Elderly and Patients with Large Breast Volume Have an Increased Risk of Seroma Formation after Mastectomy-Results of the SerMa Pilot Study.

The collective of the SerMa pilot study included 100 cases of primary breast cancer or Carcinoma in situ who had undergone a mastectomy procedure with or without reconstruction of the breast using an implant or expander at Augsburg University Hospital between 12/2019 and 12/2022. The study aimed to investigate possible causes of seroma formation; reported here are the clinicopathological correlations between seroma formation and tumor biology and surgical procedures. Seroma occurred significantly more often in patients with older age (median patient age in cases with seroma was 73 years vs. 52 years without seroma; p < 0.001). In addition, patients with larger mastectomy specimen were significantly more likely to develop seroma (median ablation weight in cases with seroma 580 g vs. 330 g without seroma; p < 0.001). Other significant parameters for seroma formation were BMI (p = 0.005), grading (p = 0.015) and tumor size (p = 0.036). In addition, with insertion of implant or expander, a seroma occurred significantly less frequently (p < 0.001). In a binary logistic regression, age in particular was confirmed as a significant risk factor. In contrast, tumor biological characteristics, number of lymph nodes removed or affected showed no significant effect on seroma formation. The present study shows the need for patient education about the development of seroma in particular in older patients and patients with large breast volumes within the preoperative surgical clarification. These clinicopathological data support the previously published results hypothesizing that seroma formation is related to autoimmune/inflammatory processes and will be tested on a larger collective in the planned international multicenter SerMa study.

Th2/Th17 cell associated cytokines found in seroma fluids after breast cancer surgery.

PURPOSE: The development of a seroma after breast cancer surgery is a common postoperative complication seen after simple mastectomy and axillary surgery. We could recently demonstrate that breast cancer patients undergoing a simple mastectomy with subsequent seroma formation developed a T-helper cell increase within the aspirated fluid measured by flow cytometry. The same study revealed a Th2 and/or a Th17 immune response in peripheral blood and seroma fluid of the same patient. Based on these results and within the same study population, we now analyzed the Th2/Th17 cell associated cytokine content as well as the best known clinical important cytokine IL-6. METHODS: Multiplex cytokine measurements (IL-4, IL-5, IL-13, IL-10, IL-17, and IL-22) were done on 34 seroma fluids (Sf) after fine needle aspiration of patients who developed a seroma after a simple mastectomy. Serum of the same patient (Sp) and that of healthy volunteers (Sc) were used as controls. RESULTS: We found the Sf to be highly cytokine rich. Almost all analyzed cytokines were significantly higher in abundance in the Sf compared to Sp and Sc, especially IL-6, which promotes Th17 differentiation as well as suppresses Th1 differentiation in favor of Th2 development. CONCLUSION: Our Sf cytokine measurements reflect a local immune event. In contrast, former study results on T-helper cell populations in both Sf and Sp tend to demonstrate a systemic immune process.

Clinical Knowledge Platform (CKP): A Collaborative Ecosystem to Share Interoperable Clinical Forms, Viewers, and Order Sets with Various EMRs.

A large number of Electronic Medical Records (EMR) are currently available with a variety of features and architectures. Existing studies and frameworks presented some solutions to overcome the problem of specification and application of clinical guidelines toward the automation of their use at the point of care. However, they could not yet support thoroughly the dynamic use of medical knowledge in EMRs according to the clinical contexts and provide local application of international recommendations. This study presents the development of the Clinical Knowledge Platform (CKP): a collaborative interoperable environment to create, use, and share sets of information elements that we entitled Clinical Use Contexts (CUCs). A CUC could include medical forms, patient dashboards, and order sets that are usable in various EMRs. For this purpose, we have identified and developed three basic requirements: an interoperable, inter-mapped dictionary of concepts leaning on standard terminologies, the possibility to define relevant clinical contexts, and an interface for collaborative content production via communities of professionals. Community members work together to create and/or modify, CUCs based on different clinical contexts. These CUCs will then be uploaded to be used in clinical applications in various EMRs. With this method, each CUC is, on the one hand, specific to a clinical context and on the other hand, could be adapted to the local practice conditions and constraints. Once a CUC has been developed, it could be shared with other potential users that can consume it directly or modify it according to their needs.

