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BackgroundSevere 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.MethodsSpectral 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 validateex vivoresults.ResultsWe 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 vivoinfected 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.ConclusionsCollectively, 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.

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.

Highlights • Removal of the non-functioning part of the lung eliminates the air/vascular shunt. • it may cause an improvement of cardiorespiratory function. • single lung resection is possible with the functional futility of the removed part., 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.

In Myasthenia Gravis (MG) thymic pathologies are often present and thymectomy is used as treatment. By flow cytometry we elucidated alterations of naive CD4+ T cell homeostasis in MG patients and patients with thymoma. MG patients showed increased absolute numbers of CD31- centralnaive CD4+ T cells. Thymoma patients displayed a significantly higher fraction of peripheral blood CD31+ thymicnaive T cells. We show an altered naive CD4+ T cell homeostasis in MG patients that might predispose to autoimmunity. Aberrant generation of T cells in thymoma can be detected by an increased frequency of CD31+ thymicnaive CD4+ T cells in the periphery.

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’.

Background Endoscopic lung volume reduction (ELVR) with valves has been suggested to be the key strategy for patients with severe emphysema and concomitant low diffusing capacity of the lung for carbon monoxide (DLCO). However, robust evidence is still missing. We therefore aim to compare clinical outcomes in relation to DLCO for patients treated with ELVR. Methods We assessed DLCO at baseline and 3 months follow-up and compared pre- and postprocedural pulmonary function test, quality of life, exercise capacity and adverse events. This is a retrospective subanalysis of prospectively collected data from the German Lung Emphysema Registry. Results In total, 121 patients treated with ELVR were analysed. Thirty-four patients with a DLCO ≤20% and 87 patients with a DLCO >20% showed similar baseline characteristics. After ELVR, there was a decrease of residual volume (both p20% (p20%: 16.1%; p=0.728). However, there were no significant differences in other adverse events between both groups. Conclusions ELVR improves lung function as well as quality of life in patients with DLCO >20% and DLCO ≤20%. Adverse events did not differ between groups. Therefore, ELVR should be considered as a treatment option, even in patients with a very low DLCO., Endoscopic lung volume reduction with endobronchial valves can be safely performed in patients with a very low diffusing capacity of the lung (DLCO). Clinical effectiveness is comparable to patients with higher DLCO. https://bit.ly/3cOgDK1

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%) (P0.001). 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.

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.

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

ZusammenfassungDie Myasthenia gravis (MG) hat in den letzten Jahren zahlreiche Fortschritte in der Erforschung der Pathophysiologie, der Charakterisierung von Subgruppen sowie der Erweiterung der multimodalen Therapie erfahren. Insbesondere gilt das auch für die Rolle der Thymektomie (Thx). Für die Thymom-assoziierte MG ist die Thx streng indiziert. Auf Basis großer Kohortenstudien über die letzten Jahrzehnte wurde die Thx aber auch zentraler Bestandteil der immunmodulierenden MG-Therapie bei MG-Patienten ohne Thymom-Nachweis. Da randomisierte Studien fehlten, blieb jedoch eine Restunsicherheit zum Stellenwert der Thx. In der MGTX-Studie konnte die Wirksamkeit der Thx nun zweifelsfrei nachgewiesen werden 1. Eine signifikante Verbesserung der myasthenen Beschwerden und die Reduktion der immunsuppressiven Medikamente zeigten sich vor allem für die im jungen Erwachsenenalter erworbene MG (EOMG) bei Durchführung einer kompletten Resektion des Thymusgewebes. Da die MGTX-Studie nur Patienten mit generalisiertem Verlauf und Acetylcholinrezeptor-Antikörpernachweis eingeschlossen hatte, die jünger als 65 Jahre waren, wird derzeit die Bedeutung der Thx bei den anderen relevanten Subgruppen, wie der juvenilen MG, der Altersmyasthenie, der okulären MG sowie den Patienten mit fehlendem Autoantikörper-Nachweis untersucht. Auch die derzeit vorherrschende Auffassung, dass Patienten mit MuSK-Antikörpernachweis nicht von einer Thx profitieren, wird auf Basis der widersprüchlichen Daten neu geprüft werden müssen. Aus chirurgischer Sicht wird auf Basis des in der MGTX-Studie eingesetzten Thx-Verfahrens der komplett-erweiterten medianen Sternotomie momentan der Stellenwert der minimalinvasiven thorakoskopischen Verfahren als schonende Alternative geprüft. Für die weitere Ausdifferenzierung der Thx-Verfahren wären aus klinisch-wissenschaftlicher Sicht randomisiert-kontrollierte Studien im Vergleich zum offenen Thx-Verfahren wünschenswert. Schon jetzt gelingt es jedoch unter Anwendung der Roboterassistenz, alle Ansprüche an die Thx aus chirurgischer, klinisch-neurologischer sowie Patientensicht optimal zu erfüllen. Aufgrund ethischer Aspekte werden daher andere Wege des wissenschaftlichen Vergleichs der verschiedenen Operationsverfahren in den Mittelpunkt rücken.

