Effects of a high-caloric diet and physical exercise on brain metabolite levels: a combined proton MRS and histologic study - Auer, Matthias K.; Sack, Markus; Lenz, Jenny N.; Jakovcevski, Mira; Biedermann, Sarah V.; Falfan-Melgoza, Claudia; Deussing, Jan; Steinle, Joerg; Bielohuby, Maximilian; Bidlingmaier, Martin; Pfister, Frederik; Stalla, Guenter K.; et al. (Journal of Cerebral Blood Flow and Metabolism, 2015)
Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS). It has been suggested that one mechanism in this context is the promotion of neuroinflammation. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating the effects of physical exercise in a cafeteria-diet mouse model on CNS metabolites by means of in vivo proton magnetic resonance spectroscopy ((1)HMRS). In addition postmortem histologic and real-time (RT)-PCR analyses for inflammatory markers were performed. Cafeteria diet induced obesity and hyperglycemia, which was only partially moderated by exercise. It also induced several changes in CNS metabolites such as reduced hippocampal glutamate (Glu), choline-containing compounds (tCho) and N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamic acid (NAAG) (tNAA) levels, whereas opposite effects were seen for running. No association of these effects with markers of central inflammation could be observed. These findings suggest that while voluntary wheel running alone is insufficient to prevent the unfavorable peripheral sequelae of the diet, it counteracted many changes in brain metabolites. The observed effects seem to be independent of neuroinflammation.
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Effects of glucose concentration in the tumor microenvironment on Non Small Lung Cancer (NSCLC) Progression - Gähler, Alexander; Hohenberger, Katja; Tausche, Patrick; Chiriac, Mircea-Teodor; Rauh, Manfred; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Neurath-Finotto, Susetta (JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

EFFECTS OF NEUROGENIC CGRP ON RENAL AFFERENT PEPTIDERGIC NEURONS - Veelken, Roland; Raschke, Giulia; Ditting, Tilmann; Ott, Christian; Schmieder, Roland; Amann, Kerstin Ute; Rodionova, Kristina (2018)
EVALuna2:204843

Effects of the Non-Neutralizing Humanized Monoclonal Anti-Adrenomedullin Antibody Adrecizumab on Hemodynamic and Renal Injury in a Porcine Two-Hit Model - Thiele, Christoph; Simon, Tim Philipp; Szymanski, Jeanine; Daniel, Christoph; Golias, Christos; Hartmann, Oliver; Struck, Joachim; Martin, Lukas; Marx, Gernot; Schuerholz, Tobias (Shock, 2020)
Adrenomedullin is a vasoactive peptide that improves endothelial barrier function in sepsis, but may also cause hypotension and organ failure. Treatment with a non-neutralizing monoclonal anti-adrenomedullin antibody showed improvement in murine sepsis models. We tested the effects of the humanized monoclonal anti-adrenomedullin antibody Adrecizumab in a porcine two hit model of hemorrhagic and septic shock.In this randomized, blinded study 12 German Landrace pigs were bled to half of baseline mean arterial pressure for 45 minutes. Sepsis was induced using an E.coli clot placed into the abdominal cavity 6 hours after hemorrhagic shock. Animals received either 2 mg/kg BW anti-adrenomedullin antibody or vehicle solution immediately after sepsis induction. After 4 hours, resuscitation was initiated using balanced crystalloids and noradrenalin to maintain a CVP of 8-12 mmHg, a MAP ≥ 65mmHg and a ScvO2 ≥70% for another 8 hours. Hemodynamic parameters, laboratory parameters and kidney histology were assessed.The amount of volume resuscitation was significantly lower and significantly less animals developed a septic shock in the antibody-treated group, compared to the vehicle group. Kidney histology showed significantly lower granulocytes in both cortex and medulla in antibody-treated animals, while the remaining four kidney measures (serum creatinine and urine output and cortical and medullary injury in histopathology) did not reach the significance levels. After induction of sepsis, plasma adrenomedullin increased immediately in both groups, but increased quicker and more pronounced in the antibody group.In this two hit shock model, treatment with an anti-adrenomedullin antibody significantly increased plasma adrenomedullin levels, while significantly less animals developed septic shock and renal granulocyte extravasation was significantly reduced. Thus, therapy with Adrecizumab may provide benefit in sepsis, and clinical investigation of this drug candidate is warranted.
CRIS-Team Scopus Importer:2020-06-30

Efficacy of anti-PD(L)1 treatment in patients with metastatic urothelial cancer based on mRNA- and protein- based PD-L1 determination: Results from the multicentric, retrospective FOsMIC trial - Jarczyk, J.; Wirtz, R.; Roghmann, F.; Juette, H.; Kriegmair, M. C.; Worst, T. S.; Sikic, D.; Wach, S.; Taubert, Helge; Wullich, Bernd; Weyerer, Veronika; Stöhr, Robert; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Efficacy of neoadjuvant pertuzumab in addition to chemotherapy and trastuzumab in routine clinical treatment of patients with primary breast cancer: a multicentric analysis - Fasching, Peter; Hartkopf, Andreas D.; Gaß, Paul; Häberle, Lothar; Akpolat-Basci, Leyla; Hein, Alexander; Volz, Bernhard; Taran, Florin-Andrei; Nabieva, Naiba; Pott, Birgit; Overkamp, Friedrich; Einarson, Hanna; et al. (Breast Cancer Research and Treatment, 2019)
PurposeNeoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials.MethodsIn a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors.ResultspCR with complete disappearance of all tumor cells was seen in 30.2% (n=58) of patients treated with CTX/TZM and in 52.8% (n=57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49-4.02). Mastectomy rates were not influenced by the therapy.ConclusionsThe results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.
CRIS-Team WoS Importer:2019-03-15

EGFR Mutation Testing Using Liquid Biopsy Technology for Patients with Advanced EGFR-Mutant NSCLC - Seitz, Jan; Moskalev, Evgeny; Fuchs, Florian; Haller, Florian; Hartmann, Arndt (2018)
EVALuna2:34073

Eine übermäßige Phagozytose von Myelomzellen induziert Pyroptose in Myelom-assoziierten Makrophagen und beeinträchtigt die Wirksamkeit therapeutischer Antikörper - Flamann, Cindy; Biedermann, Alexander; Mougiakakos, D.; Bitterer, Katrin; Karg, K.; Bittenbring, J.; Büttner-Herold, Maike; Liebisch, G.; Leffler, M.; Lischer, Christopher; Eberhardt, Martin; Vera-Gonzales, J.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Einfluss des Klimawandels auf Infektionskrankheiten in der Nephrologie - Kraft, Leonie; Schmidt-Chanasit, Jonas; Paul, Gregor; Amann, Kerstin Ute; Latus, Jörg (Die Nephrologie, 2023)
Climate change is one of the most important challenges of our time. While at first sight the danger seems to emanate from extreme weather situations and natural disasters, the risk of a possible increase or change in the pathogen spectrum of infectious diseases should not be ignored. We do not yet know much about the spread of infectious diseases due to global warming. Most scenarios are derived from statistical climate models and what the future will look like is difficult to estimate. In addition, the lack of epidemiological data and different mandatory reporting of infectious diseases make the risk assessment more difficult. Furthermore, the spread of infectious diseases is not only dependent on higher temperatures. Changes in the use of agricultural land, socioeconomic factors with population growth and migration, access to clean drinking water, and innovations in the healthcare and reporting systems will continue to change the pattern of infectious diseases. Infectious diseases will affect the nephrology community in different ways in the coming years and decades. Some, such as hantavirus infections, are obvious as acute kidney injury is characteristic for this disease. Others have an indirect effect, through septic or prerenal kidney injury or because most of the patients belong to vulnerable groups and are particularly in need of protection. In the case of febrile illnesses, many of the diseases mentioned should be considered as differential diagnoses in the future, even without a suitable travel history.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Arbovirus infections; Global warming; Kidney injury; Metazoonoses; Vector-borne pathogens

Einführung in die Nierenpathologie - Büttner-Herold, Maike; Amann, Kerstin Ute (Die Pathologie, 2024)
In recent decades, nephropathology has developed worldwide as a subspeciality of pathology, which requires special methodological and technical equipment to process the material and specific clinical and pathological expertise to interpret the findings. These special requirements mean that nephropathology is not available at all pathology institutes, but is carried out on a large scale in a few highly specialised centres. The history of nephropathology, or in a narrower sense the specialised histopathological examination of kidney biopsies, began in 1958 with the first use or performance of a kidney biopsy [1]. It thus replaced the practice of urinalysis, which had been common since the Middle Ages, as a diagnostic tool for kidney diseases. Specialised techniques such as immunofluorescence or immunohistology but also electron microscopy are required to assess specific renal changes, for which the examination of renal biopsies is one of the few remaining routine applications today. In Germany and German-speaking countries, the discipline developed thanks to the work of outstanding people in the field of pathology who were primarily involved in this discipline and had the necessary technical and human resources in their laboratories to ensure that these biopsies could be analysed.
CRIS-Team Scopus Importer:2024-03-29
Keywords: Electron microscopy; Immunohistology; Light microscopy; Renal biopsy; Renal specimens

Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis - Sun, Qinxue; Baues, Maike; Klinkhammer, Barbara M.; Ehling, Josef; Djudjaj, Sonja; Drude, Natascha; Daniel, Christoph; Amann, Kerstin Ute; Kramann, Rafael; Kim, Hyojin; Saez-Rodriguez, Julio; Weiskirchen, Ralf; et al. (Science Translational Medicine, 2019)
Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.
CRIS-Team WoS Importer:2019-04-16

Electrically Conductive Collagen-PEDOT:PSS Hydrogel Prevents Post-Infarct Cardiac Arrhythmia and Supports hiPSC-Cardiomyocyte Function - Roshanbinfar, Kaveh; Schiffer, Miriam; Carls, Esther; Angeloni, Miriam; Kolesnik-Gray, Maria; Schrüfer, Stefan; Schubert, Dirk W.; Ferrazzi, Fulvia; Krstic, Vojislav; Fleischmann, Bernd K.; Roell, Wilhelm; Engel, Felix (Advanced Materials, 2024)
Myocardial infarction (MI) causes cell death, disrupts electrical activity, triggers arrhythmia, and results in heart failure, whereby 50–60% of MI-associated deaths manifest as sudden cardiac deaths (SCD). The most effective therapy for SCD prevention is implantable cardioverter defibrillators (ICDs). However, ICDs contribute to adverse remodeling and disease progression and do not prevent arrhythmia. This work develops an injectable collagen-PEDOT:PSS (poly(3,4-ethylenedioxythiophene) polystyrene sulfonate) hydrogel that protects infarcted hearts against ventricular tachycardia (VT) and can be combined with human induced pluripotent stem cell (hiPSC)-cardiomyocytes to promote partial cardiac remuscularization. PEDOT:PSS improves collagen gel formation, micromorphology, and conductivity. hiPSC-cardiomyocytes in collagen-PEDOT:PSS hydrogels exhibit near-adult sarcomeric length, improved contractility, enhanced calcium handling, and conduction velocity. RNA-sequencing data indicate enhanced maturation and improved cell-matrix interactions. Injecting collagen-PEDOT:PSS hydrogels in infarcted mouse hearts decreases VT to the levels of healthy hearts. Collectively, collagen-PEDOT:PSS hydrogels offer a versatile platform for treating cardiac injuries.
CRIS-Team Scopus Importer:2024-05-10
Keywords: arrhythmia; cardiac tissue engineering; collagen; electrically conductive; PEDOT:PSS

Electroconductive Biohybrid Hydrogel for Enhanced Maturation and Beating Properties of Engineered Cardiac Tissues - Roshanbinfar, Kaveh; Vogt, Lena; Greber, Boris; Diecke, Sebastian; Boccaccini, Aldo R.; Scheibel, Thomas; Engel, Felix (Advanced Functional Materials, 2018)
Keywords: electroconductive hydrogels; maturation; tissue engineering; heart; hiPSC

Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) in Penile Squamous Cell Carcinoma-No Evidence for a Role in Carcinogenesis. - Fiegl, August; Wendler, Olaf; Giedl, Josef; Gaisa, Nadine T.; Richter, Georg; Campean, Valentina; Burger, Maximilian; Simmer, Femke; Nagtegaal, Iris; Wullich, Bernd; Bertz, Simone; Hartmann, Arndt; et al. (Current Oncology, 2024)
Penile squamous cell carcinoma (pSCC) is a rare malignancy with a global incidence ranging from 0.1 to 0.7 per 100,000 males. Prognosis is generally favorable for localized tumors, but metastatic pSCC remains challenging, with low survival rates. The role of novel biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI), in predicting the response to immune checkpoint inhibitors (ICIs) has been investigated in various cancers. However, MSI has not been observed in pSCC, limiting immunotherapy options for this patient subgroup. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are a distinct form of genomic instability associated with deficient MSH3 expression, which has been proposed as a potential biomarker in several cancers. This study investigates EMAST and MSH3 expression in a cohort of 78 pSCC cases using PCR, fragment analysis and immunohistochemistry. For the detection of EMAST, the stability of five microsatellite markers (D9S242, D20S82, MYCL1, D8S321 and D20S85) was analyzed. None of the cases showed an instability. As for MSH3 immunohistochemistry, all analyzable cases showed retained MSH3 expression. These results strongly suggest that neither EMAST nor MSH3 deficiency is involved in the carcinogenesis of pSCC and do not represent reliable predictive biomarkers in this entity. Furthermore, these findings are in full agreement with our previous study showing a very low frequency of MSI and further support the thesis that EMAST and MSI are strongly interconnected forms of genomic instability. Further research is needed to explore novel therapeutic targets and predictive biomarkers for immunotherapy in this patient population.
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Elevated n-3/n-6 PUFA ratio in early life diet reverses adverse intrauterine kidney programming in female rats - Voggel, Jenny; Fink, Gregor; Zelck, Magdalena; Wohlfarth, Maria; Post, Julia M.; Bindila, Laura; Rauh, Manfred; Amann, Kerstin Ute; Alcazar, Miguel A. Alejandre; Doetsch, Joerg; Nuesken, Kai-Dietrich; Nuesken, Eva (Journal of Lipid Research, 2022)
Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female rats, we investigated 1) how an elevated di-etary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular pro-tein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intra-uterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncom-promised pregnancy. On postnatal (P) days P2-P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and pro-teomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydrox-yeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus miti-gating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proin-flammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.
CRIS-Team WoS Importer:2022-12-02

Emerging Entities and New Diagnostic Markers for Head and Neck Soft Tissue and Bone Tumors - Franchi, Alessandro; Thompson, Lester D.R.; Hernandez-Prera, Juan C.; Agaimy, Abbas; Williams, Michelle D.; Mikkelsen, Lauge H.; Bishop, Justin A.; Willems, Stefan M.; Hellquist, Henrik; Ferlito, Alfio (Advances in Anatomic Pathology, 2021)
Bone and soft tissue tumors of the head and neck are relatively uncommon tumors that often represent a diagnostic challenge because of the wide range of entities that must be considered in the differential diagnosis. Over the past few years, classification of bone and soft tissue tumors has evolved primarily because of substantial contributions from molecular genetics, with the identification of new markers that are increasingly used to complement histopathologic findings in the routine diagnostic workup. This review focuses on the recently described mesenchymal tumors that preferentially involve the head and neck region, with a focus on the most relevant novel immunohistochemical and molecular findings, including gene fusions and mutations, that can help in the diagnosis and in the assessment of clinical behavior.
CRIS-Team Scopus Importer:2021-04-19

EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells - Lindner, Pablo; Paul, Sushmita; Eckstein, Markus; Hampel, Chuanpit; Muenzner, Julienne K.; Erlenbach-Wuensch, Katharina; Ahmed, Husayn P.; Mahadevan, Vijayalakshmi; Brabletz, Thomas; Hartmann, Arndt; Vera, Julio; Schneider-Stock, Regine (Cell Death & Disease, 2020)
Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial–mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.
CRIS-Team Scopus Importer:2020-03-20

En-bloc resection of bladder tumours (ERBT): current and future perspectives - Struck, J. P.; Kramer, M. W.; Merseburger, A. S.; Hartmann, Arndt; Herrmann, T. R. W. (Aktuelle Urologie, 2017)
Limitations inherent in the conventional transurethral resection of bladder tumours, the standard approach for diagnosis and treatment of bladder cancer, are well known: staging errors due to insufficient resection depth as well as intravesical tumour fragmentation, both of which make histopathological evaluation difficult. The purpose of this review is to present recent clinical data on the en-bloc resection of bladder tumours (ERBT), which has been demonstrated to offer a high potential to overcome these limitations. The recent findings show that ERBT provides a good resection quality with varying detection rates for tunica muscularis, which is a surrogate marker for resection quality regarding muscle-invasive tumours. ERBT can be performed using all energy sources. Available data show no relevant difference with regard to perioperative morbidity compared with cTURB. No conclusions can be drawn regarding the impact of ERBT on recurrence as the data are partly controversial. This has to be defined by further studies.
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Endocytoscopy for assessing histologic inflammation in ulcerative colitis: development and prospective validation of the ELECT (ErLangen Endocytoscopy in ColiTis) score (with videos) - Vitali, Francesco; Morgenstern, Nadine; Eckstein, Markus; Atreya, Raja; Waldner, Maximilian; Hartmann, Arndt; Neurath, Markus; Rath, Timo (Gastrointestinal Endoscopy, 2022)
Background and Aims: Apart from endoscopic healing as an established treatment goal in patients with inflammatory bowel disease (IBD), histologic remission is an emerging endpoint that might even better predict disease outcome, especially in ulcerative colitis (UC). Within this study, we aimed to evaluate whether endocytoscopy (EC) as an in vivo contact microscopy technology can accurately assess histologic inflammation and predict the further course of disease in UC patients. Methods: Initially, a new and intuitive EC score reflecting the entire spectrum of microscopic disease activity in UC was consensually developed. Subsequently, this score was independently validated in 46 patients with UC who underwent close-meshed follow-up during which major adverse outcomes (MAOs; defined as disease flare, IBD-related hospitalization, IBD-related surgery, necessity for initiation or escalation therapy) were recorded. Results of EC grading of inflammatory activity were compared against 2 validated histologic scores in UC. Diagnostic performance of endoscopic remission under white-light endoscopy (Mayo Endoscopic Score and Ulcerative Colitis Endoscopic Index of Severity), EC, and histology were compared for the prediction of MAOs. Results: Endocytoscopic assessment of inflammatory activity in UC based on the newly developed ErLangen Endocytoscopy in ColiTis score showed strong correlation with histopathologic scoring (Robarts Histopathology Index, r = .70; Nancy Histologic Index, r = .73) and was superior to white-light endoscopy for grading of microscopic disease activity, with a sensitivity of 88%, specificity of 95.2%, and area under the curve of .916. Furthermore, EC exhibited a high interobserver agreement for in vivo grading of microscopic inflammation and was comparably accurate as histopathology for forecasting the occurrence of MAOs in UC. Conclusions: Endocytoscopic grading of inflammatory activity along a newly developed scoring system enabled real-time histology in UC patients and better predicted clinical outcome in UC patients than endoscopic remission.
CRIS-Team Scopus Importer:2022-12-16

Endogenous Retroviral-K Envelope Is a Novel Tumor Antigen and Prognostic Indicator of Renal Cell Carcinoma - Weyerer, Veronika; Strissel, Pamela; Stohr, Christine; Eckstein, Markus; Wach, Sven; Taubert, Helge; Brandl, Lisa; Geppert, Carol-Immanuel; Wullich, Bernd; Cynis, Holger; Beckmann, Matthias; Seliger, Barbara; et al. (Frontiers in Oncology, 2021)
Renal cell carcinoma (RCC) is one of the ten most common cancers for men and women with an approximate 75% overall 5-year survival. Sixteen histological tumor subtypes exist and the most common are papillary, chromophobe and clear cell renal cell carcinoma (ccRCC) representing 85% of all RCC. Although epigenetically silenced, endogenous retroviral (ERV) genes become activated in tumors and function to ignite immune responses. Research has intensified to understand ERV protein function and their role as tumor antigens and targets for cancer (immune) therapy. ERV-K env is overexpressed and implicated as a therapeutic target for breast cancer, however studies in RCC are limited. In this investigation a human RCC tissue microarray (TMA) (n=374) predominantly consisting of the most common histological tumor subtypes was hybridized with an ERV-K env antibody and correlated with patient clinical data. TMA results showed the highest amount of ERV-K env protein expression and the strongest significant membrane expression in ccRCC versus other RCC subtypes. High ERV-K env total protein expression of all tumor subtypes significantly correlated with low tumor grading and a longer disease specific survival using multivariable analyses. Cell proliferation and invasion were assayed using the kidney cell lines HEK293 with wild-type p53 and a ccRCC cell line MZ1257RC mutated for p53. Transfecting these cell lines with a codon optimized ERV-K113 env overexpressing CMV vector was performed with or without 5'-Aza-2'-deoxycytidine (Aza) treatment to sustain promoter de-methylation. MZ1257RC showed induction of ERV-K113 expression and significantly increased both proliferation and invasion in the presence or absence of Aza. HEK293 cells demonstrated a restriction of ERV-K113 env expression and invasion with no changes in proliferation in the absence of Aza. However, in the presence of Aza despite increased ERV-K113 env expression, an inhibition of HEK293 proliferation and a further restriction of invasion was found. This study supports ERV-K env as a single prognostic indicator for better survival of RCC, which we propose represents a new tumor antigen. In addition, ERV-K env significantly regulates proliferation and invasion depending on p53 status and Aza treatment.
CRIS-Team WoS Importer:2021-05-14
Keywords: tumor antigen; renal cell carcinoma; patient prognosis; p53; ERV-K; invasion; azacytidine; endogenous retrovirus

Endometrial Dating Method Detects Individual Maturation Sequences During the Secretory Phase - Alfer, Joachim; Fattahi, Amir; Bleisinger, Nathalie; Krieg, JÜrgen; Behrens, Rolf; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Classen-Linke, Irmgard; Popovici, Roxana M. (In Vivo, 2020)
BACKGROUND/AIM: This study assessed whether a new immunohistochemical dating method allows precise endometrial dating allowing optimal timing for embryo transfer. PATIENTS AND METHODS: A novel method was used for endometrial dating, with parameters including menstrual cycle days, Noyes histological criteria, along with immunohistochemical expression pattern of estrogen and progesterone receptors and proliferation marker Ki-67. Endometrial maturation was analyzed on days +5 to +10 after ovulation or progesterone administration in 217 biopsies from 151 subfertile patients during the secretory phase. RESULTS: Endometrial maturation varied individually, occurring 1.68±1.67 days late. Comparison of histological maturation with clinical days after ovulation showed a delay of about 2 days. CONCLUSION: Endometrial maturation requires 8 days, rather than the expected 6 days, to reach the histological mid-secretory phase. This is not a delay and is also seen in fertile patients. The new analysis method used is superior to that using Noyes criteria alone and provides a better basis for determining conditions for optimal timing of embryo transfers.
CRIS-Team Scopus Importer:2020-07-17
Keywords: Endometrial dating; endometrial receptivity; estrogen receptor; progesterone receptor; window of implantation

Endometrial delay is found to be part of a normal individual dynamic transformation process - Alfer, Joachim; Popovici, Roxana M.; Fattahi, Amir; Krieg, Juergen; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Bleisinger, Nathalie (Archives of Gynecology and Obstetrics, 2021)
Purpose: Limited information is clinically available concerning endometrial receptivity; assessing endometrial transformation status is therefore an urgent topic in assisted reproductive technology. This study aimed to investigate individual endometrial transformation rates during the secretory phase in subfertile patients using personal endometrial transformation analysis. Methods: Monitoring was carried out during the secretory phase to obtain endometrial receptivity profiles. For the investigation, two endometrial biopsies were taken within one menstrual cycle. The extended endometrial dating was based on the Noyes criteria, combined with immunohistochemical analyses of hormone receptors and proliferation marker Ki-67. Biopsies were taken mainly at days ovulation (OV, n = 76)/hormone replacement therapy (HRT, n = 58) + 5 and + 10. Results: The results of the two biopsies were correlated with the clinically expected day of the cycle and showed temporal delays or hypercompensations, diverging from the expected cycle days by 0.5–5 days. In comparison with the first biopsies, the transformation rate in the second biopsies showed compensation, augmented delay, or constant transformation in 48.69, 22.37, and 28.94% of cases for ovulation in natural cycles and 56.89, 25.85, and 17.26% for HRT cycles, respectively. Conclusion: The study revealed an individually dynamic transformation process of the endometrium, with the ability to compensate or enlarge an initial “delay”, which is now identified as a normal individual transformation process during the secretory phase. This information is of great importance for the scientific investigation of dynamic changes in endometrial tissue, as well as for the timing of embryo transfers.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Delay; Endometrium; Maturation; Receptivity

Endometriosis as a risk factor for ovarian or endometrial cancer - results of a hospital-based case-control study - Burghaus, Stefanie; Haeberle, Lothar; Schrauder, Michael G.; Heusinger, Katharina; Thiel, Falk; Hein, Alexander; Wachter, David; Strehl, Johanna; Hartmann, Arndt; Ekici, Arif Bülent; Renner, Stefan; Beckmann, Matthias; et al. (BMC Cancer, 2015)
No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer.In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use.Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41).This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis.
EVALuna2:6731

Endoscopic therapy of Zenker's diverticulum using a novel endoscopic scissor - the Clutch Cutter device - Neumann, Helmut; Loeffler, Silke; Rieger, Stefanie; Kretschmer, Claudia; Naegel, Andreas (Endoscopy, 2015)
EVALuna2:2014

End-stage renal disease after sarcoma therapy - case 3/2014 - Baumann, D.; Amann, Kerstin Ute; Schlatter, E.; Ciarimboli, G.; Kopp, H. G.; Müller, M.; Kluba, T.; Bakos, G.; Steinke, I.; Bunz, H.; Weyrich, P.; Artunc, F. (Deutsche Medizinische Wochenschrift, 2014)
A 67-year-old male patient developed progressive renal failure following successful treatment of a soft tissue sarcoma that comprised surgical resection after neoadjuvant radiochemotherapy with the application of doxorubicin (cumulative dose 180 mg/m²) and ifosfamide (cumulative dose 33 g/m²).Plasma creatinine concentration was elevated to 4.5 mg/dl. Upon detection of glucosuria and ?1-microglobulinuria renal biopsy was performed.Histologic analysis revealed massively injured tubules that could be explained by a toxic effect of ifosfamide. Glomeruli were not affected and appeared normal. After two months of conservative therapy, the patient developed an uremic syndrome requiring hemodialysis. Ever since kidney function did not recover albeit preserved diuresis.Ifosfamide can cause end-stage renal disease by a tubulotoxic effect that may be the result of a selective intracellular uptake into the proximal tubule via the human organic cation transporter 2 (OCT2).
EVALuna2:25473

Engineering of vascularized transplantable bone tissues: induction of axial vascularization in an osteoconductive matrix using an arteriovenous loop. - Kneser, Ulrich; Polykandriotis, Elias; Ohnolz, Jan; Heidner, Kristina; Grabinger, Lucia; Euler, Simon; Amann, Kerstin Ute; Heß, Andreas; Brune, Kay; Greil, Peter; Stürzl, Michael; Horch, Raymund E. (Tissue Engineering -Larchmont, 2006)
This study demonstrates for the first time successful vascularization of solid porous matrices by means of an AV loop. Injection of osteogenic cells into axially prevascularized matrices may eventually create functional bioartificial bone tissues for reconstruction of large defects. Vascularization remains an obstacle to engineering of larger volume bone tissues. Our aim was to induce axial vascularization in a processed bovine cancellous bone (PBCB) matrix using an arteriovenous (AV) loop (artery, vein graft, and vein). Custom-made PBCB discs (9 x 5 mm) were implanted into rats. In group A (n = 19), the matrices were inserted into microsurgically constructed AV loops between the femoral vessels using a vein graft from the contralateral side. In group B (n = 19), there was no vascular carrier. The matrices were encased in isolation chambers. After 2, 4, and 8 weeks, the animals were perfused with India ink via the abdominal aorta. Matrices were explanted and subjected to histological and morphometric analysis. Results were compared with intravital dynamic micro & magnetic resonance imaging and scanning electron microscopy images of vascular corrosion replicas. In group A, significant vascularization of the matrix had occurred by the 8th week. At this time, vascular remodeling with organization into vessels of different sizes was evident. Blood vessels originated from all 3 zones of the AV loop. Group A was significantly superior to group B in terms of vascular density and vascularization kinetics. DISCUSSION INTRODUCTION METHODS RESULTS

Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma - Kachler, Katerina; Bailer, Maximilian; Heim, Lisanne; Schumacher, Fabian; Reichel, Martin; Holzinger, Corinna D.; Trump, Sonja; Mittler, Susanne; Monti, Juliana; Trufa, Denis; Rieker, Ralf; Hartmann, Arndt; et al. (Cancer Research, 2017)
The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. ©2017 AACR.
EVALuna2:4034

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease - Arndt, Stephanie; Wacker, Eva; Dorn, Christoph; Koch, Andreas; Saugspier, Michael; Thasler, Wolfgang E.; Hartmann, Arndt; Bosserhoff, Anja Katrin; Hellerbrand, Claus (Gut, 2015)
Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease.BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6(-/-)) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets.BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6(-/-) compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6(-/-) mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs.Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy.
EVALuna2:4714

Enhancement of engineered cardiac tissues by promotion of hiPSC-cardiomyocyte proliferation - Hesselbarth, Ramona; Esser, Tilman; Roshanbinfar, Kaveh; Schrüfer, Stefan; Schubert, Dirk W.; Engel, Felix (EUROPEAN HEART JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-10

Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands - Haller, Florian; Bieg, Matthias; Will, Rainer; Koerner, Cindy; Weichenhan, Dieter; Bott, Alexander; Ishaque, Naveed; Lutsik, Pavlo; Moskalev, Evgeny; Müller, Susanna; Baehr, Marion; Woerner, Angelika; et al. (Nature Communications, 2019)
The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC.
EVALuna2:35381

Enhancing biofabrication: Shrink-resistant collagen-hyaluronan composite hydrogel for tissue engineering and 3D bioprinting applications - Roshanbinfar, Kaveh; Evans, Austin Donnelly; Samanta, Sumanta; Kolesnik-Gray, Maria; Fiedler, Maren; Krstic, Vojislav; Engel, Felix; Oommen, Oommen P. (Biomaterials, 2025)
Biofabrication represents a promising technique for creating tissues for regeneration or as models for drug testing. Collagen-based hydrogels are widely used as suitable matrix owing to their biocompatibility and tunable mechanical properties. However, one major challenge is that the encapsulated cells interact with the collagen matrix causing construct shrinkage. Here, we present a hydrogel with high shape fidelity, mimicking the major components of the extracellular matrix. We engineered a composite hydrogel comprising gallic acid (GA)-functionalized hyaluronic acid (HA), collagen I, and HA-coated multiwall carbon nanotubes (MWCNT). This hydrogel supports cell encapsulation, exhibits shear-thinning properties enhancing injectability and printability, and importantly significantly mitigates shrinkage when loaded with human fibroblasts compared to collagen I hydrogels (∼20 % vs. > 90 %). 3D-bioprinted rings utilizing human fibroblast-loaded inks maintain their shape over 7 days in culture. Furthermore, inclusion of HAGA into collagen I hydrogels increases mechanical stiffness, radical scavenging capability, and tissue adhesiveness. Notably, the here developed hydrogel is also suitable for human induced pluripotent stem cell-derived cardiomyocytes and allows printing of functional heart ventricles responsive to pharmacological treatment. Cardiomyocytes behave similar in the newly developed hydrogels compared to collagen I, based on survival, sarcomere appearance, and calcium handling. Collectively, we developed a novel material to overcome the challenge of post-fabrication matrix shrinkage conferring high shape fidelity.
CRIS-Team Scopus Importer:2025-02-21
Keywords: 3D bioprinting; Cardiac; Hydrogel; Shrink-resistant; Shrinkage; Tissue engineering

Enhancing Form Stability: Shrink-Resistant Hydrogels Made of Interpenetrating Networks of Recombinant Spider Silk and Collagen-I - Ng, Xuen J.; Esser, Tilman; Trossmann, Vanessa T.; Rudisch, Christoph; Fiedler, Maren; Roshanbinfar, Kaveh; Lamberger, Zan; Stahlhut, Philipp; Lang, Gregor; Scheibel, Thomas; Engel, Felix (Advanced Healthcare Materials, 2025)
Tissue engineering enables the production of tissues and organ-like structures as models for drug testing and mechanistical studies or functional replacements for injured tissues. Available cytocompatible materials are limited in number, suffer from insufficient mechanical properties, and cells interacting with them often cause construct shrinkage. As shape is important for function, identifying cytocompatible, shrink-resistant materials are a major aim. Here, it is shown that hydrogels made of interpenetrating networks of collagen-I and recombinant spider silk protein eADF4(C16)-RGD nanofibrils exhibit synergistic and tunable mechanical properties. Composite hydrogels allow cell adhesion and spreading and are resistant to shrinkage mediated by fibroblasts, C2C12 myoblasts, and human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. Myoblasts differentiate and fuse into myotubes, and hiPSC-cardiomyocytes can be cultured long-term, show spontaneous contractions, and remain drug responsive. Collectively, a novel composite material is developed to overcome the challenge of post-fabrication matrix shrinkage conferring high shape fidelity suitable for tissue engineering.
CRIS-Team Scopus Importer:2025-04-11
Keywords: biopolymer; cardiac tissue engineering; compaction; heart; shrinkage

