Construction and analysis of tissue microarrays in the era of digital pathology: a pilot study targeting CDX1 and CDX2 in a colon cancer cohort of 612 patients - Nolte, Sarah; Zlobec, Inti; Lugli, Alessandro; Hohenberger, Werner; Croner, Roland; Merkel, Susanne; Hartmann, Arndt; Geppert, Carol-Immanuel; Rau, Tilman (Journal of Pathology: Clinical Research, 2017)
CDX1 and CDX2 are possibly predictive biomarkers in colorectal cancer. We combined digitally-guided (next generation) TMA construction (ngTMA) and the utility of digital image analysis (DIA) to assess accuracy, tumour heterogeneity and the selective impact of different combined intensity-percentage levels on prognosis.CDX1 and CDX2 immunohistochemistry was performed on ngTMAs covering normal tissue, tumour centre and invasive front. The percentages of all epithelial cells per staining intensity per core were analysed digitally. Beyond classical prognosis analysis following REMARK guidelines, we investigated pre-analytical conditions, three different types of heterogeneity (mosaic-like, targeted and haphazard) and influences on cohort segregation and patient selection. The ngTMA-DIA approach produced robust biomarker data with infrequent core loss and excellent on-target punching. The detailed assessment of tumour heterogeneity could - except for a certain diffuse mosaic-like heterogeneity - exclude differences between the invasive front and tumour centre, as well as detect haphazard clonal heterogeneous elements. Moreover, lower CDX1 and CDX2 counts correlated with mucinous histology, higher TNM stage, higher tumour grade and worse survival (p < 0.01, all). Different protein expression intensity levels shared comparable prognostic power and a great overlap in patient selection. The combination of ngTMA with DIA enhances accuracy and controls for biomarker analysis. Beyond the confirmation of CDX1 and CDX2 as prognostically relevant markers in CRC, this study highlights the greater robustness of CDX2 in comparison to CDX1. For the assessment of CDX2 protein loss, cut-points as percentage data of complete protein loss can be deduced as a recommendation.
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Contrast-Enhanced Multispectral Optoacoustic Tomography for Functional Assessment of the Gastrointestinal Tract - Paulus, Lars-Philip; Bühler, Adrian; Wagner, Alexandra; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Rother, Ulrich; Eckstein, Markus; Lang, Werner; Hörning, André; et al. (Advanced Science, 2023)
Real-time imaging and functional assessment of the intestinal tract and its transit pose a significant challenge to conventional clinical diagnostic methods. Multispectral optoacoustic tomography (MSOT), a molecular-sensitive imaging technology, offers the potential to visualize endogenous and exogenous chromophores in deep tissue. Herein, a novel approach using the orally administered clinical-approved fluorescent dye indocyanine green (ICG) for bedside, non-ionizing evaluation of gastrointestinal passage is presented. The authors are able to show the detectability and stability of ICG in phantom experiments. Furthermore, ten healthy subjects underwent MSOT imaging at multiple time points over eight hours after ingestion of a standardized meal with and without ICG. ICG signals can be visualized and quantified in different intestinal segments, while its excretion is confirmed by fluorescent imaging of stool samples. These findings indicate that contrast-enhanced MSOT (CE-MSOT) provides a translatable real-time imaging approach for functional assessment of the gastrointestinal tract.
CRIS-Team Scopus Importer:2023-06-30
Keywords: indocyanine green; intestine; multispectral optoacoustic tomography; optoacoustics; photoacoustics

Contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression - Hartmann, Philipp; Trufa, Denis; Hohenberger, Katja; Tausche, Patrick; Trump, Sonja; Mittler, Susanne; Geppert, Carol-Immanuel; Rieker, Ralf; Schieweck, Oliver; Sirbu, Horia; Hartmann, Arndt; Neurath-Finotto, Susetta (Scientific Reports, 2023)
Neoplasms of the lungs are the leading cause of cancer incidence and mortality worldwide. Although immunotherapy has increased the overall survival of patients with lung cancer, there is the need to improve this treatment. At this regard, blood lipid levels are thought to be linked to cancer risk and thus a preventive intervention through regulation of the nutrition of patients with lung cancer is gaining much attention. In this study, we therefore asked about the contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression. We measured different serum lipids and analyzed cholesterol synthesis enzymes 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and acetyl-coenzyme A cholesterol acetyltransferase 1 (ACAT1) as well as the cholesterol cellular export protein ATP-binding cassette (ABC) A-1 mRNA by quantitative PCR (qPCR) in the control and tumoral regions of post-surgery lung tissues to analyze the accumulation of cholesterol in cancer cells in a cohort of patients with lung adenocarcinoma (LUAD). We found that triglycerides in serum directly correlated with the body mass index (BMI) in patients with LUAD. By contrast, we found that high-density lipoprotein (HDL) cholesterol inversely correlated with the BMI, C-reactive protein (CRP) and overall survival and total cholesterol inversely correlated with the tumor diameter, serum CRP and overall survival in these LUAD patients. Functionally, the role of cholesterol is indispensable for the growth and development of normal animal cells where it is tightly regulated. Excess of cellular cholesterol regulated by HMGCR is converted to cholesteryl esters by the enzyme ACAT1 and exported extracellularly by the cholesterol transporter ABCA1. Here we found HMGCR and ACAT1 upregulated and ABCA1 downregulated in the lung's tumoral region of our LUAD cohort, indicating cholesterol dysregulated cellular export in lung tumor cells.
CRIS-Team Scopus Importer:2023-04-21

Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis - Böttcher, Martin; Bruns, Heiko; Lu, Junyan; Chartomatsidou, E.; Papakonstantinou, N.; Mentz, K.; Büttner-Herold, Maike; Zenz, Thorsten; Herling, M.; Huber, Wolfgang; Ghia, P.; Stamatopoulos, Kostas; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

Conventional (bone-type) giant cell tumor of the larynx: the first case with proven H3-3A: c.103G >T (p.Gly35Trp) mutation - Laco, Jan; Vosmikova, Hana; Satankova, Jana; Dedkova, Jana; Mejzlik, Jan; Chrobok, Viktor; Agaimy, Abbas (Virchows Archiv, 2024)
CRIS-Team Scopus Importer:2024-12-06

Correction: Collective forces of tumor spheroids in three-dimensional biopolymer networks. - Mark, Christoph; Grundy, Thomas J.; Strissel, Pamela; Böhringer, David; Grummel, Nadine; Gerum, Richard; Steinwachs, Julian; Hack, Carolin; Beckmann, Matthias; Eckstein, Markus; Strick, Reiner; O'Neill, Geraldine M.; et al. (eLife, 2020)
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Correction to: Anatomical locations in the oral cavity where surgical resections of oral squamous cell carcinomas are associated with a close or positive margin—a retrospective study (Clinical Oral Investigations, (2018), 22, 4, (1625-1630), 10.1007/s00784-018-2424-z) - Kerker, Florian; Adler, Werner; Brunner, Kathrin; Möst, Tobias; Wurm, Matthias; Nkenke, Emeka; Neukam, Friedrich Wilhelm; von Wilmowsky, Cornelius (Clinical Oral Investigations, 2019)
The following note was inadvertently omitted from the published paper: This work was performed in (partial) fulfillment of the requirements for the first author’s obtaining the degree Dr. med. dent.
CRIS-Team Scopus Importer:2019-05-02

Correction to: Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA (European Journal of Nuclear Medicine and Molecular Imaging, (2019), 10.1007/s00259-019-04649-1) - Schmidkonz, Christian; Krumbholz, Manuela; Atzinger, Armin; Cordes, Michael; Götz, Theresa; Prante, Olaf; Ritt, Philipp; Schaefer, Christiane; Agaimy, Abbas; Hartmann, Wolfgang; Roessig, Claudia; Froehlich, Birgit; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2020)
The original version on this paper contained an error. The author names, though correctly appeared in the PDF version, were incorrectly displayed in indexing sites. This error occurred because of the incorrect tagging of their names in themetadata of this article. The purpose of this Erratum is the correction of metadata. Therefore, indexing sites should now reflect their names as Schmidkonz C, Krumbholz M, Atzinger A, Cordes M, Goetz TI, Prante O, Ritt P, Schaefer C, Agaimy A, Hartmann W, Rössig C, Fröhlich B, Bäuerle T, Dirksen U, Kuwert T, Metzler M. The original article has been corrected.
CRIS-Team Scopus Importer:2020-02-25

Correction to: Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases (Modern Pathology, (2021), 10.1038/s41379-021-00923-6) - Farcaş, Mihaela; Gatalica, Zoran; Trpkov, Kiril; Swensen, Jeffrey; Zhou, Ming; Alaghehbandan, Reza; Williamson, Sean R.; Magi-Galluzzi, Cristina; Gill, Anthony J.; Tretiakova, Maria; Lopez, Jose I.; Montiel, Delia Perez; et al. (Modern Pathology, 2021)
The original version of this article unfortunately contained a mistake. There was a misspelling in Michael Bonert’s name as well as in his affiliation. The authors apologize for the error. The original article has been corrected.
CRIS-Team Scopus Importer:2021-11-12

Correction to: 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 (Modern Pathology, (2021), 34, 4, (770-785), 10.1038/s41379-020-00684-8) - 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, 2021)
The original version of this article unfortunately contained a mistake in an author name. Zarifa Yusifli was stated as Zerife Yusufli. We apologize for the mistake. The original article has been corrected.
CRIS-Team Scopus Importer:2021-06-18

Correction to: Long-term endothelial dysfunction in irradiated vessels: an immunohistochemical analysis (Strahlentherapie und Onkologie, (2019), 195, 1, (52-61), 10.1007/s00066-018-1382-3) - Preidl, Raimund; Möbius, Patrick; Weber, Manuel; Amann, Kerstin Ute; Neukam, Friedrich Wilhelm; Kesting, Marco Rainer; Geppert, Carol-Immanuel; Wehrhan, Falk (Strahlentherapie und Onkologie, 2020)
The original version of this article unfortunately contained a mistake. The correct version of the Acknowledgements is given below: Acknowledgements This study was supported by the ELAN-Fond (University of Erlangen-Nürnberg). The authors thank Carsten Kronauer and Florian Obstmeier for conducting the immunohistochemical staining and detecting the expression of mediators.
CRIS-Team Scopus Importer:2020-01-21

Correction to: Multicenter evaluation of an automated, multiplex, RNA-based molecular assay for detection of ALK, ROS1, RET fusions and MET exon 14 skipping in NSCLC (Virchows Archiv, (2024), 10.1007/s00428-024-03778-9) - Melchior, Linea; Hirschmann, Astrid; Hofman, Paul; Bontoux, Christophe; Concha, Angel; Mrabet‑Dahbi, Salima; Vannuffel, Pascal; Watkin, Emmanuel; Putzová, Martina; Scarpino, Stefania; Cayre, Anne; Martin, Paloma; et al. (Virchows Archiv, 2024)
In the original version of this article, the given and family names of the authors were interchanged. The names were displayed correctly in all versions at the time of publication. The original article has been corrected.
CRIS-Team Scopus Importer:2024-05-17

Correction to: Multi-institutional re-evaluation of prognostic factors in chromophobe renal cell carcinoma: proposal of a novel two-tiered grading scheme (Virchows Archiv, (2019), 10.1007/s00428-019-02710-w) - Ohashi, Riuko; Martignoni, Guido; Hartmann, Arndt; Caliò, Anna; Segala, Diego; Stöhr, Christine; Wach, Sven; Erlmeier, Franziska; Weichert, Wilko; Autenrieth, Michael; Schraml, Peter; Rupp, Niels J.; et al. (Virchows Archiv, 2020)
The legends of Figs. 1 and 3 in the published original version of the above article are incorrect.
CRIS-Team Scopus Importer:2020-03-20

Correction to: The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence (World Journal of Urology, (2015), 33, 7, (973-979), 10.1007/s00345-015-1510-y) - Karl, A.; Buchner, A.; Tympner, C.; Kirchner, T.; Ganswindt, U.; Belka, C.; Ganzer, R.; Burger, M.; Eder, F.; Hofstädter, F.; Schilling, D.; Sievert, K.; et al. (World Journal of Urology, 2020)
In multivariate analysis, GS of the regular prostatectomy specimen was the only statistically significant parameter for pT2R1 prostate cancer.
CRIS-Team Scopus Importer:2020-02-28

Correlation between referral cytology and in-house colposcopy-guided cytology for detecting early cervical neoplasia - Schulmeyer, Carla; Stübs, Frederik; Gaß, Paul; Renner, Stefan; Hartmann, Arndt; Strehl, Johanna; Mehlhorn, Grit; Geppert, Carol-Immanuel; Adler, Werner; Beckmann, Matthias; Koch, Martin (Archives of Gynecology and Obstetrics, 2019)
Purpose: The current cervical cancer screening program in Germany recommends that the results showing suspected HPV infection should be further examined in specialized colposcopy units. This study aimed to correlate externally documented Pap smear results with in-house colposcopy-guided Pap cytology results and compare colposcopy-guided biopsy and postoperative histopathology results. Methods: Clinical data were analyzed from 3627 examinations in 2844 patients who visited a university certified dysplasia unit from 2014 to 2017; 2212 patients underwent complete assessments, including Pap smear, colposcopy, HPV testing, colposcopy-guided biopsy, and/or surgery. The results were analyzed descriptively. Results: External and in-house Pap results were consistent in 1054 ofthe 2212 patients (47.65%). Referral cytology showed a higher grade than in-house in 456 (20.61%) and a lower grade in 702 (31.74%). Using the histopathological findings as the gold standard, overdiagnosis in the referral cytology was noted in 180 patients (13.19%), underdiagnosis in 263 (19.27%), and concordant findings in 922 (67.55%). For in-house cytology, overdiagnosis was found in 133 patients (10.74%), underdiagnosis in 192 (15.51%), and accurate diagnosis with congruent cytology and histopathology findings in 913 (73.75%). Conclusions: The rate of detection of cervical abnormalities differs significantly depending on whether the examination is performed routinely or in specialized units. Colposcopy-guided Pap smears correlate significantly better with histology than referral cytology results without colposcopic guidance. More severe lesions were also detected more accurately.
CRIS-Team Scopus Importer:2019-12-20
Keywords: Cervical cancer screening; Cervical intraepithelial neoplasia (CIN); Dysplasia; High-grade squamous intraepithelial lesion (HSIL); Low-grade squamous intraepithelial lesion (LSIL); Pap smear; Precancerous lesions of the cervix

Correlation of CTNNB1 Mutation Status with Progression Arrest Rate in RECIST Progressive Desmoid-Type Fibromatosis Treated with Imatinib: Translational Research Results from a Phase 2 Study of the German Interdisciplinary Sarcoma Group (GISG-01) - Kasper, Bernd; Gruenwald, Viktor; Reichardt, Peter; Bauer, Sebastian; Hohenberger, Peter; Haller, Florian (Annals of Surgical Oncology, 2016)
CTNNB1 gene mutations are the molecular key events in the majority of sporadic desmoid-type fibromatosis (DF). The specific S45F mutation has been reported to be associated with a more aggressive clinical course in DF. For the current study, the CTNNB1 mutation status was analyzed in DF samples from the prospective German Interdisciplinary Sarcoma Group (GISG) phase 2 study evaluating imatinib to induce progression arrest in DF Response Evaluation Criteria In Solid Tumors (RECIST) progressive patients.Thirty-seven patients were treated with a planned dose of imatinib 800 mg daily over 2 years (NCT01137916). The progression arrest rate (PAR) after 6 months of treatment was the primary endpoint of the study. CTNNB1 exon 3 mutation status was analyzed using Sanger sequencing.Thirty-three (97 %) of 34 patients reaching the primary endpoint were evaluable for CTNNB1 mutation exon 3 status. T41A mutations accounted for 30.3 % of the study samples and S45 mutations for 48.5 %, whereas CTNNB1 wild-type status was found in 21.2 %. The respective PAR at 6 months was 70, 81, and 43 %. Patients harboring CTNNB1 mutations demonstrated a higher PAR compared to wild-type DF. There was a statistically significant difference comparing patients with S45F mutations (85 % PAR) versus wild-type status (p = 0.05).Mutations at position S45 were overrepresented in the GISG-01 trial recruiting RECIST progressive patients only. The positive correlation of CTNNB1 mutation status with the progression arrest rate after imatinib therapy supports the idea of a potential predictive impact of the mutation status on DF treatment decision making.
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Correlation of enhanced thrombospondin-1 expression, TGF-β signalling and proteinuria in human type-2 diabetic nephropathy - Hohenstein, Bernd; Daniel, Christoph; Hausknecht, Birgit; Boehmer, Kirsten; Riess, Regine; Amann, Kerstin Ute; Hugo, Christian (Nephrology Dialysis Transplantation, 2008)
Background. Activation of the thrombospondin-1 (TSP-1)-TGF-β pathway by glucose and the relevance of TSP-1-dependent activation of TGF-β for renal matrix expansion, renal fibrosis and sclerosis have previously been demonstrated by our group in in vivo and in vitro studies. Design and methods. We investigated renal biopsies (n = 40) and clinical data (n = 30) of patients with diabetic nephropathy. Ten kidneys without evidence of renal disease served as controls. Glomerular and cortical expression of TSP-1, p-smad2/3, fibrosis and glomerular sclerosis (PAS) were assessed by immunhistochemical staining and related with clinical data. Results. Glomerular (g) and cortical (c) TSP-1 were increased during diabetic nephropathy (g: 2.62 ± 2.65; c: 4.5 ± 4.2) compared to controls (g: 0.67 ± 0.7; c: 1.5 ± 1.2). P-smad2/3 was significantly increased (g: 16.7 ± 12.9; c: 148.7 ± 92.8) compared to controls (g: 7.1 ± 3.6; c: 55 ± 25; P < 0.05). TSP-1 was coexpressed with p-smad2/3 as an indicator of TGF-β activation. TSP-1 correlated with enhanced tubulointerstitial p-smad2/3 positivity (r = 0.39 and r = 0.4, P < 0.05) and glomerular p-smad2/3 correlated with proteinuria (r = 0.35, P < 0.05). Conclusions. In summary, the present study suggests a functional activity of the TSP-1/TGF-β axis, especially in the tubulointerstitium of patients with diabetic nephropathy. The positive correlation of glomerular p-smad2/3 positivity with proteinuria further supports the importance of the TSP-1/TGF-β system as a relevant mechanism for progression of human type-2 diabetic nephropathy. © The Author [2008].
Created from Fastlane, Scopus look-up
Keywords: Diabetic nephropathy; Proteinuria; TGF-β; TSP-1; Tubulointerstitium

Correlation of Hif1a expression of primary oral squamous cell carcinomas with histomorphologic parameters and macrophage polarization - Wehrhan, Falk; Möbius, Patrick; Amann, Kerstin Ute; Geppert, Carol-Immanuel; Preidl, Raimund; Ries, Jutta; Neukam, Friedrich Wilhelm; Weber, Manuel (2018)
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Correlation of histological and macroscopic findings in peritoneal endometriosis - Strehl, Johanna; Hackl, Janina; Wachter, David; Klingsiek, Peter; Burghaus, Stefanie; Renner, Stefan; Fasching, Peter; Hartmann, Arndt; Beckmann, Matthias (International Journal of Clinical and Experimental Pathology, 2014)
In the last two decades, a color based concept of disease activity in peritoneal endometriosis has been in use in the clinical context, with red lesions being considered active and black or white lesions being interpreted as less active or dormant.Our aim was to analyze 4 main color categories of peritoneal endometriosis (black, white, red and brown) in one single patient group using histomorphological and immunohistochemical methods.65 endometriosis lesions (30 black, 17 white, 11 brown, 7 red) were resected from 47 premenopausal, nulliparous women which had not received exogenous hormones for at least six months prior to the operation. Specimen workup, histomorphological analysis and immunohistochemical analysis were performed in a standardized manner.The color categories showed a broad overlap in proliferative activity and hormone receptor expression. Differences were found in lesion morphology. Adjacent stromal reaction in particular showed a marked increase from red through brown and black to white lesions. Differences were also seen in gland pattern and gland content.Lesion colors in peritoneal endometriosis seem to be determined by gland content and a varying adjacent stromal reaction and more likely reflect an aging process than different levels of disease activity.
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Correlation of RANK and RANKL with mammographic density in primary breast cancer patients - Wunderle, Marius; Heindl, Felix; Behrens, Annika; Häberle, Lothar; Hack, Carolin; Heusinger, Katharina; Hübner, Hanna; Gaß, Paul; Rübner, Matthias; Schulz-Wendtland, Rüdiger; Erber, Ramona; Hartmann, Arndt; et al. (Archives of Gynecology and Obstetrics, 2024)
Purpose: The receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) have been shown to promote proliferation of the breast and breast carcinogenesis. The objective of this analysis was to investigate whether tumor-specific RANK and RANKL expression in patients with primary breast cancer is associated with high percentage mammographic density (PMD), which is a known breast cancer risk factor. Methods: Immunohistochemical staining of RANK and RANKL was performed in tissue microarrays (TMAs) from primary breast cancer samples of the Bavarian Breast Cancer Cases and Controls (BBCC) study. For RANK and RANKL expression, histochemical scores (H scores) with a cut-off value of > 0 vs 0 were established. PMD was measured in the contralateral, non-diseased breast. Linear regression models with PMD as outcome were calculated using common predictors of PMD (age at breast cancer diagnosis, body mass index (BMI) and parity) and RANK and RANKL H scores. Additionally, Spearman rank correlations (ρ) between PMD and RANK and RANKL H score were performed. Results: In the final cohort of 412 patients, breast cancer-specific RANK and RANKL expression was not associated with PMD (P = 0.68). There was no correlation between PMD and RANK H score (Spearman’s ρ = 0.01, P = 0.87) or RANKL H score (Spearman’s ρ = 0.04, P = 0.41). RANK expression was highest in triple-negative tumors, followed by HER2-positive, luminal B-like and luminal A-like tumors, while no subtype-specific expression of RANKL was found. Conclusion: Results do not provide evidence for an association of RANK and RANKL expression in primary breast cancer with PMD.
CRIS-Team Scopus Importer:2024-06-14
Keywords: Breast cancer; Immunohistochemistry; Mammographic density; RANK expression; RANKL expression

Correlations Between Interleukin-11 Expression and Hypertensive Kidney Injury in a Rat Model of Renovascular Hypertension - Menendez-Castro, Carlos; Cordasic, Nada; Dambietz, Thomas; Veelken, Roland; Amann, Kerstin Ute; Hartner, Andrea; Hilgers, Karl Friedrich (American Journal of Hypertension, 2020)
BACKGROUND: Interleukin-11 (IL-11) is a pleiotropic cytokine of the interleukin-6 family. Recent studies revealed its crucial role in the development of cardiovascular fibrosis. In this study we examined IL-11 expression levels in the heart and the kidney exposed to high blood pressure in renovascular hypertensive rats and their correlations to fibrotic markers and kidney injury. METHODS: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats. IL-11 expression was measured by real-time polymerase chain reaction in the left ventricle and the right kidney. The correlation of cardiac IL-11 expression with biomarkers of renal fibrosis was assessed. We further investigated IL-11 expression in 2K1C rats grouped into rats with malignant vs. nonmalignant hypertension (distinguishing criteria: weight loss, number of fibrinoid necrosis, and onion skin lesions). RESULTS: Thirty-five days after clipping, mean arterial pressure was significantly increased in 2K1C. Renal IL-11 expression was elevated in 2K1C. In the heart there was only a trend toward higher IL-11 expression in 2K1C. IL-11 in the kidney in 2K1C correlated with the expression of transforming growth factor (TGF)-β1/2, collagens, fibronectin, osteopontin, as well as tissue inhibitors of metalloprotease 1/2. There were also correlations of IL-11 with tissue collagen expansion, number of activated fibroblasts and serum creatinine, but no correlation with mean arterial pressure. Renal expression of IL-11 was highest in rats with malignant hypertension. CONCLUSIONS: Renal IL-11 expression of renovascular hypertensive rats is markedly increased and correlates with profibrotic markers and loss of function and might therefore serve as a biomarker for the severity of hypertensive nephrosclerosis.
CRIS-Team Scopus Importer:2020-04-14
Keywords: blood pressure; hypertension; interleukin-11 (IL-11); malignant hypertension; renal fibrosis; two-kidney one-clip renovascular hypertension (2K1C)

Corrigendum: A TNFR2-specific TNF fusion protein with improved in vivo activity. - Gamboa Vargas, Juan; Wagner, Jennifer; Shaikh, Haroon; Lang, Isabell; Medler, Juliane; Anany, Mohamed; Steinfatt, Tim; Peña Mosca, Josefina; Haack, Stephanie; Dahlhoff, Julia; Büttner-Herold, Maike; Graf, Carolin; et al. (Frontiers in Immunology, 2023)
[This corrects the article DOI: 10.3389/fimmu.2022.888274.].
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Corrigendum: Complement activation via the lectin and alternative pathway in patients with severe COVID-19(Front. Immunol., (2022), 13, (835156), 10.3389/fimmu.2022.835156) - Niederreiter, Janina; Eck, Christine; Ries, Tajana; Hartmann, Arndt; Märkl, Bruno; Büttner-Herold, Maike; Amann, Kerstin Ute; Daniel, Christoph (Frontiers in Immunology, 2023)
In the published article, information in the Acknowledgments was mistakenly not included in the publication. A correction has been made to Acknowledgments:
CRIS-Team Scopus Importer:2023-10-20
Keywords: autopsy; complement deposition; COVID-19; kidney; lectin pathway; lung

Corrigendum to “Indirect comparison of capmatinib treatment from GEOMETRY mono-1 trial to SOC in German patients with locally advanced or metastatic NSCLC harboring METex14 skipping mutations” [Eur J Cancer 207 (2024) 114158](S0959804924008141)(10.1016/j.ejca.2024.114158) - Kron, Anna; Scheffler, Matthias; Wiesweg, Marcel; Hummel, Horst Dieter; Kulhavy, Jonas; Gatteloehner, Stefan; Kollmeier, Jens; Schubart, Christoph; Groß, Thorben; Demes, Melanie Christin; Keymel, Stefanie; Joosten, Maria; et al. (European Journal of Cancer, 2024)
The authors removed the study acronym ‘RECAP’ throughout the article. The authors would like to add the following to acknowledgement section of the publication.
CRIS-Team Scopus Importer:2024-11-08

Corrigendum to "Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes" [European Urology Oncology (2023)]. - Eckstein, Markus; Matek, Christian; Wagner, Paul; Erber, Ramona; Büttner-Herold, Maike; Wild, Peter J.; Taubert, Helge; Wach, Sven; Sikic, Danijel; Wullich, Bernd; Geppert, Carol-Immanuel; Compérat, Eva M.; et al. (European Urology Oncology, 2023)
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Co-staining of microRNAs and their target proteins by miRNA in situ hybridization and immunohistofluorescence on prostate cancer tissue microarrays - Eckstein, Markus; Sailer, Verena; Nielsen, Boye Schnack; Wittenberg, Thomas; Wiesmann, Veit; Lieb, Verena; Nolte, Elke; Hartmann, Arndt; Kristiansen, Glen; Wernert, Nicolas; Wullich, Bernd; Taubert, Helge; et al. (Laboratory Investigation, 2019)
The co-expression of miRNAs and their target proteins was studied on tissue microarrays from different prostate cancer (PCa) patients. PCa of primary Gleason pattern 4 (GP4), lymph node metastases of GP4, distant metastases, and normal tissue from the transitional and peripheral zones were co-stained by fluorescent miRNA in situ hybridization (miRisH) and protein immunohistofluorescence (IHF). The miRNAs and corresponding target proteins include the pairs miR-145/ERG, miR-143/uPAR, and miR-375/SEC23A. The fluorescence-stained and scanned tissue microarrays (TMAs) were evaluated by experienced uropathologists. The pair miR-145/ERG showed an exclusive staining for miR-145 in the nuclei of stromal cells, both in tumor and normal tissue, and for ERG in the cytoplasm with/without co-expression in the nucleus of tumor cells. The pair miR-143/uPAR revealed a clear distinction between miR-143 in the nuclei of stromal cells and uPAR staining in the cytoplasm of tumor cells. Metastases (lymph node and distant) however, showed tumor cells with cytoplasmic staining for miR-143/uPAR. In normal tissues, beside the nuclei of the stroma cells, gland cells could also express miR-143 and uPAR in the cytoplasm. miR-375 showed particular staining in the nucleoli of GP4 and metastatic samples, suggesting that nucleoli play a special role in sequestering proteins and miRNAs. Combined miRisH/IHF allows for the study of miRNA expression patterns and their target proteins at the single-cell level.
CRIS-Team Scopus Importer:2019-06-28

COVID-19 effects on the kidney. - Amann, Kerstin Ute; Boor, P.; Wiech, T.; Singh, Jeeshan; Vonbrunn, Eva; Knöll, Antje; Hermann, Maike; Büttner-Herold, Maike; Daniel, Christoph; Hartmann, Arndt (Pathologe, 2021)
Apart from pulmonary disease, acute kidney injury (AKI) is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). The SARS-CoV‑2 virus has been detected in renal tissue. Patients with chronic kidney disease (CKD) before and on dialysis and specifically renal transplant patients represent a particularly vulnerable population. The increasing number of COVID-19 infected patients with renal involvement led to an evolving interest in the analysis of its pathophysiology, morphology and modes of virus detection in the kidney. Meanwhile, there are ample data from several autopsy and kidney biopsy studies that differ in the quantity of cases as well as in their quality. While the detection of SARS-CoV‑2 RNA in the kidney leads to reproducible results, the use of electron microscopy for visualisation of the virus is difficult and currently critically discussed due to various artefacts. The exact contribution of indirect or direct effects on the kidney in COVID-19 are not yet known and are currently the focus of intensive research.
EVALuna2:421391

COVID-19 effects on the kidney - Amann, Kerstin Ute; Boor, P.; Wiech, T.; Singh, Jeeshan; Vonbrunn, Eva; Knöll, Antje; Hermann, Maike; Büttner-Herold, Maike; Daniel, Christoph; Hartmann, Arndt (Pathologe, 2021)
Apart from pulmonary disease, acute kidney injury (AKI) is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). The SARS-CoV-2 virus has been detected in renal tissue. Patients with chronic kidney disease (CKD) before and on dialysis and specifically renal transplant patients represent a particularly vulnerable population. The increasing number of COVID-19 infected patients with renal involvement led to an evolving interest in the analysis of its pathophysiology, morphology and modes of virus detection in the kidney. Meanwhile, there are ample data from several autopsy and kidney biopsy studies that differ in the quantity of cases as well as in their quality. While the detection of SARS-CoV-2 RNA in the kidney leads to reproducible results, the use of electron microscopy for visualisation of the virus is difficult and currently critically discussed due to various artefacts. The exact contribution of indirect or direct effects on the kidney in COVID-19 are not yet known and are currently the focus of intensive research.
CRIS-Team WoS Importer:2021-02-19

COVID-19 und Nierenbefall - Amann, Kerstin Ute; Boor, P.; Wiech, T. (Nephrologe, 2020)
Apart from the pulmonary disease, acute kidney injury is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could also be detected in renal tissue. Patients with chronic kidney disease and on dialysis as well as kidney transplantation patients represent a particularly vulnerable population. The increasing number of patients infected with SARS-CoV‑2 has aroused increased interest in the exact pathophysiology and morphology of kidney damage as well as the direct detection of the virus in the kidneys, which in contrast to the lungs is overall more difficult to perform. Meanwhile, data from several large autopsy and kidney biopsy studies are now available. While the detection of SARS-CoV‑2 RNA in tissue leads to consistently reproducible results, the use of electron microscopy for visualization of the virus is critically discussed due to various artefacts. The exact and direct effects of SARS-CoV‑2 on the kidneys are not yet known in detail and are currently the focus of intensive research.
CRIS-Team Scopus Importer:2020-12-25
Keywords: Acute renal insufficiency; Acute tubular injury; Chronic kidney disease; Coronavirus; Virus detection

Craniofacial Osteosarcoma—Pilot Study on the Expression of Osteobiologic Characteristics and Hypothesis on Metastasis - Weber, Manuel; Söder, Stephan; Sander, Janina; Ries, Jutta; Geppert, Carol-Immanuel; Kesting, Marco Rainer; Wehrhan, Falk (Frontiers in Oncology, 2020)
Background: Craniofacial osteosarcomas (COS) and extracranial osteosarcomas (EOS) show distinct clinical differences. COS show a remarkably lower incidence of metastases and a better survival. However, in contrast to EOS, they show a poor response to neoadjuvant chemotherapy. Tumor-associated macrophages and their polarization as well as developmental biological signaling pathways are possible candidates for explaining the clinical differences between COS and EOS. The aim of the study was to analyze differential expression of macrophage markers and important regulators of these pathways. Methods: Twenty osteosarcoma cases (10 COS and 10 EOS) were immunohistochemically stained to assess CD68, CD11c, CD163, MRC1, Gli1, and Gli2 expression. Statistical differences between COS and EOS were tested using the Mann–Whitney U test. Additionally, the paper describes an example of multidisciplinary treatment of a patient suffering from COS and discusses the surgical challenges in treatment and rehabilitation of COS. Results: COS showed a significantly (p < 0.05) increased infiltration of CD11c-positive M1 macrophages and a shift toward M1 polarization compared to EOS. Additionally, COS revealed a significantly (p < 0.05) lower Gli1 expression than EOS. Conclusion: The reduced Gli1 expression in COS can be interpreted as reduced activation of the Hedgehog (Hh) signaling pathway. The increased M1 polarization and reduced Hh activation in COS could explain the low incidence of metastases in these osteosarcomas.
CRIS-Team Scopus Importer:2020-07-17
Keywords: craniofacial osteosarcoma; Gli1; hedgehog; M1; M2; macrophage polarization; osteosarcoma of the jaw

