Publications by authors named "Annalen Bleckmann"

60 Publications

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention.

Cells 2021 Jan 12;10(1). Epub 2021 Jan 12.

Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Münster, Germany.

The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.
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http://dx.doi.org/10.3390/cells10010142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828172PMC
January 2021

Long-Term Follow-Up on Systemic Bevacizumab Treatment in Recurrent Respiratory Papillomatosis.

Laryngoscope 2020 Dec 31. Epub 2020 Dec 31.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a primarily benign disease affecting the entire respiratory tract. Treatment is challenging and usually involves surgical interventions and adjuvant medications. Previously, promising results on systemic administration of bevacizumab have been reported. However, experience on long-term systemic use in patients with RRP is not yet available. Here, we present our long-term follow-up on RRP patients undergoing systemic bevacizumab treatment.

Study Design: Case series.

Methods: To describe experience on long-term systemic bevacizumab administration, we performed the underlying investigation. Clinical, radiological, and bronchoscopy data were collected.

Results: To date, a total of n = 5 patients has been treated with systemic bevacizumab at Muenster University Hospital. With a median follow-up since first systemic bevacizumab administration of 95.5 months long-term follow-up is illustrated. Following bevacizumab treatment partial remission or very good partial remission were achieved in all patients. After papilloma recurrence/progression due to bevacizumab discontinuation, further response was documented in all patients in whom bevacizumab was started again. In one patient, bevacizumab was discontinued due to loss of efficacy. Lung cancer developed in one patient with pulmonary papillomatosis prior to bevacizumab administration whereas three patients suffered from malignant transformation during bevacizumab treatment. Systemic bevacizumab led to long-term reduction in surgical interventions in all patients. Except from mild proteinuria and hypertension in two patients therapy was well tolerated.

Conclusions: Systemic bevacizumab represents a promising long-term treatment option for aggressive forms of papillomatosis. Rate of malignant transformation under bevacizumab treatment, optimal treatment schedule, and influence on survival should be further evaluated in clinical trials.

Level Of Evidence: 4 Laryngoscope, 2020.
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http://dx.doi.org/10.1002/lary.29351DOI Listing
December 2020

To treat or not to treat: A rare case of response to pembrolizumab-based immunotherapy-chemotherapy in non-small cell lung cancer with acute liver failure due to multiple bile duct metastases.

Thorac Cancer 2021 Feb 27;12(4):553-556. Epub 2020 Dec 27.

Department of Medicine A: Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

About 40% of non-small lung cancer (NSCLC) patients have metastatic disease at the time of diagnosis. However, metastatic NSCLC in the biliary duct system is extremely rare. A high proportion of patients with acute liver failure due to advanced NSCLC do not receive any treatment due to organ dysfunction or poor performance status. Here, we report a case of successful treatment with chemoimmunotherapy in a young woman with obstructive jaundice and acute hepatic failure due to multiple intrahepatic bile duct metastases. KEY POINTS: Significant findings of the study Chemotherapy in NSCLC patients with liver failure is a therapeutic challenge. Acute hepatic failure are often exclusion criteria for therapy of NSCLC. Some reports showed a benefit of ICIs plus chemotherapy for NSCLC with liver metastases. What this study adds Combination of ICIs and chemotherapy is effective and safe in critically ill patients with lung cancer and impaired liver function.
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http://dx.doi.org/10.1111/1759-7714.13793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882375PMC
February 2021

An extracellular vesicle-related gene expression signature identifies high-risk patients in medulloblastoma.

Neuro Oncol 2020 Nov 11. Epub 2020 Nov 11.

Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.

Background: Medulloblastoma (MB) is a malignant brain tumor in childhood. It comprises four subgroups with different clinical behaviors. The aim of this study was to characterize the transcriptomic landscape of MB, both at the level of individual tumors as well as in large patient cohorts.

Methods: We used a combination of single-cell transcriptomics, cell culture models and biophysical methods such as nanoparticle tracking analysis and electron microscopy, to investigate intercellular communication in the MB tumor niche.

Results: Tumor cells of the SHH-MB subgroup show a differentiation blockade. These cells undergo extensive metabolic reprogramming. The gene expression profiles of individual tumor cells show a partial convergence with those of tumor-associated glial and immune cells. One possible cause is the transfer of extracellular vesicles (EVs) between cells in the tumor niche. We were able to detect EVs in co-culture models of MB tumor cells and oligodendrocytes. We also identified a gene expression signature, EVS, which shows overlap with the proteome profile of large oncosomes from prostate cancer cells. This signature is also present in MB patient samples. A high EVS expression is one common characteristic of tumors that occur in high-risk patients from different MB subgroups or subtypes.

Conclusions: With EVS, our study uncovered a novel gene expression signature that has a high prognostic significance across MB subgroups.
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http://dx.doi.org/10.1093/neuonc/noaa254DOI Listing
November 2020

Impact of pre-OP independence in patients with limited brain metastases on long-term survival.

BMC Cancer 2020 Oct 8;20(1):973. Epub 2020 Oct 8.

Clinic for Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.

