhibitor, CHIR99021. By RNA-seq profiling of GSK-3ß knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction.

Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. METHODS: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results. RESULTS: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection. CONCLUSIONS: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.

A predictive model of lymph node metastasis for thymic epithelial tumours.

OBJECTIVES: Thymic epithelial tumours (TETs) are relatively rare indolent malignancies in the mediastinum. Lymph node metastasis (LNM) is an important prognostic indicator for TETs; however, the pattern of LNM involved in TETs has yet to be elucidated. METHODS: Patients diagnosed with histologically confirmed thymoma (A-B3), thymic carcinomas and thymic neuroendocrine tumours, between 1988 and 2016 were identified from the Surveillance, Epidemiology, and End Results database. Univariable and multivariable logistic regression analyses were applied to identify the predictors for LNM. The predictive nomogram was built from the independent risk factors and measured using the concordance statistic. RESULTS: The overall proportion of TETs with LNM was 18.5% (200/1048). The rate of LNM in thymoma, thymic carcinomas and thymic neuroendocrine tumours was 6.8% (42/622), 30.2% (100/331) and 61.1% (58/95), respectively. According to the logistic regression analysis, histology type and T stage were independent factors correlated with LNM. A predictive nomogram model was developed with a concordance statistic of 0.807 (95% confidence interval: 0.773-0.841), which was significantly better than the T stage (P < 0.001) while had limited benefit to the histology type (P = 0.047). The calibration curve for the nomogram comparing the predicted and actual probabilities after bias correction showed good agreement. CONCLUSIONS: Nodal involvement was not uncommon in TETs. Main factors related to LNM in TETs were histology type and T stage. The probability of LNM could be well calculated using the predictive model.

Minimally invasive thymectomy for myasthenia gravis favours left-sided approach and low severity class.

OBJECTIVES: Complete thymectomy is a key component of the optimal treatment for myasthenia gravis. Unilateral, minimally invasive approaches are increasingly utilized with debate about the optimal laterality approach. A right-sided approach has a wider field of view, while a left-sided approach accesses potentially more thymic tissue. We aimed to assess the impact of laterality on perioperative and medium-term outcomes, and to identify predictors of a 'good outcome' using standard definitions. METHODS: We performed a multicentre review of 123 patients who underwent a minimally invasive thymectomy for myasthenia gravis between January 2000 and August 2015, with at least 1-year follow-up. The Myasthenia Gravis Foundation of America standards were followed. A 'good outcome' was defined by complete stable remission/pharmacological remission/minimal manifestations 0, and a 'poor outcome' by minimal manifestations 1-3. Univariate and multivariable logistic regression analyses were performed to assess factors associated with a 'good outcome'. RESULTS: Ninety-two percent of thymectomies (113/123) were robotic-assisted. The left-sided approach had a shorter median operating time than a right-sided: 143 (interquartile range, IQR 110-196) vs 184 (IQR 133-228) min, P = 0.012. At a median of 44 (IQR 27-75) months, the left-sided approach achieved a 'good outcome' (46%, 31/68) more frequently than the right-sided (22%, 12/55); P = 0.011. Multivariable analysis identified a left-sided approach and Myasthenia Gravis Foundation of America class I/II to be associated with a 'good outcome'. CONCLUSIONS: A left-sided thymectomy may be preferred over a right-sided approach in patients with myasthenia gravis given the shorter operating times and potential for superior medium-term symptomatic outcomes. A lower severity class is also associated with a 'good outcome'.

Reversion of Pneumolysin-Induced Executioner Caspase Activation Redirects Cells to Survival.