C-reactive protein flare predicts response to anti-PD-(L)1 immune checkpoint blockade in metastatic urothelial carcinoma - Klümper, Niklas; Sikic, Danijel; Saal, Jonas; Büttner, Thomas; Goldschmidt, Franziska; Jarczyk, Jonas; Becker, Philippe; Zeuschner, Philip; Weinke, Maximilian; Kalogirou, Charis; Breyer, Johannes; Burger, Maximilian; et al. (European Journal of Cancer, 2022)
Purpose: Robust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response. Methods: We conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS). Results: Objective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P < 0.001). CRP flare response was associated with prolonged PFS and OS (P < 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07–0.48, P < 0.001). Conclusion: CRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Biomarker; Bladder cancer; C-reactive protein; CRP flare; CRP flare-Response; Immune checkpoint blockade; Immunotherapy; Long-flare; Metastatic urothelial carcinoma

C-reactive protein flare-response predicts long-term efficacy to first-line anti-PD-1-based combination therapy in metastatic renal cell carcinoma - Klumper, Niklas; Schmucker, Philipp; Hahn, Oliver; Hoh, Benedikt; Mattigk, Angelika; Banek, Severine; Ellinger, Jorg; Heinzelbecker, Julia; Sikic, Danijel; Eckstein, Markus; Strauss, Arne; Zengerling, Friedemann; et al. (Clinical and Translational Immunology, 2021)
Objectives. Immune checkpoint blockade (IO) has revolutionised the treatment of metastatic renal cell carcinoma (mRCC). Early C-reactive protein (CRP) kinetics, especially the recently introduced CRP flare-response phenomenon, has shown promising results to predict IO efficacy in mRCC, but has only been studied in second line or later. Here, we aimed to validate the predictive value of early CRP kinetics for 1st-line treatment of mRCC with alpha PD-1 plus either alpha CTLA-4 (IO+IO) or tyrosine kinase inhibitor (IO+TKI). Methods. In this multicentre retrospective study, we investigated the predictive potential of early CRP kinetics during 1st-line IO therapy. Ninety-five patients with mRCC from six tertiary referral centres with either IO+IO (N = 59) or IO+TKI (N = 36) were included. Patients were classified as CRP flare-responders, CRP responders or non-CRP responders as previously described, and their oncological outcome was compared. Results. Our data validate the predictive potential of early CRP kinetics in 1st-line immunotherapy in mRCC. CRP responders, especially CRP flare-responders, had significantly prolonged progression-free survival (PFS) compared with non-CRP responders (median PFS: CRP flare-responder: 19.2 months vs. responders: 16.2 vs. non-CRP responders: 5.6, P < 0.001). In both the IO+IO and IO+TKI subgroups, early CRP kinetics remained significantly associated with improved PFS. CRP flare-response was also associated with long-term response >= 12 months. Conclusions. Early CRP kinetics appears to be a low-cost and easy-to-implement on-treatment biomarker to predict response to 1st-line IO combination therapy. It has potential to optimise therapy monitoring and might represent a new standard of care biomarker for immunotherapy in mRCC.
CRIS-Team WoS Importer:2021-12-31

CREB1 is affected by the microRNAs miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p and correlates with adverse clinicopathological features in renal cell carcinoma - Friedrich, Michael; Heimer, Nadine; Stoehr, Christine; Steven, André; Wach, Sven; Taubert, Helge; Hartmann, Arndt; Seliger, Barbara (Scientific Reports, 2020)
The transcription factor cAMP response element-binding protein (CREB1) has been shown to be involved in diverse biological pathways including the regulation of cell proliferation, apoptosis, cell cycle progression, and metastasis. In this context, aberrant expression of CREB1 and the functional consequences are well investigated in a number of hematopoietic and solid tumors. However, CREB1 expression and underlying control mechanisms are only poorly analyzed in renal cell carcinoma (RCC). The present study confirmed a deregulation of CREB1 protein in the clear cell type of RCC (ccRCC) and analysis of in-house ccRCC cell lines suggested a post-transcriptional control. The combination of miRNA enrichment assay, in silico analysis and molecular biological approaches revealed four novel CREB1-regulating miRNAs, namely miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p. Categorizing RCC samples as CREB1 negative or positive, respectively, the expression of these miRNAs was found to be inversely correlated with CREB1 protein levels. Analyzing 453 consecutive RCC tumors by immunohistochemistry, weakly negative, but significant correlations of CREB1 with tumor stage and grade, vascular invasion (V1) and lymphovascular invasion (L1) were found. In this respect, ccRCC might differ from other solid tumors like esophageal squamous-cell carcinoma or glioma.
CRIS-Team Scopus Importer:2020-05-02

CRISPR-mediated fluorescent tagging of endogenous PCM1 enables live cell imaging of non-centrosomal MTOC formation in muscle cells - Becker, Robert; Engel, Felix (2018)
EVALuna2:34442

Critical role of spatial interaction between CD8? and Foxp3? cells in human gastric cancer: the distance matters - Feichtenbeiner, Anita; Haas, Matthias; Büttner, Maike; Grabenbauer, Gerhard; Fietkau, Rainer; Distel, Luitpold (Cancer Immunology Immunotherapy, 2014)
In various cancer types, an abundance of FoxP3(+) regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8(+) T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8(+) and FoxP3(+) TILs and their prognostic impact in human gastric cancer.Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8(+) and FoxP3(+) TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years).High intraepithelial infiltration of CD8(+) and FoxP3(+) TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54%, p = 0.04 and 85 vs. 59%, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30-110 ?m) versus nonfunctional distances of CD8(+) and FoxP3(+) TILs, 10-year survival rates differed between 89 and 55% (p = 0.009), respectively.Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3(+) TILs must be located within a distance between 30 and 110 ?m of CD8(+) T cells to positively impact on prognosis.
EVALuna2:18176

Critical size defect regeneration using PEG-mediated BMP-2 gene delivery and the use of cell occlusive barrier membranes - the osteopromotive principle revisited - Wehrhan, Falk; Amann, Kerstin Ute; Molenberg, Aart; Lutz, Rainer; Neukam, Friedrich Wilhelm; Schlegel, Karl Andreas (Clinical Oral Implants Research, 2013)
Objective: The objective of this study was to investigate if osseous regeneration can be accelerated by involvement of periosteal tissue. Bone defect regeneration could be accelerated by the involvement of periosteal tissue if osteogenic cell signalling is maintained within the defect. It was questioned if local cell-mediated BMP-2 gene delivery makes a cell occlusive membrane dispensable during bone critical size defect regeneration. Methods: PEG matrix (degradation time 10 days) and PEG membrane (degradation time 120 days) were used in the pig calvarial model. Cylindrical (1 × 1 cm) critical size defects (CSD) (9 per animal; 20 animals) were filled with: (i) particulated autologous bone, covered with PEG membrane (group 1); (ii) HA/TCP, covered with PEG membrane (group 2); (iii) HA/TCP, mixed with PEG matrix (group 3); and (iv) HA/TCP mixed with BMP-2-transfected osteoblasts and PEG matrix (group 4). BMP-2/4 gene transfer: liposomal in vitro transfection of BMP-2/V5-tag fusion-protein. Quantitative histomorphometry (toluidine blue staining) after 2, 4 and 12 weeks assessed bone formation. Semiquantitative immunohistochemistry estimated the expression of BMP-2, V5-tag, Runx-2 and Sox9. Results: PEG matrix embedded BMP-2 expressing cells presented higher bone formation (P < 0.05) than HA/TCP + PEG matrix defect filling or PEG membrane covering (HA/TCP filling) after 12 weeks. Highest expression of BMP-2, Runx-2 and lowest expression of fibrous tissue marker Sox9 was seen in the BMP-2 group. Conclusion: PEG matrix embedded BMP-2 expressing cells are capable to maintain osteogenic signalling and to accelerate osseous defect regeneration in absence of a cell occlusive membrane. © 2012 John Wiley & Sons A/S.
CRIS-Team Scopus Importer:2024-05-13
Keywords: BMP; Bone regeneration; Gene transfer; Hydrogel; Immunohistochemistry; Osteogenesis

CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis - Rousselle, Anthony; Sonnemann, Janis; Amann, Kerstin Ute; Mildner, Alexander; Lodka, Dorte; Kling, Lovis; Bieringer, Markus; Schneider, Udo; Leutz, Achim; Enghard, Philipp; Kettritz, Ralph; Schreiber, Adrian (Annals of the Rheumatic Diseases, 2022)
Objectives Myeloid cell activation by antineutrophil cytoplasmic antibody (ANCA) is pivotal for necrotising vasculitis, including necrotising crescentic glomerulonephritis (NCGN). In contrast to neutrophils, the contribution of classical monocyte (CM) and non-classical monocyte (NCM) remains poorly defined. We tested the hypothesis that CMs contribute to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and that colony-stimulating factor-2 (CSF2, granulocyte-macrophage colony-stimulating factor (GM-CSF)) is an important monocyte-directed disease modifier. Methods Myeloperoxidase (MPO)-immunised MPO-/- mice were transplanted with haematopoietic cells from wild-type (WT) mice, C-C chemokine receptor 2 (CCR2)(-/-) mice to abrogate CM, or transcription factor CCAAT-enhancer-binding protein beta (C/EBP beta)(-/-) mice to reduce NCM, respectively. Monocytes were stimulated with CSF2, and CSF2 receptor subunit beta (CSF2rb)-deficient mice were used. Urinary monocytes and CSF2 were quantified and kidney Csf2 expression was analysed. CSF2-blocking antibody was used in the nephrotoxic nephritis (NTN) model. Results Compared with WT mice, CCR2(-/-) chimeric mice showed reduced circulating CM and were protected from NCGN. C/EBP beta(-/-) chimeric mice lacked NCM but developed NCGN similar to WT chimeric mice. Kidney and urinary CSF2 were upregulated in AAV mice. CSF2 increased the ability of ANCA-stimulated monocytes to generate interleukin-1 beta and to promote T(H)17 effector cell polarisation. CSF2rb(-/-) chimeric mice harboured reduced numbers of kidney T(H)17 cells and were protected from NCGN. CSF2 neutralisation reduced renal damage in the NTN model. Finally, patients with active AAV displayed increased urinary CM numbers, CSF2 levels and expression of GM-CSF in infiltrating renal cells. Conclusions CMs but not NCMs are important for inducing kidney damage in AAV. CSF2 is a crucial pathological factor by modulating monocyte proinflammatory functions and thereby T(H)17 cell polarisation.
CRIS-Team WoS Importer:2022-04-29

CT analysis of left ventricular function predicts short term survival in patients following transcatheter aortic valve implantation: 1-year outcome data - Ijgua, Mohamed; Arnold, Martin; Eckstein, Markus; Smolka, S.; Bittner, Daniel O.; Ammon, Fabian; Kondruweit, Markus; Moshage, Maximilian; Achenbach, Susanne; Marwan, Mohamed (European Heart Journal, 2022)
CRIS-Team WoS Importer:2023-03-03

CTLA4 promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma - Klümper, Niklas; Ralser, Damian J.; Zarbl, Romina; Schlack, Katrin; Schrader, Andres Jan; Rehlinghaus, Marc; Hoffmann, Michele J.; Niegisch, Guenter; Uhlig, Annemarie; Trojan, Lutz; Steinestel, Julie; Steinestel, Konrad; et al. (Journal for ImmunoTherapy of Cancer, 2021)
Background In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that CTLA4 promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate CTLA4 methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC. Methods CTLA4 methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, CTLA4 methylation as well as CD8 + T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post-tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation. Results CTLA4 promoter hypomethylation was significantly correlated with CTLA4 mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p<0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, CTLA4 promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of CTLA4 hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, CTLA4 promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003). Conclusions Our study suggests CTLA4 methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.
CRIS-Team Scopus Importer:2021-09-10
Keywords: biomarkers; immunotherapy; kidney neoplasms; tumor; urologic neoplasms

CTNNB1 (?-Catenin)-altered Neoplasia: A Review Focusing on Soft Tissue Neoplasms and Parenchymal Lesions of Uncertain Histogenesis. - Agaimy, Abbas; Haller, Florian (Advances in Anatomic Pathology, 2016)
?-catenin (CTNNB1) is a key regulatory molecule of the Wnt signaling pathway, which is important for tissue homeostasis and regulation of cell proliferation, differentiation, and function. Abnormal stabilization and nuclear accumulation of ?-catenin as a consequence of missense mutations or alternative molecular mechanisms occurs at a high frequency in a variety of epithelial cancers. In mesenchymal neoplasia, the role of ?-catenin has been traditionally considered limited to desmoid-type fibromatosis. However, the spectrum of ?-catenin-driven (?-catenin-altered) neoplasia of mesenchymal origin has been steadily widening to include, in addition to desmoid tumors, a variety of benign and intermediate-biology neoplasms of soft tissue (intranodal palisaded myofibroblastoma), head and neck (juvenile nasopharyngeal angiofibroma and sinonasal hemangiopericytoma/glomangiopericytoma), and ovarian (microcystic stromal tumor) origin. In addition, several old and newly reported distinctive site-specific ?-catenin-driven parenchymal neoplasms of uncertain histogenesis have been well characterized in recent studies, including solid-pseudopapillary neoplasm of the pancreas and its recently described ovarian counterpart, sclerosing hemangioma of lung and calcifying nested stromal-epithelial tumor of the liver. This review addresses the most relevant pathobiological and differential diagnostic aspects of ?-catenin-altered neoplasms with emphasis on site-specific histologic and biological variations. In addition, the morphologic overlap and analogy as well as distinctness between these uncommon tumors will be presented and discussed. Furthermore, a note is made on association of some of these lesions with hereditary tumor syndromes, in particular with the familial adenomatous polyposis coli.
EVALuna2:6756

CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling - Danek, Veronika; Tureckova, Jolana; Hübner, Kerstin; Erlenbach-Wünsch, Katharina; Baranova, Petra; Dobes, Jan; Balounova, Jana; Simova, Michaela; Novosadova, Vendula; Madureira Trufen, Carlos Eduardo; Prochazkova, Michaela; Talacko, Pavel; et al. (Cancer Letters, 2025)
Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.
CRIS-Team Scopus Importer:2025-04-18
Keywords: Colorectal cancer; CUL4A; HUWE1; Ubiquitination

Current pathological and molecular aspects of bladder cancer - Hartmann, Arndt; Schwamborn, K.; Kristiansen, G.; Knuechel-Clarke, R. (Onkologe, 2018)
Background and results. Key data of the World Health Organization (WHO) classification from 2016 for the entity of urinary bladder cancer are summarized in the first part of this article. Unequivocal diagnostic terms in addition to clinical data of the findings in the bladder are an important basis in order to expedite a better molecular genetic understanding of tumors and their formation. At the same time increasing molecular data show the possibilities for definitive statements on subtypes and variants of urothelial cancer up to initial data on therapy response, so that overall substantial progress has been achieved for bladder cancer. Last but not least, greater certainty on the use of immunohistochemical investigations can be deduced from the molecular genetic data. Immunohistochemistry plays an important role in the definition of the urothelial entity (e. g. for metastases) and in the definitive assignment of malignancies and the differentiation from reactive changes, e.g. with the staining of targeted molecules within the immune checkpoint control, immunohistochemistry also provides a predictive component. Conclusion. Novel genetic and proteomic methods are increasingly being used for the diagnostics of urine and tissue of the urinary tract.
EVALuna2:34263

Cutting-edge microangio-CT: new dimensions in vascular imaging and kidney morphometry - Hlushchuk, Ruslan; Zubler, Cédric; Barré, Sébastien; Shokiche, Carlos Correa; Schaad, Laura; Röthlisberger, Raphael; Wnuk, Monika; Daniel, Christoph; Khoma, Oleksiy; Tschanz, Stefan A.; Reyes, Mauricio; Djonov, Valentin (American Journal of Physiology-Renal Physiology, 2017)
In the last decades the contrast-enhanced microCT-imaging of whole animal kidney became increasingly important. The visualization was mainly limited to middle-sized vessels. Since modern desktop microCT-scanners provide the necessary detail resolution, we developed an approach for rapid visualization and consistent assessment of kidney vasculature and glomeruli number. This method is based on ?Angiofil®, a new polymerizing contrast agent with homogenous X-ray absorption, which provides continuous filling of the complete vasculature and enables correlative imaging approaches. For rapid and reliable kidney morphometry the microangioCT-datasets from GDNF+/- mice and their wildtype littermates were used. The results were obtained much faster compared to the current gold standard, histology-based stereology, and without processing artefacts. The histology-based morphometry was afterwards done on the same kidneys. Both approaches revealed that the GDNF+/- male mice had more than 30% fewer glomeruli. Futhermore, our approach allows defining sites of interest for further histological investigation, i.e., correlative morphology. The polymerized ?Angiofil stays in perfused vessels and is auto-fluorescent what greatly facilitates matching of histological sections with microangioCT-data. The presented approach is time-efficient and reliable qualitative and quantitative methodology. Besides glomerular morphometry the microangioCT-data can be used for qualitative and quantitative analysis of the kidney vasculature and correlative morphology.
EVALuna2:25561

CXCL12 promotes glycolytic reprogramming in acute myeloid leukemia cells via the CXCR4/mTOR axis - Braun, Michael; Qorraj, M.; Büttner, Maike; Klein, F. A.; Saul, D.; Aigner, M.; Huber, W.; Mackensen, Andreas; Jitschin, R.; Mougiakakos, Dimitrios (Leukemia, 2016)
EVALuna2:25512

CXCL5 drives neutrophil recruitment in TH17-mediated GN - Disteldorf, Erik M.; Krebs, Christian F.; Paust, Hans-Joachim; Turner, Jan-Eric; Nouailles, Geraldine; Tittel, Andre; Meyer-Schwesinger, Catherine; Stege, Gesa; Brix, Silke; Velden, Joachim; Wiech, Thorsten; Helmchen, Udo; et al. (Journal of the American Society of Nephrology, 2015)
Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in TH17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen- and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic TH17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in TH17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens.
EVALuna2:25509

CXCR2 expression on neutrophil granulocytes in peripheral tumor is associated with shorter survival in oral squamous cell carcinoma - Spörl, Silvia; Erber, Ramona; Gerken, M.; Wittenberg, M.; Fischer, R.; Taxis, J.; Hartmann, Arndt; Geppert, Carol-Immanuel; Mamilos, A.; Mackensen, Andreas; Reichert, T.; Spanier, G.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Cyclosporine A responsive congenital nephrotic syndrome with single heterozygous variants in NPHS1, NPHS2, and PLCE1 - Eichinger, Anna; Ponsel, Sabine; Bergmann, Carsten; Guenthner, Roman; Hoefele, Julia; Amann, Kerstin Ute; Lange-Sperandio, Baerbel (Pediatric Nephrology, 2018)
BACKGROUND: Congenital nephrotic syndrome (CNS) is primarily a monogenetic disease, with the majority of cases due to changes in five different genes: the nephrin (NPHS1), podocin (NPHS2), Wilms tumor 1 (WT1), laminin ß2 (LAMB2), and phospholipase C epsilon 1 (PLCE1, NPHS3) gene. Usually CNS is not responsive to immunosuppressive therapy, but treatment with ACE inhibitors, AT1 receptor blockade and/or indomethacin can reduce proteinuria. If the disease progresses to end-stage renal disease, kidney transplantation is the therapy of choice. CASE-DIAGNOSIS: Here, we present the case of a 4-month-old girl with congenital nephrotic syndrome. Upon admission, the patient presented with life-threatening anasarca, hypoalbuminemia, proteinuria, and impaired growth. There was no evidence of an infectious or immunological etiology. The genetic evaluation revealed a heterozygous variant in NPHS1 (p.Arg207Trp), in NPHS2 (p.Ser95Phe) as well as in PLCE1 (p.Ala1045Ser) and did not explain CNS. In addition to daily parenteral albumin infusions plus furosemide, a pharmacological antiproteinuric therapy was started to reduce protein excretion. Based on the genetic results, immunosuppressive therapy with prednisolone was initiated, but without response. However, following cyclosporine A treatment, the patient achieved complete remission and now has good renal function, growth, and development. CONCLUSIONS: A profound search for the cause of CNS is necessary but has its limitations. The therapeutic strategy should be adapted when the etiology remains unclear.
EVALuna2:34430

Cytokeratin 5 and cytokeratin 20 inversely correlate with tumour grading in Ta non-muscle-invasive bladder cancer - Muilwijk, Tim; Akand, Murat; Van Der Aa, Frank; De Coninck, Vincent; Claessens, Marc; Hente, Robert; Eckstein, Markus; Allory, Yves; Libbrecht, Louis; Joniau, Steven; Gevaert, Thomas (Journal of Cellular and Molecular Medicine, 2021)
Cytokeratin 5 is a marker of basal molecular subtypes of muscle-invasive bladder cancer (MIBC), which correlates with worse overall survival compared to luminal subtypes. Our observations have not confirmed CK5 as a marker of high-grade (HG) disease in Ta non-muscle-invasive bladder cancer (NMIBC). Therefore, to understand the basal-luminal immunohistochemistry profile in Ta NMIBC, we performed immunohistochemistry for CK5, P40, P63 (basal), GATA3 and CK20 (luminal) and studied the correlation with HG and clinical outcome in 109 patients with Ta NMIBC. HG and low-grade (LG) diseases were scored in each patient. Four different CK5 patterns were evaluated: absent (median 41.3%), normal (72.5%), rising (84.4%) and full thickness (23.9%). The median percentage of GATA3 was 100%. HG disease and CK5 expression and rising CK5 pattern had a significant inverse correlation, whereas HG disease and CK20 expression had a significant positive correlation. We also found a significant inverse correlation between CK5 expression and CK20 expression. Quantitative PCR confirmed that the presence of CK5 correlated with up-regulation of CK5 RNA. None of the markers could differentiate patients with regard to clinical outcome. Our results suggest a role for CK5 and CK20 in differentiating between LG and HG disease in Ta NMIBC.
CRIS-Team WoS Importer:2021-07-16

Cytology and High-Risk Human Papillomavirus Test for Cervical Cancer Screening Assessment - Stübs, Frederik; Koch, Martin C.; Dietl, Anna; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Mehlhorn, Grit; Schulmeyer, Carla; Gaß, Paul (Diagnostics, 2022)
Background: A new nationwide screening strategy was implemented in Germany in January 2020. No data are available for women referred to certified dysplasia units for secondary clarification after primary diagnosis by a local physician. We therefore investigated combined testing with Papanicolaou smears and high-risk human papillomavirus (hrHPV) and compared the data with the final histological findings. Methods: Between January 2015 and October 2020, all referred women who underwent colposcopy of the uterine cervix in our certified dysplasia unit were included. Cytology findings were classified using the Munich III nomenclature. Results: A total of 3588 colposcopies were performed in 3118 women, along with Pap smear and hrHPV co-testing, followed by histology. Women with Pap II-p (ASC-US) and a positive hrHPV co-test had a 22.4% risk for cervical intraepithelial neoplasia (CIN) 3/high-grade squamous intraepithelial lesion (HSIL). The risk of CIN 3/HSIL was 83.8% in women with Pap IVa-p (HSIL) and a positive hrHPV co-test. A positive hrHPV co-test increased the risk for HSIL+ (OR 5.942; 95% CI, 4.617 to 7.649; p < 0.001) as compared to a negative hrHPV co-test. Conclusions: The accuracy of Pap smears is comparable with the screening results. A positive hrHPV test increases the risk for HSIL+ fivefold. Colposcopy is necessary to diagnose HSIL+ correctly.
CRIS-Team WoS Importer:2022-08-12

Cytology and HPV Co-Testing for Detection of Vaginal Intraepithelial Neoplasia: A Retrospective Study. - Stübs, Frederik; Dietl, Anna; Koch, Martin C.; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Mehlhorn, Grit; Beckmann, Matthias; Schulmeyer, Carla; Heindl, Felix; Emons, Julius; et al. (Cancers, 2023)
(1) Background: Vaginal intraepithelial neoplasia (VaIN) is a rare premalignant disease caused by persistent human papillomavirus (HPV) infection. Diagnosing VaIN is challenging; abnormal cytology and positive HPV tests are usually the first signs, but published data on their accuracy for detecting it are rare and contradictory. The aim of this study is to compare the results of hrHPV and cytology co-testing with the histological findings of the vagina. (2) Methods: In the certified Dysplasia Unit at Erlangen University Hospital, cytology and HPV samples from the uterine cervix or vaginal wall after hysterectomy were obtained between 2015 and 2023 and correlated with histological findings in biopsies from the vaginal wall. Women without vaginal biopsy findings or concomitant cervical disease were excluded. (3) Results: In all, 279 colposcopies in 209 women were included. The histological results were: benign (n = 86), VaIN I/vLSIL (n = 116), VaIN II/vHSIL (n = 41), VaIN III/vHSIL (n = 33), and carcinoma (n = 3). Accuracy for detecting VaIN was higher in women with previous hysterectomies. Positive HPV testing during colposcopy increased the likelihood for VaIN II/III/vHSIL threefold. The detection rate for VaIN III/vHSIL was 50% after hysterectomy and 36.4% without hysterectomy. (4) Conclusions: Women with risk factors for VaIN, including HPV-16 infection or prior HPV-related disease, need careful work-up of the entire vaginal wall. Hysterectomy for HPV-related disease and a history of cervical intraepithelial neoplasia (CIN) also increased the risk for VaIN II/III/vHSIL.
EVALuna2:540622

Cytology and hrHPV for cervical cancer screening assessment - Stübs, Frederik; Koch, M. C.; Dietl, Anna; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Mehlhorn, G.; Gaß, Paul; Schulmeyer, Carla (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2 - Maiuthed, Arnatchai; Ninsontia, Chuanpit; Erlenbach-Wuensch, Katharina; Ndreshkjana, Benardina; Muenzner, Julienne K.; Caliskan, Aylin; Ahmed, Husayn P.; Chaotham, Chatchai; Hartmann, Arndt; Roehe, Adriana Vial; Mahadevan, Vijayalakshmi; Chanvorachote, Pithi; et al. (Cancers, 2018)
The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up-regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21T145D transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients.
EVALuna2:118614

Cytosolic 5 '-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites - Patzak, Melanie S.; Kari, Vijayalakshmi; Patil, Shilpa; Hamdan, Feda H.; Goetze, Robert G.; Brunner, Marius; Gaedcke, Jochen; Kitz, Julia; Jodrell, Duncan; Richards, Frances M.; Pilarsky, Christian; Grützmann, Robert; et al. (EBioMedicine, 2019)
Background: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy.
CRIS-Team WoS Importer:2019-03-22

Cytotoxic and immunosuppressive inflammatory cells predict regression and prognosis following neoadjuvant radiochemotherapy of oesophageal adenocarcinoma - Göbel, Holger H.; Büttner-Herold, Maike; Fuhrich, Nicole; Aigner, Thomas; Grabenbauer, Gerhard G.; Distel, Luitpold (Radiotherapy and Oncology, 2020)
Background and purpose: Tumour infiltrating lymphocytes (TIL) and tumour associated macrophages (TAM) play a key role in anticancer immunosurveillance. We studied their influence on response to neoadjuvant radiochemotherapy (RCT) and prognosis in patients with oesophageal adenocarcinoma (OAC). Materials and methods: Between 10/2004 and 06/2018, pre-RCT biopsy-specimens were available from 76 patients with locally advanced, non-metastatic OAC scheduled for trimodality therapy. We evaluated intra- and peritumoural expression of FoxP3+-, CD8+-TIL and CD68+-, CD163+-TAM, contemplating cell density, cell ratios and cell-to-cell distances to determine a possible influence on tumour regression grade (TRG) and survival. Median follow-up time for all patients was 18 months (IQR 9–43), and 54 months (25–97) for surviving patients. Data were analysed using risk analysis, logrank test and Cox regression. Results: Poor tumour regression was detected for cN+ (RR 0.77 [95% CI 0.66–0.90], p = 0.001), low intratumoural FoxP3+/CD8+ ratio (RR 0.75 [0.60–0.96], p = 0.020), high peritumoural CD163+/CD68+ ratio (RR 0.77 [0.60–0.99], p = 0.045) and high intratumoural TAM density (RD −0.44 [−0.82 to −0.06], p = 0.023). Apart from poor resection quality and TRG, pretherapeutic high peritumoural CD8+ infiltration (HR 2.36 [1.21–4.61], p = 0.012) and short intratumoural FoxP3+ to CD8+ cell-to-cell distances in middle ranged CD8+ density (HR 2.55 [1.00–6.52], p = 0.050) were significant unfavourable prognostic factors in multivariate analysis. Conclusions: Immunologic parameters, such as CD8+-, FoxP3+-TIL and CD68+-, CD163+-TAM, were identified to be of independent predictive and prognostic value in patients with OAC. Further and independent validation of these biomarkers by a large size dataset may urgently be contemplated.
CRIS-Team Scopus Importer:2020-03-20
Keywords: CD163+; CD68+; CD8+; FoxP3+; Oesophageal adenocarcinoma; Radiochemotherapy

Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy - Eckstein, Markus; Strissel, Pamela; Strick, Reiner; Weyerer, Veronika; Wirtz, Ralph; Pfannstiel, Carolin; Wullweber, Adrian; Lange, Fabienne; Erben, Philipp; Stöhr, Robert; Bertz, Simone; Geppert, Carol-Immanuel; et al. (Journal for ImmunoTherapy of Cancer, 2020)
Background Assessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit. Patients and methods Gene expression of CD3Z, CD8A and CXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival. Results The gene expression signature of CXCL9, CD3Z and CD8A correlates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44-0.74; TCGA: ρ-range: 0.56-0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with 'inflamed high' tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort). Conclusion The gene expression signature of CD3Z, CD8A and CXCL9 can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.
CRIS-Team Scopus Importer:2020-06-05
Keywords: immunology; pathology; urology

DAPK1 loss triggers tumor invasion in colorectal tumor cells - Steinmann, Sara; Kunze, Philipp; Hampel, Chuanpit; Eckstein, Markus; Bertram Bramsen, Jesper; Muenzner, Julienne K.; Carlé, Birgitta-Elisabeth; Ndreshkjana, Benardina; Kemenes, Stephan; Gasparini, Pierluigi; Friedrich, Oliver; Andersen, Claus; et al. (Cell Death & Disease, 2019)
Colorectal cancer (CRC) is one of the leading cancer-related causes of death worldwide. Despite the improvement of surgical and chemotherapeutic treatments, as of yet, the disease has not been overcome due to metastasis to distant organs. Hence, it is of great relevance to understand the mechanisms responsible for metastasis initiation and progression and to identify novel metastatic markers for a higher chance of preventing the metastatic disease. The Death-associated protein kinase 1 (DAPK1), recently, has been shown to be a potential candidate for regulating metastasis in CRC. Hence, the aim of the study was to investigate the impact of DAPK1 protein on CRC aggressiveness. Using CRISPR/Cas9 technology, we generated DAPK1-deficient HCT116 monoclonal cell lines and characterized their knockout phenotype in vitro and in vivo. We show that loss of DAPK1 implemented changes in growth pattern and enhanced tumor budding in vivo in the chorioallantoic membrane (CAM) model. Further, we observed more tumor cell dissemination into chicken embryo organs and increased invasion capacity using rat brain 3D in vitro model. The novel identified DAPK1-loss gene expression signature showed a stroma typical pattern and was associated with a gained ability for remodeling the extracellular matrix. Finally, we suggest the DAPK1-ERK1 signaling axis being involved in metastatic progression of CRC. Our results highlight DAPK1 as an anti-metastatic player in CRC and suggest DAPK1 as a potential predictive biomarker for this cancer type.
CRIS-Team Scopus Importer:2019-12-10