Background: Brain metastasis represents a major complication with a significantly shorter overall survival of many oncological diseases, in particular of lung cancer, breast cancer and malignant melanoma patients. However, despite the poor prognosis, sometimes clinical decision-making, between on the one hand not to harm the patient and on the other hand not withholding a potential therapeutic option, is very challenging. Thus the aim of this retrospective study was to compare various scores, including scores for activities of daily living (ADL) before resection of brain metastases and to analyse their impact on survival.

Methods: Our single institution retrospective patient cohort (N = 100) with a median age of 63.6 years, which had all undergone resection of one or more brain metastases, was categorized using the original patient files. The cohort includes 52 patients with lung cancer, 27 patients with breast cancer, 8 patients with colorectal carcinoma and 13 patients with kidney cancer. To categorize, we used different score systems which were capable to evaluate the patient in relation to self-sufficiency, activity and self-determination as part of ADL. The retrospective analysis includes the ECOG-Status, Karnofsky-Index, Barthel-Index, ASA-Classification and Katz-Index. Pre-processing and the analysis of the data was implemented using KNIME, where we used the R-plugin nodes to perform the final statistical tests with R.

Results: Our analysis reveals that most of the ADL scores we tested are able to give a reliable prediction on overall survival after brain metastasis surgery. The survival rates decrease significantly with a lower score in all tested score systems, with the exception of the ASA-Risk score. In particular, the Katz Index < 6 was identified to have a significant correlation with a lower cancer specific survival (CSS) (HR 3.33, 95%-CI [2.17-5.00]; p-Value = 9.6*10), which is easy to use and has reproducible measurements.

Conclusions: Pre-operative independence assessment by indices of ADL represents a predictor for overall survival after resection of brain metastases. Especially the easily, objectively and rapidly applicable Katz-Score is a very helpful tool to assess the pre-operative status, which could be additionally included in clinical decision making in daily practice.
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http://dx.doi.org/10.1186/s12885-020-07459-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545555PMC
October 2020

Survival after resection of brain metastases with white light microscopy versus fluorescence-guidance: A matched cohort analysis of the Metastasys study data.

Oncotarget 2020 Aug 11;11(32):3026-3034. Epub 2020 Aug 11.

Department of Neurosurgery, University of Medicine Goettingen, Goettingen, Germany.

Background: Metastatic brain disease continues to have a dismal prognosis. Previous studies achieved a reduction of local recurrence rates by aggressively resecting the peritumoral zone (supramarginal resection) or using 5-aminolaevulinic acid (5-ALA) fluorescence. The aim of the present study is to assess whether the use of 5-ALA has an impact on local recurrence or survival compared to conventional white light microscopic tumor resection.

Materials And Methods: We included consecutive patients who underwent surgical resection of brain metastases. Two groups were compared: In the "white light" group, resection was performed with conventional microscopy. In the 5-ALA group, fluorescence guided peritumoral resection was additionally performed after standard microscopic resection. In-brain recurrence and mortality were compared between groups.

Results: = 175 patients were included in the study. All baseline parameters were similarly distributed with no significant difference between surgical groups. Local in-brain recurrence occurred in 21/175 patients (12%) with a rate of 15/119 (12.6%) in the white light and 6/56 (10.7%) in the 5-ALA group ( = 0.720). The use of 5-ALA influenced neither in-brain recurrence (OR 0.59 [CI = 95% 0.18; 1.99], = 0.40) nor mortality (OR 0.71 [CI = 95% 0.27; 1.85], = 0.49).

Conclusions: The use of 5-ALA did not result in lower in-brain recurrence or mortality compared to the use of white light microscopy. The most prominent predictors of survival remain favorable preoperative performance status, a low tumor diameter and the absence of multiple cerebral lesions.
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http://dx.doi.org/10.18632/oncotarget.27688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429181PMC
August 2020

Microvesicles in Cancer: Small Size, Large Potential.

Int J Mol Sci 2020 Jul 28;21(15). Epub 2020 Jul 28.

Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37075 Göttingen, Germany.

Extracellular vesicles (EV) are secreted by all cell types in a tumor and its microenvironment (TME), playing an essential role in intercellular communication and the establishment of a TME favorable for tumor invasion and metastasis. They encompass a variety of vesicle populations, among them the well-known endosomal-derived small exosomes (Exo), but also larger vesicles (diameter > 100 nm) that are shed directly from the plasma membrane, the so-called microvesicles (MV). Increasing evidence suggests that MV, although biologically different, share the tumor-promoting features of Exo in the TME. Due to their larger size, they can be readily harvested from patients' blood and characterized by routine methods such as conventional flow cytometry, exploiting the plethora of molecules expressed on their surface. In this review, we summarize the current knowledge about the biology and the composition of MV, as well as their role within the TME. We highlight not only the challenges and potential of MV as novel biomarkers for cancer, but also discuss their possible use for therapeutic intervention.
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http://dx.doi.org/10.3390/ijms21155373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432491PMC
July 2020

Top-level gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis.

Transl Lung Cancer Res 2020 Jun;9(3):603-616

Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.

Background: amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup.

Methods: A total of 373 unselected patients with NSCLC were consecutively tested for gene copy number (GCN) by FISH. Mean GCN, /CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data.

