[ERAS Implementation in Thoracic Surgery]. / ERAS-Implementierung in der Thoraxchirurgie.

This manuscript provides an overview of the principles and requirements for implementing the ERAS program in thoracic surgery.The ERAS program optimises perioperative management of elective lung resection procedures and is based on the ERAS Guidelines for Thoracic Surgery of the ERAS Society. The clinical measures are described as in the current literature, with a focus on postoperative outcome. There are currently 45 enhanced recovery items covering four perioperative phases: from the prehospital admission phase (patient education, screening and treatment of potential risk factors such as anaemia, malnutrition, cessation of nicotine or alcohol abuse, prehabilitation, carbohydrate loading) to the immediate preoperative phase (shortened fasting period, non-sedating premedication, prophylaxis of PONV and thromboembolic complications), the intraoperative measures (antibiotic prophylaxis, standardised anaesthesia, normothermia, targeted fluid therapy, minimally invasive surgery, avoidance of catheters and probes) through to the postoperative measures (early mobilisation, early nutrition, removal of a urinary catheter, hyperglycaemia control). Most of these measures are based on scientific studies, with a high level of evidence and aim to reduce general postoperative complications.The ERAS program is an optimised perioperative treatment approach aiming to improve the postoperative recovery in patients after elective lung resection by reducing the overall complication rates and overall morbidity.

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Development and systematic evaluation of decellularization protocols in different application models for diaphragmatic tissue engineering.

BACKGROUND: Tissue engineered bioscaffolds based on decellularized composites have gained increasing interest for treatment of various diaphragmatic impairments, including muscular atrophies and diaphragmatic hernias. Detergent-enzymatic treatment (DET) constitutes a standard strategy for diaphragmatic decellularization. However, there is scarce data on comparing DET protocols with different substances in distinct application models in their ability to maximize cellular removal while minimizing extracellular matrix (ECM) damage. METHODS: We decellularized diaphragms of male Sprague Dawley rats with 1 % or 0.1 % sodium dodecyl sulfate (SDS) and 4 % sodium deoxycholate (SDC) by orbital shaking (OS) or retrograde perfusion (RP) through the vena cava. We evaluated decellularized diaphragmatic samples by (1) quantitative analysis including DNA quantification and biomechanical testing, (2) qualitative and semiquantitative analysis by proteomics, as well as (3) qualitative assessment with macroscopic and microscopic evaluation by histological staining, immunohistochemistry and scanning electron microscopy. RESULTS: All protocols produced decellularized matrices with micro- and ultramorphologically intact architecture and adequate biomechanical performance with gradual differences. The proteomic profile of decellularized matrices contained a broad range of primal core and ECM-associated proteins similar to native muscle. While no outstanding preference for one singular protocol was determinable, SDS-treated samples showed slightly beneficial properties in comparison to SDC-processed counterparts. Both application modalities proved suitable for DET. CONCLUSION: DET with SDS or SDC via orbital shaking or retrograde perfusion constitute suitable methods to produce adequately decellularized matrices with characteristically preserved proteomic composition. Exposing compositional and functional specifics of variously treated grafts may enable establishing an ideal processing strategy to sustain valuable tissue characteristics and optimize consecutive recellularization. This aims to design an optimal bioscaffold for future transplantation in quantitative and qualitative diaphragmatic defects.