DAPK and cytoskeleton-associated functions - Ivanovska, Jelena; Mahadevan, Vijayalakshmi; Schneider-Stock, Regine (Apoptosis, 2014)
Death-associated protein kinase (DAPK) undergoes activation in response to various death stimuli, and they have been associated with an increase in DAPK catalytic activity. One of the most prominent features of DAPK-induced cell death is the effect on the cytoskeleton, including loss of matrix attachment, and membrane blebbing. One known cytoskeletal-associated substrate of DAPK is the myosin-II light chain, phosphorylated by DAPK on Ser(19), thus stabilizing actin stress fibres. Moreover, paxillin, a component of focal adhesions, was found to be localized in close proximity to the tips of the DAPK-positive filaments, indicating that stress fibres containing DAPK extend to focal contacts. Forced expression of DAPK in multiple cell types results in morphological changes such as cell rounding, membrane blebbing, shrinking and detachment. During directed migration, DAPK functions as a potent inhibitor of cell polarization, as evidenced by its perturbation of the formation of static protrusion at the leading edge. Furthermore, DAPK inhibits random migration by suppressing directional persistence. One of the studies considered DAPK as an anoikis inducer. Others showed that DAP-kinase inhibits the activities of cell surface integrins by converting them into an inactive conformation. Biochemical experiments have established the DAPK binding to Syntaxin1 and its subsequent phosphorylation at Ser(188) in a Ca(2+) dependent manner. This phosphorylation event has been shown to decrease the binding of Syntaxin to MUNC18-1, a protein critically involved in synaptic vesicle docking. Here, we have investigated the structural interactions that modulate DAPK phosphorylation with Syntaxin and its functional role in binding to the MUNC18-1 to regulate vesicle docking. This review will summarize our current knowledge of the role of DAPK on cytoskeleton reorganization and report the mechanisms that regulate these changes.
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DAPK-HSF1 interaction as a positive-feedback mechanism stimulating TNF-induced apoptosis in colorectal cancer cells - Benderska, Natalya; Ivanovska, Jelena; Rau, Tilman; Schulze-Luehrmann, Jan; Mohan, Suma; Chakilam, Saritha; Gandesiri, Muktheshwar; Ziesche, Elisabeth; Fischer, Thomas; Söder, Stephan; Agaimy, Abbas; Distel, Luitpold; et al. (Journal of Cell Science, 2014)
Death-associated protein kinase (DAPK) is a serine-threonine kinase with tumor suppressor function. Previously, we demonstrated that tumor necrosis factor (TNF) induced DAPK-mediated apoptosis in colorectal cancer. However, the protein-protein interaction network associated with TNF-DAPK signaling still remains unclear. We identified HSF1 as a new DAPK phosphorylation target in response to low concentrations of TNF and verified a physical interaction between DAPK and HSF1 both in vitro and in vivo. We show that HSF1 binds to the DAPK promoter. Transient overexpression of HSF1 protein led to an increase in DAPK mRNA level and consequently to an increase in the amount of apoptosis. By contrast, treatment with a DAPK-specific inhibitor as well as DAPK knockdown abolished the phosphorylation of HSF1 at Ser230 (pHSF1(Ser230)). Furthermore, translational studies demonstrated a positive correlation between DAPK and pHSF1(Ser230) protein expression in human colorectal carcinoma tissues. Taken together, our data define a novel link between DAPK and HSF1 and highlight a positive-feedback loop in DAPK regulation under mild inflammatory stress conditions in colorectal tumors. For the first time, we show that under TNF the pro-survival HSF1 protein can be redirected to a pro-apoptotic program.
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DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells - Ivanovska, Jelena; Zlobec, Inti; Forster, Stefan; Karamitopoulou, Eva; Dawson, Heather; Koelzer, Viktor Hendrik; Agaimy, Abbas; Garreis, Fabian; Söder, Stephan; Laqua, William; Lugli, Alessandro; Hartmann, Arndt; et al. (Oncotarget, 2015)
Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation.
EVALuna2:4438

Daratumumab for the treatment of refractory ANCA-associated vasculitis - Ostendorf, Lennard; Burns, Marie; Wagner, Dimitrios Laurin; Enghard, Philipp; Amann, Kerstin Ute; Mei, Henrik; Eckardt, Kai-Uwe; Seelow, Evelyn; Schreiber, Adrian (RMD Open, 2023)
Objective Treatment-refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening condition without evidence-based treatment options. One emerging treatment option for several antibody-mediated autoimmune diseases is the anti-CD38 antibody daratumumab, which depletes autoantibody-secreting plasma cells.Methods We treated two patients with severe life-threatening AAV with renal and pulmonary manifestation despite induction therapy with rituximab and cyclophosphamide with four to eight doses of 1800 mg daratumumab. We followed clinical and immunological responses.Results The first patient with myeloperoxidase-ANCA-positive microscopic polyangiitis had resolution of pneumonitis and pleuritis and stabilisation of kidney function after daratumumab. The second patient with proteinase 3-ANCA-positive granulomatosis with polyangiitis, diffuse alveolar haemorrhage necessitating extracorporeal membrane oxygenation (ECMO) and acute kidney failure, requiring kidney replacement therapy, was weaned off ECMO, mechanical ventilation and dialysis and discharged home after daratumumab. Clinical improvement was paralleled by a strong reduction in serum ANCA levels as well as total IgG, indicating depletion of plasma cells. Apart from the depletion of CD38+ natural killer cells, blood leucocyte levels were not notably influenced by daratumumab. Only mild adverse events, such as hypogammaglobulinaemia and an upper respiratory tract infection occurred.Conclusion Daratumumab was safe and effective in inducing remission in two patients with severe treatment-refractory AAV, warranting prospective clinical trials to establish safety and efficacy.
CRIS-Team Scopus Importer:2023-01-20
Keywords: Autoimmune Diseases; Systemic vasculitis; Treatment

Darbepoetin alpha reduces oxidative stress and chronic inflammation in atherosclerotic lesions of apo e deficient mice in experimental renal failure - Arend, Nicole; Hilgers, Karl Friedrich; Campean, Valentina; Karpe, Britta; Cordasic, Nada; Klanke, Bernd; Amann, Kerstin Ute (PLoS ONE, 2014)
Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction.Apo E knockout mice underwent unilateral (Unx, n = 20) or subtotal (Snx, n = 26) nephrectomy or sham operation (Sham, n = 16). Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta.Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters.Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment elevated serum urea. Elevation of hematocrit might be a favorable effect in anemic Snx animals but a thrombogenic risk in Sham animals.
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Das muskelinvasive und metastasierte Urothelkarzinom aus Sicht der Pathologie - Klümper, Niklas; Kalogirou, Charis; Eckstein, Markus (Aktuelle Urologie, 2024)
Muscle-invasive and metastatic urothelial carcinoma is a heterogeneous disease with a broad morphological and molecular spectrum. The amendment of the WHO classification has resulted in some changes in the nomenclature and classification of muscle-invasive and metastatic urothelial carcinomas. Due to the increasing individualisation of therapeutic options, the correct diagnosis of morphological variants of urothelial carcinoma, which are associated with specific molecular alterations, is becoming more and more important. The morphological variants also correlate with molecular subtypes of urothelial carcinoma. In addition, both morphological and molecular subtypes are associated with immunological and other molecular characteristics that could be relevant for modern immunotherapies or antibody- drug conjugates, e. g. in the form of PD-L1 and NECTIN- 4 status. With the pending approval of erdafitinib (FGFR3 inhibitor), molecular tumour boards for patients with metastatic urothelial carcinoma will also become more important in the future.
CRIS-Team Scopus Importer:2025-02-04
Keywords: histopathological risk factors; immunological risk factors; molecular pathology; molecular subtypes; Urothelial carcinoma

Das muskelinvasive und metastasierte Urothelkarzinom der Harnblase: Aktueller Stand histopathologischer, molekularer und immunologischer Prognose- und Prädiktionsfaktoren - Bertz, Simone; Bahlinger, Veronika; Lange, Fabienne; Hartmann, Arndt; Eckstein, Markus (Die Pathologie, 2024)
Background: Muscle-invasive and metastatic urothelial carcinoma (UC) represents a heterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. Aims: This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Results and discussion: Muscle-invasive and metastatic UC exhibits a wide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.
CRIS-Team Scopus Importer:2024-08-16
Keywords: B7-H1 antigen; Disease progression; Immunotherapy; Molecular pathology; Transitional cell carcinoma

Data Set for the Reporting of Carcinomas of the Nasopharynx and Oropharynx Explanations and Recommendations of the Guidelines From the International Collaboration on Cancer Reporting - Lewis, James S.; Adelstein, David J.; Agaimy, Abbas; Carlson, Diane L.; Faquin, William C.; Helliwell, Tim; Hille, Jos; Ng, Tony; Nicholls, John M.; O'Sullivan, Brian; Thompson, Lester D. R. (Archives of Pathology & Laboratory Medicine, 2019)
The International Collaboration on Cancer Reporting was established to internationally unify and standardize the pathologic reporting of cancers based on collected evidence, as well as to allow systematic data collection across institutions and countries to guide cancer care in the future. An expert panel was convened to identify the minimum data set of elements that should be included in cancer reporting from tumors of the nasopharynx and oropharynx. Specifically, there has been a significant change in practice as a result of identifying oncogenic viruses, including human papillomavirus and Epstein-Barr virus, because they preferentially affect the oropharynx and nasopharynx, respectively. For these anatomic sites, when viral association is taken into account, usually reported elements of in situ versus invasive tumor, depth of invasion, and degree of differentiation are no longer applicable. Thus, guidance about human papillomavirus testing in oropharyngeal carcinomas and Epstein-Barr virus testing in nasopharyngeal carcinomas is highlighted. Further, the clinical and the pathologic differences in staging as proposed by the 8th edition of the Union for International Cancer Control are incorporated into the discussion, pointing out several areas of continued study and further elaboration. A summary of the International Collaboration on Cancer Reporting guidelines for oropharyngeal and nasopharyngeal carcinomas is presented, along with discussion of the salient evidence and practical issues.
CRIS-Team WoS Importer:2019-04-12

Datasets for reporting of soft-tissue sarcoma: recommendations from the International Collaboration on Cancer Reporting (ICCR) - Dei Tos, Angelo Paolo; Webster, Fleur; Agaimy, Abbas; Bovée, Judith; Dickson, Brendan; Doyle, Leona; Dry, Sarah; Gronchi, Alessandro; Hameed, Meera; Hemmings, Chris; Liegl-Atzwanger, Bernadette; Thway, Khin; et al. (Histopathology, 2023)
Aims: Soft-tissue tumours are rare and both accurate diagnosis and proper treatment represent a global challenge. Current treatment guidelines also recommend review by specialised pathologists. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of soft-tissue sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of international pathology and cancer organisations. Methods and results: According to the ICCR's guidelines for dataset development, an international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialised soft-tissue sarcoma experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, which included a synoptic reporting guide, were published on the ICCR website. Conclusion: These first international datasets for soft-tissue sarcomas are aimed to promote high-quality, standardised pathology reporting. Their adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve patient's management.
CRIS-Team Scopus Importer:2023-01-27
Keywords: biopsy; checklist; dataset; guidelines; ICCR; resection; soft-tissue sarcoma; synoptic report

Death-associated kinase (DAPK): a cancer "gene chameleon" - Schneider-Stock, Regine (Apoptosis, 2014)
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Death-associated protein kinase: A molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review) - Steinmann, Sara; Scheibe, Kristina; Erlenbach-Wuensch, Katharina; Neufert, Clemens; Schneider-Stock, Regine (International Journal of Oncology, 2015)
The cytoskeleton-associated serine/threonine kinase death-associated protein kinase (DAPK) has been described as a cancer gene chameleon with functional antagonistic duality in a cell type and context specific manner. The broad range of interaction partners and substrates link DAPK to inflammatory processes especially in the gut. Herein we summarize our knowledge on the role of DAPK in different cell types that play a role under inflammatory conditions in the gut. Besides some promising experimental data suggesting DAPK as an interesting drug target in inflammatory bowel disease there are many open questions regarding direct evidence for a role of DAPK in intestinal inflammation.
EVALuna2:1972

Deceased Donor Kidney Transplantation in the Eurotransplant Senior Program (ESP): A Single-Center Experience from 2008 to 2013 - Jacobi, Johannes; Beckmann, Sophie; Heller, Katharina; Hilgers, Karl Friedrich; Apel, Hendrik; Spriewald, Bernd; Eckardt, Kai-Uwe; Amann, Kerstin Ute (Annals of Transplantation, 2016)
BACKGROUND The aim of this study was to evaluate the outcome after transplantation of deceased allografts in donor/recipient pairs aged >=65 years enrolled in the Eurotransplant Senior Program (ESP). MATERIAL AND METHODS In this retrospective cohort study we evaluated data from 89 patients transplanted under the ESP protocol from 2008 to 2013. Outcome parameters included graft and patient survival, rate of biopsy-proven acute rejections (BPAR), peri- and post-operative complications, tumor development, development of donor-specific antibodies (DSA), and the prognostic role of preimplantation biopsies. RESULTS One-year patient and allograft survival rates were 92.1% and 84.3%, respectively. During follow-up, 23 (26%) patients died; the major cause of death was sepsis, followed by cardiovascular events and malignancies. BPAR episodes were frequent within the first year ( 33%) and overall were less common in patients treated with tacrolimus. Post-transplant malignancies were seen in 15 (17%) patients. During follow-up, 16 (18%) patients developed DSA; patients with delayed graft function (DGF) were more likely to develop DSA (p=0.029). A higher preimplantation biopsy score was associated with DGF but did not predict later graft outcome. CONCLUSIONS The results highlight increased risks in ESP transplant candidates and the importance of careful surveillance of this patient group.
EVALuna2:3834

Deceased donor urinary Dickkopf-3 associates with future allograft function following kidney transplantation - Fallois, Jonathan de; Günzel, Anna; Daniel, Christoph; Stumpf, Julian; Busch, Martin; Pein, Ulrich; Paliege, Alexander; Amann, Kerstin Ute; Wiech, Thorsten; Hantmann, Elena; Wolf, Gunter; Pfeifer, Felix; et al. (American Journal of Transplantation, 2024)
Predicting future kidney allograft function is challenging. Novel biomarkers, such as urinary Dickkopf-3 (uDKK3), may help guide donor selection and improve allograft outcomes. In this prospective multicenter pilot trial, we investigated whether donor uDKK3 reflects organ quality and is associated with future allograft function. We measured uDKK3/crea ratios (uDKK3/crea) from 95 deceased and 46 living kidney donors. Prenephrectomy uDKK3/crea levels were 100× higher in deceased than in living donors (9888 pg/mg vs 113 pg/mg; P < .001). Among deceased donor transplantations, recipients were stratified by their corresponding uDKK3/crea donor levels ranging below (group A, n = 68) or above (group B, n = 65) median. The primary end point of best estimated glomerular filtration rate (eGFR) within the first 3 months after kidney transplantation was superior in group A (56.3 mL/min/1.73 m2) than that in group B (44.2 mL/min/1.73 m2; P = .0139). Second, the composite clinical end point consisting of death, allograft failure or eGFR decline >50% occurred less frequent in group A. By mixed linear regression modeling, donor uDKK3/crea remained an independent predictor of eGFR after transplantation, with a slope of −4.282 mL/min/1.73 m2 per logarithmic increase in donor uDKK3/crea. In summary, uDKK3 may serve as a noninvasive, donor-dependent biomarker for assessing organ quality and future allograft function.
CRIS-Team Scopus Importer:2024-10-18
Keywords: biomarker; DKK3; donor; kidney transplantation; recipient

Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases with Literature Review and Proposal of Diagnostic Criteria - Agaimy, Abbas; Stöhr, Robert; Hornung, Annkathrin; Popp, Judith; Erdmann, Michael; Heinzerling, Lucie; Hartmann, Arndt (American Journal of Surgical Pathology, 2021)
Dedifferentiated melanoma (DM) and undifferentiated melanoma (UM) is defined as a primary or metastatic melanoma showing transition between conventional and undifferentiated components (DM) or lacking histologic and immunophenotypic features of melanoma altogether (UM). The latter is impossible to verify as melanoma by conventional diagnostic tools alone. We herein describe our experience with 35 unpublished cases to expand on their morphologic, phenotypic, and genotypic spectrum, along with a review of 50 previously reported cases (total: 85) to establish the diagnostic criteria. By definition, the dedifferentiated/undifferentiated component lacked expression of 5 routinely used melanoma markers (S100, SOX10, Melan-A, HMB45, Pan-melanoma). Initial diagnoses (known in 66 cases) were undifferentiated/unclassified pleomorphic sarcoma (n=30), unclassified epithelioid malignancy (n=7), pleomorphic rhabdomyosarcoma (n=5), other specific sarcoma types (n=6), poorly differentiated carcinoma (n=2), collision tumor (n=2), atypical fibroxanthoma (n=2), and reactive osteochondromatous lesion (n=1). In only 11 cases (16.6%) was a diagnosis of melanoma considered. Three main categories were identified: The largest group (n=56) comprised patients with a history of verified previous melanoma who presented with metastatic DM or UM. Axillary or inguinal lymph nodes, soft tissue, bone, and lung were mainly affected. A melanoma-compatible mutation was detected in 35 of 48 (73%) evaluable cases: BRAF (n=20; 40.8%), and NRAS (n=15; 30.6%). The second group (n=15) had clinicopathologic features similar to group 1, but a melanoma history was lacking. Axillary lymph nodes (n=6) was the major site in this group followed by the lung, soft tissue, and multiple site involvement. For this group, NRAS mutation was much more frequent (n=9; 60%) than BRAF (n=3; 20%) and NF1 (n=1; 6.6%). The third category (n=14) comprised primary DM (12) or UM (2). A melanoma-compatible mutation was detected in only 7 cases: BRAF (n=2), NF1 (n=2), NRAS (n=2), and KIT exon 11 (n=1). This extended follow-up study highlights the high phenotypic plasticity of DM/UM and indicates significant underrecognition of this aggressive disease among general surgical pathologists. The major clues to the diagnosis of DM and UM are: (1) presence of minimal differentiated clone in DM, (2) earlier history of melanoma, (3) undifferentiated histology that does not fit any defined entity, (4) locations at sites that are unusual for undifferentiated/unclassified pleomorphic sarcoma (axilla, inguinal, neck, digestive system, etc.), (5) unusual multifocal disease typical of melanoma spread, (6) detection of a melanoma-compatible gene mutation, and (7) absence of another genuine primary (eg, anaplastic carcinoma) in other organs.
CRIS-Team Scopus Importer:2021-02-05
Keywords: BRAF; chondrosarcoma; dedifferentiated melanoma; giant cell tumor; KIT; NRAS; osteosarcoma; pleomorphic sarcoma; rhabdomyosarcoma; undifferentiated melanoma

Dedifferentiated liposarcoma composed predominantly of rhabdoid/epithelioid cells: a frequently misdiagnosed highly aggressive variant - Agaimy, Abbas; Michal, Michael; Hadravsky, Ladislav; Michal, Michal (Human Pathology, 2018)
Dedifferentiated liposarcoma is one of the most common sarcoma types in adults with a predilection for the retroperitoneum. We have recently encountered 6 cases of DDL composed predominantly of rounded, rhabdoid or epithelioid cells mimicking rhabdoid melanoma, epithelioid rhabdomyosarcoma or undifferentiated carcinoma. Patients were 5 males and one female aged 64 to 81 years (median, 68). Tumors originated in the retroperitoneum (n = 5; 3 in the psoas muscle) and deep soft tissue of the thigh (n = 1). All 3 patients with follow-up died of metastatic disease within 4 to 8 months. Preoperative biopsy diagnoses never suggested dedifferentiated liposarcoma as a possibility; instead carcinoma, rhabdomyosarcoma and lymphoma were on top of suggestions. Five resected tumors were composed predominantly (70%-100%) of anaplastic rounded to oval rhabdoid cells with prominent central nucleoli and paranuclear rhabdoid inclusions. Bi- and multinucleation was a constant feature. The background stroma showed variable myxoid changes and minor mixed inflammatory cells. Two cases showed homologous dedifferentiation and another had sclerosing spindle cell nodule but a well-differentiated lipomatous component was not seen in any. One biopsied case showed solely monotonous small round blue cells with scattered rhabdoid cells. Immunohistochemistry showed expression of MDM2 (6/6), CDK4 (5/6), pancytokeratin AE/1 AE3 (4/6) and diffusely desmin and myogenin (2/6). All cases showed high-level co-amplification of MDM2/CDK4 by in situ hybridization. The SWI/SNF complex components (SMARCB1, SMARCA2, SMARCA4, ARID1A and PBRM1) were intact in all cases. This highly aggressive liposarcoma variant needs to be distinguished from a variety of neoplasms including undifferentiated carcinoma, melanoma, lymphoma, rhabdomyosarcoma and others. (C) 2018 Elsevier Inc. All rights reserved.
EVALuna2:34874

Deep hypothermic circulatory arrest or tepid regional cerebral perfusion: impact on haemodynamics and myocardial integrity in a randomized experimental trial - Kellermann, Stephanie; Janssen, Carina; Münch, Frank; Koch, Anna Maria; Schneider-Stock, Regine; Cesnjevar, Robert; Rueffer, Andre (Interactive Cardiovascular and Thoracic Surgery, 2017)
OBJECTIVES: Organ protective management during aortic arch surgery comprises deep hypothermic (18°C) circulatory arrest (DHCA), or moderate hypothermia (28°C/ 'tepid') with regional cerebral perfusion (TRCP). The aim of this experimental study was to evaluate the effect of distinct organ protective management on hemodynamic performance and myocardial integrity. METHODS: Ten male piglets were randomized to group DHCA (n = 5) or TRCP (n = 5) group and operated on cardiopulmonary bypass (CPB) with 60 min of aortic cross-clamping. Blood gas analysis was performed throughout the experiment. Haemodynamic assessment was performed using a thermodilution technique before and after CPB. Myocardial biopsies were taken 2 h after CPB and evaluated using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling assay and western blot analysis. RESULTS: At reperfusion, levels of central venous saturation were significantly higher (P = 0.016) and levels of lactate significantly lower (P = 0.029) in the DHCA group. After CPB, thermodilution measurements revealed higher stroke volume and lower peripheral resistance in the TRCP group (P = 0.012 and 0.037). At the end of the experiment, no significant differences regarding laboratory and haemodynamic parameters were evident. All specimens showed enrichment of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling-positive cells exclusively at the left ventricular subendocardium with no difference between groups and equal concentrations of cyclo-oxygenase-2. CONCLUSIONS: TRCP is associated with decreased peripheral resistance and higher stroke volume immediately after CPB. However, this beneficial effect is contrasted by signs of lower body hypoperfusion, which is expressed by lower central venous saturations and higher lactate levels. Distinct strategies of organ protection did not seem to affect apoptotic/necrotic and inflammatory changes in the left ventricular myocardium.
EVALuna2:33490

Deep learning-based classification of blue light cystoscopy imaging during transurethral resection of bladder tumors - Ali, Nairveen; Bolenz, Christian; Todenhöfer, Tilman; Stenzel, Arnulf; Deetmar, Peer; Kriegmair, Martin; Knoll, Thomas; Porubsky, Stefan; Hartmann, Arndt; Popp, Jürgen; Kriegmair, Maximilian C.; Bocklitz, Thomas (Scientific Reports, 2021)
Bladder cancer is one of the top 10 frequently occurring cancers and leads to most cancer deaths worldwide. Recently, blue light (BL) cystoscopy-based photodynamic diagnosis was introduced as a unique technology to enhance the detection of bladder cancer, particularly for the detection of flat and small lesions. Here, we aim to demonstrate a BL image-based artificial intelligence (AI) diagnostic platform using 216 BL images, that were acquired in four different urological departments and pathologically identified with respect to cancer malignancy, invasiveness, and grading. Thereafter, four pre-trained convolution neural networks were utilized to predict image malignancy, invasiveness, and grading. The results indicated that the classification sensitivity and specificity of malignant lesions are 95.77% and 87.84%, while the mean sensitivity and mean specificity of tumor invasiveness are 88% and 96.56%, respectively. This small multicenter clinical study clearly shows the potential of AI based classification of BL images allowing for better treatment decisions and potentially higher detection rates.
CRIS-Team Scopus Importer:2021-06-11

Deep learning for diagnosis and survival prediction in soft tissue sarcoma - Foersch, S.; Eckstein, Markus; Wagner, D. C.; Gach, F.; Woerl, A. C.; Geiger, J.; Glasner, C.; Schelbert, S.; Schulz, S.; Porubsky, S.; Kreft, A.; Hartmann, Arndt; et al. (Annals of Oncology, 2021)
Background: Clinical management of soft tissue sarcoma (STS) is particularly challenging. Here, we used digital pathology and deep learning (DL) for diagnosis and prognosis prediction of STS. Patients and methods: Our retrospective, multicenter study included a total of 506 histopathological slides from 291 patients with STS. The Cancer Genome Atlas cohort (240 patients) served as training and validation set. A second, multicenter cohort (51 patients) served as an additional test set. The use of the DL model (DLM) as a clinical decision support system was evaluated by nine pathologists with different levels of expertise. For prognosis prediction, 139 slides from 85 patients with leiomyosarcoma (LMS) were used. Area under the receiver operating characteristic (AUROC) and accuracy served as main outcome measures. Results: The DLM achieved a mean AUROC of 0.97 (±0.01) and an accuracy of 79.9% (±6.1%) in diagnosing the five most common STS subtypes. The DLM significantly improved the accuracy of the pathologists from 46.3% (±15.5%) to 87.1% (±11.1%). Furthermore, they were significantly faster and more certain in their diagnosis. In LMS, the mean AUROC in predicting the disease-specific survival status was 0.91 (±0.1) and the accuracy was 88.9% (±9.9%). Cox regression showed the DLM's prediction to be a significant independent prognostic factor (P = 0.008, hazard ratio 5.5, 95% confidence interval 1.56-19.7) in these patients, outperforming other risk factors. Conclusions: DL can be used to accurately diagnose frequent subtypes of STS from conventional histopathological slides. It might be used for prognosis prediction in LMS, the most prevalent STS subtype in our cohort. It can also help pathologists to make faster and more accurate diagnoses. This could substantially improve the clinical management of STS patients.
CRIS-Team Scopus Importer:2021-08-20
Keywords: artificial intelligence; clinical decision support system; deep learning; digital pathology; prognosis prediction; soft tissue sarcoma

Deep Learning Predicts Molecular Subtype of Muscle-invasive Bladder Cancer from Conventional Histopathological Slides - Woerl, Ann Christin; Eckstein, Markus; Geiger, Josephine; Wagner, Daniel C.; Daher, Tamas; Stenzel, Philipp; Fernandez, Aurélie; Hartmann, Arndt; Wand, Michael; Roth, Wilfried; Foersch, Sebastian (European Urology, 2020)
Background: Muscle-invasive bladder cancer (MIBC) is the second most common genitourinary malignancy, and is associated with high morbidity and mortality. Recently, molecular subtypes of MIBC have been identified, which have important clinical implications. Objective: In the current study, we tried to predict the molecular subtype of MIBC samples from conventional histomorphology alone using deep learning. Design, setting, and participants: Two cohorts of patients with MIBC were used: (1) The Cancer Genome Atlas Urothelial Bladder Carcinoma dataset including 407 patients and (2) our own cohort including 16 patients with treatment-naïve, primary resected MIBC. This resulted in a total of 423 digital whole slide images of tumor tissue to train, validate, and test the deep learning algorithm to predict the molecular subtype. Outcome measurements and statistical analysis: Various accuracy measurements including the area under the receiver operating characteristic curves were used to evaluate the deep learning model. A sliding window approach to visualize classification was used. Class activation maps were used to identify image features that are most relevant to call a specific class. Results and limitations: The deep learning model showed great performance in the prediction of the molecular subtype of MIBC patients from hematoxylin and eosin (HE) slides alone—similar to or better than pathology experts. Using different visualization techniques, we identified new histopathological features that were most relevant to our model. Conclusions: Deep learning can be used to predict important molecular features in MIBC patients from HE slides alone, potentially improving the clinical management of this disease significantly. Patient summary: In patients with bladder cancer, a computer program found changes in the appearance of tumor tissue under the microscope and used these to predict genetic alterations. This could potentially benefit patients. By using a comprehensive deep learning model, we were able to predict the molecular subtype of muscle-invasive bladder cancer from conventional histopathological slides alone, with good to excellent performance.
CRIS-Team Scopus Importer:2020-05-05
Keywords: Deep learning; Histopathology; Molecular subtype; Muscle-invasive bladder cancer

Defective autophagosome formation in p53-null colorectal cancer reinforces crocin-induced apoptosis - Amin, Amr; Bajbouj, Khuloud; Koch, Anna Maria; Gandesiri, Muktheshwar; Schneider-Stock, Regine (International Journal of Molecular Sciences, 2015)
Crocin, a bioactive molecule of saffron, inhibited proliferation of both HCT116 wild-type and HCT116 p53(-/-) cell lines at a concentration of 10 mM. Flow cytometric analysis of cell cycle distribution revealed that there was an accumulation of HCT116 wild-type cells in G1 (55.9%, 56.1%) compared to the control (30.4%) after 24 and 48 h of crocin treatment, respectively. However, crocin induced only mild G2 arrest in HCT116 p53(-/-) after 24 h. Crocin induced inefficient autophagy in HCT116 p53(-/-) cells, where crocin induced the formation of LC3-II, which was combined with a decrease in the protein levels of Beclin 1 and Atg7 and no clear p62 degradation. Autophagosome formation was not detected in HCT116 p53(-/-) after crocin treatment predicting a nonfunctional autophagosome formation. There was a significant increase of p62 after treating the cells with Bafilomycin A1 (Baf) and crocin compared to crocin exposure alone. Annexin V staining showed that Baf-pretreatment enhanced the induction of apoptosis in HCT116 wild-type cells. Baf-exposed HCT116 p53(-/-) cells did not, however, show any enhancement of apoptosis induction despite an increase in the DNA damage-sensor accumulation, ?H2AX indicating that crocin induced an autophagy-independent classical programmed cell death.
EVALuna2:6730

Deficiency of the Interleukin 17/23 Axis Accelerates Renal Injury in Mice With Deoxycorticosterone Acetate+Angiotensin II-Induced Hypertension - Krebs, Christian F.; Lange, Sascha; Niemann, Gianina; Rosendahl, Alva; Lehners, Alexander; Meyer-Schwesinger, Catherine; Stahl, Rolf A. K.; Benndorf, Ralf A.; Velden, Joachim; Paust, Hans-Joachim; Panzer, Ulf; Ehmke, Heimo; et al. (Hypertension, 2014)
T cells participate in angiotensin II (Ang II)-induced hypertension. However, the specific subsets of T cells that are important in the end-organ damage are unknown. T-helper 17 cells are a recently identified subset that produces interleukin 17 (IL-17) and requires interleukin 23 (IL-23) for expansion. To evaluate the role of the T-helper 17 immune response in hypertensive renal and cardiac end-organ damage, hypertension was induced with deoxycorticosterone acetate (DOCA)+Ang II in wild-type (n=39) and IL-17-deficient (n=31) mice. The injury was evaluated at day 4 and day 14. To inactivate the IL-17/IL-23 axis at a different point, DOCA+Ang II hypertension was also induced in IL-23p19-deficient mice. Renal infiltration by T-helper 17 cells was increased in hypertensive wild-type mice. Systolic blood pressure did not differ between hypertensive IL-17-deficient and wild-type mice. Three days after induction of hypertension, a significantly higher albuminuria was found in IL-17-deficient than in wild-type mice (196±64 versus 58±16 mg/mg albumin/creatinine). Histology revealed significantly more glomerular injury (1.04±0.06 versus 0.67±0.05) and renal infiltration of ?? T cells in IL-17-deficient than in wild-type mice after 14 days. Similarly, significantly higher albuminuria, glomerular injury, and ?? T cell infiltration were found in IL-23p19-deficient mice with DOCA+Ang II-induced hypertension. DOCA+Ang II also induced cardiac damage as assessed by heart weight, cardiac fibrosis, as well as expression of fetal genes and matrix components, but no significant differences were found among IL-17(-/-), IL-23p19(-/-), and wild-type mice. IL-17/IL-23 deficiency accelerates DOCA+Ang II-induced albuminuria and hypertensive renal but not cardiac end-organ damage.
EVALuna2:25454

Deficient CD247 expression is a typical histopathological characteristic of thymomas with cortical features - Christopoulos, Petros; Chung, Inn; Bozorgmehr, Farastuk; Muley, Thomas; Meister, Michael; Kobinger, Sonja; Marx, Alexander; Thomas, Michael; Winter, Hauke; Herpel, Esther; Rieker, Ralf; Fisch, Paul; et al. (Histopathology, 2018)
EVALuna2:205511

Defined morphological criteria allow reliable diagnosis of colorectal serrated polyps and predict polyp genetics - Rau, Tilman; Agaimy, Abbas; Gehoff, Anastasia; Geppert, Carol-Immanuel; Jung, Klaus; Knobloch, Katharina; Langner, Cord; Lugli, Alessandro; Groenbus-Lurkin, Irene; Nagtegaal, Iris D.; Rueschoff, Josef; Saegert, Xavier; et al. (Virchows Archiv, 2014)
Criteria for the diagnosis of serrated colorectal lesions (hyperplastic polyp, sessile serrated adenoma without or with dysplasia–which we called mixed polyp–and traditional serrated adenoma) for which consensus has been reached should be validated for applicability in daily practice in terms of inter-observer reproducibility and their association with clinical features and (epi)genetic events. A study set was created from a consecutive series of colorectal polyps (n = 1,926) by selecting all sessile serrated adenomas, traditional serrated adenomas and mixed polyps. We added consecutive series of hyperplastic polyps, classical adenomas and normal mucosa samples for a total of 200 specimens. With this series, we conducted an inter-observer study, encompassing ten pathologists with gastrointestinal pathology experience from five European countries, in three rounds in which all cases were microscopically evaluated. An assessment of single morphological criteria was included, and these were correlated with clinical parameters and the mutation status of KRAS, BRAF and PIK3CA and the methylation status of MLH1. Gender, age and localisation were significantly associated with certain types of lesions. Kappa statistics revealed moderate to good inter-observer agreement for polyp classification (? = 0.56 to 0.63), but for single criteria, this varied considerably (? = 0.06 to 0.82). BRAF mutations were frequently found in hyperplastic polyps (86 %, 62/72) and sessile serrated adenomas (80 %, 41/51). KRAS mutations occurred more frequently in traditional serrated adenomas (78 %, 7/9) and less so in classical adenomas (20 %, 10/51). Single morphological criteria for sessile serrated adenomas showed significant correlation with BRAF mutation (all p <= 0.001), and those for classical adenomas or traditional serrated adenoma correlated significantly with KRAS mutation (all p < 0.001). Therefore, single well-defined morphological criteria are predictive for genetic alterations in colorectal polyps.
EVALuna2:6595

