The bioelectric mechanisms of local calcium dynamics in cancer cell proliferation: an extension of the A549 in silico cell model.

Introduction: Advances in molecular targeting of ion channels may open up new avenues for therapeutic approaches in cancer based on the cells' bioelectric properties. In addition to in-vitro or in-vivo models, in silico models can provide deeper insight into the complex role of electrophysiology in cancer and reveal the impact of altered ion channel expression and the membrane potential on malignant processes. The A549 in silico model is the first computational cancer whole-cell ion current model that simulates the bioelectric mechanisms of the human non-small cell lung cancer cell line A549 during the different phases of the cell cycle. This work extends the existing model with a detailed mathematical description of the store-operated Ca2+ entry (SOCE) and the complex local intracellular calcium dynamics, which significantly affect the entire electrophysiological properties of the cell and regulate cell cycle progression. Methods: The initial model was extended by a multicompartmental approach, addressing the heterogenous calcium profile and dynamics in the ER-PM junction provoked by local calcium entry of store-operated calcium channels (SOCs) and uptake by SERCA pumps. Changes of cytosolic calcium levels due to diffusion from the ER-PM junction, release from the ER by RyR channels and IP3 receptors, as well as corresponding PM channels were simulated and the dynamics evaluated based on calcium imaging data. The model parameters were fitted to available data from two published experimental studies, showing the function of CRAC channels and indirectly of IP3R, RyR and PMCA via changes of the cytosolic calcium levels. Results: The proposed calcium description accurately reproduces the dynamics of calcium imaging data and simulates the SOCE mechanisms. In addition, simulations of the combined A549-SOCE model in distinct phases of the cell cycle demonstrate how Ca2+ - dynamics influence responding channels such as KCa, and consequently modulate the membrane potential accordingly. Discussion: Local calcium distribution and time evolution in microdomains of the cell significantly impact the overall electrophysiological properties and exert control over cell cycle progression. By providing a more profound description, the extended A549-SOCE model represents an important step on the route towards a valid model for oncological research and in silico supported development of novel therapeutic strategies.

Maternal COVID-19 causing intrauterine foetal demise with microthrombotic placental insufficiency: a case report.

BACKGROUND: Pregnant women have an increased risk of getting infected with SARS-CoV-2 and are more prone to severe illness. Data on foetal demise in affected pregnancies and its underlying aetiology is scarce and pathomechanisms remain largely unclear. CASE: Herein we present the case of a pregnant woman with COVID-19 and intrauterine foetal demise. She had no previous obstetric or gynaecological history, and presented with mild symptoms at 34 + 3 weeks and no signs of foetal distress. At 35 + 6 weeks intrauterine foetal death was diagnosed. In the placental histopathology evaluation, we found inter- and perivillous fibrin depositions including viral particles in areas of degraded placental anatomy without presence of viral entry receptors and SARS-CoV-2 infection of the placenta. CONCLUSION: This case demonstrates that maternal SARS-CoV-2 infection in the third trimester may lead to an unfavourable outcome for the foetus due to placental fibrin deposition in maternal COVID-19 disease possibly via a thrombogenic microenvironment, even when the foetus itself is not infected.

Lipid Nanoparticles as a Shuttle for Anti-Adipogenic miRNAs to Human Adipocytes.

Obesity and type 2 diabetes are major health burdens for which no effective therapy is available today. One treatment strategy could be to balance the metabolic functions of adipose tissue by regulating gene expressions using miRNAs. Here, we have loaded two anti-adipogenic miRNAs (miR26a and miR27a) into a pegylated lipid nanoparticle (PEG-LNP) formulation by a single-step microfluidic-assisted synthesis step. For the miRNA-loaded LNPs, the following system properties were determined: particle size, zeta potential, miRNA complexation efficiency, and cytotoxicity. We have used a human preadipocyte cell line to address the transfection efficiency and biological effects of the miRNA candidates at the gene and protein level. Our findings revealed that the upregulation of miR27a in preadipocytes inhibits adipogenesis by the downregulation of PPARγ and the reduction of lipid droplet formation. In contrast, miR26a transfection in adipocytes induced white adipocyte browning detected as the upregulation of uncoupling protein 1 (UCP1) as a marker of non-shivering thermogenesis. We conclude that the selective delivery of miRNAs by PEG-LNPs to adipocytes could offer new perspectives for the treatment of obesity and related metabolic diseases.