Eosinophiles solide und zystisches Nierenzellkarzinom (ESC-NZK) - Hartmann, Arndt; Agaimy, Abbas (Pathologe, 2021)
Despite its descriptive name, eosinophilic, solid, and cystic renal cell carcinoma (ESC-RCC) represents a distinctive epithelial renal tumor entity defined by characteristic clinicopathological and molecular features. ESC-RCC occurs predominantly in women and is characterized in the majority of cases by sporadic (somatic) TSC mutations. A small subset of cases, however, affects patients with TSC germline mutations (tuberous sclerosis syndrome). TSC mutations have therefore been shown to be pathogenetic in this type of tumor. Most tumors present as small (pT1) well circumscribed but not encapsulated lesions with variable macrocystic spaces on their cut surface. Immunohistochemically, their CD117−/CK7−/CK20+ profile is characteristic. Although the tumor cell nuclei of the ESC-RCC occasionally correspond to ISUP/WHO grade 2–3, these tumors are essentially indolent with aggressive cases being only rarely observed. Single case reports have documented effective treatment of aggressive cases with mTOR inhibitors. ESC-RCC needs to be distinguished from a variety of eosinophilic RCC types with secondary cystic changes including cystic SDH-deficient RCC, the recently proposed eosinophilic vacuolated tumor (EVT; also mTOR-related), oncocytoma, and low-grade oncocytic tumor (LOT). The generally indolent behavior and frequent TSC/mTOR alterations in ESC-RCC, EVT, and some LOTs raise the question of whether these lesions represent independent tumor entities or are merely morphological variants on the spectrum of eosinophilic low-grade TSC/mTOR-related neoplasms.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Eosinophilic renal tumors; Human mTOR protein; Kidney neoplasms; TOR serine-threonine kinases; Tuberous sclerosis

Eosinophilic cystitis mimicking bladder cancer—considerations on the management based upon a case report and a review of the literature - Schmitz-Draeger, Bernd J.; Skutetzki, Andreas; Rieker, Ralf J.; Schwab, Siegfried A.; Stöhr, Robert; Bismarck, Ekkehardt; Savov, Orlin; Ebert, Thomas; Benderska-Soeder, Natalya; Hartmann, Arndt (Virchows Archiv, 2021)
The hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and infiltration of various organs with eosinophils. Eosinophilic cystitis (EC), mimicking bladder cancer clinically but also in ultrasound and in radiographic imaging, is one potential manifestation of the HES occurring in adults as well as in children. This case report describes the course of disease in a 57-year-old male presenting with severe gait disorders and symptoms of a low compliance bladder caused by a large retropubic tumor. After extensive urine and serologic examination and histologic confirmation of EC the patient was subjected to medical treatment with cetirizine and prednisolone for 5 weeks. While gait disorders rapidly resolved, micturition normalized only 10 months after initiation of therapy. Based upon this course the authors recommend patience and reluctance concerning radical surgical intervention in EC.• Genetic alterations (e.g., BRAF mutations) may predispose for the disease
CRIS-Team Scopus Importer:2021-03-05
Keywords: Bladder tumor; Eosinophilic cystitis; Hypereosinophilic syndrome; Inflammatory pseudotumor

Eosinophilic gastroenteritis with refractory ulcer disease and gastrointestinal bleeding as a rare manifestation of seronegative gastrointestinal food allergy - Raithel, Martin; Hahn, Markus; Donhuijsen, Konrad; Hagel, Alexander; Nagel, Andreas; Rieker, Ralf J.; Neurath, Markus; Reinshagen, Max (Nutrition Journal, 2014)
Gastrointestinal bleeding and iron deficiency anaemia may cause severe symptoms and may require extensive diagnostics and substantial amounts of health resources.This case report focuses on the clinical presentation of a 22 year old patient with recurrent gastrointestinal bleeding from multilocular non-healing ulcers of the stomach, duodenum and jejunum over a period of four years. Extensive gastroenterological and allergological standard diagnostic procedures showed benign ulcerative lesions with tissue eosinophilia, but no conclusive diagnosis. Multiple diagnostic procedures were performed, until finally, endoscopically guided segmental gut lavage identified locally produced, intestinal IgE antibodies by fluoro-enzyme-immunoassay.IgE antibody concentrations at the intestinal level were found to be more-fold increased for total IgE and food-specific IgE against nuts, rye flour, wheat flour, pork, beef and egg yolk compared with healthy controls.Thus, a diet eliminating these allergens was introduced along with antihistamines and administration of a hypoallergenic formula, which resulted in complete healing of the multilocular ulcers with resolution of gastrointestinal bleeding. All gastrointestinal lesions disappeared and total serum IgE levels dropped to normal within 9 months. The patient has been in remission now for more than two years.Eosinophilic gastroenteritis (EG) is well known to induce refractory ulcer disease. In this case, the mechanisms for intestinal damage and gastrointestinal bleeding were identified as local gastrointestinal type I allergy. Therefore, future diagnostics in EG should also be focused on the intestinal level as identification of causative food-specific IgE antibodies proved to be effective to induce remission in this patient.
EVALuna2:1913

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases - Mihaela, Farcas; Zoran, Gatalica; Kiril, Trpkov; Jeffrey, Swensen; Ming, Zhou; Reza, Alaghehbandan; Williamson, Sean R.; Cristina, Magi-Galluzzi; Gill, Anthony J.; Maria, Tretiakova; Lopez, Jose; Delia, Perez Montiel; et al. (Modern Pathology, 2021)
A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.
CRIS-Team WoS Importer:2021-09-24

Epidemiology and survival of HPV-related tonsillar carcinoma - Psychogios, Georgios; Alexiou, Christoph; Agaimy, Abbas; Brunner, Kathrin; Koch, Michael; Mantsopoulos, Konstantinos; Tomppert, Andrea; Iro, Heinrich (Cancer Medicine, 2014)
The aim of this study was to determine the proportion of human papilloma virus (HPV)-positive cases in tonsillar carcinomas and investigate its development over the last decade. Further aim was to show the oncologic results in accord to HPV status and various treatment modalities. A retrospective study was conducted between 2000 and 2012 and included 275 patients treated for tonsillar carcinoma. P16 immunohistochemistry was used as a surrogate marker for HPV-associated carcinogenesis. A total of 101 (36.7%) patients proved to be p16 positive and 174 p16 negative. 80.2% of the p16-positive cases presented with T1-2 tumor. Of the early-stage patients, 79% of the p16-positive and 52.3% of the p16-negative presented with lymph node metastases. The percentage of p16-positive patients increased from 23.2% in the period 2005-2007 to 58.6% in the period 2010-2012 in the whole population and from 30.9% to 76.9% in T1-2 carcinomas. Early T-category p16-positive carcinomas had significantly better disease-specific survival (92.4% vs. 75.5%, P = 0.007) and overall survival (OS, 79.6% vs. 54.3%, P < 0.001) compared to p16-negative tumors. This study showed an increase in the percentage of p16-positive patients in tonsillar carcinoma from 23.2% in the years between 2005 and 2007 to 58.6% between 2010 and 2012. The majority (80.2%) of p16-positive patients presented with early T-category tumor but most of these (79.0%) had also lymph node metastases. Nevertheless, p16-positive patients had excellent oncologic results after surgery and adjuvant radiotherapy and could be considered for de-escalation of treatment.
EVALuna2:6679

Epidemiology, molecular, and genetic methodologies to evaluate causes of CKDu around the world: report of the Working Group from the ISN International Consortium of Collaborators on CKDu - Anand, Shuchi; Caplin, Ben; Gonzalez-Quiroz, Marvin; Schensul, Stephen L.; Bhalla, Vivek; Parada, Xavier; Nanayakkara, Nishantha; Fire, Andrew; Levin, Adeera; Friedman, David J.; Aguilar-Gonzalez, Angie; Abbot, Kevin; et al. (Kidney International, 2019)
CRIS-Team WoS Importer:2019-12-06

Epigenetic inactivation of ITIH5 promotes bladder cancer progression and predicts early relapse of pT1 high-grade urothelial tumours - Rose, Michael; Gaisa, Nadine T.; Antony, Pia; Fiedler, David; Heidenreich, Axel; Otto, Wolfgang; Denzinger, Stefan; Bertz, Simone; Hartmann, Arndt; Karl, Alexander; Knüchel, Ruth; Dahl, Edgar (Carcinogenesis, 2014)
Inter-?-trypsin inhibitor heavy chain 5 (ITIH5) has been associated with tumour suppression in various cancers. However, its putative role in bladder cancer is completely unknown. Therefore, we initiated a study analysing ITIH5 expression as well as its prognostic and functional impact on human urothelial cancers (UCs). Expression analysis showed a clear down-regulation of ITIH5 mRNA in 61% (n = 45) of UCs, especially in muscle-invasive tumours (P < 0.001). ITIH5 loss in UCs was further evident on protein level (65.5%, n = 55) as detected by immunohistochemistry. DNA methylation analysis demonstrated tumour-specific ITIH5 promoter methylation in 50% of papillary none-invasive pTa (n = 30) and 68% of invasive (n = 28) UCs. Aberrant ITIH5 promoter methylation in bladder tumours was tightly linked (P < 0.001) with loss of ITIH5 mRNA expression, which was furthermore functionally confirmed by demethylation analysis in cell lines. Pyrosequencing analysis revealed that ITIH5 promoter hypermethylation was closely associated with progressive bladder cancers. Subsequently, a large cohort (n = 120) of clinically challenging pT1 high-grade UC was analysed for ITIH5 expression. Of clinical significance, we found an association between loss of ITIH5 expression and unfavourable prognosis of UC patients without distant metastasis at first diagnosis (recurrence-free survival; hazard ratio: 4.35, P = 0.048). Functionally, ITIH5 re-expression in human RT112 bladder cancer cells led to both suppression of cell migration and inhibition of colony spreading. Hence, we provide evidence that down-regulation of ITIH5 by aberrant DNA hypermethylation may provoke invasive phenotypes in human bladder cancer. Moreover, ITIH5 protein might become a prognostic biomarker for relapse risk stratification in high-grade UC patients.
EVALuna2:6568

Epigenetic Regulation of CD133 in Gastrointestinal Stromal Tumors - Geddert, Helene; Braun, Alexander; Kayser, Claudia; Dimmler, Arno; Faller, Gerhard; Agaimy, Abbas; Haller, Florian; Moskalev, Evgeny (American Journal of Clinical Pathology, 2017)
This study ascertained the regulation of the stem cell marker CD133 and its potential applicability for prognostication of gastrointestinal stromal tumors (GISTs).A total of 95 resected GISTs were included in the study. CD133 protein expression was assessed immunohistochemically on tissue microarrays. Methylation percentage was quantified by pyrosequencing. Gene expression in cell lines GIST48b and GIST882 upon treatment with DNA demethylation agent 5-aza-2'-deoxycytidine was analyzed by quantitative polymerase chain reaction.The expression of hypermethylated CD133 could be reactivated in the GIST cell line upon hypomethylation with the drug. Similarly, in patient material, CD133 methylation percentage correlated inversely with the protein expression and reflected tumor size with hypermethylation in small (<2 cm) tumors and virtually no methylation in large (>10 cm) GISTs. The gene's methylation percentage and expression level were clearly specific to anatomic sites and distinct driver mutations. KIT -mutant gastric GISTs exhibited significantly lower methylation degrees and concomitant high CD133 protein abundance compared with KIT -mutant GISTs from the small intestine. CD133 hypermethylation was documented in PDGFRA -mutant gastric GISTs along with low CD133 expression compared with KIT -mutant gastric GISTs. High CD133 expression was a prognosticator of shorter disease-free survival in all patients. In a subgroup of KIT -mutant gastric GISTs, low CD133 methylation degree was correlated with a shorter disease-free survival.Our results strongly suggest epigenetic regulation of CD133 expression by promoter methylation in GISTs. Pending further validation studies, high abundance of the protein can serve as a marker for malignant GISTs.
EVALuna2:6853

EPIGENETIC REGULATION OF FRA2 BY JMJD3 REGULATES FIBROBLAST ACTIVATION IN SYSTEMIC SCLEROSIS - Bergmann, C.; Brandt, Adrian; Dees, Clara; Wohlfahrt, T.; Zhang, Y.; Chen, Chih-Wei; Mallano, T.; Liang, Ruifang; Kagwiria, R.; Kam, P. -S.; Bozec, Aline; Abraham, D.; et al. (2017)
EVALuna2:35037

Epigenetic regulation of p21cip1/waf1 in human cancer - Ocker, Matthias; Al Bitar, Samar; Monteiro, Ana; Gali-Muhtasib, Hala; Schneider-Stock, Regine (Cancers, 2019)
p21cip1/waf1 is a central regulator of cell cycle control and survival. While mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. These mechanisms include promoter hypermethylation as well as additional pathways such as histone acetylation or methylation. The epigenetic regulators include writers, such as DNA methyltransferases (DNMTs); histone acetyltransferases (HATs) and histone lysine methyltransferases; erasers, such as histone deacetylases (HDACs); histone lysine demethylases [e.g., the Lysine Demethylase (KDM) family]; DNA hydroxylases; readers, such as the methyl-CpG-binding proteins (MBPs); and bromodomain-containing proteins, including the bromo-and extraterminal domain (BET) family. We further discuss the roles that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play in the epigenetic control of p21cip1/waf1 expression and its function in human cancers.
CRIS-Team Scopus Importer:2019-10-22
Keywords: DNA methylation; Epigenetic eraser; Epigenetic reader; Epigenetic writer; Histone acetylation; Histone methylation; LncRNA; MiRNA; P21

Epigenetic regulation of the putative breast cancer metastasis suppressor gene SCN4B - Hilgers, L.; Hartmann, Arndt; Fasching, Peter; Villwock, S.; Moll, L.; Roger, S.; Knuechel-Clarke, R.; Steib, F.; Dahl, E. D. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart - Perrino, Cinzia; Barabasi, Albert-Laszlo; Condorelli, Gianluigi; Davidson, Sean Michael; De Windt, Leon; Dimmeler, Stefanie; Engel, Felix; Hausenloy, Derek John; Hill, Joseph Addison; Van Laake, Linda Wilhelmina; Lecour, Sandrine; Leor, Jonathan; et al. (Cardiovascular Research, 2017)
Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human 'diseasome'. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era.
EVALuna2:25534

Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus - Korn, Marina; Steffensen, Marie; Brandl, Carolin; Royzman, Dmytro; Daniel, Christoph; Winkler, Thomas; Nitschke, Lars (Frontiers in Immunology, 2023)
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that displays considerable heterogeneity not only in its symptoms, but also in its environmental and genetic causes. Studies in SLE patients have revealed that many genetic variants contribute to disease development. However, often its etiology remains unknown. Existing efforts to determine this etiology have focused on SLE in mouse models revealing not only that mutations in specific genes lead to SLE development, but also that epistatic effects of several gene mutations significantly amplify disease manifestation. Genome-wide association studies for SLE have identified loci involved in the two biological processes of immune complex clearance and lymphocyte signaling. Deficiency in an inhibitory receptor expressed on B lymphocytes, Siglec-G, has been shown to trigger SLE development in aging mice, as have mutations in DNA degrading DNase1 and DNase1l3, that are involved in clearance of DNA-containing immune complexes. Here, we analyze the development of SLE-like symptoms in mice deficient in either Siglecg and DNase1 or Siglecg and DNase1l3 to evaluate potential epistatic effects of these genes. We found that germinal center B cells and follicular helper T cells were increased in aging Siglecg-/- x Dnase1-/- mice. In contrast, anti-dsDNA antibodies and anti-nuclear antibodies were strongly increased in aging Siglecg-/- x Dnase1l3-/- mice, when compared to single-deficient mice. Histological analysis of the kidneys revealed glomerulonephritis in both Siglecg-/- x Dnase1-/- and Siglecg-/- x Dnase1l3-/- mice, but with a stronger glomerular damage in the latter. Collectively, these findings underscore the impact of the epistatic effects of Siglecg with DNase1 and Dnase1l3 on disease manifestation and highlight the potential combinatory effects of other gene mutations in SLE.
CRIS-Team Scopus Importer:2023-03-31
Keywords: autoimmunity; B cell signaling; inhibitory receptors; lymphocytes; mouse models

Epithelial-Myoepithelial Carcinoma: Frequent Morphologic and Molecular Evidence of Preexisting Pleomorphic Adenoma, Common HRAS Mutations in PLAG1-intact and HMGA2-intact Cases, and Occasional TP53, FBXW7, and SMARCB1 Alterations in High-grade Cases - El Hallani, Soufiane; Udager, Aaron M.; Bell, Diana; Fonseca, Isabel; Thompson, Lester D. R.; Assaad, Adel; Agaimy, Abbas; Luvison, Alyssa M.; Miller, Caitlyn; Seethala, Raja R.; Chiosea, Simion (American Journal of Surgical Pathology, 2018)
We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.
EVALuna2:34892

Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation - Martínez Sánchez, Luz del Carmen; Phuong Anh Ngo,; Pradhan, Rashmita; Becker, Lukas S; Böhringer, David; Soteriou, Despina; Kubankova, Marketa; Schweitzer, Christine; Koch, Tatyana; Thonn, Veronika; Erkert, Lena; Stolzer, Iris; et al. (Gut, 2022)
Objective Increased apoptotic shedding has been linked to intestinal barrier dysfunction and development of inflammatory bowel diseases (IBD). In contrast, physiological cell shedding allows the renewal of the epithelial monolayer without compromising the barrier function. Here, we investigated the role of live cell extrusion in epithelial barrier alterations in IBD. Design Taking advantage of conditional GGTase and RAC1 knockout mice in intestinal epithelial cells (Pggt1b (i Delta IEC) and Rac1 (i Delta IEC) mice), intravital microscopy, immunostaining, mechanobiology, organoid techniques and RNA sequencing, we analysed cell shedding alterations within the intestinal epithelium. Moreover, we examined human gut tissue and intestinal organoids from patients with IBD for cell shedding alterations and RAC1 function. Results Epithelial Pggt1b deletion led to cytoskeleton rearrangement and tight junction redistribution, causing cell overcrowding due to arresting of cell shedding that finally resulted in epithelial leakage and spontaneous mucosal inflammation in the small and to a lesser extent in the large intestine. Both in vivo and in vitro studies (knockout mice, organoids) identified RAC1 as a GGTase target critically involved in prenylation-dependent cytoskeleton dynamics, cell mechanics and epithelial cell shedding. Moreover, inflamed areas of gut tissue from patients with IBD exhibited funnel-like structures, signs of arrested cell shedding and impaired RAC1 function. RAC1 inhibition in human intestinal organoids caused actin alterations compatible with arresting of cell shedding. Conclusion Impaired epithelial RAC1 function causes cell overcrowding and epithelial leakage thus inducing chronic intestinal inflammation. Epithelial RAC1 emerges as key regulator of cytoskeletal dynamics, cell mechanics and intestinal cell shedding. Modulation of RAC1 might be exploited for restoration of epithelial integrity in the gut of patients with IBD.
CRIS-Team WoS Importer:2022-03-25

ERBB2/ ERBB3-mutated S100/ SOX10-positive unclassified high-grade uterine sarcoma: first detailed description of a novel entity - Agaimy, Abbas; Dermawan, Josephine K.; Haller, Florian; Semrau, Sabine; Meidenbauer, Norbert; Stöhr, Robert; Lax, Sigurd; Hartmann, Arndt; Zou, Ying S.; Xing, Deyin; Tögel, Lars; Gross, John M.; et al. (Virchows Archiv, 2024)
With the increasing use of innovative next generation sequencing (NGS) platforms in routine diagnostic and research settings, the genetic landscape of uterine sarcomas has been dynamically evolving during the last two decades. Notably, the majority of recently recognized genotypes in uterine sarcomas represent gene fusions, while recurrent oncogene mutations of diagnostic and/ or therapeutic value have been rare. Recently, a distinctive aggressive uterine sarcoma expressing S100 and SOX10, but otherwise lacking diagnostic morphological, immunophenotypic and molecular features of other uterine malignancies has been presented in a scientific abstract form (USCAP, 2023), but detailed description and delineation of the entity is still missing. We herein describe two high-grade unclassified uterine sarcomas characterized by spindle to round cell morphology and diffuse expression of S100 and SOX10, originating in the uterine body and cervix of 53- and 45-year-old women and carrying an ERBB3 (p.Glu928Gly) and an ERBB2 (p.Val777Leu) mutation, respectively. Both tumors harbored in addition genomic HER2 amplification, ATRX mutation and CDKN2A deletion. Methylation studies revealed a methylome most similar to MPNST-like tumors, but distinct from melanoma, MPNST, clear cell sarcoma, and endometrial stromal sarcoma. Case 1 died of progressive peritoneal metastases after multiple trials of chemotherapy 47 months after diagnosis. Case 2 is a recent case who presented with a cervical mass, which was biopsied. This study defines a novel heretofore unrecognized aggressive uterine sarcoma with unique phenotypic and genotypic features. Given the potential value of targeting HER2, recognizing this tumor type is mandatory for appropriate therapeutic strategies and for better future delineation of the entity.
CRIS-Team Scopus Importer:2024-09-06
Keywords: EGFR; Molecular profiling; nerve sheath tumor; Targeted therapy; Tyrosine kinase fusions; Undifferentiated uterine sarcoma

ERBB2 Expression as Potential Risk-Stratification for Early Cystectomy in Patients with pT1 Bladder Cancer and Concomitant Carcinoma in situ - Breyer, Johannes; Otto, Wolfgang; Wirtz, Ralph M.; Wullich, Bernd; Keck, Bastian; Erben, Philipp; Kriegmair, Maximilian C.; Stoehr, Robert; Eckstein, Markus; Laible, Mark; Schlombs, Kornelia; Eidt, Sebastian; et al. (Urologia Internationalis, 2017)
Background/Aims/Objectives: It is difficult to identify patients with a non-muscle-invasive bladder cancer (NMIBC) at stage pT1 with concomitant carcinoma in situ (Cis) who will benefit from an early cystectomy.We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues of patients with NMIBC. Messenger ribonucleic acid (mRNA) expression of progesterone receptor (PGR), estrogen receptor (ESR1), ERBB2, and marker of proliferation Ki-67 (MKI67) was measured by single-step reverse transcription quantitative real-time polymerase chain reaction using RNA-specific TaqMan assays. Relative gene expression was determined by the normalization of 2 reference genes (CALM2, B2M) using the 40 ??CT method and relative gene expression was correlated to the histopathological stage and oncological outcome.Of 302 patients with pT1 NMIBC in the initial transurethral resection of the bladder, 65 had a concomitant Cis. Elevated ERBB2 expression (>40.1) significantly correlated with progress in patients with and without concomitant Cis (p = 0.020 and p = 0.049, respectively). For the subgroup of pT1 with concomitant Cis, elevated ERBB2 expression significantly discriminated between a high-risk group of 55% progression-free survival (PFS) and a low-risk group of 90% PFS after a 5-year follow-up (p = 0.020). Cox-regression analysis revealed ERBB2 expression as the only independent prognostic factor for PFS (p = 0.0037).High mRNA expression of ERBB2 can identify patients with pT1 NMIBC with concomitant Cis, who have a high risk of progression and might benefit from an early cystectomy.
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Erratum to: DAPK plays an important role in panobinostat-induced autophagy and commits cells to apoptosis under autophagy deficient conditions - Gandesiri, Muktheshwar; Chakilam, Saritha; Ivanovska, Jelena; Benderska, Natalya; Ocker, Matthias; Di Fazio, Pietro; Feoktistova, Maria; Gali-Muhtasib, Hala; Rave-Fraenk, Margret; Prante, Olaf; Christiansen, Hans; Leverkus, Martin; et al. (Apoptosis, 2016)
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Erratum to 'Deep hypothermic circulatory arrest or tepid regional cerebral perfusion: impact on haemodynamics and myocardial integrity in a randomized experimental trial' [Interact CardioVasc Thorac Surg 2018;26:667-672] - Kellermann, Stephanie; Janssen, Carina; Muench, Frank; Koch, Anna Maria; Schneider-Stock, Regine; Cesnjevar, Robert; Rueffer, Andre (Interactive Cardiovascular and Thoracic Surgery, 2018)
EVALuna2:33948

Erratum to: Eosinophilic, solid, and cystic renal cell carcinoma (ESC-RCC) (Der Pathologe, (2021), 42, 6, (565-570), 10.1007/s00292-021-00998-7) Erratum zu: Eosinophiles solide und zystisches Nierenzellkarzinom (ESC-NZK) (Der Pathologe, (2021), 42, 6, (565-570), 10.1007/s00292-021-00998-7) - Hartmann, Arndt; Agaimy, Abbas (Pathologe, 2021)
CRIS-Team Scopus Importer:2021-11-05

Erratum to: ‘Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis’ [J Hepatol (2024) 80:268-281, (S0168827823052352), (10.1016/j.jhep.2023.10.035)] - Ghallab, Ahmed; González, Daniela; Strängberg, Ellen; Hofmann, Ute; Myllys, Maiju; Hassan, Reham; Hobloss, Zaynab; Brackhagen, Lisa; Begher-Tibbe, Brigitte; Duda, Julia C.; Drenda, Carolin; Kappenberg, Franziska; et al. (Journal of Hepatology, 2025)
In this article, owing to a typesetter error, the supplementary video files were incorrectly named. This has now been updated online. The publisher apologises for any inconvenience caused.
CRIS-Team Scopus Importer:2025-04-01

Erratum to 'Predictive value of lymphangiogenesis and proliferation markers on mRNA level in urothelial carcinoma of the bladder after radical cystectomy' [Urologic Oncology: Seminars and Original Investigations 36/12 (2018) 505-534] - Martini, Thomas; Heinkele, Jakob; Mayr, Roman; Weis, Cleo-Aron; Wezel, Felix; Wahby, Sarah; Eckstein, Markus; Schnoeller, Thomas; Breyer, Johannes; Wirtz, Ralph; Ritter, Manuel; Bolenz, Christian; et al. (Urologic Oncology-Seminars and Original Investigations, 2019)
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Erratum zu Mitteilungen der Deutschen Gesellschaft für Pathologie (Der Pathologe, (2021), 42, 3, (352-353), 10.1007/s00292-021-00931-y) - Joehrens, Korinna; Baretton, Gustavo; Schildhaus, Hans-Ulrich; Agaimy, Abbas; Scheel, Andreas; Schwammborn, Kristina; Laenger, Florian; Tiemann, Markus; Dietel, Manfred (Pathologe, 2021)
CRIS-Team Scopus Importer:2021-09-03

Erratum zu: Testung auf Mismatch-Reparatur-Defizienz und Mikrosatelliteninstabilität: Eine fokussierte Aktualisierung (Die Pathologie, (2023), 44, 5, (301-310), 10.1007/s00292-023-01209-1) - Rüschoff, Josef; Schildhaus, Hans-Ulrich; Rüschoff, Jan Hendrik; Jöhrens, Korinna; Bocker-Edmonston, Tina; Dietmaier, Wolfgang; Bläker, Hendrik; Baretton, Gustavo; Horst, David; Dietel, Manfred; Hartmann, Arndt; Klauschen, Frederick; et al. (Die Pathologie, 2023)
CRIS-Team Scopus Importer:2023-09-08

Escalation in mucus cystatin 2, pappalysin-A, and periostin levels over time predict need for recurrent surgery in chronic rhinosinusitis with nasal polyps - Müller, Sarina Katrin; Wendler, Olaf; Nocera, Angela; Grundtner, Philipp; Schlegel, Patrick; Agaimy, Abbas; Iro, Heinrich; Bleier, Benjamin S. (International Forum of Allergy and Rhinology, 2019)
Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is treated using oral/topical steroids and surgery. Despite maximal medical therapy, some patients remain recalcitrant. Mucus cystatin 2, pappalysin-A, and periostin can predict the presence of CRSwNP and correlate with disease severity. This study was designed to determine whether prospective sampling of these mucus proteins could predict medical failure and the need for revision surgery. Methods: This investigation was an institutional review board‒approved, prospective study of 66 patients with CRSwNP. All patients underwent surgery, administration of topical/oral steroids, and outpatient mucus sampling at 10 time-points over 2 years. Five proteins, including cystatin 2 (CST2), pappalysin-A (PAPP-A), and periostin (PST), were analyzed and correlated with subjective parameters (including scores on the 22-item Sino-Nasal Outcomes Test [SNOT-22]). Variables were then analyzed and compared between those requiring revision surgery within 2 years (n = 5) and those with stable disease (n = 61). Results: All patients demonstrated a significant decline in CST2, PAPP-A, and periostin after their initial surgery. The recalcitrant group demonstrated escalations in all proteins despite steroids, with levels higher than those of the stable group at 1 year (CST2: 258.1 ± 205.2 pg/mL vs 235.3 ± 275.7 pg/mL, p = 0.86; PAPP-A: 170.3 ± 150.4 pg/mL vs 74.6 ± 106.7 pg/mL, p < 0.05; periostin: 188.8 ± 192.4 ng/mL vs 54.5 ± 47.6 ng/mL, p < 0.001). Escalation in all proteins correlated significantly with worsening SNOT-22 score at each time-point (domain 1: 8.2 ± 1.3 vs 5.5 ± 1.1; p < 0.05). Conclusion: Early recurrences and medical recalcitrance in CRSwNP may be predicted noninvasively through the serial, prospective sampling of mucus CST2, PAPP-A, and periostin levels. These biosignatures may help to predict disease course and guide individualized therapy.
CRIS-Team Scopus Importer:2019-08-30
Keywords: biomarker; chronic rhinosinusitis; mucus; noninvasive; recurrence

ESC Working Group Cellular Biology of the Heart: Position Paper: improving the preclinical assessment of novel cardioprotective therapies - Lecour, Sandrine; Botker, Hans E.; Condorelli, Gianluigi; Davidson, Sean M.; Garcia-Dorado, David; Engel, Felix; Ferdinandy, Peter; Heusch, Gerd; Madonna, Rosalinda; Ovize, Michel; Ruiz-Meana, Marisol; Schulz, Rainer; et al. (Cardiovascular Research, 2014)
Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.
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ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure - Madonna, Rosalinda; Van Laake, Linda W.; Botker, Hans Erik; Davidson, Sean M.; De Caterina, Raffaele; Engel, Felix; Eschenhagen, Thomas; Fernandez-Aviles, Francesco; Hausenloy, Derek J.; Hulot, Jean-Sebastien; Lecour, Sandrine; Leor, Jonathan; et al. (Cardiovascular Research, 2019)
Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF.
CRIS-Team WoS Importer:2019-04-12

ESC Working Group on Cellular Biology of the Heart: Tissue Engineering and Cell-Based Therapies for Cardiac Repair in Ischemic Heart Disease and Heart Failure - Madonna, Rosalinda; Van Laake, Linda W.; Botker, Hans Erik; Davidson, Sean M.; De Caterina, Raffaele; Engel, Felix; Eschenhagen, Thomas; Fernandez-Aviles, Francesco; Hausenloy, Derek J.; Hulot, Jean Sebastien; Lecour, Sandrine; Leor, Jonathan; et al. (Cardiovascular Research, 2019)
Morbidity and mortality from ischemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g., hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas and thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel tissue engineering strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF.
EVALuna2:35428

ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC) - Breyer, Johannes; Wirtz, Ralph M.; Laible, Mark; Schlombs, Kornelia; Erben, Philipp; Kriegmair, Maximilian Christian; Stoehr, Robert; Eidt, Sebastian; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt; Otto, Wolfgang (Virchows Archiv, 2016)
Pathological staging and grading are crucial for risk assessment in non-muscle-invasive bladder cancer (NMIBC). Molecular grading might support pathological evaluation and minimize interobserver variability. In this study, the well-established breast cancer markers ESR1, PGR, ERBB2, and MKI67 were evaluated as potential molecular markers to support grading and staging in NMIBC. We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with NMIBC. Messenger RNA (mRNA) expression of the aforementioned markers was measured by single-step reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) using RNA-specific TaqMan assays. Relative gene expression was determined by normalization to two reference genes (CALM2 and B2M) using the 40(-??CT) method and correlated to histopathological stage and grade. Pathological assessment was performed by an experienced uropathologist. Statistical analysis was performed using the SAS software JMP 9.0.0 version and GraphPad Prism 5.04. Of 381 cases of NMIBC, samples of 100 pTa and 255 pT1 cases were included in the final study. Spearman rank correlation revealed significant correlations between grade and expression of MKI67 (r = 0.52, p < 0.0001), ESR1 (r = 0.25, p < 0.0001), and ERBB2 (r = 0.18, p = 0.0008). In Mann-Whitney tests, MKI67 was significantly different between all grades (p < 0.0001), while ESR1 (p = 0.0006) and ERBB2 (p = 0.027) were significantly different between G2 and G3. Higher expression of MKI67 (r = 0.49; p < 0.0001), ERBB2 (r = 0.22; p < 0.0001), and ESR1 (r = 0.18; p = 0.0009) mRNA was positively correlated with higher stage. MKI67 (p < 0.0001), ERBB2 (p = 0.0058), and PGR (p = 0.0007) were significantly different between pTa and pT1. In NMIBC expression of ESR1, ERBB2 and MKI67 are significantly different between stage and grade. This potentially provides objective parameters for pathological evaluation.
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Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice - Bohnert, Bernhard N.; Gonzalez-Menendez, Irene; Dörffel, Thomas; Schneider, Jonas C.; Xiao, Mengyun; Janessa, Andrea; Kalo, M. Zaher; Fehrenbacher, Birgit; Schaller, Martin; Casadei, Nicolas; Amann, Kerstin Ute; Daniel, Christoph; et al. (Disease Models & Mechanisms, 2021)
Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinuria in mice, is related to the single-nucleotide polymorphism (SNP) C6418T of the Prkdc gene encoding for the DNA-repair enzyme DNA-PKcs. In addition, plasminogen (Plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the Prkdc gene in C57BL/6 (PrkdcC6418/C6418) and 129S1/SvImJ (PrkdcT6418/T6418) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with PrkdcT6418/T6418 developed proteinuria. Genetic deficiency of Plg (Plg-/-) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of Plg in Plg+/+ mice after doxorubicin injection involving histone H2B as Plg receptor. In doxorubicin-resistant C57BL/6 mice, Plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two-hit process requiring the C6418T SNP in the Prkdc gene and subsequent glomerular binding of Plg.
CRIS-Team Scopus Importer:2021-10-15
Keywords: DNA-pkcs; Doxorubicin; Nephropathy; Plasminogen; Prkdc

Establishment of Real-Time Multispectral Imaging for the Detection of Bladder Cancer Using a Preclinical in Vivo Model - Meessen, Sabine; Rother, Jan; Zheng, Xi; Eckstein, Markus; Kriegmair, Maximilian C.; Hernandez, David; Grychtol, Bartlomiej; Deliolanis, Nikolaos C.; Bolenz, Christian; Gunes, Cagatay (Bladder Cancer, 2020)
BACKGROUND: Emerging imaging technologies such as real-time multispectral imaging (rMSI) hold great potential for simultaneous visualization of multiple target structures using fluorophores on various tumours including bladder cancer (BC). These technologies, however, require a multi-step preclinical evaluation process, including mouse models.
CRIS-Team WoS Importer:2020-10-16

Ethylene glycol poisoning - Garibashvili, Tamara; Roeder, Maximilian; Pfluegler, Carolin; Breckner, Martin; Amann, Kerstin Ute; Heckmann, Josef G. (Practical Neurology, 2022)
CRIS-Team WoS Importer:2022-10-21

ETV6 Gene Rearrangements Characterize a Morphologically Distinct Subset of Sinonasal Low-grade Non-intestinal-type Adenocarcinoma: A Novel Translocation-associated Carcinoma Restricted to the Sinonasal Tract - Andreasen, Simon; Skálová, Alena; Agaimy, Abbas; Bishop, Justin A.; Laco, Jan; Leivo, Ilmo; Franchi, Alessandro; Larsen, Stine R.; Erentaite, Daiva; Ulhøi, Benedicte P.; von Buchwald, Christian; Melchior, Linea C.; et al. (American Journal of Surgical Pathology, 2017)
Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease.
EVALuna2:6881

Europe-side external quality assessment (EQA) of RNA based testing of ER, PR, HER2 and Ki67 in invasive breast cancer - Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Stöhr, Robert; Beckmann, Matthias; Zentgraf, M.; Rübner, Matthias; Hübner, Hanna; Fischer, J.; Guerini Rocco, E.; Viale, G.; Cayre, A.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-06-26

Evaluation of a Hybrid Capture–Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes - Kroeze, Leonie I.; de Voer, Richarda M.; Kamping, Eveline J.; von Rhein, Daniel; Jansen, Erik A.M.; Hermsen, Mandy J.W.; Barberis, Massimo C.P.; Botling, Johan; Garrido-Martin, Eva M.; Haller, Florian; Lacroix, Ludovic; Maes, Brigitte; et al. (Journal of Molecular Diagnostics, 2020)
Stratification of patients for targeted and immune-based therapies requires extensive genomic profiling that enables sensitive detection of clinically relevant variants and interrogation of biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI). Detection of single and multiple nucleotide variants, copy number variants, MSI, and TMB was evaluated using a commercially available next-generation sequencing panel containing 523 cancer-related genes (1.94 megabases). Analysis of formalin-fixed, paraffin-embedded tissue sections and cytologic material from 45 tumor samples showed that all previously known MSI-positive samples (n = 7), amplifications (n = 9), and pathogenic variants (n = 59) could be detected. TMB and MSI scores showed high intralaboratory and interlaboratory reproducibility (eight samples tested in 11 laboratories). For reliable TMB analysis, 20 ng DNA was shown to be sufficient, even for relatively poor-quality samples. A minimum of 20% neoplastic cells was required to minimize variations in TMB values induced by chromosomal instability or tumor heterogeneity. Subsequent analysis of 58 consecutive lung cancer samples in a diagnostic setting was successful and revealed sufficient somatic mutations to generate mutational signatures in 14 cases. In conclusion, the 523-gene assay can be applied for evaluation of multiple DNA-based biomarkers relevant for treatment selection.
CRIS-Team Scopus Importer:2020-06-02

Evaluation of a Wireless Localization System for Nonpalpable Breast Lesions - Feasibility and Cost-effectiveness in Everyday Clinical Routine - Heindl, Felix; Schulz-Wendtland, Rüdiger; Jud, Sebastian; Erber, Ramona; Hack, Carolin; Preuss, Caroline; Behrens, Annika; Pöschke, Patrik; Emons, Julius (In Vivo, 2022)
BACKGROUND/AIM: Smaller, earlier-stage breast tumors are being found in breast cancer screening, and neoadjuvant chemotherapy is the gold standard when chemotherapy is indicated. Precise marking and localization of the tumor are thus becoming increasingly important. Wire-free localization techniques are under investigation in order to reduce presurgical radiography, pain, the risk of wire dislocation, and allow scheduling flexibility for patients and surgery departments. PATIENTS AND METHODS: This single-center observational study from June 2020 to October 2021 included 15 patients with mammographically or sonographically detected nonpalpable breast lesions. Radiofrequency identification (RFID) tags were placed preoperatively under ultrasound or radiologic guidance to localize lesions for planned surgery. All patients underwent breast conservation surgery, including one bilateral and one targeted axillary dissection. RESULTS: Histology identified two benign and 13 malignant lesions, including three ductal carcinomas in situ and 11 invasive breast cancers. Placement, control radiography, and handling of the RFID tag were feasible in everyday routine for different radiologists and surgeons and managed cost-effectively. All of the RFID tags were found in the specimen radiographs. CONCLUSION: The feasibility and cost-effectiveness of this non-wire localization method were demonstrated in this rather small cohort of patients. Further studies including larger numbers of patients are needed to confirm the method's accuracy.
CRIS-Team Scopus Importer:2022-10-07
Keywords: Breast cancer; localization; RFID; surgery

Evaluation of different diagnostic methods for identification of FGFR alteration in advanced urothelial carcinomas: Proficiency results based on multiple RNA extraction kits and mutation detection methods - Weyerer, Veronika; Stöhr, Robert; Juette, H.; Wirtz, R.; Eckstein, Markus; Roghmann, F.; Breyer, J.; Porubsky, S.; Sikic, D.; Bolenz, C.; Kriegmair, M. C.; Hartmann, Arndt; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Evaluation of endocervical curettage (ECC) in colposcopy for detecting cervical intraepithelial lesions - Behrens, Annika; Dietl, Anna; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Mehlhorn, Grit; Koch, Martin C.; Schulmeyer, Carla; Seibold, Anja; Gaß, Paul; et al. (Archives of Gynecology and Obstetrics, 2024)
Purpose: Diagnostic challenges in colposcopy arise especially in women aged 50 or older, with postmenopausal status and transformation zone type 3 (TZ3). Endocervical curettage (ECC) is a valuable tool for diagnosing intracervical lesions. The aim of this retrospective analysis was to evaluate the use of ECC in colposcopy for detecting cervical intraepithelial lesions. Methods: A retrospective study was carried out of colposcopies performed in the certified Dysplasia Unit at Erlangen University Hospital between July 2016 and June 2023. Pap and human papillomavirus (HPV) results were correlated with the histologic findings via ECC, obtained during examinations or surgery. The primary outcome was the rate of accuracy between the colposcopic and histologic findings with regard to cytology, age of patients, and type of transformation zone (TZ). Results: A total of 429 colposcopies in 413 women with histologic samples obtained via ECC were included in the final analysis. In all, 355 women had TZ3. Among patients with TZ3, evidence of high-grade lesions and invasive carcinoma was also found in women with normal or low-grade abnormal cytology. For patients with normal colposcopic findings, cervical intraepithelial neoplasia (CIN) 2 and CIN 3/adenocarcinoma in situ (AIS) were found in 56 patients (16%), and invasive carcinoma was found in four patients (0.1%). Conclusion: This analysis suggests that ECC is a valuable tool in the diagnosis of cervical intraepithelial neoplasia, especially for patients who present with a normal colposcopy of the cervix and vagina but have either recurrent abnormal cytologic findings or high-grade abnormal cytology indicating CIN 2 +.
CRIS-Team Scopus Importer:2024-11-08
Keywords: Cervical cancer; Cervical cancer screening assessment; Cervical intraepithelial neoplasia; Colposcopy; Cytology; Endocervical curettage

Evaluation of FAM19A4/miR124-2 methylation performance in the management of CIN3 diagnosed pregnant women - Hampl, Monika; Hesselink, Albertus T.; Meijer, Chris J. L. M.; Denecke, Agnieszka; Einhorn, Ina; Reinecke-Luethge, Axel; Geppert, Carol-Immanuel; Jentschke, Matthias; Petry, Karl U.; Hillemanns, Peter (International Journal of Cancer, 2022)
Pregnant women diagnosed with CIN3 have high regression rates after delivery. Biomarkers are needed to only identify pregnant women with progressive CIN requiring treatment to reduce overreferral and overtreatment. In our study we evaluated the performance of the FAM19A4/miR124-2 methylation test for molecular triage on FFPE samples of CIN3+-diagnosed pregnant women with known clinical course over time as well in a cross-sectional setting. In this German multicenter retrospective study biopsy material was collected from pregnant women diagnosed with cervical cancer (n = 16), with CIN3 that progressed to cancer during pregnancy (n = 7), with CIN3 that regressed to CIN1 or less within 6 months after delivery (n = 41), without CIN (n = 16), CIN3 covering 3-4 quadrants (n = 14) and randomly selected CIN3 (n = 41). FAM19A4/miR124-2 methylation analysis was performed blinded on first diagnosis. All pregnant women with cervical cancer and with CIN3 progressing to cancer tested positive for FAM19A4/miR124-2 methylation (100%, 22/22). In the regressing CIN3 group 47.5% and in the group without CIN 21.6% tested methylation positive. High-volume CIN3 and random selected CIN3 were methylation-positive in 91.7% and 82.1%, respectively. Methylation levels were significantly higher in progressive CIN3 and cancer compared to the controls (P < .0005). The likelihood ratio of a negative methylation test (LR-) for progressive CIN3+ was 0 (95% CI: 0-0.208). A negative FAM19A4/miR124-2 methylation test can rule out progressive CIN disease in pregnant women diagnosed with CIN3. This can help the clinician by managing these pregnant women with conservative follow-up until after delivery.
CRIS-Team WoS Importer:2022-07-01

Evaluation of FGFR Alteration Status in Urothelial Tumors - Bahlinger, Veronika; Eckstein, Markus; Hartmann, Arndt; Stöhr, Robert (Urothelial Carcinoma - Methods and Protocols, 2023)
FGFR alterations in urothelial carcinoma are key driver alterations of tumorigenesis and are long recognized. In 2019 the Food and Drug Administration (FDA) approved the first pan-FGFR inhibitor, as the first specific targeted therapy in urothelial carcinoma. To receive the drug, alteration testing is required, and only alteration carriers can profit of this new agent. Due to this clinical need of detection and analysis of FGFR, here we describe two distinct and specific analytical methodologies: the SNaPshot analysis of nine FGFR3 point mutations and the QIAGEN therascreen® FGFR RGQ RT-PCR Kit, the FDA-approved companion diagnostic kit.
CRIS-Team Scopus Importer:2023-07-21
Keywords: FGFR testing; Inhibitor; QIAGEN therascreen; SNaPshot analysis; Targeted therapy; Urothelial carcinoma

Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma - Mikuteit, Marie; Zschäbitz, Stefanie; Stoehr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Ströbel, Philipp; Becker, Frank; Wülfing, Christian; Barth, Peter; Stöckle, Michael; et al. (Urologia Internationalis, 2023)
Introduction: Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. Methods: The patients' sample collection is a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. Results: In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas- groups did not significantly differ in any tumor or patient characteristics. Conclusion: Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.
CRIS-Team Scopus Importer:2023-08-11

Evaluation of Nectin-4 and Trop-2: Implications for Patient Outcomes and Therapy in Penile Cancer - Mink, Jan Niklas; Eckstein, Markus; Khalmurzaev, Oybek; Pryalukhin, Alexey; Geppert, Carol-Immanuel; Lohse, Stefan; Bende, Kristóf; Lobo, João; Henrique, Rui; Loertzer, Hagen; Steffens, Joachim; Jerónimo, Carmen; et al. (Modern Pathology, 2025)
Metastatic penile cancer (PC) continues to have a poor prognosis because of inadequate treatment options. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates (ADCs) that have significantly improved the prognosis of several other tumor types and are, therefore, promising candidates for the successful treatment of metastatic PC. We examined the expression of ADC targets Nectin-4 and Trop-2 in an international multicenter cohort of 203 PC patients both in the primary tumor and in metastases. In addition, we evaluated their prognostic values. Either intermediate or high Nectin-4 membrane expression was found in 28.0% of primary tumors and 18.8% of metastases. The expression in primary tumor decreased significantly with increasing T stage (P ≤ .001). It did not correlate with human papillomavirus status (P = .307) and was not associated with metastasis-free survival, cancer-specific survival, or overall survival. Nectin-4 expression levels at the tumor front and in metastases were significantly associated with each other (P = .005). Trop-2 was detected on the membrane of almost all samples with intermediate or high expression (primary tumor, 98.1%; metastasis, 100%). It was not associated with metastasis-free survival, cancer-specific survival, or overall survival. The expression at tumor front was significantly increased in human papillomavirus–positive tumors (P = .005). Neither Nectin-4 nor Trop-2 was found to be of prognostic value in PC. Enfortumab vedotin therapy seems promising for selected patients with high Nectin-4 expression, which should be confirmed in PC metastases before treatment is considered. Trop-2 is highly expressed in almost all PCs, and therefore, it is a very interesting potential target for sacituzumab govitecan therapy. Both ADCs warrant investigation in clinical trials focusing on PC.
CRIS-Team Scopus Importer:2025-05-23
Keywords: antibody-drug conjugate; immunohistochemistry; Nectin-4; penile squamous cell carcinoma; Trop-2

EVALUATION OF OPTOACOUSTIC IMAGING FOR ANALYSIS OF PLACENTAL VILLOUS VASCULARIZATION - Hübner, Hanna; Knieling, Ferdinand; Faschingbauer, Florian; Rübner, Matthias; Kehl, Sven; Beckmann, Matthias; Rascher, Wolfgang; Hartner, Andrea; Fahlbusch, Fabian (2018)
EVALuna2:208000

Evaluation of Potential Targeted Therapy and Molecular Subtype in Large Nested Variant of Urothelial Carcinoma (LNUC) - Weyerer, Veronika; Eckstein, Markus; Comperat, Eva; Juette, Hendrik; Gaisa, Nadine; Allory, Yves; Stoehr, Robert; Wullich, Bernd; Roupret, Morgan; Hartmann, Arndt; Bertz, Simone (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Evaluation of Prognostic Parameters to Identify Aggressive Penile Carcinomas - Mink, Jan Niklas; Khalmurzaev, Oybek; Pryalukhin, Alexey; Geppert, Carol-Immanuel; Lohse, Stefan; Bende, Kristóf; Lobo, João; Henrique, Rui; Loertzer, Hagen; Steffens, Joachim; Jerónimo, Carmen; Wunderlich, Heiko; et al. (Cancers, 2023)
Background: Advanced penile carcinoma is characterized by poor prognosis. Most data on prognostic factors are based on small study cohorts, and even meta-analyses are limited in patient numbers. Therefore, there is still a lack of evidence for clinical decisions. In addition, the most recent TNM classification is questionable; in line with previous studies, we found that it has not improved prognosis estimation. Methods: We evaluated 297 patients from Germany, Russia, and Portugal. Tissue samples from 233 patients were re-analyzed by two experienced pathologists. HPV status, p16, and histopathological parameters were evaluated for all patients. Results: Advanced lymph node metastases (N2, N3) were highly significantly associated with reductions in metastasis-free (MFS), cancer-specific (CS), and overall survival (OS) rates (p = <0.001), while lymphovascular invasion was a significant parameter for reduced CS and OS (p = 0.005; p = 0.007). Concerning the primary tumor stage, a significant difference in MFS was found only between pT1b and pT1a (p = 0.017), whereas CS and OS did not significantly differ between T categories. In patients without lymph node metastasis at the time of primary diagnosis, lymphovascular invasion was a significant prognostic parameter for lower MFS (p = 0.032). Histological subtypes differed in prognosis, with the worst outcome in basaloid carcinomas, but without statistical significance. HPV status was not associated with prognosis, either in the total cohort or in the usual type alone. Conclusion: Lymphatic involvement has the highest impact on prognosis in penile cancer, whereas HPV status alone is not suitable as a prognostic parameter. The pT1b stage, which includes grading, as well as lymphovascular and perineural invasion in the T stage, seems questionable; a revision of the TNM classification is therefore required.
CRIS-Team Scopus Importer:2023-10-20
Keywords: histological subtype; HPV; p16; penile cancer; prognosis

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study - Koebel, M.; Madore, J.; Ramus, S. J.; Clarke, B. A.; Pharoah, P. D. P.; Deen, S.; Bowtell, D. D.; Odunsi, K.; Menon, U.; Morrison, C.; Lele, S.; Bshara, W.; et al. (British Journal of Cancer, 2014)
Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.
EVALuna2:6660

Evolution of PD-1 and PD-L1 Gene and Protein Expression in Primary Tumors and Corresponding Liver Metastases of Metastatic Bladder Cancer - Eckstein, Markus; Sikic, Danijel; Strissel, Pamela; Erlmeier, Franziska (European Urology, 2018)
EVALuna2:35883

EWSR1::ATF1 fusions characterize a group of extra-abdominal epithelioid and round cell mesenchymal neoplasms, phenotypically overlapping with sclerosing epithelioid fibrosarcomas, and intra-abdominal FET::CREB fusion neoplasms - Rekhi, Bharat; Dermawan, Josephine K.; Fritchie, Karen J.; Zimpfer, Annette; Mohammad, Tareq M.; Ali, Fatima S.; Nandy, Koushik; Zou, Youran; Stöhr, Robert; Agaimy, Abbas (Virchows Archiv, 2024)
With the increasing use of next generation sequencing in soft tissue pathology, particularly in neoplasms not fitting any World Health Organization (WHO) category, the spectrum of EWSR1 fusion-associated soft tissue neoplasms has been expanding significantly. Although recurrent EWSR1::ATF1 fusions were initially limited to a triad of mesenchymal neoplasms including clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma and malignant gastrointestinal neuroectodermal tumor (MGNET), this family has been expanding. We herein describe 4 unclassified extra-abdominal soft tissue (n = 3) and bone (n = 1) neoplasms displaying epithelioid and round cell morphology and carrying an EWSR1::ATF1 fusion. Affected were 3 males and 1 female aged 20–56 years. All primary tumors were extra-abdominal and deep-seated (chest wall, mediastinum, deltoid, and parapharyngeal soft tissue). Their size ranged 4.4–7.5 cm (median, 6.2). One patient presented with constitutional symptoms. Surgery with (2) or without (1) neo/adjuvant therapy was the treatment. At last follow-up (8–21 months), 2 patients developed progressive disease (1 recurrence; 1 distant metastasis). The immunophenotype of these tumors is potentially misleading with variable expression of EMA (2 of 3), pankeratin (2 of 4), synaptophysin (2 of 3), MUC4 (1 of 3), and ALK (1 of 3). All tumors were negative for S100 and SOX10. These observations point to the existence of heretofore under-recognized group of epithelioid and round cell neoplasms of soft tissue and bone, driven by EWSR1::ATF1 fusions, but distinct from established EWSR1::ATF1-associated soft tissue entities. Their overall morphology and immunophenotype recapitulate that of the emerging EWSR1/FUS::CREB fusion associated intra-abdominal epithelioid/round cell neoplasms. Our cases point to a potentially aggressive clinical behavior. Recognizing this tumor type is mandatory to delineate any inherent biological and/or therapeutic distinctness from other, better-known sarcomas in the differential diagnosis including sclerosing epithelioid fibrosarcoma.
CRIS-Team Scopus Importer:2024-07-26
Keywords: Ewing sarcoma; Genetic landscape; Mimics; Precision medicine; Profiling; Targeted next-generation sequencing

EWSR1-FUSION-NEGATIVE, SMARCB1-DEFICIENT PRIMARY PULMONARY MYXOID SARCOMA - Agaimy, Abbas; Duell, Thomas; Morresi-Hauf, Alicia T. (Polish Journal of Pathology, 2017)
Primary pulmonary myxoid sarcoma (PPMS) is a recently defined rare neoplasm with histological and molecular similarity to extraskeletal myxoid chondrosarcoma. To date, 20 cases have been reported. A 48-year-old man presented with a huge mass filling the right hemithorax and extending into the tracheobronchial system. Histological findings were consistent with PPMS. Immunohistochemistry was positive for vimentin, CD10, and EMA, but other lineage-specific markers were negative. SMARCB1 (INI1) expression was lost in the tumour cells. FISH analysis (EWSR1, FUS, NR4A3, and SMARCB1) revealed no abnormalities. This case suggests SMARCB1 loss as a possible alternative molecular event driving EWSR1-negative PPMS.
EVALuna2:34886

EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers - Michal, Michael; Rubin, Brian P.; Agaimy, Abbas; Kosemehmetoglu, Kemal; Rudzinski, Erin R.; Linos, Konstantinos; John, Ivy; Gatalica, Zoran; Davis, Jessica L.; Liu, Yajuan J.; Mckenney, Jesse K.; Billings, Steven D.; et al. (Modern Pathology, 2020)
The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18–60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.
CRIS-Team Scopus Importer:2020-10-16

EWSR1::POU2AF3(COLCA2) Sarcoma: An Aggressive, Polyphenotypic Sarcoma With a Head and Neck Predilection. - Koshyk, Olena; Dehner, Carina A.; van den Hout, Mari F.C.M.; Bempt, Isabelle Vanden; Sciot, Raf; Huang, Hsuan-Ying; Agaimy, Abbas; Din, Nasir Ud; Klubíčková, Natálie; Mosaieby, Elaheh; Skálová, Alena; Michalová, Květoslava; et al. (Modern Pathology, 2023)
EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of "neuroendocrine-appearing" round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.
EVALuna2:568060

EWSR1-SMAD3-rearranged Fibroblastic Tumor An Emerging Entity in an Increasingly More Complex Group of Fibroblastic/Myofibroblastic Neoplasms - Michal, Michael; Berry, Ryan S.; Rubin, Brian P.; Kilpatrick, Scott E.; Agaimy, Abbas; Kazakov, Dmitry V.; Steiner, Petr; Ptakova, Nikola; Martinek, Petr; Hadravsky, Ladislav; Michalova, Kvetoslava; Szep, Zoltan; et al. (American Journal of Surgical Pathology, 2018)
Three cases of superficial acral fibroblastic spindle cell neoplasms with EWSR1-SMAD3 fusion have been recently reported. Their differential diagnosis is broad, primarily comprising rare tumors from the fibroblastic/myofibroblastic category. The aim of this report is to present 4 new cases of this entity and to discuss the appropriate differential diagnosis. Also, as the ERG antibody seems to be a characteristic marker for these tumors, we analyzed ERG immunostaining characteristics in potential mimics of this entity. All cases in our cohort occurred in women aged 5 to 68 years (mean, 36.5 y). Two were located on the hand, 1 on foot, and the last case arose on the calf. The tumor size ranged from 1 to 1.5 cm in the greatest dimension, with a mean size of 1.2 cm. Except for one recent case, follow-up was available, ranging from 7 to 18 years (mean, 11.7 y), with a recurrence noted in 1 case after 10 years. All tumors were subcutaneous and showed 2 main components. One consisted of bland, spindled cells with elongated nuclei which were round when observed on the cross-section. These cells mostly grew in relatively hypercellular, well-organized, and intersecting fascicles. The second component was prominently hyalinized and paucicellular, but lacked calcifications. Both components showed either a distinct zonation pattern, or they were randomly intermingled with each other. In all 3 analyzable tumors, next-generation sequencing showed EWSR1-SMAD3 gene fusion in each case. By fluorescence in situ hybridization, one tested case also revealed unbalanced rearrangement of the EWSR1 gene. All 4 cases showed strong, diffuse nuclear expression of ERG, whereas none of the mimics stained with this antibody except for weak to moderate staining in calcifying aponeurotic fibromas (9/10 cases). Two tumors showed focal weak to moderate expression of SAT-B2. The 4 herein presented cases further broaden the clinicopathologic spectrum of tumors with EWSR1-SMAD3 gene fusion. They also confirm that they represent a novel entity for which we propose the name EWSR1-SMAD3-rearranged fibroblastic Tumor. Our study also proves that in the context of fibroblastic/myofibroblastic tumors, ERG immunohistochemistry is a relatively specific marker for these neoplasms.
EVALuna2:34866

Exceptional response to neoadjuvant targeted therapy with the selective RET inhibitor selpercatinib in RET-fusion-associated sarcoma - Schrenk, Karin G.; Weschenfelder, Wolfram; Spiegel, Christian; Agaimy, Abbas; Stöhr, Robert; Hartmann, Arndt; Gassler, Nikolaus; Drescher, Robert; Freesmeyer, Martin; Malouhi, Amer; Buerckenmeyer, Florian; Aschenbach, Rene; et al. (Journal of Cancer Research and Clinical Oncology, 2022)
With the increasing use of next-generation sequencing, highly effective targeted therapies have been emerging as treatment options for several cancer types. Recurrent gene-fusions have been recognized in sarcomas; however, options for targeted therapy remain scarce. Here, we describe a case of a sarcoma, associated with a RET::TRIM33-fusion gene with an exceptional response to a neoadjuvant therapy with the selective RET inhibitor selpercatinib. Resected tumor revealed subtotal histopathologic response. This is the first report of successful targeted therapy with selpercatinib in RET-fusion-associated sarcomas. As new targeted therapies are under development, similar treatment options may become available for sarcoma patients.
CRIS-Team WoS Importer:2023-01-06

Exosomal ROR1 in peritoneal fluid identifies peritoneal disseminated PDAC and is associated with poor survival - Mittelstädt, Anke; Anthuber, Anna; David, Paul; Podolska, Malgorzata; Benard, Alan; Brunner, Maximilian; Krautz, Christian; Jacobsen, Anne; Denz, Axel; Weber, Klaus; Merkel, Susanne; Hackner, Danilo; et al. (Frontiers in Immunology, 2024)
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters. Methods: Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed. Results: PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482). Conclusion: With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC.
CRIS-Team Scopus Importer:2024-06-14
Keywords: biomarker; exosomes; PDAC; peritoneal carcinomatosis; peritoneal fluid; peritoneal lavage; ROR1; targeted therapy

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients - Fuchs, Talia L.; Maclean, Fiona; Turchini, John; Vargas, A. Cristina; Bhattarai, Selina; Agaimy, Abbas; Hartmann, Arndt; Kao, Chia-Sui; Ellis, Carla; Bonert, Michael; Leroy, Xavier; Kunju, Lakshmi P.; et al. (Modern Pathology, 2021)
Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.
CRIS-Team WoS Importer:2021-12-31

Expanding the molecular spectrum of gene fusions in endometrial stromal sarcoma: Novel subunits of the chromatin remodeling complexes PRC2 and NuA4/TIP60 as alternative fusion partners - Dermawan, Josephine K. K.; Dashti, Nooshin; Chiang, Sarah; Turashvili, Gulisa; Dickson, Brendan C. C.; Ellenson, Lora H. H.; Kirchner, Martina; Stenzinger, Albrecht; Mechtersheimer, Gunhild; Agaimy, Abbas; Antonescu, Cristina R. R. (Genes Chromosomes & Cancer, 2022)
Endometrial stromal sarcomas (ESS) are morphologically and molecularly heterogeneous. We report novel gene fusions (EPC1::EED, EPC1::EZH2, ING3::PHF1) identified by targeted RNA sequencing in five cases. The ING3::PHF1-fusion positive ESS presented in a 58-year-old female as extrauterine mesocolonic, ovarian masses, and displayed large, monomorphic ovoid-to-epithelioid cells arranged in solid sheets. The patient remained alive with disease 13 months after surgery. The three ESS with EPC1::EED occurred in the uterine corpus in patients with a median age of 58 years (range 27-62 years). One tumor showed a uniform epithelioid nested morphology, while the other two were composed of monomorphic spindle cells in fascicles with elevated mitotic figures, focal tumor cell necrosis, and lymphovascular invasion. At a median follow-up of 20 months, two patients developed local recurrence, including one with concomitant distant metastasis, while one patient remained free of disease. All three patients were alive at the last follow-up. The EPC1::EZH2-fusion positive ESS presented in a 52-year-old female in the uterus, and displayed uniform spindled cells arranged in short fascicles, with focally elevated mitotic activity but without necrosis. The patient remained free of disease 3 months after surgery. All cases were diffusely positive for CD10; four diffusely express estrogen and progesterone receptors. Our study expands the molecular spectrum of EPC1 and PHF1-related gene fusions in ESS to include additional novel subunits of the PRC2 and/or NuA4/TIP60 complexes. These cases displayed a monomorphic epithelioid or spindled phenotype, spanning low-grade and high-grade cytomorphology, all expressing CD10 and commonly ER and PR, and are prone to local and/or distant spread.
CRIS-Team WoS Importer:2022-12-23

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease - Schmitt, Heike; Billmeier, Ulrike; Dieterich, Walburga; Rath, Timo; Sonnewald, Sophia; Reid, Stephen; Hirschmann, Simon; Hildner, Kai; Waldner, Maximilian; Mudter, Jonas; Hartmann, Arndt; Grützmann, Robert; et al. (Gut, 2018)
OBJECTIVE: Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy. DESIGN: Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS. RESULTS: Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23. CONCLUSIONS: Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.
EVALuna2:34305

Experimental renal transplantation in rats improves cardiac dysfunction caused by chronic kidney disease while LVH persists - Hagmayer, Linda; Mayer, Christina; Ebert, Nadja; Amann, Kerstin Ute; Daniel, Christoph (Frontiers in Cardiovascular Medicine, 2023)
Background: Chronic kidney disease (CKD) causes congestive heart failure (CHF) with systolic dysfunction and left ventricular hypertrophy (LVH), which is a major contributor to increased mortality in CKD patients. It remains unclear whether cardiovascular changes that occur during the course of CKD can be reversed when renal function is restored by transplantation. Methods: To investigate this, chronic kidney disease was established in F344 rats by subtotal nephrectomy (SNx) for 8 weeks, followed by transplantation of a functional kidney from an isogenic F344 donor. SNx rats without transplantation and sham-operated animals served as controls. Renal function was assessed before and throughout the experiment. In addition, cardiac ultrasound was performed at weeks 0, 8, 12 and 16. At the end of the experiment, intra-arterial blood pressure was measured and kidneys and hearts were histologically and molecularly examined. Results: Eight weeks after SNx, rats developed marked renal dysfunction associated with significant glomerulosclerosis and tubulointerstitial fibrosis, but also an increase in left ventricular mass. After transplantation, renal function normalized but relative heart weight and ventricular mass as assessed by ultrasound scans showed no reduction compared with SNx controls. However, left ventricular wall thickness, fractional shortening and ejection fraction was normalized by renal transplantation. At 8 weeks after kidney transplantation, cardiac expression of BNP and FGF23 was also at levels comparable to healthy controls, whereas these factors were significantly increased in SNx rats. Cardiac fibrosis, as measured by fibronectin mRNA expression, was completely normalized, whereas cardiac fibronectin protein was still slightly but not significantly increased in transplanted animals compared to controls. In addition, the myofibroblast marker collagen 1, as assessed by immunohistochemistry, was significantly increased in SNx rats and also normalized by renal transplantation. Interestingly, CD68+ macrophages were significantly reduced in the hearts of SNx rats and in transplanted animals at slightly higher levels compared to controls. Conclusion: Restoration of renal function by kidney transplantation normalized early cardiac changes at most functional and molecular levels, but did not completely reverse LVH. However, further studies are needed to determine whether restoration of renal function can also reverse LVH at a later time point.
CRIS-Team Scopus Importer:2023-08-11
Keywords: cardiac hypertrophy; chronic kidney disease; FGF23; fibrosis; renal tranplantation