In recent years much progress has been made in the investigation of the pathophysiology, characterizing subgroups, and extension of multimodal treatment of myasthenia gravis (MG). This applies especially to the role of thymectomy (Thx). Thymectomy is always indicated for thymoma-associated myasthenia gravis. Furthermore, based on large cohort studies, during recent decades thymectomy has also become a central part of immune-modulating MG therapy in patients without thymoma. The lack of randomized studies, however, caused a certain persistent reluctance as to the significance of thymectomy. The current MGTX trial has shown the effectiveness of thymectomy. A significant improvement of myasthenic complaints and the reduction of immunosuppressive medication was primarily shown for acquired early-onset MG (EOMG) with complete resection of all thymic tissue. Because the MGTX study only included patients younger than 65 years with generalized MG and positive for acetylcholine-receptor antibodies, at present the significance of Thx for other relevant subgroups as juvenile MG, MG in older patients, ocular MG, as well as seronegative patients is under investigation. Even the prevailing opinion of no benefit of thymectomy for MuSk-positive patients probably needs reevaluation based on ambiguous findings. With respect to surgery, based on the exclusive performance of extended median sternotomy for MG in the MGTX, the value of thoracoscopic modifications for thymectomy as a minimally-invasive alternative is currently under evaluation. For clinical reasons further judgment regarding different minimally-invasive thymectomy techniques compared to the conventional open procedures in the form of randomized comparative studies would be required. Currently, however, an experience-based robotic-assisted thoracoscopic unilateral approach to thymectomy meets all requirements related to surgical, clinical-neurological and patient aspects. Ethical reasons, therefore, will lead to other strategies for comparison of different surgical techniques.

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.

Although myasthenia gravis (MG) is a classic autoantibody-mediated disease, T cells are centrally involved in its pathogenesis. In recent years a number of studies have analyzed the role of CD4+ FoxP3+ regulatory T cells (Treg) in the disease with contradictory results. Here, the generation of Treg was significantly reduced in thymoma as compared to thymic hyperplasia and normal thymus tissue (p=0.0002). In the peripheral blood, Treg subsets classified according to CD49d, HELIOS and CD45RA expression changed after thymectomy and in the long-term course of immunosuppression. Compared to healthy volunteers the frequency of CD45RA+FoxP3low Treg was reduced in MG patients in general (p=0.037) and in particular in patients without immunosuppression (p=0.036). In our study, thymectomy and immunosuppressive treatment were associated with changes in Treg subpopulations. The reduced frequency of CD45RA+FoxP3low Treg we observed in MG patients might play a role in MG pathogenesis.

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.

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.

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.

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. 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. 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. 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.

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.

