A20 as a novel prognostic factor for recurrence and patients' survival in oral squamous cell carcinoma - Spörl, Silvia; Erber, Ramona; Gerken, M.; Fischer, R.; Taxis, J.; Meier, J. K.; Geppert, Carol-Immanuel; Hartmann, Arndt; Beckhove, P.; Mackensen, Andreas; Reichert, T.; Spanier, G.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

A20 as a Potential New Tool in Predicting Recurrence and Patient’s Survival in Oral Squamous Cell Carcinoma - Spoerl, Steffen; Erber, Ramona; Gerken, Michael; Taxis, Juergen; Ludwig, Nils; Nieberle, Felix; Biermann, Niklas; Geppert, Carol-Immanuel; Ettl, Tobias; Hartmann, Arndt; Beckhove, Philipp; Reichert, Torsten E.; et al. (Cancers, 2023)
A20, known as a potent inhibitor of NF-κB signaling, has been characterized in numerous clinical as well as preclinical studies. Recently, especially in various malignant diseases, the prognostic and therapeutic relevance of A20 was investigated. In oral squamous cell carcinoma (OSCC) however, the characterization of A20 is uncharted territory. We analyzed a tissue microarray (TMA) of 229 surgically-treated OSCC patients (2003–2013). Immunohistochemical (IHC) stainings were performed for A20 and CD3; additionally, standard haematoxylin-eosin staining was applied. IHC findings were correlated with a comprehensive dataset, comprising clinical and pathohistological information. A20 expression was analyzed in tumor cells as well as in tumor infiltrating lymphocytes (TILs) and correlated with the overall survival (OS) and recurrence-free survival (RFS) using uni- and multivariable Cox regression. The median follow-up time was 10.9 years and the A20 expression was significantly decreased in CD3+ TILs compared to mucosa-infiltrating lymphocytes (MILs). In the Kaplan–Meier analyses, higher A20 expression in TILs was correlated with better OS (p = 0.017) and RFS (p = 0.020). In the multivariable survival analysis, A20 overexpression correlated with improved OS (HR: 0.582; 95% CI 0.388–0.873, p = 0.009) and RFS (HR 0.605; 95% CI 0.411–0.889, p = 0.011). Our results indicate a novel prognostic role for A20 in OSCC. Due to its elevated expression in TILs, further research is highly desirable, which therefore could offer new therapeutic opportunities for patients suffering from OSCC.
CRIS-Team Scopus Importer:2023-02-24
Keywords: A20; oral squamous cell carcinoma; OSCC; tissue microarray; TNFAIP3

A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices - Bichlmayer, Eva Marie; Mahl, Lina; Hesse, Leo; Pion, Eric; Haller, Victoria; Moehwald, Andreas; Hackl, Christina; Werner, Jens M.; Schlitt, Hans J.; Schwarz, Siegfried; Kainz, Philipp; Brochhausen, Christoph; et al. (Cells, 2022)
(1) Background: Autosomal dominant polycystic kidney disease (ADPKD) is a frequent monogenic disorder that leads to progressive renal cyst growth and renal failure. Strategies to inhibit cyst growth in non-human cyst models have often failed in clinical trials. There is a significant need for models that enable studies of human cyst growth and drug trials. (2) Methods: Renal tissue from ADPKD patients who received a nephrectomy as well as adult mouse kidney slices were cultured on a chorioallantoic membrane (CAM) for one week. The cyst volume was monitored by microscopic and CT-based applications. The weight and angiogenesis were quantified. Morphometric and histological analyses were performed after the removal of the tissues from the CAM. (3) Results: The mouse and human renal tissue mostly remained vital for about one week on the CAM. The growth of cystic tissue was evaluated using microscopic and CT-based volume measurements, which correlated with weight and an increase in angiogenesis, and was accompanied by cyst cell proliferation. (4) Conclusions: The CAM model might bridge the gap between animal studies and clinical trials of human cyst growth, and provide a drug-testing platform for the inhibition of cyst enlargement. Real-time analyses of mouse kidney tissue may provide insights into renal physiology and reduce the need for animal experiments.
CRIS-Team Scopus Importer:2022-08-12
Keywords: 3D in vivo model; ADPKD; chorioallantoic membrane (CAM) model; human renal cystic tissue; mouse kidney slices; polycystic kidney disease

AA amyloidosis in inflammatory active malignant paraganglioma - Ihne, Sandra; Kircher, Malte; Papagianni, Aikaterini; Goetze, Oliver; Morbach, Caroline; Werner, Rudolf A.; Zeller, Daniel; Sommer, Claudia; Rosenwald, Andreas; Amann, Kerstin Ute; Linke, Reinhold P.; Lapa, Constantin; et al. (Amyloid-Journal of Protein Folding Disorders, 2022)
CRIS-Team WoS Importer:2022-02-11

Aberrant CD68 expression is a rare pitfall in the diagnosis of primary amelanotic malignant melanoma in ascites fluid - Krugmann, J.; Sterlacci, W.; Veits, L.; Vieth, M.; Rieker, R. J.; Altmann, T.; Sokolowski, T.; Fend, F. (Cytopathology, 2016)
EVALuna2:6807

Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad - Haller, Florian; Moskalev, Evgeny; Faucz, Fabio R.; Barthelmeß, Sarah; Wiemann, Stefan; Bieg, Matthias; Assie, Guillaume; Bertherat, Jerome; Schaefer, Inga-Marie; Otto, Claudia; Rattenberry, Eleanor; Maher, Eamonn R.; et al. (Endocrine-Related Cancer, 2014)
Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.
EVALuna2:6647

Aberrant expression of glyceraldehyde-3-phosphate dehydrogenase (Gapdh) in warthin tumors - Mandic, Robert; Agaimy, Abbas; Pinto-Quintero, Daniel; Roth, Katrin; Teymoortash, Afshin; Schwarzbach, Hans; Stoehr, Christine; Rodepeter, Fiona R.; Stuck, Boris A.; Bette, Michael (Cancers, 2020)
The Warthin tumor represents the second most frequent benign tumor of the parotid gland and is characterized by the presence of oncocytes rich in structurally and functionally altered mitochondria. Next to its role in metabolism, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is also implicated in cellular mitophagy. Immunohistochemistry was carried out on Warthin tumor and normal control (parotid gland with striated ducts) tissues, using anti-GAPDH specific antibodies followed by digital image analysis. Laser capture microdissection was used to isolate the oncocytic tumor cell and normal control striated duct compartments for RNA extraction and qPCR. Warthin tumor oncocytes exhibited a markedly spotted GAPDH staining pattern exhibiting cells with cytoplasmic and nuclear, only nuclear or none GAPDH staining. A significantly lower (p < 0.0001) total GAPDH signal was detected in Warthin tumor oncocytes. Similarly, significantly lower (p < 0.005) GAPDH mRNA levels were seen in oncocytes compared with normal ductal cells. To exclude the possibility of this GAPDH staining pattern being a general feature of oncocytic neoplasms of different organs, we tested a cohort of renal oncocytoma and oncocytic chromophobe carcinoma; none showed this type of staining. The observed progressive GAPDH loss in Warthin tumor oncocytes could be implicated in the pathogenesis of Warthin tumors.
CRIS-Team Scopus Importer:2020-06-02
Keywords: GAPDH; Mitophagy; Oncocyte; Warthin tumor

Ability of 18F-FDG Positron Emission Tomography Radiomics and Machine Learning in Predicting KRAS Mutation Status in Therapy-Naive Lung Adenocarcinoma - Zhang, Ruiyun; Shi, Kuangyu; Hohenforst-Schmidt, Wolfgang; Steppert, Claus; Sziklavari, Zsolt; Schmidkonz, Christian; Atzinger, Armin; Hartmann, Arndt; Vieth, Michael; Förster, Stefan (Cancers, 2023)
Objective: Considering the essential role of KRAS mutation in NSCLC and the limited experience of PET radiomic features in KRAS mutation, a prediction model was built in our current analysis. Our model aims to evaluate the status of KRAS mutants in lung adenocarcinoma by combining PET radiomics and machine learning. Method: Patients were retrospectively selected from our database and screened from the NSCLC radiogenomic dataset from TCIA. The dataset was randomly divided into three subgroups. Two open-source software programs, 3D Slicer and Python, were used to segment lung tumours and extract radiomic features from 18F-FDG-PET images. Feature selection was performed by the Mann–Whitney U test, Spearman’s rank correlation coefficient, and RFE. Logistic regression was used to build the prediction models. AUCs from ROCs were used to compare the predictive abilities of the models. Calibration plots were obtained to examine the agreements of observed and predictive values in the validation and testing groups. DCA curves were performed to check the clinical impact of the best model. Finally, a nomogram was obtained to present the selected model. Results: One hundred and nineteen patients with lung adenocarcinoma were included in our study. The whole group was divided into three datasets: a training set (n = 96), a validation set (n = 11), and a testing set (n = 12). In total, 1781 radiomic features were extracted from PET images. One hundred sixty-three predictive models were established according to each original feature group and their combinations. After model comparison and selection, one model, including wHLH_fo_IR, wHLH_glrlm_SRHGLE, wHLH_glszm_SAHGLE, and smoking habits, was validated with the highest predictive value. The model obtained AUCs of 0.731 (95% CI: 0.619 0.843), 0.750 (95% CI: 0.248 1.000), and 0.750 (95% CI: 0.448 1.000) in the training set, the validation set and the testing set, respectively. Results from calibration plots in validation and testing groups indicated that there was no departure between observed and predictive values in the two datasets (p = 0.377 and 0.861, respectively). Conclusions: Our model combining 18F-FDG-PET radiomics and machine learning indicated a good predictive ability of KRAS status in lung adenocarcinoma. It may be a helpful non-invasive method to screen the KRAS mutation status of heterogenous lung adenocarcinoma before selected biopsy sampling.
CRIS-Team Scopus Importer:2023-10-27
Keywords: KRAS; lung adenocarcinoma; machine learning; PET; radiomic features

Absolute quantification of DcR3 and GDF15 from human serum by LC-ESI MS - Lancrajan, Ioana Maria; Schneider-Stock, Regine; Naschberger, Elisabeth; Schellerer, Vera; Stürzl, Michael; Enz, Ralf (Journal of Cellular and Molecular Medicine, 2015)
Biomarkers are widely used in clinical diagnosis, prognosis and therapy monitoring. Here, we developed a protocol for the efficient and selective enrichment of small and low concentrated biomarkers from human serum, involving a 95% effective depletion of high-abundant serum proteins by partial denaturation and enrichment of low-abundant biomarkers by size exclusion chromatography. The recovery of low-abundance biomarkers was above 97%. Using this protocol, we quantified the tumour markers DcR3 and growth/differentiation factor (GDF)15 from 100 ?l human serum by isotope dilution mass spectrometry, using (15) N metabolically labelled and concatamerized fingerprint peptides for the both proteins. Analysis of three different fingerprint peptides for each protein by liquid chromatography electrospray ionization mass spectrometry resulted in comparable concentrations in three healthy human serum samples (DcR3: 27.23 ± 2.49 fmol/ml; GDF15: 98.11 ± 0.49 fmol/ml). In contrast, serum levels were significantly elevated in tumour patients for DcR3 (116.94 ± 57.37 fmol/ml) and GDF15 (164.44 ± 79.31 fmol/ml). Obtained data were in good agreement with ELISA and qPCR measurements, as well as with literature data. In summary, our protocol allows the reliable quantification of biomarkers, shows a higher resolution at low biomarker concentrations than antibody-based strategies, and offers the possibility of multiplexing. Our proof-of-principle studies in patient sera encourage the future analysis of the prognostic value of DcR3 and GDF15 for colon cancer patients in larger patient cohorts.
EVALuna2:4708