Explainable convolutional neural networks for assessing head and neck cancer histopathology - Dörrich, Marion; Hecht, Markus; Fietkau, Rainer; Hartmann, Arndt; Iro, Heinrich; Gostian, Antoniu-Oreste; Eckstein, Markus; Kist, Andreas (Diagnostic Pathology, 2023)
Purpose: Although neural networks have shown remarkable performance in medical image analysis, their translation into clinical practice remains difficult due to their lack of interpretability. An emerging field that addresses this problem is Explainable AI. Methods: Here, we aimed to investigate the ability of Convolutional Neural Networks (CNNs) to classify head and neck cancer histopathology. To this end, we manually annotated 101 histopathological slides of locally advanced head and neck squamous cell carcinoma. We trained a CNN to classify tumor and non-tumor tissue, and another CNN to semantically segment four classes - tumor, non-tumor, non-specified tissue, and background. We applied Explainable AI techniques, namely Grad-CAM and HR-CAM, to both networks and explored important features that contributed to their decisions. Results: The classification network achieved an accuracy of 89.9% on previously unseen data. Our segmentation network achieved a class-averaged Intersection over Union score of 0.690, and 0.782 for tumor tissue in particular. Explainable AI methods demonstrated that both networks rely on features agreeing with the pathologist’s expert opinion. Conclusion: Our work suggests that CNNs can predict head and neck cancer with high accuracy. Especially if accompanied by visual explanations, CNNs seem promising for assisting pathologists in the assessment of cancer sections.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Classification; Explainable AI; Head and neck cancer; Histopathology; Semantic segmentation

Explaining and Evaluating Deep Tissue Classification by Visualizing Activations of Most Relevant Intermediate Layers - Mohammed, Aliya; Geppert, Carol-Immanuel; Hartmann, Arndt; Kuritcyn, Petr; Bruns, Volker; Schmid, Ute; Wittenberg, Thomas; Benz, Michaela; Finzel, Bettina (Current Directions in Biomedical Engineering, 2022)
Deep Learning-based tissue classification may support pathologists in analyzing digitized whole slide images. However, in such critical tasks, only approaches that can be validated by medical experts in advance to deployment, are suitable. We present an approach that contributes to making automated tissue classification more transparent. We step beyond broadly used visualizations for last layers of a convolutional neural network by identifying most relevant intermediate layers applying Grad-CAM. A visual evaluation by a pathologist shows that these layers assign relevance, where important morphological structures are present in case of correct class decisions. We introduce a tool that can be easily used by medical experts for such validation purposes for any convolutional neural network and any layer. Visual explanations for intermediate layers provide insights into a neural network's decision for histopathological tissue classification. In future research also the context of the input data must be considered.
Created from Fastlane, Scopus look-up
Keywords: Deep Learning; Digital Pathology; Evaluation; Grad-CAM; Intelligent user interface; XAI

Exploring membranous NECTIN-4 expression patterns and enfortumab vedotin response in prostate cancer - Weiten, Richard; Bernhardt, Marit; Niemann, Max; Kristiansen, Glen; Grünwald, Viktor; Ritter, Manuel; Hölzel, Michael; Eckstein, Markus; Alajati, Abdullah; Klümper, Niklas; Krausewitz, Philipp (Journal of Cellular and Molecular Medicine, 2024)
Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130–150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.
CRIS-Team Scopus Importer:2024-08-09
Keywords: antibody-drug conjugates; enfortumab vedotin; mCRPC; NECTIN-4; prostate cancer

Exploring the MIR143-UPAR Axis for the Inhibition of Human Prostate Cancer Cells In Vitro and In Vivo - Wach, Sven; Brandl, Madeleine; Borchardt, Hannes; Weigelt, Katrin; Lukat, Sabine; Nolte, Elke; Al-Janabi, Omar; Hart, Martin; Grässer, Friedrich; Giedl, Josef; Jung, Rudolf; Stöhr, Robert; et al. (Molecular Therapy - Nucleic Acids, 2019)
MIR143 is pathologically downregulated and may function as a tumor suppressor in prostate cancer. Likewise, the urokinase plasminogen activator receptor (UPAR) is overexpressed in prostate carcinoma, representing a negative prognostic marker and putative therapeutic target gene. In this paper, we establish UPAR as a new direct target of MIR143. Luciferase reporter gene constructs identify one of the two in silico-predicted binding sites as functionally relevant for direct MIR143 binding to the 3′ UTR, and, concomitantly, transfection of MIR143 reduces UPAR protein levels in prostate carcinoma cells in vitro. Inhibitory effects on cell proliferation and colony formation, spheroid growth and integrity, and cell viability are extensively analyzed, and they are compared to direct small interfering RNA (siRNA)-mediated uPAR knockdown or combined microRNA (miRNA)-siRNA treatment. Switching to a therapeutically more relevant in vivo model, we demonstrate tumor-inhibitory effects of MIR143 replacement therapy by systemic treatment of mice bearing subcutaneous PC-3 tumor xenografts with MIR143 formulated in polymeric nanoparticles. This efficient, nanoparticle-mediated delivery of intact MIR143 mediates the marked downregulation of uPAR protein, but not mRNA levels, thus indicating translational inhibition rather than mRNA degradation. In summary, we identify UPAR as a direct target gene of MIR143, and we establish the therapeutic anti-tumor potential of nanoparticle-based MIR143 replacement in prostate cancer.
CRIS-Team Scopus Importer:2019-05-07
Keywords: MIR143; miRNA replacement; PEI nanoparticles; prostate cancer; urokinase plasminogen activator receptor; xenograft

Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts - Ruedel, Anke; Dietrich, Peter; Schubert, Thomas; Hofmeister, Simone; Hellerbrand, Claus; Boßerhoff, Anja Katrin (International Journal of Clinical and Experimental Pathology, 2015)
Activated synovial fibroblasts in rheumatoid arthritis (RASF) play a critical role in the pathology of rheumatoid arthritis (RA). Recent studies suggested that deregulation of microRNAs (miRs) affects the development and progression of RA. Therefore, we aimed to identify de-regulated miRs in RASF and to identify target genes that may contribute to the aggressive phenotype of RASF. Quantitative real-time PCR revealed a marked downregulation of miR-188-5p in synovial tissue samples of RA patients as well as in RASF. Exposure to the cytokine interleukine-1? lead to a further downregulation of miR-188-5p expression levels compared to control cells. Re-expression of miR-188-5p in RASF by transient transfection significantly inhibited cell migration. However, miR-188-5p re-expression had no effects on glycosaminoglycan degradation or expression of repellent factors, which have been previously shown to affect the invasive behavior of RASF. In search for target genes of miR-188-5p in RASF we performed gene expression profiling in RASF and found a strong regulatory effect of miR-188-5p on the hyaluronan binding protein KIAA1199 as well as collagens COL1A1 and COL12A1, which was confirmed by qRT-PCR. In silico analysis revealed that KIAA1199 carries a 3'UTR binding site for miR-188-5p. COL1A1and COL12A1 showed no binding site in the mRNA region, suggesting an indirect regulation of these two genes by miR-188-5p. In summary, our study showed that miR-188-5p is down-regulated in RA in vitro and in vivo, most likely triggered by an inflammatory environment. MiR-188-5p expression is correlated to the activation state of RASF and inhibits migration of these cells. Furthermore, miR-188-5p is directly and indirectly regulating the expression of genes, which may play a role in extracellular matrix formation and destruction in RA. Herewith, this study identified potential novel therapeutic targets to inhibit the development and progression of RA.
EVALuna2:4744

Expression and localization of axin 2 in colorectal carcinoma and its clinical implication - Schaal, Ute; Grenz, Sandra; Merkel, Susanne; Rau, Tilman; Hadjihannas, Michel; Kremmer, Elisabeth; Chudasama, Priya; Croner, Roland S.; Behrens, Jürgen; Stürzl, Michael; Naschberger, Elisabeth (International Journal of Colorectal Disease, 2013)
Purpose: Aberrant activation of the Wnt/β-catenin pathway plays a major role in the development of colorectal carcinoma (CRC). Axin 2 is a key protein of this pathway and is upregulated in CRC. Here, we investigated RNA- and protein expression of axin 2 in CRC tissues at the single cell level. Moreover, the association of axin 2 with prognosis and survival was investigated in a large cohort of CRC patients (n = 280). Methods: Localization and expression of axin 2 and β-catenin was investigated using in situ hybridization and immunohistochemical staining. The quantitative expression levels of axin 2 were determined using RT-qPCR. The association of axin 2 expression with prognosis and survival of the patients was determined by statistical analysis (logrank test, Kaplan-Meier). Results: Our results confirmed the upregulation of axin 2 in CRC and showed that it is broadly expressed in the cytoplasm of the tumor epithelial cells both, in the tumor center and at the invasion front. Axin 2 was rarely expressed by tumor stromal cells and only weakly by normal colonic epithelial cells. Staining of β-catenin and axin 2 in consecutive CRC tissue sections revealed that nuclear translocation of β-catenin in the tumor front was not associated with changes in the cytoplasmic localization of axin 2. Axin 2 did not show any association with proven prognostic factors or survival of the CRC patients. Conclusion: The generally increased expression of axin 2 in all tumor stages as compared to normal tissue suggests an initiating pathogenic function in the development of CRC. © 2013 Springer-Verlag Berlin Heidelberg.
Created from Fastlane, Scopus look-up
Keywords: β-Catenin; Axin 2; Colorectal carcinoma; Wnt/β-catenin signaling

Expression and Localization of Lung Surfactant Proteins in Human Testis - Beileke, Stephanie; Claassen, Horst; Wagner, Walter; Matthies, Cord; Ruf, Christian; Hartmann, Arndt; Garreis, Fabian; Paulsen, Friedrich; Schicht, Martin; Bräuer, Lars (PLoS ONE, 2015)
Surfactant proteins (SPs) have been described in various tissues and fluids including tissues of the nasolacrimal apparatus, airways and digestive tract. Human testis have a glandular function as a part of the reproductive and the endocrine system, but no data are available on SPs in human testis and prostate under healthy and pathologic conditions.The aim of the study was the detection and characterization of the surfactant proteins A, B, C and D (SP-A, SP-B, SP-C, SP-D) in human testis. Additionally tissue samples affected by testicular cancer were investigated.Surfactant proteins A, B, C and D were detected using RT-PCR in healthy testis. By means of Western blot analysis, these SPs were detected at the protein level in normal testis, seminoma and seminal fluid, but not in spermatozoa. Expression of SPs was weaker in seminoma compared to normal testicular tissue. SPs were localized in combination with vimentin immunohistochemically in cells of Sertoli and Leydig.Surfactant proteins seem to be inherent part of the human testis. By means of physicochemical properties the proteins appear to play a role during immunological and rheological process of the testicular tissue. The presence of SP-B and SP-C in cells of Sertoli correlates with their function of fluid secretion and may support transportation of spermatozoa. In seminoma the expression of all SP's was generally weaker compared to normal germ cells. This could lead to a reduction of immunomodulatory and rheology processes in the germ cell tumor.
EVALuna2:4444

Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta - Hübner, Hanna; Rascher, Wolfgang; Strick, Reiner; Kehl, Sven; Heindl, Felix; Wachter, David; Beckmann, Matthias; Fahlbusch, Fabian B.; Rübner, Matthias; Hartner, Andrea (Reproductive Sciences, 2017)
INTRODUCTION: Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. METHODS: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg-3 cells with different RA derivates and 2'-deoxy-5-azacytidine (AZA) to induce DNA demethylation. RESULTS: RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines. DISCUSSION: RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication.
EVALuna2:34222

Expression and role of the immune checkpoint regulator PD-L1 in the tumor-stroma interplay of pancreatic ductal adenocarcinoma - Daunke, Tina; Beckinger, Silje; Rahn, Sascha; Krüger, Sandra; Heckl, Steffen; Schäfer, Heiner; Wesch, Daniela; Pilarsky, Christian; Eckstein, Markus; Hartmann, Arndt; Röcken, Christoph; Wandmacher, Anna Maxi; et al. (Frontiers in Immunology, 2023)
Introduction: Immune checkpoint inhibitors (ICI), e.g., targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor PD-1, have markedly improved the therapy of many cancers but so far failed in pancreatic ductal adenocarcinoma (PDAC). Macrophages represent one of the most abundant immune cell populations within the tumor microenvironment (TME) of PDAC being able to either support or restrain tumor progression depending on their phenotype. To better understand treatment failure of PD-L1/PD-1 inhibitors in PDAC, this study examined PD-L1 expression in the context of a dynamic TME in PDAC with a particular focus on the impact of macrophages. Methods: Formalin-fixed and paraffin embedded tissue samples of primary PDAC tissues and corresponding liver metastases were used for immunohistochemical analyses. Serial sections were stained with antibodies detecting Pan-Cytokeratin, CD68, CD163, CD8, and PD-L1.To investigate whether the PD-1/PD-L1 axis and macrophages contribute to immune escape of PDAC cells, a stroma enriched 3D spheroid coculture model was established in vitro, using different PDAC cell lines and macrophages subtypes as well as CD8+ T cells. Functional and flow cytometry analyses were conducted to characterize cell populations. Results: Immunohistochemical analyses revealed that PD-L1 is mainly expressed by stroma cells, including macrophages and not PDAC cells in primary PDAC tissues and corresponding liver metastases. Notably, high local abundance of macrophages and strong PD-L1 staining were commonly found at invasion fronts of tumoral lesions between CD8+ T cells and tumor cells. In order to investigate whether PD-L1 expressing macrophages impact the response of PDAC cells to treatment with PD-L1/PD-1 inhibitors, we developed a spheroid model comprising two different PDAC cell lines and different ratios of in vitro differentiated primary M1- or M2-like polarized macrophages. In line with our in situ findings, high PD-L1 expression was observed in macrophages rather than PDAC cells, which was further increased by the presence of PDAC cells. The effector phenotype of co-cultured CD8+ T cells exemplified by expression of activation markers and release of effector molecules was rather enhanced by PDAC macrophage spheroids, particularly with M1-like macrophages compared to mono-culture spheroids. However, this was not associated with enhanced PDAC cell death. ICI treatment with either Durvalumab or Pembrolizumab alone or in combination with Gemcitabine hardly affected the effector phenotype of CD8+ T cells along with PDAC cell death. Thus, despite strong PD-L1 expression in macrophages, ICI treatment did not result in an enhanced activation and cytotoxic phenotype of CD8+ T cells. Conclusion: Overall, our study revealed novel insights into the interplay of PDAC cells and macrophages in the presence of ICI.
CRIS-Team Scopus Importer:2023-08-25
Keywords: 3D co-culture; immune checkpoint inhibitor; immune evasion; macrophages; pancreatic cancer; tumor microenvironment

Expression of AR-V7 (Androgen receptor variant 7) protein in granular cytoplasmic structures is an independent prognostic factor in prostate cancer patients - König, Paul; Eckstein, Markus; Jung, Rudolf; Abdulrahman, Amer; Guzman, Juan; Weigelt, Katrin; Serrero, Ginette; Hayashi, Jun; Geppert, Carol-Immanuel; Stöhr, Robert; Hartmann, Arndt; Wullich, Bernd; et al. (Cancers, 2020)
Prostate cancer (PCa) is the second most common cancer, causing morbidity and mortality among men world-wide. The expression of the androgen receptor (AR) and its splice variants is a crucial factor of prostate cancer biology that has not been comprehensively studied in PCa tumors. The aim of this study was to characterize the protein expression of the AR and its splice variant, AR-V7, and their subcellular distributions in PCa by immunohistochemistry and to correlate the results to the clinicopathological data and prognosis. Immunohistochemical staining for AR and AR-V7 was performed on a tissue microarray (TMA) with specimens from 410 PCa patients using an immunoreactive score (IRS) or only the percentage of AR-V7 staining in cytoplasmic granules. Nuclear or cytoplasmic AR staining was not associated with prognosis. AR-V7 staining was only occasionally observed in the nucleus. However, AR-V7 staining in the cytoplasm or in cytoplasmic granules was associated with relapse-free survival (RFS). AR-V7 staining of the cytoplasm was associated with a shorter RFS, whereas AR-V7 staining of cytoplasmic granules was associated with a longer RFS. In a multivariate Cox’s regression analysis, only negative (<5%) AR-V7 staining of cytoplasmic granules remained an independent prognostic factor for RFS (HR = 5.3; p = 0.006). In a further subgroup analysis by multivariate Cox’s regression analysis, AR-V7 was an independent prognostic factor in the following groups: age ≤ 65 (HR = 9.7; p = 0.029), negative CK20 staining (HR = 7.0; p = 0.008), and positive perineural invasion (HR = 3.7; p = 0.034). Altogether, AR-V7 protein in granular cytoplasmic structures is an independent prognostic factor for RFS in PCa patients.
CRIS-Team Scopus Importer:2020-09-25
Keywords: AR; AR-V7; Gleason score; Perineural invasion; Prognosis; Prostate cancer; Relapse-free survival; RFS

Expression of disialoganglioside GD2 in breast cancer subtypes - Gaß, Paul; Kailayangiri, Sareetha; Hübner, Hanna; Rübner, Matthias; Hartmann, Arndt; Häberle, Lothar; Völkl, Simon; Mackensen, Andreas; Landgraf, Laura; Schulz-Wendtland, Rüdiger; Farwick, Nicole; Roessig, Claudia; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Expression of GP88 (Progranulin) Protein Is an Independent Prognostic Factor in Prostate Cancer Patients - Abdulrahman, Amer; Eckstein, Markus; Jung, Rudolf; Guzman, Juan; Weigelt, Katrin; Serrero, Ginette; Yue, Binbin; Geppert, Carol-Immanuel; Stöhr, Robert; Hartmann, Arndt; Wullich, Bernd; Wach, Sven; et al. (Cancers, 2019)
Prostate cancer, the second most common cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study was to characterize GP88 protein expression in PCa by immunohistochemistry and to correlate the findings to the clinico-pathological data and prognosis. Immunohistochemical staining for GP88 was performed by TMA with samples from 442 PCa patients using an immunoreactive score (IRS). Altogether, 233 cases (52.7%) with negative GP88 staining (IRS < 2) and 209 cases (47.3%) with positive GP88 staining (IRS >= 2) were analyzed. A significant positive correlation was found for the GP88 IRS with the PSA value at prostatectomy and the cytoplasmic cytokeratin 20 IRS, whereas it was negatively associated with follow-up times. The association of GP88 staining with prognosis was further studied by survival analyses (Kaplan-Meier, univariate and multivariate Cox's regression analysis). Increased GP88 protein expression appeared as an independent prognostic factor for overall, disease-specific and relapse-free survival in all PCa patients. Interestingly, in the subgroup of younger PCa patients (<= 65 years), GP88 positivity was associated with a 3.8-fold (p = 0.004), a 6.0-fold (p = 0.008) and a 3.7-fold (p = 0.003) increased risk for death, disease-specific death and occurrence of a relapse, respectively. In the PCa subgroup with negative CK20 staining, GP88 positivity was associated with a 1.8-fold (p = 0.018) and a 2.8-fold increased risk for death and disease-specific death (p = 0.028). Altogether, GP88 protein positivity appears to be an independent prognostic factor for PCa patients.
CRIS-Team WoS Importer:2020-01-28

Expression of Immune Phenotypes in Rectal Cancer after neoadjuvant Chemoradiotherapy - Schnellhardt, Sören; Hirneth, Johannes; Büttner-Herold, Maike; Daniel, Christoph; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Expression of Nectin-4 in Chromophobe Renal Cell Carcinoma in a Multicenter Cohort: Early Prognostic and Therapeutic Considerations - Mikuteit, Marie; Zschäbitz, Stefanie; Autenrieth, Michael; Weichert, Wilko; Hartmann, Arndt; Steffens, Sandra; Erlmeier, Franziska (Oncology, 2024)
Introduction: Nectin-4 is a member of the nectin family and a calcium-independent immunoglobulin-like transmembrane protein that contributes to tumor growth and angiogenesis in malignant tumors. A nectin-4-directed antibody drug conjugate, enfortumab vedotin-ejf, has recently been approved for treatment in urothelial cancer and is currently under investigation in other tumor entities such as breast, lung, and prostate cancer. In non-clear cell renal cell carcinoma (RCC), vascular endothelial growth factor (VEGF)- directed tyrosine kinase inhibitors and checkpoint inhibitors are currently treatments of choice. However, due to the rarity of disease treatment recommendations for chromophobe RCC (chRCC) are limited and new therapeutic agents urgently needed. In this study, we investigated the expression and prognostic impact of nectin-4 in a large cohort of chRCC. Methods: Patients who underwent renal surgery due to chRCC were recruited. Clinical data were retrospectively evaluated. Tumor specimen was analyzed for nectin-4 expression by immunohistochemistry. Results: Eighty-one chRCC patients were eligible for analysis. In 15 (18.5%) samples, tumors were positive for nectin-4. No significant associations were found for nectin-4 expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis disclosed a 5-year overall survival for nectin-4- negative and nectin-4-positive tumors of 91.8% versus 100.0% (p = 0.316, log rank). Conclusions: In chRCC, a small subset of tumors expresses nectin-4 potentially amenable to nectin-4-directed treatment. Expression of nectin-4 is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.
CRIS-Team Scopus Importer:2024-06-07
Keywords: Chromophobe histology; Nectin-4; Renal cell carcinoma; Survival

Expression of nectin-4 in papillary renal cell carcinoma - Zschabitz, Stefanie; Mikuteit, Marie; Stoehr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Stroebel, Philipp; Becker, Frank; Wuelfing, Christian; Barth, Peter; Stoeckle, Michael; et al. (Discover Oncology, 2022)
Background: Nectin-4 contributes to tumor proliferation, lymphangiogenesis and angiogenesis in malignant tumors and is an emerging target in tumor therapy. In renal cell carcinoma (RCC) VEGF-directed tyrosine kinase inhibitors and checkpoint inhibitors are currently treatments of choice. Enfortumab vedotin-ejf (EV) is an antibody drug conjugate that targets Nectin-4. The aim of our study was to investigate the expression of Nectin-4 in a large cohort of papillary RCC specimens. Patients and methods: Specimens were derived from the PANZAR consortium (Erlangen, Heidelberg, Herne, Homburg, Mainz, Mannheim, Marburg, Muenster, LMU Munich, TU Munich, and Regensburg). Clinical data and tissue samples from n = 190 and n = 107 patients with type 1 and 2 pRCC, respectively, were available. Expression of Nectin-4 was determined by immunohistochemistry (IHC). Results: In total, Nectin-4 staining was moderately or strongly positive in of 92 (48.4%) of type 1 and 39 (36.4%) type 2 of pRCC cases. No associations between Nectin-4 expression and age at diagnosis, gender, grading, and TNM stage was found. 5 year overall survival rate was not statistically different in patients with Nectin-4 negative versus Nectin-4 positive tumors for the overall cohort and the pRCC type 2 subgroup, but higher in patient with Nectin-4 positive pRCC type 1 tumors compared to Nectin-4 negative tumors (81.3% vs. 67.8%, p = 0.042). Conclusion: Nectin-4 could not be confirmed as a prognostic marker in pRCC in general. Due to its high abundance on pRCC specimens Nectin-4 is an interesting target for therapeutical approaches e.g. with EV. Clinical trials are warranted to elucidate its role in the pRCC treatment landscape.
CRIS-Team Scopus Importer:2022-10-07
Keywords: Nectin 4; Papillary renal cell carcinoma

Expression of neuroendocrine markers in different molecular subtypes of breast carcinoma - Wachter, David; Hartmann, Arndt; Beckmann, Matthias; Fasching, Peter; Hein, Alexander; Bayer, Christian M.; Agaimy, Abbas (BioMed Research International, 2014)
Carcinomas of the breast with neuroendocrine features are incorporated in the World Health Organization classification since 2003 and include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas/small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. Neuroendocrine differentiation is known to be more common in certain low-grade histologic special types and has been shown to mainly cluster to the molecular (intrinsic) luminal A subtype.We analyzed the frequency of neuroendocrine differentiation in different molecular subtypes of breast carcinomas of no histologic special type using immunohistochemical stains with specific neuroendocrine markers (chromogranin A and synaptophysin).We found neuroendocrine differentiation in 20% of luminal B-like carcinomas using current WHO criteria (at least 50% of tumor cells positive for synaptophysin or chromogranin A). In contrast, no neuroendocrine differentiation was seen in luminal A-like, HER2 amplified and triple-negative carcinomas. Breast carcinomas with neuroendocrine differentiation presented with advanced stage disease and showed aggressive behavior.We conclude that neuroendocrine differentiation is more common than assumed in poorly differentiated luminal B-like carcinomas. Use of specific neuroendocrine markers is thus encouraged in this subtype to enhance detection of neuroendocrine differentiation and hence characterize the biological and therapeutic relevance of this finding in future studies.
EVALuna2:6612

Expression of PD-1 and CTLA-4 Are Negative Prognostic Markers in Renal Cell Carcinoma - Kahlmeyer, Andreas; Stoehr, Christine; Hartmann, Arndt; Goebell, Peter; Wullich, Bernd; Wach, Sven; Taubert, Helge; Erlmeier, Franziska (Journal of Clinical Medicine, 2019)
Immuno-oncological therapy with checkpoint inhibition (CI) has become a new standard treatment in metastatic renal cell carcinoma (RCC), but the prognostic value of the expression of CI therapy target molecules is still controversial. 342 unselected consecutive RCC tumor samples were analyzed regarding their PD-1, PD-L1, and CTLA-4 expression by immunohistochemistry (IHC). The prognostic values for cancer-specific survival (CSS) and overall survival (OS) were analyzed for those not exposed to CI therapy. The expression of PD-1 in tumor-infiltrating mononuclear cells (TIMC) and PD-L1 in tumor cells was detected in 9.4% and 12.3%, respectively (Immune reactive score (IRS) > 0). Furthermore, PD-L1 expression in TIMC (IRS > 0) and CTLA-4 expression in TIMC (>1% positive cells) was detected in 4.8% and 6.3%. PD-1 expression and CTLA-4 expression were significantly associated with a worse OS and CSS in log rank survival analysis and univariate Cox regression analysis. CTLA-4 expression is a prognostic marker that is independently associated with a worse outcome in multivariate Cox regression analysis in the whole cohort (OS: p = 0.013; CSS: p = 0.048) as well as in a non-metastatic subgroup analysis (OS: p = 0.028; CSS: p = 0.022). Patients with combined CTLA-4 expression and PD-1-expression are at highest risk in OS and CSS. In RCC patients, PD-1 expression in TIMC and CTLA-4 expression in TIMC are associated with a worse OS and CSS. The combination of PD-1 expression in TIMC and CTLA-4 expression in TIMC might identify high risk patients. This is, to our knowledge, the first description of CTLA-4 expression to be a prognostic marker in RCC.
CRIS-Team WoS Importer:2019-06-25

Expression of Prostate-specific Membrane Antigen (PSMA) in Papillary Renal Cell Carcinoma - Overview and Report on a Large Multicenter Cohort - Zschaebitz, Stefanie; Erlmeier, Franziska; Stoehr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Stroebel, Philipp; Becker, Frank; Wuelfing, Christian; Barth, Peter; Stoeckle, Michael; et al. (Journal of Cancer, 2022)
Prostate specific membrane antigen (PSMA) is an emerging diagnostic and therapeutic target in prostate cancer. 68 Ga-PSMA-labeled hybrid imaging is used for the detection of prostate primary tumors and metastases. Therapeutic applications such as Lutetium-177 PSMA radionuclide therapy or bispecific antibodies that target PSMA are currently under investigation within clinical trials. The expression of PSMA, however, is not specific to prostate-tissue. It has been described in the neovascular endothelium of different types of cancer such as breast cancer, and clear cell renal cell carcinoma (ccRCC). The aim of this study was to analyze PSMA expression in papillary RCC (pRCC) type 1 and type 2, the most common non-ccRCC subtypes, and to evaluate the potential of PSMA-targeted imaging and treatment in pRCC. Formalin-fixed, paraffin-embedded tissue samples of primary tumors were analyzed for PSMA expression by immunohistochemistry. Out of n=374 pRCC specimens from the multicenter PANZAR consortium, n=197 pRCC type 1 and n=110 type 2 specimens were eligible for analysis and correlated with clinical data. In pRCC type 1 PSMA staining was positive in 4 of 197 (2.0%) samples whereas none (0/110) of the pRCC type 2 samples were positive for PSMA in this large cohort of pRCC patients. No significant PSMA expression was detected in pRCC. Reflecting current clinical evaluation of PMSA expression in RCC do not encourage further analysis in papillary subtypes.
CRIS-Team WoS Importer:2022-04-15
Keywords: prostate specific membrane antigen; papillary renal cell carcinoma; kidney cancer

Expression of Prostate-specific Membrane Antigen (PSMA) in papillary renal cell carcinoma (pRCC) - Zschaebitz, S.; Erlmeier, Franziska; Stoehr, Christine; Polifka, Iris; Schrader, A. J.; Hartmann, Arndt; Ivanyi, P.; Steffens, S. (ONCOLOGY RESEARCH AND TREATMENT, 2019)
CRIS-Team WoS Importer:2020-10-02

Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology - Mocker, Alexander; Schmidt, Marius; Hübner, Hanna; Wachtveitl, Rainer; Cordasic, Nada; Menendez-Castro, Carlos; Hartner, Andrea; Fahlbusch, Fabian (International Journal of Molecular Sciences, 2019)
In humans, retinoic acid receptor responders (RARRES) have been shown to be altered in third trimester placentas complicated by the pathologies preeclampsia (PE) and PE with intrauterine growth restriction (IUGR). Currently, little is known about the role of placental Rarres in rodents. Therefore, we examined the localization and expression of Rarres1 and 2 in placentas obtained from a Wistar rat model of isocaloric maternal protein restriction (E18.5, IUGR-like features) and from an eNOS-knockout mouse model (E15 and E18.5, PE-like features). In both rodent models, Rarres1 and 2 were mainly localized in the placental spongiotrophoblast and giant cells. Their placental expression, as well as the expression of the Rarres2 receptor chemokine-like receptor 1 (CmklR1), was largely unaltered at the examined gestational ages in both animal models. Our results have shown that RARRES1 and 2 may have different expression and roles in human and rodent placentas, thereby underlining immanent limitations of comparative interspecies placentology. Further functional studies are required to elucidate the potential involvement of these proteins in early placentogenesis.
EVALuna2:209516

Expression of the Alpha8 Integrin Chain Facilitates Phagocytosis by Renal Mesangial Cells - Marek, Ines; Becker, Robert; Fahlbusch, Fabian B.; Menendez-Castro, Carlos; Rascher, Wolfgang; Daniel, Christoph; Volkert, Gudrun; Hartner, Andrea (Cellular Physiology and Biochemistry, 2018)
BACKGROUND/AIMS: Healing of mesangioproliferative glomerulonephritis involves degradation of excess extracellular matrix, resolution of hypercellularity by apoptosis and phagocytosis of apoptotic cells. Integrin receptors participate in the regulation of phagocytosis. In mice deficient for alpha8 integrin (Itga8-/-) healing of glomerulonephritis is delayed. As Itga8 is abundant in mesangial cells (MC) which are non-professional phagocytes, we hypothesized that Itga8 facilitates phagocytosis of apoptotic cells and matrix components by MC. METHODS: MC were isolated from wild type (WT) and Itga8-/- mice. Latex beads were coated with matrix components. Apoptosis was induced by cisplatin in macrophages and in DiI-stained MC. After coincubation of latex beads or apoptotic cells with MC, the phagocytosis rate was detected in WT and Itga8-/- MC via fluorescence microscopy and FACS analysis. RESULTS: Itga8-/- MC showed reduced phagocytosis of matrix-coated beads and apoptotic cells compared to WT MC. Reduction of stress fibers was observed in Itga8-/- compared to WT MC. Inhibition of cytoskeletal reorganization by inhibition of Rac1 or ROCK during phagocytosis significantly decreased the rate of phagocytosis by WT MC but not by Itga8-/- MC. CONCLUSION: The expression of Itga8 facilitates phagocytosis in MC, likely mediated by Itga8-cytoskeleton interactions. An impairment of MC phagocytosis might thus contribute to a delayed glomerular regeneration in Itga8-/- mice.
EVALuna2:34300

Expression of the Immune Modulators of the PD-1: PD-L1 Axis in oral Leukoplakia - Ries, Jutta; Wehrhan, Falk; Baran, Christoph; Agaimy, Abbas; Danzer, Eva; Bolzel, Stella; Büttner-Herold, Maike; Kesting, Marco Rainer; Weber, Manuel (2020)
EVALuna2:216185