A machine learning tool to improve prediction of mediastinal lymph node metastases in non-small cell lung cancer using routinely obtainable [18F]FDG-PET/CT parameters.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), accuracy of [18F]FDG-PET/CT for pretherapeutic lymph node (LN) staging is limited by false positive findings. Our aim was to evaluate machine learning with routinely obtainable variables to improve accuracy over standard visual image assessment. METHODS: Monocentric retrospective analysis of pretherapeutic [18F]FDG-PET/CT in 491 consecutive patients with NSCLC using an analog PET/CT scanner (training + test cohort, n = 385) or digital scanner (validation, n = 106). Forty clinical variables, tumor characteristics, and image variables (e.g., primary tumor and LN SUVmax and size) were collected. Different combinations of machine learning methods for feature selection and classification of N0/1 vs. N2/3 disease were compared. Ten-fold nested cross-validation was used to derive the mean area under the ROC curve of the ten test folds ("test AUC") and AUC in the validation cohort. Reference standard was the final N stage from interdisciplinary consensus (histological results for N2/3 LNs in 96%). RESULTS: N2/3 disease was present in 190 patients (39%; training + test, 37%; validation, 46%; p = 0.09). A gradient boosting classifier (GBM) with 10 features was selected as the final model based on test AUC of 0.91 (95% confidence interval, 0.87-0.94). Validation AUC was 0.94 (0.89-0.98). At a target sensitivity of approx. 90%, test/validation accuracy of the GBM was 0.78/0.87. This was significantly higher than the accuracy based on "mediastinal LN uptake > mediastinum" (0.7/0.75; each p < 0.05) or combined PET/CT criteria (PET positive and/or LN short axis diameter > 10 mm; 0.68/0.75; each p < 0.001). Harmonization of PET images between the two scanners affected SUVmax and visual assessment of the LNs but did not diminish the AUC of the GBM. CONCLUSIONS: A machine learning model based on routinely available variables from [18F]FDG-PET/CT improved accuracy in mediastinal LN staging compared to established visual assessment criteria. A web application implementing this model was made available.

[Robot-assisted Mediastinal Surgery]. / Roboter-assistierte Mediastinalchirurgie.

Because of the many important anatomical structures located closely together at very small distances, mediastinal surgery has been traditionally demanding and challenging within thoracic surgery. With their great variability, mediastinal masses in the anterior, middle or posterior mediastinal compartment result in surgical indications with different principle focuses. The technical opportunities of robotic assistance can thereby most effectively support the requirement of precision for all oncological aspects. Anterior mediastinal operations are most often performed, thymectomy being the most common operation. The radicality of thymectomy is of special importance. The worldwide tremendous development of robot-assisted mediastinal surgery confirms its initial and continuous role as a pacemaker for minimally invasive thoracic surgery.

Reducing Immunosuppression in Patients with De Novo Lung Carcinoma after Liver Transplantation Could Significantly Prolong Survival.

(1) Background: Liver transplantation (LT) is an established treatment for selected patients with end-stage liver disease resulting in a subsequent need for long-term immunosuppressive therapy. With cumulative exposure to immunosuppression (IS), the risk for the development of de novo lung carcinoma increases. Due to limited therapy options and prognosis after diagnosis of lung cancer, the question of the mode and extent of IS in this particular situation is raised. (2) Methods: All patients diagnosed with de novo lung cancer in the follow-up after LT were identified from the institution's register of liver allograft recipients (Charité-Universitätsmedizin Berlin, Germany) transplanted between 1988 and 2021. Survival analysis was performed based on the IS therapy following diagnosis of lung cancer and the oncological treatment approach. (3) Results: Among 3207 adult LTs performed in 2644 patients at our institution, 62 patients (2.3%) developed de novo lung carcinoma following LT. Lung cancer was diagnosed at a median interval of 9.7 years after LT (range 0.7-27.0 years). Median survival after diagnosis of lung carcinoma was 13.2 months (range 0-196 months). Surgical approach with curative intent significantly prolonged survival rates compared to palliative treatment (median 67.4 months vs. 6.4 months). Reduction of IS facilitated a significant improvement in survival (median 38.6 months vs. 6.7 months). In six patients (9.7%) complete IS weaning was achieved with unimpaired liver allograft function. (4) Conclusion: Reduction of IS therapy after the diagnosis of de novo lung cancer in LT patients is associated with prolonged survival. The risk of acute rejection does not appear to be increased with restrictive IS management. Therefore, strict reduction of IS should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.

The single-cell transcriptional landscape of lung carcinoid tumors.

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown. To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFß and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data. Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the noninflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.

[Mediastinal Tumors]. / Mediastinale Tumore.