Defining Ewing and Ewing-like small round cell tumors (SRCT): The need for molecular techniques in their categorization and differential diagnosis. A study of 200 cases - Machado, Isidro; Navarro, Lara; Pellin, Antonio; Navarro, Samuel; Agaimy, Abbas; Tardio, Juan C.; Karseladze, Apollon; Petrov, Semyon; Scotlandi, Katia; Picci, Piero; Llombart-Bosch, Antonio (Annals of Diagnostic Pathology, 2016)
Differentiation of Ewing sarcoma family of tumors (ESFT) and Ewing-like tumors remains problematic. Certain ESFT with morphological and immunohistochemical (IHC) profiles lack the EWSR1-ETS transcript. To improve diagnostic accuracy we investigated the presence of several specific transcripts in 200 small round cell tumors (SRCT) displaying ESFT morphology and immunophenotype in which EWSR1 FISH analysis was non-informative or negative.200 tumors (formalin-fixed, paraffin-embedded) were analyzed by RT-PCR. All tumors were tested for EWSR1-ETS, EWSR1/WT1, PAX3/7-FOX01 or SYT/SSX transcripts, and the negative tumors were subsequently analyzed for CIC/DUX4, BCOR/CCNB3 and CIC/FOX04 transcripts.133 (66.5%) ESFT displayed one of the above EWSR1-ETS translocations. Three cases (1.5%) revealed the SYT-SSX transcript for Synovial sarcoma, and one (0.5%) a EWSR1-WT1 transcript for Desmoplastic Small Round Cell tumor. The CIC-DUX4 translocation was found in six Ewing-like tumors (3%) with CD99 positivity. The BCOR-CCNB3 gene fusion was observed in 5 tumors (2.5%) displaying round or spindle cells with strong CCNB3 IHC expression in 3 tumors. Moreover, RT-PCR failed to detect any gene fusion transcripts in 19 tumors (9.5%) and were considered "undifferentiated small round cell sarcoma" (SRCS). Molecular biology results were non-informative in 33 SRCTs (16.5%) due to RNA degradation through inadequate fixation and/or decalcification.Our analysis of 200 SRCTs confirms the molecular heterogeneity of neoplasms with ESFT morphology and highlight that molecular studies with RT-PCR including new emerging gene fusion transcripts are mandatory for the diagnosis when EWSR1 FISH is negative or non-informative. The incidence of CIC-DUX4, BCOR-CCNB3 and CIC-FOX04 transcripts was relatively low. A small group of Ewing-like sarcomas or undifferentiated SRCS remains unclassified. Adopting appropriate tissue fixation and processing protocols is important to avoid degradation of fixed/embedded tissue when no frozen tumor is available.
EVALuna2:6748

Defining intra-tumoral and systemic immune biomarkers for locally advanced head-and-neck cancer – detailed protocol of a prospective, observatory multicenter trial (ImmunBioKHT) and first results of the immunophenotyping of the patients’ peripheral blood - Donaubauer, Anna-Jasmina; Frey, Benjamin; Weber, Manuel; Allner, Moritz; Vogl, Christoph; Almajali, Omar; Kuczera, Lukas; Tamse, Henriette; Balk, Matthias; Müller-Hübner, Sarina Katrin Ursel; Eckstein, Markus; Zülch, Lilli; et al. (Frontiers in Oncology, 2024)
The approval and effectiveness of immune checkpoint inhibitors in head-and-neck squamous cell carcinoma (HNSCC) highlights the role of the immune system in this tumor entity. HNSCCs not only interacts with the immune system in the tumor tissue, but also induce systemic effects that may be additionally influenced by further factors such as the microbiome. Nonetheless, reliable immunological biomarkers that predict treatment response and outcome in HNSCC patients are lacking. The currently available biomarkers are mainly limited to analyses from tumor biopsies, while biomarkers from liquid biopsies, such as peripheral blood are not well-established. Thus, the here presented trial aims to identify interactions of intra-tumoral and systemic immune responses and to define prognostic immune signatures. Consequently, not only samples from the tumor tissue, but also from peripheral blood and the microbiome will be studied/are being evaluated and correlated with the clinical outcome. In this prospective, multi-center trial, 1000 HNSCC patients and 100 patients in the control cohort with non-tumor head-and-neck surgery will be enrolled. The local immune status from of the tumor and the microbiome will be sampled before treatment. In addition, the systemic immune status from peripheral blood will be analyzed before and after surgery and after the adjuvant and definitive radio-chemotherapy (RCT). Clinical baseline characteristics and outcome will additionally be collected. Data mining and modelling approaches will finally be applied to identify interactions of local and systemic immune parameters and to define prognostic immune signatures based on the evaluated immune markers. Approval from the institutional review board of the Friedrich-Alexander-Universität Erlangen-Nürnberg was granted in December 2021 (application number 21-440-B). By now, 150 patients have been enrolled in the intervention cohort. The results will be disseminated to the scientific audience and the general public via presentations at conferences and publication in peer-reviewed journal
CRIS-Team Scopus Importer:2024-10-04
Keywords: HNSCC; immune monitoring; immunological biomarker; liquid biopsy; prospective clinical trial

Degenerative DNA alterations in osteoarthritis - Söder, Stephan (Pathologe, 2016)
Osteoarthritis is a complex disease involving not only the cartilage but also the adjacent bone and the synovial membrane. The etiology of osteoarthritis involves multiple factors. Unlike secondary forms of osteoarthritis, which are the result of other diseases or excessive mechanical stress, the origins of primary forms of osteoarthritis lie within the cartilage. In primary osteoarthritis complex interactions of cytokines leading to a derangement of homeostasis have been discovered, which lead to a slow and progressive degeneration of the cartilage and bone, ultimately resulting in destruction of the joint. Damage to the cartilage matrix is caused by an increased activity of matrix metalloproteases induced by catabolic cytokines. One of the initial events triggering these processes might be degenerative DNA alterations causing local defects in multiple genes leading to an impaired function of chondrocytes and a phenotype similar to senescence.
EVALuna2:6911

DEK-AFF2 Carcinoma of the Sinonasal Region and Skull Base Detailed Clinicopathologic Characterization of a Distinctive Entity - Rooper, Lisa M.; Agaimy, Abbas; Dickson, Brendan C.; Dueber, Julie C.; Eberhart, Charles G.; Gagan, Jeffrey; Hartmann, Arndt; Khararjian, Armen; London, Nyall R.; Macmillan, Christina M.; Palsgrove, Doreen N.; Nix, J. Stephen; et al. (American Journal of Surgical Pathology, 2021)
A novel DEK-AFF2 fusion was recently reported in 4 nonkeratinizing squamous cell carcinomas of the sinonasal region and skull base, including 1 with exceptional response to immunotherapy, but it is not yet clear if this rearrangement defines a unique clinicopathologic category or represents a rare event. This study aims to characterize a larger cohort of carcinomas with DEK-AFF2 fusions to assess whether they truly constitute a distinctive entity. Among 27 sinonasal and skull base nonkeratinizing squamous cell carcinoma that were negative for human papillomavirus and Epstein-Barr virus, RNA sequencing identified DEK-AFF2 fusions in 13 cases (48%). Nine were centered in the nasal cavity, 2 in the middle ear/temporal bone, 1 in the nasopharynx, and 1 in the orbit. These tumors displayed recurrent histologic features including (1) complex endophytic and exophytic, frequently papilloma-like growth, (2) transitional epithelium with eosinophilic to amphophilic cytoplasm, (3) absent or minimal keratinization with occasional compact keratin pearls, (4) monotonous nuclei, and (5) prominent tumor-infiltrating neutrophils or stromal lymphocytes. This appearance not only overlaps with high-grade basaloid sinonasal carcinomas but also with benign papillomas and tumors reported as low-grade papillary Schneiderian carcinoma. However, DEK-AFF2 carcinomas showed frequent local recurrence, cervical lymph node metastases, and distant metastasis with 2 deaths from disease, confirming they are aggressive malignancies despite relatively bland histology. Overall, the distinctive molecular, histologic, and clinical features of DEK-AFF2 carcinomas suggest they represent a unique entity in the sinonasal region. This tumor merits increased pathologic recognition to better understand its prognostic and therapeutic implications.
CRIS-Team WoS Importer:2021-11-26

Deletion of Gas2l3 in mice leads to specific defects in cardiomyocyte cytokinesis during development - Stopp, Sabine; Gruendl, Marco; Fackler, Marc; Malkmus, Jonas; Leone, Marina; Naumann, Ronald; Frantz, Stefan; Wolf, Elmar; Von Eyss, Bjoern; Engel, Felix; Gaubatz, Stefan (Proceedings of the National Academy of Sciences of the United States of America, 2017)
GAS2L3 is a recently identified cytoskeleton-associated protein that interacts with actin filaments and tubulin. The in vivo function of GAS2L3 in mammals remains unknown. Here, we show that mice deficient in GAS2L3 die shortly after birth because of heart failure. Mammalian cardiomyocytes lose the ability to proliferate shortly after birth, and further increase in cardiac mass is achieved by hypertrophy. The proliferation arrest of cardiomyocytes is accompanied by binucleation through incomplete cytokinesis. We observed that GAS2L3 deficiency leads to inhibition of cardiomyocyte proliferation and to cardiomyocyte hypertrophy during embryonic development. Cardiomyocyte-specific deletion of GAS2L3 confirmed that the phenotype results from the loss of GAS2L3 in cardiomyocytes. Cardiomyocytes from Gas2l3-deficient mice exhibit increased expression of a p53-transcriptional program including the cell cycle inhibitor p21. Furthermore, loss of GAS2L3 results in premature binucleation of cardiomyocytes accompanied by unresolved midbody structures. Together these results suggest that GAS2L3 plays a specific role in cardiomyocyte cytokinesis and proliferation during heart development.
EVALuna2:25556

Delivering the precision oncology paradigm: reduced R&D costs and greater return on investment through a companion diagnostic informed precision oncology medicines approach - Henderson, Raymond H.; French, Declan; Stewart, Elaine; Smart, Dave; Idica, Adam; Redmond, Sandra; Eckstein, Markus; Clark, Jordan; Sullivan, Richard; Keeling, Peter; Lawler, Mark (Journal of Pharmaceutical Policy and Practice, 2023)
Background: Precision oncology medicines represent a paradigm shift compared to non-precision oncology medicines in cancer therapy, in some situations delivering more clinical benefit, and potentially lowering healthcare costs. We determined whether employing a companion diagnostic (CDx) approach during oncology medicines development delivers effective therapies that are within the cost constraints of current health systems. R&D costs of developing a medicine are subject to debate, with average estimates ranging from 765 million (m) to 4.6 billion (b). Our aim was to determine whether precision oncology medicines are cheaper to bring from R&D to market; a secondary goal was to determine whether precision oncology medicines have a greater return on investment (ROI). Method: Data on oncology medicines approved between 1997 and 2020 by the US Food and Drug Administration (FDA) were analysed from the Securities and Exchange Commission (SEC) filings. Data were compiled from 10-K, 10-Q, and 20-F financial performance filings on medicines’ development costs through their R&D lifetime. Clinical trial data were split into clinical trial phases 1–3 and probability of success (POS) of trials was calculated, along with preclinical costs. Cost-of-capital (CoC) approach was applied and, if appropriate, a tax rebate was subtracted from the total. Results: Data on 42 precision and 29 non-precision oncology medicines from 56 companies listed by the National Cancer Institute which had complete data available were analysed. Estimated mean cost to deliver a new oncology medicine was 4.4b (95% CI, 3.6–5.2b). Costs to bring a precision oncology medicine to market were 1.1b less (3.5b; 95% CI, 2.7–4.5b) compared to non-precision oncology medicines (4.6b; 95% CI, 3.5–6.1b). The key driver of costs was POS of clinical trials, accounting for a difference of 591.3 m. Additional data analysis illustrated that there was a 27% increase in return on investment (ROI) of precision oncology medicines over non-precision oncology medicines. Conclusion: Our results provide an accurate estimate of the R&D spend required to bring an oncology medicine to market. Deployment of a CDx at the earliest stage substantially lowers the cost associated with oncology medicines development, potentially making them available to more patients, while staying within the cost constraints of cancer health systems.
CRIS-Team Scopus Importer:2023-07-21

Der Einfluss des Kapseldefektes als Risikofaktor für die Rezidivbildung beim pleomorphen Adenom der Glandula parotidea - Buchta, Peter; Thimsen, Vivian; Iro, Ann-Kristin; Agaimy, Abbas; Iro, Heinrich; Mantsopoulos, Konstantinos (Laryngo-Rhino-Otologie, 2021)
Objective Aim of this study was to enlighten various aspects of the capsular defect of a pleomorphic adenoma and to analyze its influence on recurrence rate with the help of our data and the relevant literature. Material and Methods The clinical records and histopathological findings of all patients who underwent parotidectomy for pleomorphic adenoma between 2006 and 2020 were evaluated retrospectively. The histological slides of all tumours were critically re-evaluated for this study by an experienced head and neck pathologist. The records of the cases with a capsular defect were examined for information on age, gender, type of surgery and surgical outcome. Results A total of 845 patients were included in the primary group.7 (0.8%) recurrences were detected, all of these were resected without a capsular rupture. Positive margins were found in 37 cases (4.4%). In 13/37 cases the capsular defect was detected intraoperatively, whereas the defect was only identified histopathologically in 24 of the 37 cases. In the group of the intraoperative capsular opening, with a median follow-up of 62 months, the sonographic examination suspected a unilocular recurrence of the pleomorphic adenoma in two cases. Conclusion The intraoperative capsule opening does not inevitably seem to lead to a pre-programmed recurrence.
CRIS-Team Scopus Importer:2021-07-09
Keywords: capsule; capsule opening; parotid gland; pleomorphic adenoma; recurrence; recurrence rate

Der histopathologische „Abdruck“ des Paradigmenwechsels in der Behandlung des parotidealen pleomorphen Adenoms - Mant﻿so﻿pou﻿los, Kons﻿tan﻿ti﻿nos; Iro, Ann Kristin; Agaimy, Abbas; Iro, Heinrich (HNO, 2021)
CRIS-Team Scopus Importer:2021-07-02

Dermatofibrosarcoma protuberans: Surgical management of a challenging mesenchymal tumor - Wiesmüller, Felix; Agaimy, Abbas; Perrakis, Aristotelis; Arkudas, Andreas; Horch, Raymund E.; Grützmann, Robert; Vassos, Nikolaos (World Journal of Surgical Oncology, 2019)
Introduction: Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade malignant mesenchymal tumor of the soft tissue, characterized by slow infiltrative growth and common local recurrence, with rare distant metastases. Patients and methods: We present a retrospective study of nineteen patients who were diagnosed with DFSP and operated at our institution in > 10-year period. We examined the clinicopathological parameters with special emphasis on the margin status regarding the clinical outcome and the follow-up. Results: A total of eight cases underwent re-excision at our institution following primary excision or incisional biopsy performed at a different institution. Seven cases received excision after incisional biopsy at our institution. Four patients developed recurrent disease following primary excision with histological R0 margins at other institutions and received re-excision at our institution. All excisions at our institution resulted in R0 margins with no recurrence recorded at last follow-up (6 to 175; mean 84 months). The mean margin for those who received resection at our institution was 1.67 cm. Negative margins upon primary excision were achieved using a mean margin width of 2.04 cm. Most common tumor localization was the trunk (10 cases). Conclusion: Awareness of this rare entity is important for a prompt diagnosis and a proper management of the disease. The greatest clinical challenge in the management of DFSP is achieving local control. Complete excision of the tumor with surgical margin widths of at least 2 cm is recommended.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Cutaneous lesions; Dermatofibrosarcoma protuberans; DFSP; Mesenchymal tumor; Wallace rule of 9s

Description of the EuroTARGET cohort: A European collaborative project on TArgeted therapy in renal cell cancer-GEnetic- and tumor-related biomarkers for response and toxicity - Van Der Zanden, Loes F. M.; Vermeulen, Sita H.; Oskarsdottir, Arna; Maurits, Jake S. F.; Diekstra, Meta H. M.; Ambert, Valentin; Cambon-Thomsen, Anne; Castellano, Daniel; Fritsch, Achim; Garcia Donas, Jesus; Guarch Troyas, Rosa; Guchelaar, Henk-Jan; et al. (Urologic Oncology-Seminars and Original Investigations, 2017)
OBJECTIVE: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort. METHODS AND MATERIALS: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses. RESULTS: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy. CONCLUSIONS: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available.
EVALuna2:34249

Designing of spider silk proteins for human induced pluripotent stem cell-based cardiac tissue engineering - Esser, Tilman; Trossmann, Vanessa T.; Lentz, Sarah; Engel, Felix; Scheibel, T (Materials Today Bio, 2021)
Materials made of recombinant spider silk proteins are promising candidates for cardiac tissue engineering, and their suitability has so far been investigated utilizing primary rat cardiomyocytes. Herein, we expanded the tool box of available spider silk variants and demonstrated for the first time that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes attach, contract, and respond to pharmacological treatment using phenylephrine and verapamil on explicit spider silk films. The hiPSC-cardiomyocytes contracted for at least 14 days on films made of positively charged engineered Araneus diadematus fibroin 4 (eADF4(κ16)) and three different arginyl-glycyl-aspartic acid (RGD)-tagged spider silk variants (positively or negatively charged and uncharged). Notably, hiPSC-cardiomyocytes exhibited different morphologies depending on the spider silk variant used, with less spreading and being smaller on films made of eADF4(κ16) than on RGD-tagged spider silk films. These results indicate that spider silk engineering is a powerful tool to provide new materials suitable for hiPSC-based cardiac tissue engineering.
CRIS-Team Scopus Importer:2021-06-25

Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults - Thomas, Christian; Wefers, Annika; Bens, Susanne; Nemes, Karolina; Agaimy, Abbas; Oyen, Florian; Vogelgesang, Silke; Rodriguez, Fausto J.; Brett, Francesca M.; McLendon, Roger; Bodi, Istvan; Burel-Vandenbos, Fanny; et al. (Acta Neuropathologica, 2019)
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15–61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.
CRIS-Team Scopus Importer:2019-11-26

Detection of ESR1 Mutations in Single Circulating Tumor Cells on Estrogen Deprivation Therapy but Not in Primary Tumors from Metastatic Luminal Breast Cancer Patients - Franken, André; Honisch, Ellen; Reinhardt, Florian; Meier-Stiegen, Franziska; Yang, Liwen; Jaschinski, Sandra; Esposito, Irene; Alberter, Barbara; Polzer, Bernhard; Hübner, Hanna; Fasching, Peter; Pancholi, Sunil; et al. (Journal of Molecular Diagnostics, 2020)
Mutations in the ligand-binding domain (LBD) of the ESR1 gene result in resistance to estrogen deprivation therapy (EDT) in breast cancer. Their detection might enable optimization of therapy strategies. However, the predictive utility of the primary tumor (PT) is limited, and obtaining serial biopsies of metastatic lesions is challenging. To underline their application as a liquid biopsy, single circulating tumor cells (CTCs) were analyzed with a next-generation sequencing approach for the ESR1 coding region. CTCs from 46 metastatic luminal breast cancer patients were enriched using CellSearch system and isolated by micromanipulation. Their genomic DNA was amplified and the ESR1 gene was sequenced. Furthermore, tissue samples from corresponding PTs and/or metastatic lesions were investigated. ESR1 mutations were detected in 12 patients—exclusively in patients treated with EDT (P = 0.048). In seven cases mutations were located in the hotspot regions in the LBD. Six novel mutations were identified. ESR1 mutations were absent in PT tissue samples and were detected only in metastases obtained after CTC characterization. Single-cell CTC analysis for ESR1 mutations could be of clinical value to identify patients who progress under EDT and therefore benefit from an early switch to an alternative endocrine therapy or other treatment regimens. Furthermore, our data indicate that mutations outside the LBD's hotspot regions might also contribute to resistance to EDT.
CRIS-Team Scopus Importer:2019-12-20

Detection of expressional changes induced by intrauterine growth restriction in the developing rat mammary gland via exploratory pathways analysis - Beinder, Lea; Fährmann, Nina; Wachtveitl, Rainer; Winterfeld, Ilona; Hartner, Andrea; Menendez-Castro, Carlos; Rauh, Manfred; Ruebner, Matthias; Hübner, Hanna; Nögel, Stephanie; Dörr, Helmuth-Günther; Rascher, Wolfgang; et al. (PLoS ONE, 2014)
Intrauterine growth restriction (IUGR) is thought to lead to fetal programming that in turn contributes to developmental changes of many organs postnatally. There is evidence that IUGR is a risk factor for the development of metabolic and cardiovascular disease later in life. A higher incidence of breast cancer was also observed after IUGR. This could be due to changes in mammary gland developmental pathways. We sought to characterise IUGR-induced alterations of the complex pathways of mammary development at the level of the transcriptome in a rat model of IUGR, using pathways analysis bioinformatics.We analysed the mammary glands of Wistar rats with IUGR induced by maternal low protein (LP) diet at the beginning (d21) and the end (d28) of pubertal ductal morphogenesis. Mammary glands of the LP group were smaller in size at d28, however did not show morphologic changes. We identified multiple differentially expressed genes in the mammary gland using Agilent SurePrint arrays at d21 and d28. In silico analysis was carried out using Ingenuity Pathways Analysis. In mammary gland tissue of LP rats at d21 of life a prominent upregulation of WT1 and CDKN1A (p21) expression was observed. Differentially regulated genes were associated with the extracellular regulated kinase (ERK)-1/-2 pathway. Western Blot analysis showed reduced levels of phosphorylated ERK-1/-2 in the mammary glands of the LP group at d21. To identify possible changes in circulating steroid levels, serum LC-Tandem mass-spectrometry was performed. LP rats showed higher serum progesterone levels and an increased corticosterone/dehydrocorticosterone-ratio at d28.Our data obtained from gene array analysis support the hypothesis that IUGR influences pubertal development of the rat mammary gland. We identified prominent differential regulation of genes and pathways for factors regulating cell cycle and growth. Moreover, we detected new pathways which appear to be programmed by IUGR.
EVALuna2:17429

Detection of Fusobacterium nucleatum in Patients with Colitis-Associated Colorectal Cancer - Dregelies, Theresa; Haumaier, Franziska; Sterlacci, William; Backert, Steffen; Vieth, Michael (Current Microbiology, 2023)
Fusobacterium nucleatum is supposed to play a critical role in the development of colorectal cancer. The species has also been associated with ulcerative colitis (UC) that can progress into colorectal cancer, however, the involvement of bacteria in this process remains unclear. We analysed 177 colon biopsies obtained from patients during screening, including 20 healthy controls, 56 UC cases and 69 cases at different stages of progression to colitis-associated cancer (CAC); 32 samples of sporadic colorectal carcinoma (sCRC) were also included. The presence of F. nucleatum was detected by quantitative real-time PCR (qPCR). Our data show an association between the presence of the bacteria and the progression of carcinogenesis in UC patients. In 39.5% of CAC samples F. nucleatum was detected, compared to only 1.8% in UC cases. The bacteria were detected in 6.3% of samples with initial neoplastic transformation, so-called low-grade dysplasia (LGD), whereas high-grade dysplasia (HGD) resulted in 33.3% of samples positive for F. nucleatum. The fraction of F. nucleatum-positive samples from sCRC cases was 56.3%, which was not significantly different to the CAC group. We conclude that F. nucleatum is associated with the occurrence and progression of colon carcinogenesis, rather than with UC itself.
CRIS-Team Scopus Importer:2023-08-11

Detection of gene fusions using targeted next-generation sequencing: a comparative evaluation - Heydt, Carina; Wölwer, Christina B.; Velazquez Camacho, Oscar; Wagener-Ryczek, Svenja; Pappesch, Roberto; Siemanowski, Janna; Rehker, Jan; Haller, Florian; Agaimy, Abbas; Worm, Karl; Herold, Thomas; Pfarr, Nicole; et al. (Bmc Medical Genomics, 2021)
Background: Gene fusions represent promising targets for cancer therapy in lung cancer. Reliable detection of multiple gene fusions is therefore essential. Methods: Five commercially available parallel sequencing assays were evaluated for their ability to detect gene fusions in eight cell lines and 18 FFPE tissue samples carrying a variety of known gene fusions. Four RNA-based assays and one DNA-based assay were compared; two were hybrid capture-based, TruSight Tumor 170 Assay (Illumina) and SureSelect XT HS Custom Panel (Agilent), and three were amplicon-based, Archer FusionPlex Lung Panel (ArcherDX), QIAseq RNAscan Custom Panel (Qiagen) and Oncomine Focus Assay (Thermo Fisher Scientific). Results: The Illumina assay detected all tested fusions and showed the smallest number of false positive results. Both, the ArcherDX and Qiagen panels missed only one fusion event. Among the RNA-based assays, the Qiagen panel had the highest number of false positive events. The Oncomine Focus Assay (Thermo Fisher Scientific) was the least adequate assay for our purposes, seven fusions were not covered by the assay and two fusions were classified as uncertain. The DNA-based SureSelect XT HS Custom Panel (Agilent) missed three fusions and nine fusions were only called by one software version. Additionally, many false positive fusions were observed. Conclusions: In summary, especially RNA-based parallel sequencing approaches are potent tools for reliable detection of targetable gene fusions in clinical diagnostics.
CRIS-Team Scopus Importer:2021-03-19
Keywords: DNA-Seq; FISH; Gene fusion; NGS; RNA-seq

Detection of microcalcifications in spiral breast computed tomography with photon-counting detector is feasible: A specimen study - Wetzl, Matthias; Wenkel, Evelyn; Balbach, Eva; Dethlefsen, Ebba; Hartmann, Arndt; Emons, Julius; Kuhl, Christiane; Beckmann, Matthias; Uder, Michael; Ohlmeyer, Sabine (Diagnostics, 2021)
The primary objective of the study was to compare a spiral breast computed tomography system (SBCT) to digital breast tomosynthesis (DBT) for the detection of microcalcifications (MCs) in breast specimens. The secondary objective was to compare various reconstruction modes in SBCT. In total, 54 breast biopsy specimens were examined with mammography as a standard reference, with DBT, and with a dedicated SBCT containing a photon-counting detector. Three different reconstruction modes were applied for SBCT datasets (Recon1 = voxel size (0.15 mm)3, smooth kernel; Recon2 = voxel size (0.05 mm)3, smooth kernel; Recon3 = voxel size (0.05 mm)3, sharp kernel). Sensitivity and specificity of DBT and SBCT for the detection of suspicious MCs were analyzed, and the McNemar test was used for comparisons. Diagnostic confidence of the two readers (Likert Scale 1 = not confident; 5 = completely confident) was analyzed with ANOVA. Regarding detection of MCs, reader 1 had a higher sensitivity for DBT (94.3%) and Recon2 (94.9%) compared to Recon1 (88.5%; p < 0.05), while sensitivity for Recon3 was 92.4%. Respectively, reader 2 had a higher sensitivity for DBT (93.0%), Recon2 (92.4%), and Recon3 (93.0%) compared to Recon1 (86.0%; p < 0.05). Specificities ranged from 84.7–94.9% for both readers (p > 0.05). The diagnostic confidence of reader 1 was better with SBCT than with DBT (DBT 4.48 ± 0.88, Recon1 4.77 ± 0.66, Recon2 4.89 ± 0.44, and Recon3 4.75 ± 0.72; DBT vs. Recon1/2/3: p < 0.05), while reader 2 found no differences. Sensitivity and specificity for the detection of MCs in breast specimens is equal for DBT and SBCT when a small voxel size of (0.05 mm)3 is used with an equal or better diagnostic confidence for SBCT compared to DBT.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Breast cancer; Microcalcifications; Reconstruction modes; Spiral breast CT

Determinants Affecting the Clinical Implementation of a Molecularly Informed Molecular Tumor Board Recommendation: Experience from a Tertiary Cancer Center. - Tögel, Lars; Schubart, Christoph; Lettmaier, Sebastian; Neufert, Clemens; Hoyer, Juliane; Wolff, Kerstin; Moskalev, Evgeny; Stöhr, Robert; Agaimy, Abbas; Wiesmann da Silva Reis, André; Wullich, Bernd; Mackensen, Andreas; et al. (Cancers, 2023)
Molecular Tumor Boards (MTBs) converge state-of-the-art next-generation sequencing (NGS) methods with the expertise of an interdisciplinary team consisting of clinicians, pathologists, human geneticists, and molecular biologists to provide molecularly informed guidance in clinical decision making to the treating physician. In the present study, we particularly focused on elucidating the factors impacting on the clinical translation of MTB recommendations, utilizing data generated from gene panel mediated comprehensive genomic profiling (CGP) of 554 patients at the MTB of the Comprehensive Cancer Center Erlangen, Germany, during the years 2016 to 2020. A subgroup analysis of cases with available follow-up data (n = 332) revealed 139 cases with a molecularly informed MTB recommendation, which was successfully implemented in the clinic in 44 (31.7%) of these cases. Here, the molecularly matched treatment was applied in 45.4% (n = 20/44) of cases for ≥6 months and in 25% (n = 11/44) of cases for 12 months or longer (median time to treatment failure, TTF: 5 months, min: 1 month, max: 38 months, ongoing at data cut-off). In general, recommendations were preferentially implemented in the clinic when of high (i.e., tier 1) clinical evidence level. In particular, this was the case for MTB recommendations suggesting the application of PARP, PIK3CA, and IDH1/2 inhibitors. The main reason for non-compliance to the MTB recommendation was either the application of non-matched treatment modalities (n = 30)/stable disease (n = 7), or deteriorating patient condition (n = 22)/death of patient (n = 9). In summary, this study provides an insight into the factors affecting the clinical implementation of molecularly informed MTB recommendations, and careful considerations of these factors may guide future processes of clinical decision making.
EVALuna2:545872
Keywords: Molecular Tumor Board; clinical decision making; precision medicine; molecular pathology; real-world data; cancer care

Detyrosinated tubulin is decreased in fetal vessels of preeclampsia placentas - Huebner, H.; Knoerr, B.; Betzler, A.; Kehl, Sven; Baier, F.; Wachter, David Lukas; Strick, Reiner; Beckmann, Matthias; Fahlbusch, F. B.; Rübner, Matthias; Hartner, Andrea (Placenta, 2018)
INTRODUCTION: Preeclampsia is a hypertensive, gestational disease, which is still the leading cause of pregnancy related morbidity and mortality. The impairment of placental angiogenesis and vascularization is discussed to be of etiopathologic relevance. Deytrosination and tyrosination of α-tubulin is important for the stability and dynamics of microtubules. An increase of α-tubulin detyrosination leads to microtubule stabilization, which is an essential prerequisite for physiologic vascular tube morphogenesis during angiogenesis. So far, little is known about the specific localization of detyrosinated (detyr) and tyrosinated (tyr) tubulin in the placenta and its relevance for preeclampsia. METHODS: Placental expression of detyr- and tyr-tubulin was analyzed by immunohistochemistry, immunofluorescence and western blot. For western blot quantification we used biopsies from healthy placentas (n = 21) and placentas from pregnancies complicated with small for gestational age (n = 5), preeclampsia (n = 5) or both (n = 5). RESULTS: Specific placental localization of detyr-tubulin was detected in the fetal endothelial cells of the placenta. Villous and extravillous trophoblasts as well as villous stroma cells were tyr-tubulin positive. Detyr-tubulin protein expression was significantly decreased in placentas complicated by preeclampsia. CONCLUSIONS: In summary, we report an accumulation of detyr-tubulin in villous vessels of the placenta and a significantly reduced level of detyr-tubulin in placental biopsies of preeclampsia cases. The reduction of placental detyr-tubulin in preeclampsia could suggest a deficit in villous vascular plasticity and might be associated with the impaired arborization of the disease.
EVALuna2:34296

Developing Classifications of Laryngeal Dysplasia: The Historical Basis - Hellquist, Henrik; Ferlito, Alfio; Makitie, Antti A.; Thompson, Lester D. R.; Bishop, Justin A.; Agaimy, Abbas; Hernandez-Prera, Juan C.; Gnepp, Douglas R.; Willems, Stefan M.; Slootweg, Pieter J.; Rinaldo, Alessandra (Advances in Therapy, 2020)
During the last 60 years numerous significant attempts have been made to achieve a widely acceptable terminology and histological grading for laryngeal squamous intraepithelial lesions. While dysplasia was included in the pathology of the uterine cervix already in 1953, the term dysplasia was accepted in laryngeal pathology first after the Toronto Centennial Conference on Laryngeal Cancer in 1974. In 1963 Kleinsasser proposed a three-tier classification, and in 1971 Kambic and Lenart proposed a four-tier classification. Since then, four editions of the World Health Organisation (WHO) classification have been proposed (1978, 1991, 2005 and 2017). Several terms such as squamous intraepithelial neoplasia (SIN) and laryngeal intraepithelial neoplasia (LIN) are now being abandoned and replaced by squamous intraepithelial lesions (SIL). The essential change between the 2005 and 2017 WHO classifications is the attempt to induce a simplification from a four- to a two-tier system. The current WHO classification (2017) thus recommends the use of a two-tier system with reasonably clear histopathological criteria for the two groups: low-grade and high-grade dysplasia. Problems with interobserver variability apart, subjectivities and uncertainties remain, but to a lesser degree. Ongoing and additional molecular studies may help to clarify underlying events that will increase our understanding and possibly can facilitate our attempts to obtain an even better classification. The classification needs to be easier for the general pathologist to perform and easier for the clinician to interpret. These two objectives are equally important to provide each patient the best personalised treatment available for squamous intraepithelial lesions.
CRIS-Team Scopus Importer:2020-05-12
Keywords: Laryngeal dysplasia; Laryngeal precancerous lesions; Laryngeal precursor lesions; WHO classification

Development and assessment of single-cell image classification systems for haematological cytomorphology using convolutional neural networks - Matek, Christian (VIRCHOWS ARCHIV, 2022)
CRIS-Team WoS Importer:2022-09-16