Thymectomy is necessary for thymic tumors and an essential part of the therapeutic strategy for myasthenia gravis. Within a century, the history of thymectomy has been characterized by the development of minimally-invasive surgical techniques. The latest refinement is robotic-assisted thymectomy. The perioperative management including anesthesia is described. The stepwise operative technique starts with special positioning of the patient. The preferred conduct of the operation is provided. For anatomical reasons the left side is preferred for the unilateral approach. The extended thymectomy is necessary to achieve the best outcome. This includes resection of the contralateral cardiophrenic tissue. Tips for performing the operation are included and pitfalls are described. All essential steps of the operation are illustrated. The advantages of robotic technology optimized by the described approach and consist of surgeon-directed 3-D vision, magnification, multiple arcs of instrument movement, tremorless precision, and potentially the most thorough mediastinal dissection of all minimally invasive surgical options. The review of the supportive literature for thymectomy in the treatment of myasthenia gravis is described; especially the recently published prospective randomized trial comparing medical therapy to thymectomy, showing superiority of thymectomy. It is likely that the impact will increase the number of patients seeking thymectomy.

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.

Robotic thymectomy with the da Vinci robotic system is the latest development in the surgery of thymic gland. Thymectomy for myasthenia gravis is best offered to patients with seropositive acetylcholine receptor antibodies and who are seronegative for muscle-specific kinase protein. The robotic operation technique is indicated in all patients with myasthenia gravis in association with a resectable thymoma, typically Masaoka-Koga stages I and II.

Whether there is a general perturbation of B and plasma cell subsets in myasthenia gravis (MG) has not been investigated so far. Here we performed a detailed flow cytometric analysis of blood and if available thymic tissue in order to detect MG-specific and therapy-induced changes. We observed significant differences in the distribution of B cell subsets in MG patients, yet these were mainly attributable to medical treatment. Furthermore MG is associated with significantly increased frequencies of plasma cells that were especially activated in purely ocular disease manifestation. In contrast to thymoma, B cell subset distribution in hyperplastic thymus could be distinguished from peripheral blood, however both tissues were not significantly enriched with plasma cells. Thus B cell differentiation in general is not defective in MG, but modified by therapy and enhanced frequencies of plasma cells can be detected in MG patients.

New techniques using vascular clips or ultrasonically activated shears have been suggested to shorten operation time without compromising safety. The objective of the CLIVIT Trial was to compare ligatures with vascular clips for hemostasis in elective benign thyroid surgery. This multicenter, randomized, controlled, parallel group superiority trial was conducted in 13 German surgical centers. Patients scheduled for at least subtotal resection bilaterally were intraoperatively randomized. The primary endpoint was resection time. Secondary endpoints were the amount of postoperative bleeding, reoperation due to bleeding, wound infection, temporary (reversal within 12 months) and permanent (over 1 year) recurrent laryngeal nerve (RLN) paralysis, length of hospital stay, and safety. Registration: ISRCTN 96901396. Two hundred fifty patients were treated with ligatures and 241 with vascular clips. No differences in patients' baseline and surgical characteristics were observed. No difference was detected for mean resection time (clip 63.5 min ± 29.6, ligature 66.1 min ± 29.3, P = 0.258). Postoperative bleeding (mean 86 ml ± 93), reoperation due to bleeding (clips 4, ligature 2), wound infections (clips 4, ligature 4), postoperative hospital stay (mean 3.0 ± 1.9), and safety data also did not vary significantly. The rates of temporary and permanent RLN paralysis were 6.9 % (34/491) and 2.9 % (14/491), respectively. Not using a surgical drain (123 patients) was not associated with a higher rate of complications. Vascular clips did not reduce the resection time. However, a 2.9 % rate of permanent RLN paralysis is of concern. Drains in elective surgery may be of no benefit.