Results: Based on the variability of obtained data a top-level category of amplification was newly defined (>90th percentile of average GCN; ≥10 gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected ( mutation or exon 14 skipping mutation). In this top-level group, there were no mutations or or alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 23.6 months). Worse prognosis did not depend on initial stage or treatment.

Conclusions: The newly defined top-level category of amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.
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http://dx.doi.org/10.21037/tlcr-19-339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354108PMC
June 2020

Treatment response to idelalisib in a patient with immunodeficiency-associated Burkitt lymphoma harboring a PIK3CA H1047R mutation.

Ann Hematol 2021 Jan 20;100(1):277-279. Epub 2020 Mar 20.

Department of Haematology and Medical Oncology, University Medicine Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1007/s00277-020-03974-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782442PMC
January 2021

5-Aminolevulinic Acid Fluorescence Indicates Perilesional Brain Infiltration in Brain Metastases.

World Neurosurg X 2020 Jan 16;5:100069. Epub 2019 Dec 16.

Department of Neurosurgery, University Medical Center Göttingen, Georg-August-University of Göttingen, Göttingen, Germany.

Background: In glioma surgery, 5-aminolevulinic acid (5-ALA) fluorescence reflects tumor infiltration, and fluorescence-assisted resection correlates with higher removal rates and improved progression-free survival. Recent studies report that a sizable proportion of brain metastases exhibit peritumoral infiltration on the cellular level. There is little information regarding whether 5-ALA is useful to guide surgery in the peritumoral zone in metastases. The aim of this study was to assess histologically whether 5-ALA fluorescence accurately reflects metastatic brain infiltration.

Methods And Materials: Fluorescence-assisted tumor resection was performed in 27 patients with brain metastases. Patients received 20 mg/kg 5-ALA 3 hours before anesthesia. After resection, biopsy specimens of the surrounding parenchyma were analyzed for 5-ALA fluorescence and histologic evidence of infiltrating tumor cells. The correlation between 5-ALA positivity and immunohistochemical evidence of tumor in the peritumoral zone was also assessed.

Results: Of 27 metastases, 23 (85%) were 5-ALA positive. For qualitative tissue analysis, 110 of 125 samples were collected. Metastatic infiltration was present in 49 samples with faint or red fluorescence; 33 samples without fluorescence were tumor-free. The presence of metastatic infiltration correlated with fluorescence ( < 0.001). Tumor infiltration correlated with fluorescence (blue fluorescence 0.09% ± 0.04% and red or faint fluorescence 3.26%;  = 0.003).

Conclusions: Infiltration of surrounding brain tissue is a common finding in brain metastases in selected primary tumors. 5-ALA fluorescence correlates with tumor cell infiltration and might guide more radical resection.
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http://dx.doi.org/10.1016/j.wnsx.2019.100069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026613PMC
January 2020

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

Eur Heart J 2020 May;41(20):1903-1914

Clinic of Cardiology and Pneumology, University Medical Center Göttingen, 37099 Göttingen, Germany.

Aims : Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.

Methods And Results : One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson's trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].

Conclusion : Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.
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http://dx.doi.org/10.1093/eurheartj/ehaa033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242071PMC
May 2020

Clinical application of genomic high-throughput data: Infrastructural, ethical, legal and psychosocial aspects.

Eur Neuropsychopharmacol 2020 02 20;31:1-15. Epub 2019 Dec 20.

Department of Medical Informatics, University Medical Center Göttingen, Von-Siebold-Straße 3, 37075 Göttingen, Germany.

Genomic high-throughput technologies (GHTT) such as next-generation sequencing represent a fast and cost-effective tool toward a more comprehensive understanding of the molecular background of complex diseases. However, technological advances contrast with insufficient application in clinical practice. Thus, patients, physicians, and other professionals are faced with tough challenges that forestall the efficient and effective implementation. With the increasing application of genetic testing, it is of paramount importance that physicians and other professionals in healthcare recognize the restrictions and potential of GHTT, in order to understand and interpret the complex data in the context of health and disease. At the same time, the growing volume and complexity of data is forever increasing the need for sustainable infrastructure and state-of-the-art tools for efficient data management, including their analysis and integration. The large pool of sensitive information remains difficult to interpret and fundamental questions spanning from billing to legal, social, and ethical issues have still not been resolved. Here we summarize and discuss these obstacles in an interdisciplinary context and suggest ways to overcome them. Continuous discussion with clinicians, data managers, biostatisticians, systems medicine experts, ethicists, legal scholars, and patients illuminates the strengths, weakness, and current practices in the pipeline from biomaterial to sequencing and data management. This discussion also highlights the new, cross-disciplinary working collaborations to realize the wide-ranging challenges in clinical genomics including the exceptional demands placed on the staff preparing and presenting the data, as well as the question as to how to report the data and results to patients.
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http://dx.doi.org/10.1016/j.euroneuro.2019.09.008DOI Listing
February 2020

LEF1 supports metastatic brain colonization by regulating glutathione metabolism and increasing ROS resistance in breast cancer.

Int J Cancer 2020 06 11;146(11):3170-3183. Epub 2019 Nov 11.

Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany.

More than half of all brain metastases show infiltrating rather than displacing growth at the macro-metastasis/organ parenchyma interface (MMPI), a finding associated with shorter survival. The lymphoid enhancer-binding factor-1 (LEF1) is an epithelial-mesenchymal transition (EMT) transcription factor that is commonly overexpressed in brain-colonizing cancer cells. Here, we overexpressed LEF1 in an in vivo breast cancer brain colonization model. It shortened survival, albeit without engaging EMT at the MMPI. By differential proteome analysis, we identified a novel function of LEF1 as a regulator of the glutathione (GSH) system, the principal cellular redox buffer. LEF1 overexpression also conferred resistance against therapeutic GSH depletion during brain colonization and improved management of intracellular ROS. We conclude that besides EMT, LEF1 facilitates metastasis by improving the antioxidative capacity of epithelial breast cancer cells, in particular during colonization of the brain parenchyma.
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http://dx.doi.org/10.1002/ijc.32742DOI Listing
June 2020

Sarcopenia as Prognostic Factor in Lung Cancer Patients: A Systematic Review and Meta-analysis.

Anticancer Res 2019 Sep;39(9):4603-4612

Department of Thoracic and Cardiovascular Surgery University Medical Center, Georg-August University, Göttingen, Germany

Background/aim: Sarcopenia describes the loss of skeletal muscle mass. While this condition is associated with a high mortality in cancer patients, its influence on survival is still underestimated.

Patients And Methods: A systematic review for articles was performed using the PubMed database, Cochrane Library, Biomed Central, Science Direct and by manual search. We used data of overall survival in sarcopenic patients for assessing the death risk. We extracted hazard ratio estimates from univariate and multivariate Cox proportional hazards models for meta-analysis.

Results: A total of 15 studies were eligible for meta-analysis including a total of 2,521 lung cancer patients. Univariate meta-analysis revealed a two-fold increased death risk in sarcopenic patients; multivariate meta-analysis yielded a significant, three-fold elevated risk of death. This higher mortality is independent of tumour stage.

Conclusion: Muscle loss is an independent risk factor for increased death risk in lung cancer patients independent of cancer stage. This argues for implementing screening for sarcopenia into cancer care.
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http://dx.doi.org/10.21873/anticanres.13640DOI Listing
September 2019

Utilizing Molecular Network Information via Graph Convolutional Neural Networks to Predict Metastatic Event in Breast Cancer.

Stud Health Technol Inform 2019 Sep;267:181-186

Medical Bioinformatics, University Medical Center Göttingen.

Gene expression data is commonly available in cancer research and provides a snapshot of the molecular status of a specific tumor tissue. This high-dimensional data can be analyzed for diagnoses, prognoses, and to suggest treatment options. Machine learning based methods are widely used for such analysis. Recently, a set of deep learning techniques was successfully applied in different domains including bioinformatics. One of these prominent techniques are convolutional neural networks (CNN). Currently, CNNs are extending to non-Euclidean domains like graphs. Molecular networks are commonly represented as graphs detailing interactions between molecules. Gene expression data can be assigned to the vertices of these graphs, and the edges can depict interactions, regulations and signal flow. In other words, gene expression data can be structured by utilizing molecular network information as prior knowledge. Here, we applied graph CNN to gene expression data of breast cancer patients to predict the occurrence of metastatic events. To structure the data we utilized a protein-protein interaction network. We show that the graph CNN exploiting the prior knowledge is able to provide classification improvements for the prediction of metastatic events compared to existing methods.
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http://dx.doi.org/10.3233/SHTI190824DOI Listing
September 2019

Reconstruction of Different Modes of WNT Dependent Protein Networks from Time Series Protein Quantification.

Stud Health Technol Inform 2019 Sep;267:175-180

University Medical Center Göttingen, Hematology & Medical Oncology, 37099 Göttingen.

Protein signaling networks are crucial cornerstones in cellular responses. Deregulation causes various diseases, including cancer. One pathway that is frequently deregulated in cancer is the WNT signaling pathway. It has been shown that WNT signaling is highly context-dependent and the availability of receptors and ligands determines downstream signaling. In order to reveal which signaling pathways are activated by a specific receptor-ligand combination, we overexpressed the non-canonical WNT receptor ROR2 in the human breast cancer cell line MCF-7 and stimulated it with its putative ligand WNT11. Based on characterization of the cells by Reverse Phase Protein Array (RPPA), we integrated the proteomic data by network reconstruction analysis with prior knowledge from a pathway database. Using this approach, we were able to identify novel edges that differed upon ROR2 overexpression and WNT11 stimulation.
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http://dx.doi.org/10.3233/SHTI190823DOI Listing
September 2019

Cerebral metastases: do size, peritumoral edema, or multiplicity predict infiltration into brain parenchyma?

Acta Neurochir (Wien) 2019 05 15;161(5):1037-1045. Epub 2019 Mar 15.

Department of Neurosurgery, Medical Center, Georg August University of Göttingen, Göttingen, Germany.