Development and Evaluation of a Semi-automated Segmentation Tool and a Modified Ellipsoid Formula for Volumetric Analysis of the Kidney in Non-contrast T2-Weighted MR Images - Seuß, Hannes; Janka, Rolf Matthias; Pruemmer, Marcus; Hammon, Rebecca; Theis, Ragnar; Sandmair, Martin; Amann, Kerstin Ute; Bäuerle, Tobias; Uder, Michael; Hammon, Matthias; Cavallaro, Alexander Josef (Journal of Digital Imaging, 2017)
Volumetric analysis of the kidney parenchyma provides additional information for the detection and monitoring of various renal diseases. Therefore the purposes of the study were to develop and evaluate a semi-automated segmentation tool and a modified ellipsoid formula for volumetric analysis of the kidney in non-contrast T2-weighted magnetic resonance (MR)-images. Three readers performed semi-automated segmentation of the total kidney volume (TKV) in axial, non-contrast-enhanced T2-weighted MR-images of 24 healthy volunteers (48 kidneys) twice. A semi-automated threshold-based segmentation tool was developed to segment the kidney parenchyma. Furthermore, the three readers measured renal dimensions (length, width, depth) and applied different formulas to calculate the TKV. Manual segmentation served as a reference volume. Volumes of the different methods were compared and time required was recorded. There was no significant difference between the semi-automatically and manually segmented TKV (p = 0.31). The difference in mean volumes was 0.3 ml (95% confidence interval (CI), -10.1 to 10.7 ml). Semi-automated segmentation was significantly faster than manual segmentation, with a mean difference = 188 s (220 vs. 408 s); p < 0.05. Volumes did not differ significantly comparing the results of different readers. Calculation of TKV with a modified ellipsoid formula (ellipsoid volume × 0.85) did not differ significantly from the reference volume; however, the mean error was three times higher (difference of mean volumes -0.1 ml; CI -31.1 to 30.9 ml; p = 0.95). Applying the modified ellipsoid formula was the fastest way to get an estimation of the renal volume (41 s). Semi-automated segmentation and volumetric analysis of the kidney in native T2-weighted MR data delivers accurate and reproducible results and was significantly faster than manual segmentation. Applying a modified ellipsoid formula quickly provides an accurate kidney volume.
EVALuna2:14622

Development and validation of a classification and scoring system for the diagnosis of oral squamous cell carcinomas through confocal laser endomicroscopy - Oetter, Nicolai; Knipfer, Christian; Rohde, Maximilian; von Wilmowsky, Cornelius; Maier, Andreas; Brunner, Kathrin; Adler, Werner; Neukam, Friedrich Wilhelm; Neumann, Helmut; Stelzle, Florian (Journal of Translational Medicine, 2016)
Confocal laser endomicroscopy (CLE) is an optical biopsy method allowing in vivo microscopic imaging at 1000-fold magnification. It was the aim to evaluate CLE in the human oral cavity for the differentiation of physiological/carcinomatous mucosa and to establish and validate, for the first time, a scoring system to facilitate CLE assessment.The study consisted of 4 phases: (1) CLE-imaging (in vivo) was performed after the intravenous injection of fluorescein in patients with histologically confirmed carcinomatous oral mucosa; (2) CLE-experts (n = 3) verified the applicability of CLE in the oral cavity for the differentiation between physiological and cancerous tissue compared to the gold standard of histopathological assessment; (3) based on specific patterns of tissue changes, CLE-experts (n = 3) developed a classification and scoring system (DOC-Score) to simplify the diagnosis of oral squamous cell carcinomas; (4) validation of the newly developed DOC-Score by non-CLE-experts (n = 3); final statistical evaluation of their classification performance (comparison to the results of CLE-experts and the histopathological analyses).Experts acquired and edited 45 sequences (260 s) of physiological and 50 sequences (518 s) of carcinomatous mucosa (total: 95 sequences/778 s). All sequences were evaluated independently by experts and non-experts (based on the newly proposed classification system). Sensitivity (0.953) and specificity (0.889) of the diagnoses by experts as well as sensitivity (0.973) and specificity (0.881) of the non-expert ratings correlated well with the results of the present gold standard of tissue histopathology. Experts had a positive predictive value (PPV) of 0.905 and a negative predictive value (NPV) of 0.945. Non-experts reached a PPV of 0.901 and a NPV of 0.967 with the help of the DOC-Score. Inter-rater reliability (Fleiss` kappa) was 0.73 for experts and 0.814 for non-experts. The intra-rater reliability (Cronbach's alpha) of the experts was 0.989 and 0.884 for non-experts.CLE is a suitable and valid method for experts to diagnose oral cancer. Using the DOC-Score system, an accurate chair-side diagnosis of oral cancer is feasible with comparable results to the gold standard of histopathology-even in daily clinical practice for non-experienced raters.
EVALuna2:2055

Development and Validation of a Confocal Laser Endomicroscopy-Based Score for In Vivo Assessment of Mucosal Healing in Ulcerative Colitis Patients - Hundorfean, Gheorghe; Chiriac, Mircea T.; Mihai, Sidonia; Hartmann, Arndt; Mudter, Jonas; Neurath, Markus (Inflammatory Bowel Diseases, 2017)
Background: Endoscopic monitoring is fundamental for evaluating the therapeutic response in IBD, but a validated endomicroscopic mucosal healing (MH) score is not available to date. However, confocal laser endomicroscopy (CLE) might define MH more precisely than conventional endoscopy. The major aim was to establish and validate an MH score for ulcerative colitis (UC), based on CLE. Methods: In an initial pilot study (n = 10), various CLE changes were analyzed for identification of reproducible criteria for establishing a CLE score. Four reproducible CLE criteria were implemented in a following validation study. Subsequently, active UC patients (n = 23, Mayo score ≥6) were prospectively included and underwent colonoscopy with CLE before and after 3 anti-TNF applications. Patients were clinically followed over a period of 3 years. The endomicroscopic MH score (eMHs; range, 0-4) was compared with histopathology and endoscopy scores from the same colonic location. Results: The eMHs showed high sensitivity, specificity, and accuracy values (100% with 95% confidence interval [CI] of 15.81%-100%; 93.75% with 95% CI of 69.77%-99.84%, and 94.44%, respectively). The eMHs showed a good correlation with the histological Gupta score (rs = 0.82, P < 0.0001) and the endoscopic Mayo subscore (rs = 0.81%, P < 0.0001). Sixty percent of therapy responders presented an eMHs <1, which translated into long-lasting clinical remission and reduced hospitalization, steroid, and surgery need. Conclusions: CLE can accurately assess MH based on the newly developed and statistically validated eMHs in UC, and it is superior in predicting the long-lasting clinical outcome based on both descriptive and functional barrier imaging (NCT01417728).
EVALuna2:33794

Development of a flow cytometry-based whole-blood prognostic immune signature in metastatic cancer patients treated with immune checkpoint inhibitors - Zhou, Jianguo; Donaubauer, Anna-Jasmina; Frey, Benjamin; Becker, Ina; Rutzner, Sandra; Eckstein, Markus; Sun, R.; Ma, H.; Schubert, Philipp; Schweizer, C.; Fietkau, Rainer; Deutsch, E.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Development of a novel immunocompetent murine tumor model for urothelial carcinoma using in vivo electroporation - Soleder, Stefan; Gengenbacher, Nicolas; Mogler, Carolin; Eckstein, Markus; Runge, Anja; Kriegmair, Maximilian C.; Augustin, Hellmut G. (Scientific Reports, 2024)
A lack of advanced preclinical mouse tumor models impedes the progress in urothelial carcinoma research. We present here a novel fast, robust, reliable, and highly reproducible model for the genetic induction of bladder cancer in immunocompetent mice. Different sets of oncogenic transposons (Cmyc, Kras) and Cre drivers were transfected into the murine bladder wall of two different genetic backgrounds (Trp53fl/fl and BrafV600E, Ptenfl/fl, Ctnnb1exon3-fl/fl). Transfection was carried out using in vivo electroporation of the bladder after surgical exploration and transmural or transurethral intravesical plasmid injection. Up to 100% of animals developed urothelial carcinomas of the bladder. Time to tumor onset ranged from 16 to 97 days with a median of approximately 23 days in the fastest groups. Histological examination identified orthotopic urothelial carcinomas in most cases, in some experimental groups up to 100%. The resulting tumors were highly invasive and often metastatic. Metastases were found in up to 100% of tumor bearing mice per group. Taken together, this study establishes the proof-of-principle that in vivo electroporation can be versatilely employed as a reliable, fast, and robust method for the highly reproducible induction of urothelial carcinomas in the murine bladder wall. This novel murine tumor model could pave the way towards more easily modelling subtype specific urothelial carcinomas in mice.
CRIS-Team Scopus Importer:2024-11-08

DEVELOPMENT OF APPROACHES FOR A TWO-LAYER PATCH COMBINING ELECTROSPINNING AND 3D PRINTING WITH IMPROVED ELECTRICAL STIMULUS TRANSMISSION AND SELF-REGULATING VISCOELASTIC PROPERTIES FOR APPLICATION IN CARDIAC TISSUE ENGINEERING - Boccaccini, Aldo R.; Vogt, Lena; Ruther, Florian; Roshanbinfar, Kaveh; Engel, Felix (TISSUE ENGINEERING PART A, 2022)
CRIS-Team WoS Importer:2022-08-12

Development of head and neck pathology in Europe - Hellquist, Henrik; Agaimy, Abbas; Stenman, Goran; Franchi, Alessandro; Nadal, Alfons; Skalova, Alena; Leivo, Ilmo; Zidar, Nina; Simpson, Roderick H. W.; Slootweg, Pieter J.; Hernandez-Prera, Juan C.; Ferlito, Alfio (Virchows Archiv, 2022)
This review gives a brief history of the development of head and neck pathology in Europe from a humble beginning in the 1930s to the explosive activities the last 15 years. During the decades before the introduction of immunohistochemistry in the 1980s, head and neck pathology grew as a subspeciality in many European countries. In the late 1940s, the Institute of Laryngology and Otology with its own pathology laboratory was founded in London, and in 1964 the World Health Organization (WHO) International Reference Centre for the Histological Classification of Salivary Tumours was established at the Bland-Sutton Institute of Pathology, also in London. International collaboration, and very much so in Europe, led to the publication of the first WHO Classification of Salivary Gland Tumours in 1972. In the 1960s, a salivary gland register was organised in Hamburg and in Cologne the microlaryngoscopy was invented enabling microscopic endoscopic examination and rather shortly afterwards a carbon dioxide laser attached to the microscope became established and laryngeal lesions could be treated by laser vaporisation. During the last three decades, the use of immunohistochemistry supplemented with cytogenetic and refined molecular techniques has greatly facilitated the pathological diagnostics of head and neck lesions and has had a huge impact on research. Collaboration between different European centres has drastically increased partly due to establishment of scientific societies such as the Head and Neck Working Group (HNWG) within the European Society of Pathology and the International Head and Neck Scientific Group (IHNSG). A very large number of European pathologists have contributed to the 2nd, 3rd and 4th WHO books, and are involved in the upcoming 5th edition. Accredited educational meetings and courses are nowadays regularly arranged in Europe. Numerous textbooks on head and neck pathology have been written and edited by European pathologists. The increased collaboration has created larger series of tumours for research and new entities, mainly defined by their genetic abnormalities, are continuously emerging from Europe, particularly regarding salivary gland neoplasms and "undifferentiated" sinonasal tumours. These findings have led to a better and more precise classification and open the possibilities for new treatment strategies.
CRIS-Team WoS Importer:2022-01-21

Diabetes and prognosis in a breast cancer cohort - Schrauder, Michael; Fasching, Peter A.; Häberle, Lothar; Lux, Michael P.; Rauh, Claudia; Hein, Alexander; Bayer, Christian M.; Heusinger, Katharina; Hartmann, Arndt; Strehl, Johanna D.; Wachter, David; Schulz-Wendtland, Rüdiger; et al. (Journal of Cancer Research and Clinical Oncology, 2011)
Purpose: Epidemiological studies indicated that type 2 diabetes mellitus may increase breast cancer risk and mortality. The aim of this retrospective cohort study was to examine the effect of diabetes on the clinical course and the prognosis of early stage breast cancer in relation to tumour and patient characteristics. Methods: The cohort analyzed in this study consisted of 4,056 patients with invasive primary breast cancer. We compared overall survival, distant metastasis-free survival and local recurrence free survival between breast cancer patients with and without diabetes. Results: In our cohort 276 breast cancer patients (6.8%) were affected by diabetes compared to 3,780 patients (93.2%) without diabetes. Women with diabetes were significantly older, had larger tumours, and a higher rate of lymph node involvement. After a follow-up period of 5 years, stratification for age and adjustment for other prognostic factors, overall mortality following breast cancer was significantly higher in diabetic breast cancer patients (hazard ratio, HR 1.92; 95% confidence interval, CI 1.49-2.48). We found no significant differences in distant metastasis-free survival and local recurrence free survival between the two groups, but we found a slightly significant higher rate of distant metastasis in the group of patients with diabetes and oestrogen receptor negative tumours (HR 2.28; CI 1.31-3.97). Conclusion: In this study, patients with diabetes and oestrogen receptor negative breast cancer had a more than 2-fold higher risk for distant metastasis compared to patients without diabetes. Diabetes was also associated with an almost 2-fold increase in mortality within the 5 years follow-up period. © 2010 Springer-Verlag.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Breast cancer; Cohort study; Diabetes mellitus; Distant metastasis; Local recurrence; Survival

Diabetes mellitus negatively affects peri-implant bone formation in the diabetic domestic pig - von Wilmowsky, Cornelius; Stockmann, Philipp; Harsch, Igor; Amann, Kerstin Ute; Metzler, Philipp; Lutz, Rainer; Möst, Tobias; Neukam, Friedrich Wilhelm; Schlegel, Karl Andreas (Journal of Clinical Periodontology, 2011)
Aim: Diabetes mellitus is classified as a relative contraindication for implant treatment, and higher failure rates have been seen in diabetic patients. The aim of the present study was to investigate the effect of diabetes on peri-implant bone formation in an animal model of human bone repair. Materials and Methods: Diabetes was induced by an intra-venous application of streptozotocin (90 mg/kg) in 15 domestic pigs. Implants were placed after significant histopathological changes in the hard and soft tissues were verified. The bone-implant contact (BIC), peri-implant bone mineral density (BMD), and expression of collagen type-I and osteocalcin proteins were qualitatively evaluated 4 and 12 weeks after implantation. Fifteen animals served as healthy controls. Results: Diabetes caused pathological changes in the soft and hard tissues. The BIC and BMD were significantly reduced in the diabetic group after 4 and 12 weeks. Collagen type-I was increased in the diabetic group at both time points, whereas osteocalcin was reduced in the diabetic group. Conclusions: Poorly controlled diabetes negatively affects peri-implant bone formation and bone mineralization. These findings have to be taken into consideration for diabetic patients with an indication for implant therapy. © 2011 John Wiley & Sons A/S.
CRIS-Team Scopus Importer:2024-05-13
Keywords: bone; diabetes; implants; osseointegration; pig

Diagnosis of malignancy in oropharyngeal confocal laser endomicroscopy using GPT 4.0 with vision - Sievert, Matti; Aubreville, Marc; Müller, Sarina Katrin; Eckstein, Markus; Breininger, Katharina; Iro, Heinrich; Goncalves, Miguel (European Archives of Oto-Rhino-Laryngology, 2024)
Purpose: Confocal Laser Endomicroscopy (CLE) is an imaging tool, that has demonstrated potential for intraoperative, real-time, non-invasive, microscopical assessment of surgical margins of oropharyngeal squamous cell carcinoma (OPSCC). However, interpreting CLE images remains challenging. This study investigates the application of OpenAI’s Generative Pretrained Transformer (GPT) 4.0 with Vision capabilities for automated classification of CLE images in OPSCC. Methods: CLE Images of histological confirmed SCC or healthy mucosa from a database of 12 809 CLE images from 5 patients with OPSCC were retrieved and anonymized. Using a training data set of 16 images, a validation set of 139 images, comprising SCC (83 images, 59.7%) and healthy normal mucosa (56 images, 40.3%) was classified using the application programming interface (API) of GPT4.0. The same set of images was also classified by CLE experts (two surgeons and one pathologist), who were blinded to the histology. Diagnostic metrics, the reliability of GPT and inter-rater reliability were assessed. Results: Overall accuracy of the GPT model was 71.2%, the intra-rater agreement was κ = 0.837, indicating an almost perfect agreement across the three runs of GPT-generated results. Human experts achieved an accuracy of 88.5% with a substantial level of agreement (κ = 0.773). Conclusions: Though limited to a specific clinical framework, patient and image set, this study sheds light on some previously unexplored diagnostic capabilities of large language models using few-shot prompting. It suggests the model`s ability to extrapolate information and classify CLE images with minimal example data. Whether future versions of the model can achieve clinically relevant diagnostic accuracy, especially in uncurated data sets, remains to be investigated.
CRIS-Team Scopus Importer:2024-02-23
Keywords: Confocal laser endomicroscopy; GPT; Head and neck malignancies; Oropharyngeal squamous cell carcinoma

Diagnostic accuracy of contrast-enhanced computed tomography in assessing bone invasion in patients with oral squamous cell carcinoma - Struckmeier, Ann-Kristin; Buchbender, Mayte; Agaimy, Abbas; Kesting, Marco Rainer (Clinical Oral Investigations, 2024)
Objectives: This study aimed to evaluate the diagnostic accuracy of contrast-enhanced computed tomography (CT) in detecting bone invasion in oral squamous cell carcinoma (OSCC) patients and to explore clinicopathological factors associated with its reliability. Materials and methods: 417 patients underwent preoperative contrast-enhanced CT followed by radical surgery. The presence or absence of bone invasion served as the outcome variable, with histopathologic examination of the resection specimen considered the gold standard. Statistical analyses, comprising correlation analyses and the determination of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were conducted. Results: CT exhibited 76.85% sensitivity, 82.20% specificity, 47.14% PPV, and 89.67% NPV. False-positive and false-negative rates were 11.27% and 5.99%, respectively. Artifacts affected assessment in 44 patients, but not in those with bone invasion. Tumor size, depth of invasion (DOI), tumor localization at the upper jaw, lymphatic invasion, and perineural invasion correlated with incorrect identification of bone invasion (Chi-square, p < 0.05). Conclusions: Despite utilizing thin-section CT, notable false-positive and false-negative results persisted. Patients with T3 tumors, DOI ≥ 10 mm, or upper jaw tumors are at higher risk for misidentification of bone invasion. Combining multiple methods may enhance diagnostic accuracy, and the integration of artificial intelligence or tracking electrolyte disturbances by tumor depth profiling shows promise for further assessment of bone invasion before histopathology. Clinical relevance: Surgeons should consider these insights when planning tumor resection. Supplementary imaging may be warranted in cases with high risk factors for misidentification. Further methodological advancements are crucial for enhancing diagnostic precision.
CRIS-Team Scopus Importer:2024-05-24
Keywords: Bone invasion; Computed tomography; Diagnostic accuracy; Oral squamous cell carcinoma

Diagnostic accuracy of contrast-enhanced computed tomography in assessing cervical lymph node status in patients with oral squamous cell carcinoma - Struckmeier, Ann-Kristin; Yekta, Ebrahim; Agaimy, Abbas; Kopp, Markus; Buchbender, Mayte; Möst, Tobias; Lutz, Rainer; Kesting, Marco Rainer (Journal of Cancer Research and Clinical Oncology, 2023)
Objective: Accurate preoperative prediction of lymph node (LN) status plays a pivotal role in determining the extension of neck dissection (ND) required for patients with oral squamous cell carcinoma (OSCC). This study aims to evaluate the diagnostic accuracy of contrast-enhanced computed tomography (CT) in detecting LN metastases (LNMs) and to explore clinicopathological factors associated with its reliability. Methods: Data from 239 patients with primary OSCC who underwent preoperative CT and subsequent radical surgery involving ND were retrospectively reviewed. Suspicious LNs were categorized into three groups: accentuated (< 10 mm), enlarged (≥ 10 mm), and melted. Statistical analysis encompassing correlation and comparative analysis, and determination of sensitivity, specificity, PPV, and NPV were performed. Results: Overall, sensitivity was significantly higher in the accentuated LNs group (83.54%) compared to the melted LNs group (39.24%, p < 0.05, t test). Conversely, specificity was significantly higher in the melted LNs group (98.19%) compared to the accentuated LNs group (55.15%, p < 0.05, t test). Accentuated LNs exhibited a false negative rate of 13.00%. False positive rates were 51.80%, 30.26% and 8.82%, respectively. Diagnostic accuracy for detecting LNMs in level IIa and IIb exceeded that of level III. Patients with solely accentuated LNs were more likely to have a small, well-differentiated tumor. However, no distinctions emerged in terms of the occurrence of T4 tumors among the three groups. Conclusion: CT proves sufficient to predict LNMs in patients with OSCC. Looking ahead, the potential integration of artificial intelligence and deep learning holds promise to further enhance the reliability of CT in LNMs detection. However, this prospect necessitates further investigation.
CRIS-Team Scopus Importer:2023-11-03
Keywords: Computed tomography; Diagnostic accuracy; Lymph node metastasis; Oral squamous cell carcinoma

Diagnostic and predictive molecular pathology of head and neck neoplasms - Agaimy, Abbas; Weichert, W.; Haller, F.; Hartmann, Arndt (Pathologe, 2018)
As a result of some seminal observations as well as a consequence of increasing use of modern and innovative molecular diagnostic technologies, a variety of new genetic aberrations have been discovered in head and neck neoplasms of different anatomic locations and histogenetic origins. These advances resulted in the establishment of new molecularly defined disease entities. On the other hand, some of these new genetic biomarkers paved the way to potentially promising novel therapeutic opportunities. Diverse old (well known in other entities) and newly discovered translocations and gene fusions represent the leading subgroup of these genetic aberrations. They have been detected not only in malignant epithelial neoplasms (carcinomas) of the salivary glands, but also in carcinomas from other head and neck sites as well as diverse mesenchymal tumors. In addition to these gene fusions, several activating mutations (such as CTNNB1 in sinonasal glomangiopericytoma) as well as inactivating mutations or deletions (like SMARCB1 loss in sinonasal carcinomas) were detected as new molecular markers. In the present review we summarize the relevant molecular alterations in topographically and histopathologically distinct tumors of the head and neck region with emphasis on recently established molecular markers.
EVALuna2:34103

Diagnostic and Prognostic Implications of FGFR3high/Ki67high Papillary Bladder Cancers - Geelvink, Mirja; Babmorad, Armin; Maurer, Angela; Stöhr, Robert; Grimm, Tobias; Bach, Christian; Knuechel, Ruth; Rose, Michael; Gaisa, Nadine T. (International Journal of Molecular Sciences, 2018)
Prognostic/therapeutic stratification of papillary urothelial cancers is solely based upon histology, despite activated FGFR3-signaling was found to be associated with low grade tumors and favorable outcome. However, there are FGFR3-overexpressing tumors showing high proliferation-a paradox of coexisting favorable and adverse features. Therefore, our study aimed to decipher the relevance of FGFR3-overexpression/proliferation for histopathological grading and risk stratification. N = 142 (n = 82 pTa, n = 42 pT1, n = 18 pT2-4) morphologically G1⁻G3 tumors were analyzed for immunohistochemical expression of FGFR3 and Ki67. Mutation analysis of FGFR3 and TP53 and FISH for FGFR3 amplification and rearrangement was performed. SPSS 23.0 was used for statistical analysis. Overall FGFR3high/Ki67high status (n = 58) resulted in a reduced ∆mean progression-free survival (PFS) (p < 0.01) of 63.92 months, and shorter progression-free survival (p < 0.01; mean PFS: 55.89 months) in pTa tumors (n = 50). FGFR3mut/TP53mut double mutations led to a reduced ∆mean PFS (p < 0.01) of 80.30 months in all tumors, and FGFR3mut/TP53mut pTa tumors presented a dramatically reduced PFS (p < 0.001; mean PFS: 5.00 months). Our results identified FGFR3high/Ki67high papillary pTa tumors as a subgroup with poor prognosis and encourage histological grading as high grade tumors. Tumor grading should possibly be augmented by immunohistochemical stainings and suitable clinical surveillance by endoscopy should be performed.
EVALuna2:205512

Diagnostic Impact of Crypt Branching in Patients With Crohn's Disease: A Validation Study - Lang-Schwarz, Corinna; Rubio, Carlos A.; Vieth, Michael (Anticancer Research, 2022)
BACKGROUND/AIM: Crypt branching in inflammatory bowel diseases (IBD) was previously classified into symmetric (CSB) and asymmetric branching (CAB). We aimed to validate the inter-rater agreement of the assessment of crypt branching (also called crypt fission) in patients with Crohn's disease (CD) and to elucidate its potential diagnostic impact. PATIENTS AND METHODS: A total of 100 colon biopsies from patients with active CD were analyzed. Two cohorts of patients with ulcerative colitis (UC) and infectious colitis, respectively, served as controls (UC-controls/infectious controls). Three pathologists scored the total number of branching crypts (TBC) as well as the number of CSB and CAB. RESULTS: Inter-rater agreement ranged from moderate to good for TBC and CAB in the study cohort. The study cohort showed significantly higher counts of TBC, CSB, and CAB than the infectious controls (p<0.001 for TBC, p=0.008 for CSB, and p<0.001 for CAB). Cases with CD showed more TBC and CAB compared to cases with UC (p=0.001 each). CONCLUSION: Inter-rater agreement for crypt branching is reliable in patients with CD. Crypt branching was shown to be an additional histologic feature to distinguish active CD from infectious colitis. Additionally, it could be helpful in the distinction between CD and UC.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Crohn’s disease; Crypt branching; histopathology

Diagnostic impact of percutaneous renal biopsy - Kitterer, Daniel; Guerzing, Katharina; Segerer, Stephan; Alscher, M. Dominik; Amann, Kerstin Ute; Braun, Niko; Latus, Joerg (Clinical Nephrology, 2015)
Ultrasound-guided percutaneous renal biopsy (PRB) is an important diagnostic tool for nephrologists. Athough widely used and without question of pivotal importance for the diagnosis of renal diseases, little systematic data regarding standardized indications, outcomes, or consequences for this procedure are available. The aim of this study was to compare the clinically suspected diagnosis with the morphological results and the potential impact of PRB on the treatment of the patient.205 patients who underwent PRB of the native kidney within a 4-year period were included in this retrospective analysis. The biopsy results (BR), discharge diagnosis (DD), and the suspected diagnoses (SD) of the attending nephrologists prior to biopsy were documented.Mean age of the patients was 58 (range 44 - 77) years. The majority of patients (61%) received PRB during an acute disease phase, whereas 39% had elective PRB. Percutaneous biopsy of the native kidney led to a discharge diagnosis in 92% of the patients, with low complication rates (with 3 out of 205 patients had major bleeding complications). In 2/3, the nephrologists were correct with the suspected diagnosis prior to the biopsy. In 74% of the biopsies, a disease was identified that was potentially responsive to treatment modification.In summary, PRB was found to be a safe procedure that confirmed the suspected clinical diagnosis in two thirds of patients. As one third of the histopathological analyses demonstrated a non-suspected disease, the biopsies were of major importance for the correct treatment of the patients.
EVALuna2:25522

Diagnostic potential of major and trace elements in the serum of bladder cancer patients - Wach, Sven; Weigelt, Katrin; Michalke, Bernhard; Lieb, Verena; Stoehr, Robert; Keck, Bastian; Hartmann, Arndt; Wullich, Bernd; Taubert, Helge; Chaudhri, Anwar (Journal of Trace Elements in Medicine and Biology, 2018)
Major and trace elements may play a role in the diagnosis of diseases. In this study, we investigated the concentration of 26 major and trace elements in the serum by inductively coupled plasma (ICP) - optical emission spectrometry (OES) and ICP-sector field-mass spectrometry (sf-MS). We analyzed the serum from a discovery cohort of 6 bladder cancer (BCa) patients and 12 healthy controls as well as from a validation cohort of 21 BCa patients, 29 non-tumor bladder patients (with acute and chronic inflammation) and 18 healthy controls. Patients were recruited after written consent was obtained at one medical center. Serum was prepared from peripheral blood prior to surgical treatment. Differences in the levels of major and trace elements were determined by a nonparametric Mann-Whitney test and Kruskal-Wallis statistics. In the discovery cohort, we measured significantly increased levels of calcium, mercury, potassium, lithium, nickel, phosphorus and strontium and a significantly decreased level of sodium in BCa patients compared with healthy controls. These findings were reassessed in our validation cohort. We measured significantly increased levels of boron, calcium, cadmium, copper, chromium, lead, lithium, potassium, magnesium, nickel, sulfur, strontium, titan, vanadium and zinc and significantly decreased levels of iron and molybdenum. When we studied the concordance for the discovery and validation cohorts, concentrations of five elements were detected as significantly increased in BCa patients compared with healthy controls: calcium, lithium, potassium, nickel, and strontium. Interestingly, the levels of three elements (calcium, potassium and strontium) were also significantly increased in non-tumor bladder patients compared with healthy controls. But no element was significantly altered between non-tumor bladder patients and BCa patients. In summary, we suggest that determination of the elements calcium, lithium, nickel and strontium in the serum could be a new and promising tool for the early diagnosis of BCa.
EVALuna2:32785

Diagnostics and prognostic evaluation in renal cell tumors: the German S3 guidelines recommendations - Junker, Kerstin; Hallscheidt, Peter; Wunderlich, Heiko; Hartmann, Arndt (World Journal of Urology, 2022)
The German guidelines on renal cell carcinoma (RCC) have been developed at highest level of evidence based on systematic literature review. In this paper, we are presenting the current recommendations on diagnostics including preoperative imaging and imaging for stage evaluation as well as histopathological classification. The role of tumor biopsy is further discussed. In addition, different prognostic scores and the status of biomarkers in RCC are critically evaluated.
CRIS-Team Scopus Importer:2022-03-25
Keywords: Imaging; Prognosis; Renal cell carcinoma; S3 guideline; Tumor biopsy

Diagnostic value of 3D dynamic contrast-enhanced magnetic resonance imaging in lymph node metastases of head and neck tumors: a correlation study with histology - Treutlein, Christoph; Stollberg, Adrian; Scherl, Claudia; Agaimy, Abbas; Ellmann, Stephan; Iro, Heinrich; Lell, Michael; Uder, Michael; Bäuerle, Tobias (Acta Radiologica Open, 2020)
Background: Accurate staging of cervical lymph nodes (LN) is pivotal for further clinical management of patients with head and neck cancer. Functional magnetic resonance imaging (MRI) such as three-dimensional (3D) dynamic contrast-enhanced (DCE) acquisition might improve the diagnosis of cervical LN metastases.
CRIS-Team WoS Importer:2020-09-25

Diagnostic Value of MAML2 Rearrangements in Mucoepidermoid Carcinoma - Thierauf, Julia C.; Farahani, Alex A.; Indave, B. Iciar; Bard, Adam Z.; White, Valerie A.; Smith, Cameron R.; Marble, Hetal; Hyrcza, Martin D.; Chan, John K.C.; Bishop, Justin; Shi, Qiuying; Ely, Kim; et al. (International Journal of Molecular Sciences, 2022)
Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. To assess the diagnostic relevance of MAML2, we examined our 5‐year experience in prospective testing of 8106 solid tumors using RNA‐seq panel testing in combinations with a two‐round Delphi‐based scenario survey. The prevalence of MAML2+ across all tumors was 0.28% (n = 23/8106) and the majority of MAML2+ cases were found in head and neck tumors (78.3%), where the overall prevalence was 5.9% (n = 18/307). The sensitivity of MAML2 for MEC was 60% and most cases (80%) were submitted for diagnostic confirmation; in 24% of cases, the MAML2 results changed the working diagnosis. An independent survey of 15 experts showed relative importance indexes of 0.8 and 0.65 for “confirmatory MAML2 testing” in suspected MEC and ASC, respectively. Real‐world evidence confirmed that the added value of MAML2 is a composite of an imperfect confirmation test for MEC and a highly specific exclusion tool for the diagnosis of ASC. Real‐world evidence can help move a rare molecular‐genetic biomarker from an emerging tool to the clinic.
CRIS-Team Scopus Importer:2022-04-22
Keywords: adenosquamous; biomarker; CRTC; fusion gene; molecular testing; mucoepidermoid; next‐generation sequencing

DICER1-Mutated Botryoid Fibroepithelial Polyp of the Parotid Duct: Report of the First Case - Erber, Ramona; Preidl, Raimund; Stöhr, Robert; Haller, Florian; Hartmann, Arndt; Kesting, Marco Rainer; Agaimy, Abbas (Head and Neck Pathology, 2021)
DICER1, a member of the ribonuclease III family, is involved in the biogenesis of microRNAs and, hence, it influences gene expression regulation. DICER1 germline (associated with the inherited DICER1 syndrome) or somatic mutations have been linked to tumorigenesis in histogenetically diverse benign and malignant neoplasms in different organs including pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, poorly differentiated thyroid carcinoma, thyroblastoma, intracranial sarcoma and gonadal Sertoli-Leydig cell tumors in addition to others. Moreover, rare botryoid (giant) fibroepithelial polyps may harbor this mutation. Herein, we describe the first reported case of a DICER1-mutated botryoid fibroepithelial polyp occurring within the parotid duct of a 65-year-old female who has no other features or family history of the DICER1 syndrome. Based on its distinctive morphology, we tested this lesion specifically for DICER1 mutations and confirmed the presence of a pathogenic DICER1 variant with a low allele frequency, consistent with a somatic mutation.
CRIS-Team WoS Importer:2021-07-30