Impairment of Cognitive Function in Different Domains Early After Lung Transplantation.

In this prospective observational pilot study patients with the diagnosis of end-stage lung disease and listed for lung transplantation underwent a cognitive function test battery before and after lung transplantation to investigate postoperative cognitive function in three domains (visual and verbal memory, executive functioning, concentration/speed of processing). Additionally we investigated intraoperative risk factors for postoperative cognitive dysfunction. In total, 24 patients were included in this pilot study. The incidence of postoperative cognitive dysfunction was 58.3%. In the cognitive dysfunction group, the domains executive functioning and concentration/attention were significantly impaired whereas memory was not affected. Patients with cognitive impairment had a significantly longer ICU stay. The strongest independent risk factor for the development of cognitive dysfunction was operation time. No influence of cerebral oxygen desaturations on cognitive dysfunction was found. This might have important implications for early psychological rehabilitation strategies in this high-risk patient collective.

Genomic epidemiology reveals multiple introductions of SARS-CoV-2 followed by community and nosocomial spread, Germany, February to May 2020.

BackgroundIn the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data.AimWe applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata.MethodsWe investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission.ResultsWe identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions.ConclusionsEarly spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.

MicroRNA-93 acts as an "anti-inflammatory tumor suppressor" in glioblastoma.

BACKGROUND: Inflammation is an important driver of malignant glioma disease. Inflammatory mediators are not only produced by immune cells in the tumor microenvironment, but also by glioblastoma (GBM) cells themselves creating a mutually reinforcing loop. We here aimed at identifying an "anti-inflammatory switch" that allows to dampen inflammation in GBM. METHODS: We used human GBM specimens, primary cultures, and cell lines. The response of GBM cells toward inflammatory stimuli was tested by incubation with supernatant of stimulated human immune cells. Expression levels were measured by whole transcriptome microarrays and qRT-PCR, and protein was quantified by LUMINEX and SDS-PAGE. MicroRNA binding to 3'UTRs was analyzed by luciferase assays. Proliferation rates were determined by flow cytometry, and invasion and angiogenesis were studied using migration and endothelial tube formation assays. RESULTS: We demonstrated GBM cells to secrete high amounts of proinflammatory mediators in an inflammatory microenvironment. We found miR-93 as a potential "anti-inflammatory tumor suppressor" dramatically downregulated in GBM. Concordantly, cytokine secretion dropped after miR-93 re-expression. Transfection of miR-93 in GBM cells led to down-regulation of hubs of the inflammatory networks, namely, HIF-1α and MAP3K2 as well as IL-6, G-CSF, IL-8, LIF, IL-1ß, COX2, and CXCL5. We showed only COX2 and CXCL5 to be indirectly regulated by miR-93 while all other genes are true targets. Phenotypically, re-expression of miR-93 in GBM cells substantially suppressed proliferation, migration, and angiogenesis. CONCLUSIONS: Alleviating GBM-derived inflammation by re-expression of miR-93 may be a powerful tool to mitigate these tumors' aggressiveness and holds promise for new clinical approaches.

Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4.