A case of multiple familial trichoepitheliomas responding to treatment with the Hedgehog signaling pathway inhibitor vismodegib - Baur, Vera; Papadopoulos, Thomas; Kazakov, Dmitry; Agaimy, Abbas; Hartmann, Arndt; Isbary, Georg; Wirtz, Ralph M.; Schultz, Erwin S. (Virchows Archiv, 2018)
Multiple familial trichoepitheliomas (MFT) is an autosomal dominantly inherited disease characterized by multiple skin appendage tumors. We describe a patient showing a continuous spectrum of follicular differentiated neoplasms including classical trichoepitheliomas but also infiltrative growing and finally metastasizing malignant follicular differentiated tumors. Germline mutation analysis revealed a nonsense mutation in the cylindromatosis (CYLD) gene. Gene expression analysis by real-time PCR of tumor tissue showed overexpression of glioma-associated oncogene Gli1 mRNA. Treatment with the Hedgehog pathway inhibitor vismodegib resulted in a significant regression of the highly differentiated trichoepitheliomas. Gli upregulation is indicative of an active Hedgehog signaling pathway. We hypothesize that its upregulation is indirectly caused by CYLD mutation which promotes tumor development. Vismodegib treatment could thus provide a new treatment option for patients with this debilitating disorder.
EVALuna2:34604

Accelerated Partial Breast Irradiation: Frequent non-professional Phagocytosis in Patients with early, Hormone Receptor-positive Breast Cancer is associated with good Survival - Bauer, Marcus; Schnellhardt, S.; Rosahl, M. -C; Erber, Ramona; Ott, Oliver; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Accelerated Partial Breast Irradiation: Identification of High Risk Tumors in Early Hormone Receptor-positive Breast Cancer by Macrophage Shift Classification - Schnellhardt, S.; Erber, Ramona; Büttner-Herold, Maike; Rosahl, M. -C; Ott, Oliver; Strnad, Vratislav; Beckmann, Matthias; King, L.; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Accelerated partial breast irradiation: Macrophage polarisation shift classification identifies high-risk tumours in early hormone receptor-positive breast cancer - Schnellhardt, Sören; Erber, Ramona; Büttner-Herold, Maike; Rosahl, Marie Charlotte; Ott, Oliver; Strnad, Vratislav; Beckmann, Matthias; King, Lillian; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (Cancers, 2020)
Studies have demonstrated correlations between accumulations of tumour-associated macrophages (TAMs), especially of M2-like phenotype, and increased mortality in advanced breast cancer. We investigated the prognostic potential of both main macrophage phenotypes in early hormone receptor-positive (HR+) breast cancer. The studied cohort of 136 patients participated in an institutional APBI phase II trial. Patient selection was characterized by HR+, small tumour size and no metastasis. Tissue microarrays from pre-RT resection samples were double stained for CD68/CD163 using immunohistochemistry. CD68+/CD163− cells were considered M1-like macrophages and CD68+/CD163+ was representative of M2-like macrophages. M1 and M2 macrophage densities were analysed semi-automatically in the stromal and intraepithelial tumour compartment. Low M1 and high M2 densities were strongly associated with decreased disease-free survival (DFS). Combined TAM phenotype densities were studied after defining a macrophage shift classification: M1-shifted (M1 high, M2 low) and non-shifted (M1 low, M2 low; M1 high, M2 high) tumours entailed a favourable outcome. In contrast, M2-shifted (M1 low, M2 high) TAM populations were associated with extremely reduced DFS. Thus, the full predictive potential of TAMs was revealed in a combined analysis of both phenotypes. The M2-shifted subgroup of tumours is classified as high-risk and probably not suitable for partial breast irradiation.
CRIS-Team Scopus Importer:2020-02-25
Keywords: Accelerated partial breast irradiation; CD163; CD68; Early breast cancer; Hormone receptor-positive; Prognosis; Tumour associated macrophages

Accuracy Analysis of a Next-Generation Tissue Microarray on Various Soft Tissue Samples of Wistar Rats - Werry, Jan-Erik; Müller, Stefan; Wehrhan, Falk; Geppert, Carol-Immanuel; Frohwitter, Gesche; Kaemmerer, Peer W.; Möst, Tobias; Lutz, Rainer; Homm, Andi; Kesting, Marco Rainer; Weber, Manuel; Ries, Jutta (Applied Sciences, 2021)
This study aimed to investigate accuracy in different sectional planes of the TMA Grand Master (3DHISTECH) Workstation in various soft tissue samples collected from Wistar rats. A total of 108 animals were sacrificed and 963 tissue specimens collected from 12 soft-tissue types. A total of 3307 tissue cores were punched and transferred into 40 recipient TMA blocks. Digital image analysis was performed. Core loss showed a significant correlation with tissue type and was highest in skin tissue (p < 0.001), renal medulla and femoral artery, nerve, and vein bundle (p < 0.01). Overall, 231 of 3307 tissue cores (7.0%) were lost. Hit rate analysis was performed in 1852 punches. The target was hit completely, partially and missed totally by 89.4%, 7.2% and 2.2%. A total of 54.5% of punches had good accuracy with less than 200 mu m deviation from the centre of the targeted region and 92.6% less than 500 mu m. Accuracy decreases with greater sectional depth. In the deepest sectional plane of roughly 0.5 mm median depth, almost 90% of cores had a deviation below 500 mu m. Recommendations for automated TMA creation are given in this article. The ngTMA(R)-method has proven accurate and reliable in different soft tissues, even in deeper sectional layers.
CRIS-Team WoS Importer:2021-07-09

Accuracy of colposcopic findings in detecting vaginal intraepithelial neoplasia: a retrospective study - Stuebs, F. A.; Adler, W.; Beckmann, Matthias; Gaß, Paul; Hartmann, Arndt; Mehlhorn, G.; Renner, S. K.; Schulmeyer, Carla; Strehl, J.; Koch, Matthias (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Accuracy of colposcopic findings in detecting vaginal intraepithelial neoplasia: a retrospective study - Stuebs, Frederik A.; Koch, Martin; Mehlhorn, Grit; Gaß, Paul; Schulmeyer, Carla; Hartmann, Arndt; Strehl, Johanna; Adler, Werner; Beckmann, Matthias; Renner, Stefan (Archives of Gynecology and Obstetrics, 2020)
Purpose: Malignancies of the vagina are rare, but colposcopy-directed biopsies play a major role in detecting vaginal intraepithelial lesions. Data of accuracy in detecting neoplasia of the vagina are very rare compared to accuracy in detecting cervical neoplasia. The aim of this study was to evaluate the accuracy of colposcopy-directed biopsy in comparison with clinical findings of the examiner. Methods: The accuracy of colposcopy-directed biopsy was compared with the clinical finding in relation to the patient’s age and the examiner’s level of training. This was done in combination with PAP-smear, HPV-test results, and the history of other malignancies of the lower genital tract. The data were collected between January 2014 and February 2018 at the certified Dysplasia Unit of the University Hospital Erlangen. Results: In total, 253 biopsies from 253 women from the vagina were obtained. The overall accuracy of biopsy in comparison with clinical finding was 52.17% for all entities—benign lesions, low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and vaginal carcinoma. The accuracy for detecting HSIL was 82.46% (47/57), with an underdiagnosis rate of 15.79% and an overdiagnosis rate of 1.79%. Conclusion: With a sensitivity of over 80%, colposcopy-directed biopsy plays an important role in detecting vaginal–HSIL. A highly experienced practitioner is increasing the sensitivity in detecting vaginal–HSIL. Careful examination is required in women with a history of HSIL of the lower genital tract or with simultaneous neoplasia because they are of greater risk of developing vaginal malignancies. The combination of careful clinical work up, PAP-smear, HPV-testing, and colposcopy-guided biopsy is crucial in detecting vaginal–HSIL.
CRIS-Team Scopus Importer:2020-02-04
Keywords: Colposcopy-directed biopsy; High-grade squamous intraepithelial lesion (HSIL); Vaginal cancer; Vaginal intraepithelial neoplasia (VaIN)

Accuracy of colposcopy-directed biopsy in detecting early cervical neoplasia: a retrospective study - Stuebs, Frederik A.; Schulmeyer, Carla E.; Mehlhorn, Grit; Gaß, Paul; Kehl, Sven; Renner, Simone K.; Renner, Stefan; Geppert, Carol-Immanuel; Adler, Werner; Hartmann, Arndt; Beckmann, Matthias; Koch, Martin (Archives of Gynecology and Obstetrics, 2019)
PurposeColposcopy-directed biopsy is a cornerstone method for diagnosing cervical intraepithelial neoplasia. The aim of this study was to evaluate the accuracy of colposcopy-directed biopsy in comparison with definitive surgery.MethodsThe accuracy of colposcopy-directed biopsy was compared with the final histology in relation to different types of transformation zone (TZ), the patient's age, and the examiner's level of training.ResultsThe overall accuracy of biopsy in comparison with definitive surgery was 71.9% for all entitiesbenign lesions, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions (HSILs), and cervical carcinomawith an underdiagnosis rate of 11.8% and an overdiagnosis rate of 16.5%. The accuracy for detecting HSIL was 88% (401/455), with an underdiagnosis rate of 10.5% and overdiagnosis rate of 1.3%. The accuracy rates for detecting HSIL in women with TZ1, TZ2, or TZ3 were 92.2, 90.5, and 76.5%, respectively. The accuracy rates for detecting HSIL in the different age groups were 93.1% (age 0-34), 83.6% (age 34-55), and 80% (age 55 or older).ConclusionsA combination of the colposcopic findings, cytology, human papillomavirus testing, and colposcopy-directed biopsy is necessary for the correct diagnosis of HSIL. The accuracy rate depends on the TZ and the patient's age. The examiner's level of training does not have any substantial influence on the accuracy.
CRIS-Team WoS Importer:2019-03-08

Accuracy of radiological tumour size assessment and the risk for re-excision in a cohort of primary breast cancer patients - Meier-Meitinger, Martina; Rauh, Claudia; Adamietz, B.; Fasching, Peter; Schwab, Siegfried; Häberle, Lothar; Hein, Alexander; Bayer, Christian M.; Bani, Mayada; Lux, Michael P.; Hartmann, Arndt; Wachter, David Lukas; et al. (Ejso, 2012)
Background: Re-operations after breast conserving surgery (BCS) are necessary, when specimen margins are not free of breast cancer cells. This study explored the accuracy of preoperative tumour size assessment and its influence on the rate of re-excisions and mastectomies. Methods: The study included 1591 patients with invasive breast cancer, who were planned for BCS. Patient, staging and tumor characteristics were evaluated concerning their influence on re-excision and mastectomy rates. Patient and tumor characteristics comprised histopathological tumour size, HER2 status, multifocality, in situ component, grading (G), nodal status and hormone receptor (HR) status. Staging characteristics included deviation from pathological tumour size as measured by clinical examination, sonography and mammography. Results: In 1316 patients (83%) sufficient treatment was possible with one operation. 275 patients (17%) had to undergo at least one further surgery as a result of positive specimen margins. In 138 patients (9%) mastectomy was ultimately necessary. In patients with a positive HER2 status, a larger tumour size, underestimation by ultrasound, an in situ component and multifocality, the risk for a re-operation was about doubled. Tumour size deviation in the mammogram or the clinical tumour size assessment did not have significant influence to the re-excision rates. Conclusion: Tumour size and accurate presurgical assessment of the tumour size itself are independent predictors for the need of a second surgery or even a mastectomy in patients for whom a primary BCS was planned. © 2011 Elsevier Ltd. All rights reserved.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Breast cancer; Mastectomy; Re-excision; Tumour size; Ultrasound