Background: Brain metastases (BMs) are the most frequent malignancy of the central nervous system. Previous research suggested that some metastases show infiltrative behavior rather than sharp demarcation. We hypothesized that three magnetic resonance (MR) imaging parameters-(a) tumor size, (b) extent of peritumoral edema, and (c) presence of multiple BMs-are predictors of cellular invasion beyond the surgically identifiable tumor margins.

Methods: We performed a post hoc analysis on prospectively collected data of patients with BMs. Biopsies beyond the resection margin and immunohistochemistry were performed to assess infiltration status. The three MR imaging parameters were dichotomized into diameters ≤ 30 mm ("small") and > 30 mm ("large"), amount of peritumoral edema "extended" and "limited," and "multiple BMs" and "single BMs," respectively. The association between infiltration status and imaging parameters was calculated using chi-square test.

Results: Biopsy beyond the resection margin was performed in 77 patients; 49 (63.6%) had supramarginal infiltration and 28 patients (36.4%) showed no infiltration. Histological evidence of tumor infiltration was found in 25/41 patients with smaller lesions (61%) and in 24/36 with larger lesions (66.7%, p = 0.64), in 28/44 patients with limited (63.6%) and in 21/33 patients with extended edema (63.6%, p = 1.0), in 28/45 patients (62.2%) with single BM and in 21/32 patients (65.6%) with multiple BMs (p = 0.81).

Conclusions: Based on the post hoc analysis of our prospective trial data, we could not confirm the hypothesis that infiltration of brain parenchyma beyond the glial pseudocapsule is associated with the MR imaging parameters tumor size, extent of edema, or multiplicity of metastases.
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http://dx.doi.org/10.1007/s00701-019-03842-3DOI Listing
May 2019

PI3K: A master regulator of brain metastasis-promoting macrophages/microglia.

Glia 2018 11 25;66(11):2438-2455. Epub 2018 Oct 25.

Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.

Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis-promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan-PI3K Class I inhibitor with a good blood-brain-barrier penetrance, reduced their metastasis-promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
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http://dx.doi.org/10.1002/glia.23485DOI Listing
November 2018

FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis.

Oncotarget 2018 Aug 14;9(63):32204-32218. Epub 2018 Aug 14.

Institute of Pathology, University Hospital Göttingen, Göttingen, Germany.

Objectives: Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established.

Methods: We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors () and their ligands ( and ) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression . Results were correlated with clinico-pathologic data and molecular subtypes.

Results: Primary tumors showed (6.3%) and (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111).

Conclusions: We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.
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http://dx.doi.org/10.18632/oncotarget.25941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114946PMC
August 2018

Using RNA-Seq Data for the Detection of a Panel of Clinically Relevant Mutations.

Stud Health Technol Inform 2018 ;253:217-221

Department of Medical Statistics, University Medical Center Göttingen.

Somatic single nucleotide variants (SNVs) are genomic events with increasing implications in cancer treatment. The clinical standard for SNVs detection is whole genome/exome sequencing (WGS/WES) in matched tumor-normal samples. Yet, this is a very costly approach both economically and biologically and very often only tumor samples are sequenced. On the other hand, RNA sequencing (RNA-Seq) is the most popular technology to study gene expression, and has also the potential for a cost-effective identification of SNVs as an alternative to tumor-only WES. Here we present a method for the identification of SNVs in tumor-only RNA-Seq data putting a special focus on a small panel of clinically relevant SNVs. For evaluation purposeswe analyzed matched tumor-normal WEStumor-only RNA-Seq data from 14 cancer patients. We compared SNVs detected in i) RNA-Seq by our method, ii) WES tumor-only by Mutect2 and iii) WES matched tumor-normal by Mutect2. We did a detailed evaluation for a reduced panel of clinically relevant SNVs and reliably identified in RNA-Seq data a subset of mutations for which we had pathological annotation. Hence, RNA-Seq rises as a cost-effective option to detect in parallel gene expression as well as a small panel of clinically relevant SNVs in research.
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November 2018

Interhospital transport of ARDS patients on extracorporeal membrane oxygenation.

J Artif Organs 2019 Mar 18;22(1):53-60. Epub 2018 Aug 18.

Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Management, University Medical Center Göttingen, Göttingen, Germany.

Veno-venous extracorporeal membrane oxygenation (ECMO) can be a lifesaving therapy for patients with severe acute respiratory distress syndrome (ARDS). ECMO is a technically complex and challenging procedure and should therefore only be performed in specialized centers. Transporting ARDS patients to ECMO centers for treatment can be dangerous because of the risk of hypoxemia during transport. This raises the question if ECMO should not be already initiated in the transferring hospital before transport. Over a 5-year period, we studied ARDS patients who had been transported to our department by our mobile ECMO team for further treatment after ECMO had already been initiated at the referring hospital. Data for analysis were obtained from our patient data management system (PDMS), the referral documents, and from the referring hospitals. Seventy-five patients meeting the selection criteria were studied. All had been successfully cannulated in the transferring hospitals. They were transported to our ECMO center by helicopter (n = 34) or mobile intensive care units (n = 41). No patient died during transport. Forty four of the patients were transported at night. Twenty-six patients (35%) died in our intensive care unit due to a therapy refractory course, comorbidities or limitation of therapy. Patients on ECMO therapy can be safely transferred to a specialist center. Setting up ECMO in an unfamiliar location and the subsequent patient transport can be very challenging and should only be performed by a highly trained, experienced team.
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http://dx.doi.org/10.1007/s10047-018-1065-yDOI Listing
March 2019

High-frequency oscillatory ventilation guided by transpulmonary pressure in acute respiratory syndrome: an experimental study in pigs.