BACKGROUND: The second intron of Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4), an important hub in the pro-invasive MAPK pathway, harbors miR-744. There is accumulating evidence that intronic micro-RNAs (miRNAs) are capable of either supporting or restraining functional pathways of their host genes, thereby creating intricate regulative networks. We thus hypothesized that miR-744 regulates glioma migration by interacting with its host's pathways. METHODS: Patients' tumor specimens were obtained stereotactically. MiR-744 was overexpressed in U87, T98G, and primary glioblastoma (GBM) cell lines. Cell mobility was studied using migration and Boyden chamber assays. Protein and mRNA expression was quantified by SDS-PAGE and qRT-PCR. Interactions of miR-744 and 3'UTRs were analyzed by luciferase reporter assays, and SMAD2/3, p38, and beta-Catenin activities by TOP/FOPflash reporter gene assays. RESULTS: As compared to a normal brain, miR-744 levels were dramatically decreased in GBM samples and in primary GBM cell lines. Astrocytoma WHO grade II/III exhibited intermediate expression levels. Re-expression of miR-744 in U87, T98G, and primary GBM cell lines induced focal growth and impaired cell mobility. Luciferase activity of 3'UTR reporter constructs revealed the pro-invasive factors TGFB1 and DVL2 as direct targets of miR-744. Re-expression of miR-744 reduced levels of TGFB1, DVL2, and the host MAP2K4, and mitigated activity of TGFB1 and DVL2 downstream targets SMAD2/3 and beta-Catenin. TGFB1 knock-down repressed MAP2K4 expression. CONCLUSION: MiR-744 acts as an intrinsic brake on its host. It impedes MAP2K4 functional pathways through simultaneously targeting SMAD-, beta-Catenin, and MAPK signaling networks, thereby strongly mitigating pro-migratory effects of MAP2K4. MiR-744 is strongly repressed in glioma, and its re-expression might attenuate tumor invasiveness.

Idiopathic internal mammary artery aneurysm.

Aneurysms of the internal mammary artery are extremely rare, and their presentation and treatment are variable. Since these aneurysms often tend to rupture and cause haemothorax and life-threatening conditions, the knowledge of secure treatment options is indispensable. We here report the case of an idiopathic internal mammary aneurysm in a 46-year-old man. Open surgical resection of the aneurysm was performed in this case without any complications. The postoperative course was uneventful and the patient was in a good physical condition without any vascular or neurological abnormalities during follow-up.

MicroRNA-665 is involved in the regulation of the expression of the cardioprotective cannabinoid receptor CB2 in patients with severe heart failure.

The myocardial endocannabinoid system has been linked to stress response and cardioprotection. In chronic heart failure (CHF), protective CB2 receptors are markedly up-regulated while CB1 receptors are slightly down-regulated. We here provide evidence that myocardial CB receptors are subject to microRNA regulation. By a combined computational and experimental approach we show that CB1 receptors are regulated by miR-494, and CB2 receptors are targeted by miR-665. Moreover, we demonstrate that in CHF, miR-665 expression is significantly decreased while miR-494 is slightly increased, which is concordant with the previously reported alterations of CB receptors. These results suggest that in CHF, altered expression of specific miRNAs may contribute to a compensatory response of the diseased myocardium.

Indocyanine green clearance as an outcome prediction tool in cardiac surgery: a prospective study.

PURPOSE: To evaluate the role of plasma disappearance rate of indocyanine green (PDR-ICG) as an outcome prediction tool in cardiac surgery. PATIENTS AND METHODS: One hundred ninety patients undergoing coronary artery bypass grafting, valve surgery or combined procedures were enrolled. PDR-ICG measurements along with standard lab values were performed preoperative and on postoperative days 1, 2, and on discharge from the intensive care unit. Adverse outcomes were defined as prolonged length of stay in the intensive care unit and/or mortality. Two groups were defined according to length of stay in the intensive care unit (≤ 3 days vs >3 days). RESULTS: PDR-ICG values differed significantly for all time points between the groups. In a multivariate model, in patients over 65 years with a EuroSCORE below 8.5, a preoperative PDR-ICG value below 12.85%/min was the strongest independent predictor for prolonged intensive care unit stay (>3 days). A preoperative PDR-ICG value below 8.2%/min was the strongest independent predictor for mortality in a multivariate analysis including age, cardiac function, and EuroSCORE. CONCLUSIONS: In addition to the established scores, PDR-ICG may provide valuable information for the assessment of perioperative morbidity and mortality in cardiac surgery. Pre- and early postoperative measurements may help to identify patients at risk for developing perioperative complications.

Daptomycin as supportive treatment option in patients developing mediastinitis after open cardiac surgery.