DICER1 mutation-positive Giant Botryoid Fibroepithelial polyp of the urinary bladder mimicking embryonal rhabdomyosarcoma - Eckstein, Markus; Agaimy, Abbas; Woenckhaus, Joachim; Winter, Alexander; Bittmann, Iris; Janzen, Joerg; Bertz, Simone; Haller, Florian; Hartmann, Arndt (Human Pathology, 2018)
Fibroepithelial polyps of the urinary tract are rare lesions. They occur mainly in the upper urinary tract of children. A high disease prevalence has been reported in families with pleuropulmonary blastoma. Here we present a case of a 46-year-old woman who presented with a giant botryoid fibroepithelial polyp of the urinary bladder. Histologically, the lesion showed prominent botryoid features with an embryonal rhabdomyosarcoma-like cambium layer lacking nuclear or cellular atypia. Immunohistochemical analysis ruled out rhabdomyoblastic differentiation. Next generation sequencing was performed on the polyp tissue and revealed two pathogenic mutations in the dicer1 ribonuclease III (DICER1) gene (c.[5439G>T]; p.[Glu1813Asp] and c.[1525C>T]; p.[Arg509*]). The Glu1813Asp DICER1 mutation has been reported in the germline of families with pleuropulmonary blastoma. Thus, our findings support the role of DICER1 mutations in the pathogenesis of fibroepithelial polyps of the urinary tract.
EVALuna2:35238

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury - Deuse, Tobias; Hua, Xiaoqin; Wang, Dong; Maegdefessel, Lars; Heeren, Joerg; Scheja, Ludger; Bolanos, Juan P.; Rakovic, Aleksandar; Spin, Joshua M.; Stubbendorff, Mandy; Ikeno, Fumiaki; Laenger, Florian; et al. (Nature, 2014)
Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (??m) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ??m hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ??m and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.
EVALuna2:25471

Die Akkreditierung in der Pathologie und Neuropathologie in Deutschland: Rahmenbedingungen und Voraussetzungen - Curelea, S.; Hartmann, Arndt; Varnai-Haendel, A. (Die Pathologie, 2022)
Accreditation in pathology and neuropathology in Germany is based on the requirements of the DIN EN ISO/IEC 17020 standard, which defines general requirements for the bodies performing inspections. In Germany, the national accreditation body of the Federal Republic of Germany (DAkkS) assumes the official task of accreditation. Evaluation in this area is based on a comprehensive assessment by board-certified pathologists (inspection) and is focused on correct diagnosis. The requirement of the DIN EN ISO 15189 standard on quality and competence in medical laboratories is taken into account. In Germany, more than 100 institutes of pathology and neuropathology have successfully performed the accreditation process. Interest in accreditation has been significantly growing in recent months, especially due to changes in the European law with the "Verordnung EO 2017/746 des Europaischen Parlaments und des Rates vom 05. April 2017 uber Invitro-Diagnostica". However, accreditation is a demanding process that requires very good preparation. Necessary resources for accreditation should be secured before starting the process. Important framework conditions and requirements, but also some challenges that can arise during the accreditation process, are summarized in this article.
CRIS-Team WoS Importer:2022-08-12

Die Komplementkaskade in der Nierenpathologie - Vonbrunn, Eva; Daniel, Christoph (Die Pathologie, 2024)
The complement cascade comprises a variety of soluble and cell surface proteins and is an important component of the innate immune system. When the cascade is triggered by any of the three activation pathways, the complement system rapidly produces large amounts of protein fragments that are potent mediators of inflammatory, vasoactive, and metabolic responses. All activation pathways lead to the terminal complement cascade with the formation of the membrane attack complex, which lyses cells by forming membrane pores. Although the complement system is essential for pathogen defense and homeostasis, excessive or uncontrolled activation can lead to tissue damage. Recent research shows that the complement system is activated in almost all kidney diseases, even those not traditionally considered immune-mediated. In directly complement-mediated kidney diseases, complement factors or regulators are defective, afunctional or inactivated by antibodies. In many other renal diseases, the complement system is activated secondarily as a result of renal damage and is therefore involved in the pathogenesis of the disease, but is not the trigger. The detection of complement deposits is also used to diagnose kidney disease. This review describes the structure of the complement system and the effects of its dysregulation as a cause and modulator of renal disease.
CRIS-Team Scopus Importer:2024-04-26
Keywords: Antibodies; C3G; Immune system; Lectin; Microangiopathy

Differences and Similarities in the Pattern of Early Metabolic and Morphologic Response after Induction Chemo-Immunotherapy versus Induction Chemotherapy Alone in Locally Advanced Squamous Cell Head and Neck Cancer - Beck, Michael; Semrau, Sabine; Haderlein, Marlen; Gostian, Antoniu-Oreste; Hartwich, Julius; Müller, Sarina Katrin; Kallies, Annett; Geppert, Carol-Immanuel; Schonath, Miriam; Putz, Florian; Gaipl, Udo; Frey, Benjamin; et al. (Cancers, 2022)
Simple Summary There are differences and similarities when assessing the short-term therapeutic response of chemotherapy and chemotherapy plus immunotherapy using imaging techniques, which may be necessary to make treatment decisions in malignant head and neck tumors. After both chemo- and immunochemotherapy, remission becomes measurable in cross-sectional and metabolic diagnostics after only one cycle of therapy, with (18)FDG-PET/CT predicting complete remission of tumor cells in a representative biopsy better than MRI/CT examination in both therapeutic modalities. While complete tumor remission is highly likely (88%) after immunochemotherapy in tumors with low residual activity (<= 40% of initial SUV), this is less common after chemotherapy alone (65%). In metabolic nonresponse with more than 80% residual activity, the probability of complete remission nevertheless is low after chemotherapy alone (6%). After immunochemotherapy, these false nonresponders are common (35%), requiring additional diagnostics by deep biopsy. Cases of pseudoprogression with an increase of SUVmax of more than 125% of the baseline were not observed. Background: In head and neck cancer patients, parameters of metabolic and morphologic response of the tumor to single-cycle induction chemotherapy (IC) with docetaxel, cis- or carboplatin are used to decide the further course of treatment. This study investigated the effect of adding a double immune checkpoint blockade (DICB) of tremelimumab and durvalumab to IC on imaging parameters and their significance with regard to tumor cell remission. Methods: Response variables of 53 patients treated with IC+DICB (ICIT) were compared with those of 104 who received IC alone. Three weeks after one cycle, pathologic and, in some cases, clinical and endoscopic primary tumor responses were evaluated and correlated with a change in 18F-FDG PET and CT/MRI-based maximum-standardized uptake values (SUVmax) before (SUV(max)pre), after treatment (SUV(max)post) and residually (resSUV(max) in % of SUV(max)pre), and in maximum tumor diameter (D-max) before (D(max)pre) and after treatment (D(max)post) and residually (resD). Results: Reduction of SUVmax and D-max occurred in both groups; values were SUV(max)pre: 14.4, SUV(max)post: 6.6, D(max)pre: 30 mm and D(max)post: 23 mm for ICIT versus SUV(max)pre: 16.5, SUV(max)post: 6.4, D(max)pre: 21 mm, and D(max)post: 16 mm for IC alone (all p < 0.05). ResSUV(max) was the best predictor of complete response (IC: AUC: 0.77; ICIT: AUC: 0.76). Metabolic responders with resSUV(max) <= 40% tended to have a higher rate of CR to ICIT (88%; n = 15/17) than to IC (65%; n = 30/46; p = 0.11). Of the metabolic nonresponders (resSUV(max) > 80%), 33% (n = 5/15) achieved a clinical CR to ICIT versus 6% (n = 1/15) to IC (p = 0.01). Conclusions: ICIT and IC quickly induce a response and 18F-FDG PET is the more accurate modality for identifying complete remission. The rate of discrepant response, i.e., pCR with metabolic nonresponse after ICIT was >30%.
CRIS-Team WoS Importer:2022-10-21

Differences in Inflammation and Bone Resorption between Apical Granulomas, Radicular Cysts, and Dentigerous Cysts - Weber, Manuel; Ries, Jutta; Büttner-Herold, Maike; Geppert, Carol-Immanuel; Kesting, Marco Rainer; Wehrhan, Falk (Journal of Endodontics, 2019)
Introduction: Dental cysts can be of inflammatory (radicular cysts) or noninflammatory (dentigerous cysts) origin. Apical periodontitis is a necrosis of the pulp and infection of the root canal causing the development of apical granulomas or radicular cysts. The immunology of granuloma and cyst formation is important because modern root filling materials are immunologically active and can contribute to the resolution of apical granulomas. In contrast, radicular cysts often require apicectomy. A better understanding of the pathophysiology of inflammation and bone resorption in apical periodontitis could be the basis for developing new root filling materials with superior immunomodulatory properties. Methods: Forty-one apical granulomas, 23 radicular cysts, and 23 dentigerous cysts were analyzed in this study. A tissue microarray of the 87 consecutive specimens was created, and human leukocyte antigen–DR isotype (HLA-DR)-, CD83-, receptor activator of nuclear factor kappa B ligand–, macrophage colony-stimulating factor (MCSF)-, galectin-3 (Gal3)-, CD4-, and CD8-positive cells were detected by immunohistochemistry. Tissue microarrays were digitized, and the expression of markers was quantitatively assessed. Results: HLA-DR, CD83, MCSF, and Gal3 expression was significantly (P < .05) higher in radicular cysts compared with apical granulomas. HLA-DR, CD83, MCSF, receptor activator of nuclear factor kappa B ligand, and Gal3 expression in dentigerous cysts was significantly (P < .05) lower than in both periapical lesions (apical granulomas and radicular cysts). CD4 and CD8 infiltration was not statistically different between apical granulomas and radicular cysts. Dentigerous cysts showed a significantly (P < .05) lower T-cell infiltration than apical periodontitis. The CD4/CD8 ratio was not significantly different between the analyzed groups. Conclusions: The development of radicular cysts in apical periodontitis is associated with an increased expression of myeloid inflammatory markers and bone resorption parameters. Antigen-presenting cells and myeloid cells might be more relevant for the pathogenesis of apical periodontitis than T cells. Increased inflammation might promote the formation of radicular cysts and more pronounced bone resorption.
CRIS-Team Scopus Importer:2019-09-27
Keywords: Apical granuloma; apical periodontitis; bone resorption; follicular cyst; periapical lesion; radicular cysts

Differences in kidney-specific DPP-4 inhibition by linagliptin and sitagliptin - Luippold, Gerd; Mark, Michael; Klein, Thomas; Amann, Kerstin Ute; Daniel, Christoph (Diabetes Research and Clinical Practice, 2018)
The two dipeptidyl peptidase (DPP)-4 inhibitors, linagliptin and sitagliptin, were shown to exert different binding kinetics in vitro. Twenty-four hours after oral dosing particularly in vivo inhibition of renal-specific DPP-4 activity was more sustained in Sprague Dawley rats after exposure to linagliptin than it was after sitagliptin.
EVALuna2:34421

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; Stoehr, Robert; Juette, Hendrik; Wirtz, Ralph; Eckstein, Markus; Roghmann, Florian; Breyer, Johannes; Porubsky, Stefan; Sikic, Danijel; Bolenz, Christian; Kriegmair, Maximilian; Hartmann, Arndt; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

DIFFERENT FORMS OF AFFERENT NERVE INPUT IN CARDIAC AND RENAL DISEASE IN RATS? - Rodionova, Kristina; Ditting, Tilmann; Pickny, Lisa; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Differential Diagnosis of Interstitial Allograft Rejection and BKV Nephropathy by T-cell Receptor Sequencing - Stervbo, Ulrik; Nienen, Mikalai; Hecht, Jochen; Viebahn, Richard; Amann, Kerstin Ute; Westhoff, Timm H.; Babel, Nina (Transplantation, 2020)
CRIS-Team Scopus Importer:2020-04-10

Differential prognostic value of MYC immunohistochemistry in subtypes of papillary renal cell carcinoma - Bellut, Julia; Bertz, Simone; Nolte, Elke; Stoehr, Christine; Polifka, Iris; Lieb, Verena; Herrmann, Edwin; Jung, Rudolf; Hartmann, Arndt; Wullich, Bernd; Taubert, Helge; Wach, Sven (Scientific Reports, 2017)
The histomorphological subtyping of papillary renal cell carcinomas (pRCCs) has improved the predictions of patients' long-term survival. Based on our previous results, we hypothesized that the MYC proto-oncogene would show differential expression in pRCC subtypes. Using a multi-institutional cohort of 204 pRCC patients we assessed the additional value of the immunohistochemical markers MYC, MINA53, and Ki67 in predicting patient's long-term survival. The clinical endpoints were overall survival (OS) and cancer-specific survival (CSS). Nomograms were constructed to predict each patient's risk of death (OS). The incorporation of the MYC staining patterns allowed the stratification of pRCC type 1 patients into better and worse prognostic groups. None of the patients with pRCC type 1 tumors and favorable MYC staining patterns died from tumor-related causes. This prognostic value was independent of the patient's age at surgery, the pathological tumor stage and presence of lymph node invasion. we could show that the immunohistochemical assessment of MYC and the histomorphological subtyping of pRCC stratifies pRCC type 1 tumors with regard to OS and CSS. The determination of the histomorphologic pRCC subtype in combination with the MYC immunohistochemical staining patterns allows a more accurate prediction of patients' individual risk of death.
EVALuna2:33570

Differentiating primary and secondary FSGS using non-invasive urine biomarkers. - Catanese, Lorenzo; Siwy, Justyna; Wendt, Ralph; Amann, Kerstin Ute; Beige, Joachim; Hendry, Bruce; Mischak, Harald; Mullen, William; Paterson, Ian; Schiffer, Mario; Wolf, Michael; Rupprecht, Harald (Clinical Kidney Journal, 2024)
BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is divided into genetic, primary (p), uncertain cause, and secondary (s) forms. The subclasses differ in management and prognosis with differentiation often being challenging. We aimed to identify specific urine proteins/peptides discriminating between clinical and biopsy-proven pFSGS and sFSGS. METHODS: Sixty-three urine samples were collected in two different centers (19 pFSGS and 44 sFSGS) prior to biopsy. Samples were analysed using capillary electrophoresis-coupled mass spectrometry. For biomarker definition, datasets of age-/sex-matched normal controls (NC, n = 98) and patients with other chronic kidney diseases (CKDs, n = 100) were extracted from the urinary proteome database. Independent specificity assessment was performed in additional data of NC (n = 110) and CKD (n = 170). RESULTS: Proteomics data from patients with pFSGS were first compared to NC (n = 98). This resulted in 1179 biomarker (P < 0.05) candidates. Then, the pFSGS group was compared to sFSGS, and in a third step, pFSGS data were compared to data from different CKD etiologies (n = 100). Finally, 93 biomarkers were identified and combined in a classifier, pFSGS93. Total cross-validation of this classifier resulted in an area under the receiving operating curve of 0.95. The specificity investigated in an independent set of NC and CKD of other etiologies was 99.1% for NC and 94.7% for CKD, respectively. The defined biomarkers are largely fragments of different collagens (49%). CONCLUSION: A urine peptide-based classifier that selectively detects pFSGS could be developed. Specificity of 95%-99% could be assessed in independent samples. Sensitivity must be confirmed in independent cohorts before routine clinical application.
EVALuna2:552743

Different Prevalence of Alarm, Dyspeptic and Reflux Symptoms in Patients with Cardia and Non-cardia Gastric Cancer - Franck, Caspar; Zimmermann, Nadja; Goni, Elisabetta; Lippert, Hans; Ridwelski, Karsten; Kruschewski, Martin; Kreuser, Nicole; Lingohr, Philipp; Schildberg, Claus; Vassos, Nikolaos; Waidmann, Oliver; Peitz, Ulrich; et al. (Journal of Gastrointestinal and Liver Diseases, 2021)
Background & Aims: Symptoms of patients with gastric cancer (GC) are often unspecific and differences in symptoms between patients with cardia and non-cardia GC have been poorly investigated. We aimed to characterize symptoms of patients with cardia and non-cardia GC. Methods: Patients with cardia (Siewert type II and III) and non-cardia GC were recruited in the German multicenter cohort of the Gastric Cancer Research (staR) study between 2013 and 2017. Alarm, dyspeptic and reflux symptoms at the time of presentation were documented using a self-administered questionnaire. Results: A completed self-administered questionnaire was available for 568/759 recruited patients (132 cardia GC, 436 non-cardia GC, male 61%, mean age 64 years). Dyspeptic symptoms were more common in patients with non-cardia GC (69.0 vs. 54.5%, p=0.0024). Cardia GC patients reported more frequently alarm symptoms (69.7 vs. 44.7%, p<0.0001), and were more likely to have Union for International Cancer Control (UICC) stage III-IV (54.1vs. 38.9%, p=0.0034). Especially, dysphagia and weight loss were more common in patients with cardia GC (49.2 vs. 6.4 %, p<0.0001 and 37.1 vs. 25.7%, p=0.02, respectively). No differences between the two groups were observed with respect to reflux symptoms. Patients with alarm symptoms were more likely to have UICC stage III-IV at presentation (69.4 vs. 42.9%, p<0.0001). Conclusions: In clinical practice the symptom pattern at presentation may serve as a hint for tumor localization. Despite the fact that they are common in the general population, dyspeptic symptoms offer a chance for earlier GC detection. Thus, in patients with dyspeptic symptoms who fail empiric approaches, endoscopy should not be delayed.
CRIS-Team WoS Importer:2022-01-07

Diffuse Neuromatosis of Intrahepatic and Extrahepatic Bile Ducts as a Rare Cause of Jaundice - Vassos, Nikolaos; Perrakis, Aristotelis; Schmid, Axel; Croner, Roland S.; Grützmann, Robert; Agaimy, Abbas (Visceral Medicine, 2020)
Background: Neuroma of the biliary tree is extremely rare with no more than 100 cases reported so far. They mostly present with obstructive jaundice and have been commonly described after surgery or abdominal trauma. Although involvement of the extrahepatic bile duct is far more common, occurrence in the intrahepatic ducts has not so far been reported. Case Report: We describe 3 cases of diffuse biliary tree neuroma affecting 3 females aged 53-68 years. None had a history of neurofibromatosis type1. All presented with progressive obstructive jaundice with no evidence of gallstones. A history of previous surgery was noted in 2 patients. Initial impression on clinical and imaging examination was highly suspicious for bile duct carcinoma in 2 patients. Histology showed diffuse neuromatous proliferation replacing and thickening the bile duct walls. The third patient had concurrent neuroma and recurrent cholangiocarcinoma causing great clinical confusion as initial biopsy showed only benign neuroma, but CA 19-9 was steadily increasing, necessitating a second biopsy which then confirmed recurrent carcinoma. Conclusion: This uncommon cause of long-distance bile duct stenosis and progressive jaundice should be included in the differential diagnosis of bile duct neoplasms, in particular when there is a previous surgical history in this abdominal region.
CRIS-Team Scopus Importer:2020-12-18
Keywords: Bile duct neuroma; Bile duct stenosis; Cholangiocarcinoma; Jaundice; Neuromatosis

Digital odyssey: lessons learnt from a reverse transition from a digital to a manual pathology workflow - Caputo, Alessandro; Angeloni, Miriam; Merolla, Francesco; Vatrano, Simona; Ferrazzi, Fulvia; Fraggetta, Filippo (Journal of Clinical Pathology, 2024)
In the fully digital Caltagirone pathology laboratory, a reverse shift from a digital to a manual workflow occurred due to a server outage in September 2023. Here, insights gained from this unplanned transition are explored. Surveying the affected pathologists and technicians revealed unanimous preferences for the time-saving and error-reducing capabilities of the digital methodology. Conversely, the return to manual methods highlighted increased dissatisfaction and reduced efficiency, emphasising the superiority of digital workflows. This case study underscores that transition challenges are not inherent to digital workflows but to transitioning itself, advocating for the adoption of digital technologies in all pathology practices.
CRIS-Team Scopus Importer:2024-02-09
Keywords: Laboratory Personnel; Process Assessment; Health Care; TELEPATHOLOGY

Digital pathology imaging and computer-aided diagnostics as a novel tool for standardization of evaluation of aganglionic megacolon (Hirschsprung disease) histopathology - Schilling, Florian; Geppert, Carol-Immanuel; Strehl, Johanna; Hartmann, Arndt; Kürten, Stefanie; Brehmer, Axel; Jabari, Samir (Cell and Tissue Research, 2018)
Based on a recently introduced immunohistochemical panel (Bachmann et al. 2015) for aganglionic megacolon (AM), also known as Hirschsprung disease, histopathological diagnosis, we evaluated whether the use of digital pathology and 'machine learning' could help to obtain a reliable diagnosis. Slides were obtained from 31 specimens of 27 patients immunohistochemically stained for MAP2, calretinin, S100β and GLUT1. Slides were digitized by whole slide scanning. We used a Definiens Developer Tissue Studios as software for analysis. We configured necessary parameters in combination with 'machine learning' to identify pathological aberrations. A significant difference between AM- and non-AM-affected tissues was found for calretinin (AM 0.55% vs. non-AM 1.44%) and MAP2 (AM 0.004% vs. non-AM 0.07%) staining measurements and software-based evaluations. In contrast, S100β and GLUT1 staining measurements and software-based evaluations showed no significant differences between AM- and non-AM-affected tissues. However, no difference was found in comparison of suction biopsies with resections. Applying machine learning via an ensemble voting classifier, we achieved an accuracy of 87.5% on the test set. Automated diagnosis of AM by applying digital pathology on immunohistochemical panels was successful for calretinin and MAP2, whereas S100β and GLUT1 were not effective in diagnosis. Our method suggests that software-based approaches are capable of diagnosing AM. Our future challenge will be the improvement of efficiency by reduction of the time-consuming need for large pre-labelled training data. With increasing technical improvement, especially in unsupervised training procedures, this method could be helpful in the future.
EVALuna2:35208

Digital volumetric assessment of CIS and tumor mass compliments conventional histopathological assessment in muscle-invasive urothelial bladder cancer - Lange, Fabienne; Geppert, Carol-Immanuel; Bahlinger, Veronika; Bertz, Simone; Stöhr, Robert; Sikic, Danijel; Taubert, Helge; Wach, Sven; Wullich, Bernd; Hartmann, Arndt; Eckstein, Markus (Virchows Archiv, 2024)
Carcinoma in situ (CIS) of the bladder is a known parameter regarding the prognosis and recurrence tendency of urothelial carcinomas. Nevertheless, there is little evidence whether the amount of CIS or other precursor lesions, as well as the quantified tumor mass of muscle-invasive urothelial carcinoma, has an influence on the survival or recurrence rate of affected patients. From 80 patients with muscle invasive urothelial bladder cancer and radical cystectomy, 23 samples each were obtained as part of a whole organ mapping in a single institution study, in which the precursor lesions and tumor area were digitally measured and further correlated to pathological standard parameters, patient survival, molecular luminal and basal subtypes, and immune infiltration. Significant correlations were found between tumor mass and surface lining CIS amount for pT-stage, lymphovascular invasion, and perineural infiltration. Furthermore, an increased tumor mass as well as an increased amount of CIS combined with an increased tumor mass showed a significantly reduced survival rate in multivariable analysis (HR = 2.75; P = 0.019 vs. HR = 3.54; P = 0.002) as well as a significantly increased recurrence. No correlations could be found with molecular subtypes and immune infiltration. The exact measurement of the tumor mass with and without the CIS surface area, whether manually or, more specifically, digitally, could be incorporated into routine diagnostics and implemented as an independent predictor for patient post-surgical outcomes. It can therefore serve as an additional predictor for risk stratification and, if necessary, intensified follow-up care or therapy.
CRIS-Team Scopus Importer:2024-07-26
Keywords: Muscle invasive bladder cancer; Prognosis; Radical cystectomy; Survival; Urothelial carcinoma; Urothelial carcinoma in situ

Digit ratio (2D:4D) and academic success as measured by achievement in the academic degree "Habilitation" - Tektas, Ozan Yueksel; Kapsner, Lorenz; Lemmer, Miriam; Bouna-Pyrrou, Polyxeni; Lewczuk, Piotr; Lenz, Bernd; Kornhuber, Johannes (PLoS ONE, 2019)
Introduction
CRIS-Team WoS Importer:2019-03-15

Direct 3D‐Bioprinting of hiPSC‐derived Cardiomyocytes to Generate Functional Cardiac Tissues - Esser, Tilman; Anspach, Annalise; Muenzebrock, Katrin; Kah, Delf-Thorge Eric; Schrüfer, Stefan; Schenk, Joachim; Heinze, Katrin G.; Schubert, Dirk W.; Fabry, Ben; Engel, Felix (Advanced Materials, 2023)
3D-bioprinting is a promising technology to produce human tissues as drug screening tool or for organ repair. However, direct printing of living cells has proven difficult. Here, we present a method to directly 3D-bioprint human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes embedded in a collagen-hyaluronic acid ink generating centimeter-sized functional ring- and ventricle-shaped cardiac tissues in an accurate and reproducible manner. The printed tissues contained hiPSC-derived cardiomyocytes with well-organized sarcomeres and exhibited spontaneous and regular contractions, which persisted for several months and were able to contract against passive resistance. Importantly, beating frequencies of the printed cardiac tissues could be modulated by pharmacological stimulation. This approach opens up new possibilities for generating complex functional cardiac tissues as models for advanced drug screening or as tissue grafts for organ repair or replacement.<br

Direct 3D printing of hiPSC-cardiomyocytes in collagen-based bioinks - Esser, Tilman; Engel, Felix (EUROPEAN HEART JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-10

Discovery of a novel soluble Neuropilin-2 isoform with antiangiogenic and antitumorigenic activity - Mayr, Thomas; Dix, Paul L.; Hasheminasab, Sayed-Mohammad; Hampel, Chuanpit; Sylvester, Marc; Schneberger, Niels; Foerster, Sarah; Hagelueken, Gregor; Dutta, Samikshan; Kristiansen, Glen; Schneider-Stock, Regine; Datta, Kaustubh; et al. (CANCER RESEARCH, 2022)
CRIS-Team WoS Importer:2023-04-07

Discovery of Novel TULP4/ACTN4/EWSR1/ACTB::MYB and ESRRG::DNM3 Fusions Expands Molecular Landscape of Adenoid Cystic Carcinoma beyond Fusions between MYB/MYBL1 and NFIB Genes - Skálová, Alena; Klubícková, Natálie; Bradová, Martina; Agaimy, Abbas; Rupp, Niels J.; Damjanov, Ivan; Kolnikova, Georgina; Martínek, Petr; Šteiner, Petr; Grossmann, Petr; Vanecek, Tomas; Michal, Michal; et al. (American Journal of Surgical Pathology, 2024)
Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs in all major and minor salivary gland and seromucous gland sites. AdCCs of salivary gland origin have long been categorized as fusiondefined carcinomas owing to the almost consistent presence of fusion genes MYB::NFIB, or less commonly MYBL1::NFIB. We collected a cohort of 95 cases of AdCC, which were largely characterized by canonical fusions MYB::NFIB (49 cases) or MYBL1::NFIB (9 cases). In additional 11 cases of AdCC, rearrangements in MYB or NFIB genes were detected by FISH. In addition, NGS revealed novel noncanonical fusion transcripts EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, MYB:: TULP4, and ACTN4::MYB, each of them in 1 case. The tumors that showed noncanonical fusions had features of metatypical AdCC with a diverse architecture, lobulated multinodular growth pattern, and hypercellular peripheral palisading of nuclei (2 cases), tubular hypereosinophilia (2 cases), and pale eosinophilic to vacuolated (bubbly) cytoplasm (3 cases). Our study documented 3 cases of AdCC of salivary glands harboring novel gene fusions TULP4::MYB, ACTN4::MYB, and ACTB::MYB, in 1 case each, which have not been described before. A rare EWSR1::MYB fusion was detected in 1 case. Moreover, 1 case of sinonasal metatypical AdCC showed EWSR1 rearrangement detected by FISH. Also, 1 case with an ESRRG::DNM3 fusion of unknown significance is described in this study. These discoveries illustrate how broad molecular profiling will expand understanding of changes in known entities.
CRIS-Team Scopus Importer:2024-09-20
Keywords: adenoid cystic carcinoma; novel ESRRG::DNM3 gene fusion; salivary gland neoplasm; sinonasal; TULP4/ACTN4/EWSR1/ACTB::MYB gene fusion

Discrimination analysis of breast calcifications using x-ray dark-field radiography - Rauch, Thomas; Rieger, Jens; Pelzer, Georg; Horn, Florian; Erber, Ramona; Wunderle, Marius; Emons, Julius; Nabieva, Naiba; Fuhrich, Nicole; Michel, Thilo; Hartmann, Arndt; Fasching, Peter; et al. (Medical Physics, 2020)
Background X-ray dark-field radiography could enhance mammography by providing more information on imaged tissue and microcalcifications. The dark field signal is a measure of small angle scattering and can thus provide additional information on the imaged materials. This information can be useful for material distinction of calcifications and the diagnosis of breast cancer by classifying benign and malign association of these calcifications.
CRIS-Team WoS Importer:2020-03-06

Discrimination between Inflammatory and Fibrotic Activity in Crohn's Disease-Associated Ileal-Colonic Anastomotic Strictures by Combined Ga-68-FAPI-46 and F-18-FDG-PET/CT Imaging - Beck, Michael; Kuwert, Torsten; Atzinger, Armin; Gerner, Maximilian; Hartmann, Arndt; Saake, Marc; Uder, Michael; Neurath, Markus; Atreya, Raja (Visceral Medicine, 2024)
Introduction: The development of an intestinal stricture in patients with Crohn s disease represents an important and frequent complication, reflecting the progressive nature of the disease. Depending on the inflammatory and fibrotic composition of the stricture, intensified medical therapy, interventional endoscopy, or surgical intervention is required. However, currently available diagnostic approaches can only assess the level of inflammation, but not the degree of fibrosis, limiting rational therapeutic management of Crohn s disease patients. Recently, prolyl endopeptidase fibroblast activating protein (FAP) has been functionally implicated in fibrotic tissue remodelling, indicating it as a promising target for detection of sites of fibrotic tissue remodelling. Thus, intestinal fibrosis might be visualized using Gallium-68 labelled inhibitors of FAP (FAPI). While F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT is a standard diagnostic tool for visualizing inflammatory processes, we combined Ga- 68-FAPI-46-PET/CT and F-18-FDG-PET/CT to differentiate predominantly fibrotic or inflammatory areas in Crohn s disease patients with ileo-colonic strictures. Methods: In our study, we analysed three Crohn s disease patients with anastomotic ileo-colonic strictures who underwent both dynamic Ga-68-FAPI-46-PET/CT and static F-18-FDG-PET/CT imaging to assess the level of visualized fibrotic areas within the stricture and differentiate it from inflammatory ones. PET images were analysed both visually and quantitatively. Furthermore, conventional MR enterography and endoscopy were performed in parallel to correlate observed findings. Two of the included patients underwent surgery and the histological specimen were analysed for the level of inflammation and fibrosis, which results were similarly compared to the findings of the PET imaging procedures. Results: Different uptake patterns of Ga-68- FAPI-46 could be observed in the anastomotic ileo-colonic strictures of the examined Crohn s disease patients, respectively. Immunohistochemical analyses demonstrated that there was a correlation between the level of Ga-68- FAPI-46 uptake and severity of fibrosis, while FDG uptake correlated with the inflammatory activity in the analysed strictures. Discussion: The combination with F-18-FDGPET/CT represents a promising imaging modality to distinguish inflammation from fibrosis and guide subsequent therapy in stricturing Crohn s disease patients, warranting further studies.
CRIS-Team Scopus Importer:2025-02-04
Keywords: Crohn s disease; FAPI-PET/CT; Fibrosis; Ga-68-FAPI-46; Strictures

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging - Schmidkonz, Christian; Rauber, Simon; Atzinger, Armin; Agarwal, Rahul; Götz, Theresa Ida; Soare, Alina; Cordes, Michael; Prante, Olaf; Prante, Olaf; Bergmann, Christina; Kleyer, Arnd; Ritt, Philipp; et al. (Annals of the Rheumatic Diseases, 2020)
Objectives To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG 4 -related disease. Methods In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG 4 -related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68 Ga-FAP inhibitor (FAPI)-04), 18 F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18 F-FDG and 68 Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. Results Using combination of 68 Ga-FAPI-04 and 18 F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG 4 -related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18 F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG 4 + cells in histology, while 68 Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. Conclusion FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG 4 -related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG 4 -related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
CRIS-Team Scopus Importer:2020-10-30
Keywords: fibroblasts; health care; inflammation; outcome assessment

DISRUPTION OF TFH:B CELL CROSSTALK PREVENTS ANTIBODY-MEDIATED REJECTION IN AN EXPERIMENTAL KIDNEY TRANSPLANT MODEL - Steines, L.; Poth, H.; Schuster, A.; Amann, Kerstin Ute; Banas, B.; Bergler, T. (TRANSPLANT INTERNATIONAL, 2020)
CRIS-Team WoS Importer:2020-11-06