Expression of the Immunohistochemical Markers CK5, CD117, and EGFR in Molecular Subtypes of Breast Cancer Correlated with Prognosis - Schulmeyer, Carla; Fasching, Peter; Häberle, Lothar; Meyer, Julia; Schneider, Michael; Wachter, David; Rübner, Matthias; Pöschke, Patrik; Beckmann, Matthias; Hartmann, Arndt; Erber, Ramona; Gaß, Paul (Diagnostics, 2023)
Molecular-based subclassifications of breast cancer are important for identifying treatment options and stratifying the prognosis in breast cancer. This study aimed to assess the prognosis relative to disease-free survival (DFS) and overall survival (OS) in patients with triple-negative breast cancer (TNBC) and other subtypes, using a biomarker panel including cytokeratin 5 (CK5), cluster of differentiation 117 (CD117), and epidermal growth factor receptor (EGFR). This cohort–case study included histologically confirmed breast carcinomas as cohort arm. From a total of 894 patients, 572 patients with early breast cancer, sufficient clinical data, and archived tumor tissue were included. Using the immunohistochemical markers CK5, CD117, and EGFR, two subgroups were formed: one with all three biomarkers negative (TBN) and one with at least one of those three biomarkers positive (non-TBN). There were significant differences between the two biomarker subgroups (TBN versus non-TBN) in TNBC for DFS (p = 0.04) and OS (p = 0.02), with higher survival rates (DFS and OS) in the non-TBN subgroup. In this study, we found the non-TBN subgroup of TNBC lesions with at least one positive biomarker of CK5, CD117, and/or EGFR, to be associated with longer DFS and OS.
CRIS-Team Scopus Importer:2023-02-24
Keywords: CD117; CK5; early breast cancer; EGFR; prognosis; therapy; triple-negative breast cancer

Expression of the LIM homeobox domain transcription factor ISL1 (Islet-1) is frequent in rhabdomyosarcoma but very limited in other soft tissue sarcoma types - Erlenbach-Wuensch, Katharina; Haller, Florian; Taubert, Helge; Wuerl, Peter; Hartmann, Arndt; Agaimy, Abbas (Pathology, 2014)
The transcription factor ISL1 (islet-1) has emerged as a useful marker for metastatic pancreatic well differentiated neuroendocrine neoplasms, but recent studies showed wider expression in poorly differentiated neuroendocrine carcinomas from different sites as well as poorly differentiated neuroblastoma. Expression of ISL1 in soft tissue sarcomas has not been studied before.We evaluated ISL1 expression in 249 soft tissue tumour specimens from 249 patients and 17 precursor cell lymphoblastic lymphomas (ALL). ISL1 was not detected in any of 63 liposarcomas of different subtypes, 55 leiomyosarcomas, 22 solitary fibrous tumours, 20 undifferentiated pleomorphic/spindle cell sarcomas, 13 small cell synovial sarcomas and 17 ALL cases. Variable nuclear expression was detected in rhabdomyosarcoma (15/25, 60%), rhabdomyoblastic areas of malignant müllerian mixed tumours (5/5), Ewing sarcoma (2/12, very weak) and monophasic fibrous synovial sarcoma (2/29). More extensive staining (moderate to strong) was restricted to rhabdomyosarcoma. Taken by histological subtype, ISL1 was expressed more frequently in alveolar (9/11, 82%) versus non-alveolar (6/14, 43%) rhabdomyosarcoma. ISL1 is commonly expressed in rhabdomyosarcoma, particularly the alveolar subtype and should be distinguished from poorly differentiated neuroendocrine and neuroblastic neoplasms. Awareness of this finding helps to avoid misinterpretation as neuroendocrine neoplasms that would result in inappropriate therapeutic and prognostic consequences.
EVALuna2:6594

Expression of the p53 Inhibitors MDM2 and MDM4 as Outcome Predictor in Muscle-invasive Bladder Cancer - Kriegmair, Maximilian Christian; Balk, Matthias; Wirtz, Ralph; Steidler, Annette; Weis, Cleo-Aron; Breyer, Johannes; Hartmann, Arndt; Bolenz, Christian; Erben, Philipp (Anticancer Research, 2016)
To evaluate the prognostic role of the p53-upstream inhibitors MDM2, MDM4 and its splice variant MDM4-S in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC).mRNA Expression levels of MDM2, MDM4 and MDM4-S were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) in 75 RC samples. Logistic regression analyses identified predictors of recurrence-free (RFS) and cancer-specific survival (CSS).High expression was found in 42% (MDM2), 27% (MDMD4) and 91% (MDM4-S) of tumor specimens. Increased MDM2 expression was significantly associated with higher tumor stage (p=0.05) and lymphovascular invasion (LVI) (p=0.041). In the univariate analysis, low MDM4 expression (hazard ratio (HR)=5.93; p=0.002; HR=3.00; p=0.047), but not MDM2 (HR=1.63; p=0.222; HR=1.59; p=0.27), were associated with RFS and CSS. In the multivariate analysis, the combination of low MDM4 and high MDM2 was significant for RFS and CSS (HR=14.9; p=0.001; HR=5.63; p=0.019).The combination of MDM2 and MDM4 expression is an independent predictor in patients undergoing RC for MIBC.
EVALuna2:6922

Expression of transforming growth factor beta 1-related signaling proteins in irradiated vessels - Preidl, Raimund; Moebius, Patrick; Weber, Manuel; Amann, Kerstin Ute; Neukam, Friedrich Wilhelm; Schlegel, Andreas; Wehrhan, Falk (Strahlentherapie und Onkologie, 2015)
Microvascular free tissue transfer is a standard method in head and neck reconstructive surgery. However, previous radiotherapy of the operative region is associated with an increased incidence in postoperative flap-related complications and complete flap loss. As transforming growth factor beta (TGF-?) 1 and galectin-3 are well known markers in the context of fibrosis and lectin-like oxidized low-density lipoprotein 1 (LOX-1) supports vascular atherosclerosis, the aim of this study was to evaluate the expression of TGF-?1 and related markers as well as LOX-1 in irradiated vessels.To evaluate the expression of galectin-3, Smad 2/3, TGF-?1, and LOX-1, 20 irradiated and 20 nonirradiated arterial vessels were used for immunohistochemical staining. We semiquantitatively assessed the ratio of stained cells/total number of cells (labeling index).Expression of galectin-3, Smad 2/3, and TGF-?1 was significantly increased in previously irradiated vessels compared with nonirradiated controls. Furthermore, LOX-1 was expressed significantly higher in irradiated compared with nonirradiated vessels.Fibrosis-related proteins like galectin-3, Smad 2/3, and TGF-?1 are upregulated after radiotherapy and support histopathological changes leading to vasculopathy of the irradiated vessels. Furthermore, postoperative complications in irradiated patients can be explained by increased endothelial dysfunction caused by LOX-1 in previously irradiated patients. Consequently, not only TGF-?1 but also galectin-3inhibitors may decrease complications after microsurgical tissue transfer.
EVALuna2:24387

Extra-abdominal and intra-abdominal FET::CREM fusion mesenchymal neoplasms: comparative clinicopathological study of 9 new cases further supporting a distinct potentially aggressive sarcoma and report of novel sites - Agaimy, Abbas; Blakely, Morgan; Breimer, Gerben E.; Hölsken, Annett; Koppes, Sjors A.; Meidenbauer, Norbert; Rijken, Johannes A.; Schad, Arno; Simon, Adrian G.; Stöhr, Robert; Bishop, Justin A.; Din, Nasir Ud (Virchows Archiv, 2024)
With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET(EWSR1/FUS)::CREB(CREM/ATF1) fused unclassified neoplasms has been reported followed by recent recognition of an analogous extra-abdominal category of unclassified neoplasms carrying EWSR1::ATF1 fusions. We describe 9 additional tumors (5 extra-abdominal and 4 abdominal) carrying an EWSR1::CREM (n = 8) and FUS::CREM (n = 1) fusion. Patients were 7 females and 2 males aged 10 to 75 years (median, 34). Extra-abdominal tumors originated in the head and neck (2 sinonasal, 1 orbital) and soft tissues (1 gluteal, 1 inguinal). Abdominal tumors involved stomach (2), mesentery (1), and kidney (1). Tumor size ranged from 3.5 to 11 cm (median, 6). Treatment was radical surgery with (5) or without (2) neo/adjuvant radio/chemotherapy. Extended follow-up of 5 patients (21–52 months; median, 24) showed an aggressive course in two (40%); one died of disseminated metastases 52 months after several intensified chemotherapy regimens, and one was alive with progressive abdominal disease at 21 months. The immunophenotype of the two subcohorts was significantly overlapping with variable expression of EMA (7 of 8), keratin AE1/AE3 (5 of 9), CD99 (4 of 7), MUC4 (2 of 8), ALK (3 of 8), synaptophysin (3 of 9), chromogranin (1 of 8), CD34 (3 of 6), CD30 (1 of 6), PAX8 (1 of 7), and inhibin (1 of 7), but no reactivity with desmin (0 of 8), S100 (0 of 8), and SOX10 (0 of 8). This series further solidifies the notion that FET::CREB fusions are not limited to the triad of angiomatoid fibrous histiocytoma, clear cell sarcoma, and malignant gastrointestinal neuroectodermal tumor, but characterize an emerging family of potentially aggressive neoplasms occurring at both intra- and extra-abdominal sites. These tumors underscore the promiscuity of the FET::CREB fusions and highlight the pivotal role of phenotype-oriented classification of these neoplasms that share the same genotype, still featuring significant biological and behavioral distinctness.
CRIS-Team Scopus Importer:2024-12-06
Keywords: Constitutional symptoms; Ewing sarcoma; Genetic landscape; Next generation sequencing; Precision medicine; Profiling

Extracapsular dissection in the parapharyngeal space: benefits and potential pitfalls - Mantsopoulos, K.; Müller, Sandra; Agaimy, Abbas; Goncalves, M.; Koch, Matthias; Wüst, Wolfgang; Bohr, Christopher; Iro, Heinrich (British Journal of Oral and Maxillofacial Surgery, 2017)
The aim of this study was to investigate the benefits and potential pitfalls of transcervical extracapsular dissection in the treatment of parotid gland tumours in the parapharyngeal space. We retrospectively evaluated the records of all patients with parapharyngeal parotid gland lesions treated between 2000 and 2015 by transcervical extracapsular dissection. Patients having revision operations and patients whose records were not complete were excluded, leaving 49 patients in the study. We found acceptable oncological and functional outcomes throughout. Special attention should be paid in cases with multilobular growth of the tumour on magnetic resonance imaging, satellite tumours of pleomorphic adenomas, tumours in broad contact with the inner surface of the deep lobe, and lesions suspected of malignancy. Extracapsular dissection in the parapharyngeal region is associated with acceptable oncological and functional outcomes. These outcomes can be expected only after a thorough assessment of patient's history and preoperative imaging.
EVALuna2:6890

Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo - Mycielska, Maria E.; Dettmer, Katja; Ruemmele, Petra; Schmidt, Katharina; Prehn, Cornelia; Milenkovic, Vladimir M.; Jagla, Wolfgang; Madej, Gregor M.; Lantow, Margareta; Schladt, Moritz; Cecil, Alexander; Koehl, Gudrun E.; et al. (Cancer Research, 2018)
Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.Significance: Uptake of extracellular citrate through pmCiC can be blocked with gluconate to reduce tumor growth and to alter metabolic characteristics of tumor tissue. Cancer Res; 78(10); 2513-23. ©2018 AACR.
EVALuna2:35102

Extracellular DNA traps in inflammation, injury and healing - Daniel, Christoph; Leppkes, Moritz; Munoz, Luis Enrique; Muñoz, Luis E.; Schley, Gunnar; Schett, Georg; Herrmann, Martin (Nature Reviews Nephrology, 2019)
Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is especially prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathological roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of pathology associated with the release of extracellular DNA traps is mainly determined by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
CRIS-Team Scopus Importer:2019-07-09

Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology - Sluijter, Joost Petrus Gerardus; Davidson, Sean Michael; Boulanger, Chantal M.; Buzas, Edit Iren; De Kleijn, Dominique Paschalis Victor; Engel, Felix; Giricz, Zoltan; Hausenloy, Derek J.; Kishore, Raj; Lecour, Sandrine; Leor, Jonathan; Madonna, Rosalinda; et al. (Cardiovascular Research, 2018)
Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit.
EVALuna2:25557

Extracorporeal perfusion - reduced to a one-way infusion. - Taeger, Christian Dirk; Friedrich, Oliver; Horch, Raymund E.; Drechsler, Caroline; Weigand, Annika; Hopf, Fabio; Geppert, Carol-Immanuel; Münch, Frank; Birkholz, Torsten; Wenzel, Carina; Geis, Sebastian; Prantl, Lukas; et al. (Clinical hemorheology and microcirculation, 2017)
BACKGROUND Extracorporeal perfusion (EP) is moving into focus of research in reconstructive and transplantation medicine for the preservation of amputates and free tissue transplants. The idea behind EP is the reduction of ischemia-related cell damage between separation from blood circulation and reanastomosis of the transplant. Most experimental approaches are based on a complex system that moves the perfusate in a circular course. OBJECTIVE AND METHODS In this study, we aimed to evaluate if a simple perfusion by an infusion bag filled with an electrolyte solution can provide acceptable results in terms of flow stability, oxygen supply and viability conservation for EP of a muscle transplant. The results are compared to muscles perfused with a pump system as well as muscles stored under ischemic conditions with a one-time intravasal flushing with Jonosteril. RESULTS With this simple method a sufficient oxygen supply could be achieved and functionality could be maintained between 3.35 times and 4.60 times longer compared to the control group. Annexin V positive nuclei, indicating apoptosis, increased by 9.7% in the perfused group compared to 24.4% in the control group. CONCLUSIONS Overall, by decreasing the complexity of the system, EP by one-way infusion can become more feasible in clinical situation

Extramedullary plasmacytoma: Tumor occurrence and therapeutic concepts-A follow-up - Holler, Adrian; Cicha, Iwona; Eckstein, Markus; Haderlein, Marlen; Poettler, Marina; Rappl, Anja; Iro, Heinrich; Alexiou, Christoph (Cancer Medicine, 2022)
Background Extramedullary plasmacytoma (EMP) is a solitary tumor consisting of neoplastic plasma cells, with very little to no bone marrow involvement. EMPs are usually located in the head and neck region, but can also occur along the digestive tract, in lungs, or extremities. Methods Following our publication on EMP, which appeared in 1999 (Cancer 85:2305-14), we conducted a literature search for EMP-related reports published between 1999 and 2021. The documented cases, as well as 14 of our own patients from the ENT Clinic Erlangen, were extensively analyzed. Results Between 1998 and 2021, 1134 patients with EMP were reported, for whom information about the tumor localization was available. Among those, 62.4% had EMP in the head and neck area and 37.6% in other body regions. Data on therapy were reported in 897 patients, including 34.3% who received radiation, 28.1% surgery, 22.6% a combination of surgery and radiation, and 15.9% another therapy. In 76.9% patients no recurrence or transformation to multiple myeloma (MM) was reported, 12.8% showed local recurrence and 10.2% developed MM. Radiotherapy alone was associated with a tendency for increased occurrence of MM. In patients with EMP of head and neck area, combination therapy (surgery and radiation) resulted in a 5-year overall survival rate of 98.3%, surgery alone of 92.4%, and radiotherapy of 92.7%. Conclusions Collectively, our analyses indicate that surgical resection alone can achieve long-term tumor control in patients with EMP, if the tumor can be removed within safe limits without causing serious functional impairment. However, if this is not certain, either radiation or a combination of surgery and radiation therapy is suggested as an effective means of local tumor control.
CRIS-Team WoS Importer:2022-05-27
Keywords: extramedullary plasmacytoma; non-Hodgkin lymphoma; survival; therapy; tumor outcomes

F18-FDG PET/CT imaging early predicts pathologic complete response to induction chemoimmunotherapy of locally advanced head and neck cancer: preliminary single-center analysis of the checkrad-cd8 trial - Beck, Michael; Hartwich, J.; Eckstein, Markus; Schmidt, D.; Gostian, Antoniu-Oreste; Müller-Hübner, Sarina Katrin Ursel; Rutzner, Sandra; Gaipl, Udo; Von Der Gruen, J.; Illmer, T.; Hautmann, M. G.; Klautke, G.; et al. (Annals of Nuclear Medicine, 2022)
Aim: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy. Methods: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3–14 days before (pre-ICIT) and 21–28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu). Results: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value. Conclusion: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value. Trial registry: ClinicalTrials.gov identifier: NCT03426657.
CRIS-Team Scopus Importer:2022-05-20
Keywords: FDG-PET/CT; Head neck cancer; HNSCC; Immunotherapy; Induction therapy

Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells - Schödel, Johannes; Bohr, Daniela; Klanke, Bernd; Schley, Gunnar; Schlötzer-Schrehardt, Ursula; Warnecke, Christina; Kurtz, Armin; Amann, Kerstin Ute; Eckardt, Kai-Uwe; Willam, Carsten (Kidney International, 2010)
The two hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that regulate the response to hypoxia. Recently, the factor inhibiting HIF (FIH1) was identified as a molecular oxygen-dependent dioxygenase that blunts the transcriptional activity of HIF and has also been implicated in HIF-dependent and-independent hypoxia responses. Interestingly, HIF accumulation in the kidney has been shown to confer renal protection and to also cause glomerular injury or enhance renal fibrosis. In order to better understand the regulation of hypoxia-inducible genes, we determined the expression of FIH1 in the kidney and its functional role in isolated renal cells. FIH1 was expressed only in distal tubules and in podocytes, thus showing a very distinct expression pattern, partially overlapping with sites of HIF-1α expression. In tubular cells, RNA silencing of FIH1 caused transcriptional activation of HIF target genes during hypoxia. In contrast, FIH1 silencing in podocytes enhanced transcription of hypoxia-inducible genes in an HIF-independent manner. Using the anti-Thy.1 rat model of glomerulonephritis, we found a gradual decrease of glomerular FIH1 expression during disease progression paralleled by an increase in hypoxia-inducible genes including CXCR4, a mediator of glomerular inflammation. Thus, FIH1 appears to be a suppressor of oxygen-dependent genes in the kidney, operating through HIF-dependent and-independent mechanisms. © 2010 International Society of Nephrology.
CRIS-Team Scopus Importer:2024-05-13
Keywords: cell biology and structure; hypoxia; immunohistochemistry; podocyte; tubule cells

Factors influencing downstaging after neoadjuvant long-course chemoradiotherapy in rectal carcinoma - Kohl, Valerie; Weber, Klaus; Brunner, Maximilian; Geppert, Carol-Immanuel; Fietkau, Rainer; Grützmann, Robert; Semrau, Sabine; Merkel, Susanne (International Journal of Colorectal Disease, 2022)
Purpose This single-centre cohort study was designed to identify factors that can predict primary tumour downstaging by neoadjuvant chemoradiotherapy (nCRT) in rectal carcinoma. Methods Prospectively collected data from 555 patients with clinical T category (cT) cT3-4 rectal carcinoma treated between 1995 and 2019 were retrospectively analysed. All patients received long-term neoadjuvant chemoradiotherapy followed by surgery with curative intent at the Department of Surgery, University Hospital Erlangen, Germany. Patient-, tumour- and treatment-related factors with a potential impact on the downstaging of rectal carcinoma to pathological T category (pT) ≤ ypT2 and ypT0 were analysed in univariate and multivariate logistic regression analyses. The prognosis of patients with and without downstaging of the primary tumour was compared. Results A total of 288 (51.9%) patients showed downstaging to ≤ ypT2. Eighty-six (15.5%) patients achieved clinical complete regression (ypT0). In the multivariate logistic regression analysis, the factors cT category, BMI, ECOG score, CEA, histological type, extension in the rectum and year of the start of treatment were found to be independent factors for predicting downstaging to ≤ ypT2 after neoadjuvant chemoradiotherapy. The year of treatment initiation also remained an independent significant predictor for pathological complete regression. The prognosis was superior in patients with downstaging to ≤ ypT2 in terms of locoregional and distant recurrence as well as disease-free and overall survival. Conclusion Factors predicting downstaging after long-term nCRT could be identified. This may be helpful for counselling patients and selecting the optimal treatment for patients with advanced rectal carcinoma.
CRIS-Team WoS Importer:2022-05-27
Keywords: Rectal carcinoma; Neoadjuvant chemoradiotherapy; Downstaging; Tumour regression; Prediction of pathological response; Prognostic factors

Factors Influencing the Outcome of Head and Neck Cancer of Unknown Primary (HNCUP) - Rupp, Robin; Mantsopoulos, Konstantinos; Sievert, Matti; Gostian, Magdalena; Allner, Moritz; Grundtner, Philipp; Eckstein, Markus; Iro, Heinrich; Hecht, Markus; Gostian, Antoniu-Oreste; Balk, Matthias (Journal of Clinical Medicine, 2022)
Background: This study on patients with head and neck cancer of unknown primary (HNCUP) assesses the impact of surgical and non-surgical treatment modalities and the tumour biology on the oncological outcome. Methods: A total of 80 patients with HNCUP (UICC I-IV) were treated with simultaneous neck dissection followed by adjuvant therapy, between 1 January 2007 and 31 March 2020. As the primary objective, the influence of treatment modalities on the overall survival (OS), the disease-specific survival (DSS) and the progression-free survival (PFS) were analysed in terms of cox regression and recursive partitioning. The tumour biology served as secondary objectives. Results: The 5-year OS for the entire cohort was 67.7%, (95% CI: 54.2-81.2%), the 5-year DSS was 82.3% (72.1-92.5%) and the 5-year PFS was 72.8% (61.8-83.8%). Cox regression revealed that patients undergoing adjuvant radiotherapy only had a four times higher risk to die compared to patients receiving chemoradiation therapy (HR = 4.45 (1.40; 14.17), p = 0.012). The development of distant metastases had a significantly negative impact on OS (HR = 8.24 (3.21-21.15), p < 0.001) and DSS (HR = 23.79 (6.32-89.56), p < 0.001). Recursive portioning underlined the negative influence of distant metastases on OS (3.2-fold increase in death probability) and DSS (4.3-fold increase in death probability), while an UICC stage of IVb increased the risk for further progression of the disease by a factor of 2. Conclusions: The presence of distant metastases as well as adjuvant treatment with radiation without concomitant chemotherapy, were among others, significant predictors for the overall survival of HNCUP patients, with distant metastases being the most significant predictor.
CRIS-Team WoS Importer:2022-06-10

FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival - Eisenhut, Felix; Heim, Lisanne; Trump, Sonja; Mittler, Susanne; Sopel, Nina; Andreev, Katerina; Ferrazzi, Fulvia; Ekici, Arif Bülent; Rieker, Ralf; Springel, Rebekka; Assmann, Vera Elisabeth; Lechmann, Matthias; et al. (OncoImmunology, 2017)
Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1? levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1? and Tbet and was downregulated in immunosuppressive CD4(+)CD25(+)Foxp3(+)CTLA4(+) T cells. TGF?, a tumor suppressor factor, as well as siRNA to FAM13A, suppressed both isoforms of FAM13A and inhibited tumor cell proliferation. RNA-Seq analysis confirmed this finding. Moreover, siRNA to FAM13A induced TGF? levels. Finally, in experimental tumor cell migration, FAM13A was induced and TGF? accelerated this process by inducing cell migration, HIF1?, and the FAM13A RhoGAP isoform. Furthermore, siRNA to FAM13A inhibited tumor cell proliferation and induced cell migration without affecting HIF1?. In conclusion, FAM13A is involved in tumor cell proliferation and downstream of TGF? and HIF1?, FAM13A RhoGAP is associated with Th1 gene expression and lung tumor cell migration. These findings identify FAM13A as key regulator of NSCLC growth and progression.
EVALuna2:6835

FAM96A is a novel pro-apoptotic tumor suppressor in gastrointestinal stromal tumors - Schwamb, Bettina; Pick, Robert; Fernandez, Sara Beatriz Mateus; Voelp, Kirsten; Heering, Jan; Doetsch, Volker; Boesser, Susanne; Jung, Jennifer; Beinoraviciute-Kellner, Rasa; Wesely, Josephine; Zoernig, Inka; Hammerschmidt, Matthias; et al. (International Journal of Cancer, 2015)
The ability to escape apoptosis is a hallmark of cancer-initiating cells and a key factor of resistance to oncolytic therapy. Here, we identify FAM96A as a ubiquitous, evolutionarily conserved apoptosome-activating protein and investigate its potential pro-apoptotic tumor suppressor function in gastrointestinal stromal tumors (GISTs). Interaction between FAM96A and apoptotic peptidase activating factor 1 (APAF1) was identified in yeast two-hybrid screen and further studied by deletion mutants, glutathione-S-transferase pull-down, co-immunoprecipitation and immunofluorescence. Effects of FAM96A overexpression and knock-down on apoptosis sensitivity were examined in cancer cells and zebrafish embryos. Expression of FAM96A in GISTs and histogenetically related cells including interstitial cells of Cajal (ICCs), "fibroblast-like cells" (FLCs) and ICC stem cells (ICC-SCs) was investigated by Northern blotting, reverse transcription-polymerase chain reaction, immunohistochemistry and Western immunoblotting. Tumorigenicity of GIST cells and transformed murine ICC-SCs stably transduced to re-express FAM96A was studied by xeno- and allografting into immunocompromised mice. FAM96A was found to bind APAF1 and to enhance the induction of mitochondrial apoptosis. FAM96A protein or mRNA was dramatically reduced or lost in 106 of 108 GIST samples representing three independent patient cohorts. Whereas ICCs, ICC-SCs and FLCs, the presumed normal counterparts of GIST, were found to robustly express FAM96A protein and mRNA, FAM96A expression was much reduced in tumorigenic ICC-SCs. Re-expression of FAM96A in GIST cells and transformed ICC-SCs increased apoptosis sensitivity and diminished tumorigenicity. Our data suggest FAM96A is a novel pro-apoptotic tumor suppressor that is lost during GIST tumorigenesis.
EVALuna2:6719

Familial acute aortic dissection associated with a novel ACTA2 germline variant - Strecker, Thomas; Wiesmueller, Felix; Rudnik-Schoeneborn, Sabine; Hoyer, Juliane; Wiesmann da Silva Reis, André; Weyand, Michael; Agaimy, Abbas (Virchows Archiv, 2022)
Aortic dissection is a life-threatening cardiovascular disease. Hereditary disorders are responsible for a small percentage of cases. Nonetheless, it is important to identify genetic causes, as they are often autosomal dominantly inherited and are of life-saving importance if we can identify persons at risk. Mutations of the ACTA2 gene are the most common cause of non-syndromic familial aortic disease. Exploration of the genetic background in suspected familial cases and determination of the exact etiology are mandatory for management and establishing appropriate follow-up strategies due to the risk of fatal recurrences. Herein, we present a 21-year-old male with a familial acute aortic dissection associated with novel ACTA2 germline variant and discuss the management and surveillance considerations.
CRIS-Team WoS Importer:2022-08-05

Fast whole-slide cartography in colon cancer histology using superpixels and CNN classification - Wilm, Frauke; Benz, Michaela; Bruns, Volker; Baghdadlian, Serop; Dexl, Jakob; Hartmann, David; Kuritcyn, Petr; Weidenfeller, Martin; Wittenberg, Thomas; Merkel, Susanne; Hartmann, Arndt; Eckstein, Markus; et al. (Journal of Medical Imaging, 2022)
Purpose: Automatic outlining of different tissue types in digitized histological specimen provides a basis for follow-up analyses and can potentially guide subsequent medical decisions. The immense size of whole-slide-images (WSIs), however, poses a challenge in terms of computation time. In this regard, the analysis of nonoverlapping patches outperforms pixelwise segmentation approaches but still leaves room for optimization. Furthermore, the division into patches, regardless of the biological structures they contain, is a drawback due to the loss of local dependencies.
CRIS-Team WoS Importer:2022-05-13

Fatal Encephalitis Associated with Borna Disease Virus 1 - Korn, Klaus; Coras, Roland; Bobinger, Tobias; Herzog, Sibylle M.; Lücking, Hannes; Stoehr, Roland; Huttner, Hagen; Hartmann, Arndt; Enßer, Armin (New England Journal of Medicine, 2018)
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Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman - Olmes, David G.; Agaimy, Abbas; Kloska, Stephan; Linker, Ralf (BMJ Case Reports, 2014)
An 80-year-old woman presented with weight loss, fatigue, dizziness and a brain stem lesion. Extensive work-up revealed lymphomatoid granulomatosis (LYG) with primary clinical manifestation in the central nervous system (CNS), a rare Epstein-Barr virus-driven multisystem lymphoproliferative disorder, to be causative for the symptoms. Immunochemotherapy consisting of rituximab and temozolomide was started, but the disease progressed and the patient subsequently died. Histology, diagnostic criteria, differential diagnosis and treatment options for LYG with CNS involvement are discussed. This case demonstrates that LYG with CNS involvement may necessitate more aggressive treatment approaches than combination therapy with rituximab and temozolomide.
EVALuna2:6736

Fatal Puumala Hantavirus Infection in a Patient with Common Variable Immunodeficiency (CVID) - Steininger, Philipp; Herbst, Larissa; Bihlmaier, Karl; Willam, Carsten; Koerper, Sixten; Schrezenmeier, Hubert; Klueter, Harald; Pfister, Frederick; Amann, Kerstin Ute; Weiss, Sabrina; Krueger, Detlev H.; Zimmermann, Robert; et al. (Microorganisms, 2023)
Puumala hantavirus (PUUV) infections usually show a mild or moderate clinical course, but may sometimes also lead to life-threatening disease. Here, we report on a 60-year-old female patient with common variable immunodeficiency (CVID) who developed a fatal PUUV infection with persistent renal failure, thrombocytopenia, and CNS infection with impaired consciousness and tetraparesis. Hantavirus-specific antibodies could not be detected due to the humoral immunodeficiency. Diagnosis and virological monitoring were based on the quantitative detection of PUUV RNA in blood, cerebrospinal fluid, bronchial lavage, and urine, where viral RNA was found over an unusually extended period of one month. Due to clinical deterioration and virus persistence, treatment with ribavirin was initiated. Additionally, fresh frozen plasma (FFP) from convalescent donors with a history of PUUV infection was administered. Despite viral clearance, the clinical condition of the patient did not improve and the patient died on day 81 of hospitalization. This case underlines the importance of the humoral immune response for the course of PUUV disease and illustrates the need for PCR-based virus diagnostics in those patients. Due to its potential antiviral activity, convalescent plasma should be considered in the therapy of severe hantavirus diseases.
CRIS-Team Scopus Importer:2023-03-10
Keywords: common variable immunodeficiency; convalescent plasma; encephalitis; Puumala hantavirus; ribavirin

"Fat-rich" (Spindle Cell-poor) Variants of Atypical Spindle Cell Lipomatous Tumors Show Similar Morphologic, Immunohistochemical and Molecular Features as "Dysplastic Lipomas" Are They Related Lesions? - Michal, Michael; Agaimy, Abbas; Contreras, Alejandro Luina; Michal, Michal; Fetsch, John F. (American Journal of Surgical Pathology, 2019)
CRIS-Team WoS Importer:2019-02-27

Feasibility of intraoperative assessment of safe surgical margins during laryngectomy with confocal laser endomicroscopy: A pilot study - Sievert, Matti; Oetter, Nicolai; Aubreville, Marc; Stelzle, Florian; Maier, Andreas; Eckstein, Markus; Mantsopoulos, Konstantinos; Gostian, Antoniu Oreste; Müller, Sarina Katrin; Koch, Michael; Agaimy, Abbas; Iro, Heinrich; et al. (Auris Nasus Larynx, 2021)
Objective: This pilot study aimed to assess the feasibility of intraoperative assessment of safe margins with Confocal Laser Endomicroscopy (CLE) during planned partial or total laryngectomy. Methods: Eight patients with confirmed larynx squamous cell carcinoma (SCC) and planned partial or total laryngectomy were included in this study in March 2020. Two head and neck surgeons and one pathologist were asked to classify carcinoma or healthy epithelium in a sample of 94 representative sequences (5.640 images), blinded to the histological results (H&E staining). Results: Healthy mucosa areas showed epithelium with cells of uniform size and shape with distinct cytoplasmic membranes and regular vessel architecture. CLE optical biopsy of SCC demonstrated a disorganized arrangement of variable cellular morphology. We calculated an accuracy, sensitivity, specificity, PPV, and NPV of 80.1%, 72.3%, 87.9%, 85.7%, and 76.1%, respectively. A distinct transition between healthy appearing tissue and suspicious lesions could also be detected. Conclusion: CLE can be easily integrated into the intraoperative setting, generate real-time, in-vivo microscopic images of the larynx for evaluation and demarcation of cancer. If validated in further studies, CLE could eventually contribute to a less radical approach by enabling a more precise evaluation of the cancer margin.
CRIS-Team Scopus Importer:2021-01-29
Keywords: Confocal laser endomicroscopy; Laryngeal cancer; Safe surgical margins