Crit Care 2018 May 9;22(1):121. Epub 2018 May 9.

Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Management, University Medical Center Göttingen, Göttingen, Germany.

Background: Recent clinical studies have not shown an overall benefit of high-frequency oscillatory ventilation (HFOV), possibly due to injurious or non-individualized HFOV settings. We compared conventional HFOV (HFOV) settings with HFOV settings based on mean transpulmonary pressures (P) in an animal model of experimental acute respiratory distress syndrome (ARDS).

Methods: ARDS was induced in eight pigs by intrabronchial installation of hydrochloric acid (0.1 N, pH 1.1; 2.5 ml/kg body weight). The animals were initially ventilated in volume-controlled mode with low tidal volumes (6 ml kg) at three positive end-expiratory pressure (PEEP) levels (5, 10, 20 cmHO) followed by HFOV and then HFOV P each at PEEP 10 and 20. The continuous distending pressure (CDP) during HFOV was set at mean airway pressure plus 5 cmHO. For HFOV P it was set at mean P plus 5 cmHO. Baseline measurements were obtained before and after induction of ARDS under volume controlled ventilation with PEEP 5. The same measurements and computer tomography of the thorax were then performed under all ventilatory regimens at PEEP 10 and 20.

Results: Cardiac output, stroke volume, mean arterial pressure and intrathoracic blood volume index were significantly higher during HFOV P than during HFOV at PEEP 20. Lung density, total lung volume, and normally and poorly aerated lung areas were significantly greater during HFOV, while there was less over-aerated lung tissue in HFOV P. The groups did not differ in oxygenation or extravascular lung water index.

Conclusion: HFOV P is associated with less hemodynamic compromise and less pulmonary overdistension than HFOV. Despite the increase in non-ventilated lung areas, oxygenation improved with both regimens. An individualized approach with HFOV settings based on transpulmonary pressure could be a useful ventilatory strategy in patients with ARDS. Providing alveolar stabilization with HFOV while avoiding harmful distending pressures and pulmonary overdistension might be a key in the context of ventilator-induced lung injury.
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http://dx.doi.org/10.1186/s13054-018-2028-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943989PMC
May 2018

Isolated metastasis of an EGFR-L858R-mutated NSCLC of the meninges: the potential impact of CXCL12/CXCR4 axis in EGFR NSCLC in diagnosis, follow-up and treatment.

Oncotarget 2018 Apr 10;9(27):18844-18857. Epub 2018 Apr 10.

Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.

Brain and leptomeningeal metastasis (LMM) of non-small cell lung cancer is still associated with poor prognosis. Moreover, the current diagnostic standard for LMM often yields false negative results and the scientific progress in this field is still unsatisfying. We present a case of a 71-year old patient with an isolated LMM. While standard diagnostics could only diagnose a cancer of unknown primary, the use of [Ga]-Pentixafor-PET/CT (CXCR4-PET/CT, a radiotracer targeting CXCR4) and a liquid biopsy of the cerebrospinal fluid revealed the primary NSCLC. The detection of L858R-EGFR, a common driver mutation in NSCLC, enabled us to treat the patient with Afatinib and monitor treatment using [Ga]-Pentixafor PET/CT. To estimate the impact of CXCR4 signaling and its ligands in NSCLC brain metastasis we looked at their expression and correlation with EGFR mutations in a primary and brain metastasis data set and investigated the previously described binding of extracellular ubiquitin to CXCR4. In conclusion, we describe a novel approach to improve diagnostics towards LMM and underline the impact of the CXCL12/CXCR4 axis in brain metastasis in a subset of NSCLC patients. We cannot confirm a correlation of CXCR4 expression with EGFR mutations or the binding of extracellular ubiquitin as previously reported.
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http://dx.doi.org/10.18632/oncotarget.24787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922360PMC
April 2018

From somatic variants towards precision oncology: Evidence-driven reporting of treatment options in molecular tumor boards.

Genome Med 2018 03 15;10(1):18. Epub 2018 Mar 15.

Department of Medical Statistics, University Medical Center Göttingen, 37073, Göttingen, Germany.

Background: A comprehensive understanding of cancer has been furthered with technological improvements and decreasing costs of next-generation sequencing (NGS). However, the complexity of interpreting genomic data is hindering the implementation of high-throughput technologies in the clinical context: increasing evidence on gene-drug interactions complicates the task of assigning clinical significance to genomic variants.

Methods: Here we present a method that automatically matches patient-specific genomic alterations to treatment options. The method relies entirely on public knowledge of somatic variants with predictive evidence on drug response. The output report is aimed at supporting clinicians in the task of finding the clinical meaning of genomic variants. We applied the method to 1) The Cancer Genome Atlas (TCGA) and Genomics Evidence Neoplasia Information Exchange (GENIE) cohorts and 2) 11 patients from the NCT MASTER trial whose treatment discussions included information on their genomic profiles.