Apoptosis is an indispensable mechanism for eliminating infected cells and activation of executioner caspases is considered to be a point of no return. Streptococcus pneumoniae, the most common bacterial pathogen causing community-acquired pneumonia, induces apoptosis via its pore-forming toxin pneumolysin, leading to rapid influxes of mitochondrial calcium [Ca2+]m as well as fragmentation, and loss of motility and membrane potential, which is accompanied by caspase-3/7 activation. Using machine-learning and quantitative live-cell microscopy, we identified a significant number of alveolar epithelial cells surviving such executioner caspase activation after pneumolysin attack. Precise single-cell analysis revealed the [Ca2+]m amplitude and efflux rate as decisive parameters for survival and death, which was verified by pharmacological inhibition of [Ca2+]m efflux shifting the surviving cells towards the dying fraction. Taken together, we identified the regulation of [Ca2+]m as critical for controlling the cellular fate under pneumolysin attack, which might be useful for therapeutic intervention during pneumococcal infection.

Effect of Lymph Node Dissection on the Prognosis of Thymic Carcinomas and Thymic Neuroendocrine Tumors.

We aimed to analyze the effect of lymph node dissection (LND) and accurate lymph node (LN) status on the survival and prognosis of patients with thymic carcinomas (TCs) and thymic neuroendocrine tumors (TNETs) undergoing surgical treatment. The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgical resection for TCs and TNETs during 1998-2016. LN status were defined as no LND (LND-), pathologically negative with LND (N0), and LN metastasis positive (N+). We investigated outcomes of LN status together with other clinicopathological features for overall survival (OS). Subgroup analyses were performed between LND-, N0, and N+ cohorts using propensity score matching, to analyze the significance of LND in prognosis. A total of 812 patients were enrolled, including 623 with TCs and 189 with TNETs. The proportion of LN metastasis positive in TNETs was 58.8% which was significantly higher than that in TCs (30%) (P < 0.001). In multivariable Cox analysis of OS, patients with LND- had a significantly worse prognosis than those with N0 (P = 0.018); there was no difference between N+ and LND- (P = 0.560). After propensity score matching, patients with N0 still had better survival than those with LND- and N+ in subgroup univariable and multivariable analyses of OS; however, the survival of patients with LND- and N+ was not significantly different in multivariable analysis. It was demonstrated that LND in TCs and TNETs can clarify the status of LN metastasis, to more accurately evaluate patients' long-term prognosis.

Single lung resection: The limits of the possible. Clinical report.

INTRODUCTION: Single lung resection remains a challenge due to the preservation of the respiratory reserve. This report presents that case of a female patient with bilateral fibrotic-cavitary pulmonary tuberculosis complicated with empyema on the right lung. Only 3.5 lung segments were left after a multistage surgery. PRESENTATION OF CASE: The first stage included draining of empyema and transsternal transmediastinal right main bronchus occlusion. Then, upper lobectomy with partial S6 resection of the left lung, followed by pleuropneumonectomy was performed. At a follow-up of two years and 10 months, patient's condition was good. DISCUSSION: Although single lung surgery has been possible over half a century ago, it remains a high-risk intervention. CONCLUSION: With the removal of the non-functioning parenchyma and elimination of the air/vascular shunt, single lung resection volume exceeding lobectomy is possible, which may improve cardiorespiratory function.

Thymectomy in ocular myasthenia gravis before generalization results in a higher remission rate.

OBJECTIVES: This study aimed to compare the outcomes of patients with ocular myasthenia gravis (OMG) who underwent thymectomy before generalization with the outcomes of those who underwent thymectomy after generalization. METHODS: We retrospectively reviewed patients who underwent robotic thymectomy for myasthenia gravis between January 2003 and February 2018. Patients who presented with purely ocular symptoms at myasthenia gravis onset were eligible for inclusion. Exclusion criteria were patients who were lost to follow-up and patients who underwent re-thymectomy. Patients with OMG who developed generalization before thymectomy were categorized into gOMG group and those who did not were categorized into OMG group. The primary outcome was complete stable remission according to the Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS). RESULTS: One hundred and sixty-five (66 males and 99 females) out of 596 patients with myasthenia gravis were eligible for inclusion. Of these, there were 73 and 92 patients undergoing thymectomy before and after the generalization of OMG, respectively. After propensity score matching, a data set of 130 patients (65 per group) was formed and evaluating results showed no statistical differences between the 2 groups. The estimated cumulative probabilities of complete stable remission at 5 years were 49.5% [95% confidence interval (CI) 0.345-0.611] in the OMG group and 33.4% (95% CI 0.176-0.462) in the gOMG group (P = 0.0053). Similar results were also found in patients with non-thymomatous subgroup [55 patients per group, OMG vs gOMG, 53.5% (95% CI 0.370-0.656) vs 28.9% (95% CI 0.131-0.419), P = 0.0041]. CONCLUSIONS: Thymectomy in OMG before generalization might result in a higher rate of complete stable remission than thymectomy after generalization.