If mediastinal tumours cause symptoms these are related to their anatomical localization or a paraneoplastic syndrome. The differential diagnosis is based on the clinical situation with finding the lesion, and, furthermore, taking into account the age and sex of the patient, and the mediastinal compartment where the lesion is located. Cross-sectional radiographic diagnostic is essential for defining the therapeutic strategy. The anterior mediastinum is dominated by thymic tumours, mediastinal lymphomas, germ cell tumours and ectopic mediastinal poiters. The middle mediastinal compartment is the most frequent place of mediastinal cystic tumours, whereas the posterior mediastinum is the domain of neurogenic tumours. For selected cases a tissue biopsy is required. Surgery is the mainstay for most mediastinal tumours. Median sternotomy is the most frequent conventional surgical technique while minimally invasive surgery with thoracoscopic and above all robot assisted operation techniques are increasingly frequent. Combined chemotherapy and modern radiotherapy are essential components of the comprehensive treatment for mediastinal tumours.

[Current State of ERAS Implementation in Thoracic Surgery in Germany]. / Aktuelle ERAS-Implementierung in der Thoraxchirurgie an deutschen Kliniken.

BACKGROUND, OBJECTIVES: In recent years, ERAS treatment pathways have found their way into many surgical fields, as they reduce complications and accelerate postoperative recovery. For thoracic surgery, the first ERAS guidelines were published by the ERAS Society and the European Society of Thoracic Surgeons (ESTS) in 2019. We have now evaluated how ERAS-items are implemented in clinical practice by using an online survey. MATERIAL AND METHODS: An online survey was conducted from 12/5/2021 until 1/6/2021. The survey consisted of 22 questions focusing on the key elements of an ERAS program according to the published ERAS guidelines. Results were summarised, descriptively analysed and put into context with the current literature. RESULTS: Of 155 thoracic surgeons, 32 responded to the survey. In 28.1% (n = 9) of the hospitals, an ERAS core unit was established, and a database to record the ERAS items existed in 15.6% (n = 5). Only 3.1% (n = 1) kept an ERAS-diary preoperatively. A so-called Carboloading was conducted at 15.6% (n = 5) of surgeons. Standard PONV prophylaxis was administered to 59.4% (n = 19) of the patients. In most cases (84.4%, n = 29), a single drain was inserted into the pleural cavity during anatomic resections. In 3% (n = 1) of the centres two drains, in 12.5% (n = 4) no drainage was placed. The most commonly applied initial suction was -10 cmH2O (75%, n = 24). Suction ≤ 2 cmH2O was used by only two of those interviewed. Drainage removal took place in 50% (n = 16) of cases between the 1st or 2nd POD, in 34.4% of cases (n = 11) between the 3rd and 4th POD and in 9.4% (n = 3) the drain remained longer than the 4th POD. The first postoperative mobilisation took place in 71.9% (n = 23) of the centres on the day of the operation. CONCLUSIONS: The implementation of ERAS guidelines varies in Germany between centres. Certain perioperative processes are covered sufficiently, but the implementation of key features of ERAS is yet to be fully established in clinical practice. The first steps in this direction have already been taken and lay the foundation for cooperation across centres.

Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma.

Recent developments in immuno-oncology demonstrate that not only cancer cells, but also the tumor microenvironment can guide precision medicine. A comprehensive and in-depth characterization of the tumor microenvironment is challenging since its cell populations are diverse and can be important even if scarce. To identify clinically relevant microenvironmental and cancer features, we applied single-cell RNA sequencing to ten human lung adenocarcinomas and ten normal control tissues. Our analyses revealed heterogeneous carcinoma cell transcriptomes reflecting histological grade and oncogenic pathway activities, and two distinct microenvironmental patterns. The immune-activated CP²E microenvironment was composed of cancer-associated myofibroblasts, proinflammatory monocyte-derived macrophages, plasmacytoid dendritic cells and exhausted CD8+ T cells, and was prognostically unfavorable. In contrast, the inert N³MC microenvironment was characterized by normal-like myofibroblasts, non-inflammatory monocyte-derived macrophages, NK cells, myeloid dendritic cells and conventional T cells, and was associated with a favorable prognosis. Microenvironmental marker genes and signatures identified in single-cell profiles had progonostic value in bulk tumor profiles. In summary, single-cell RNA profiling of lung adenocarcinoma provides additional prognostic information based on the microenvironment, and may help to predict therapy response and to reveal possible target cell populations for future therapeutic approaches.