Results: Our reporting strategy showed a substantial number of patients with actionable variants in the analyses of TCGA and GENIE samples. Notably, it was able to reproduce experts' treatment suggestions in a retrospective study of 11 patients from the NCT MASTER trial. Our results establish a proof of concept for comprehensive, evidence-based reports as a supporting tool for discussing treatment options in tumor boards.

Conclusions: We believe that a standardized method to report actionable somatic variants will smooth the incorporation of NGS in the clinical context. We anticipate that tools like the one we present here will become essential in summarizing for clinicians the growing evidence in the field of precision medicine. The R code of the presented method is provided in Additional file 6 and available at https://github.com/jperera-bel/MTB-Report .
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http://dx.doi.org/10.1186/s13073-018-0529-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856211PMC
March 2018

Characterisation of tumour-derived microvesicles in cancer patients' blood and correlation with clinical outcome.

J Extracell Vesicles 2017 16;6(1):1340745. Epub 2017 Jul 16.

Department of Haematology/Medical Oncology, University Medical Centre Göttingen, Göttingen, Germany.

To evaluate whether tumour-derived microvesicles (T-MV), originating from the plasma membrane, represent suitable cancer biomarkers, we isolated MV from peripheral blood samples of cancer patients with locally advanced and/or metastatic solid tumours ( = 330, including 79 head & neck cancers, 74 lung cancers, 41 breast cancers, 28 colorectal cancers and 108 with other cancer forms) and controls ( = 103). Whole MV preparations were characterised using flow cytometry. While MV carrying the tumour-associated proteins MUC1, EGFR and EpCAM were found to be enhanced in a tumour-subtype-specific way in patients' blood, expression of the matrix metalloproteinase inducer EMMPRIN was increased independent of tumour type. Higher levels of EMMPRIN-MV correlated significantly with poor overall survival, whereas the other markers were prognostic only in specific tumour subgroups. By combining all four tumour-associated antigens, cancer patients were separated from healthy controls with an AUC of up to 0.85. , whole MV preparations from cancer patients, in contrast to those of controls, induced a tumour-supporting phenotype in macrophages and increased tumour cell invasion, which was dependent on the highly glycosylated isoform of EMMPRIN. In conclusion, the detection of T-MV in whole blood, even in minor amounts, is feasible with standard techniques, proves functionally relevant and correlates with clinical outcome.
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http://dx.doi.org/10.1080/20013078.2017.1340745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533131PMC
July 2017

Ror2 Signaling and Its Relevance in Breast Cancer Progression.

Front Oncol 2017 26;7:135. Epub 2017 Jun 26.

Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.

Breast cancer is a heterogeneous disease and has been classified into five molecular subtypes based on gene expression profiles. Signaling processes linked to different breast cancer molecular subtypes and different clinical outcomes are still poorly understood. Aberrant regulation of Wnt signaling has been implicated in breast cancer progression. In particular Ror1/2 receptors and several other members of the non-canonical Wnt signaling pathway were associated with aggressive breast cancer behavior. However, Wnt signals are mediated multiple complex pathways, and it is clinically important to determine which particular Wnt cascades, including their domains and targets, are deregulated in poor prognosis breast cancer. To investigate activation and outcome of the Ror2-dependent non-canonical Wnt signaling pathway, we overexpressed the Ror2 receptor in MCF-7 and MDA-MB231 breast cancer cells, stimulated the cells with its ligand Wnt5a, and we knocked-down Ror1 in MDA-MB231 cells. We measured the invasive capacity of perturbed cells to assess phenotypic changes, and mRNA was profiled to quantify gene expression changes. Differentially expressed genes were integrated into a literature-based non-canonical Wnt signaling network. The results were further used in the analysis of an independent dataset of breast cancer patients with metastasis-free survival annotation. Overexpression of the Ror2 receptor, stimulation with Wnt5a, as well as the combination of both perturbations enhanced invasiveness of MCF-7 cells. The expression-responsive targets of Ror2 overexpression in MCF-7 induced a Ror2/Wnt module of the non-canonical Wnt signaling pathway. These targets alter regulation of other pathways involved in cell remodeling processing and cell metabolism. Furthermore, the genes of the Ror2/Wnt module were assessed as a gene signature in patient gene expression data and showed an association with clinical outcome. In summary, results of this study indicate a role of a newly defined Ror2/Wnt module in breast cancer progression and present a link between Ror2 expression and increased cell invasiveness.
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http://dx.doi.org/10.3389/fonc.2017.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483589PMC
June 2017

The adaptation of colorectal cancer cells when forming metastases in the liver: expression of associated genes and pathways in a mouse model.

BMC Cancer 2017 05 19;17(1):342. Epub 2017 May 19.

Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg - August - University Goettingen, Göttingen, Germany.

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in men and women. Systemic disease with metastatic spread to distant sites such as the liver reduces the survival rate considerably. The aim of this study was to investigate the changes in gene expression that occur on invasion and expansion of CRC cells when forming metastases in the liver.