Improvement of Pain Symptoms in Musculoskeletal Diseases After Multimodal Spa Therapy in the Austrian Gastein Valley-A Study Based on Longitudinal Registry Data.

Objective: The study aim was to investigate the course of pain in rest and motion in seven different rheumatic diseases (RMD), prior and after multimodal spa therapy including low-dose radon treatment and at 3-, 6-; and 9-month follow up. Methods: Complete data from the radon indication registry including information on 561 subjects with RMD were analysed to explore the association of timepoint of measurement with pain in rest and motion. For this purpose, linear regression models adjusted for RMD-type, age, sex and body mass index (BMI) were applied. Results: The mean age of the sample was 55 years, the average body mass index was 26.8, and 275 subjects were women. Pain scores were significantly improved at all-time points compared to baseline. Pain courses were different for each RMD with the largest improvement seen in fibromyalgia. Conclusion: Timing spa facility visits according to RMD-specific pain courses may result in sustained pain reduction.

CD39 abrogates platelet-derived factors induced IL-1ß expression in the human placenta.

Tissue insults in response to inflammation, hypoxia and ischemia are accompanied by the release of ATP into the extracellular space. There, ATP modulates several pathological processes, including chemotaxis, inflammasome induction and platelet activation. ATP hydrolysis is significantly enhanced in human pregnancy, suggesting that increased conversion of extracellular ATP is an important anti-inflammatory process in preventing exaggerated inflammation, platelet activation and hemostasis in gestation. Extracellular ATP is converted into AMP, and subsequently into adenosine by the two major nucleotide-metabolizing enzymes CD39 and CD73. Here, we aimed to elucidate developmental changes of placental CD39 and CD73 over gestation, compared their expression in placental tissue from patients with preeclampsia and healthy controls, and analyzed their regulation in response to platelet-derived factors and different oxygen conditions in placental explants as well as the trophoblast cell line BeWo. Linear regression analysis showed a significant increase in placental CD39 expression, while at the same time CD73 levels declined at term of pregnancy. Neither maternal smoking during first trimester, fetal sex, maternal age, nor maternal BMI revealed any effects on placental CD39 and CD73 expression. Immunohistochemistry detected both, CD39 and CD73, predominantly in the syncytiotrophoblast layer. Placental CD39 and CD73 expression were significantly increased in pregnancies complicated with preeclampsia, when compared to controls. Cultivation of placental explants under different oxygen conditions had no effect on the ectonucleotidases, whereas presence of platelet releasate from pregnant women led to deregulated CD39 expression. Overexpression of recombinant human CD39 in BeWo cells decreased extracellular ATP levels after culture in presence of platelet-derived factors. Moreover, platelet-derived factors-induced upregulation of the pro-inflammatory cytokine, interleukin-1ß, was abolished by CD39 overexpression. Our study shows that placental CD39 is upregulated in preeclampsia, suggesting an increasing demand for extracellular ATP hydrolysis at the utero-placental interface. Increased placental CD39 in response to platelet-derived factors may lead to enhanced conversion of extracellular ATP levels, which in turn could represent an important anti-coagulant defense mechanism of the placenta.

A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer.

AIM: Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. METHODS: Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. RESULTS: We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. CONCLUSIONS: IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance.

Patient-Reported Quality of Care for Osteoarthritis in General Practice in South Tyrol, Italy: Protocol for Translation, Validation and Assessment of the OsteoArthritis Quality Indicator Questionnaire (OA-QI).