Unraveling the role of ectopic thymic tissue in patients undergoing thymectomy for myasthenia gravis.

Extended thymectomy has been considered the goal of surgery for myasthenia gravis (MG) mainly due to the existence of ectopic thymic tissue. Recently, ectopic thymic tissue has attracted increasing attention in patients with MG following thymectomy. However, the specific role of ectopic thymic tissue in patients with MG is still under debate. A systematic search of the literature was performed on PubMed and Medline according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISM) statement. Studies evaluating the rate of ectopic thymic tissue in patients with MG with or without thymoma were included. Extraction was performed for all eligible studies and the rate of ectopic thymic tissue at common locations was calculated. Eighteen out of fifty-nine studies were eligible for inclusion, of which ten studies reported the common locations of ectopic thymic tissue in mediastinal fat. Of these ten studies, the presence of ectopic thymic tissue was investigated in different anatomical locations in 882 patients, of whom, 509 patients (58%) have at least one positive location with the most common ones being anterior mediastinal fat, pericardiophrenic angles, aortopulmonary window, cervical region (pretracheal fat) and lateral to phrenic nerves. On the other hand, nine studies analyzed the influence of the presence of ectopic thymic tissue on the clinical outcomes of MG patients. Of these, six found that the presence of ectopic thymic tissue in MG patients is a significant predictor of poor outcome after thymectomy, however, the other three did not find a significance. Altogether, ectopic thymic tissue is likely to present in more than a half of patients undergoing thymectomy for MG. Besides, MG patients who have ectopic thymic tissue after thymectomy do not seem to have as good outcome as those who have not.

Current status and evolution of robotic-assisted thoracic surgery in Germany-results from a nationwide survey.

BACKGROUND: Robot-assisted surgery has made a significant entry into surgical practice within Germany, including thoracic surgery. As no published data exists regarding robotic-assisted thoracic surgery (RATS), we conducted a survey to investigate its current status. METHODS: We performed a nationwide survey of all centers active in RATS, using a standardized questionnaire. The annual number of operations, mean duration of surgery, docking time, length of hospital stay(s), conversions, chest tube duration, the RATS program start date, robot system used, operating room capacity, and staplers and instruments used were recorded. RESULTS: Of the 22 centers contacted, 14 responded. In total, 786 RATS interventions were recorded. Most were anatomical lung resections, comprising 372 (bi-) lobectomies and 80 segmentectomies. During the study period, eight bronchoplastic procedures were performed robotically. There were 93 wedge lung resections, 148 thymectomies, 26 sympathectomies, and 59 other RATS procedures, and a single-center series of around 1,000 RATS thymectomies (excluded from statistical analysis). The average incision-suture time of the RATS lobectomy was 245 (range, 80-419) minutes, average residence time seven days. The conversion rate was 6.7% across all interventions, with significant inter-intervention differences. All surveyed centers plan to further expand RATS, with OR capacity being a frequent impediment. Five RATS interventions were performed in Germany in 2013, versus 320 in 2018. CONCLUSIONS: Overall, RATS is becoming more established in everyday clinical practice in Germany. The number of operations, active centers, and trained RATS surgeons has increased steadily since 2013. A German-speaking operation course for entry into RATS already exists. Even extended resections can be carried out safely, and RATS has become standard procedure in some centers.

Uniportal video-assisted thoracoscopic surgery for the treatment of thoracic emergencies.