Accuracy of vulvoscopic findings in detecting early vulvar neoplasia - Stuebs, F. A.; Mehlhorn, G.; Gaß, Paul; Schulmeyer, Carla; Adler, Werner; Strehl, J.; Hartmann, Arndt; Beckmann, Matthias; Renner, S. K.; Koch, Matthias (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Acid sphingomyelinase promotes endothelial stress response in systemic inflammation and sepsis - Chung, Ha-Yeun; Hupe, Daniel C.; Otto, Gordon P.; Sprenger, Marcel; Bunck, Alexander C.; Dorer, Michael J.; Bockmeyer, Clemens L.; Deigner, Hans-Peter; Graeler, Markus H.; Claus, Ralf A. (Molecular Medicine, 2016)
The pathophysiology of sepsis involves activation of acid sphingomyelinase (SMPD1) with subsequent generation of the bioactive mediator ceramide. We herein evaluated the hypothesis that the enzyme exerts biological effects in endothelial stress response. Plasma-secreted sphingomyelinase activity, ceramide generation and lipid raft formation were measured in human microcirculatory endothelial cells (HMEC-1) stimulated with serum obtained from sepsis patients. Clustering of receptors relevant for signal transduction was studied by immuno staining. The role of SMPD1 for macrodomain formation was tested by pharmacological inhibition. To confirm the involvement of the stress enzyme, direct inhibitors (amino bisphosphonates) and specific downregulation of the gene was tested with respect to ADAMTS13 expression and cytotoxicity. Plasma activity and amount of SMPD1 were increased in septic patients dependent on clinical severity. Increased breakdown of sphingomyelin to ceramide in HMECs was observed following stimulation with serum from sepsis patients in vitro. Hydrolysis of sphingomyelin, clustering of receptor complexes, such as the CD95L/Fas-receptor, as well as formation of ceramide enriched macrodomains was abrogated using functional inhibitors (desipramine and NB6). Strikingly, the stimulation of HMECs with serum obtained from sepsis patients or mixture of proinflammatory cytokines resulted in cytotoxicity and ADAMTS13 downregulation which was abrogated using desipramine, amino bisphosphonates and genetic inhibitors. SMPD1 is involved in the dysregulation of ceramide metabolism in endothelial cells leading to macrodomain formation, cytotoxicity and downregulation of ADAMTS13 expression. Functional inhibitors, such as desipramine, are capable to improve endothelial stress response during sepsis and might be considered as a pharmacological treatment strategy to favor the outcome.
EVALuna2:25519

A collagen-binding protein enables molecular imaging of kidney fibrosis in vivo - Baues, Maike; Klinkhammer, Barbara M.; Ehling, Josef; Gremse, Felix; van Zandvoort, Marc A.M.J.; Reutelingsperger, Chris P.M.; Daniel, Christoph; Amann, Kerstin Ute; Bábíčková, Janka; Kiessling, Fabian; Floege, Jürgen; Lammers, Twan; et al. (Kidney International, 2019)
Pathological deposition of collagen is a hallmark of kidney fibrosis. To illustrate this process we employed multimodal optical imaging to visualize and quantify collagen deposition in murine models of kidney fibrosis (ischemia-reperfusion or unilateral ureteral obstruction) using the collagen-binding adhesion protein CNA35. For in vivo imaging, we used hybrid computed tomography-fluorescence molecular tomography and CNA35 labeled with the near-infrared fluorophore Cy7. Upon intravenous injection, CNA35-Cy7 accumulation was significantly higher in fibrotic compared to non-fibrotic kidneys. This difference was not detected for a non-specific scrambled version of CNA35-Cy7. Ex vivo, on kidney sections of mice and patients with renal fibrosis, CNA35-FITC co-localized with fibrotic collagen type I and III, but not with the basement membrane collagen type IV. Following intravenous injection, CNA35-FITC bound to both interstitial and perivascular fibrotic areas. In line with this perivascular accumulation, we observed significant perivascular fibrosis in the mouse models and in biopsy sections from patients with chronic kidney disease using computer-based morphometry quantification. Thus, molecular imaging of collagen using CNA35 enabled specific non-invasive quantification of kidney fibrosis. Collagen imaging revealed significant perivascular fibrosis as a consistent component next to the more commonly assessed interstitial fibrosis. Our results lay the basis for further probe and protocol optimization towards the clinical translation of molecular imaging of kidney fibrosis.
CRIS-Team Scopus Importer:2019-12-17
Keywords: chronic kidney disease (CKD); collagen; extracellular matrix; molecular imaging; non-invasive imaging; renal fibrosis

A comparison between p16-positive head and neck cancer of unknown primary (HPV-HNCUP) and oropharyngeal squamous cell carcinoma (HPV-OPSCC): are they the same disease? - Balk, Matthias; Rupp, Robin; Sievert, Matti; Mantsopoulos, Konstantinos; Allner, Moritz; Grundtner, Philipp; Müller-Hübner, Sarina Katrin Ursel; Eckstein, Markus; Iro, Heinrich; Hecht, Markus; Gostian, Antoniu-Oreste (European Archives of Oto-Rhino-Laryngology, 2023)
Introduction: The following study aimed to answer the question if HPV-HNCUP and HPV-OPSCC are the same disease. Propensity score matching (PSM) was used to compare the oncological outcomes of both groups, in particular the 5-year overall survival rate (OS), the 5-year disease specific survival rate (DSS) and the 5-year progression free survival rate (PFS). Materials and methods: Firstly, between January 1st, 2007, and March 31st, 2020 a total of 131 patients were treated with HNCUP at our Department. Out of these, 21 patients with a confirmed positive p16 status were referred to surgery followed by adjuvant therapy. Secondly, between January 1st, 2000, and January 31st, 2017, a total of 1596 patients were treated with an OPSSC at our Department. Out of these, 126 patients with a confirmed positive p16 status were referred to surgery followed by adjuvant therapy. After PSM, 84 patients with HPV-OPSCC and 21 HPV-HNCUP remained in the study for further comparison. Results: The OS was 63.5% (95% CI 39.4–87.6) for HPV-HNCUP and 88.9% (95% CI 90.4–100.0) for HPV-OPSCC patients and therefore, significantly lower for the first mentioned (p = 0.013). The DSS was also significantly impaired for HPV-HNCUP (71.0%, 95% CI 46.3–95.7), in comparison with HPV-OPSCC patients (95.5%, 95% CI 90.4–100.0; p = 0.002). The PFS for HPV-HNCUP patients was lower (75.6%, 95% CI 54.0–97.2) yet not significantly different to HPV-OPSCC (90.4%, 95% CI 83.5–97.3; p = 0.067). Conclusions: The results presented demonstrate a significant reduced OS and DSS for HPV-HNCUP patients. Accordingly, in our study HPV-HNCUP and HPV-OPSCC are two different entities with a different oncological outcome.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Cancer of unknown primary; Head and neck cancer; HPV-HNCUP; HPV-OPSCC; Neck dissection; Oropharyngeal cancer

A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1 -altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1 - amplified Versus GLI1- rearranged Tumors. - Saoud, Carla; Agaimy, Abbas; Dermawan, Josephine K.; Chen, Jie Fu; Rosenblum, Marc K.; Dickson, Brendan C.; Dashti, Nooshin; Michal, Michael; Kosemehmetoglu, Kemal; Din, Nasir Ud; Albritton, Karen; Agaram, Narasimhan P.; et al. (American Journal of Surgical Pathology, 2024)
GLI1 -altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1 -altered mesenchymal neoplasms to date, including 23 GLI1- amplified and 15 GLI1 -rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1- rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1 -amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1 -amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1- amplified tumors. GLI1 -amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1 -amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1 -rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1 -amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1- rearranged group. Despite comparable progression rates, GLI1 -amplified tumors had a shorter median progression-free survival compared with GLI1 -rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1 -altered mesenchymal tumors.
EVALuna2:570328

Acoustic radiation force impulse (ARFI) and high-frequency ultrasound of the liver surface for the diagnosis of compensated liver cirrhosis - Pfeifer, Lukas; Görtz, Rüdiger; Sturm, Jörg; Wachter, David; Riener, M. O.; Schwitulla, Judith; Bernatik, T.; Neurath, Markus; Strobel, Deike (Ultraschall in der Medizin, 2014)
To evaluate the diagnostic value of acoustic radiation force impulse (ARFI) and high-frequency ultrasound of the liver surface, using histology as a gold standard for the diagnosis of compensated liver cirrhosis.73 patients without ascites undergoing liver biopsy were included in the study. The left and right liver lobes were examined with ARFI and high-frequency ultrasound. Liver surface irregularity was quantified using image analysis software to calculate the difference between the real surface and the approximated physiological surface through a 20 mm standardized line.There is a significant difference between cirrhotic and non-cirrhotic patients for both quantified liver surface (QLS) and ARFI (p < 0.001). The mean values for QLS of the left lobe were 0.71 ± 0.24 mm and 1.17 ± 0.80 mm, of the right lobe 0.56 ± 0.26 mm and 0.87 ± 0.26 mm for non-cirrhotic and cirrhotic patients, respectively. The mean values of ARFI measurements of the left lobe were 2.04 ± 0.76 m/s and 2.85 ± 0.81 m/s, of the right lobe 1.65 ± 0.61 m/s and 3.02 ± 0.77 m/s for non-cirrhotic and cirrhotic patients, respectively. Diagnostic accuracy (AUROC) was 0.78/0.80 for QLS and 0.77/0.91 for ARFI of the left/right lobe, respectively. ARFI of the right lobe is significantly better than ARFI of the left (p = 0.023) or QLS of the left (p = 0.025)/right (p = 0.046) lobe of the liver.Assessment of liver surface irregularity by high-frequency ultrasound (QLS) is a useful diagnostic test for the assessment of compensated liver cirrhosis. ARFI of the right liver lobe is significantly better than high-frequency ultrasound (QLS of the left/right lobe of the liver) and ARFI of the left lobe of the liver.
EVALuna2:1858

Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion - Roeder, Sebastian S.; Barnes, Taylor J.; Lee, Jonathan S.; Kato, India; Eng, Diana G.; Kaverina, Natalya V.; Sunseri, Maria W.; Daniel, Christoph; Amann, Kerstin Ute; Pippin, Jeffrey W.; Shankland, Stuart J. (Kidney International, 2017)
The glycoprotein CD44 is barely detected in normal mouse and human glomeruli, but is increased in glomerular parietal epithelial cells following podocyte injury in focal segmental glomerulosclerosis (FSGS). To determine the biological role and regulation of CD44 in these cells, we employed an in vivo and in vitro approach. Experimental FSGS was induced in CD44 knockout and wild-type mice with a cytotoxic podocyte antibody. Albuminuria, focal and global glomerulosclerosis (periodic acid-Schiff stain), and collagen IV staining were lower in CD44 knockout compared with wild-type mice with FSGS. Parietal epithelial cells had lower migration from Bowman's capsule to the glomerular tuft in CD44 knockout mice with disease compared with wild type mice. In cultured murine parietal epithelial cells, overexpressing CD44 with a retroviral vector encoding CD44 was accompanied by significantly increased collagen IV expression and parietal epithelial cell migration. Because our results showed de novo co-staining for activated ERK1/2 (pERK) in parietal epithelial cells in experimental FSGS, and also in biopsies from patients with FSGS, two in vitro strategies were employed to prove that pERK regulated CD44 levels. First, mouse parietal epithelial cells were infected with a retroviral vector for the upstream kinase MEK-DD to increase pERK, which was accompanied by increased CD44 levels. Second, in CD44-overexpressing parietal epithelial cells, decreasing pERK with U0126 was accompanied by reduced CD44. Finally, parietal epithelial cell migration was higher in cells with increased and reduced in cells with decreased pERK. Thus, pERK is a regulator of CD44 expression, and increased CD44 expression leads to a pro-sclerotic and migratory parietal epithelial cell phenotype.
EVALuna2:25535