BACKGROUND: Evidence-based recommendations for the treatment of knee and hip osteoarthritis are similar internationally. Nevertheless, clinical practice varies across countries. Instruments for measuring quality have been developed to improve health care through targeted interventions. Studies on health service quality must consider the structural and cultural characteristics of countries, because each of their strengths and weaknesses differ. However, such instruments for health-related patient-reported outcomes for osteoarthritis have not yet been validated in German and Italian languages. OBJECTIVES: In order to be able to set targeted measures for the improvement of prevention and non-surgical treatment of osteoarthritis in South Tyrol, Italy, the quality of care must be recorded. Therefore, the aim of the project is to update, translate, and validate the OsteoArthritis Quality Indicator (OA-QI) questionnaire version 2, an established and validated questionnaire in Norwegian and English, for Germany and Italy. The second aim is to determine the quality of care for osteoarthritis of the hip and knee in a sample of patients who consult general practice in South Tyrol, and for comparison with patients who are admitted to rehabilitative spa-treatments for osteoarthritis in the state of Salzburg, Austria. DISCUSSION: The results of this study will enable the identification and closure of gaps in osteoarthritis care. Although it is expected that body weight and exercise will play special roles, other areas of nonsurgical care might also be involved.

Decreased phrenic nerve compound muscle action potential, inspiratory muscle strength, and exercise capacity after COVID-19.

Objectives: Respiratory muscle weakness with higher ventilatory demands were reported even in patients recovering from only mild COVID-19 symptoms. Aim of this study was to assess the function of phrenic nerve and inspiratory respiratory muscle as well as cardiopulmonary exercise capacity in patients with prolonged exertional dyspnea after COVID-19 infection. Methods: In this observational exploratory study, electrophysiological examination of the phrenic nerve, inspiratory muscle capacity as well as lung function test, 6-min walk distance (6MWD) and cardiopulmonary exercise test, have been performed in 22 patients post COVID-19 diagnosis (post-CoV). Results: Exercise capacity (peak workload, Wpeak % predicted and peak oxygen uptake, VO2peak % predicted) were significantly affected in the post-CoV patients (61.8 ± 23.3 Wpeak % and 70.9 ± 22.3 VO2peak %). Maximum inspiratory pressure (MIP) was reduced (60.1 ± 25.5 mbar). In 6 of the 22 patients the electrophysiological response of the phrenic nerve was pathologically decreased (reduced compound muscle action potential, CMAP), while nerve conduction velocity (NCV) was normal, which corresponds to reduced muscle fiber contraction capacity. Positive relationships were demonstrated between 6MWD and MIP (rs = 0.88) as well as quality of life questionnaire (CRQ) and MIP (rs = 0.71) only in patients with reduced CMAP. Discussion: Respiratory muscle weakness and exercise capacity is associated with reduced phrenic nerve CMAP without signs of neuropathy. This indicates that muscle fiber pathology of the diaphragm may be one pathophysiological factor for the prolonged respiratory symptoms after COVID-19 infections.

Sustained improvements in EQ-5D utility scores and self-rated health status in patients with ankylosing spondylitis after spa treatment including low-dose radon - an analysis of prospective radon indication registry data.