ObjectiveRadical thymectomy has become more popular in the comprehensive treatment of myasthenia gravis. Minimally invasive techniques are increasingly used for thymectomy. The most recent development in robotic thoracoscopic surgery has been successfully applied for mediastinal pathologies. To establish robotic technique as a standard, the results of high-volume centers and comparison with traditional surgery are mandatory.MethodsIn a retrospective cohort study, the results of 79 thoracoscopic thymectomies (October 1994 to December 2002) were compared with the results of 74 robotic thoracoscopic thymectomies (January 2003 to August 2006). Data from both series were collected prospectively. In both groups, all patients had myasthenia gravis. Both cohorts were compared with respect to severity of disease, gender, age, histology, and postoperative morbidity. All patients were analyzed for quantification of improvement of disease according to the Myasthenia Gravis Foundation of America.ResultsThere were no differences in age distribution and severity of myasthenia gravis. The dominant histologic finding was follicular hyperplasia of the thymus in both groups with a significantly higher percentage in the thoracoscopic thymectomy series (68% vs 45%, P

Complete thymectomy (Thx) is a crucial part of treatment for myasthenia gravis (MG) and thymoma. The discussion about the necessity of radical, complete Thx and reduced invasiveness has led to no less than 14 different surgical approaches for Thx. The latest development is robotic-assisted surgery. Though its impact on minimally invasive surgery is not yet clear, it seems to be most promising for surgery in remote, narrow anatomical regions like the mediastinum. One hundred six consecutive robotic-assisted thymectomies (rThx) with the da Vinci robotic surgical system were performed between January 2003 and April 2007 in a prospective single-center study. Postoperative morbidity was recorded according to the Myasthenia Gravis Foundation of America (MGFA) classification. With zero mortality, the overall postoperative morbidity rate was 2%. The cumulative complete stable remission rate of MG was > 40% for all patients, and there was no statistical difference as compared to non-thymomatous MG patients. The cumulative rate of minimal manifestations (MM0-MM3) according to the MGFA classification showed a postoperative improvement in quality of life for most of the patients. The da Vinci robotic system allowed for technical refinements of the well-defined operation technique of thoracoscopic Thx (tThx). From the technical point of view, rThx has advantages for mediastinal dissection. rThx had a shorter learning curve. There might be better outcome results for rThx in MG patients, as compared with nonrobotic tThx. Therefore, rThx is a promising technique for minimally invasive Thx.

Parathyroid carcinoma is a rare disease leading to severe hypercalcemia due to hyperparathyroidism. Surgery is the primary treatment option. A more progressive form of the disease is characterized by parathyrotoxicosis, and subsequent hypercalcemia is the most common cause of death. We report a case presenting with severe hypercalcemia due to parathyrotoxicosis from parathyroid carcinoma treated for the first time using the monoclonal antibody denosumab as a rescue therapy and present long-term follow-up data. The 71-year-old patient presented with severe hypercalcemia due to metastatic parathyroid carcinoma. Despite undergoing treatment with bisphosphonates, cinacalcet hydrochloride, and forced diuresis, the patient`s condition deteriorated rapidly due to resistant hypercalcemia. Surgery performed because of spinal metastasis and forced diuresis lowered calcium levels, albeit they remained in the hypercalcemic range and significantly increased when forced diuresis was stopped. Considering a palliative situation to overcome hypercalcemia, we decided to administer denosumab, a monoclonal antibody that binds to the receptor activator of nuclear factor-kappa B ligand. After a single subcutaneous administration of 60 mg denosumab, calcium levels normalized within one day. Subsequent denosumab injections led to permanent control of serum calcium for more than 2 years despite rising parathyroid hormone levels and repeated surgeries. Together with recent cases in the literature supporting our observation, we believe that denosumab is relevant for future trials and represents an effective tool to control hypercalcemia in patients with advanced stages of parathyroid cancer. Learning points Severe hypercalcemia is the most common cause of death in patients with parathyroid carcinoma. The monoclonal antibody denosumab rapidly lowered severely elevated serum calcium levels due to parathyrotoxicosis. Denosumab was effective in the long-term treatment of hypercalcemia despite progression of parathyroid carcinoma.