BACKGROUND: Mediastinitis is a severe complication after cardiac surgery. While improvement of prophylaxis and of medical and surgical therapy has reduced its incidence, the treatment of mediastinitis continues to be a challenging problem. Within this study, we report the successful use of daptomycin as supportive therapy in patients developing mediastinitis after open cardiac surgery. METHODS: The records of 21 consecutive patients who developed mediastinitis after cardiac surgery were retrospectively reviewed. After diagnosis, all patients received surgical debridement and antibiotic therapy with daptomycin. All patients were followed up to death or discharge. RESULTS: Clinical improvement after combined surgical and antibiotic therapy with daptomycin was found in 90.5% of the patients. The median time until clinical improvement occurred was 5 [4/6] days. Daptomycin was well-tolerated and no major adverse events during therapy were observed observed. CONCLUSIONS: This study provides new and helpful information regarding the beneficial use of daptomycin as supportive treatment option in patients developing mediastinitis after cardiac surgery.

Haematocrit is invalid for estimating red cell volume: a prospective study in male volunteers.

BACKGROUND: Although haematocrit and haemoglobin value are concentrations, they are commonly used to guide clinical decisions involving red cell and plasma volumes. A study challenging this convention systematically co-determined and compared these measures. MATERIALS AND METHODS: Using a non-radioactive double-tracer technique to assess blood volume components, measurements were taken once in 46 healthy male endurance athletes. The best predictors of blood composition were derived from the first 36 athletes by automated stepwise forward selection of non-invasive metric parameters (age, weight, height, body surface area and body mass index) and the resulting formulae validated in the remaining ten volunteers. Haematocrit, haemoglobin concentration, red cell volume and plasma volume were measured again 4 weeks later in eight randomly selected volunteers. RESULTS: Red cell volume (2,282±283 mL) did not correlate with either haematocrit (0.42±0.02) or haemoglobin concentration (14.2±0.8, P>0.05, resp.), but was predictable from body surface area (red cell volume [mL]=1,547 × body surface area [m2]-723; r=.88, P<0.01). A similar accuracy was unobtainable using any potential predictor for plasma or blood volume, haematocrit or haemoglobin concentration. Red cell volume showed high intra-individual stability when measured again after 4 weeks, whereas plasma volume oscillated in both directions by up to 22%. DISCUSSION: Only red cell volume shows sufficiently stable intra- and interindividual values to be an accurate, objective indicator of normality in blood composition. The measurement technique is feasible in the outpatient setting and this parameter provides effective, robust, and readily available diagnostic information that might be useful in numerous clinical situations. Its clinical significance does, however, remain to be demonstrated.

Medical suppression of hypercortisolemia in Cushing's syndrome with particular consideration of etomidate.

Cushing's syndrome is associated with excessive cortisol secretion by the adrenal gland or ectopic tumours and may result in diabetes, hypertension, and life-threatening infections with high mortality rates especially in the case of surgical resection. Although surgical resection is the treatment of choice, patients may benefit from preceding medical therapy. This may especially be useful as an adjunctive approach in emergency settings, if patients cannot undergo surgery, if surgery or radiotherapy fails, or if the tumour recurs. Medical therapy can be categorized in three different groups-inhibition of steroidogenesis, suppression of adrenocorticotropic hormone, and antagonism of the glucocorticoid receptor. However, the majority of common drugs are not available for parenteral administration, which may evoke a management problem in emergency settings or in patients unable to tolerate oral medication. The carboxylated imidazole etomidate is a well known parenteral induction agent for general anaesthesia. Besides its hypnotic properties, etomidate also has α-adrenergic characteristics and inhibits the enzyme 11-deoxycortisol ß-hydroxylase, which catalyzes the final step of the conversion of cholesterol to cortisol. Adverse outcomes have been reported when used for sedation in septic or trauma patients probably by its interference with steroid homeostasis. However, its capability of inhibition of the 11-deoxycortisol ß-hydroxylase leads to suppression of cortisol secretion which has been demonstrated to be a useful tool in severe and complicated hypercortisolemia. Within this article, we review the data concerning different pharmacological approaches with particular consideration of etomidate in order to suppress steroidogenesis in patients with Cushing's syndrome.