BACKGROUND: While video-assisted thoracoscopic surgery (VATS) is well accepted in the management of thoracic emergencies, uniportal VATS has not yet been studied for this indication. This paper reports the results of the treatment of chest trauma patients by uniportal VATS in a single center with extensive experience in uniportal VATS. METHODS: In this prospective study all patients who underwent uniportal VATS for thoracic surgical emergency cases, between 06/2012 and 09/2017, were included and the data were reviewed retrospectively. RESULTS: Six hundred forty-two uniportal VATS procedures were performed. Among those, 12 emergency cases could be identified. The indication was a hemothorax with active bleeding in all cases and the uniportal VATS approach was carried out after carefully evaluating all clinical factors and risks related to such a special setting. The location, extent and severity of the injuries were diagnosed and treated intraoperatively. The conversion rate was zero. The mean surgical time was 106.25 minutes [63-240], the chest tube was removed after 6.75 days in average (range, 1-25). All patients were transferred to the post anesthesia care unit (PACU) or intensive care unit (ICU) for at least one night (range, 1-25). The mean postoperative hospital stay was 10.67 days [4-26]. CONCLUSIONS: In expert hands, uniportal VATS approach seems to be a safe and feasible procedure for both, the diagnostics and management of emergency cases, such as active thoracic bleeding in cardiopulmonary stable patients.

The everlasting issue of prolonged air leaks after lobectomy for non-small cell lung cancer: A data-driven prevention planning model in the era of minimally invasive approaches.

BACKGROUND AND OBJECTIVES: Prolonged air leaks (PAL) are the most frequent complication after lobectomy for non-small cell lung cancer, even in case of minimally invasive approaches. We developed a novel score to identify high-risk patients for PAL during minimally invasive lobectomy. METHODS: A dedicated database was created. We investigated preoperative candidate features and specific intraoperative variables. Univariate and subsequent logistic regression analysis with bootstrap resampling have been used. Model performance has been assessed by reckoning the area under the receiver operating characteristics curve and the Hosmer-Lemeshow goodness of fit. RESULTS: PAL (>5 days) occurred in 72 (15.69%) patients. Five variables emerged from the model. Each one was assigned a score to provide a cumulative scoring system: forced expiratory volume in 1 second below 86% (P = 0.004, 1.5 points), body mass index <24 ( P = 0.002, 1 point), active smoking ( P = 0.001, 1.5 points), incomplete fissures ( P = 0.004, 1.5 points), and adhesions ( P = 0.0001, 1 point). The new score provided a stratification into four risk classes. CONCLUSIONS: The risk score incorporates either general or more specific variables, providing a risk stratification that could be readily applied intra- and postoperatively. Henceforth, specific technical and management measures could be properly allocated to curb PAL.

Generalization after ocular onset in myasthenia gravis: a case series in Germany.

BACKGROUND AND PURPOSE: Approximately, 50% of myasthenia gravis (MG) patients initially present with purely ocular symptoms. Of these, about 60% will develop secondary generalized MG, typically within 2 years. Risk factors for secondary generalization are still controversial. In this study, we reviewed clinical parameters, thymic pathologies and medical treatments of MG patients with purely ocular symptoms at onset to investigate risk factors for secondary generalization. METHODS: In this monocentric retrospective study, we reviewed consecutive patients who underwent robotic thymectomy between January 2003 and October 2017 in Charite Universitaetsmedizin Berlin. We used univariate and multivariate Cox proportional hazards regression models to identify factors associated with secondary generalization. Survival curves were plotted using Kaplan-Meier method and log-rank tests were performed to analyze the association between corticosteroids use and secondary generalization in subgroups defined by anti-AChR antibody status and thymic pathology. RESULTS: One hundred and eighty of 572 MG patients who underwent robotic thymectomy were eligible for inclusion, of whom 110 (61.1%) developed a secondary generalized MG over a mean follow-up time of 23.6 months. The presence of a thymoma (HR 1.659, 95% CI (1.52-2.617), P = 0.029) was the only risk factor for secondary generalization in our series. Treating with corticosteroids was associated with a lower conversion rate in ocular myasthenia patients with thymic hyperplasia (n = 55, P = 0.028), but not with other thymic pathologies including thymoma and normal or atrophic thymus. CONCLUSIONS: The conversion rate in ocular myasthenia was high in our series, predicted by the presence of a thymoma. Our findings suggest that corticosteroids can prevent secondary generalization in ocular myasthenia patients with thymic hyperplasia, which requires further research.