BACKGROUND: Patients with ankylosing spondylitis (AS) have significantly lower quality of life (QoL) than the general population. Holistic interventions addressing QoL comprise spa- or balneotherapy including radon. These interventions have shown to be beneficial in reducing pain and improving QoL in AS-patients. We explored the association of spa-therapy including low-dose radon with QoL in AS-patients over an extended time period. METHODS: Registry data collected for the "Radon indication registry" in the Austrian Gastein valley comprising data on QoL (EuroQol EQ-5D) directly before the treatment (baseline), directly(t1), 3 (t2); 6(t3) and 9(t4) months after the treatment, age, sex and body mass index (BMI) were analysed. Linear regression models explored the association of measurement time with 1) EQ-5D-5L utilities and 2) EuroQol visual analogue scale (VAS) score. Alterations of 0.05 (utilities) and 5.00 (VAS) were considered clinically relevant. RESULTS: Two-hundred-ninety-one AS-patients were included in the analyses. Forty-four percent (n = 128) were women, the mean age was 52 (SD 10) and the average BMI was 26 (SD 4). Utilities (t1: 0.09 [0.07;0.11]; t2: 0.08 [0.06; 0.10]; t3: 0.06 [0.05;0.09]; t4: 0.04 [0.02;0.06]) and VAS (t1: 11.68 [9.38; 13.97]; t2: 12.20 [9.78; 14.61]; t3: 9.70 [7.24; 12.17]; t4: 6.11 [3.57; 8.65]) were significantly higher at all timepoints compared to baseline. Improvements were clinically relevant at all timepoints in case of the VAS and until 6 months after treatment for the utilities. CONCLUSION: AS-patients who received spa therapy including radon show significantly and clinically relevant improvements in Qol until 6-9 months after treatment.

(Dis)similarities between the Decidual and Tumor Microenvironment.

Placenta-specific trophoblast and tumor cells exhibit many common characteristics. Trophoblast cells invade maternal tissues while being tolerated by the maternal immune system. Similarly, tumor cells can invade surrounding tissues and escape the immune system. Importantly, both trophoblast and tumor cells are supported by an abetting microenvironment, which influences invasion, angiogenesis, and immune tolerance/evasion, among others. However, in contrast to tumor cells, the metabolic, proliferative, migrative, and invasive states of trophoblast cells are under tight regulatory control. In this review, we provide an overview of similarities and dissimilarities in regulatory processes that drive trophoblast and tumor cell fate, particularly focusing on the role of the abetting microenvironments.

Training and Support for Hybrid Closed-Loop Therapy.

Hybrid closed-loop therapy is an emerging technology transforming the management of type 1 diabetes (T1D). Research studies demonstrate glycemic and quality of life benefits of hybrid closed-loop therapy for people with T1D. Translating these outcomes into standard clinical practice is critical for reimbursement and improving access to this technology.High-quality training is essential for achieving optimal outcomes with hybrid closed-loop therapy. Basic diabetes skills and tasks are as important, or even more important, with closed-loop therapy than with standard insulin therapy and need to be reiterated. Establishing expectations of hybrid closed-loop therapy clearly at the outset promotes long-term usage and optimal outcomes.We share key aspects of training and support for users of commercially available hybrid closed-loop systems and consider who may benefit from this technology.

Quantification of increased MUC5AC expression in airway mucus of smoker using an automated image-based approach.

Microscopic analysis of mucus quantity and composition is crucial in research and diagnostics on muco-obstructive diseases. Currently used image-based methods are unable to extract concrete numeric values of mucosal proteins, especially on the expression of the key mucosal proteins MUC5AC and MUC5B. Since their levels increase under pathologic conditions such as extensive exposure to cigarette smoke, it is imperative to quantify them to improve treatment strategies of pulmonary diseases. This study presents a simple, image-based, and high-processing computational method that allows determining the ratio of MUC5AC and MUC5B within the overall airway mucus while providing information on their spatial distribution. The presented pipeline was optimized for automated downstream analysis using a combination of bright field and immunofluorescence imaging suitable for tracheal and bronchial tissue samples, and air-liquid interface (ALI) cell cultures. To validate our approach, we compared tracheal tissue and ALI cell cultures of isolated primary normal human bronchial epithelial cells derived from smokers and nonsmokers. Our data indicated 18-fold higher levels of MUC5AC in submucosal glands of smokers covering about 8% of mucosal areas compared to <1% in nonsmoking individuals, confirming results of previous studies. We further identified a subpopulation of nonsmokers with slightly elevated glandular MUC5AC levels suggesting moderate exposure to second-hand smoke or fine particulate air pollution. Overall, this study demonstrates a novel, user-friendly and freely available tool for digital pathology and the analysis of therapeutic interventions tested in ALI cell cultures.