Activating enhancer binding protein 2 epsilon (AP-2?)-deficient mice exhibit increased matrix metalloproteinase 13 expression and progressive osteoarthritis development - Niebler, Stephan; Schubert, Thomas; Hunziker, Ernst B.; Boßerhoff, Anja Katrin (Arthritis Research & Therapy, 2015)
The transcription factor activating enhancer binding protein 2 epsilon (AP-2?) was recently shown to be expressed during chondrogenesis as well as in articular chondrocytes of humans and mice. Furthermore, expression of AP-2? was found to be upregulated in affected cartilage of patients with osteoarthritis (OA). Despite these findings, adult mice deficient for AP-2? (Tfap2e(-/-)) do not exhibit an obviously abnormal cartilaginous phenotype. We therefore analyzed embryogenesis of Tfap2e(-/-) mice to elucidate potential transient abnormalities that provide information on the influence of AP-2? on skeletal development. In a second part, we aimed to define potential influences of AP-2? on articular cartilage function and gene expression, as well as on OA progression, in adult mice.Murine embryonic development was accessed via in situ hybridization, measurement of skeletal parameters and micromass differentiation of mesenchymal cells. To reveal discrepancies in articular cartilage of adult wild-type (WT) and Tfap2e(-/-) mice, light and electron microscopy, in vitro culture of cartilage explants, and quantification of gene expression via real-time PCR were performed. OA was induced via surgical destabilization of the medial meniscus in both genotypes, and disease progression was monitored on histological and molecular levels.Only minor differences between WT and embryos deficient for AP-2? were observed, suggesting that redundancy mechanisms effectively compensate for the loss of AP-2? during skeletal development. Surprisingly, though, we found matrix metalloproteinase 13 (Mmp13), a major mediator of cartilage destruction, to be significantly upregulated in articular cartilage of adult Tfap2e(-/-) mice. This finding was further confirmed by increased Mmp13 activity and extracellular matrix degradation in Tfap2e(-/-) cartilage explants. OA progression was significantly enhanced in the Tfap2e(-/-) mice, which provided evidence for in vivo relevance. This finding is most likely attributable to the increased basal Mmp13 expression level in Tfap2e(-/-) articular chondrocytes that results in a significantly higher total Mmp13 expression rate during OA as compared with the WT.We reveal a novel role of AP-2? in the regulation of gene expression in articular chondrocytes, as well as in OA development, through modulation of Mmp13 expression and activity.
EVALuna2:4711

Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis - Akhmetshina, Alfiya; Palumbo, Katrin; Dees, Clara; Bergmann, Christina; Venalis, Paulius; Zerr, Pawel; Horn, Angelika; Kireva, Trayana; Beyer, Christian; Zwerina, Jochen; Schneider, Holm; Sadowski, Anika; et al. (Nature Communications, 2012)
The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases. © 2012 Macmillan Publishers Limited. All rights reserved.
CRIS-Team Scopus Importer:2020-07-01

Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression - Liebisch, Marita; Bondeva, Tzvetanka; Franke, Sybille; Daniel, Christoph; Amann, Kerstin Ute; Wolf, Gunter (Kidney International, 2014)
The activation of the receptor for advanced glycation end products (RAGE) is involved in the development of diabetic nephropathy. Analysis of protein phosphatase-1 indicated that advanced glycation end products did not affect its expression, but increased its phosphatase activity. Using differential display analysis we previously demonstrated that stimulation of RAGE in podocytes modulates the expression of numerous genes, among others nuclear inhibitor of protein phosphatase-1 (NIPP1). Here we found that silencing of NIPP1 induced podocyte hypertrophy, cell cycle arrest, and significantly increased protein phosphatase-1 activity. NIPP1 downregulation was associated with increased p27(Kip1) protein expression. Reporter assays revealed a transcriptional activation of nuclear factor-?B in podocytes after suppression of NIPP1. The protein level of NIPP1 was also significantly reduced in podocytes of diabetic mice. Blocking the RAGE in vivo by a soluble analog elevated the NIPP1 protein in podocytes of diabetic mice. Thus, activation of the RAGE by advanced glycation end products or other ligands suppresses NIPP1 expression in diabetic nephropathy, contributes to podocyte hypertrophy, and glomerular inflammation.
EVALuna2:25459

Acute interstitial nephritis after vaccination with BNT162b2 - Rieckmann, Sonja; Seibert, Felix S.; Hogeweg, Maximilian; Bertram, Sebastian; Doevelaar, Adrian A.N.; Amann, Kerstin Ute; Babel, Nina; Westhoff, Timm H. (Journal of Nephrology, 2022)
CRIS-Team Scopus Importer:2022-03-18
Keywords: BNT162b2; COVID-19; Interstitial nephritis; Kidney injury; Vaccination

Acute Kidney Allograft Injury Following Vitamin C Administration for Septic Shock - Mahling, Moritz; Köppen, Michael; Mühlbacher, Thomas; Amann, Kerstin Ute; Königsrainer, Alfred; Heyne, Nils; Häberle, Helene; Nadalin, Silvio; Guthoff, Martina (Kidney International Reports, 2020)
CRIS-Team Scopus Importer:2020-11-20

Acute respiratory and renal failure in a 20-year-old man - Heissner, K.; Riessen, R.; Horger, M.; Amann, Kerstin Ute; Haap, M. (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2015)
EVALuna2:25474

Acute systemic knockdown of Atg7 is lethal and causes pancreatic destruction in shRNA transgenic mice - Mainz, Laura; Sarhan, Mohamed A. F. E.; Roth, Sabine; Sauer, Ursula; Kalogirou, Charis; Eckstein, Markus; Gerhard-Hartmann, Elena; Seibert, Helen-Desiree; Voelker, Hans-Ulrich; Geppert, Carol-Immanuel; Rosenwald, Andreas; Eilers, Martin; et al. (Autophagy, 2022)
The notion that macroautophagy/autophagy is a potentially attractive therapeutic target for a variety of diseases, including cancer, largely stems from pre-clinical mouse studies. Most of these examine the effects of irreversible and organ confined autophagy deletion using site specific Cre-loxP recombination of the essential autophagy regulating genes Atg7 or Atg5. Model systems with the ability to impair autophagy systemically and reversibly at all disease stages would allow a more realistic approach to evaluate the consequences of authophagy inhibition as a therapeutic concept and its potential side effects. Here, we present shRNA transgenic mice that via doxycycline (DOX) regulable expression of a highly efficient miR30-E-based shRNA enabled knockdown of Atg7 simultaneously in the majority of organs, with the brain and spleen being noteable exceptions. Induced animals deteriorated rapidly and experienced profound destruction of the exocrine pancreas, severe hypoglycemia and depletion of hepatic glycogen storages. Cessation of DOX application restored apparent health, glucose homeostasis and pancreatic integrity. In a similar Atg5 knockdown model we neither observed loss of pancreatic integrity nor diminished survival after DOX treatment, but identified histological changes consistent with steatohepatitis and hepatic fibrosis in the recovery period after termination of DOX. Regulable Atg7-shRNA mice are valuable tools that will enable further studies on the role of autophagy impairment at various disease stages and thereby help to evaluate the consequences of acute autophagy inhibition as a therapeutic concept.
CRIS-Team WoS Importer:2022-04-08

Adamantinoma-like Ewing Sarcoma (ALES) May Harbor FUS Rearrangements : A Potential Diagnostic Pitfall - Palsgrove, Doreen N.; Foss, Robert D.; Yu, Wengdong; Garcia, Joaquin; Rooper, Lisa M.; Rekhtman, Natasha; Antonescu, Cristina; Gagan, Jeffrey; Agaimy, Abbas; Bishop, Justin A. (American Journal of Surgical Pathology, 2023)
Adamantinoma-like Ewing sarcoma (ALES) is a rare malignancy currently considered a variant of Ewing sarcoma with most known cases harboring EWSR1 rearrangements. Herein we present a series of 6 cases of EWSR1 -negative ALES. The tumors arose in the sinonasal tract (n=3), major salivary glands (submandibular gland=1; parotid=1), and anterior mediastinum (n=1) in patients ranging from 25 to 79 years of age. Most tumors were basaloid in appearance, growing in large nests separated by interlobular fibrosis without overt squamous pearls. However, 1 case closely resembled a well-differentiated neuroendocrine tumor with uniformly round nuclei, eosinophilic cytoplasm, and trabecular architecture. All cases were diffusely positive for pan-cytokeratin, p40 or p63, and CD99. A subset of cases showed diffuse reactivity for synaptophysin, including 1 sinonasal tumor which also demonstrated sustentacular S100 protein expression. Molecular testing showed FUS rearrangements in all cases. Gene partners included known ETS family members FEV (n=2) and FLI1 (n=1). Our results expand the molecular diagnostic considerations for ALES to include FUS rearrangements. We also show that ALES may harbor FUS :: FLI1 fusion, which has not been previously reported in the Ewing family of tumors. Furthermore, ALES may show unusual histologic and immunophenotypic features that can overlap with olfactory carcinoma including S100-positive sustentacular cells. ALES should be considered in the diagnostic differential of small round cell tumors and tumors with neuroendocrine differentiation with immunohistochemical workup to include p40 and CD99/NKX2.2.
CRIS-Team Scopus Importer:2023-11-03

Addition of triple negativity of breast cancer as an indicator for germline mutations in predisposing genes increases sensitivity of clinical selection criteria - Hoyer, Juliane; Vasileiou, Georgia; Uebe, Steffen; Wunderle, Marius; Kraus, Cornelia; Fasching, Peter; Thiel, Christian; Hartmann, Arndt; Beckmann, Matthias; Lux, Michael P.; Reis, André (BMC Cancer, 2018)
BACKGROUND: Breast cancer is the most common cancer in women. 12-15% of all tumors are triple-negative breast cancers (TNBC). So far, TNBC has been mainly associated with mutations in BRCA1. The presence of other predisposing genes seems likely since DNA damage repair is a complex process that involves several genes. Therefore we investigated if mutations in other genes are involved in cancer development and whether TNBC is an additional indicator of mutational status besides family history and age of onset. METHODS: We performed a germline panel-based screening of 10 high and low-moderate penetrance breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D and TP53) in 229 consecutive individuals affected with TNBC unselected for age, family history or bilateral disease. Within this cohort we compared the number of mutation carriers fulfilling clinical selection criteria with the total number of carriers identified. RESULTS: Age at diagnosis ranged from 23 to 80 years with an average age of 50.2 years. In 57 women (24.9%) we detected a pathogenic mutation, with a higher frequency (29.7%) in the group manifesting cancer before 60 years. Deleterious BRCA1 mutations occurred in 14.8% of TNBC patients. These were predominantly recurrent frameshift mutations (24/34, 70.6%). Deleterious BRCA2 mutations occurred in 5.7% of patients, all but one (c.1813dupA) being unique. While no mutations were found in CDH1 and TP53, 10 mutations were detected in one of the six other predisposition genes. Remarkably, neither of the ATM, RAD51D, CHEK2 and PALB2 mutation carriers had a family history. Furthermore, patients with non-BRCA1/2 mutations were not significantly younger than mutation negative women (p = 0.3341). Most importantly, among the 57 mutation carriers, ten (17.5%) would be missed using current clinical testing criteria including five (8%) with BRCA1/2 mutations. CONCLUSIONS: In summary, our data confirm and expand previous studies of a high frequency of germline mutations in genes associated with ineffective repair of DNA damage in women with TNBCs. Neither age of onset, contralateral disease nor family history were able to discern all mutation positive individuals. Therefore, TNBC should be considered as an additional criterion for panel based genetic testing.
EVALuna2:34811