To retrospectively determine if the use of butyl scopolamine or glucagon in the supine patient improves colonic distention and reduces the number of collapsed intestinal segments at computed tomographic (CT) colonography.This study had institutional review board approval; subject informed consent was not required. CT colonography was performed without the administration of an intravenous spasmolytic in 80 asymptomatic subjects (group 1; 45 women, 35 men; age range, 48-77 years; mean, 61.9 years). These subjects were matched with two groups of 80 subjects who were similar in age but were premedicated with glucagon (group 2; 41 women, 39 men; age range, 43-76 years; mean, 63.1 years) or butyl scopolamine (group 3; 43 women, 37 men; age range, 34-77 years; mean, 63.4 years). All 240 subjects were examined in the supine position with multisection CT and a section thickness of 1 mm after intravenous contrast agent administration and rectal carbon dioxide insufflation. The colon was divided into seven segments, and the colon length, total volume, radial distensibility, and number of non-distended segments were calculated for each subject and compared among the three groups. Statistical analysis was performed with analysis of variance and chi2 testing.Mean bowel length was not significantly different among the groups. Mean colon volumes and radial distensibilities, respectively, were 1.84 L and 3.69 cm in group 1, 2.14 L and 3.98 cm in group 2, and 2.35 L and 4.23 cm in group 3; differences in colon volume and radial distensibility were significant only between group 1 and group 3 (P.001). At CT colonography, 29 segments in 20 group 1 subjects were collapsed, 23 segments in 12 group 2 subjects were collapsed, and 11 segments in six group 3 subjects were collapsed (P = .016).Premedication with butyl scopolamine or, less effectively, glucagon improves colonic distention in the supine subject.

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 lungex vivoco-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) inhibitsStreptococcus pneumoniae-induced interleukin (IL)-1β release. The lack of IL-1β 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 theS. pneumoniae-induced IL-1β–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-1β 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.

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Thymectomy is relatively indicated and most frequently performed in patients with the autoimmune disease myasthenia gravis. In particular, the indication for thymectomy, as well as the long-term improvement of myasthenia gravis, may depend on patient-derived factors such as gender, age, the severity of myasthenia, the duration of symptoms, the interval between diagnosis and thymectomy, the presence/absence of a thymoma, the serologic investigation (anti–acetylcholine receptor [anti-AChR], anti–muscle-specific kinase [anti-MuSK], or no antibodies), the amount of medication and necessity of immunosuppression, and other comorbidities. There is an absolute indication for thymectomy in patients with thymoma, an epithelium-derived tumor of the anterior mediastinum that may or may not be accompanied by myasthenia gravis. Other rare indications are ectopic mediastinal intrathymic parathyroid glands and different forms of multiple endocrine neoplasia with anticipated thymic carcinoma.

Tumor-like lesions of the mediastinum consisting exclusively of mature pancreatic tissue are rare. Most authors regard these lesions as developmental abnormalities. We report the case of a 17-year-old male who presented with progressive dyspnea due to a large mediastinal tumor with accompanying pericardial effusion. Percutaneous core needle biopsies showed differentiated pancreatic tissue with chronic inflammation and cystic transformation. On this basis, heterotopic pancreatic tissue of the mediastinum, a lesion occasionally reported in the literature, was suspected and the lesion was excised. The histopathological workup of the surgically excised lesion, in the first place, supported the primary diagnosis. However, after extensive sampling of the lesion, the diagnosis had to be changed to mature teratoma with subtotal unidirectional pancreatic differentiation. We hypothesize that at least some of those cases reported in the literature as "heterotopic pancreatic tissue of the mediastinum" may be in fact unidirectionally differentiated teratomas and should therefore be regarded and treated as true neoplasms rather than developmental abnormalities.