Disruption of Tfh:B Cell Interactions Prevents Antibody-Mediated Rejection in a Kidney Transplant Model in Rats: Impact of Calcineurin Inhibitor Dose - Steines, Louisa; Poth, Helen; Schuster, Antonia; Amann, Kerstin Ute; Banas, Bernhard; Bergler, Tobias (Frontiers in Immunology, 2021)
We aimed to investigate the mechanisms of humoral immune activation in ABMR using a MHC-mismatched rat kidney transplant model. We applied low dose cyclosporine A (loCNI) to allow donor-specific antibody (DSA) formation and rejection and high dose cyclosporine A (hiCNI) for non-rejection. DSA and leukocyte subsets were measured by flow cytometry. Germinal centers (GC), T follicular helper cells (Tfh), plasma cells and interleukin-21 (IL-21) expression were analyzed by immunofluorescence microscopy. Expression of important costimulatory molecules and cytokines was measured by qRT-PCR. Allograft rejection was evaluated by a nephropathologist. We found that DSA formation correlated with GC frequency and expansion, and that GC size was linked to the number of activated Tfh. In hiCNI, GC and activated Tfh were virtually absent, resulting in fewer plasma cells and no DSA or ABMR. Expression of B cell activating T cell cytokine IL-21 was substantially inhibited in hiCNI, but not in loCNI. In addition, hiCNI showed lower expression of ICOS ligand and IL-6, which stimulate Tfh differentiation and maintenance. Overall, Tfh:B cell crosstalk was controlled only by hiCNI treatment, preventing the development of DSA and ABMR. Additional strategies targeting Tfh:B cell interactions are needed for preventing alloantibody formation and ABMR.
CRIS-Team Scopus Importer:2021-06-25
Keywords: antibody-mediated rejection; B cell activation; calcineurin inhibitor; donor-specific antibodies; kidney transplantation; T follicular helper cells

Dissecting TSC2-mutated renal and hepatic angiomyolipomas in an individual with ARID1B-associated intellectual disability - Popp, Bernt; Agaimy, Abbas; Kraus, Cornelia; Knaup, Karl; Ekici, Arif Bülent; Uebe, Steffen; Reis, André; Wiesener, Michael; Zweier, Christiane (BMC Cancer, 2019)
Background: Several subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex. Methods: We analyzed tumor and healthy tissue samples with exome and panel sequencing. Results: Additionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs. Conclusion: This unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance.
CRIS-Team Scopus Importer:2019-05-21
Keywords: Angiomyolipoma; ARID1B; Mosaic; Neurodevelopmental disorders; TSC2; Tuberous sclerosis complex

Disseminated cancer cells detected by immunocytology in lymph nodes of NSCLC patients are highly prognostic and undergo parallel molecular evolution - Elsner, Felix; Hoffmann, Martin; Fahrioglu-Yamaci, Rezan; Czyz, Zbigniew; Feliciello, Giancarlo; Mederer, Tobias; Polzer, Bernhard; Treitschke, Steffi; Rümmele, Petra; Weber, Florian; Wiesinger, Hellmuth; Robold, Tobias; et al. (Journal of Pathology, 2022)
In melanoma, immunocytology (IC) after sentinel lymph node disaggregation not only enables better quantification of disseminated cancer cells (DCCs) than routine histopathology (HP) but also provides a unique opportunity to detect, isolate, and analyse these earliest harbingers of metachronous metastasis. Here, we explored lymph node IC in non-small cell lung cancer (NSCLC). For 122 NSCLC patients, 220 lymph nodes (LNs) were split in half and prepared for IC and HP. When both methods were compared, IC identified 22% positive patients as opposed to 4.5% by HP, revealing a much higher sensitivity of IC (p < 0.001). Assessment of all available 2,952 LNs of the same patients by HP uncovered additional patients escaping detection of lymphatic tumour spread by IC alone, consistent with the concept of skip metastasis. A combined lymph node status of IC and complete HP on a larger cohort of patients outperformed all risk factors in multivariable analysis for prognosis (p < 0.001; RR = 2.290; CI 1.407–3.728). Moreover, isolation of DCCs and single-cell molecular characterization revealed that (1) LN-DCCs differ from primary tumours in terms of copy number alterations and selected mutations and (2) critical alterations are acquired during colony formation within LNs. We conclude that LN-IC in NSCLC patients when combined with HP improves diagnostic precision, has the potential to reduce total workload, and facilitates molecular characterization of lymphatically spread cancer cells, which may become key for the selection and development of novel systemic therapies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
CRIS-Team Scopus Importer:2022-10-07
Keywords: disseminated cancer cell; early metastasis; molecular evolution of NSCLC; prognosis

Disseminated Multifocal Intracerebral Bleeding Events in Three Coronavirus Disease 2019 Patients on Extracorporeal Membrane Oxygenation As Rescue Therapy. - Bihlmaier, Karl; Coras, Roland; Willam, Carsten; Grampp, Steffen; Jabari, Samir; Eichhorn, Philip; Haller, Florian; Kuramatsu, Joji; Schwab, Stefan; Castellanos, Ixchel; Birkholz, Torsten; Schüttler, Jürgen; et al. (Critical Care Explorations, 2020)
Objectives: To describe three coronavirus disease 2019 patients suffering from acute respiratory distress syndrome under venovenous extracorporeal membrane oxygenation therapy and tight anticoagulation monitoring presenting a novel pattern of multifocal brain hemorrhage in various degrees in all cerebral and cerebellar lobes. Design: Clinical observation of three patients. Post mortem examinations. Setting: Two ICUs at the University Hospital Erlangen. Patients: Three patients (medium age 56.6 yr, two male with hypertension and diabetes, one female with no medical history) developed severe acute respiratory distress syndrome on the basis of a severe acute respiratory syndrome coronavirus 2 infection. All required mechanical ventilation and venovenous extracorporeal membrane oxygenation support. Interventions: Clinical observation, CT, data extraction from electronic medical records, and post mortem examinations. Main Results: We report on an unusual multifocal bleeding pattern in the white matter in three cases with severe acute respiratory distress syndrome due to coronavirus disease 2019 undergoing venovenous extracorporeal membrane oxygenation therapy. Bleeding pattern with consecutive herniation was found in CT scans as well as in neuropathologic post mortem examinations. Frequency for this unusual brain hemorrhage in coronavirus disease 2019 patients with extracorporeal membrane oxygenation therapy at our hospital is currently 50%, whereas bleeding events in extracorporeal membrane oxygenation patients generally occur at 10-15%. Conclusions: Multifocality and high frequency of the unusual white matter hemorrhage pattern suggest a coherence to coronavirus disease 2019. Neuropathological analyses showed circumscribed thrombotic cerebrovascular occlusions, which eventually led to microvascular and later on macrovascular disseminated bleeding events. However, signs of cerebrovascular inflammation could not be detected. Polymerase chain reaction analyses of brain tissue or cerebrospinal fluid remained negative. Increased susceptibility for fatal bleeding events should be taken into consideration in terms of systemic anticoagulation strategies in coronavirus disease 2019.
EVALuna2:313697
Keywords: acute respiratory distress syndrome; cerebral microhemorrhage; coronavirus disease 2019; extracorporeal membrane oxygenation; intracerebral bleeding

Distant metastases in colorectal carcinoma: A proposal for a new M1 subclassification - Merkel, Susanne; Weber, K.; Croner, R. S.; Golcher, H.; Göhl, Jonas; Agaimy, Abbas; Semrau, S.; Wein, Axel; Hohenberger, Werner; Wittekind, C.; Siebler, Jürgen (Ejso, 2016)
In 2010, the seventh Tumour-Node-Metastasis (TNM) cancer staging system of the International Union for Cancer Control (UICC) and the American Joint Committee of Cancer (AJCC) introduced a subdivision of M1 in the TNM classification of colorectal carcinomas. For the eighth TNM edition which will be released in the autumn of 2016 and will become effective in January 2017 new proposals are appreciated. The aim of our study was to define a new and better proposal for M1 subclassification.In a total of 814 patients with stage IV colorectal carcinoma treated between 1995 and 2013 prognostic factors were analysed in univariate and multivariate analyses.Advanced age, treatment in the earlier period 1995-2003, involvement of multiple metastatic sites, and non-curative resection were found to be independent prognostic factors. In patients with only one metastatic site, survival was good in patients with liver or lung metastasis, moderate in patients with metastasis of the peritoneum or non-regional lymph nodes and poor in patients with other rarely metastatic involved organs. The new proposal defines M1a, Metastasis confined to one organ: liver or lung (2-year survival 51.6%); M1b, Metastasis confined to one organ: peritoneum or non-regional lymph nodes, or Metastasis confined to liver plus lung (2-year survival 39.4%); and M1c, Metastasis confined to one organ: all other sites, or Metastasis in more than one organ, except liver plus lung (2-year survival 21.6%).The new proposal can identify three prognostic groups in stage IV colorectal carcinomas with significant differences in survival.
EVALuna2:2060

Distinct genetic alterations and luminal molecular subtype in nested variant of urothelial carcinoma - Weyerer, Veronika; Weisser, Rebecca; Moskalev, Evgeny; Haller, Florian; Stöhr, Robert; Eckstein, Markus; Zinnall, Ulrike; Gaisa, Nadine T.; Comperat, Eva; Perren, Aurel; Keck, Bastian; Allory, Yves; et al. (Histopathology, 2019)
Aims Nested variant of urothelial carcinoma (NVUC) is rare, and only a few small series exist. Molecular characteristics and the classifying marker profile as well as therapeutic targets of this specific variant are mostly unknown. The aim of this study was to characterise NVUC at the molecular level in one of the largest cohorts to date. In addition, we applied an immunohistochemical marker panel in order to define the molecular subtype. Methods and results Sixty NVUC cases were collected from different departments. TERT promoter mutation analysis was carried out in all samples using SNaPshot analysis. Targeted sequencing of 48 cancer-related genes by next-generation sequencing (NGS) analysis was performed in a subset of 26 cases. Immunohistochemical markers CD44, CK5, CK14, EGFR, p63, FOXA1, GATA3, CD24 and CK20 were used to elucidate the molecular subtype. A total of 62.5% of NVUC cases harboured a mutation of the TERT promoter. Additionally, TP53, JAK3 and CTNNB1 were among the most frequently mutated genes identified by NGS analysis. Subtyping revealed that all NVUC express luminal markers such as CD24, FOXA1, GATA3 and CK20. Conclusions In summary, NVUC belong to the luminal molecular subtype. Moreover, a subset of NVUC seems to be characterised by mutations of the Wnt and inflammatory pathways, including JAK3 mutations, indicating a different biological background compared to conventional urothelial bladder cancer.
CRIS-Team WoS Importer:2019-11-01

Distinct genetic alterations and luminal molecular subtype in nested variant of urothelial carcinoma - Weyerer, Veronika; Weisser, R.; Moskalev, Evgeny; Haller, Florian; Stoehr, R.; Eckstein, Markus; Zinnall, U.; Gaisa, N. T.; Comperat, E.; Perren, A.; Keck, Bastian; Allory, Y.; et al. (Virchows Archiv, 2019)
CRIS-Team WoS Importer:2019-09-27

Distinct increased outliers among 136 rectal cancer patients assessed by ?H2AX - Kroeber, Jana; Wenger, Barbara; Schwegler, Manuela; Daniel, Christoph; Schmidt, Manfred; Djuzenova, Cholpon S.; Polat, Buelent; Flentje, Michael; Fietkau, Rainer; Distel, Luitpold (Radiation Oncology, 2015)
In recent years attention has focused on ?H2AX as a very sensitive double strand break indicator. It has been suggested that ?H2AX might be able to predict individual radiosensitivity. Our aim was to study the induction and repair of DNA double strand breaks labelled by ?H2AX in a large cohort.In a prospective study lymphocytes of 136 rectal cancer (RC) patients and 59 healthy individuals were ex vivo irradiated (IR) and initial DNA damage was compared to remaining DNA damage after 2 Gy and 24 hours repair time and preexisting DNA damage in unirradiated lymphocytes. Lymphocytes were immunostained with anti-?H2AX antibodies and microscopic images with an extended depth of field were acquired. ?H2AX foci counting was performed using a semi-automatic image analysis software.Distinct increased values of preexisting and remaining ?H2AX foci in the group of RC patients were found compared to the healthy individuals. Additionally there are clear differences within the groups and there are outliers in about 12% of the RC patients after ex vivo IR.The ?H2AX assay has the capability to identify a group of outliers which are most probably patients with increased radiosensitivity having the highest risk of suffering radiotherapy-related late sequelae.
EVALuna2:18245

Distinct mircobiomes in right- and left-sided colon cancer - Langheinrich, Melanie C.; Wirtz, Stefan; Kneis, Barbara; Weber, Klaus; Brunner, Maximilian; Krautz, Christian; Trebicka, Jonel; Agaimy, Abbas; Grützmann, Robert; Kersting, Stephan (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin-induced hemolytic-uremic syndrome in mice - Pirschel, Wiebke; Mestekemper, Antonio N.; Wissuwa, Bianka; Krieg, Nadine; Kröller, Sarah; Daniel, Christoph; Gunzer, Florian; Tolosano, Emanuela; Bauer, Michael; Amann, Kerstin Ute; Heinemann, Stefan H.; Coldewey, Sina M. (Kidney International, 2022)
Thrombotic microangiopathy, hemolysis and acute kidney injury are typical clinical characteristics of hemolytic-uremic syndrome (HUS), which is predominantly caused by Shiga-toxin–producing Escherichia coli. Free heme aggravates organ damage in life-threatening infections, even with a low degree of systemic hemolysis. Therefore, we hypothesized that the presence of the hemoglobin- and the heme-scavenging proteins, haptoglobin and hemopexin, respectively impacts outcome and kidney pathology in HUS. Here, we investigated the effect of haptoglobin and hemopexin deficiency (haptoglobin-/-, hemopexin-/-) and haptoglobin treatment in a murine model of HUS-like disease. Seven-day survival was decreased in haptoglobin-/- (25%) compared to wild type mice (71.4%), whereas all hemopexin-/- mice survived. Shiga-toxin–challenged hemopexin-/- mice showed decreased kidney inflammation and attenuated thrombotic microangiopathy, indicated by reduced neutrophil recruitment and platelet deposition. These observations were associated with supranormal haptoglobin plasma levels in hemopexin-/- mice. Low dose haptoglobin administration to Shiga-toxin–challenged wild type mice attenuated kidney platelet deposition and neutrophil recruitment, suggesting that haptoglobin at least partially contributes to the beneficial effects. Surrogate parameters of hemolysis were elevated in Shiga-toxin–challenged wild type and haptoglobin-/- mice, while signs for hepatic hemoglobin degradation like heme oxygenase-1, ferritin and CD163 expression were only increased in Shiga-toxin–challenged wild type mice. In line with this observation, haptoglobin-/- mice displayed tubular iron deposition as an indicator for kidney hemoglobin degradation. Thus, haptoglobin and hemopexin deficiency plays divergent roles in Shiga-toxin–mediated HUS, suggesting haptoglobin is involved and hemopexin is redundant for the resolution of HUS pathology.
CRIS-Team Scopus Importer:2022-03-25
Keywords: acute kidney injury; haptoglobin; hemolysis; hemolytic-uremic syndrome; hemopexin; iron homeostasis; Shiga toxin

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases - Wopperer, Florian; Knaup, Karl; Stanzick, Kira J.; Schneider, Karen; Jobst-Schwan, Tilman; Ekici, Arif Bülent; Uebe, Steffen; Wenzel, Andrea; Schliep, Stefan; Schürfeld, Carsten; Seitz, Randolf; Bernhardt, Wanja; et al. (Kidney International, 2022)
Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.
CRIS-Team Scopus Importer:2022-07-15
Keywords: ADTKD; Alport syndrome; exome; MITKD; MUC1; UMOD

DLL3 Expression in Neuroendocrine Carcinomas and Neuroendocrine Tumours: Insights From a Multicentric Cohort of 1294 Pulmonary and Extrapulmonary Neuroendocrine Neoplasms - Schmitt, Maxime; Bohnenberger, Hanibal; Bartsch, Detlef Klaus; Wagner, Daniel Christoph; Litmeyer, Anne Sophie; Grass, Albert; Rinke, Anja; Koch, Christine; Kremer, Marcus; Evert, Matthias; Märkl, Bruno; Quaas, Alexander; et al. (Endocrine Pathology, 2025)
Delta-like ligand 3 (DLL3) is frequently expressed in pulmonary small cell neuroendocrine carcinoma (SCNEC) and has emerged as a promising therapeutic target. However, limited data on DLL3 expression in other neuroendocrine neoplasms (NEN), such as extrapulmonary SCNEC, large cell neuroendocrine carcinomas (LCNEC), mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), gastroenteropancreatic neuroendocrine tumours (GEP-NET), and pulmonary carcinoids, impedes an estimation if other types of NEN might be suitable candidates for anti-DLL3 therapies. We evaluated DLL3 expression in 1294 NEN and 479 non-neuroendocrine carcinomas, correlating the findings with histological subtypes, tumour localisation, and overall survival (OS). Furthermore, we explored the concordance of DLL3 expression during metastatic progression in 67 paired primary NEN and metastases. DLL3 expression was significantly higher in NEC (64.0%) compared to GEP-NET and pulmonary carcinoids (10.1%, p < 0.001), particularly in SCNEC (80.4%), followed by LCNEC (62.6%) and MiNEN (28.6%). DLL3 was common in pulmonary carcinoids (41.5%), but rare in GEP-NET (5.1%) and non-neuroendocrine carcinomas (1.3%). Overall DLL3 expression was highly concordant between metastases and corresponding primary NEN (92.5%, p < 0.001). In univariable analyses, DLL3-expressing pulmonary carcinoids (p = 0.005) and GEP-NET (p = 0.018) were associated with decreased OS, but this was not retained in multivariable analyses adjusting for stage and grade (p = n. s.). No prognostic impact was observed in pulmonary (p = 0.708) or GEP-NEC (p = 0.87). Our study highlights significant differences in DLL3 expression across NEN subtypes and localisations, with largely concordant expression in metastases. DLL3-based therapies may be effective in many NEC and pulmonary carcinoids, while DLL3 appears to be a minor therapeutic target for GEP-NET and non-neuroendocrine carcinomas.
CRIS-Team Scopus Importer:2025-04-11
Keywords: DLL3; Neuroendocrine carcinoma; Neuroendocrine neoplasms; Neuroendocrine tumour

DMBT1 expression and neutrophil-to-lymphocyte ratio during necrotizing enterocolitis are influenced by impaired perfusion due to cardiac anomalies. - Diez, Sonja; Besendörfer, Manuel; Weyerer, Veronika; Hartmann, Arndt; Moosmann, Julia; Weiss, Christel; Renner, Marcus; Müller, Hanna (Molecular and Cellular Pediatrics, 2022)
BACKGROUND: Deleted in malignant brain tumors 1 (DMBT1) is involved in innate immunity and epithelial differentiation. It has been proven to play a role in various states of inflammation or hypoxia of fetal gastrointestinal and pulmonary diseases. Discrimination of pathogenesis in necrotizing enterocolitis (NEC) based on cardiac status improves the understanding of NEC in different patient subgroups. We aimed at examining DMBT1 expressions regarding their association with cardiac status leading to impaired intestinal perfusion, intraoperative bacteria proof, and a fulminant course of NEC. METHODS: Twenty-eight patients with NEC were treated surgically between 2010 and 2019 at our institution. DMBT1 expression was examined in intestinal sections using immunohistochemistry to detect DMBT1 protein. Associations of clinical parameters and DMBT1 expression were analyzed. RESULTS: We examined DMBT1 levels in 10 patients without cardiac defects and 18 patients with persisting ductus arteriosus (PDA) and congenital heart defects (CHD). Compared to patients without cardiac malformations, DMBT1 levels tended to score higher in patients with PDA/CHD (p = 0.2113) and were negatively correlated with C-reactive protein in these infants (p = 0.0172; r = - 0.5533). The number of DMBT1-expressing macrophages was elevated in the PDA/CHD-subgroup (p = 0.0399). Ratios of neutrophils and monocytes to lymphocytes were significantly higher in infants with PDA/CHD (p = 0.0319 and 0.0493). DMBT1 expression was significantly associated with positive bacterial culture of intraoperative swabs (p = 0.0252) and DMBT1 expression of the serosa was associated with a fulminant course of NEC (p = 0.0239). CONCLUSIONS: This study demonstrates that DMBT1 expression may be influenced by cardiac anomalies with an impaired intestinal perfusion in the neonatal intestine. NEC in PDA/CHD infants is associated with more DMBT1-positive macrophages and a significantly elevated neutrophil-to-lymphocyte ratio.
EVALuna2:497662
Keywords: DMBT1; Deleted in malignant brain tumors 1; Necrotizing enterocolitis; Congenital heart disease; Neutrophil-to-lymphocyte ratio; Monocyte-to-lymphocyte ratio

DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells - Gehring, Annemarie; Hübner, Kerstin; Rani, H.; Erlenbach-Wünsch, Katharina; Merkel, Susanne; Mahadevan, Vijayalakshmi; Grützmann, Robert; Hartmann, Arndt; Schneider-Stock, Regine (Scientific Reports, 2024)
TROP2 is a powerful cancer driver in colorectal cancer cells. Divergent epigenetic regulation mechanisms for the corresponding TACSTD2 gene exist such as miRNAs or DNA methylation. However, the role of TACSTD2 promoter hypermethylation in colorectal cancer has not been investigated yet. In this study, TROP2 expression strongly correlated with promoter methylation in different colorectal tumor cell lines. Treatment with 5-Azacytidine, a DNMT1 inhibitor, led to demethylation of the TACSTD2 promoter accompanied by an increase in TROP2 protein expression. TROP2 expression correlated with promoter methylation in vivo in human colon tumor tissue, thereby verifying promoter methylation as an important factor in the regulation of TROP2 expression in colorectal cancer. When performing a ChIP-Seq analysis in HCT116 and HT29 cells, we found that TACSTD2 promoter demethylation was accompanied by tri-methylation of H3K4. In silico analysis of GSE156613 data set confirmed that a higher binding of histone mark H3K4me3 around the TACSTD2 promoter was found in TACSTD2 high expressing tumors of colon cancer patients compared to the corresponding adjacent tumor tissue. Moreover, the link between TROP2 and the H3K4me3 code was even evident in tumors showing high intratumoral heterogeneity for TROP2 staining. Our data provide novel evidence for promoter demethylation and simultaneous gains of the active histone mark H3K4me3 across CpG-rich sequences, both being complementary mechanisms in the transcriptional regulation of TACSTD2 in colon cancer. The functional consequences of TROP2 loss in colorectal cancer needs to be further investigated.
CRIS-Team Scopus Importer:2024-02-16

DNA methylation and chromatin modifiers in colorectal cancer - Vymetalkova, Veronika; Vodicka, Pavel; Vodenkova, Sona; Alonso, Sergio; Schneider-Stock, Regine (Molecular Aspects of Medicine, 2019)
Colorectal carcinogenesis is a multistep process involving the accumulation of genetic alterations over time that ultimately leads to disease progression and metastasis. Binding of transcription factors to gene promoter regions alone cannot explain the complex regulation pattern of gene expression during this process. It is the chromatin structure that allows for a high grade of regulatory flexibility for gene expression. Posttranslational modifications on histone proteins such as acetylation, methylation, or phosphorylation determine the accessibility of transcription factors to DNA. DNA methylation, a chemical modification of DNA that modulates chromatin structure and gene transcription acts in concert with these chromatin conformation alterations. Another epigenetic mechanism regulating gene expression is represented by small non-coding RNAs. Only very recently epigenetic alterations have been included in molecular subtype classification of colorectal cancer (CRC). In this chapter, we will provide examples of the different epigenetic players, focus on their role for epithelial-mesenchymal transition and metastatic processes and discuss their prognostic value in CRC.
CRIS-Team Scopus Importer:2019-05-09
Keywords: Chromatin remodeling; Colorectal cancer; DNA methylation; Epigenetics; Epithelial-to-mesenchymal transition; Histone modifications; miRNA; Prognosis; Stemness

DNA methylation of the LEP gene is associated with craving during alcohol withdrawal - Hillemacher, Thomas; Weinland, Christian; Lenz, Bernd; Kraus, Thomas; Heberlein, Annemarie; Glahn, Alexander; Muschler, Marc A. N.; Bleich, Stefan; Kornhuber, Johannes; Frieling, Helge (Psychoneuroendocrinology, 2015)
Different studies have described evidence for an association between leptin serum levels and craving in alcohol dependent patients. As leptin expression is regulated by DNA methylation we investigated changes of DNA methylation of the LEP gene promoter region in alcohol dependent patients undergoing withdrawal. Results show that low methylation status is associated with increasing serum leptin levels and elevation of craving for alcohol in the referring patients group. These findings point towards a pathophysiological relevance of changes in DNA methylation of the LEP gene promoter region in alcohol dependence.
EVALuna2:23715

DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer - Teschendorff, Andrew E.; Gao, Yang; Jones, Allison; Rübner, Matthias; Beckmann, Matthias; Wachter, David; Fasching, Peter; Widschwendter, Martin (Nature Communications, 2016)
Identifying molecular alterations in normal tissue adjacent to cancer is important for understanding cancer aetiology and designing preventive measures. Here we analyse the DNA methylome of 569 breast tissue samples, including 50 from cancer-free women and 84 from matched normal cancer pairs. We use statistical algorithms for dissecting intra- and inter-sample cellular heterogeneity and demonstrate that normal tissue adjacent to breast cancer is characterized by tens to thousands of epigenetic alterations. We show that their genomic distribution is non-random, being strongly enriched for binding sites of transcription factors specifying chromatin architecture. We validate the field defects in an independent cohort and demonstrate that over 30% of the alterations exhibit increased enrichment within matched cancer samples. Breast cancers highly enriched for epigenetic field defects, exhibit adverse clinical outcome. Our data support a model where clonal epigenetic reprogramming towards reduced differentiation in normal tissue is an important step in breast carcinogenesis.
EVALuna2:6810

DNA Methylation Profiling of Salivary Gland Tumors Supports and Expands Conventional Classification - Jurmeister, Philipp; Leitheiser, Maximilian; Arnold, Alexander; Capilla, Emma Payá; Mochmann, Liliana H.; Zhdanovic, Yauheniya; Schleich, Konstanze; Jung, Nina; Chimal, Edgar Calderon; Jung, Andreas; Kumbrink, Jörg; Harter, Patrick; et al. (Modern Pathology, 2024)
Tumors of the major and minor salivary glands histologically encompass a diverse and partly overlapping spectrum of frequent diagnostically challenging neoplasms. Despite recent advances in molecular testing and the identification of tumor-specific mutations or gene fusions, there is an unmet need to identify additional diagnostic biomarkers for entities lacking specific alterations. In this study, we collected a comprehensive cohort of 363 cases encompassing 20 different salivary gland tumor entities and explored the potential of DNA methylation to classify these tumors. We were able to show that most entities show specific epigenetic signatures and present a machine learning algorithm that achieved a mean balanced accuracy of 0.991. Of note, we showed that cribriform adenocarcinoma is epigenetically distinct from classical polymorphous adenocarcinoma, which could support risk stratification of these tumors. Myoepithelioma and pleomorphic adenoma form a uniform epigenetic class, supporting the theory of a single entity with a broad but continuous morphologic spectrum. Furthermore, we identified a histomorphologically heterogeneous but epigenetically distinct class that could represent a novel tumor entity. In conclusion, our study provides a comprehensive resource of the DNA methylation landscape of salivary gland tumors. Our data provide novel insight into disputed entities and show the potential of DNA methylation to identify new tumor classes. Furthermore, in future, our machine learning classifier could support the histopathologic diagnosis of salivary gland tumors.
CRIS-Team Scopus Importer:2024-10-25
Keywords: diagnostic biomarkers; DNA methylation; machine learning; salivary gland tumors

DNA-methylation signature accurately differentiates pancreatic cancer from chronic pancreatitis in tissue and plasma - Wu, Yenan; Seufert, Isabelle; Al-Shaheri, Fawaz N.; Kurilov, Roman; Bauer, Andrea S.; Manoochehri, Mehdi; Moskalev, Evgeny; Brors, Benedikt; Tjaden, Christin; Giese, Nathalia A.; Hackert, Thilo; Büchler, Markus W.; et al. (Gut, 2023)
Objective: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases. Misdiagnoses in both directions, however, have severe consequences for patients. We set out to identify molecular markers for a clear distinction between PDAC and CP. Design: Genome-wide variations of DNA-methylation, messenger RNA and microRNA level as well as combinations thereof were analysed in 345 tissue samples for marker identification. To improve diagnostic performance, we established a random-forest machine-learning approach. Results were validated on another 48 samples and further corroborated in 16 liquid biopsy samples. Results: Machine-learning succeeded in defining markers to differentiate between patients with PDAC and CP, while low-dimensional embedding and cluster analysis failed to do so. DNA-methylation yielded the best diagnostic accuracy by far, dwarfing the importance of transcript levels. Identified changes were confirmed with data taken from public repositories and validated in independent sample sets. A signature of six DNA-methylation sites in a CpG-island of the protein kinase C beta type gene achieved a validated diagnostic accuracy of 100% in tissue and in circulating free DNA isolated from patient plasma. Conclusion: The success of machine-learning to identify an effective marker signature documents the power of this approach. The high diagnostic accuracy of discriminating PDAC from CP could have tremendous consequences for treatment success, once the result from still a limited number of liquid biopsy samples would be confirmed in a larger cohort of patients with suspected pancreatic cancer.
CRIS-Team Scopus Importer:2023-10-06
Keywords: chronic pancreatitis; pancreatic cancer

Do ANCAs make the difference in lupus nephritis? - Amann, Kerstin Ute (Kidney International, 2017)
There has been much debate as to whether the distinction between lupus nephritis class IV-S and class IV-G is clinically relevant and whether antineutrophil cytoplasmic antibodies are pathomechanistically involved because they have been associated with the more necrotic and pauci-inflammatory phenotype of lupus nephritis that is more often seen in class IV-S. Recent data show that antineutrophil cytoplasmic antibody positivity indeed influences the histological pattern of lupus nephritis and is associated with worse baseline renal function and more active lupus serology.
EVALuna2:25558

Does stimulation with human gonadotropins and gonadotropin-releasing hormone agonist enhance and accelerate the developmental capacity of oocytes in human ovarian tissue xenografted into severe combined immunodeficient mice? - Lotz, Laura; Schneider, Heike; Hackl, Janina; Wachter, David; Hoffmann, Inge; Jurgons, Roland; Beckmann, Matthias; Dittrich, Ralf (Fertility and Sterility, 2014)
To assess the capacity of human frozen-thawed ovarian follicles matured in xenografts to form metaphase II (MII) oocytes after xenotransplantation and exogenous stimulation.Prospective controlled animal study.University hospital gynecology research unit.Ovarian fragments were obtained from 17 women with malignant diseases who wished to cryopreserve ovarian tissue for later pregnancy before chemotherapy.Eighty-eight female severe combined immunodeficient (SCID) mice.Cryopreserved human ovarian tissue was grafted into oophorectomized SCID mice. The mice were divided into three groups: Group A received hMG alone every 2 days for a maximum of 24 weeks; group B additionally received nRH agonist (GnRHa) every 4 weeks; and group C was an untreated control group.Follicular density, morphology, proliferation, oocyte maturation, malignant cell contamination.Follicle survival and development were similar in all three groups. No significant interactions between the stimulation protocols and grafting duration were noted. Three MII oocytes were observed in grafted follicles. Two MII oocytes were harvested without stimulation. None of the mice showed signs of reintroduced malignancy, nor did microscopic evaluation of the grafts raise any suspicion of residual malignant disease.After xenotransplantation, human primordial follicles can be matured to MII oocytes even without stimulation. Administering human gonadotropin and GnRHa does not enhance the developmental capacity of xenografted oocytes. The optimal stimulation schedule for grafted tissue remains unknown.
EVALuna2:6659

Domain generalization across tumor types, laboratories, and species — Insights from the 2022 edition of the Mitosis Domain Generalization Challenge - Aubreville, Marc; Stathonikos, Nikolas; Donovan, Taryn A.; Klopfleisch, Robert; Ammeling, Jonas; Ganz, Jonathan; Wilm, Frauke; Veta, Mitko; Jabari, Samir; Eckstein, Markus; Annuscheit, Jonas; Krumnow, Christian; et al. (Medical Image Analysis, 2024)
Recognition of mitotic figures in histologic tumor specimens is highly relevant to patient outcome assessment. This task is challenging for algorithms and human experts alike, with deterioration of algorithmic performance under shifts in image representations. Considerable covariate shifts occur when assessment is performed on different tumor types, images are acquired using different digitization devices, or specimens are produced in different laboratories. This observation motivated the inception of the 2022 challenge on MItosis Domain Generalization (MIDOG 2022). The challenge provided annotated histologic tumor images from six different domains and evaluated the algorithmic approaches for mitotic figure detection provided by nine challenge participants on ten independent domains. Ground truth for mitotic figure detection was established in two ways: a three-expert majority vote and an independent, immunohistochemistry-assisted set of labels. This work represents an overview of the challenge tasks, the algorithmic strategies employed by the participants, and potential factors contributing to their success. With an F1 score of 0.764 for the top-performing team, we summarize that domain generalization across various tumor domains is possible with today's deep learning-based recognition pipelines. However, we also found that domain characteristics not present in the training set (feline as new species, spindle cell shape as new morphology and a new scanner) led to small but significant decreases in performance. When assessed against the immunohistochemistry-assisted reference standard, all methods resulted in reduced recall scores, with only minor changes in the order of participants in the ranking.
CRIS-Team Scopus Importer:2024-04-05
Keywords: Challenge; Deep Learning; Domain generalization; Histopathology; Mitosis