FDG-PET/CT for pretherapeutic lymph node staging in non-small cell lung cancer: A tailored approach to the ESTS/ESMO guideline workflow.

OBJECTIVES: In patients with NSCLC, current ESTS and ESMO guidelines recommend invasive lymph node (LN) staging with EBUS-TBNA even if FDG-PET/CT is negative for mediastinal LNs if at least one of three risk factors is present (cN1, non-peripheral primary or primary >3 cm). Modified workflows to avoid unnecessary invasive procedures were evaluated. MATERIALS AND METHODS: Monocentric retrospective analysis of pretherapeutic FDG-PET/CT in 247 patients with NSCLC (62 % male; age, 68 [43-88] years) using an analog or digital PET/CT scanner. PET windowing was standardized. LNs were positive if 'LN uptake > mediastinal blood pool' or short axis >10 mm. Surgery or EBUS-TBNA served as reference for diagnostic accuracy per LN station. In all patients with negative mediastinal LNs by PET/CT, LN histology from surgery was available. RESULTS: Among 700 L N stations analyzed, 180 were malignant. Sensitivity and specificity of PET/CT per LN station were 93 % and 71 %. Following current guidelines, 76 patients with mediastinal negative PET/CT required confirmatory invasive staging. Only 5/76 patients had unexpected pN2 (all had adenocarcinoma). In a modified approach, confirmatory invasive staging was confined to patients with mediastinal negative PET/CT who showed all three risk factors. Using this modification, EBUS-TBNA could have been omitted in 62 (82 %) of the 76 patients who required EBUS-TBNA based on current recommendation. Among these 62 patients, only one patient had unsuspected pN2 (single-level) while the remaining 61 of 62 omitted EBUS-TBNA were deemed unnecessary because mediastinal LNs were confirmed to be negative. No multi-level pN2 would have been missed. CONCLUSION: In the current analysis, 82 % of EBUS-TBNA procedures in patients with mediastinal negative PET/CT could have been omitted by modifying the current guideline workflow as proposed (i.e., restricting EBUS-TBNA in patients with cN0/1 to those with all three risk factors). This was consistent with different PET/CT scanners. Prospective confirmation is required.

[COVID-19 Pandemic in Germany: The Current Situation in Thoracic Surgery]. / COVID-19-Pandemie in Deutschland: Die aktuelle Lage in der Thoraxchirurgie.

BACKGROUND: The new COVID-19 pandemic has an impact on routine thoracic surgery. Various concepts and recommendations are being pursued to protect patients and hospital staff. However, the implementation of these recommendations may depend on the existing infrastructure, local conditions and in-house procedural instructions. MATERIAL AND METHOD: Between 11th May and 26th May 2020, an anonymous online survey on the topic of COVID-19 was conducted among thoracic surgeons in Germany. The survey consisted of 16 questions on the local COVID-19 case numbers, protective measures, procedural instructions and treatment concepts. The results were summarised, descriptively analysed and discussed. RESULTS: The response rate of 42.6% (n = 66), included replies from 23 (34.8%) specialised hospitals, 18 (27.3%) maximum care hospitals and 14 (21.2%) university clinics. COVID-19-positive patients were treated in 65 (99%) clinics and 37.9% of the clinics also performed surgery on COVID-19-positive patients. Nasopharyngeal swabs were the main instrument for COVID-19 patient testing (in 95.4% of the clinics). Test results influenced decisions on treatment in 71.2% of the clinics. In 59.1% of clinics, safety equipment was supplemented with FFP2 masks and eye protection during thoracic surgeries due to the COVID-19 pandemic. DISCUSSION: Almost all thoracic surgeons reported that they had treated patients with COVID-19 and half of them also had performed surgery on COVID-19-positive patients. The applied procedural instructions as well as the effects of COVID-19 on treatment decisions and patient-doctor contact differed between the reporting clinics.

Validation of Independent Prognostic Value of Asphericity of 18F-Fluorodeoxyglucose Uptake in Non-Small-Cell Lung Cancer Patients Undergoing Treatment With Curative Intent.