A deep-learning workflow to predict upper tract urothelial carcinoma protein-based subtypes from H&E slides supporting the prioritization of patients for molecular testing - Angeloni, Miriam; van Doeveren, Thomas; Lindner, Sophia; Volland, Patrick; Schmelmer, Jorina; Foersch, Sebastian; Matek, Christian; Stöhr, Robert; Geppert, Carol-Immanuel; Heers, Hendrik; Wach, Sven; Taubert, Helge; et al. (Journal of Pathology: Clinical Research, 2024)
Upper tract urothelial carcinoma (UTUC) is a rare and aggressive, yet understudied, urothelial carcinoma (UC). The more frequent UC of the bladder comprises several molecular subtypes, associated with different targeted therapies and overlapping with protein-based subtypes. However, if and how these findings extend to UTUC remains unclear. Artificial intelligence-based approaches could help elucidate UTUC's biology and extend access to targeted treatments to a wider patient audience. Here, UTUC protein-based subtypes were identified, and a deep-learning (DL) workflow was developed to predict them directly from routine histopathological H&E slides. Protein-based subtypes in a retrospective cohort of 163 invasive tumors were assigned by hierarchical clustering of the immunohistochemical expression of three luminal (FOXA1, GATA3, and CK20) and three basal (CD44, CK5, and CK14) markers. Cluster analysis identified distinctive luminal (N = 80) and basal (N = 42) subtypes. The luminal subtype mostly included pushing, papillary tumors, whereas the basal subtype diffusely infiltrating, non-papillary tumors. DL model building relied on a transfer-learning approach by fine-tuning a pre-trained ResNet50. Classification performance was measured via three-fold repeated cross-validation. A mean area under the receiver operating characteristic curve of 0.83 (95% CI: 0.67–0.99), 0.8 (95% CI: 0.62–0.99), and 0.81 (95% CI: 0.65–0.96) was reached in the three repetitions. High-confidence DL-based predicted subtypes showed significant associations (p < 0.001) with morphological features, i.e. tumor type, histological subtypes, and infiltration type. Furthermore, a significant association was found with programmed cell death ligand 1 (PD-L1) combined positive score (p < 0.001) and FGFR3 mutational status (p = 0.002), with high-confidence basal predictions containing a higher proportion of PD-L1 positive samples and high-confidence luminal predictions a higher proportion of FGFR3-mutated samples. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes. Taken together, our DL workflow can predict protein-based UTUC subtypes, associated with the presence of targetable alterations, directly from H&E slides.
CRIS-Team Scopus Importer:2024-03-29
Keywords: deep-learning; digital pathology; immunohistochemistry; protein-based subtypes; targeted therapy; upper tract urothelial carcinoma; whole slide images

Adenomatoid Tumor of the Uterus: A Report of 6 Unusual Cases with Prominent Cysts including 4 with Diffuse Myometrial Involvement, 4 with Uterine Serosal Involvement, and 2 Presenting in Curettage Specimens - Lerias, Sofia; Ariyasriwatana, Chai; Agaimy, Abbas; Erber, Ramona; Young, Robert H.; Oliva, Esther (International Journal of Gynecological Pathology, 2020)
We evaluated the clinicopathologic features of 6 adenomatoid tumors of the uterus with unusual features. All the tumors differed grossly from the usual adenomatoid tumor, typically being ill-defined and occupying >50% of the myometrium, essentially replacing it in 4. The neoplasm extended to the endometrium in 2 cases and in one of these it formed an intracavitary mass; in both the tumor was first diagnosed in a curettage. In the other 4 cases, the adenomatoid tumor was discovered in a hysterectomy specimen performed for irregular vaginal bleeding (3 patients), and the finding of a pelvic mass on a computed tomography scan in a patient with right lower quadrant pain. The tumors extended to the uterine serosa in the form of small grape-like vesicles or cysts in 4 cases. All tumors contained the typical small often irregularly shaped spaces but also had prominent cysts. When cysts involved the serosa, the microscopic appearance mimicked that of peritoneal inclusion cysts. In one case with serosal involvement, a prominent papillary pattern was also present. The cysts were typically closely packed with minimal intervening stroma but were occasionally separated by conspicuous smooth muscle bundles. The stroma in one case was extensively hyalinized. Two tumors were focally infarcted. A striking, but minor, solid growth in which the tumor cells were arranged in tightly packed nests or interanastomosing cords and trabeculae was seen in 2 tumors. The unusual gross and microscopic features of these tumors can cause significant diagnostic difficulty and bring into the differential diagnosis entities that are usually not realistic considerations. The presentation of 2 tumors in a curettage specimen represents an unusual clinical aspect.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Adenomatoid tumor; Cystic; Diffuse; Endometrium; Papillary; Serosa

Adhesion GPCR Gpr126 (Adgrg6) Expression Profiling in Zebrafish, Mouse, and Human Kidney. - Cazorla-Vázquez, Salvador; Kösters, Peter; Bertz, Simone; Pfister, Frederick; Daniel, Christoph; Dedden, Mark; Zundler, Sebastian; Jobst-Schwan, Tilman; Amann, Kerstin Ute; Engel, Felix (Cells, 2023)
Adhesion G protein-coupled receptors (aGPCRs) comprise the second-largest class of GPCRs, the most common target for approved pharmacological therapies. aGPCRs play an important role in development and disease and have recently been associated with the kidney. Several aGPCRs are expressed in the kidney and some aGPCRs are either required for kidney development or their expression level is altered in diseased kidneys. Yet, general aGPCR function and their physiological role in the kidney are poorly understood. Here, we characterize in detail Gpr126 (Adgrg6) expression based on RNAscope® technology in zebrafish, mice, and humans during kidney development in adults. Gpr126 expression is enriched in the epithelial linage during nephrogenesis and persists in the adult kidney in parietal epithelial cells, collecting ducts, and urothelium. Single-cell RNAseq analysis shows that gpr126 expression is detected in zebrafish in a distinct ionocyte sub-population. It is co-detected selectively with slc9a3.2, slc4a4a, and trpv6, known to be involved in apical acid secretion, buffering blood or intracellular pH, and to maintain high cytoplasmic Ca2+ concentration, respectively. Furthermore, gpr126-expressing cells were enriched in the expression of potassium transporter kcnj1a.1 and gcm2, which regulate the expression of a calcium sensor receptor. Notably, the expression patterns of Trpv6, Kcnj1a.1, and Gpr126 in mouse kidneys are highly similar. Collectively, our approach permits a detailed insight into the spatio-temporal expression of Gpr126 and provides a basis to elucidate a possible role of Gpr126 in kidney physiology.
EVALuna2:539836
Keywords: adhesion GPCR; kidney development; Gpr126; parietal epithelial cell; collecting duct; urothelium; ionocytes; zebrafish; RNAscope

Adhesion GPCRs in Kidney Development and Disease - Cazorla-Vázquez, Salvador; Engel, Felix (Frontiers in Cell and Developmental Biology, 2018)
Chronic kidney disease (CKD) represents the fastest growing pathology worldwide with a prevalence of >10% in many countries. In addition, kidney cancer represents 5% of all new diagnosed cancers. As currently no effective therapies exist to restore kidney function after CKD- as well as cancer-induced renal damage, it is important to elucidate new regulators of kidney development and disease as new therapeutic targets. G protein-coupled receptors (GPCRs) represent the most successful class of pharmaceutical targets. In recent years adhesion GPCRs (aGPCRs), the second largest GPCR family, gained significant attention as they are present on almost all mammalian cells, are associated to a plethora of diseases and regulate important cellular processes. aGPCRs regulate for example cell polarity, mitotic spindle orientation, cell migration, and cell aggregation; all processes that play important roles in kidney development and/or disease. Moreover, polycystin-1, a major regulator of kidney development and disease, contains a GAIN domain, which is otherwise only found in aGPCRs. In this review, we assess the potential of aGPCRs as therapeutic targets for kidney disease. For this purpose we have summarized the available literature and analyzed data from the databases The Human Protein Atlas, EURExpress, Nephroseq, FireBrowse, cBioPortal for Cancer Genomics and the National Cancer Institute Genomic Data Commons data portal (NCIGDC). Our data indicate that most aGPCRs are expressed in different spatio-temporal patterns during kidney development and that altered aGPCR expression is associated with a variety of kidney diseases including CKD, diabetic nephropathy, lupus nephritis as well as renal cell carcinoma. We conclude that aGPCRs present a promising new class of therapeutic targets and/or might be useful as diagnostic markers in kidney disease.
EVALuna2:34820

Adhesion G Protein-Coupled Receptor Gpr126 (Adgrg6) Expression Profiling in Diseased Mouse, Rat, and Human Kidneys - Kösters, Peter; Cazorla Vázquez, Salvador; Krüger, René; Daniel, Christoph; Vonbrunn, Eva; Amann, Kerstin Ute; Engel, Felix (Cells, 2024)
Uncovering the function of understudied G protein-coupled receptors (GPCRs) provides a wealth of untapped therapeutic potential. The poorly understood adhesion GPCR Gpr126 (Adgrg6) is widely expressed in developing kidneys. In adulthood, Gpr126 expression is enriched in parietal epithelial cells (PECs) and epithelial cells of the collecting duct and urothelium. Whether Gpr126 plays a role in kidney disease remains unclear. Here, we characterized Gpr126 expression in diseased kidneys in mice, rats, and humans. RT-PCR data show that Gpr126 expression is altered in kidney disease. A quantitative RNAscope® analysis utilizing cell type-specific markers revealed that Gpr126 expression upon tubular damage is mainly increased in cell types expressing Gpr126 under healthy conditions as well as in cells of the distal and proximal tubules. Upon glomerular damage, an increase was mainly detected in PECs. Notably, Gpr126 expression was upregulated in an ischemia/reperfusion model within hours, while upregulation in a glomerular damage model was only detected after weeks. An analysis of kidney microarray data from patients with lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), hypertension, and diabetes as well as single-cell RNA-seq data from kidneys of patients with acute kidney injury and chronic kidney disease indicates that GPR126 expression is also altered in human kidney disease. In patients with FSGS, an RNAscope® analysis showed that GPR126 mRNA is upregulated in PECs belonging to FSGS lesions and proximal tubules. Collectively, we provide detailed insights into Gpr126 expression in kidney disease, indicating that GPR126 is a potential therapeutic target.
CRIS-Team Scopus Importer:2024-05-31
Keywords: adhesion GPCR; collecting duct; focal segmental glomerulosclerosis; Gpr126; human; kidney disease; parietal epithelial cell; RNAscope; urothelium

Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma - Hosni, Sana; Kilian, Viola; Kl€umper, Niklas; Gabbia, Daniela; Sieckmann, Katharina; Corvino, Dillon; Winkler, Anja; Saponaro, Miriam; W€orsd€orfer, Karin; Schmidt, Doris; Hahn, Oliver; Zanotto, Ilaria; et al. (Cancer Research, 2024)
Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer in a paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3; also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared with their progenitors. Pharmacologic inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies. SIGNIFICANCE: Acquired resistance to FGFR inhibition can be rapidly promoted by paracrine activation of the NRG1/HER3 axis mediated by adipocyte precursors and can be overcome by the combination of pertuzumab and erdafitinib treatment. See related commentary by Kolonin and Anastassiou, p. 648.
CRIS-Team Scopus Importer:2024-03-15

Adult type granulosa cell tumor of the testis with a heterologous sarcomatous component: case report and review of the literature - Schubert, Thomas E. O.; Stoehr, Robert; Hartmann, Arndt; Schoene, Sabrina; Loebelenz, Mathias; Mikuz, Gregor (Diagnostic Pathology, 2014)
Adult testicular granulosa cell tumors are rare sex cord- stromal tumors of which only 45 have been previously reported. As compared with their ovarian counterparts, these tumors may follow a more aggressive course because the proportion of malignant cases is higher. We report here a unique case of a 78-year Caucasian with a left sided adult type granulosa cell tumor with a heterologous sarcomatous tumor component. A heterologous sarcomatous component has occasionally been observed in ovarian tumors but never in testicular granulosa cell tumors. The sarcomatous component showed a higher number of mitotic figures (1/Hpf) and a marked proliferation rate (up to 50% Ki 67 positive cells) compared with the granulosa type tumor component. CD 99 and the progesterone receptor were positive in both tumor components, inhibin and calretinin only in the granulosa cells, and pancytokeratin only in the sarcomatouse one. Key words: testis - ovary - granulosa cells - sarcoma - inhibin Runing title: testicular sarcomatous granulosa tumor.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6959043481207016.
EVALuna2:6605