Automated Quantitative Image Evaluation of Antigen Retrieval Methods for 17 Antibodies in Placentation and Implantation Diagnostic and Research.

Immunostaining in clinical routine and research highly depends on standardized staining methods and quantitative image analyses. We qualitatively and quantitatively compared antigen retrieval methods (no pretreatment, pretreatment with pepsin, and heat-induced pretreatment with pH 6 or pH 9) for 17 antibodies relevant for placenta and implantation diagnostics and research. Using our newly established, comprehensive automated quantitative image analysis approach, fluorescent signal intensities were evaluated. Automated quantitative image analysis found that 9 out of 17 antibodies needed antigen retrieval to show positive staining. Heat induction proved to be the most efficient form of antigen retrieval. Eight markers stained positive after pepsin digestion, with ß-hCG and vWF showing enhanced staining intensities. To avoid the misinterpretation of quantitative image data, the qualitative aspect should always be considered. Results from native placental tissue were compared with sections of a placental invasion model based on thermo-sensitive scaffolds. Immunostaining on placentas in vitro leads to new insights into fetal development and maternal pathophysiological pathways, as pregnant women are justifiably excluded from clinical studies. Thus, there is a clear need for the assessment of reliable immunofluorescent staining and pretreatment methods. Our evaluation offers a powerful tool for antibody and pretreatment selection in placental research providing objective and precise results.

Systematic Review of the Application of Perinatal Derivatives in Animal Models on Cutaneous Wound Healing.

Knowledge of the beneficial effects of perinatal derivatives (PnD) in wound healing goes back to the early 1900s when the human fetal amniotic membrane served as a biological dressing to treat burns and skin ulcerations. Since the twenty-first century, isolated cells from perinatal tissues and their secretomes have gained increasing scientific interest, as they can be obtained non-invasively, have anti-inflammatory, anti-cancer, and anti-fibrotic characteristics, and are immunologically tolerated in vivo. Many studies that apply PnD in pre-clinical cutaneous wound healing models show large variations in the choice of the animal species (e.g., large animals, rodents), the choice of diabetic or non-diabetic animals, the type of injury (full-thickness wounds, burns, radiation-induced wounds, skin flaps), the source and type of PnD (placenta, umbilical cord, fetal membranes, cells, secretomes, tissue extracts), the method of administration (topical application, intradermal/subcutaneous injection, intravenous or intraperitoneal injection, subcutaneous implantation), and the type of delivery systems (e.g., hydrogels, synthetic or natural biomaterials as carriers for transplanted cells, extracts or secretomes). This review provides a comprehensive and integrative overview of the application of PnD in wound healing to assess its efficacy in preclinical animal models. We highlight the advantages and limitations of the most commonly used animal models and evaluate the impact of the type of PnD, the route of administration, and the dose of cells/secretome application in correlation with the wound healing outcome. This review is a collaborative effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the preclinical application of PnD in wound healing.

Transposable elements as new players in neurodegenerative diseases.

Neurodegenerative diseases (NDs), including the most prevalent Alzheimer's disease and Parkinson disease, share common pathological features. Despite decades of gene-centric approaches, the molecular mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered 'junk' DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP-43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.

Adolescents' Experiences of Using a Smartphone Application Hosting a Closed-loop Algorithm to Manage Type 1 Diabetes in Everyday Life: Qualitative Study.