BACKGROUND: In patients with non-small-cell lung cancer (NSCLC), asphericity (ASP) of the primary tumor's metabolic tumor volume (MTV) has shown prognostic significance. This study aimed at validation in an independent and sufficiently large cohort. PATIENTS AND METHODS: A retrospective study was performed of 311 NSCLC patients undergoing 18F-fluorodeoxyglucose positron emission tomography / computed tomography (18F-FDG PET/CT) before curatively intended treatment (always including surgery). A total of 140 patients had International Union Against Cancer (UICC) stage I disease, 78 had stage II disease, and 93 had stage III disease (adenocarcinoma, n = 153; squamous-cell carcinoma, n = 141). Primary tumor MTV was delineated with semiautomated background-adapted threshold relative to the standardized maximum uptake value (SUVmax). Cox regression (progression-free survival [PFS] and overall survival [OS]) analysis for positron emission tomography (MTV, ASP, SUVmax) as well as for clinical (T/N descriptor, UICC stages), histologic, and treatment variables (Rx/1 vs. R0 resection, chemotherapy/radiotherapy yes/no) were performed. RESULTS: Events (progression and relapse) occurred in 167 of 311 patients; 137 died (median survivor follow-up, 37 months). In multivariable Cox regression for OS, ASP > 33.3% (hazard ratio, 1.58 [1.04-2.39]), male sex (1.84), age (1.04 per year), Eastern Cooperative Oncology Group performance status ≥ 2 versus 0/1 (2.68), stage II versus I (1.96), and Rx/1 versus R0 resection (2.1) were significant. Among separate UICC stages, ASP only predicted OS in stage II (optimal, > 19.5%; median OS, 33 vs. 59 months). Regarding PFS, ASP > 21.2%, male sex, Eastern Cooperative Oncology Group performance status ≥ 2, stage II versus I disease, and Rx/1 resection were prognostic. ASP remained prognostic for stage II disease (optimal, > 19.5%; PFS, 12 vs. 47 months). Log-rank test for ASP was significant at any cutoff ≥ 18% (OS) or from 9% to 59% (PFS). CONCLUSION: ASP was validated as prognostic factor for PFS and OS in patients with NSCLC and curative treatment intent, especially stage II. High ASP in stage II could imply intensified treatment or intensified follow-up.

Next generation sequencing of lung adenocarcinoma subtypes with intestinal differentiation reveals distinct molecular signatures associated with histomorphology and therapeutic options.

OBJECTIVES: We aim to provide a better understanding of the molecular landscape of primary lung adenocarcinomas with intestinal differentiation. MATERIAL AND METHODS: Five invasive mucinous adenocarcinomas (IMA) and seven pulmonary enteric adenocarcinomas (PEAD) were included in this study. Furthermore, we analyzed six pulmonary colloid adenocarcinomas (CAD), including one primary tumor, one metastasis, and two sample pairs consisting of the primary colloid lung tumor and a matching metastasis and an acinar component, respectively. All samples were characterized using immunohistochemistry (TTF-1, CK7, CK20, CDX2, Ki-67, ALK and PD-L1) and a next generation sequencing panel covering 404 cancer-related genes (FoundationOne® gene panel). RESULTS AND CONCLUSION: While Ki-67 expression was comparably low in IMA (range: 8-15%) and in primary CAD (range: 5-8%), we observed considerably higher proliferation rates in the non-colloid tumor compartment (16%) and metastases (72%) from CAD, as well as in the PEAD-group (36-71%). The overall tumor mutational burden was lowest in IMA (2.5 mutations per megabase), intermediate in CAD (5.8 mutations per megabase) and highest in PEAD (16.8 mutations per megabase). KRAS mutations were frequent in all three tumor subtypes, but TP53 mutations were mostly limited to PEAD. While chromosomal alterations were rare in IMA, we discovered MYC amplifications in three of four CAD. Comparing primary and metastatic CAD, we observed the acquisition of multiple mutations and chromosomal alterations. PEAD had a variety of chromosomal alterations, including two cases with RICTOR amplification. PD-L1 expression (20%, 50% and 80% of tumor cells) was limited to three PEAD samples, only. In conclusion, we provide a detailed insight into the molecular alterations across and within the different subtypes of pulmonary adenocarcinomas with intestinal differentiation. From a clinical perspective, we provide data on potential treatment strategies for patients with PEAD, including immunotherapy.