Feasibility of sentinel lymph node detection by near-infrared endoscopy in squamous cell carcinoma of the oral cavity: A pilot study - Sievert, Matti; Goncalves, Miguel; Eckstein, Markus; Iro, Heinrich; Koch, M. (European Review for Medical and Pharmacological Sciences, 2020)
OBJECTIVE: Near-Infrared (NIR) fluorescence imaging is a novel technique for intraoperative sentinel lymph node (SLN) identification. It has demonstrated promising results in several surgical specialties. The study aims to evaluate the feasibility of identifying the SLN by indocyanine green (ICG) enhanced NIR endoscopy in squamous cell carcinoma of the oral cavity (OCSCC). PATIENTS AND METHODS: Seven patients with (cT1-3 N0) OCSCC were included. We injected 1-1.25 ml of ICG (5 mg/ml) at four to five points around the primary. After the elevation of a platysma flap and posterior retraction of the sternocleidomastoid muscle, fluorescence images were taken via IMAGE1 STM NIR/ICG system to define the SLN(s). We sampled fluorescence marked SLN(s) stratified to lymph node levels, followed by level-specified elective neck dissection. RESULTS: The detection of at least one unilateral or bilateral SLN (range 1-5) was possible in every case. The fluorescence signal occurred, on average, 5.0 ± 2.2 minutes after injection. A total of 22 SLN could be identified. Among 331 histo-logically examined lymph nodes we could detect one micrometastasis, which was correctly defined as SLN (1/22). There were no false-negative findings. No adverse reactions to ICG occurred. CONCLUSIONS: Our first results are indicating the concept of SLN concerning OCSCC after the application of real-time NIR fluorescence endoscopy. However, this has to be verified by more extended studies.
CRIS-Team Scopus Importer:2020-12-11
Keywords: Indocyanine green; Near-infrared-imaging; Neck dissection; Oral cavity squamous cell carcinoma; Sentinel node biopsy

Festschrift in honor of professor Ellen Catharina Zwarthoff - Bangma, Chris; Boormans, Joost; De Jong, Christiaan; Van Kessel, Kim; Zuiverloon, Tahlita C. M.; Theodorescu, Dan; Knowles, Margaret; Hartmann, Arndt (Bladder Cancer, 2019)
CRIS-Team WoS Importer:2020-01-17

Fever of unknown origin, giant cell arteritis, and aortic dissection - Hofheinz, K.; Bertz, Simone; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2017)
Giant cell arteritis is one of the most frequent causes of pyrexia of unknown origin after infectious or malignant causes have been ruled out. In this case report we describe a 66-year old female patient, who after five weeks of remitting fever developed a life-threatening, painless severe aortic dissection. The timely use of modern imaging technologies such as magnetic resonance angiography or positron emission computed tomography could in the future be of help to recognize aortic involvement early and to avoid this devastating complication in patients with fever of unknown origin.
EVALuna2:6833

FGF1-mediated cardiomyocyte cell cycle reentry depends on the interaction of FGFR-1 and Fn14 - Novoyatleva, Tatyana; Sajjad, Amna; Pogoryelov, Denys; Patra, Chinmoy; Schermuly, Ralph T.; Engel, Felix (The FASEB Journal, 2014)
Fibroblast growth factors (FGFs) signal through FGF receptors (FGFRs) mediating a broad range of cellular functions during embryonic development, as well as disease and regeneration during adulthood. Thus, it is important to understand the underlying molecular mechanisms that modulate this system. Here, we show that FGFR-1 can interact with the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) resulting in cardiomyocyte cell cycle reentry. FGF1-induced cell cycle reentry in neonatal cardiomyocytes could be blocked by Fn14 inhibition, while TWEAK-induced cell cycle activation was inhibited by blocking FGFR-1 signaling. In addition, costimulation experiments revealed a synergistic effect of FGF1 and TWEAK in regard to cardiomyocyte cell cycle induction via PI3K/Akt signaling. Overexpression of Fn14 with either FGFR-1 long [FGFR-1(L)] or FGFR-1 short [FGFR-1(S)] isoforms resulted after FGF1/TWEAK stimulation in cell cycle reentry of >40% adult cardiomyocytes. Finally, coimmunoprecipitation and proximity ligation assays indicated that endogenous FGFR-1 and Fn14 interact with each other in cardiomyocytes. This interaction was strongly enhanced in the presence of their corresponding ligands, FGF1 and TWEAK. Taken together, our data suggest that FGFR-1/Fn14 interaction may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control cardiomyocyte cell cycle reentry.
EVALuna2:25462

FGFR3 Mutation Status and FGFR3 Expression in a Large Bladder Cancer Cohort Treated by Radical Cystectomy: Implications for Anti-FGFR3 Treatment? - van Rhijn, Bas W.G.; Mertens, Laura S.; Mayr, Roman; Bostrom, Peter J.; Real, Francisco X.; Zwarthoff, Ellen C.; Boormans, Joost L.; Abas, Cheno; van Leenders, Geert J.L.H.; Götz, Stefanie; Hippe, Katrin; Bertz, Simone; et al. (European Urology, 2020)
Oncogenic fibroblast growth factor receptor 3 (FGFR3) mutations were associated with favorable bladder cancer in a series of 1000 radical cystectomy cases. Moreover, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with overexpression only.
CRIS-Team Scopus Importer:2020-07-24
Keywords: Bladder; Cancer; Cystectomy; Expression; FGFR3; Mutation; Urothelial carcinoma

FGFR3::TACC3 fusions in head and neck carcinomas: a study of nine cases highlighting phenotypic heterogeneity, frequent HPV association, and a morphologically distinct subset in favor of a putative entity - Agaimy, Abbas; Antonescu, Cristina R.; Bell, Diana; Breimer, Gerben E.; Dermawan, Josephine K.; Kester, Lennart A.; Laco, Jan; Rijken, Johannes A.; Whaley, Rumeal D.; Stöhr, Robert; Cramer, Thomas; Bishop, Justin A. (Virchows Archiv, 2024)
The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion–positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9–21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.
CRIS-Team Scopus Importer:2024-10-25
Keywords: FGFR; Gene fusions; RNA sequencing; Sinonasal; Targeted therapy; Tyrosine kinase inhibitor

Fiber rich food suppressed airway inflammation, GATA3 + Th2 cells, and FcεRIα+ eosinophils in asthma. - Schenzel, Alicia; Geiger, Adriana; Nendel, Elvedina; Yang, Zuqin; Krammer, Susanne; Leberle, Anna; Brunst, Ann Kathrin; Trump, Sonja; Mittler, Susanne; Rauh, Manfred; Geppert, Carol-Immanuel; Tausche, Patrick; et al. (Frontiers in Nutrition, 2024)
BACKGROUND: Allergic Asthma is a disease presenting various endotypes and no current therapies act curative but alleviate disease symptoms. Dietary interventions are gaining increasing importance in regulating immune responses. Furthermore, short chain fatty acids (SFCA), as the main products of dietary fiber's fermentation by the gut bacteria, ameliorate the pathogenesis and disease burden of different illnesses including asthma. Nevertheless, the connection and crosstalk between the gut and lung is poorly understood. OBJECTIVE: In this work, the role of high fiber diet on the development of allergic asthma at baseline and after exacerbation of disease induced by respiratory viruses was investigated. METHODS: Hereby, SCFA in serum of asthmatic and non-asthmatic pre-school children before and after airway disease symptoms were analyzed. Moreover, the effect of high fiber diet in vivo in a murine model of house dust mite extract (HDM) induced allergic asthma and in the end in isolated lung and spleen cells infected ex vivo with Rhinovirus was analyzed. RESULTS: In this study, a decrease of the SCFA 3-Hydroxybutyric acid in serum of asthmatic children after symptomatic episodes at convalescent visit as compared to asthmatic and control children at baseline visit was observed. In experimental asthma, in mice fed with high fiber diet, a reduced lung GATA3 + Th2 type mediated inflammation, mucus production and collagen deposition and expression of Fc epsilon receptor Ia (FcεRIa) in eosinophils was observed. By contrast, the CD8+ memory effector T cells were induced in the lungs of asthmatic mice fed with high fiber diet. Then, total lung cells from these asthmatic mice fed with either standard food or with fiber rich food were infected with RV ex vivo. Here, RV1b mRNA was found significantly reduced in the lung cells derived from fiber rich food fed mice as compared to those derived from standard food fed asthmatic mice. Looking for the mechanism, an increase in CD8+ T cells in RV infected spleen cells derived from fiber rich fed asthmatic mice, was observed. CONCLUSION: Convalescent preschool asthmatic children after a symptomatic episode have less serum ß-Hydroxybutyric acid as compared to control and asthmatic children at baseline visit. Fiber rich diet associated with anti-inflammatory effects as well as anti-allergic effects by decreasing Type 2 and IgE mediated immune responses and inducing CD8+ memory effector T cells in a murine model of allergic asthma. Finally, ex vivo infection with Rhinovirus (RV) of total lung cells from asthmatic mice fed with fiber rich food led to a decreased RV load as compared to mice fed with standard food. Moreover, spleen cells derived from asthmatic mice fed with fiber rich food induced CD8+ T cells after ex vivo infection with RV. CLINICAL IMPLICATIONS: Dietary interventions with increased content in natural fibers like pectins would ameliorate asthma exacerbations. Moreover, respiratory infection in asthma downregulated SCFA in the gut contributing to asthma exacerbations.
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Fibroblast growth factor receptor-1 as a potential therapeutic target in sinonasal cancer - Schroeck, Andreas; Goeke, Friederike; Wagner, Patrick; Bode, Maike; Franzen, Alina; Huss, Sebastian; Agaimy, Abbas; Ihrler, Stephan; Kirsten, Robert; Kristiansen, Glen; Bootz, Friedrich; Lengerke, Claudia; et al. (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2014)
Despite multimodal treatment, sinonasal malignancies have an unfavorable prognosis. The purpose of this study was to elucidate if these tumors harbor amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, which has recently been identified as a potential therapeutic target in squamous cell lung cancer.One hundred twelve primary tumors (including squamous cell carcinoma [SCC], carcinoma associated with an inverted papilloma, sinonasal undifferentiated carcinoma [SNUC], adenocarcinoma, adenoid cystic carcinoma [ACC], esthesioneuroblastoma, and 9 corresponding lymph node metastases) were assessed by fluorescence in situ hybridization (FISH) for FGFR1 copy number status. Human papillomavirus (HPV) status was assessed by p16 immunohistochemical as a surrogate marker.FGFR1 amplification was found in subsets of sinonasal SCCs (20%), carcinomas associated with an inverted papilloma (33%), and SNUCs (5%). In all cases, metastatic tumor samples shared the same FGFR1 amplification status as the corresponding primary tumor tissue. None of the FGFR1-amplified tumors expressed p16.FGFR1 amplification represents a potential molecular target in a subset of patients with sinonasal cancer. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1253-1257, 2014.
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Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup - Baldia, Philipp H.; Maurer, Angela; Heide, Timon; Rose, Michael; Stoehr, Robert; Hartmann, Arndt; Williams, Sarah V.; Knowles, Margaret A.; Knuechel, Ruth; Gaisa, Nadine T. (Oncotarget, 2016)
Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p < 0.001), and unfavourable clinical outcome (p = 0.001). Our findings are consistent with the results of the TCGA data set for the "squamous-like" subtype of bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA "squamous-like" subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies.
EVALuna2:6882

Fibroblast growth factor receptor (FGFR) gene amplifications are rare events in bladder cancer - Fischbach, Anna; Rogler, Anja; Erber, Ramona; Stoehr, Robert; Poulsom, Richard; Heidenreich, Axel; Schneevoigt, Birte-Swantje; Hauke, Sven; Hartmann, Arndt; Knüchel, Ruth; Veeck, Jürgen; Gaisa, Nadine T. (Histopathology, 2015)
Activating point mutations and protein overexpression of fibroblast growth factor receptors (FGFRs), especially FGFR3, are frequent events in bladder cancer. Little is known about gene amplifications, therefore we characterized amplification of FGFR1-3 by fluorescence in-situ hybridization (FISH).Tumours of 153 patients (n = 65 pTa low-grade, n = 15 pTa high-grade, n = 37 pT1, n = 20 pT2, n = 10 pT3, n = 6 pT4) were analysed by FISH for FGFR1-3 copy numbers and screened for FGFR3 mutations and immunohistochemical protein expression. Amplifications of FGFR1 were found in 1.6% (two of 122), FGFR2 in 0.8% (one of 121) and FGFR3 in 3.4% (five of 145). All amplifications were high-level amplifications, not overlapping with polysomy. Amplifications were found in papillary/papillary-invasive tumour parts, and predominantly in tumours with enhanced Ki67 index (>10%), aberrant CK20 expression, and low p53 expression. All FGFR3-amplified samples showed concomitant FGFR3 mutations and FGFR3 protein overexpression. FGFR amplifications were not associated significantly with gender, age, grade or stage in statistical analyses.FGFR amplifications are rare events in bladder cancer, with FGFR3 amplification being the most prevalent (3.4% of cases). Concomitant FGFR3 mutations and protein overexpression indicate that FGFR3-mediated signalling in these tumours would probably be highly active. This patient subgroup may be particularly suited to FGFR-targeted pharmacotherapy.
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Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells - Shaikh, Haroon; Pezoldt, Joern; Mokhtari, Zeinab; Vargas, Juan Gamboa; Le, Duc Dung; Mosca, Josefina Peña; Viera, Estibaliz Arellano; Kern, Michael A.G.; Graf, Caroline; Beyersdorf, Niklas; Lutz, Manfred B.; Riedel, Angela; et al. (JCI Insight, 2022)
Acute graft versus host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) inflicted by alloreactive T cells primed in secondary lymphoid organs (SLOs) and subsequent damage to aGvHD target tissues. In recent years, Treg transfer and/or expansion has emerged as a promising therapy to modulate aGvHD. However, cellular niches essential for fostering Tregs to prevent aGvHD have not been explored. Here, we tested whether and to what extent MHC class II (MHCII) expressed on Ccl19+ fibroblastic reticular cells (FRCs) shape the donor CD4+ T cell response during aGvHD. Animals lacking MHCII expression on Ccl19-Cre-expressing FRCs (MHCIIΔCcl19) showed aberrant CD4+ T cell activation in the effector phase, resulting in exacerbated aGvHD that was associated with significantly reduced expansion of Foxp3+ Tregs and invariant NK T (iNKT) cells. Skewed Treg maintenance in MHCIIΔCcl19 mice resulted in loss of protection from aGvHD provided by adoptively transferred donor Tregs. In contrast, although FRCs upregulated costimulatory surface receptors, and although they degraded and processed exogenous antigens after myeloablative irradiation, FRCs were dispensable to activate alloreactive CD4+ T cells in 2 mouse models of aGvHD. In summary, these data reveal an immunoprotective, MHCII-mediated function of FRC niches in secondary lymphoid organs (SLOs) after allo-HCT and highlight a framework of cellular and molecular interactions that regulate CD4+ T cell alloimmunity.
CRIS-Team Scopus Importer:2022-12-16

Fibronectin is up-regulated in podocytes by mechanical stress - Kliewe, Felix; Kaling, Sören; Lötzsch, Henriette; Artelt, Nadine; Schindler, Maximilian; Rogge, Henrik; Schröder, Sindy; Scharf, Christian; Amann, Kerstin Ute; Daniel, Christoph; Lindenmeyer, Maja T.; Cohen, Clemens D.; et al. (The FASEB Journal, 2019)
Hypertension is one of the central causes of kidney damage. In the past it was shown that glomerular hypertension leads to morphologic changes of podocytes and effacement and is responsible for detachment of these postmitotic cells. Because we have shown that podocytes are mechanosensitive and respond to mechanical stress by reorganization of the actin cytoskeleton in vitro, we look for mechanotransducers in podocytes. In this study, we demonstrate that the extracellular matrix protein fibronectin (Fn1) might be a potential candidate. The present study shows that Fn1 is essential for the attachment of podocytes during mechanical stress. By real-time quantitative PCR as well as by liquid chromatography-mass spectrometry, we found a significant up-regulation of Fn1 caused by mechanical stretch (3 d, 0.5 Hz, and 5% extension). To study the role of Fn1 in cultured podocytes under mechanical stress, Fn1 was knocked down (Fn1 KD) by a specific small interfering RNA. Additionally, we established a Fn1 knockout (KO) podocyte cell line (Fn1 KO) by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). During mechanical stress, a significant loss of podocytes (>80%) was observed in Fn1 KD as well as Fn1 KO podocytes compared with control cells. Furthermore, Fn1 KO podocytes showed a significant down-regulation of the focal adhesion proteins talin, vinculin, and paxillin and a reduced cell spreading, indicating an important role of Fn1 in adhesion. Analyses of kidney sections from patients with diabetic nephropathy have shown a significant up-regulation of FN1 in contrast to control biopsies. In summary, we show that Fn1 plays an important role in the adaptation of podocytes to mechanical stress.-Kliewe, F., Kaling, S., Lötzsch, H., Artelt, N., Schindler, M., Rogge, H., Schröder, S., Scharf, C., Amann, K., Daniel, C., Lindenmeyer, M. T., Cohen, C. D., Endlich, K., Endlich, N. Fibronectin is up-regulated in podocytes by mechanical stress.
EVALuna2:204845
Keywords: Fn1; extracellular matrix; hypertension; mechanical load; diabetic nephropathy

Filtration based assessment of CTCs and CellSearch® based assessment are both powerful predictors of prognosis for metastatic breast cancer patients - Hübner, Hanna; Fasching, Peter; Gumbrecht, Walter; Jud, Sebastian; Rauh, Claudia; Matzas, Mark; Paulicka, Peter; Friedrich, Katja; Lux, Michael P.; Volz, Bernhard; Gaß, Paul; Häberle, Lothar; et al. (BMC Cancer, 2018)
The assessment of circulating tumor cells (CTCs) has been shown to enable monitoring of treatment response and early detection of metastatic breast cancer (MBC) recurrence. The aim of this study was to compare a well-established CTC detection method based on immunomagnetic isolation with a new, filtration-based platform.In this prospective study, two 7.5 ml blood draws were obtained from 60 MBC patients and CTC enumeration was assessed using both the CellSearch® and the newly developed filtration-based platform. We analyzed the correlation of CTC-positivity between both methods and their ability to predict prognosis. Overall survival (OS) was calculated and Kaplan-Meier curves were estimated with thresholds of >=1 and >=5 detected CTCs.The CTC positivity rate of the CellSearch® system was 56.7% and of the filtration-based platform 66.7%. There was a high correlation of CTC enumeration obtained with both methods. The OS for patients without detected CTCs, regardless of the method used, was significantly higher compared to patients with one or more CTCs (p < 0.001). The median OS of patients with no CTCs vs. >= 1 CTC assessed by CellSearch® was 1.83 years (95% CI: 1.63-2.02) vs. 0.74 years (95% CI: 0.51-1.52). If CTCs were detected by the filtration-based method the median OS times were 1.88 years (95% CI: 1.74-2.03) vs. 0.59 years (95% CI: 0.38-0.80).The newly established EpCAM independently filtration-based system is a suitable method to determine CTC counts for MBC patients. Our study confirms CTCs as being strong predictors of prognosis in our population of MBC patients.
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Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression - Nitz, U.; Gluz, O.; Huober, J.; Kreipe, H. H.; Kates, R. E.; Hartmann, Arndt; Erber, Ramona; Scholz, M.; Lisboa, B.; Mohrmann, S.; Moebus, V.; Augustin, D.; et al. (Annals of Oncology, 2014)
Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only.A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors.Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (>= 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01).EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.ClinicalTrials.gov, NCT02115204.
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Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression (vol 25, pg 1551, 2014) - Nitz, U.; Gluz, O.; Huober, J.; Kreipe, H. H.; Kates, R. E.; Hartmann, Arndt; Erber, Ramona; Moustafa, Z.; Scholz, M.; Lisboa, B.; Mohrmann, S.; Moebus, V.; et al. (Annals of Oncology, 2017)
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Fine needle aspiration cytology of lymph nodes in breast cancer follow-up is a feasible alternative to watchful waiting and to histology - Hammon, Matthias; Dankerl, Peter; Janka, Rolf Matthias; Wachter, David; Hartmann, Arndt; Schulz-Wendtland, Rüdiger; Uder, Michael; Wenkel, Evelyn (BMC Women's Health, 2015)
Early detection of loco-regional breast cancer recurrence improves patients' overall survival, as treatment can be initiated or active treatment can be changed. If a suspicious lymph node is diagnosed during a follow-up exam, surgical excision is often performed. The aim of this study was to evaluate the diagnostic performance of the minor invasive ultrasound-guided fine-needle aspiration cytology (FNAC) in sonomorphologically suspicious lymph nodes in breast cancer follow-up.Between April 2010 and November 2012, we performed ultrasound-guided FNAC in 38 sonographically suspicious lymph nodes of 37 breast cancer follow-up patients. Cytological specimens were evaluated if the sample material was sufficient for diagnosis and if they contained cancer cells. Patients with negative cytology were followed up clinically and sonographically. To evaluate the diagnostic performance we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for physical examination, the different sonomorphological malignancy criteria and FNAC.In 36/38 (94.7 %) lymph nodes, the pathologist had enough material to establish a final diagnosis; in 2/38 (5.3 %) lymph nodes, the probe material was non-evaluable during cytology, these 2 were excluded from further statistical evaluation. Cytology revealed malignancy in 21 lymph nodes and showed no evidence for malignancy in 15 lymph nodes. There was no evidence for malignant disease in follow-up exams in the 15 cytologically benign lymph nodes with an average follow-up time of 3 years. The diagnostic performances of physical examination and FNAC were: Sensitivity 52/100 %, specificity 88/100 %, PPV 85/100 %, NPV 60/100 %, respectively.Our preliminary results show that FNAC is a safe and fast diagnostic approach for the evaluation of suspicious lymph nodes in the follow-up of patients with breast cancer and, thus, together with follow-up represents a feasible alternative to surgery.
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Fine particulate matter (PM2.5) induces microRNA-192–5p causing glomerular damage - Yarbakht, Melina; Sarau, George; Xu, Yanyi; Fang, Xinyi; Mirzaei, Zeynab; Krüger, René; Xiao, Yalan; Usman, Arslan; Daniel, Christoph; Schiffer, Mario; Christiansen, Silke; Müller-Deile, Janina (Ecotoxicology and Environmental Safety, 2025)
An association between air pollution and the incidence of membranous glomerulonephritis (MGN) has been shown in epidemiological studies. However, the causality of this relationship and data on potential pathomechanisms are still missing. Anti-phospholipase A2 receptor (PLA2R1) antibodies, upregulation of microRNA-192–5p, and decreased expression of its podocyte target nephronectin (NPNT) in patients with MGN have been shown, but the trigger for these regulations remained unknown. The current study aimed to assay the possible role of PM2.5 in the pathogenesis of MGN. In this study, we characterized particulate matter (PM2.5) collected on air filters in Shanghai by scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray fluorescence, microwave plasma atomic emission spectroscopy, nanoparticle tracking analysis, and Raman spectroscopy. Cultured human podocytes, zebrafish, and mice were exposed to PM2.5 to assess possible effects on glomerular function and ultrastructure. PM2.5 caused a reduction of podocyte-specific markers and upregulation of microRNA-192–5p. Moreover, NPNT/npnt/Npnt were downregulated, while PLA2R1/pla2r1/Pla2r1 were upregulated. PM2.5 was able to cause edema, proteinuria, and glomerular damage with loosening of the glomerular basement membrane and partial podocyte effacement in zebrafish larvae. BulkRNA seq analysis and qPCR of zebrafish larvae showed an increase in inflammatory response and oxidative stress due to the exposure to PM2.5. Long-term exposure of mice to ambient PM2.5 induced glomerular damage, albuminuria, and upregulation of pulmonary microRNA-192–5p. Therefore, air pollution might be involved in developing MGN through inflammatory pathways and the induction of microRNA-192–5p, which targets gene expression important for glomerular cell function.
CRIS-Team Scopus Importer:2025-05-23
Keywords: Air pollution; glomerulus; membranous glomerulonephritis; PM; podocytes; proteinuria; zebrafish model

First Presentation of idiopathic Mast Cell Activation Syndrome (MCAS) in a Young Person: Association with Histamine and Salicylate Intolerance as well as an important Differential Diagnosis in gastroenterological Problem Patients - Raithel, Martin; Rechenauer, Tobias; Goetze, Thomas; Siebenlist, Gregor; Rueckel, Aline; Baenkler, Hanns-Wolf; Hartmann, Arndt; Haller, Florian; Hoerning, Andre (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

First report from the German COVID-19 autopsy registry - von Stillfried, Saskia; Bülow, Roman David; Röhrig, Rainer; Boor, Peter; Böcker, Jana; Schmidt, Jens; Tholen, Pauline; Majeed, Raphael; Wienströer, Jan; Weis, Joachim; Bremer, Juliane; Knüchel, Ruth; et al. (The Lancet Regional Health - Europe, 2022)
Background: Autopsies are an important tool in medicine, dissecting disease pathophysiology and causes of death. In COVID-19, autopsies revealed e.g., the effects on pulmonary (micro)vasculature or the nervous system, systemic viral spread, or the interplay with the immune system. To facilitate multicentre autopsy-based studies and provide a central hub supporting autopsy centres, researchers, and data analyses and reporting, in April 2020 the German COVID-19 Autopsy Registry (DeRegCOVID) was launched. Methods: The electronic registry uses a web-based electronic case report form. Participation is voluntary and biomaterial remains at the respective site (decentralized biobanking). As of October 2021, the registry included N=1129 autopsy cases, with 69271 single data points including information on 18674 available biospecimens gathered from 29 German sites. Findings: In the N=1095 eligible records, the male-to-female ratio was 1·8:1, with peaks at 65-69 and 80-84 years in males and >85 years in females. The analysis of the chain of events directly leading to death revealed COVID-19 as the underlying cause of death in 86% of the autopsy cases, whereas in 14% COVID-19 was a concomitant disease. The most common immediate cause of death was diffuse alveolar damage, followed by multi-organ failure. The registry supports several scientific projects, public outreach and provides reports to the federal health authorities, leading to legislative adaptation of the German Infection Protection Act, facilitating the performance of autopsies during pandemics. Interpretation: A national autopsy registry can provide multicentre quantitative information on COVID-19 deaths on a national level, supporting medical research, political decision-making and public discussion. Funding: German Federal Ministries of Education and Research and Health. Hintergrund: Obduktionen sind ein wichtiges Instrument in der Medizin, um die Pathophysiologie von Krankheiten und Todesursachen zu untersuchen. Im Rahmen von COVID-19 wurden durch Obduktionen z.B. die Auswirkungen auf die pulmonale Mikrovaskulatur, das Nervensystem, die systemische Virusausbreitung, und das Zusammenspiel mit dem Immunsystem untersucht. Um multizentrische, auf Obduktionen basierende Studien zu erleichtern und eine zentrale Anlaufstelle zu schaffen, die Obduktionszentren, Forscher sowie Datenanalysen und -berichte unterstützt, wurde im April 2020 das deutsche COVID-19-Autopsieregister (DeRegCOVID) ins Leben gerufen. Methoden: Das elektronische Register verwendet ein webbasiertes elektronisches Fallberichtsformular. Die Teilnahme ist freiwillig und das Biomaterial verbleibt am jeweiligen Standort (dezentrales Biobanking). Im Oktober 2021 umfasste das Register N=1129 Obduktionsfälle mit 69271 einzelnen Datenpunkten, die Informationen über 18674 verfügbare Bioproben enthielten, die von 29 deutschen Standorten gesammelt wurden. Ergebnisse: In den N=1095 ausgewerteten Datensätzen betrug das Verhältnis von Männern zu Frauen 1,8:1 mit Spitzenwerten bei 65-69 und 80-84 Jahren bei Männern und >85 Jahren bei Frauen. Die Analyse der Sequenz der unmittelbar zum Tod führenden Ereignisse ergab, dass in 86 % der Obduktionsfälle COVID-19 die zugrunde liegende Todesursache war, während in 14 % der Fälle COVID-19 eine Begleiterkrankung war. Die häufigste unmittelbare Todesursache war der diffuse Alveolarschaden, gefolgt von Multiorganversagen. Das Register unterstützt mehrere wissenschaftliche Projekte, die Öffentlichkeitsarbeit und liefert Berichte an die Bundesgesundheitsbehörden, was zu einer Anpassung des deutschen Infektionsschutzgesetzes führte und die Durchführung von Obduktionen in Pandemien erleichtert. Interpretation: Ein nationales Obduktionsregister kann multizentrische quantitative Informationen über COVID-19-Todesfälle auf nationaler Ebene liefern und damit die medizinische Forschung, die politische Entscheidungsfindung und die öffentliche Diskussion unterstützen. Finanzierung: Bundesministerien für Bildung und Forschung und für Gesundheit.
CRIS-Team Scopus Importer:2022-02-25
Keywords: Autopsy; Cause of Death; COVID-19; Registry; SARS-CoV-2

First Treatment of Relapsing Rapidly Progressive IgA Nephropathy With Eculizumab After Living Kidney Donation: A Case Report - Herzog, A. L.; Wanner, C.; Amann, Kerstin Ute; Lopau, K. (Transplantation Proceedings, 2017)
IgA nephropathy (IGAN) rarely can present as a crescent and progressive form leading to end-stage renal disease (ESRD) in a short period of time. Recurrence of IGAN after kidney transplantation is frequent, and complement components such as C3, C4d, and C5 seem to be involved. We present a case of a young male patient with ESRD caused by rapidly progressive IGAN and who demonstrated rapid recurrence of crescentic IGAN after kidney donation.In September 2014, a 28-year-old male patient was hospitalized due to IGAN with 60% of crescents. Cyclophosphamide, steroids, and plasmapheresis did not prevent ESRD. After 8 months of peritoneal dialysis, the patient received a blood group-compatible living donor kidney from his 57-year-old mother. Immunosuppression consisted of tacrolimus, mycophenolic acid, and steroids without induction therapy. Acute graft failure occurred 2 months later, and graft biopsy results revealed recurrence of crescentic IGAN. Cyclophosphamide was added to tacrolimus and steroid treatment, but graft function could not be restored despite viable kidney tissue in repeated biopsy specimens. Rescue therapy with 4 single doses of eculizumab was introduced while hemodialysis had already been initiated. After a cumulative dose of 1800 mg of eculizumab, kidney function did not recover.In this case, eculizumab was not effective in treating IGAN recurrence after transplantation. Therapy was started late when hemodialysis had already been initiated; an earlier start of therapy might be more effective.
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Flat intraurothelial lesions of the urinary bladder-do hyperplasia, dysplasia, and atypia of unknown significance need to exist as diagnostic entities? and how to handle in routine clinical practice - Paner, Gladell P.; Smith, Steven C.; Hartmann, Arndt; Agarwal, Piyush K.; Comperat, Eva; Amin, Mahul B. (Modern Pathology, 2022)
Classification of the putative flat preneoplastic and neoplastic lesions of the urothelium with features subthreshold for urothelial carcinoma in situ remains a challenging, indeed, vexing problem in diagnostic surgical pathology. This area, subtending lesions including flat urothelial hyperplasia, urothelial dysplasia, and atypia of unknown significance, has struggled under evolving classifications, changing criteria, and limited clinical actionability, all confounded by the recognized lack of diagnostic reproducibility. Herein, we review the state of the literature around these lesions, reviewing contemporary criteria and definitions, assessing the arguments in favor and against of retaining hyperplasia, dysplasia, and atypia of unknown significance as diagnostic entities. We clarify the intent of the original definitions for dysplasia as a lesion felt to be clearly neoplastic but with morphologic features that fall short of the threshold of urothelial carcinoma in situ. While several pathologists, including some experts in the field, conflate the term dysplasia with urothelial atypia of unknown significance, the latter is defined as a descriptive diagnosis term to express diagnostic uncertainty of a lesion of whether it is clearly reactive or neoplastic. Both molecular studies and clinical needs are considered, as we outline our approach on diagnosing each of these lesions in clinical practice. Recommendations are made to guide consistency and interoperability in future scholarship, and the place of these lesions in context of evolving trends in the field is considered.
CRIS-Team WoS Importer:2022-05-06