Pneumolysin induced mitochondrial dysfunction leads to release of mitochondrial DNA.

Streptococcus pneumoniae (S.pn.) is the most common bacterial pathogen causing community acquired pneumonia. The pore-forming toxin pneumolysin (PLY) is the major virulence factor of S.pn. and supposed to affect alveolar epithelial cells thereby activating the immune system by liberation of danger-associated molecular patterns (DAMP). To test this hypothesis, we established a novel live-cell imaging based assay to analyse mitochondrial function and associated release of mitochondrial DNA (mtDNA) as DAMP in real-time. We first revealed that bacterially released PLY caused significant changes of the cellular ATP homeostasis and led to morphologic alterations of mitochondria in human alveolar epithelial cells in vitro and, by use of spectral live-tissue imaging, in human alveoli. This was accompanied by strong mitochondrial calcium influx and loss of mitochondrial membrane potential resulting in opening of the mitochondrial permeability transition pore and mtDNA release without activation of intrinsic apoptosis. Moreover, our data indicate cellular mtDNA liberation via microvesicles, which may contribute to S.pn. related pro-inflammatory immune activation in the human alveolar compartment.

Fast-Tracking Patients Through the Diagnostic and Therapeutic Pathways of Intrathoracic Conditions: The Role of Uniportal Video-Assisted Thoracic Surgery.

Fast-tracking patients in surgery has become standard in many hospitals. This allows for a shorter hospital stay and a complete organized pathway for treating patients. The operative trauma has an important role in the patient's recovery, as has the increasing use of minimally invasive procedures. In thoracic surgery, video-assisted thoracic surgery (VATS) procedures are aimed at reducing the operative trauma. One of the latest developments of VATS is represented by the uniportal approach, whose purpose is to reduce postoperative pain and morbidity. This article reviews the current literature and the authors' experience in combining uniportal VATS technique and fast-track surgery.

Tyk2 as a target for immune regulation in human viral/bacterial pneumonia.

The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lung ex vivo co-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibits Streptococcus pneumoniae-induced interleukin (IL)-1ß release. The lack of IL-1ß resulted in the repression of bacterially induced granulocyte-macrophage colony-stimulating factor (GM-CSF) liberation. Specific inhibition of IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) completely restored the S. pneumoniae-induced IL-1ß-GM-CSF axis, leading to a reduction of bacterial growth. A preceding IAV infection of the human alveolus leads to a type I and III IFN-dependent blockade of the early cytokines IL-1ß and GM-CSF, which are key for orchestrating an adequate innate immune response against bacteria. Their virally induced suppression may result in impaired bacterial clearance and alveolar repair.Pharmacological inhibition of Tyk2 might be a new treatment option to sustain beneficial endogenous GM-CSF levels in IAV-associated secondary bacterial pneumonia.

Uniportal video-assisted thoracic surgery for major lung resections: pitfalls, tips and tricks.

Nearly six years since inception, uniportal video-assisted thoracic surgery (VATS) has become a growing part of major lung resections and has revolutionized the way thoracic surgeons treat pulmonary lesions. This technique is being touted for various benefits. It ensures direct visualization together with a better exposure of the lung and allows the chance of a digital palpation of the lesion through a small incision. Postoperative pain is reduced due to the involvement of only one intercostal space without rib spreading and muscle disruption. The comfort and aesthetics factors are improved significantly since the oncological principles and radicality of open surgery are restored. As the surgeons gain more experience in uniportal-VATS lobectomy, more complex cases can be managed by this technique. The objectives of this work are to set the basic steps for performing major lung resections (lobectomy, bilobectomy and pneumonectomy) by utilizing uniportal-VATS and to analyze some common pitfalls that thoracic surgeons face when practicing this technique and provide practical tips and tricks on how to avoid.