EWSR1 translocation in primary hyalinising clear cell carcinoma of the thymus.

AIMS: In thymic carcinomas, focal clear cell change is a frequent finding. In addition to a prominent, diffuse clear cell morphology, some of these carcinomas show an exuberant hyalinised extracellular matrix, and therefore probably represent a separate entity. However, a characteristic genomic alteration remains elusive. We hypothesised that, analogous to hyalinising clear cell carcinomas of the salivary gland, hyalinising clear cell carcinomas of the thymus might also harbour EWSR1 translocations. METHODS AND RESULTS: We identified nine archived cases of thymic carcinoma with focal clear cell features and two cases that showed remarkable hyalinised stroma and prominent, diffuse clear cell morphology. These two cases expressed p40 and were negative for Pax8, CD5, and CD117. Programmed death-ligand 1 was highly positive in one case (70%), and negative in the other one. EWSR1 translocation was identified in both cases of hyalinising clear cell carcinoma, and was absent in all nine carcinomas that showed clear cell features without substantial hyalinisation. In one of the EWSR1-translocated cases, a fusion between exon 13 and exon 6 of EWSR1 and ATF1, respectively was identified by next-generation sequencing. CONCLUSIONS: These findings suggest that the EWSR1 translocation and possibly the EWSR1-ATF1 fusion might be unifying genomic alterations for thymic clear cell carcinomas with prominent hyalinised stroma, for which we propose the term 'hyalinising clear cell carcinoma of the thymus'. Because the immunophenotype is unspecific, testing for the EWSR1 translocation might be helpful in discriminating this entity from other thymic neoplasms or metastases, in particular those with clear cell change.

Altered naive CD4+ T cell homeostasis in myasthenia gravis and thymoma patients.

In Myasthenia Gravis (MG) thymic pathologies are often present and thymectomy is used as treatment. By flow cytometry we elucidated alterations of naïve CD4+ T cell homeostasis in MG patients and patients with thymoma. MG patients showed increased absolute numbers of CD31- centralnaïve 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.

Local ablative treatment for synchronous single organ oligometastatic lung cancer-A propensity score analysis of 180 patients.

INTRODUCTION: Local ablative treatment (LAT) improves outcome in lung cancer with oligometastatic disease (OMD) and potentially leads to long term survival. The aim of this retrospective study was to evaluate and quantify the additional benefit of LAT in synchronous OMD and to further identify prognostic factors for survival. PATIENTS AND METHODS: A propensity score-matched pairs analysis was performed on a set of patient and disease variables in 180 patients, treated for synchronous single organ OMD including non small-cell and neuroendocrine lung cancer with ≤4 metastases between 2000 and 2016 in 3 lung cancer centers in Berlin, Germany. Patients either received LAT for all sites of disease (intervention group) by means of surgery or stereotactic radiotherapy, or standard chemotherapy, if necessary combined with a local treatment with palliative intent (control group). RESULTS: Median follow-up time was 32.2 and 18.8 months for the intervention and control group, respectively. Substantial benefits in median progression-free survival (PFS, 25.1 vs. 8.2 months; HR, 0.30; 95% CI, 0.21-0.43; p < 0.001) and overall survival (OS, 60.4 vs. 22.5 months; HR, 0.42; 95% CI, 0.28-0.62; p < 0.001) were associated with LAT. Histology of adenocarcinoma and T1a primaries also predicted a favorable prognosis concerning PFS and OS. More favorable nodal stage (N0-2 vs. 3) and solitary metastases were associated with an extended PFS, whereas initial ECOG-PS (0-1 vs. 2) predicted OS. CONCLUSIONS: LAT was the strongest predictor for PFS and OS in OMD with ≤4 metastases. Survival in the control group identifies OMD as a subset of lung cancer with a generally more favorable prognosis.

CD4+ FoxP3+ T regulatory cell subsets in myasthenia gravis patients.

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.