Fluorescence-guided bone resection: A histological analysis in medication-related osteonecrosis of the jaw - Wehrhan, Falk; Weber, Manuel; Neukam, Friedrich Wilhelm; Geppert, Carol-Immanuel; Kesting, Marco Rainer; Preidl, Raimund (Journal of Cranio-Maxillofacial Surgery, 2019)
Purpose: Surgical treatment of medication-related osteonecrosis of the jaw (MRONJ) consists of necrotic bone removal followed by dense mucosal closure. Fluorescence-guided surgery has become a promising tool to intraoperatively distinguish between healthy and necrotic bone. Until now, there has been a lack of histopathological studies correlating the intraoperative fluorescence situation to histopathological analyses of the respective bone areas in order to further validate this method. Materials and methods: Histopathological sections from intraoperatively detected fluorescence- and non−fluorescence-labeled bone were analyzed detecting osteocyte and collagen content, RANK(L) and TRAP expression as well as proportion of immature bone regeneration. Samples were compared with viable-looking bone areas according to the intraoperative clinical situation. Results: Staining revealed a significant decrease of osteocytes and collagen type-I fibers in necrotic, non-fluorescing areas compared to fluorescing bone (R/RGB [%]: 0.56 ± 0.38 (fluorescence positive) vs. 3.18 ± 2.22 (fluorescence negative), p = 0.041). Furthermore, the number of osteocytes was higher in fluorescing, clinically viable bone samples (cell/mm2: 151.26 ± 95.77 (fluorescence positive) vs. 0.56 ± 0.38 (fluorescence negative), p = 0.028). Additionally, the amount of immature bone was substantially increased in luminescent jaw bone (proportion of red [%]: 6.78 ± 7.00 (fluorescence positive) vs. 2.24 ± 1.36 (fluorescence negative), p = 0.442). RANK(L) and TRAP expression did not differ between the investigated areas, resembling a generalized decrease in osteocyte−osteoclast function all over the jaw (RANK(L) −positive cells per mm2: 8.97 ± 7.85 (fluorescence positive) vs. 7.76 ± 6.41 (fluorescence negative), p = 0.793; TRAP-positive cells per mm2: 0.36 ± 0.38 (fluorescence positive) vs. 0.33 ± 0.41 (fluorescence negative), p = 0.887). Conclusion: Intraoperative fluorescence-guided surgery might be more precise in identifying and resecting the necrotic bone compared to previous indicators like bone bleeding, which could be useful to further improve surgical therapy in MRONJ patients.
CRIS-Team Scopus Importer:2019-10-15
Keywords: Bisphosphonate; Bone fluorescence; BRONJ; Doxycycline; MRONJ

Follicular dendritic cell sarcoma: clinicopathologic study of 15 cases with emphasis on novel expression of MDM2, somatostatin receptor 2A, and PD-L1 - Agaimy, Abbas; Michal, Michael; Hadravsky, Ladislav; Michal, Michal (Annals of Diagnostic Pathology, 2016)
Follicular dendritic cell sarcoma (FDCS) is a rare low-grade neoplasm with the phenotype of FDC cells. This rare sarcoma has been well known for being mistaken for a variety of neoplasms (mainly meningioma), particularly at extranodal sites. Diagnosis of FDCS mainly relies on characteristic histologic appearance supplemented by immunohistochemistry and electron microscopy. In this study, we reviewed 15 FDCSs retrieved from our consultation files and stained them for newly reported or novel markers (PD-L1, Rb1, MDM2, and somatostatin receptor 2A [SSTR2A]) in addition to conventional FDC markers. Patients were 7 men and 7 women (1 unspecified) with a mean age of 47 years (20-75 years). The tumor site was lymph nodes (6) or spleen (2), both (1) and extranodal sites of head and neck (4) or abdominal cavity (2). Treatment was variable combinations of surgery and aggressive chemotherapy/radiotherapy. Four of 8 patients with follow-up died of disease within 1 to 10 years. All tumors expressed at least 1 FDC marker: CD21 (8/13), CD23 (2/13), CD35 (8/12), CNA.42 (13/14), Clusterin (8/13), Fascin (15/15) and D2-40/podoplanin (7/14). Epstein-Barr virus (EBER-1/2 in situ hybridization) was performed successfully in 10 conventional variants; all were negative. Five of 14 cases (36%) stained strongly for SSTR2A with a distinctive membranous pattern. Residual lymphoid follicles surrounding some of the tumors stained similarly for SSTR2A. Seven (54%) of 13 assessable cases showed moderate to strong membranous staining for PD-L1 in greater than 5% of the neoplastic cells. The Rb1 antigen was lost in 4 (28%) of 14 cases. MDM2 stained less than 5% to 20% of the tumor cells in 5 (36%) of 14 cases; 2 of them showed amplification by fluorescence in situ hybridization (FISH). CDK4 was negative except for weak staining in 1 of 14 cases. This study adds to the existing few clinicopathologic series on FDCS and represents the first study to show MDM2 amplification in this entity. Our results regarding frequent SSTR2A expression in FDCS are novel and might be of potential diagnostic and therapeutic relevance. SSTR2A expression in FDCS represents a further confusing factor when thinking of meningioma which uniformly expresses this receptor. FDCS occurring within the retroperitoneum and/or the abdominal cavity may closely mimic dedifferentiated liposarcoma, particularly if MDM2 positive and/or amplified and should thus be carefully assessed for expression of FDC markers.
EVALuna2:6824

Four-and-a-Half LIM-Domain Protein 2 (FHL2) Induces Neuropeptide Y (NPY) in Macrophages in Visceral Adipose Tissue and Promotes Diet-Induced Obesity - Sommer, Judith; Ehnis, Hanna; Seitz, Tatjana; Schneider, Julia; Wild, Andreas; Moceri, Sandra; Buechler, Christa; Bozec, Aline; Weber, Georg; Merkel, Susanne; Beckervordersandforth, Ruth; Steinkasserer, Alexander; et al. (International Journal of Molecular Sciences, 2023)
Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2KO), WTD feeding resulted in reduced body weight gain paralleled by enhanced energy expenditure and uncoupling protein 1 (UCP1) expression, indicative of activated thermogenesis. In human VAT, FHL2 was inversely correlated with UCP1 expression. Furthermore, macrophage infiltration and the expression of the chemokine MCP-1, a known promotor of macrophage accumulation, was significantly reduced in WTD-fed FHL2KO mice compared with wild-type (wt) littermates. While FHL2 depletion did not affect the differentiation or lipid metabolism of adipocytes in vitro, FHL2 depletion in macrophages resulted in reduced expressions of MCP-1 and the neuropeptide Y (NPY). Furthermore, WTD-fed FHL2KO mice showed reduced NPY expression in VAT compared with wt littermates, and NPY expression was enhanced in VAT resident macrophages of obese individuals. Stimulation with recombinant NPY induced not only UCP1 expression and lipid accumulation but also MCP-1 expression in adipocytes. Collectively, these findings indicate that FHL2 is a positive regulator of NPY and MCP-1 expression in macrophages and herewith closely linked to the mechanism of obesity-associated lipid accumulation and inflammation in VAT. Thus, FHL2 appears as a potential novel target to interfere with the macrophage–adipocyte crosstalk in VAT for treating obesity and related metabolic disorders.
CRIS-Team Scopus Importer:2023-11-03
Keywords: adipocytes; FHL2; macrophages; MCP-1; NPY; obesity; thermogenesis

Four subunits (αβγδ) of the epithelial sodium channel (ENaC) are expressed in the human eye in various locations - Krüger, Bettina; Schlötzer-Schrehardt, Ursula; Härteis, Silke; Zenkel, Matthias; Chankiewitz, Verena E.; Amann, Kerstin Ute; Kruse, Friedrich; Korbmacher, Christoph (Investigative Ophthalmology & Visual Science, 2012)
The epithelial sodium channel (ENaC) is typically expressed in sodium-absorbing epithelia. Several reports suggest that ENaC is also expressed in ocular tissues and may play a role in aqueous humor secretion and glaucoma. However, the precise localization of ENaC in the human eye is still unclear. Here, the authors studied ENaC expression in 12 normal human donor eyes and in six eyes of patients with glaucoma.Quantitative real-time PCR was used to investigate the expression of ?-, ?-, ?-, and ?-ENaC transcripts in ocular tissues. In addition, the authors performed immunohistochemical studies using recently generated antibodies against human ?- and ?-ENaC.At the mRNA level, all four ENaC subunits were found to be expressed in a wide range of ocular tissues from normal and glaucomatous human eyes, with the cornea, ciliary body, iris, and retina showing the highest expression levels. At the protein level, ?- and ?-ENaC subunits showed distinct distribution patterns and could be immunolocalized primarily to the cell membranes of epithelial cells of the cornea and to the conjunctiva, iris, ciliary body, lens, and retinal pigment epithelium but also to vascular endothelial cells, smooth muscle cells, stromal cells, and retinal neurons. The authors found no altered mRNA level of any subunit in glaucomatous eyes.All four ENaC subunits (????) are expressed in the normal human eye, with distinct localization of subunits possibly reflecting different functional states of the channel. The (patho-)physiological roles of ENaC in the various localizations in the eye remain to be determined.
EVALuna2:4482

FOXA1 Gene Expression for Defining Molecular Subtypes of Muscle-Invasive Bladder Cancer after Radical Cystectomy - Sikic, Danijel; Eckstein, Markus; Wirtz, Ralph M.; Jarczyk, Jonas; Worst, Thomas S.; Porubsky, Stefan; Keck, Bastian; Kunath, Frank; Weyerer, Veronika; Breyer, Johannes; Otto, Wolfgang; Rinaldetti, Sebastien; et al. (Journal of Clinical Medicine, 2020)
It remains unclear how to implement the recently revealed basal and luminal subtypes of muscle-invasive bladder cancer (MIBC) into daily clinical routine and whether molecular marker panels can be reduced. The mRNA expression of basal (KRT5) and luminal (FOXA1, GATA3, KRT20) markers was measured by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and correlated to clinicopathological features, recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS) in 80 patients with MIBC who underwent radical cystectomy. Additionally, the correlation of single markers with the basal and non-basal subtypes defined by a 36-gene panel was examined and then validated in the TCGA (The Cancer Genome Atlas) cohort. High expression of FOXA1 (p = 0.0048) and KRT20 (p = 0.0317) was associated with reduced RFS. In the multivariable analysis, only FOXA1 remained an independent prognostic marker for DFS (p = 0.0333) and RFS (p = 0.0310). FOXA1 expression (AUC = 0.79; p = 0.0007) was closest to the combined marker expression (AUC = 0.79; p = 0.0015) in resembling the non-basal subtype defined by the 36-gene panel. FOXA1 in combination with KRT5 may be used to distinguish the basal and non-basal subtypes of MIBC.
CRIS-Team WoS Importer:2020-05-26

FOXM1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage pT1 non-muscle-invasive bladder cancer - Breyer, Johannes; Wirtz, Ralph M.; Erben, Philipp; Rinaldetti, Sebastien; Worst, Thomas S.; Stoehr, Robert; Eckstein, Markus; Sikic, Danijel; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt; Otto, Wolfgang (Bju International, 2019)
OBJECTIVE: To investigate the role of forkhead box protein M1 (FOXM1) mRNA expression and its prognostic value in stage pT1 non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Clinical data and formalin-fixed paraffin-embedded tissues from transurethral resection of the bladder from patients with stage pT1 NMIBC, treated with an organ-preserving approach, were analysed retrospectively. Total RNA was isolated using commercial RNA extraction kits, and mRNA expression of FOXM1, MKI67, KRT20 and KRT5 was measured by single-step quantitative RT-PCR using RNA-specific TaqMan Assays. Statistical analysis was performed using Spearman's Rho, Wilcoxon or Kruskal-Wallis tests, Kaplan-Meier estimates of recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS) and Cox regression analysis. RESULTS: Data from 296 patients (79.4% men, median age 72 years) were available for the final evaluation. Spearman correlation analysis showed that mRNA expression of FOXM1 was significantly correlated with MKI67 (ρ: 0.6530, P < 0.001) and with the luminal subtype, reflected by the positive correlation with KRT20 (ρ: 0.2113, P < 0.001). Furthermore, there was also a strong correlation of FOXM1 expression with adverse clinical and pathological variables, such as concomitant carcinoma in situ (P = 0.05), multifocal tumours (P = 0.005) and World Health Organization 1973 grade 3 disease (P < 0.001). Kaplan-Meier analysis showed overexpression of FOMX1 to be associated with worse PFS (P = 0.028) and worse CSS (P = 0.015). FOXM1 overexpression was also shown to be a predictive risk factor for CSS (hazard ratio 1.61 [1.13-2.34], L-R chi-squared: 7.19, P = 0.007). FOXM1 overexpression identified a subgroup of patients within the luminal subtype with worse RFS (P = 0.017), PFS (P < 0.001) and CSS (P = 0.015). Patients with low FOXM1 expression had better outcomes, irrespective of instillation therapy, whereas patients with high FOXM1 expression benefitted from intravesical chemotherapy with mitomycin C. CONCLUSION: High FOXM1 expression was associated with adverse clinical and pathological features and worse outcomes, and predicted response to intravesical instillation therapy in patients with stage pT1 NMIBC.
EVALuna2:52993

FOXM1 predicts disease progression in non-muscle invasive bladder cancer - Rinaldetti, Sebastien; Wirtz, Ralph; Worst, Thomas Stefan; Hartmann, Arndt; Breyer, Johannes; Dyrskjot, Lars; Erben, Philipp (Journal of Cancer Research and Clinical Oncology, 2018)
PURPOSE: The proto-oncogene forkhead box M1 (FOXM1) is associated with poor survival in many cancers. The impact of FOXM1 expression on progression-free survival (PFS) of non-muscle invasive bladder cancer (NMIBC) has not yet been investigated. The differential expression of FOXM1 between the different molecular NMIBC subtypes has further been assessed. METHODS: Transcript levels of FOXM1 and MKI67 were determined in 460 NMIBC patients (UROMOL cohort) by RNA-Seq and validated in silico by the Chungbuk and Lund cohort (n = 277). FOXM1 and MKI67 cutoffs were identified by the minimal p value method. Variables were evaluated by multivariable Cox regression analyses in order to identify independent predictors. RESULTS: FOXM1 is an independent predictor for PFS superior to current histological, clinical and molecular staging methods. Patients with high FOXM1 expression have a 6- to 8-fold higher risk of progression in multivariable analysis (p < 0.03). Highest transcript levels were found in the Class 2 and genomically unstable molecular NMIBC subtype (p < 0.03). The proto-oncogene further positively correlated with tumor grade and stage. NMIBCs with high FOXM1 expression showed a PFS advantage when treated with intravesical BCG instillation. CONCLUSION: FOXM1 is a highly prognostic marker for disease progression of NMIBC superior to current histological, clinical and molecular staging methods and MKI67. It is mainly expressed in the Class 2 and genomically unstable molecular bladder cancer subtypes. Its role in drug resistance development makes FOXM1 valuable biomarker for NMIBC risk stratification.
EVALuna2:34602

FOXM1 predicts overall and disease specific survival in muscle-invasive urothelial carcinoma and presents a differential expression between bladder cancer subtypes - Rinaldetti, Sebastien; Wirtz, Ralph Markus; Worst, Thomas Stefan; Eckstein, Markus; Weiss, Cleo Aaron; Breyer, Johannes; Otto, Wolfgang; Bolenz, Christian; Hartmann, Arndt; Erben, Philipp (Oncotarget, 2017)
Forkhead box M1 (FOXM1) is a late cell cycle gene that plays a crucial role in carcinogenesis and chemotherapeutic drug resistance. In this study, the impact of FOXM1 expression on patient outcome was investigated for the first time in formalin fixed and paraffin embedded (FFPE) samples of chemotherapy naïve muscle-invasive bladder cancer (MIBC) patients. Expression analyses were performed on the Mannheim cohort (n=84) and validated on the independent Chungbuk cohort (n=61). In a Cox' proportional hazards model, a distinct FOXM1 expression cut-off dividing both cohorts in a 'high-risk' and 'low-risk' group has been determined. Multivariate analyses showed that FOXM1 is an independent risk factor for outcome prediction superior to the TNM system. The FOXM1 'high-risk' group had a 4- to 7-fold increased risk of death (p<0.03) and presented further an overexpression of MKI67. Recent studies showed that MIBCs can be subclassified in breast cancer-like subtypes: basal, luminal and p53-like. Here we demonstrated that FOXM1 was differentially expressed between MIBC subtypes concordant to its subtype specific expression in breast cancer. Since the proto-oncogene FOXM1 is known to play an important role in cisplatin resistance and to be a promising drug target, this study supports FOXM1 as a crucial biomarker in the personalization of MIBC therapy and urges prospective translational studies.
EVALuna2:6875

Frequence, spectrum and prognostic impact of additional malignancies in patients with gastrointestinal stromal tumors - Kramer, K.; Wolf, S.; Mayer, B.; Schmidt, S. A.; Agaimy, Abbas; Henne-Bruns, D.; Knippschild, U.; Schwab, M.; Schmieder, M. (Neoplasia, 2015)
Currently available data on prognostic implication of additional neoplasms in GIST miss comprehensive information on patient outcome with regard to overall or disease specific and disease free survival. Registry data of GIST patients with and without additional neoplasm were compared in retrospective case series. We investigated a total of 836 patients from the multi-center Ulmer GIST registry. Additionally, a second cohort encompassing 143 consecutively recruited patients of a single oncology center were analyzed. The frequency of additional malignant neoplasms in GIST patients was 31.9% and 42.0% in both cohorts with a mean follow-up time of 54 and 65 months (median 48 and 60 months), respectively. The spectrum of additional neoplasms in both cohorts encompasses gastrointestinal tumors (43.5%), uro-genital and breast cancers (34.1%), hematological malignancies (7.3%), skin cancer (7.3%) and others. Additional neoplasms have had a significant impact on patient outcome. The five year overall survival in GIST with additional malignant neoplasms (n = 267) was 62.8% compared to 83.4% in patients without other tumors (n = 569) (P < .001, HR=0.397, 95% CI: 0.298-0.530). Five-year disease specific survival was not different between both groups (90.8% versus 90.9%). 34.2% of all deaths (n = 66 of n = 193) were GIST-related. The presented data suggest a close association between the duration of follow-up and the rate of additional malignancies in GIST patients. Moreover the data indicate a strong impact of additional malignant neoplasms in GIST on patient outcome. A comprehensive follow-up strategy of GIST patients appears to be warranted.
EVALuna2:6685

Frequency and clinicopathological features of fibroelastotic changes in the gastrointestinal tract - Lichtmannegger, Ines; Goelder, Stefan; Probst, Andreas; Doenmez, Guenay; Agaimy, Abbas; Langer, Erich; Mueller, Wolfram; Zhang, Lanjing; Spatz, Hanno; Maerkl, Bruno (Virchows Archiv, 2014)
Fibroelastotic changes (FEC) and especially elastotic polyps of the gastrointestinal (GI) tract are considered rare benign lesions. They consist of accumulations of elastic fibers within the mucosal, submucosal, or muscular layer, occurring in all parts of the GI tract and often appearing as polyps, but also as diffuse non-polyp-forming deposits. They have been the subject of only a few studies. To explore the clinical and histopathological features of FEC in the GI tract, a series of 162 elastotic lesions was collected within a 2-year period. The clinical data and endoscopic findings were correlated. FEC appeared as polyp-forming lesions of the large intestine in 23 samples (14 %), all other samples concerning histological findings without an identifiable gross mass. Frequently related findings were postinterventional status (9 %), previous irradiation (7 %), and history of GI lymphoma (4 %). Eight samples (5 %) presented endoscopically with lesions justifying surgical intervention. We identified three different histological patterns of FEC, which we have called fibroelastosis, angioelastosis, and elastofibroma. Consistent with previous studies, CD34 immunohistochemical staining (performed on 38 polypoid FEC specimens) showed an increase of CD34-positive mesenchymal cells in 95 % of immunostained samples, suggesting a potential role for CD34-positive mesenchymal cells in the accumulation of elastic fibers. In conclusion, FEC are more common in the GI tract than previously recognized. They often present as a benign polyp. Many accompany other diseases like ulcers and atrophic gastritis or represent a residual finding after an intervention.
EVALuna2:6686

Frequency of activating mutations in FGFR2 exon 7 in bladder tumors from patients with early-onset and regular-onset disease - Spiegelberg, Christine; Giedl, Josef; Gaisa, Nadine T.; Rogler, Anja; Riener, Marc-Oliver; Filbeck, Thomas; Burger, Maximilian; Ruemmele, Petra; Hartmann, Arndt; Stoehr, Robert (International Journal of Clinical and Experimental Pathology, 2014)
The FGF/FGFR-system plays an important role in embryogenesis, tissue homeostasis and carcinogenesis. Mutational activation of FGFR2 resulting in aberrant FGFR2 signaling activation is known from both hereditary germ line alterations and somatic mutations in various malignancies (e.g. breast, gastric or ovarian cancer). FGFR2 mutations are mainly located within the hinge between Ig-like domains (exon 7), around the 3rd Ig-like domains and within the kinase domain. For bladder cancer only sparse data on FGFR2 mutations are available. Most interestingly a case of early-onset papillary carcinoma of the bladder showing a FGFR2 p.Pro253Arg mutation in exon 7 in a patient with Apert Syndrome was reported recently. To further evaluate the importance of FGFR2 exon 7 alterations in bladder cancer a cohort of 254 bladder tumors (cohort 1: unselected cases: n=139; cohort 2: early-onset bladder cancer cases (age at time of diagnosis<=45 years): n=115) was analyzed. Sections from formalin-fixed, paraffin-embedded bladder tumors were used for DNA isolation. After precise microdissection exon 7 of the FGFR2 gene was analyzed by direct Sanger sequencing. All cases could be analyzed successfully. Mutations in exon 7 of FGFR2 could not be detected in any of the cases. All tumors showed wild type sequence. Our data demonstrate that the recently reported association between early-onset papillary carcinoma of the bladder with germ line FGFR2 p.Pro253Arg mutation could not be found in our cohorts of sporadic bladder tumors. These results indicate that FGFR2 gene mutations might only play a minor role in bladder carcinogenesis.
EVALuna2:6601

Frequency of GNAS mutation in intramuscular myxoma - Erber, Ramona; Stöhr, Robert; Haller, Florian; Hartmann, Arndt; Agaimy, Abbas (VIRCHOWS ARCHIV, 2019)
CRIS-Team WoS Importer:2019-09-27

Frequency of microsatellite instability (MSI) in upper tract urothelial carcinoma: comparison of the Bethesda panel and the Idylla MSI assay in a consecutively collected, multi-institutional cohort - Kullmann, Friederike; Strissel, Pamela; Strick, Reiner; Stöhr, Robert; Eckstein, Markus; Bertz, Simone; Wullich, Bernd; Sikic, Danijel; Wach, Sven; Taubert, Helge; Olbert, Peter; Heers, Hendrik; et al. (Journal of Clinical Pathology, 2021)
Aims Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a poor prognosis which occurs sporadically or in few cases results from a genetic disorder called Lynch syndrome. Recently, examination of microsatellite instability (MSI) has gained importance as a biomarker: MSI tumours are associated with a better response to immunomodulative therapies. Limited data are known about the prevalence of MSI in UTUC. New detection methods using the fully automated Idylla MSI Assay facilitate analysis of increased patient numbers. Methods We investigated the frequency of MSI in a multi-institutional cohort of 243 consecutively collected UTUC samples using standard methodology (Bethesda panel), along with immunohistochemistry of mismatch repair (MMR) proteins. The same tumour cohort was retested using the Idylla MSI Assay by Biocartis. Results Using standard methodology, 230/243 tumours were detected as microsatellite stable (MSS), 4/243 tumours as MSI and 9/243 samples as invalid. In comparison, the Idylla MSI Assay identified four additional tumours as MSS, equalling 234/243 tumours; 4/243 were classified as MSI and only 5/243 cases as invalid. At the immunohistochemical level, MSI results were supported in all available cases with a loss in MMR proteins. The overall concordance between the standard and the Idylla MSI Assay was 98.35%. Time to result differed between 3 hours for Idylla MSI Assay and 2 days with the standard methodology. Conclusion Our data indicate a low incidence rate of MSI tumours in patients with UTUC. Furthermore, our findings highlight that Idylla MSI Assay can be applied as an alternative method of MSI analysis for UTUC.
CRIS-Team WoS Importer:2021-12-10

Frequency of TERT Promoter Mutations in Prostate Cancer - Stoehr, Robert; Taubert, Helge; Zinnall, Ulrike; Giedl, Josef; Gaisa, Nadine T.; Burger, Maximilian; Ruemmele, Petra; Hurst, Carolyn D.; Knowles, Margaret A.; Wullich, Bernd; Hartmann, Arndt (Pathobiology, 2015)
Recently, recurrent mutations within the core promoter of the human telomerase reverse transcriptase (TERT) gene generating consensus binding sites for ETS transcription factor family members were described in melanomas and other malignancies (e.g. bladder cancer, hepatocellular carcinoma). These mutations were discussed as early drivers for malignant transformation. In prostate cancer (PrCa) TERT expression has been associated with a poor prognosis and higher risk for disease recurrence. The underlying mechanisms for high TERT expression in PrCa have still not been clarified. To date, data on TERT promoter mutation analysis in PrCa are sparse. Therefore, we performed sequence analysis of the core promoter region of the TERT gene in an unselected cohort of prostate tumors.Sections from 167 formalin-fixed, paraffin-embedded and cryopreserved prostate tumors were microdissected and used for DNA isolation. The mutation hotspot region within the TERT core promoter (-260 to +60) was analyzed by direct Sanger sequencing or SNaPshot analysis.All cases were analyzed successfully. Mutations within the core promoter of the TERT gene were not detected in any of the cases with all tumors exhibiting a wild-type sequence.TERT core promoter mutations reported from several other malignancies were not detected in our unselected cohort of PrCa. These data indicate that alterations within the core promoter of the TERT gene do not play an important role in prostate carcinogenesis. © 2015 S. Karger AG, Basel.
EVALuna2:6706

From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on "New frontiers in cardiovascular research" - Cabrera-Fuentes, Hector A.; Aragones, Julian; Bernhagen, Juergen; Boening, Andreas; Boisvert, William A.; Botker, Hans E.; Bulluck, Heerajnarain; Cook, Stuart; Di Lisa, Fabio; Engel, Felix; Engelmann, Bernd; Ferrazzi, Fulvia; et al. (Basic Research in Cardiology, 2016)
In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome.
EVALuna2:9341

Frozen Section of Parotid Gland Tumours: The Head and Neck Pathologist as a Key Member of the Surgical Team - Mantsopoulos, Konstantinos; Bessas, Zacharias; Sievert, Matti; Müller-Hübner, Sarina Katrin Ursel; Koch, Michael; Agaimy, Abbas; Iro, Heinrich (Journal of Clinical Medicine, 2022)
Introduction: The aim of this study was to evaluate the impact of subspecialised head and neck versus general surgical pathologists on the reliability of the histopathologic evaluation during intraoperative consultation. Materials and Methods: The medical records of all patients who underwent a parotidectomy with frozen section between 2006 and 2021 were retrospectively evaluated. The frozen section was evaluated for sensitivity, specificity, accuracy, and predictive value. Assessment by two groups of pathologists (subspecialised head and neck versus general surgical pathologists) was compared, and the nature or types of misdiagnoses compared with final diagnoses on paraffin sections were analysed for the two groups. Results: Our study sample was made up of 669 cases. The mean age of patients was 57.7 years (range: 10–94 years). Of these, 490 patients had a benign lesion (73.2%), whereas 179 patients had a malignant lesion (26.8%). Frozen section had an overall accuracy of 97.6%, sensitivity for malignancy was 91.1%, specificity was 100%, PPV was 100%, and the NPV was 96.8%. The exact histologic subtype in the group of malignant tumours was correctly identified in FS in 89.4% of cases. A comparison of head and neck pathologists versus general surgical pathologists revealed a highly statistically significant difference concerning both overall detection of malignancy (p < 0.001) as well as correct identification of the histologic subtype (p < 0.001). Conclusion: Involvement of subspecialised head and neck pathologists in the intraoperative consultation for salivary gland tumours results in a gain of 19.8% more sensitivity, underlining the importance of specialisation in salivary gland pathology for the optimisation of frozen section quality.
CRIS-Team Scopus Importer:2022-03-04
Keywords: Accuracy; Benign tumour; Frozen section; Head and neck cancer; Malignant tumour; Parotid gland; Predictive value; Sensitivity; Specificity

Fully automatic HER2 tissue segmentation for interpretable HER2 scoring - Öttl, Mathias; Steenpaß, Jana; Wilm, Frauke; Qiu, Jingna; Rübner, Matthias; Lang-Schwarz, Corinna; Taverna, Cecilia; Tava, Francesca; Hartmann, Arndt; Hübner, Hanna; Beckmann, Matthias; Fasching, Peter; et al. (Journal of Pathology Informatics, 2025)
Breast cancer is the most common cancer in women, with HER2 (human epidermal growth factor receptor 2) overexpression playing a critical role in regulating cell growth and division. HER2 status, assessed according to established scoring guidelines, offers important information for treatment selection. However, the complexity of the task leads to variability in human rater assessments. In this work, we propose a fully automated, interpretable HER2 scoring pipeline based on pixel-level semantic segmentations, designed to align with clinical guidelines. Using polygon annotations, our method balances annotation effort with the ability to capture fine-grained details and larger structures, such as non-invasive tumor tissue. To enhance HER2 segmentation, we propose the use of a Wasserstein Dice loss to model class relationships, ensuring robust segmentation and HER2 scoring performance. Additionally, based on observations of pathologists' behavior in clinical practice, we propose a calibration step to the scoring rules, which positively impacts the accuracy and consistency of automated HER2 scoring. Our approach achieves an F1 score of 0.832 on HER2 scoring, demonstrating its effectiveness. This work establishes a potent segmentation pipeline that can be further leveraged to analyze HER2 expression in breast cancer tissue.
CRIS-Team Scopus Importer:2025-04-11
Keywords: Deep learning; HER2; HER2 scoring; Histopathology; Semantic segmentation

Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome - Trpkov, Kiril; Hes, Ondrej; Agaimy, Abbas; Bonert, Michael; Martinek, Petr; Magi-Galluzzi, Cristina; Kristiansen, Glen; Lueders, Christine; Nesi, Gabriella; Comperat, Eva; Sibony, Mathilde; Berney, Daniel M.; et al. (American Journal of Surgical Pathology, 2016)
Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas (RCC) are difficult to diagnose prospectively. We used immunohistochemistry (IHC) to identify fumarate hydratase (FH)-deficient tumors (defined as FH negative, 2-succinocysteine [2SC] positive) in cases diagnosed as "unclassified RCC, high grade or with papillary pattern," or "papillary RCC type 2," from multiple institutions. A total of 124 tumors (from 118 patients) were evaluated by IHC for FH and 2SC. An FH deficiency was found in 24/124 (19%) cases. An indeterminate result (only 1 marker abnormal) was found in 27/124 (22%) cases. In a tissue microarray of 776 RCCs of different types, only 2 (0.5%) tumors, initially considered papillary type 2, were FH deficient. FH mutations were found in 19/21 FH-deficient tumors (with confirmed germline mutations in 9 of 9 tumors in which germline status could be assessed) and in 1/26 FH-indeterminate tumors identified by IHC. No FH mutations were found in 2/21 FH-deficient RCCs, 25/26 FH-indeterminate RCCs, and 10/10 RCCs demonstrating FH expression by IHC. Patients with FH-deficient RCC had a median age of 44 years (range, 21 to 65 y). Average tumor size was 8.2 cm (range, 0.9 to 18 cm). FH-deficient RCCs were characterized by at least focal macronucleoli and demonstrated 2 or more growth patterns in 93% cases. Papillary was the most common (74%) and dominant (59%) pattern, whereas other common patterns included: solid (44%), tubulocystic (41%), cribriform (41%), and cystic (33%). At presentation, 57% were stage >=pT3, 52% had positive nodes, and 19% had distant metastases. After a mean follow-up of 27 months (range, 1 to 114 mo), 39% of patients were dead of disease, and 26% had disease progression. We conclude that FH and 2SC are useful IHC ancillary tools, which allow recognition of FH-deficient RCC.
EVALuna2:6823

Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening - Siegler, Lisa; Erber, Ramona; Burghaus, Stefanie; Brodkorb, Tobias; Wachter, David; Wilkinson, Nafisa; Bolton, James; Stringfellow, Helen; Haller, Florian; Beckmann, Matthias; Hartmann, Arndt; Agaimy, Abbas (Virchows Archiv, 2018)
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a rare autosomal dominant disease caused by germline mutations in the fumarate hydratase (FH) gene. Affected individuals develop cutaneous and uterine leiomyomas and aggressive RCC. To date, only few publications described the frequency and morphology of FH-deficient uterine leiomyomas. We reviewed 22 cases collected over 8 years from routine and consultation files based on distinctive histological features. In addition, we screened 580 consecutive uterine leiomyomas from 484 patients, 23 extra-uterine and 8 uterine leiomyosarcomas, and 6 leiomyomas with bizarre nuclei for FH loss using immunohistochemistry (IHC) on tissue microarrays (TMAs). All 22 FH-deficient cases were suspected on H&E sections and confirmed by FH IHC. Patients' ages ranged from 25 to 70 years (median 36). Seventeen patients had multiple nodules (2-14) measuring up to 11.8 cm. None of the patients had stigmata or family history of the HLRCC syndrome. Histologically, all FH-deficient tumors showed consistent and reproducible features as reported previously. FH loss was detected in 2/534 evaluable leiomyomas (0.4%), but in none of leiomyosarcomas. Two of six leiomyomas with bizarre nuclei were FH-deficient. FH-deficient uterine leiomyomas are rare in routine material (= 0.4%). They can be reliably identified or suspected by consistent morphological features. Our data showed predictive morphology to be superior to blind IHC screening for detecting them. The relationship of FH-deficient uterine smooth muscle tumors to the HLRCC syndrome needs further clarification.
EVALuna2:33962