Advances in heart regeneration based on cardiomyocyte proliferation and regenerative potential of binucleated cardiomyocytes and polyploidization - Leone, Marina; Engel, Felix (Clinical Science, 2019)
One great achievement in medical practice is the reduction in acute mortality of myocardial infarction due to identifying risk factors, antiplatelet therapy, optimized hospitalization and acute percutaneous coronary intervention. Yet, the prevalence of heart failure is increasing presenting a major socio-economic burden. Thus, there is a great need for novel therapies that can reverse damage inflicted to the heart. In recent years, data have accumulated suggesting that induction of cardiomyocyte proliferation might be a future option for cardiac regeneration. Here, we review the relevant literature since September 2015 concluding that it remains a challenge to verify that a therapy induces indeed cardiomyocyte proliferation. Most importantly, it is unclear that the detected increase in cardiomyocyte cell cycle activity is required for an associated improved function. In addition, we review the literature regarding the evidence that binucleated and polyploid mononucleated cardiomyocytes can divide, and put this in context to other cell types. Our analysis shows that there is significant evidence that binucleated cardiomyocytes can divide. Yet, it remains elusive whether also polyploid mononucleated cardiomyocytes can divide, how efficient proliferation of binucleated cardiomyocytes can be induced, what mechanism regulates cell cycle progression in these cells, and what fate and physiological properties the daughter cells have. In summary, we propose to standardize and independently validate cardiac regeneration studies, encourage the field to study the proliferative potential of binucleated and polyploid mononucleated cardiomyocytes, and to determine whether induction of polyploidization can enhance cardiac function post-injury.
CRIS-Team Scopus Importer:2019-06-28
Keywords: binucleation; cell cycle; heart regeneration; polyploidy; proliferation

Afferent neurons of the kidney with impaired firing pattern in inflammation – role of sodium currents? - Lale, Nena; Ditting, Tilmann; Hilgers, Karl Friedrich; Linz, Peter; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Rodionova, Kristina (Pflügers Archiv: European Journal of Physiology, 2023)
Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6% vs. control: 57%, P < 0.05). Na+ and K+ currents were not different between control renal and non-renal DRG neurons. Phasic neurons exhibited higher Na+ and K+ currents than tonic resulting in shorter APs (3.7 ± 0.3 vs. 6.1 ± 0.6 ms, P < 0.01). In neurons incubated with CXCL1, Na+ and K+ peak current density increased in phasic (Na+: − 969 ± 47 vs. − 758 ± 47 nA/pF, P < 0.01; K+: 707 ± 22 vs. 558 ± 31 nA/pF, P < 0.01), but were unchanged in tonic neurons. Phasic neurons exposed to CXCL1 showed a broader range of Na+ currents ([− 365– − 1429 nA] vs. [− 412– − 4273 nA]; P < 0.05) similar to tonic neurons. After CXCL1 exposure, significant changes in phasic neurons were observed in sodium activation/inactivation as well as a wider distribution of Na+ currents characteristic of tonic neurons. These findings indicate a subgroup of tonic neurons besides mere tonic or phasic neurons exists able to exhibit a phasic activity pattern under pathological conditions.
CRIS-Team Scopus Importer:2023-09-15
Keywords: Chemokine; Firing pattern; Phasic; Renal afferent nerve; Sodium currents; Tonic; Voltage-gated sodium channels

AFFERENT PEPTIDERGIC NERVE FIBERS - IMPORTANCE FOR THE SALT METABOLISM BEYOND THE KIDNEYS? - Ditting, Tilmann; Rodionova, Kristina; Reeh, Peter; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Ott, Christianroland; Veelken, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Afferent renal innervation in anti-Thy1.1 nephritis in rats - Rodionova, Kristina; Veelken, Roland; Hilgers, Karl Friedrich; Paulus, Eva Maria; Linz, Peter; Fischer, Michael J.M.; Schenker, Martina; Reeh, Peter; Tiegs, Gisa; Ott, Christian; Schmieder, Roland; Schiffer, Mario; et al. (American Journal of Physiology-Renal Physiology, 2020)
Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8-37 reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.
CRIS-Team Scopus Importer:2020-11-13
Keywords: afferent renal neerves; calcitonin gene-related peptide; renal inflammation; renal innervation; sympathetic innervation

AFFERENT RENAL NERVE PATHWAYS IN RATS - RESPONSIVENESS TO HIGH SALT INTAKE - Rodionova, Kristina; Ditting, Tilmann; Fahrmeier, Franziska; Ott, Chirstian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

A Firing Cannon: Bilateral Lower Limb Ischemia as a Manifestation of Cardiac Myxoma. - Elbayomi, Mohamed; Groß, Raphael; Presheet, Pathare; Agaimy, Abbas; May, Mattias; Wayend, Micheal; Heim, Christian (Thoracic and Cardiovascular Surgeon Reports, 2024)
Background Cardiac myxomas are the most common primary cardiac neoplasms. Case Description We present a case of a middle-aged lady with cardiac myxoma in her left atrium awaiting semi-elective surgery. During the preoperative period, the patient presented emergently with acute bilateral lower limb ischemia. This lady was fortunate to have these emboli fired towards a tissue with ischemia tolerance capacity. If these emboli had been directed toward the central nervous system, this patient would have experienced devastating complications and even death. Conclusion This presentation opens the debate on the timing of surgical intervention in myxoma patients.
EVALuna2:578864

A floating collagen matrix triggers ring formation and stemness characteristics in human colorectal cancer organoids - Wimmers, Daniel; Hübner, Kerstin; Dale, Trevor; Papargyriou, Aristeidis; Reichert, Maximilian; Hartmann, Arndt; Schneider-Stock, Regine (Pathology Research and Practice, 2025)
Intestinal organoids reflect the 3D structure and function of their original tissues. Organoid are typically cultured in Matrigel, an extracellular matrix (ECM) mimicking the basement membrane, which is suitable for epithelial cells but does not accurately mimic the tumour microenvironment of colorectal cancer (CRC). The ECM and particularly collagen type I is crucial for CRC progression and invasiveness. Given that efforts to examine CRC organoid invasion in a more physiologically relevant ECM have been limited, we used a floating collagen type I matrix (FC) to study organoid invasion in three patient-derived CRC organoid lines. In FC gel, organoids contract, align, and fuse into macroscopic ring structures, initiating minor branch formation and invasion fronts, phenomena unique for the collagen ECM and otherwise not observed in Matrigel-grown CRC organoids. In contrast to Matrigel, FC organoids showed basal extrusion with improper actin localization, but without change in the organoid polarity. Moreover, small clusters of vital invading cells were observed. Gene expression analysis revealed that the organoids cultured in a FC matrix presented more epithelial and stem cell-like characteristics. This novel technique of cultivating CRC organoids in a FC matrix represents an in-vitro model for studying cancer organization and matrix remodelling with increased organoid stemness potential.
CRIS-Team Scopus Importer:2025-05-09
Keywords: Collagen I; Invasiveness; Matrigel; Ring structures; Stemness; TROP2

A gene signature derived from the loss of cdkn1a (P21) is associated with CMS4 colorectal cancer - Bueno-Fortes, Santiago; Muenzner, Julienne K.; Berral-Gonzalez, Alberto; Hampel, Chuanpit; Lindner, Pablo; Berninger, Alexandra; Hübner, Kerstin; Kunze, Philipp; Bäuerle, Tobias; Erlenbach-Wünsch, Katharina; Sánchez-Santos, José Manuel; Hartmann, Arndt; et al. (Cancers, 2022)
The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.
CRIS-Team Scopus Importer:2022-01-14
Keywords: CAM model; CDKN1A; Colorectal cancer; Consensus molecular subtypes (CMS); Epithelial–mesenchymal transition (EMT); HCT116 cells; Intermediate EMT; SNAI2

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy - Mingardo, Enrico; Beaman, Glenda; Grote, Philip; Nordenskjöld, Agneta; Newman, William; Woolf, Adrian S.; Eckstein, Markus; Hilger, Alina C.; Dworschak, Gabriel C.; Rösch, Wolfgang; Ebert, Anne Karolin; Stein, Raimund; et al. (Communications Biology, 2022)
Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.
CRIS-Team Scopus Importer:2022-11-25

Age-related biological differences in children's and adolescents’ very rare tumors - Virgone, Calogero; Ben Ami, Tal; Roganovic, Jelena; Bien, Ewa; Reguerre, Yves; Ferrari, Andrea; Orbach, Daniel; Godzinski, Jan; Bisogno, Gianni; Farinha, Nuno Jorge; Bergamaschi, Luca; Alaggio, Rita; et al. (EJC Pediatric Oncology, 2023)
Very rare tumors (VRTs) in pediatric age represent many different diseases. They present an annual incidence < 2/1000,000 and correspond to about 11% of all cancers in patients aged 0–14 years. They can be roughly divided into two groups: one including tumors that are also rare in adults, and the other group includes adult-type tumors rarely encountered in children and adolescents. Although there is an obvious gap in knowledge regarding oncogenesis in pediatric cancers, there is some evidence of the involvement of various signalling pathways in the development of tumors in children and adolescents and sometimes in young adults. In addition, despite the rarity of these neoplasms, several attempts have been made to disclose the underlying mechanisms. More effort and resources have urgently to be devoted to deepening current knowledge and integrating new findings into the therapeutic approach, which nowadays relies on the treatment modalities used in adult oncology. The aim of this paper is to provide a review of the main solid VRTs occurring in both the pediatric and the adult age groups, highlighting the variability between groups in their biological and clinical course.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Biological differences; Pediatric/adolescent oncology; Very rare tumors

Aggressive Subtypes of Laryngeal Chondrosarcoma and their Clinical Behavior: A Systematic Review - Piazza, Cesare; Montenegro, Claudia; Tomasoni, Michele; Leivo, Ilmo; Stenman, Göran; Agaimy, Abbas; Simpson, Roderick H.W.; Zidar, Nina; Ferlito, Alfio (Oncology and Therapy, 2025)
Introduction: Laryngeal chondrosarcoma (CS) is a rare indolent malignant tumor. High-grade (G3), dedifferentiated (DD), and myxoid (MY) CSs are considered more aggressive subtypes due to their metastatic potential and relatively poor outcomes. The aim of this systematic review is to evaluate treatment modalities and survival outcomes in patients affected by these rarer CS subtypes. Methods: Papers published from January 1, 2000, to August 25, 2024, describing cases of laryngeal G3, DD, and MY CS were included. Results: A total of 38 patients (15 G3, 13 DD, and 10 MY) were selected. Cricoid cartilage was the most common site of origin. Total laryngectomy (TL) was often performed. Primary conservative approaches in 42.8% of patients were followed by loco-regional recurrence. Conclusions: Aggressive subtypes of CS require a radical approach because of the higher rate of loco-regional and distant recurrences compared to low-grade CS. TL with radical intent is the most common treatment, and adjuvant therapy should be considered after careful multidisciplinary discussion.
CRIS-Team Scopus Importer:2025-01-31
Keywords: Chondrosarcoma; Dedifferentiated; High grade; Laryngeal tumors; Myxoid

AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection - Garczyk, Stefan; Von Stillfried, Saskia; Antonopoulos, Wiebke; Hartmann, Arndt; Schrauder, Michael G.; Fasching, Peter; Anzeneder, Tobias; Tannapfel, Andrea; Ergoenenc, Yavuz; Knuechel, Ruth; Rose, Michael; Dahl, Edgar (PLoS ONE, 2015)
Blood-based early detection of breast cancer has recently gained novel momentum, as liquid biopsy diagnostics is a fast emerging field. In this study, we aimed to identify secreted proteins which are up-regulated both in tumour tissue and serum samples of breast cancer patients compared to normal tissue and sera. Based on two independent tissue cohorts (n = 75 and n = 229) and one serum cohort (n = 80) of human breast cancer and healthy serum samples, we characterised AGR3 as a novel potential biomarker both for breast cancer prognosis and early breast cancer detection from blood. AGR3 expression in breast tumours is significantly associated with oestrogen receptor ? (P<0.001) and lower tumour grade (P<0.01). Interestingly, AGR3 protein expression correlates with unfavourable outcome in low (G1) and intermediate (G2) grade breast tumours (multivariate hazard ratio: 2.186, 95% CI: 1.008-4.740, P<0.05) indicating an independent prognostic impact. In sera analysed by ELISA technique, AGR3 protein concentration was significantly (P<0.001) elevated in samples from breast cancer patients (n = 40, mainly low stage tumours) compared to healthy controls (n = 40). To develop a suitable biomarker panel for early breast cancer detection, we measured AGR2 protein in human serum samples in parallel. The combined AGR3/AGR2 biomarker panel achieved a sensitivity of 64.5% and a specificity of 89.5% as shown by receiver operating characteristic (ROC) curve statistics. Thus our data clearly show the potential usability of AGR3 and AGR2 as biomarkers for blood-based early detection of human breast cancer.
EVALuna2:6803