Methods: The livers of syngeneic C57BL/6NCrl mice were inoculated with 1 million CRC cells (CMT-93) via the portal vein, leading to the stable formation of metastases within 4 weeks. RNA sequencing performed on the Illumina platform was employed to evaluate the expression profiles of more than 14,000 genes, utilizing the RNA of the cell line cells and liver metastases as well as from corresponding tumour-free liver.

Results: A total of 3329 differentially expressed genes (DEGs) were identified when cultured CMT-93 cells propagated as metastases in the liver. Hierarchical clustering on heat maps demonstrated the clear changes in gene expression of CMT-93 cells on propagation in the liver. Gene ontology analysis determined inflammation, angiogenesis, and signal transduction as the top three relevant biological processes involved. Using a selection list, matrix metallopeptidases 2, 7, and 9, wnt inhibitory factor, and chemokine receptor 4 were the top five significantly dysregulated genes.

Conclusion: Bioinformatics assists in elucidating the factors and processes involved in CRC liver metastasis. Our results support the notion of an invasion-metastasis cascade involving CRC cells forming metastases on successful invasion and expansion within the liver. Furthermore, we identified a gene expression signature correlating strongly with invasiveness and migration. Our findings may guide future research on novel therapeutic targets in the treatment of CRC liver metastasis.
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http://dx.doi.org/10.1186/s12885-017-3342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437520PMC
May 2017

Long-term outcomes after TAVI in patients with different types of aortic stenosis: the conundrum of low flow, low gradient and low ejection fraction.

EuroIntervention 2017 Jun;13(3):286-293

Department of Cardiology, University Medical Center Goettingen, Goettingen, Germany.

Aims: The objective of this study was to examine the impact of guideline-defined subtypes of severe aortic stenosis (AS) on long-term outcomes after TAVI.

Methods And Results: Four hundred (400) consecutive patients who underwent TAVI (203 transapical, 197 transfemoral) at our institution 8/2008-3/2013 were followed systematically (for up to seven years). One hundred and forty-seven (147) individuals suffered from NEF-HG AS (LV-EF ≥50%, high Pmean ≥40 mmHg), 63 from LEF-HG AS (LV-EF <50%, high gradient), 77 from PLF-LG AS (LV-EF ≥50%, low gradient, stroke volume index [SVI] <35 ml/m²), and 81 from LEF-LG AS (LV-EF <50%, low gradient). LEF-LG status was associated with the highest all-cause and cardiovascular mortality and MACCE rate, whereas NEF-HG patients exhibited the best outcome (i.e., median survival 5.1 years in NEF-HG vs. 1.3 years in LEF-LG, p=0.0006; or vs. 3.3 years in PLF-LG, p=0.02). In multivariate analysis, LEF-LG status emerged as the outcome predictor with the highest hazard ratio for all-cause mortality (HR 2.86, p=0.003), cardiovascular mortality (HR 6.53, p<0.0001), and MACCE (HR 2.44, p=0.007), whereas neither baseline EF nor SVI <35 ml/m² independently predicted these endpoints.

Conclusions: These findings suggest that an assessment of LV-EF alone for outcome prediction after TAVI is inadequate; it is the guideline-defined subtype of AS that determines outcome.
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http://dx.doi.org/10.4244/EIJ-D-16-00801DOI Listing
June 2017

Diagnostic red flags: steroid-treated malignant CNS lymphoma mimicking autoimmune inflammatory demyelination.

Brain Pathol 2018 03 6;28(2):225-233. Epub 2017 Apr 6.

Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.

The presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid-treated PCNSL (ST-PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST-PCNSL patients were older than MS patients (mean age: ST-PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST-PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow-up of the patient to detect recurrent lymphoma.
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http://dx.doi.org/10.1111/bpa.12496DOI Listing
March 2018

Isolation and Characterization of Microvesicles from Peripheral Blood.

J Vis Exp 2017 01 6(119). Epub 2017 Jan 6.

Department of Hematology/Medical Oncology, University Medical Center Göttingen.

The release of extracellular vesicles (EVs) including small endosomal-derived exosomes (Exos, diameter < 100 nm) and large plasma membrane-derived microvesicles (MVs, diameter > 100 nm) is a fundamental cellular process that occurs in all living cells. These vesicles transport proteins, lipids and nucleic acids specific for their cell of origin and in vitro studies have highlighted their importance as mediators of intercellular communication. EVs have been successfully isolated from various body fluids and especially EVs in blood have been identified as promising biomarkers for cancer or infectious diseases. In order to allow the study of MV subpopulations in blood, we present a protocol for the standardized isolation and characterization of MVs from peripheral blood samples. MVs are pelleted from EDTA-anticoagulated plasma samples by differential centrifugation and typically possess a diameter of 100 - 600 nm. Due to their larger size, they can easily be studied by flow cytometry, a technique that is routinely used in clinical diagnostics and available in most laboratories. Several examples for quality control assays of the isolated MVs will be given and markers that can be used for the discrimination of different MV subpopulations in blood will be presented.
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http://dx.doi.org/10.3791/55057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408706PMC
January 2017