Thymectomy is a widely accepted treatment for most cases of myasthenia gravis and essential for the treatment of thymoma. The development of a minimally invasive procedure for thymectomy resulted in a variety of approaches for surgery on the thymic gland. The use of thoracoscopy-based techniques has continued to increase, including the latest advance in this field, robotic thymectomy.We review the rapid development and actual use of this approach by examining published reports, worldwide registries, and personal communications and by analyzing our database, which is the largest single-center experience and contains 317 thymectomies until 12/2012. The technical modifications of robotic thymectomy are also described.Since 2001, approximately 3,500 robotic thymectomies have been registered worldwide. Meanwhile, the results of approximately 500 thymectomy cases have been published. Robotic thymectomy is performed most frequently through a standardized unilateral three-trocar approach. All reports describe promising and satisfactory results for myasthenia gravis. For early-stage thymoma, robotic thymectomy is a technically sound and safe procedure with a very low complication rate and short hospital stay. Oncological outcome without recurrences is promising, but a longer follow-up is needed.The unilateral robotic technique can be considered an adequate approach for thymectomy, even with demanding anatomical configurations. Robotic thymectomy has spread worldwide over the last decade because of the promising results in myasthenia gravis and thymoma patients.

A novel influenza A virus (IAV) of the H7N9 subtype has been isolated from severely diseased patients with pneumonia and acute respiratory distress syndrome and, apparently, from healthy poultry in March 2013 in Eastern China. We evaluated replication, tropism, and cytokine induction of the A/Anhui/1/2013 (H7N9) virus isolated from a fatal human infection and two low-pathogenic avian H7 subtype viruses in a human lung organ culture system mimicking infection of the lower respiratory tract. The A(H7N9) patient isolate replicated similarly well as a seasonal IAV in explanted human lung tissue, whereas avian H7 subtype viruses propagated poorly. Interestingly, the avian H7 strains provoked a strong antiviral type I interferon (IFN-I) response, whereas the A(H7N9) virus induced only low IFN levels. Nevertheless, all viruses analyzed were detected predominantly in type II pneumocytes, indicating that the A(H7N9) virus does not differ in its cellular tropism from other avian or human influenza viruses. Tissue culture-based studies suggested that the low induction of the IFN-β promoter correlated with an efficient suppression by the viral NS1 protein. These findings demonstrate that the zoonotic A(H7N9) virus is unusually well adapted to efficient propagation in human alveolar tissue, which most likely contributes to the severity of lower respiratory tract disease seen in many patients., IMPORTANCE Humans are usually not infected by avian influenza A viruses (IAV), but this large group of viruses contributes to the emergence of human pandemic strains. Transmission of virulent avian IAV to humans is therefore an alarming event that requires assessment of the biology as well as pathogenic and pandemic potentials of the viruses in clinically relevant models. Here, we demonstrate that an early virus isolate from the recent A(H7N9) outbreak in Eastern China replicated as efficiently as human-adapted IAV in explanted human lung tissue, whereas avian H7 subtype viruses were unable to propagate. Robust replication of the H7N9 strain correlated with a low induction of antiviral beta interferon (IFN-β), and cell-based studies indicated that this is due to efficient suppression of the IFN response by the viral NS1 protein. Thus, explanted human lung tissue appears to be a useful experimental model to explore the determinants facilitating cross-species transmission of the H7N9 virus to humans.

Background. Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence because the primary target cells of other influenza viruses have not been systematically studied. Methods. We provide the first comparison of the replication, tropism, and cytokine induction of human, highly pathogenic avian influenza A virus subtype H5N1 and other animal influenza A viruses in primary human lung organ cultures. Results. Subytpe H5N1 and human-adapted subtype H1N1 and H3N2 viruses replicated efficiently in the lung tissue, whereas classic swine and low-pathogenicity avian viruses propagated only poorly. Nevertheless, all viruses examined were detected almost exclusively in type II pneumocytes, with a minor involvement of alveolar macrophages. Infection with avian viruses that have a low and high pathogenicity provoked a pronounced induction of cytokines and chemokines, while human and pandemic H1N1-2009 viruses triggered only weak responses. Conclusions. These findings show that differences in the pathogenic potential of influenza A viruses in the human lung cannot be attributed to a distinct cellular tropism. Rather, high or low viral pathogenicity is associated with a strain-specific capacity to productively replicate in type II pneumocytes and to cope with the induced cytokine response.