Domain Transfer in Histopathology using Multi-ProtoNets with Interactive Prototype Adaptation - Kletzander, Rosalie; Kuritcyn, Petr; Bruns, Volker; Benz, Michaela; Eckstein, Markus; Geppert, Carol-Immanuel; Hartmann, Arndt (Current Directions in Biomedical Engineering, 2023)
Few-shot learning addresses the problem of classification when little data or few labels are available. This is especially relevant in histopathology, where labeling must be carried out by highly trained medical experts. Prototypical Networks promise transferability to new domains by using a pre-Trained encoder and classifying by way of a prototypical representation of each class learned with few samples. We examine the applicability of this approach by attempting domain transfer from colon tissue (for training the encoder) to urothelial tissue. Furthermore, we address the problems arising from representing a class via a small amount of representatives (prototypes) by testing two different prototype calculation strategies. We compare the original "Prototype per Class"(PPC) approach to our "Prototype per Annotation"(PPA) method, which calculates one prototype for each example annotation made by the pathologist. We test the domain transfer capability of our approach on a dataset of 55 whole slide images (WSIs) containing six subtypes of urothelial carcinoma in two granularities: "Superclasses", which combines the tumorous subtypes into a single "tumor"class on top of a aggregated "healthy"and additional "necrosis"class, and "subtypes", which considers all eleven classes separately. We evaluate the classic PPC approach as well as our PPA approach on this data set. Our results show that the adaptation of the Prototypical Network from colon tissue to urothelial tissue was successful, yielding an F1 score of 0.91 for the "superclasses". Furthermore, the PPA approach performs very comparably to the PPC strategy. This makes it a viable alternative that places more value on the intent of the pathologist during annotation.
CRIS-Team Scopus Importer:2023-10-20
Keywords: domain transfer; few-shot learning; histopathology; prototype calculation strategy; Prototypical Networks; urothelial carcinoma

Donor acute kidney injury and short-term graft outcome in renal transplantation - Jacobi, Johannes; Rebhan, Dirk; Heller, Katharina; Velden, Joachim; Hilgers, Karl Friedrich; Wullich, Bernd; Eckardt, Kai-Uwe; Amann, Kerstin Ute (Clinical Transplantation, 2014)
With increased waiting times for kidney transplantation, marginal organs from expanded criteria donors (ECD) are increasingly offered for allocation. In addition to ECD status, donors may have suffered from acute kidney injury (AKI) prior to organ procurement.In this retrospective cohort study, we studied short-term allograft function in 517 kidney transplants performed between the years 2008-2014. Recipients of allografts from deceased organ donors were categorized as standard criteria donors (SCD) or ECD with or without AKI defined by RIFLE criteria.Of 382 deceased donations, 174 (45.5%) were classified as ECD and 63 (16.5%) fulfilled AKI criteria. Donor creatinine on hospital admission was similar, whereas creatinine before organ procurement differed (p < 0.001). Despite these differences, serum creatinine and eGFR at discharge and after one yr showed only minor differences between kidneys with or without AKI. In multivariate linear regression analyses, donor AKI was not a predictor of one-yr allograft function.Given the poor prognosis of dialysis patients and the increase in waiting time, kidneys from SCD and ECD donors with AKI should be allocated for transplantation. In case of ECD donors with AKI, recipients should be informed about the possibility of permanent non-function or early graft loss.
EVALuna2:3714

Donor-Derived Cell-Free DNA as a Companion Biomarker for AMR Treatment With Daratumumab: Case Series - Osmanodja, Bilgin; Akifova, Aylin; Budde, Klemens; Oellerich, Michael; Beck, Julia; Bornemann-Kolatzki, Kirsten; Schütz, Ekkehard; Velden, Joachim; Lehmann, Claudia; Krüger, Bastian Malte; Bachmann, Anette; Kowald, Jan (Transplant International, 2024)
Antibody-mediated rejection (AMR) is among the most frequent causes for graft loss after kidney transplantation. While there are no approved therapies, several case reports with daratumumab and the very recent phase 2 trial of felzartamab in AMR have indicated the potential efficacy of therapeutic interventions targeting CD38. Donor-derived cell-free DNA (dd-cfDNA) is an emerging biomarker with injury-specific release and a short half-life, which could facilitate early diagnosis of AMR and monitoring of treatment response. We describe two cases of patients with chronic active AMR, who were treated with monthly daratumumab infusions, and in whom donor-derived cell-free DNA (dd-cfDNA) was measured longitudinally to monitor treatment response. In both patients, daratumumab treatment led to stabilization of kidney function parameters, a strong decline of dd-cfDNA below the previously established threshold for rejection, and partial or complete histologic resolution of AMR activity. Our case series suggests that dd-cfDNA may be a useful companion biomarker for longitudinal monitoring of anti-CD38 treatment in patients with AMR.
CRIS-Team Scopus Importer:2024-08-30
Keywords: antibody-mediated rejection; biomarker; daratumumab; donor-derived cell-free DNA; kidney transplantation

Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model - Bernhardt, W. M.; Gottmann, U.; Doyon, F.; Buchholz, Björn; Campean, Valentina; Schödel, Johannes; Reisenbuechler, A.; Klaus, S.; Arend, M.; Flippin, L.; Willam, Carsten; Yard, B.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2009)
Long-term survival of renal allografts depends on the chronic immune response and is probably influenced by the initial injury caused by ischemia and reperfusion. Hypoxia-inducible transcription factors (HIFs) are essential for adaptation to low oxygen. Normoxic inactivation of HIFs is regulated by oxygen-dependent hydroxylation of specific prolyl-residues by prolyl-hydroxylases (PHDs). Pharmacological inhibition of PHDs results in HIF accumulation with subsequent activation of tissue-protective genes. We examined the effect of donor treatment with a specific PHD inhibitor (FG-4497) on graft function in the Fisher-Lewis rat model of allogenic kidney transplantation (KTx). Orthotopic transplantation of the left donor kidney was performed after 24 h of cold storage. The right kidney was removed at the time of KTx (acute model) or at day 10 (chronic model). Donor animals received a single dose of FG-4497 (40 mg/kg i.v.) or vehicle 6 h before donor nephrectomy. Recipients were followed up for 10 days (acute model) or 24 weeks (chronic model). Donor preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted beyond cold storage. It reduced acute renal injury (serum creatinine at day 10: 0.66 +/- 0.20 vs. 1.49 +/- 1.36 mg/dL; P < 0.05) and early mortality in the acute model and improved long-term survival of recipient animals in the chronic model (mortality at 24 weeks: 3 of 16 vs. 7 of 13 vehicle-treated animals; P < 0.05). In conclusion, pretreatment of organ donors with FG-4497 improves short-and long-term outcomes after allogenic KTx. Inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves clinical evaluation.
Keywords: hypoxia-inducible transcription factors; kidney injury; protection; transplantation

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer - Goode, Ellen L.; Block, Matthew S.; Kalli, Kimberly R.; Vierkant, Robert A.; Chen, Wenqian; Fogarty, Zachary C.; Gentry-Maharaj, Aleksandra; Toloczko, Aleksandra; Hein, Alexander; Bouligny, Aliecia L.; Jensen, Allan; Osorio, Ana; et al. (JAMA Oncology, 2017)
Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures: Overall survival time. Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. Conclusions and Relevance: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
EVALuna2:34270

Double-Sided Graphene-Enhanced Raman Scattering and Fluorescence Quenching in Hybrid Biological Structures - Sarau, George; Daniel, Christoph; Heilmann, Martin; Leuchs, Gerd; Amann, Kerstin Ute; Christiansen, Silke H. (Advanced Materials Technologies, 2021)
Due to their large contact and loading surfaces as well as high sensitivities to chemical changes, graphene-based materials (GBMs) are increasingly being employed into novel nanomedicine technologies. Here biomolecule-monolayer graphene-kidney tissue hybrid structures are studied using mapping micro-Raman and fluorescence spectroscopies. Because in this configuration graphene interacts with molecules on both sides, a double-sided graphene-enhanced Raman scattering (GERS) effect up to approximate to 10.1 is found for biomolecules adsorbed on graphene and amino acids in the kidney tissue below graphene. Moreover, graphene causes an efficient autofluorescence quenching (FLQ) up to approximate to 20% emitted by the kidney tissue. Despite the complexity of such layered materials, the intriguing simultaneous occurrence of double-sided GERS (a new development of GERS) and FLQ phenomena can be well explained by suitable molecular structure and energy level alignment between molecules and graphene. These result in effective charge transfer mediated by non-covalent interactions as indicated by correlative strain, doping, and defect analyses in graphene based on the Raman data and energy level calculations. Last, the advantages of using graphene over standard photobleaching are demonstrated. This work can be extended to other macromolecular entities toward integrating GBMs in versatile drug delivery, imaging, and sensing devices.
CRIS-Team WoS Importer:2021-08-13

Downregulation of Checkpoint Protein Kinase 2 in the Urothelium of Healthy Male Tobacco Smokers - Breyer, Johannes; Denzinger, Stefan; Hartmann, Arndt; Otto, Wolfgang (Urologia Internationalis, 2016)
With this letter to the editor we present for the first time a study on CHEK2 expression in normal urothelium of healthy male smokers, former smokers and non-smokers. We could show a statistically significant downregulation of this DNA repair gene in current smokers compared to non-smokers, suggesting that smoking downregulates CHEK2 in normal urothelium, probably associated with an early step in carcinogenesis of urothelial bladder carcinoma.
EVALuna2:6921

Downregulation of P-cadherin expression in hepatocellular carcinoma induces tumorigenicity - Bauer, Richard; Valletta, Daniela; Bauer, Karin; Thasler, Wolfgang E.; Hartmann, Arndt; Mueller, Martina; Reichert, Torsten E.; Hellerbrand, Claus (International Journal of Clinical and Experimental Pathology, 2014)
P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor.
EVALuna2:6674

DPP4-INHIBITOR LINAGLIPTIN ACCELERATES RESOLUTION OF CRESCENT FORMATION IN A RAT MODEL OF ANTI-GBM GLOMERULONEPHRITIS - Mayer, Anna-Lena; Ebert, Nadja; Klein, Thomas; Amann, Kerstin Ute; Daniel, Christoph (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2020-08-21

Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy with Severe Intercalated Disc Derangement in Humans and in Knock-In Mice - Herrmann, Harald; Cabet, Eva; Chevalier, Nicolas R.; Moosmann, Julia; Schultheis, Dorothea; Haas, Jan; Schowalter, Mirjam; Berwanger, Carolin; Weyerer, Veronika; Agaimy, Abbas; Meder, Benjamin; Müller, Oliver J.; et al. (Circulation, 2020)
Background: Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype. Methods: We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin. Results: Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed the DES variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype. Conclusions: We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.
CRIS-Team Scopus Importer:2020-12-11
Keywords: cardiomyopathies; desmin; desmosomes; intermediate filaments; intestinal pseudo-obstruction; muscle; smooth; muscle; striated

Dynamic study of the finger interphalangeal joint volar plate—motion analysis with magnetic resonance cinematography and histologic comparison - Lutter, Christoph; Kürten, Stefanie; Geppert, Carol-Immanuel; Mittelmeier, Wolfram; Klinder, Annett; Söder, Stephan; Roemer, Frank; Uder, Michael; Janka, Rolf Matthias; Bayer, Thomas (Skeletal Radiology, 2023)
Objective: We aimed to further improve knowledge about volar plate (VP) motion of the finger proximal interphalangeal joint (PIP), by analyzing the dynamic VP shape during a full range of finger flexion using magnetic resonance cinematography of the fingers (MRCF), and to compare the results with anatomical cross sections from cadaver specimens. Materials and methods: The dynamic sagittal VP shape was visualized with MRCF in a total number of 23 healthy volunteers. The length, angle, and thickness as well as the contact length of the VP to the PIP joint base were measured. Statistical analysis included t-test or rank-sum testing. Anatomical cross sections with differing degrees of PIP joint flexion were obtained from 12 cadaver specimens (fingers) for comparison. Results: Significant positive correlations between PIP joint flexion angle and VP area, length, depth and the VP contact length were found. This matched histologically to fiber rearrangements especially within the loose third VP layer. Conclusion: Our study analyzed the full range of motion dynamic VP shape of the PIP joint using MRCF. This contributes to a more precise understanding of the complex interaction of the VP with the PIP joint and may facilitate evaluation of clinical cases such as VP avulsion or pulley rupture.
CRIS-Team Scopus Importer:2023-02-17
Keywords: Dislocation; Injury; Microsurgery; MRI; Ultrasound

Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury - Tonnus, Wulf; Meyer, Claudia; Steinebach, Christian; Belavgeni, Alexia; von Mässenhausen, Anne; Gonzalez, Nadia Zamora; Maremonti, Francesca; Gembardt, Florian; Himmerkus, Nina; Latk, Markus; Locke, Sophie; Marschner, Julian; et al. (Nature Communications, 2021)
Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4cys/-) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.
CRIS-Team Scopus Importer:2021-08-06

Dysphonia as a Presenting Symptom of a Giant Left Atrial Sarcoma Developing within Five Years - Elbayomi, Mohamed; Nooh, Ehab; Weyand, Michael; Agaimy, Abbas; Harig, Frank (Thoracic and Cardiovascular Surgeon Reports, 2022)
An 83-year-old woman presented with a new onset of dyspnea and dysphonia. Physical examination revealed no abnormalities. Computerized tomography, bidimensional echocardiography, and cardiac magnetic resonance confirmed the presence of a cardiac mass in the left atrium. Surgical resection was uneventful and showed the origin of the mass in the ostium of the left inferior pulmonary vein. Histological evaluation revealed undifferentiated pleomorphic sarcoma with myxoid features. This case highlights the importance of considering cardiac neoplasms as a rare differential diagnosis, including rare and misleading clinical presentations.
CRIS-Team WoS Importer:2022-09-02

Dysplastic Lipoma A Distinctive Atypical Lipomatous Neoplasm With Anisocytosis, Focal Nuclear Atypia, p53 Overexpression, and a Lack of MDM2 Gene Amplification by FISH: A Report of 66 Cases Demonstrating Occasional Multifocality and a Rare Association With Retinoblastoma - Michal, Michael; Agaimy, Abbas; Contreras, Alejandro Luina; Svajdler, Marian; Kazakov, Dmitry V.; Steiner, Petr; Grossmann, Petr; Martinek, Petr; Hadravsky, Ladislav; Michalova, Kvetoslava; Svajdler, Peter; Szep, Zoltan; et al. (American Journal of Surgical Pathology, 2018)
In our routine and consultative pathology practices, we have repeatedly encountered an unusual subcutaneous fatty tumor with notable anisocytosis, single-cell fat necrosis, and patchy, often mild, adipocytic nuclear atypia. Because of the focal atypia, consultative cases have most often been received with concern for a diagnosis of atypical lipomatous tumor. Similar tumors have been described in small series under the designations "subcutaneous minimally atypical lipomatous tumors" and "anisometric cell lipoma." Sixty-six cases of this tumor type were collected and reviewed. Immunohistochemistry for p53, MDM2, CDK4, Retinoblastoma 1 (RB1) protein, CD34, S100, and CD163 was performed. Cases were tested for MDM2 gene amplification and RB1 gene deletion with fluorescence in situ hybridization (FISH) and for TP53 mutations by Sanger sequencing. Next-generation sequencing analysis using a panel of 271 cancer-related genes, including TP53, RB1, and MDM2, was also carried out. Our patient cohort included 57 male patients, 8 female patients, and 1 patient of unstated sex, who ranged in age from 22 to 87 years (mean: 51.2 y). All tumors were subcutaneous, with most examples occurring on the upper back, shoulders, or posterior neck (86.4%). Ten patients had multiple (2 to 5) lipomatous tumors, and the histology was confirmed to be similar in the different sites in 4 of them, including 1 patient who had a retinoblastoma diagnosed at age 1. The tumors were generally well circumscribed. At low magnification, there was notable adipocytic size variation with single-cell fat necrosis in the background associated with reactive histiocytes. Adipocytic nuclear atypia was typically patchy and characterized by chromatin coarsening, nuclear enlargement, and focal binucleation or multinucleation. Focal Lochkern change was frequent. In most instances, the degree of atypia was judged to be mild, but in 3 instances, it was more pronounced. Spindle cells were sparse or absent, and when present, cytologically bland. Thick ropy collagen bundles were absent. In all cases, p53 immunoexpression was noted (range: 2% to 20% of adipocytic nuclei), characteristically highlighting the most atypical cells. Twenty of 50 cases had MDM2 immunoreactivity, usually in <1% of the neoplastic cells, but in 4 cases, up to 10% of the cells were positive. Of 32 cases tested, 22 showed a near total loss of RB1 immunoexpression, and the remainder showed partial loss. Three of 13 cases showed RB1 gene deletion in >45% of the cells by FISH (our threshold value for reporting a positive result) with an additional 3 cases being very close to the required cutoff value. MDM2 gene amplification was absent in all 60 cases tested, including those with the greatest MDM2 immunoexpression and most pronounced atypia. All 5 tested cases showed no TP53 mutation with Sanger sequencing. Because of material quality issues, next-generation sequencing analysis could be performed in only 3 cases, and this did not reveal any recurrent mutations. All tumors were managed by simple local excision. Follow-up was available for 47 patients (range: 1 to 192 mo; mean: 27 mo) and revealed 2 local recurrences and no metastases. Dysplastic lipoma is a distinctive atypical fatty tumor variant that has p53 overexpression and RB1 gene abnormalities and lacks MDM2 gene amplification by FISH. These tumors have a strong male predominance and a notable tendency to involve the subcutaneous tissue of the shoulders, upper back and posterior neck. Multifocality is frequent (18. 9% of patients with follow-up information), and there is a rare association with retinoblastoma. This tumor warrants separation from ordinary lipoma with fat necrosis, fat-rich spindle cell lipoma and the conventional form of atypical lipomatous tumor that features MDM2 gene amplification.
EVALuna2:34865

Dysregulation of immune checkpoint molecules in oral cancer - Weber, Manuel; Lutz, Rainer; Glajzer, Jacek; Werry, Jan-Erik; Baran, Christoph; Frohwitter, Gesche; Eckstein, Markus; Kesting, Marco Rainer; Ries, Jutta (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Early C-reactive protein kinetics predicts immunotherapy response in non-small cell lung cancer in the phase III OAK trial - Saal, Jonas; Bald, Tobias; Eckstein, Markus; Ritter, Manuel; Brossart, Peter; Ellinger, Jörg; Hoelzel, Michael; Klümper, Niklas (JNCI Cancer Spectrum, 2023)
Static biomarkers like programmed death-ligand 1 (PD-L1) are insufficient to accurately predict response to immune checkpoint inhibition. Therefore, on-treatment biomarkers, which measure immediate therapy-associated changes, are currently shifting into the focus of immuno-oncology. A prime example of a simple predictive on-treatment biomarker is the early C-reactive protein (CRP) kinetics with its predictive CRP flare-response phenomenon. Here, we were able to confirm the predictive value of CRP flare-response kinetics in the pivotal phase III OAK trial (NCT02008227), which compared atezolizumab with docetaxel in patients with non-small cell lung cancer. Of note, CRP flare-response predicted favorable outcomes only in the immune checkpoint inhibition-treated subgroup, which suggests that it is an immunotherapy-specific phenomenon. In conclusion, we have for the first time validated the high predictive value of early CRP kinetics in a pivotal phase III trial, justifying the broad use of this cost-effective and easy-to-implement on-treatment biomarker to optimize therapy monitoring for patients with non-small cell lung cancer.
CRIS-Team WoS Importer:2023-05-26

Early CRP kinetics predict long-term treatment success and favorable outcomes of anti-PD-(L)1 immune checkpoint blockade in metastatic urothelial carcinoma - Klümper, Niklas; Sikic, Danijel; Saal, Jonas; Buettner, Thomas; Jarczyk, Jonas; Zeuschner, Philip; Weinke, Maximilan; Kalogirou, Charis; Breyer, Johannes; Burger, Maximilian; Nuhn, Philipp; Tully, Karl; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression - Botla, Sandeep K.; Savant, Soniya; Jandaghi, Pouria; Bauer, Andrea S.; Muecke, Oliver; Moskalev, Evgeny; Neoptolemos, John P.; Costello, Eithne; Greenhalf, William; Scarpa, Aldo; Gaida, Matthias M.; Buechler, Markus W.; et al. (Cancer Research, 2016)
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.
EVALuna2:6829

Early Ultrastructural Changes in Biopsies From Patients With Symptomatic CKD of Uncertain Etiology - Daniel, Christoph; Enghard, Philipp; Ratnatunga, Neelakanthi; Wijetunge, Sulochana; Wazil, A. W.M.; Zwiener, Christian; Barth, Johannes; Chandrajith, Rohana; Klewer, Monika; Eckardt, Kai-Uwe; Amann, Kerstin Ute; Freund, Paul; et al. (Kidney International Reports, 2023)
Introduction: Although the investigation of chronic kidney disease of uncertain etiology (CKDu) has identified many possible influencing factors in recent years, the exact pathomechanism of this disease remains unclear. Methods: In this study, we collected 13 renal biopsies from patients with symptomatic CKDu (Sym-CKDu) from Sri Lanka with well-documented clinical and socioeconomic factors. We performed light microscopy and electron microscopic evaluation for ultrastructural analysis, which was compared with 100 biopsies from German patients with 20 different kidney diseases. Results: Of the 13 Sri Lankan patients, 12 were men (92.3%), frequently employed in agriculture (50%), and experienced symptoms such as feeling feverish (83.3%), dysuria (83.3%), and arthralgia (66.6%). Light microscopic evaluation using activity and chronicity score revealed that cases represented early stages of CKDu except for 2 biopsies, which showed additional signs of diabetes. Most glomeruli showed only mild changes, such as podocyte foot process effacement on electron microscopy. We found a spectrum of early tubulointerstitial changes including partial loss of brush border in proximal tubules, detachment of tubular cells, enlarged vacuoles, and mitochondrial swelling associated with loss of cristae and dysmorphic lysosomes with electron-dense aggregates. None of these changes occurred exclusively in Sym-CKDu; however, they were significantly more frequent in these cases than in the control cohort. Conclusion: In conclusion, our findings confirm the predominant and early alterations of tubular structure in CKDu that can occur without significant glomerular changes. The ultrastructural changes do not provide concrete evidence of the cause of CKDu but were significantly more frequent in Sym-CKDu than in the controls.
CRIS-Team Scopus Importer:2023-03-17
Keywords: chronic kidney disease of uncertain etiology (CKDu); lysosomal alteration; mitochondrial swelling; renal biopsy; transmission electron microscopy; tubular injury

Easy performance of 6-color confocal immunofluorescence with 4-laser line microscopes - Eissing, Nathalie; Heger, Lukas; Baranska, Anna; Cesnjevar, Robert; Büttner, Maike; Söder, Stephan; Hartmann, Arndt; Heidkamp, Gordon Frederik; Dudziak, Diana (Immunology Letters, 2014)
Confocal laser scanning microscopy is an advanced technique for imaging tissue samples in vitro and in vivo at high optical resolution. The development of new fluorochrome variants do not only make it possible to perform multicolor flow cytometry of single cells, but in combination with high resolution laser scanning systems also to investigate the distribution of cells in lymphoid tissues by confocal immunofluorescence analyses, thus allowing the distinction of various cell populations directly in the tissue. Here, we provide a protocol for the visualization of at least six differently fluorochrome-labeled antibodies at the same time using a conventional confocal laser scanning microscope with four laser lines (405 nm, 488 nm, 555 nm, and 639 nm laser wavelength) in both murine and human tissue samples. We further demonstrate that compensation correction algorithms are not necessary to reduce spillover of fluorochromes into other channels when the used fluorochromes are combined according to their specific emission bands and the varying Stokes shift for co-excited fluorochromes with the same laser line.
EVALuna2:6626

EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees†. - Horwich, A.; Babjuk, M.; Bellmunt, J.; Bruins, H. M.; De Reijke, T. M.; De Santis, M.; Gillessen, Silke; James, Nick; Maclennan, Steven; Palou, J.; Powles, T.; Ribal, M. J.; et al. (Annals of Oncology, 2019)
BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.
EVALuna2:208656

EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort Under the Auspices of the EAU-ESMO Guidelines Committees - Witjes, J. Alfred; Babjuk, Marek; Bellmunt, Joaquim; Bruins, H. Maxim; De Reijke, Theo M.; De Santis, Maria; Gillessen, Silke; James, Nicholas; Maclennan, Steven; Palou, Juan; Powles, Tom; Ribal, Maria J.; et al. (European Urology, 2020)
Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.
CRIS-Team WoS Importer:2020-01-28

Ectopic thymic tissue and ectopic thymic tumors - Marx, A.; Ruediger, T.; Roessner, E.; Tzankov, Alexandar; De Montpreville, V. T.; Rieker, Ralf; Stroebel, P.; Weis, C. -A. (Pathologe, 2018)
Ectopic thymic tissue outside its core position in the antero-superior mediastinum is quite common owing to the complexity of embryonal thymus development, whereby reported prevalence values (1 to 90%) are heavily dependent on the method of investigation and the intensity of the workup. The debated prevalence and relevance of ectopic thymic tissue and its accessibility underlie the ongoing discussion whether modern, minimally invasive thymectomy strategies can match the proven benefit of the radical transsternal thymectomy procedure for the treatment of Myasthenia gravis. In this context, the following article covers the etiology, prevalence, and location of normal-looking, reactive, and neoplastic ectopic thymic tissue. Furthermore, ectopic tissues and tumors inside or adjacent to the thymus are mentioned.
EVALuna2:205513

Eculizumab as salvage therapy for recurrent monoclonal gammopathy-induced C3 glomerulopathy in a kidney allograft - Moog, Philipp; Jost, Philipp J.; Buettner-Herold, Maike (BMC Nephrology, 2018)
BACKGROUND: Monoclonal gammopathy causes several kinds of renal pathology. A rare and special form is monoclonal gammopathy-induced C3 glomerulopathy (MG-C3G). Like idiopathic C3G, MG-C3G frequently leads to end-stage renal disease. MG-C3G frequently recurs after renal transplantation, leading to graft failure in most of the patients. While there is some evidence for successful treatment of recurrent idiopathic C3 glomerulopathy with eculizumab after renal transplantation, nothing is known about its efficacy in the setting of recurrent MG-C3G. CASE PRESENTATION: We report a patient with recurrent MG-C3G in a renal allograft that was successfully treated with eculizumab in addition to standard immunosuppression. He had early recurrence of MG-C3G 2 months after transplantation. His graft function successively declined despite high dose steroids and plasmapheresis. Only after therapy with three cycles of bortezomib and continuous therapy with eculizumab, his graft function stabilized. He was still in clinical remission after 28 months of follow-up without having experienced major infectious complications. CONCLUSIONS: Eculizumab may be a safe and effective treatment of recurrent MG-C3G. Because of the high and early recurrence risk, renal transplantation should be reviewed carefully for every individual patient. Subsequent hematopoietic stem cell transplantation may ameliorate long-term renal allograft survival. Eculizumab might serve as a bridging therapy until stem cell transplantation.
EVALuna2:34435

Eculizumab in Pediatric Dense Deposit Disease - Oosterveld, Michiel J. S.; Garrelfs, Mark R.; Hoppe, Bernd; Florquin, Sandrine; Roelofs, Joris J. T. H.; Van Den Heuvel, L. P.; Amann, Kerstin Ute; Davin, Jean-Claude; Bouts, Antonia H. M.; Schriemer, Pietrik J.; Groothoff, Jaap W. (Clinical Journal of the American Society of Nephrology, 2015)
Dense deposit disease (DDD), a subtype of C3 glomerulopathy, is a rare disease affecting mostly children. Treatment options are limited. Debate exists whether eculizumab, a monoclonal antibody against complement factor C5, is effective in DDD. Reported data are scarce, especially in children.The authors analyzed clinical and histologic data of five pediatric patients with a native kidney biopsy diagnosis of DDD. Patients received eculizumab as therapy of last resort for severe nephritic or nephrotic syndrome with alternative pathway complement activation; this therapy was given only when the patients had not or only marginally responded to immunosuppressive therapy. Outcome measures were kidney function, proteinuria, and urine analysis.In all, seven disease episodes were treated with eculizumab (six episodes of severe nephritic syndrome [two of which required dialysis] and one nephrotic syndrome episode). Median age at treatment start was 8.4 (range, 5.9-13) years. For three treatment episodes, eculizumab was the sole immunosuppressive treatment. In all patients, both proteinuria and renal function improved significantly within 12 weeks of treatment (median urinary protein-to-creatinine ratio of 8.5 [range, 2.2-17] versus 1.1 [range, 0.2-2.0] g/g, P<0.005, and eGFR of 58 [range, 17-114] versus 77 [range, 50-129] ml/min per 1.73 m(2), P<0.01). A striking finding was the disappearance of leukocyturia within 1 week after the first eculizumab dose in all five episodes with leukocyturia at treatment initiation.In this case series of pediatric patients with DDD, eculizumab treatment was associated with reduction in proteinuria and increase in eGFR. Leukocyturia resolved within 1 week of initiation of eculizumab treatment. These results underscore the need for a randomized trial of eculizumab in DDD.
EVALuna2:25493

Editorial: Design, Synthesis, and Preclinical Testing of Innovative Anti-Cancer Compounds With a High Level of Selectivity of Action and Low Toxicity. - Ferreira, Ana Maria Da Costa; Schneider-Stock, Regine; Aiello, Francesca (Frontiers in Molecular Biosciences, 2022)
EVALuna2:515542

Editorial: Epithelial to Mesenchymal Plasticity in Colorectal Cancer - Bocci, Federico; Schneider-Stock, Regine; Banerjee, Sreeparna (Frontiers in Cell and Developmental Biology, 2022)
CRIS-Team Scopus Importer:2022-07-22
Keywords: colorectal cancer; EMT; MET; partial EMT; plasticity

Editorial for Special Issue: The Chorioallantoic Membrane (CAM) Model—Traditional and State-of-the Art Applications: The 1st International CAM Conference - Schneider-Stock, Regine; Flügen, Georg (Cancers, 2023)
CRIS-Team Scopus Importer:2023-02-17

Editorial: Methods in cardiovascular biologics and regenerative medicine - Gurusamy, Narasimman; Bergmann, Olaf; Castaldo, Clotilde; Huang, Ngan F.; Lien, Ching Ling; Tan, Jun Jie; Engel, Felix (Frontiers in Cardiovascular Medicine, 2024)
CRIS-Team Scopus Importer:2024-10-04
Keywords: 3D-bioprinting; cardiac remuscularization; methods in cardiovascular biologics; mitochondrial function; pericytes; regenerative medicine; tissue engineering; vascular grafts

Effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery: A single institutional experience - Stubbe, Franziska; Agaimy, Abbas; Ott, O.; Lettmaier, S.; Vassos, N.; Croner, R.; Hohenberger, Werner; Fietkau, Rainer; Semrau, S. (Cancer Radiotherapie, 2016)
There is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here.Between 2000 and 2011, 53 patients with UICC (2010) stage I (n=1, 1.9%), II (n=12, 22.7%) or III (n=40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5g/m(2)/day, d1-5, q28) and doxorubicin (50mg/m(2)/day, d3, q28) plus concurrent radiotherapy with a target dose of 50-64Gy (median 60Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia.At five years, the local control rate was 89.9% (±5.7%), distant metastasis-free survival 66.6% (±7.6%), and survival 83.3% (±6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III (n=21, 29.6%) and IV (n=18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate.Neoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy.
EVALuna2:6741

Effect of postoperative systemic prednisolone on short-term and long-term outcomes in chronic rhinosinusitis with nasal polyps: A multi-centered randomized clinical trial - Müller, Sarina Katrin; Wendler, Olaf; Mayr, Susanne; Traxdorf, Maximilian; Hosemann, Werner; Olze, Heidi; Steinhart, Helmut; Wiegand, Susanne; Teymoortash, Afshin; Kuehnel, Thomas; Hackenberg, Stephan; Hummel, Thomas; et al. (Frontiers in Immunology, 2023)
Introduction: The objective of this study was to determine whether postoperative additive systemic steroid administration in chronic rhinosinusitis with nasal polyps (CRSwNP) impacted selected endoscopic, subjective and objective outcome measures. Methods: This was a prospective, randomized, double-blind, placebo-controlled, noninferiority multicenter trial of n=106 patients with CRSwNP. All patients underwent primary functional endoscopic sinus surgery (FESS) followed by topical nasal steroids. Patients were randomized to a systemic steroid or placebo for 1 month. Patients were followed up for 2 years over 9 time points. The primary outcome measures were the differences between groups with respect to the nasal polyp score (NPS) and sinonasal quality of life (SNQoL). Secondary outcome measures included interactions with respect to the Lund-Kennedy score (LKS), sinonasal symptoms, general quality of life (GQoL), 16-item odor identification test scores, recurrence rates, need for revision surgery and mucus biomarker levels. Results: 106 patients were randomized to either the placebo or the systemic steroid group (n=53 per group). Postoperative systemic steroids were not superior to placebo with respect to all primary (p= 0.077) and secondary outcome measures (p>0.05 for all). Reported adverse events were similar between the two groups. Conclusion: In conclusion, the addition of postoperative systemic steroids after primary FESS did not confer a benefit over topical steroid nasal spray alone with respect to NPS, SNQOL, LKS, GQOL, sinonasal symptoms, smell scores, recurrence rates, the need for revision surgery or biomarkers over a short-term follow-up of up to 9 months and a long-term follow-up of up to 24 months in CRSwNP patients. Functional endoscopic surgery did, however, show a strong effect on all outcome measures, which remained relatively stable up to the endpoint at 2 years.
CRIS-Team Scopus Importer:2023-03-31
Keywords: chronic rhinosinusitis; long-term; nasal polyp (NP); postoperative; prednisolone; randomized controlled trial