Functional analyses and prognostic significance of SFRP1 expression in bladder cancer - Rogler, Anja; Kendziorra, Emil; Giedl, Josef; Stoehr, Christine; Taubert, Helge; Goebell, Peter; Wullich, Bernd; Stoeckle, Michael; Lehmann, Jan; Petsch, Sabrina; Hartmann, Arndt; Stoehr, Robert (Journal of Cancer Research and Clinical Oncology, 2015)
We previously showed that the Wnt-signaling antagonist SFRP1 (secreted frizzled-related protein 1) is a promising marker in bladder cancer. The aim of this study was to validate the prognostic role and analyze the functional significance of SFRP1.Four bladder cancer cell lines (RT112, RT4, J82 and BFTC905) and one urothelial cell line (UROtsa) were used for functional characterization of SFRP1 expression. Effects on viability, proliferation and wound healing were investigated, and canonical Wnt-pathway activity as well as Wnt-signaling target gene expression was analyzed. Additionally, tissue micro-arrays from two different bladder tumor cohorts were evaluated for SFRP1 expression, and associations with survival and histopathological parameters were analyzed.The cell lines RT112, RT4, J82 and UROtsa showed SFRP1 expression. In BFTC905, SFRP1 expression was inhibited by promoter hypermethylation. Wnt-pathway activity was absent in all cell lines and independent from SFRP1 expression. RT112 and BFTC905 were used for further functional characterization. SFRP1 overexpression resulted in decreased viability and migration in BFTC905 cells. Knockdown of SFRP1 expression in RT112 cells resulted only in marginal effects. In bladder tumors, SFRP1 expression was associated with lower tumor grade, but not with progression in patients with papillary bladder cancer. SFRP1 expressing papillary bladder cancer tumors also demonstrated a tendency to longer overall survival.SFRP1 is reducing malignant potential of BFTC905 cells, but not by regulation of canonical Wnt-signaling pathway. Other pathways, like non-canonical Wnt or the MAPK pathway, could be activated via SFRP1-expression loss. In bladder tumors, SFRP1 has the potential to predict outcome for a subset of papillary bladder tumors.
EVALuna2:6533

Functional genomics meta-analysis to identify gene set enrichment networks in cardiac hypertrophy - Angeloni, Miriam; Thievessen, Ingo; Engel, Felix; Magni, Paolo; Ferrazzi, Fulvia (Biological Chemistry, 2021)
In order to take advantage of the continuously increasing number of transcriptome studies, it is important to develop strategies that integrate multiple expression datasets addressing the same biological question to allow a robust analysis. Here, we propose a meta-analysis framework that integrates enriched pathways identified through the Gene Set Enrichment Analysis (GSEA) approach and calculates for each meta-pathway an empirical p-value. Validation of our approach on benchmark datasets showed comparable or even better performance than existing methods and an increase in robustness with increasing number of integrated datasets. We then applied the meta-analysis framework to 15 functional genomics datasets of physiological and pathological cardiac hypertrophy. Within these datasets we grouped expression sets measured at time points that represent the same hallmarks of heart tissue remodeling ('aggregated time points') and performed meta-analysis on the expression sets assigned to each aggregated time point. To facilitate biological interpretation, results were visualized as gene set enrichment networks. Here, our meta-analysis framework identified well-known biological mechanisms associated with pathological cardiac hypertrophy (e.g., cardiomyocyte apoptosis, cardiac contractile dysfunction, and alteration in energy metabolism). In addition, results highlighted novel, potentially cardioprotective mechanisms in physiological cardiac hypertrophy involving the down-regulation of immune cell response, which are worth further investigation.
CRIS-Team Scopus Importer:2021-06-11
Keywords: cardiac hypertrophy; pathological hypertrophy; pathway network; physiological hypertrophy; transcriptome meta-analysis

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice - Klepper, Simon; Jung, Susan; Dittmann, Lara; Geppert, Carol-Immanuel; Hartmann, Arndt; Beier, Nicole; Trollmann, Regina (International Journal of Molecular Sciences, 2022)
Experimental in vivo data have recently shown complementary neuroprotective actions of rhEPO and growth hormone (rhGH) in a neonatal murine model of hypoxic brain injury. Here, we hypothesized that rhGH and rhEPO mediate stabilization of the blood-brain barrier (BBB) and regenerative vascular effects in hypoxic injury to the developing brain. Using an established model of neonatal hypoxia, neonatal mice (P7) were treated i.p. with rhGH (4000 mu g/kg) or rhEPO (5000 IU/kg) 0/12/24 h after hypoxic exposure. After a regeneration period of 48 h or 7 d, cerebral mRNA expression of Vegf-A, its receptors and co-receptors, and selected tight junction proteins were determined using qRT-PCR and ELISA. Vessel structures were assessed by Pecam-1 and occludin (Ocln) IHC. While Vegf-A expression increased significantly with rhGH treatment (p < 0.01), expression of the Vegfr and TEK receptor tyrosine kinase (Tie-2) system remained unchanged. RhEPO increased Vegf-A (p < 0.05) and Angpt-2 (p < 0.05) expression. While hypoxia reduced the mean vessel area in the parietal cortex compared to controls (p < 0.05), rhGH and rhEPO prevented this reduction after 48 h of regeneration. Hypoxia significantly reduced the Ocln(+) fraction of cortical vascular endothelial cells. Ocln signal intensity increased in the cortex in response to rhGH (p < 0.05) and in the cortex and hippocampus in response to rhEPO (p < 0.05). Our data indicate that rhGH and rhEPO have protective effects on hypoxia-induced BBB disruption and regenerative vascular effects during the post-hypoxic period in the developing brain.
CRIS-Team WoS Importer:2022-08-26

Fusion-positive skin/adnexal carcinomas - Agaimy, Abbas (Genes Chromosomes & Cancer, 2022)
Gene fusions have been increasingly identified as central events driving oncogenesis in a variety of benign and malignant neoplasms of different histogenesis originating in diverse organs. While some fusion-driven neoplasms may occur at any body site, certain genotypes and their associated phenotypic entities cluster to specific body site/organ, albeit with variable frequencies among anatomic locations. In the last two decades, several skin adnexal entities driven by specific fusions have been described; some of them represent new entities (eg, secretory carcinoma harboring NTRK fusions), while others are old established entities with newly discovered underlying gene fusions (eg, poroid neoplasms harboring NUTM1, YAP1, and WWTR1 fusions). While limited availability of next generation sequencing tools in routine practice has largely limited and delayed discovery of fusions in old entities, the increasing availability of novel immunoantibodies as surrogates to recognize gene fusions (such as NUT and YAP1 immunohistochemistry) represents a relatively cheap, quick, and reliable routine tool for their proper recognition and appropriate classification. This review highlights the main, recently defined skin adnexal carcinomas carrying gene fusions.
CRIS-Team Scopus Importer:2022-03-11
Keywords: adnexal carcinoma; gene fusion; NUT carcinoma; NUTM1; porocarcinoma; poroma; YAP1

GAB1::ABL1 fusions define a distinctive soft tissue neoplasm, with variable perineurial differentiation, and a predilection for children and young adults - Agaimy, Abbas; Perret, Raul; Demicco, Elizabeth G.; Gross, John M.; Liu, Yajuan J.; Azmani, Rihab; Engelmann, Carsten; Schubart, Christoph; Seppet, Joosep; Stöhr, Robert; Le Loarer, François; Dickson, Brendan C. (Genes Chromosomes & Cancer, 2023)
Although well known as a fusion partner in hematological malignancies, fusion genes involving the ABL proto-oncogene 1 (ABL1), mapping to chromosomal region 9q34.12, have only been anecdotally reported in five soft tissue tumors. These neoplasms have been variously reported as perineurioma, angiofibroma, and solitary fibrous tumor, and all have harbored a GAB1::ABL1 gene fusion; however, the nosology and clinicopathological characteristics of soft tissue tumors carrying this rare fusion have not been delineated. We herein describe eight tumors containing the GAB1::ABL1 fusion and review previously reported cases in a series to define their morphological spectrum, address immunohistochemical evidence for a line of differentiation, with special reference to the presence or absence of a perineurial immunophenotype, and gather insight into their behavior. The patients included four females and four males, aged 13–37 years (median, 24 years). Two cases each originated in the shoulder area, trunk, hands, and lower extremities, with a size range of 1.5–8 cm (median, 3.4 cm). Four tumors were deep and four superficial. All tumors were morphologically similar, being composed of bland fibroblast-like spindle to ovoid cells diffusely arranged in a paucivascular fibrous to fibromyxoid stroma with variable resemblance to soft tissue perineurioma. Mitotic activity was generally low (0–8 mitoses in 10 high-power fields [HPFs]; median, 1). All lesions had at least focally infiltrative margins, but they otherwise lacked pleomorphism and necrosis. Immunohistochemistry showed focal reactivity for CD34 (5/7), epithelial membrane antigen (EMA) (3/8), claudin1 (2/3), GLUT1 (4/6), and S100 (2/7); other markers, including MUC4 (0/7), desmin (0/9), and smooth muscle actin (SMA) (0/4), were negative. RNA sequencing revealed a GAB1::ABL1 fusion in all cases with exon 6 of GAB1 fused to exon 2 of ABL1. Treatments included various forms of surgical intervention in seven cases; one tumor was biopsied only. Limited follow-up was available for five patients. One tumor regrew rapidly within 1 month to 1.5 cm after an initial marginal excision and was re-excised with close margins. Four patients were disease-free at 1, 3, 14, and 25 months of follow-up. Metastases have not, to date, been observed. This series characterizes “GAB1::ABL1 fusion-positive spindle cell neoplasm” as a distinct entity, with overlapping features with soft tissue perineurioma and predilection for children and young adults.
CRIS-Team Scopus Importer:2023-03-03
Keywords: ABL1; children; GAB1; gene fusion; perineurioma; tyrosine kinase receptors

Galectin 3 expression in primary oral squamous cell carcinomas - Weber, Manuel; Buettner-Herold, Maike; Distel, Luitpold; Ries, Jutta; Möbius, Patrick; Preidl, Raimund; Geppert, Carol-Immanuel; Neukam, Friedrich Wilhelm; Wehrhan, Falk (BMC Cancer, 2017)
Immunologic factors can promote the progression of oral squamous cell carcinomas (oscc). The phylogenetic highly conserved protein Galectin 3 (Gal3) contributes to cell differentiation and immune homeostasis. There is evidence that Gal3 is involved in the progression of oscc and influences the regulation of macrophage polarization. Macrophage polarization (M1 vs. M2) in solid malignancies like oscc contributes to tumor immune-escape. However, the relationship between macrophage polarization and Gal3 expression in oscc is not yet understood. The current study analyzes the association between histomorphologic parameters (T-, N-, L- Pn-status, grading) and Gal3 expression resp. the ratio between Gal3 expressing cells and CD68 positive macrophages in oscc specimens.Preoperative diagnostic biopsies (n = 26) and tumor resection specimens (n = 34) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and CD68 expression. The number of Gal3 expressing cells and the ratio between CD68 and Gal3 expressing cells was quantitatively assessed.In biopsy and tumor resection specimens, the number of Gal3 positive cells as well as the Gal3/CD68 ratio were significantly (p < 0.05) higher in T2 oscc compared to T1 cases. In biopsy specimens, a significantly (p < 0.05) increased Gal3 expression and Gal3/CD68 ratio was associated with the progression marker lymph vessel infiltration (L1). Tumor resection specimens of cases with lymph node metastases (N+) had a significantly (p < 0.05) increased Gal3 expression. Additionally, a high Gal3/CD68 ratio correlated significantly (p < 0.05) with higher grading (G3) in tumor resection specimens.High Gal3 expression in oscc is associated with tumor size (T-status) and parameters of malignancy (N-, L-status, grading). Gal3 might contribute to M2 macrophage mediated local immune tolerance. Gal3 expression shows association with prognosis in oscc and represent a potential therapeutic target.
EVALuna2:24446

Galectin 3 expression in regional lymph nodes and lymph node metastases of oral squamous cell carcinomas - Wehrhan, Falk; Büttner-Herold, Maike; Distel, Luitpold; Ries, Jutta; Möbius, Patrick; Preidl, Raimund; Geppert, Carol-Immanuel; Neukam, Friedrich Wilhelm; Kesting, Marco Rainer; Weber, Manuel (BMC Cancer, 2018)
BACKGROUND: Neck dissection is standard in surgical management of oral squamous cell carcinomas (oscc). However, the immunologic link between primary tumor and lymph nodes is insufficiently understood. Galectin 3 (Gal3) promotes M2 polarization of macrophages and contributes to immunosuppression. The current study analyzes the association between Gal3 expression in regional lymph nodes of oscc with histomorphologic parameters (T-, N-, L- Pn-stage, grading) of the primary tumor. Additionally, Gal3 expression is correlated with markers of macrophage polarization (M1 vs. M2). METHODS: Preoperative diagnostic biopsies (n = 26), tumor resection specimens (n = 34), tumor-free lymph nodes (n = 28) and lymph node metastases (n = 10) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and macrophage marker (CD68, CD11c, CD163 and MRC1) expression. The number of positive cells and the expression ratios were quantitatively assessed. RESULTS: High Gal3 expression in tumor-free regional lymph nodes was significantly (p < 0.05) associated with increased tumor size. The epithelial compartment of lymph node metastases showed a significantly (p < 0.05) increased Gal3 expression compared to biopsies and tumor resection specimens. Cell density of M2 macrophages was significantly (p < 0.05) and positively correlated with the number of Gal3 expressing cells in lymph nodes and tumor specimens. CONCLUSION: Gal3 expression in regional lymph nodes might be associated with oscc progression. The increased Gal3 expression in regional lymph nodes of larger tumors underlines the need of immunomodulatory treatment concepts in early-stage oscc. Blocking of Gal3 might be a therapeutic option in oral cancer.
EVALuna2:34900

Gallotannin is a DNA damaging compound that induces senescence independently of p53 and p21 in human colon cancer cells - Al-Halabi, Racha; Abou Merhi, Raghida; Chakilam, Saritha; El-Baba, Chirine; Hamade, Eva; Di Fazio, Pietro; Ocker, Matthias; Schneider-Stock, Regine; Gali-Muhtasib, Hala (Molecular Carcinogenesis, 2015)
The plant secondary metabolite gallotannin (GT) is the simplest hydrolyzable tannin shown to have anti-carcinogenic properties in several cell lines and to inhibit tumor development in different animal models. Here, we determined if GT induces senescence and DNA damage and investigated the involvement of p53 and p21 in this response. Using HCT116 human colon cancer cells wildtype for p53(+/+) /p21(+/+) and null for p53(+/+) /p21(-/-) or p53(-/-) /p21(+/+) , we found that GT induces senescence independently of p21 and p53. GT was found to increase the production of reactive oxygen species (ROS) by altering the redox balance in the cell, mainly by reducing the levels of glutathione and superoxide dismutase (SOD). Using the key antioxidants N-acetyl cysteine, dithiothreitol, SOD, and catalase, we showed that ROS were partially involved in the senescence response. Furthermore, GT-induced cell cycle arrest in S-phase in all HCT116 cell lines. At later time points, we noticed that p53 and p21 null cells escaped complete arrest and re-entered cell cycle provoking higher rates of multinucleation. The senescence induction by GT was irreversible and was accompanied by significant DNA damage as evidenced by p-H2AX staining. Our findings indicate that GT is an interesting anti colon cancer agent which warrants further study.
EVALuna2:6764

GAS2L3: Coordinator of cardiomyocyte cytokinesis? - Gruendl, Marco; Engel, Felix; Gaubatz, Stefan (Cell Cycle, 2017)
EVALuna2:25554

Gastric cancer patients less than 50 years of age exhibit significant downregulation of E-cadherin and CDX2 compared to older reference populations - Schildberg, Claus Wilhelm; Abba, Mohammed; Merkel, Susanne; Agaimy, Abbas; Dimmler, Arno; Schlabrakowski, Anne; Croner, Roland; Leupold, Joerg Hendrik; Hohenberger, Werner; Allgayer, Heike (Advances in Medical Sciences, 2014)
There is an increasing need to identify molecular markers, which can be used to prognosticate patient populations in gastric cancer. Whereas a significant number have been identified, very few have been characterized in the context of their ability to discriminate between young and old age groups in which a survival difference clearly exists.In this study, using immunohistochemistry, we evaluated three markers with proven involvement in gastric cancer. The p53 tumor suppressor, the cell adhesion glycoprotein epithelial cadherin (CDH1) and the caudal-related homeobox transcription factor (CDX2) all of these have important roles in the aetiopathogenesis and/or progression of gastric cancer.After adjustments for TNM stage, tumor grade, histopathological characteristics (Lauren classification), we found significant differences in the expression of these proteins, particularly E-cadherin and CDX2 between young and elderly patients. However, these differences did not amount to a significant difference in survival.This study demonstrates that the protein expression of p53, CDH1 and CDX2 significantly discriminates young patients with gastric cancer who have a better prognostic outlook from older patients, but this difference in expression does not contribute to a survival benefit.
EVALuna2:6583

Gastrointestinal involvement in granulomatosis with polyangiitis and microscopic polyangiitis: histological features and outcome - Latus, Joerg; Koetter, Ina; Fritz, Peter; Kimmel, Martin; Biegger, Dagmar; Ott, German; Stange, Eduard F.; Amann, Kerstin Ute; Alscher, Dominik M.; Braun, Niko (International Journal of Rheumatic Diseases, 2014)
Gastrointestinal (GI) involvement in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is rare.Medical charts of seven patients with GPA and MPA and GI involvement were reviewed regarding clinical presentation, outcome, diagnostic tools and therapy. Second, the cellular composition of the inflammatory infiltrate associated with the vascular lesions in histological samples (ileum, colon, rectum, duodenum) were investigated to identify possible treatment targets. Immunohistochemistry was done with antibodies against CD20, CD3 and CD34. Samples from a healthy control group (n = 15) were used for comparison.Mean age at onset of the first symptoms of vasculitis was 48 ± 21.3 years. At time of diagnosis GI symptoms were present in five out of seven patients (71%) and occurred during relapse of the vasculitis in two patients (29%). All patients had abdominal pain, four of seven (57%) had an acute kidney injury and three patients required renal replacement therapy. At the time of diagnosis five of seven patients (71%) required surgery and mean Birmingham Vasculitis Activity Score (BVAS) on admission was high (26.3 ± 7.7). Regarding outcome, one patient died due to gastrointestinal bleeding. Histological analysis showed significantly higher expression of CD3 in this patient compared to the control group (P = 0.02). Analysis of expression of CD20 and CD34 showed no statistically significant differences between patients with GPA and MPA with GI involvement compared to the control group.GI involvement in GPA and MPA is rare. Therapy directed at T cells might be an alternative treatment option.
EVALuna2:25467

Gastrointestinal manifestations of systemic mast cell activation disease - A practice-oriented guide to clinical picture, diagnostics and therapy Gastrointestinale Erscheinungsformen der systemischen Mastzellaktivierungserkrankung – Eine praxisorientierte Einführung in Klinik, Diagnostik und Therapie - Raithel, Martin; Homann, Jürgen; Rieker, Ralf; Molderings, Gerhard J. (Zeitschrift für Gastroenterologie, 2025)
Systemic mast cell activation disease (MCAD) is an epigenetic and genetic disease entity with a very pronounced clinical symptomatology in a variety of clinical manifestations in potentially every organ and tissue due to inappropriate release of mast cell mediators accompanied with the accumulation of both morphologically normal and mutated mast cells. Due to the prevalence of the disease of 17% in Germany, gastroenterologists and endoscopists are often unknowingly faced with MCAD in everyday clinical practice. In addition, gastroenterological examinations are an essential part of the diagnosis of MCAD. It is therefore essential for every physician working in gastroenterology to possess basic knowledge of this disease and, in particular, to be informed about its problems in the field of gastroenterology. This overview summarizes the current state of knowledge on the causes, diagnosis and treatment of the highly complex MCAD, focusing on the gastroenterological aspects.
CRIS-Team Scopus Importer:2025-02-28

Gastrointestinal stromal tumours (GIST)–development in pathology, surgery and medical therapy. Developed during the 10th German GIST-meeting, Göttingen - Agaimy, A.; Bauer, S.; Beham, A.; Bertolini, J.; Haller, F.; Koschny, R.; Maier, J.; Montemurro, M.; Perez, D.; Schaefer, I-M; Schildhaus, H-U; Wurst, C.; et al. (Zeitschrift für Gastroenterologie, 2015)
The first description of ligand-independent activating mutations in the KIT gene, which encodes the tyrosine-kinase KIT, greatly improved our understanding of gastrointestinal stromal tumour (GIST) biology. The therapeutic success in GIST has made tyrosine kinase inhibitors a "paradigm of targeted therapy". Deciphering resistance mechanisms in GIST has had implications for many other kinase-driven cancers. To exchange current knowledge within the field of GIST, the German GIST Meeting has taken place for now 10 years, traditionally in Göttingen. Subjects discussed include clinical diagnostics, pathology, surgery, and medical therapy. The following presentation gives an overview of the last meeting held in December 2013, including distinctive features in GIST and current data on the different topics.
EVALuna2:6707

GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma - De Andres, Monica P.; Jackson, Richard J.; Felipe, Irene; Zagorac, Sladjana; Pilarsky, Christian; Schlitter, Anna Melissa; Martinez De Villareal, Jaime; Jang, Gun Ho; Costello, Eithne; Gallinger, Steve; Ghaneh, Paula; Greenhalf, William; et al. (Gut, 2022)
Objective GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy. Design We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. Results GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. Conclusions GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.
CRIS-Team WoS Importer:2022-09-30

Gegen Nectin-4 gerichtete Antikörper-Wirkstoff-Konjugate als neue Behandlungsoption für Patienten mit metastasiertem Urothelkarzinom - Klümper, Niklas; Eckstein, Markus; Kunath, Frank; Heidegger, Isabel; Becker, Christoph; Rausch, Steffen (Die Urologie, 2023)
This compact review article highlights the background and importance of nectins in cancer therapy, focusing specifically on the antibody-drug conjugate enfortumab vedotin (EV) as a targeted treatment option for metastatic urothelial carcinoma. The evolving understanding of nectin-4 expression and its impact on EV therapy underscores the need for personalized approaches to ensure optimal patient outcomes. Further investigation into biomarker-guided therapies and prospective clinical trials are critical to refining patient selection and treatment strategies.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Biomarkers; Enfortumab vedotin (EV); Nectin-4 expression; Patient selection; Targeted therapies; Treatment strategies

Gelatin methacryloyl is a slow degrading material allowing vascularization and long-term use in vivo - Heltmann-Meyer, Stefanie; Steiner, Dominik; Mueller, Claudia; Schneidereit, Dominik; Friedrich, Oliver; Salehi, Sahar; Engel, Felix; Arkudas, Andreas; Horch, Raymund E. (Biomedical Materials, 2021)
In situ tissue engineering is an emerging field aiming at the generation of ready-to-use three-dimensional tissues. One solution to supply a proper vascularization of larger tissues to provide oxygen and nutrients is the arteriovenous loop (AVL) model. However, for this model, suitable scaffold materials are needed that are biocompatible/non-immunogenic, slowly degradable, and allow vascularization. Here, we investigate the suitability of the known gelatin methacryloyl (GelMA)-based hydrogel for in-situ tissue engineering utilizing the AVL model. Rat AVLs are embedded by two layers of GelMA hydrogel in an inert PTFE chamber and implanted in the groin. Constructs were explanted after 2 or 4 weeks and analyzed. For this purpose, gross morphological, histological, and multiphoton microscopic analysis were performed. Immune response was analyzed based on anti-CD68 and anti-CD163 staining of immune cells. The occurrence of matrix degradation was assayed by anti-MMP3 staining. Vascularization was analyzed by anti-alpha-smooth muscle actin staining, multiphoton microscopy, as well as expression analysis of 53 angiogenesis-related proteins utilizing a proteome profiler angiogenesis array kit. Here we show that GelMA hydrogels are stable for at least 4 weeks in the rat AVL model. Furthermore, our data indicate that GelMA hydrogels are biocompatible. Finally, we provide evidence that GelMA hydrogels in the AVL model allow connective tissue formation, as well as vascularization, introducing multiphoton microscopy as a new methodology to visualize neovessel formation originating from the AVL. GelMA is a suitable material for in situ and in vivo TE in the AVL model.
CRIS-Team WoS Importer:2021-09-17

Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma - Monteiro, Ana Carolina; Muenzner, Julienne K.; Andrade, Fernando; Rius, Flávia Eichemberger; Ostalecki, Christian; Geppert, Carol-Immanuel; Agaimy, Abbas; Hartmann, Arndt; Fujita, André; Schneider-Stock, Regine; Jasiulionis, Miriam Galvonas (Molecular Oncology, 2019)
The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P-value = 0.044) and the lymphangiogenic receptor VEGFR-3 (P-value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing-based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P-value = 0.031), ANGPT2 (P-value < 0.001), and SIX1 (P-value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio- and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.
CRIS-Team Scopus Importer:2019-06-18
Keywords: angiogenesis; biomarkers; DNA methylation; melanoma; prognosis

Gene Expression in Solitary Fibrous Tumors (SFTs) Correlates with Anatomic Localization and NAB2-STAT6 Gene Fusion Variants - Bieg, Matthias; Moskalev, Evgeny; Will, Rainer; Hebele, Simone; Schwarzbach, Matthias; Schmeck, Sanja; Hohenberger, Peter; Jakob, Jens; Kasper, Bernd; Gaiser, Timo; Ströbel, Philip; Wardelmann, Eva; et al. (American Journal of Pathology, 2021)
Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6 gene fusions, promoting constitutional up-regulation of oncogenic early growth response 1 (EGR1)-dependent gene expression. SFTs with the most common canonical NAB2 exon 4–STAT6 exon 2 fusion variant are often located in the thorax (pleuropulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2 exon 6–STAT6 exon 16/17 fusion variants typically display a cellular round to ovoid cell morphology and are often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. Here, we employed next-generation sequencing–based gene expression profiling to identify significant differences in gene expression associated with anatomic localization and NAB2-STAT6 gene fusion variants. SFTs with the NAB2 exon 4–STAT6 exon 2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription, and nuclear localization, whereas SFTs with the NAB2 exon 6–STAT6 exon 16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation, and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating co–transcription factors in the modification of chimeric NGFI-A binding protein 2 (NAB2)-STAT6–dependent deregulation of EGR1-dependent gene expression. In summary, this study establishes a potential molecular biologic basis for clinicopathologic differences in SFTs with distinct NAB2-STAT6 gene fusion variants.
CRIS-Team Scopus Importer:2021-04-02

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes. - Meagher, Nicola S.; Gorringe, Kylie L.; Wakefield, Matthew J.; Bolithon, Adelyn; Pang, Chi Nam Ignatius; Chiu, Derek S.; Anglesio, Michael S.; Mallitt, Kylie-Ann; Doherty, Jennifer A.; Harris, Holly R.; Schildkraut, Joellen M.; Berchuck, Andrew; et al. (Clinical Cancer Research, 2022)
PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
EVALuna2:513963

Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts - Agaimy, Abbas; Kasajima, Atsuko; Stöhr, Robert; Haller, Florian; Schubart, Christoph; Tögel, Lars; Pfarr, Nicole; von Werder, Alexander; Pavel, Marianne Ellen; Sessa, Fausto; Uccella, Silvia; La Rosa, Stefano; et al. (Virchows Archiv, 2023)
Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1/typical carcinoid (n = 4), NETG-2/atypical carcinoid (n = 14), and NET-G3 (n = 3). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion: two had a EWSR1::BEND2 and one case each had a KMT2A::BCOR and a TFG::ADGRG7 fusion, respectively. EWSR1 rearrangements were confirmed in both tumors with a EWSR1::BEND2 by FISH. Gene fusions were mutually exclusive with ATRX, DAXX, and MEN1 mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (n = 16) or via the TSO500 panel (n = 5), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 4/4 (100%) pancreatic versus 0/7 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1::CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.
CRIS-Team Scopus Importer:2023-02-03
Keywords: ACTH; Neuroendocrine tumor; NET; ectopic Cushing; EWSR1; BCOR fusion; BEND2 fusion; KMT2A

Gene network analysis: from heart development to cardiac therapy - Ferrazzi, Fulvia; Bellazzi, Riccardo; Engel, Felix (Thrombosis and Haemostasis, 2015)
Networks offer a flexible framework to represent and analyse the complex interactions between components of cellular systems. In particular gene networks inferred from expression data can support the identification of novel hypotheses on regulatory processes. In this review we focus on the use of gene network analysis in the study of heart development. Understanding heart development will promote the elucidation of the aetiology of congenital heart disease and thus possibly improve diagnostics. Moreover, it will help to establish cardiac therapies. For example, understanding cardiac differentiation during development will help to guide stem cell differentiation required for cardiac tissue engineering or to enhance endogenous repair mechanisms. We introduce different methodological frameworks to infer networks from expression data such as Boolean and Bayesian networks. Then we present currently available temporal expression data in heart development and discuss the use of network-based approaches in published studies. Collectively, our literature-based analysis indicates that gene network analysis constitutes a promising opportunity to infer therapy-relevant regulatory processes in heart development. However, the use of network-based approaches has so far been limited by the small amount of samples in available datasets. Thus, we propose to acquire high-resolution temporal expression data to improve the mathematical descriptions of regulatory processes obtained with gene network inference methodologies. Especially probabilistic methods that accommodate the intrinsic variability of biological systems have the potential to contribute to a deeper understanding of heart development.
EVALuna2:9255

Generation and characterization of hepatocellular carcinoma cell lines with enhanced cancer stem cell potential - Muenzner, Julienne K.; Kunze, Philipp; Lindner, Pablo; Polaschek, Sandra; Menke, Kira; Eckstein, Markus; Geppert, Carol-Immanuel; Chanvorachote, Pithi; Bäuerle, Tobias; Hartmann, Arndt; Schneider-Stock, Regine (Journal of Cellular and Molecular Medicine, 2018)
Hepatocellular carcinoma (HCC) is one of the most common causes for cancer-related death worldwide with rapidly increasing incidence and mortality rates. As for other types of cancers, also in HCC cancer stem cells (CSCs) are thought to be responsible for tumour initiation, progression and therapy failure. However, as rare subpopulations of tumour tissue, CSCs are difficult to isolate, thus making the development of suitable and reliable model systems necessary. In our study, we generated HepG2 subclones with enriched CSC potential by application of the spheroid formation method and subsequent single-cell cloning. Analyses in several 2D and 3D cell culture systems as well as a panel of functional assays both in vitro and in vivo revealed that the generated subclones displayed characteristic and sustained features of tumour initiating cells as well as highly aggressive properties related to tumour progression and metastasis. These characteristics could clearly be correlated with the expression of CSC markers that might have prognostic value in the clinical HCC setting. Therefore, we conclude that our CSC enriched HepG2 clones certainly represent suitable model systems to study the role of CSCs during HCC initiation, progression and drug resistance.
EVALuna2:34899

Gene therapy with antisense oligonucleotides silencing c-myc reduces neointima formation and vessel wall thickness in a mouse model of vein graft disease - Steger, Christina Maria; Bonaros, Nikolaos; Rieker, Ralf; Bonatti, Johannes; Schachner, Thomas (Experimental and Molecular Pathology, 2018)
Gene therapy for avoiding intimal hyperplasia of vein grafts after coronary artery bypass grafting is still discussed controversially. A promising application of gene therapy in vein grafts is the use of antisense oligonucleotides to block the expression of genes encoding cell cycle regulatory proteins in vascular smooth muscle cells. C-myc, either directly or by regulating the expression of other proteins, controls cell proliferation, apoptosis and cell survival, tissue remodeling, angiogenesis, cell metabolism, production of inflammatory and anti-inflammatory cytokines, and also participates in cell transformation. Forty C57BL/6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. Twenty mice received periadventitial administration of antisense oligonucleotides directed against c-myc (treatment group), the other twenty mice received no treatment (control group). All vein grafts were harvested two weeks after surgery, dehydrated, wax embedded, cut into slides of 2 μm thickness, stained and histologically and immunohistochemically examined under light microscope. In our study, we could show the promising effects of antisense oligonucleotide treatment in a mouse model of vein graft disease including the significant reduction of neointimal, media and total vessel wall thickness with a significantly lower percentage of SMA positive cells, elastic fibres and acid mucopolysaccharides in the neointima and media, a decreased vascularization, and a lower expression of PDGFR ß, MMP-9 and VEGF-A positive cells throughout the whole vein graft wall.
EVALuna2:205514

Genetic risk factors for ovarian cancer and their role for endometriosis risk - Burghaus, Stefanie; Fasching, Peter; Haeberle, Lothar; Rübner, Matthias; Buechner, Kathrin; Blum, Simon; Engel, Anne; Ekici, Arif Bülent; Hartmann, Arndt; Hein, Alexander; Beckmann, Matthias; Renner, Stefan (Gynecologic Oncology, 2017)
Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions.In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray(TM) analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors.rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis.As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer.
EVALuna2:6871