BACKGROUND: Closed-loop technology may help address health disparities experienced by adolescents, who are more likely to have suboptimal glycemic control than other age groups and, because of their age, find diabetes self-management particularly challenging. The CamAPS FX closed-loop has sought to address accessibility and usability issues reported by users of previous prototype systems. It comprises small components and a smartphone app used to: announce meal-time boluses, adjust ("boost" or "ease-off") closed-loop insulin delivery, customize alarms, and review/share data. We explored how using the CamAPS FX platform influences adolescents' self-management practices and everyday lives. METHODS: Eighteen adolescents were interviewed after having ≥6 months experience using the closed-loop platform. Data were analyzed thematically. RESULTS: Participants reported feeling less burdened and shackled by diabetes because closed-loop components were easier to carry/wear, finger-pricks were not required, the smartphone app provided a discreet and less stigmatizing way of managing diabetes in public, and they were able to customize alarms. Participants also reported checking and reviewing data more regularly, because they did so when using the smartphone for other reasons. Some reported challenges in school settings where use of personal phones was restricted. Participants highlighted how self-management practices were improved because they could easily review glucose data and adjust closed-loop insulin delivery using the "boost" and "ease-off" functions. Some described how using the system resulted in them forgetting about diabetes and neglecting certain tasks. CONCLUSIONS: A closed-loop system with small components and control algorithm on a smartphone app can enhance usability and acceptability for adolescents and may help address the health-related disparities experienced by this age group. However, challenges can arise from using a medical app on a device which doubles as a smartphone. TRIAL REGISTRATION: Closed Loop From Onset in Type 1 Diabetes (CLOuD); NCT02871089; https://clinicaltrials.gov/ct2/show/NCT02871089.

Perturbed DNA methylation by Gadd45b induces chromatin disorganization, DNA strand breaks and dopaminergic neuron death.

Age is a major risk factor for neurodegenerative diseases like Parkinson's disease, but few studies have explored the contribution of key hallmarks of aging, namely DNA methylation changes and heterochromatin destructuration, in the neurodegenerative process. Here, we investigated the consequences of viral overexpression of Gadd45b, a multifactorial protein involved in DNA demethylation, in the mouse midbrain. Gadd45b overexpression induced global and stable changes in DNA methylation, particularly in introns of genes related to neuronal functions, as well as on LINE-1 transposable elements. This was paralleled by disorganized heterochromatin, increased DNA damage, and vulnerability to oxidative stress. LINE-1 de-repression, a potential source of DNA damage, preceded Gadd45b-induced neurodegeneration, whereas prolonged Gadd45b expression deregulated expression of genes related to heterochromatin maintenance, DNA methylation, or Parkinson's disease. Our data indicates that aging-related alterations contribute to dopaminergic neuron degeneration with potential implications for Parkinson's disease.

Resection of isolated brain metastases in non-small cell lung cancer (NSCLC) patients - evaluation of outcome and prognostic factors: A retrospective multicenter study.

BACKGROUND AND OBJECTIVES: Brain metastases occur in about 30% of all patients with non-small cell lung cancer (NSCLC). In selected patients, long-term survival can be achieved by resection of brain metastases. In this retrospective study, we investigate the prognosis of NSCLC patients with resected brain metastases and possible prognostic factors. METHODS: In 119 patients with NSCLC and resected brain metastases, we report the following parameters: extent of resection, resection status, postoperative complications and overall survival (OS). We used the log-rank test to compare unadjusted survival probabilities and multivariable Cox regression to investigate potential prognostic factors with respect to OS. RESULTS: A total of 146 brain metastases were resected in 119 patients. The median survival was 18.0 months. Postoperative cerebral radiotherapy was performed in 86% of patients. Patients with postoperative radiotherapy had significantly longer survival (median OS 20.2 vs. 9.0 months, p = 0.002). The presence of multiple brain metastases was a negative prognostic factor (median OS 13.5 vs. 19.5 months, p = 0.006). Survival of patients with extracerebral metastases of NSCLC was significantly shorter than in patients who had exclusively brain metastases (median OS 14.0 vs. 23.1 months, p = 0.005). Both of the latter factors were independent prognostic factors for worse outcome in multivariate analysis. CONCLUSIONS: Based on these data, resection of solitary brain metastases in patients with NSCLC and controlled extracerebral tumor disease is safe and leads to an overall favorable outcome. Postoperative radiotherapy is recommended to improve prognosis.