A High Fat Diet During Pregnancy and Lactation Induces Cardiac and Renal Abnormalities in GLUT4 +/- Male Mice - Kruse, Michael; Fiallo, Ariana; Tao, Jianling; Susztak, Katalin; Amann, Kerstin Ute; Katz, Ellen B.; Charron, Maureen J. (Kidney & Blood Pressure Research, 2017)
Altered nutrients during the in utero (IU) and/or lactation (L) period predispose offspring to cardio-renal diseases in adulthood. This study investigates the effect of a high fat diet (HFD) fed to female mice during IU/L on gene expression patterns associated with heart and kidney failure and hypertension in male offspring.Female wild type (WT) mice were fed either a HFD or control chow (C) prior to mating with males with a genetic heterozygous deletion of GLUT4 (G4+/-, a model of peripheral insulin resistance and hypertension) and throughout IU/L. After weaning male offspring were placed on a standard rodent chow until 24 weeks of age.All offspring exposed to a maternal HFD showed increased heart and kidney weight and reduced cardiac insulin responsiveness. G4+/- offspring on a HFD displayed early hypertension associated with increased renal gene expression of renin and the AT1- receptors compared to G4+/- on a C diet. This group showed decreased cardiac expression of key genes involved in fatty acid oxidation compared to WT on a C diet.These results indicate an interaction between a HFD diet and genotype during early life development that can enhance susceptibility to cardio-renal diseases later in life.
EVALuna2:25542

A histopathologic and immunohistochemical study on liquification of human adipose tissue ex vivo - Huebner, Nina-Fee; Horch, Raymund E.; Polykandriotis, Elias; Rau, Tilman; Dragu, Adrian (Aesthetic Plastic Surgery, 2014)
This preliminary ex vivo study aimed to clarify the pathophysiologic mechanisms of fat tissue depletion by subcutaneous drug application. Therefore, the lipolytic effects of phosphatidylcholine plus deoxycholate (Lipostabil) (L) and of deoxycholate (DC) alone were compared with those of sodium chloride (NaCl) and hydrogen peroxide (H2O2) as control agents. The study enrolled 10 patients receiving abdominoplasty. The treatment periods for each sample and solution were 1, 3, 5, and 7 h. The samples were analyzed morphologically using hematoxylin-eosin (H&E) staining and also immunohistochemically using Caspase 3 and tumor necrosis factor (TNF)-alpha. Morphologic changes were seen best after 5 h of application time. Except for NaCl, all the samples in the H&E staining showed marked damage of adipocyte cell membranes, with the greatest disruption of normal cell architecture after hydrogen peroxide (H2O2) application. Immunohistochemistry using TNF-alpha showed positive results for the deoxycholate and Lipostabil samples and highly positive results for the H2O2 sample. Data from this study indicate that Lipostabil and deoxycholate induce pathways of cell necrosis involving TNF-alpha. These short-term experiments indicate that Lipostabil affects fat tissue in the way of a chemical-toxic destruction rather than via a physiologically induced, programmed cell death.
EVALuna2:6587

A huge left atrial mass "not a myxoma" - Strecker, Thomas; Ruemmele, Petra; Seitz, Tatjana; Nooh, Ehab (Cardiology Journal, 2017)
N/A.
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A humanized mouse identifies the bone marrow as a niche with low therapeutic IgG activity - Lux, Anja; Seeling, Michaela; Baerenwaldt, Anne; Lehmann, Birgit; Schwab, Inessa; Repp, Roland; Meidenbauer, Norbert; Mackensen, Andreas; Hartmann, Arndt; Heidkamp, Gordon Frederik; Dudziak, Diana; Nimmerjahn, Falk (Cell Reports, 2014)
Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG) activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fc? receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.
EVALuna2:6588

AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer. - Bannier, Pierre Antoine; Saillard, Charlie; Mann, Philipp; Touzot, Maxime; Maussion, Charles; Matek, Christian; Klümper, Niklas; Breyer, Johannes; Wirtz, Ralph; Sikic, Danijel; Schmitz-Dräger, Bernd; Wullich, Bernd; et al. (Nature Communications, 2024)
Pathogenic activating mutations in the fibroblast growth factor receptor 3 (FGFR3) drive disease maintenance and progression in urothelial cancer. 10-15% of muscle-invasive and metastatic urothelial cancer (MIBC/mUC) are FGFR3-mutant. Selective targeting of FGFR3 hotspot mutations with tyrosine kinase inhibitors (e.g., erdafitinib) is approved for mUC and requires FGFR3 mutational testing. However, current testing assays (polymerase chain reaction or next-generation sequencing) necessitate high tissue quality, have long turnover time, and are expensive. To overcome these limitations, we develop a deep-learning model that detects FGFR3 mutations using routine hematoxylin-eosin slides. Encompassing 1222 cases, our study is a large-scale validation of a model prescreening FGFR3 mutations for MIBC and mUC patients. In this work, we demonstrate that our model achieves high sensitivity (>93%) on advanced and metastatic cases while reducing molecular testing by 40% on average, thereby offering a cost-effective and rapid pre-screening tool for identifying patients eligible for FGFR3 targeted therapies.
EVALuna2:578143

Airtightness of lung parenchyma without a closing suture after atypical resection using the Nd:YAG Laser LIMAX 120 - Kirschbaum, Andreas; Steinfeldt, Thorsten; Gockel, Andreas; Di Fazio, Pietro; Quint, Karl; Bartsch, Detlef K. (Interactive Cardiovascular and Thoracic Surgery, 2014)
Lung metastases can be non-anatomically resected with a Nd:YAG Laser. It is recommended that the resected lung surface be sealed by slowly resorbable sutures. However, the lung tissue may be restricted by the sutures once it is re-ventilated. Thus, it was analysed whether the lung parenchyma is airtight after laser resection without suturing the defect.The pulmonary artery of unimpaired paracardial lung lobes of freshly slaughtered pigs (mean weight 46 g) was cannulated and rinsed out via a hypotonic saline-heparin solution (5000 IE) until the perfusate was clear of body fluid. The lobular bronchus was connected to an airtight ventilation tube (Fa. VYGON 520 3.5 oral tube) and ventilated pressure-controlled (PEEP + 5 cm H?O, P? = 20 cm H?O, frequency = 10/min) via a respirator. All lobes were perfused with Ringer solution at 42°C at normothermia and normotonia. In group 1 (n = 8), an atypical peripheral parenchymal resection (average resected surface: 2 × 2 cm(2)) and in group 2 (n = 8), a deep atypical parenchymal resection (average resected surface: 4 × 4 cm(2)) were performed with the Nd:YAG Laser LIMAX 120 (output power at 100 watts). After post-resection ventilation of 15 min, the resection surface was tested for airtightness and burst pressure.All group 1 lobes tested airtight under pressure-controlled ventilation. The mean burst pressure was 34.4 mbar (SD ± 3.2 mbar). Six lobes of group 2 were also completely airtight. The remaining two lobes, however, revealed a serious parenchymal leak (score 3). This was caused by the cross-opening of a segmental bronchus, although the surrounding lung parenchyma was also airtight. The mean burst pressure of these lobes was 31.7 mbar (SD ± 4.08 mbar). There was no significant difference between the two groups (P = 0.12).Peripheral lung defects after Nd:YAG Laser resection might not be sutured, since the laser-induced vaporization of the lung parenchyma seems to be initially airtight. These experimental data warrant confirmation in a controlled clinical study.
EVALuna2:6732

AKAP6 orchestrates the nuclear envelope microtubule-organizing center by linking golgi and nucleus via AKAP9 - Vergarajauregui, Silvia; Becker, Robert; Steffen, Ulrike; Sharkova, Maria; Esser, Tilman; Petzold, Jana; Billing, Florian; Kapiloff, Michael S.; Schett, Georg; Thievessen, Ingo; Engel, Felix (eLife, 2020)
The switch from centrosomal microtubule-organizing centers (MTOCs) to noncentrosomal MTOCs during differentiation is poorly understood. Here, we identify AKAP6 as key component of the nuclear envelope MTOC. In rat cardiomyocytes, AKAP6 anchors centrosomal proteins to the nuclear envelope through its spectrin repeats, acting as an adaptor between nesprin-1 alpha and Pcnt or AKAP9. In addition, AKAP6 and AKAP9 form a protein platform tethering the Golgi to the nucleus. Both Golgi and nuclear envelope exhibit MTOC activity utilizing either AKAP9, or Pcnt-AKAP9, respectively. AKAP6 is also required for formation and activity of the nuclear envelope MTOC in human osteoclasts. Moreover, ectopic expression of AKAP6 in epithelial cells is sufficient to recruit endogenous centrosomal proteins. Finally, AKAP6 is required for cardiomyocyte hypertrophy and osteoclast bone resorption activity. Collectively, we decipher the MTOC at the nuclear envelope as a bi-layered structure generating two pools of microtubules with AKAP6 as a key organizer.
CRIS-Team WoS Importer:2021-01-01

Akt and p53 are potential mediators of reduced mammary tumor growth by Chloroquine and the mTOR inhibitor RAD001 - Löhberg, Christian; Strissel, Pamela; Dittrich, Ralf; Strick, Reiner; Dittmer, Jürgen; Dittmer, Angela; Fabry, Ben; Kalender, Willi Alfred; Koch, Thorsten; Wachter, David; Groh, Nicole; Polier, Astrid; et al. (Biochemical Pharmacology, 2012)

Akute Nierenschädigung bei Leberinsuffizienz – Fall 10/2016 - Werner, Christoph R.; Wagner, Verena; Sipos, Bence; Büttner-Herold, Maike; Amann, Kerstin Ute; Haap, Michael; Malek, Nisar P.; Bitzer, Michael; Artunc, Ferruh (Deutsche Medizinische Wochenschrift, 2016)
History and admission findings: We report on a 76-year-old man presenting with painless jaundice who developed dialysis-dependent acute kidney injury. Investigations: Biliary tract was examined with endoscopy, in addition kidney biopsy was performed. Diagnosis, treatment and course: A stenosing process could be seen in the biliary tract, leading to stent implantation. However, jaundice did not resolve. Kidney biopsy revealed bile casts indicating cholemic nephropathy. After switch of concomitant medication, hyperbilirubinemia resolved and kidney function was completely restored. Conclusion: Cholestatic liver disease can cause acute kidney injury by formation of bile casts in the tubuli defining cholemic nephropathy. Resolution of cholestasis can restore kidney functio
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Akutes Nierenversagen, Raynaud-Phänomen und thrombotische Mikroangiopathie – wie passt das zusammen? - Hasan, C. W.; Scheel, M.; Baumgärtel, M. W.; Büttner-Herold, Maike; Friesicke, H. (Die Nephrologie, 2024)
CRIS-Team Scopus Importer:2025-02-04

A large-scale functional high-throughput screening identifies miR-515 and miR-519e as potent inducers of human iPSC-cardiomyocyte proliferation - Renikunta, H. V.; Lazarow, K.; Gong, Y.; Shukla, P. C.; Giral, H.; Kratzer, A.; Nageswaran, V.; Opitz, L.; Engel, Felix; Haghikia, A.; Paneni, F.; Von Kries, J. P.; et al. (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

A large-scale MicroRNA functional high-throughput screening identifies members of the MiR-515 family as potent inducers of human IPSC-cardiomyocyte proliferation - Gong, Y.; Renikunta, H.; Lazarow, K.; Giral, H.; Kratzer, A.; Opitz, L.; Haghikia, A.; Engel, Felix; Paneni, F.; Von Kries, J. P.; Streckfuss-Bomeke, K.; Landmesser, U.; et al. (SWISS MEDICAL WEEKLY, 2022)
CRIS-Team WoS Importer:2022-09-02