MicroRNAs as potential therapeutic agents in the treatment of myocardial infarction.

In spite of enormous efforts, myocardial infarction is one of the most common causes of morbidity and mortality worldwide. The molecular mechanisms underlying the pathological myocardial alterations in affected patients are not fully elucidated. Recent studies have uncovered an important regulatory role for microRNAs (miRNAs), a family of small non-coding RNA molecules which - by translational repression or messenger RNA (mRNA) degradation - primarily act as negative regulators of gene expression. MiRNAs have been identified as regulatory key players during cellular differentiation, proliferation, and apoptosis. Recent work has unveiled an important impact of miRNAs on the pathophysiology of myocardial infarction and consecutive myocardial alterations, including arrhythmia, remodelling processes, cardiac fibrosis, and hypertrophia. Additionally, specific miRNAs have been identified to be either elevated or decreased in the blood plasma after myocardial infarction. Determination of miRNA expression levels therefore offers a potential prognostic and/or predictive value. Future therapeutic concepts aiming at attenuation of ischemia-induced harm and reduction of maladaptive changes may include strategies to influence altered miRNA expression patterns. In this review, we summarize current knowledge of the modulating role of miRNAs in pathological alterations occurring in myocardial infarction as well as currently available data concerning miRNAs as diagnostic markers and therapeutic targets.

DSGeo: software tools for cross-platform analysis of gene expression data in GEO.

The Gene Expression Omnibus (GEO) is the largest resource of public gene expression data. While GEO enables data browsing, query and retrieval, additional tools can help realize its potential for aggregating and comparing data across multiple studies and platforms. This paper describes DSGeo-a collection of valuable tools that were developed for annotating, aggregating, integrating, and analyzing data deposited in GEO. The core set of tools include a Relational Database, a Data Loader, a Data Browser, and an Expression Combiner and Analyzer. The application enables querying for specific sample characteristics and identifying studies containing samples that match the query. The Expression Combiner application enables normalization and aggregation of data from these samples and returns these data to the user after filtering, according to the user's preferences. The Expression Analyzer allows simple statistical comparisons between groups of data. This seamless integration makes annotated cross-platform data directly available for analysis.

Evaluation of a large-scale biomedical data annotation initiative.

BACKGROUND: This study describes a large-scale manual re-annotation of data samples in the Gene Expression Omnibus (GEO), using variables and values derived from the National Cancer Institute thesaurus. A framework is described for creating an annotation scheme for various diseases that is flexible, comprehensive, and scalable. The annotation structure is evaluated by measuring coverage and agreement between annotators. RESULTS: There were 12,500 samples annotated with approximately 30 variables, in each of six disease categories - breast cancer, colon cancer, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Type 1 diabetes mellitus (DM). The annotators provided excellent variable coverage, with known values for over 98% of three critical variables: disease state, tissue, and sample type. There was 89% strict inter-annotator agreement and 92% agreement when using semantic and partial similarity measures. CONCLUSION: We show that it is possible to perform manual re-annotation of a large repository in a reliable manner.

Towards large-scale sample annotation in gene expression repositories.

BACKGROUND: Large repositories of biomedical research data are most useful to translational researchers if their data can be aggregated for efficient queries and analyses. However, inconsistent or non-existent annotations describing important sample details such as name of tissue or cell line, histopathological type, and subject characteristics like demographics, treatment, and survival are seldom present in data repositories, making it difficult to aggregate data. RESULTS: We created a flexible software tool that allows efficient annotation of samples using a controlled vocabulary, and report on its use for the annotation of over 12,500 samples. CONCLUSION: While the amount of data is very large and seemingly poorly annotated, a lot of information is still within reach. Consistent tool-based re-annotation enables many new possibilities for large scale interpretation and analyses that would otherwise be impossible.