Alkali therapy protects renal function, suppresses inflammation, and improves cellular metabolism in kidney disease - Pastor Arroyo, Eva Maria; Yassini, Nima; Sakiri, Elif; Russo, Giancarlo; Bourgeois, Soline; Mohebbi, Nilufar; Amann, Kerstin Ute; Joller, Nicole; Wagner, Carsten A.; Imenez Silva, Pedro Henrique (Clinical Science, 2022)
Chronic kidney disease (CKD) affects approximately 10-13% of the population worldwide and halting its progression is a major clinical challenge. Metabolic acidosis is both a consequence and a possible driver of CKD progression. Alkali therapy counteracts these effects in CKD patients, but underlying mechanisms remain incompletely understood. Here we show that bicarbonate supplementation protected renal function in a murine CKD model induced by an oxalate-rich diet. Alkali therapy had no effect on the aldosterone-endothelin axis but promoted levels of the anti-aging protein klotho; moreover, it suppressed adhesion molecules required for immune cell invasion along with reducing T-helper cell and inflammatory monocyte invasion. Comparing transcriptomes from the murine crystallopathy model and from human biopsies of kidney transplant recipients (KTRs) suffering from acidosis with or without alkali therapy unveils parallel transcriptome responses mainly associated with lipid metabolism and oxidoreductase activity. Our data reveal novel pathways associated with acidosis in kidney disease and sensitive to alkali therapy and identifies potential targets through which alkali therapy may act on CKD and that may be amenable for more targeted therapies.
CRIS-Team Scopus Importer:2022-05-06
Keywords: acid-base balance; alkali therapy; chronic kidney disease; crystal nephropathy; inflammation; metabolism

ALK, NUT, and TRK Do Not Play Relevant Roles in Gastric Cancer—Results of an Immunohistochemical Study in a Large Series - Glückstein, Marie Isabelle; Dintner, Sebastian; Miller, Silvia; Vlasenko, Dmytro; Schenkirsch, Gerhard; Agaimy, Abbas; Märkl, Bruno; Grosser, Bianca (Diagnostics, 2022)
ALK, NUT, and TRK are rare molecular aberrations that are pathognomonic for specific rare tumors. In low frequencies, however, they are found in a wide range of other tumor entities. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of the immunohistochemical expressions of ALK, NUT, and TRK in 477 adenocarcinomas of the stomach and gastroesophageal junction. Seven cases (1.5%) showed an expression of TRK. In NGS, no NTRK fusion was confirmed. No case with ALK or NUT expression was detected. ALK, NUT, and NTRK expression does not seem to play an important role in gastric carcinomas.
CRIS-Team Scopus Importer:2022-03-04
Keywords: ALK; Gastric cancer; Immunohistochemistry; NUT; TRK

ALK -rearranged Mesenchymal Neoplasms With Prominent Foamy/Pseudolipogenic Cell Morphology : Expanding the Phenotypic Spectrum of ALK Fusion Neoplasms and Report of Novel Fusion Partners. - Agaimy, Abbas; Stöhr, Robert; Fisher, Cyril; Chrisinger, John S.A.; Demicco, Elizabeth G.; Tögel, Lars; Michal, Michal; Michal, Michael (American Journal of Surgical Pathology, 2024)
The category of ALK -rearranged mesenchymal neoplasms has been evolving rapidly, with reports of morphologically diverse lesions of cutaneous, soft tissue, and visceral origin. While some of these represent morphologically defined entities harboring recurrent ALK fusions (inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma), others are unclassified by morphology with variable overlap with the tyrosine kinase family of neoplasia and their underlying ALK fusions cannot be suspected based on morphology. We herein report 3 cases that expand the anatomic, morphologic, and genotypic spectrum of ALK -rearranged unclassified neoplasms. Patients were all adults aged 46 to 69 (median: 63) who presented with a mass located in the gingiva, subcutis of the back, and submucosal posterior pharyngeal wall. The tumor size ranged from 1 to 2.7 cm (median: 1.6). Conservative surgery was the treatment in all patients. Follow-up was available for one patient who remained disease-free at 14 months. Histologically, all tumors displayed large polygonal cells with foamy to granular and lipogenic-like microvacuolated copious cytoplasm and medium-sized round nuclei with 1 or 2 prominent nucleoli. Mitoses and necrosis were not seen. The initial diagnostic impression was PEComa, inflammatory rhabdomyoblastic tumor and unclassified pseudolipogenic neoplasm. Strong cytoplasmic ALK was detected by immunohistochemistry in all cases. Other positive markers include Cathepsin K (2/2), desmin (1/3), focal MyoD1 (1/1), focal SMA (1/3), and focal EMA (1/2). Targeted RNA sequencing revealed ALK fusions with exon 20 (2 cases) and exon 19 (one case) of ALK fused to RND3 (exon 3), SQSTM1 (exon 6), and desmin (intron 6). Methylation profiling in the desmin-fused case (initially diagnosed as inflammatory rhabdomyoblastic tumor) revealed an inflammatory myofibroblastic tumor match with a low confidence score of 0.5 and a flat copy number variation (CNV) profile. No NF1 mutation was detected in this case, altogether excluding an inflammatory rhabdomyoblastic tumor. Our study highlights and expands the morphologic and anatomic diversity of ALK- fused neoplasms and documents novel fusion partners ( RND3 and desmin).
EVALuna2:570327

ALK rearranged renal cell carcinoma (ALK-RCC): a multi-institutional study of twelve cases with identification of novel partner genes CLIP1, KIF5B and KIAA1217 - Kuroda, Naoto; Trpkov, Kiril; Gao, Yuan; Tretiakova, Maria; Liu, Yajuan J.; Ulamec, Monika; Takeuchi, Kengo; Agaimy, Abbas; Przybycin, Christopher; Magi-Galluzzi, Cristina; Fushimi, Soichiro; Kojima, Fumiyoshi; et al. (Modern Pathology, 2020)
ALK rearranged renal cell carcinoma (ALK-RCC) has recently been included in 2016 WHO classification as a provisional entity. In this study, we describe 12 ALK-RCCs from 8 institutions, with detailed clinical, pathological, immunohistochemical (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) analyses. Patients’ age ranged from 25 to 68 years (mean, 46.3 years). Seven patients were females and five were males (M:F = 1:1.4). Tumor size ranged from 17 to 70 mm (mean 31.5, median 25 mm). The pTNM stage included: pT1a (n = 7), pT1b (n = 1), and pT3a (n = 4). Follow-up was available for 9/12 patients (range: 2 to 153 months; mean 37.6 months); 8 patients were alive without disease and one was alive with distant metastases. The tumors demonstrated heterogeneous, ‘difficult to classify’ morphology in 10/12 cases, typically showing diverse architectural and cellular morphologies, including papillary, tubular, tubulocystic, solid, sarcomatoid (spindle cell), rhabdoid, signet-ring cell, and intracytoplasmic vacuoles, often set in a mucinous background. Of the remaining two tumors, one showed morphology resembling mucinous tubular and spindle cell renal cell carcinoma (MTSC RCC-like) and one was indistinguishable from metanephric adenoma. One additional case also showed a focal metanephric adenoma-like area, in an otherwise heterogeneous tumor. By IHC, all tumors were diffusely positive for ALK and PAX8. In both cases with metanephric adenoma-like features, WT1 and ALK were coexpressed. ALK rearrangement was identified in 9/11 tumors by FISH. ALK fusion partners were identified by NGS in all 12 cases, including the previously reported: STRN (n = 3), TPM3 (n = 3), EML4 (n = 2), and PLEKHA7 (n = 1), and also three novel fusion partners: CLIP1 (n = 1), KIF5B (n = 1), and KIAA1217 (n = 1). ALK-RCC represents a genetically distinct entity showing a heterogeneous histomorphology, expanded herein to include unreported metanephric adenoma-like and MTSC RCC-like variants. We advocate a routine ALK IHC screening for “unclassifiable RCCs” with heterogeneous features.
CRIS-Team Scopus Importer:2020-06-05

ALK Rearrangements Characterize 2 Distinct Types of Salivary Gland Carcinomas Clinicopathologic and Molecular Analysis of 4 Cases and Literature Review - Agaimy, Abbas; Baneckova, Martina; Ihrler, Stephan; Müller, Sarina Katrin; Franchi, Alessandro; Hartmann, Arndt; Stöhr, Robert; Skalova, Alena (American Journal of Surgical Pathology, 2021)
The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediategrade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK-fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70 y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3 cm (mean, 2 cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5+, androgen-) and luminal (CK5-, androgen+) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, FS100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type non-invasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n= 2) and STRN (n= 1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9 mo; 1 alive under palliative therapy at 5 mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n= 15) and intraductal (n= 9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases.
CRIS-Team WoS Importer:2021-08-27

ALLOGRAFT INFILTRATION AND MENINGOENCEPHALITIS BY SARS-COV-2 IN A PANCREAS-KIDNEY TRANSPLANT RECIPIENT - Doevelaar, A.; Seibert, F.; Bauer, F.; Stervbo, U.; Anft, M.; Rohn, B.; Winnekendonk, G.; Dittmer, U.; Schenker, P.; Amann, Kerstin Ute; Zgoura, P.; Viebahn, R.; et al. (TRANSPLANT INTERNATIONAL, 2020)
CRIS-Team WoS Importer:2020-11-06

Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient - Westhoff, Timm H.; Seibert, Felix S.; Bauer, Frederic; Stervbo, Ulrik; Anft, Moritz; Doevelaar, Adrian A. N.; Rohn, Benjamin J.; Winnekendonk, Guido; Dittmer, Ulf; Schenker, Peter; Vonbrunn, Eva; Amann, Kerstin Ute; et al. (American Journal of Transplantation, 2020)
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) preferentially affects epithelia of the upper and lower respiratory tract. Thus, impairment of kidney function has been primarily attributed until now to secondary effects such as cytokine release or fluid balance disturbances. We provide evidence that SARS-CoV-2 can directly infiltrate a kidney allograft. A 69-year-old male, who underwent pancreas-kidney transplantation 13 years previously, presented to our hospital with coronavirus disease 2019 (COVID-19) pneumonia and impaired pancreas and kidney allograft function. Kidney biopsy was performed showing tubular damage and an interstitial mononuclear cell infiltrate. Reverse transcriptase polymerase chain reaction from the biopsy specimen was positive for SARS-CoV-2. In-situ hybridization revealed SARS-CoV-2 RNA in tubular cells and the interstitium. Subsequently, he had 2 convulsive seizures. Magnetic resonance tomography suggested meningoencephalitis, which was confirmed by SARS-CoV-2 RNA transcripts in the cerebrospinal fluid. The patient had COVID-19 pneumonia, meningoencephalitis, and nephritis. SARS-CoV-2 binds to its target cells through angiotensin-converting enzyme 2, which is expressed in a broad variety of tissues including the lung, brain, and kidney. SARS-CoV-2 thereby shares features with other human coronaviruses including SARS-CoV that were identified as pathogens beyond the respiratory tract as well. The present case should provide awareness that extrapulmonary symptoms in COVID-19 may be attributable to viral infiltration of diverse organs.
CRIS-Team Scopus Importer:2020-09-11

Alterations in key signaling pathways in sinonasal tract melanoma. A molecular genetics and immunohistochemical study of 90 cases and comprehensive review of the literature - Chlopek, Malgorzata; Lasota, Jerzy; Thompson, Lester D. R.; Szczepaniak, Magdalena; Kuzniacka, Alina; Hincza, Kinga; Kubicka, Kamila; Kaczorowski, Maciej; Newford, Michael; Liu, Yalan; Agaimy, Abbas; Biernat, Wojciech; et al. (Modern Pathology, 2022)
Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in >50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas.
CRIS-Team Scopus Importer:2022-09-02

Alterations in macrophage polarization in the craniofacial and extracranial skeleton after zoledronate application and surgical interventions – an in vivo experiment - Struckmeier, Ann-Kristin; Wehrhan, Falk; Preidl, Raimund; Mike, Melanie; Mönch, Tina; Eilers, Lea; Ries, Jutta; Trumet, Leah; Lutz, Rainer; Geppert, Carol-Immanuel; Kesting, Marco Rainer; Weber, Manuel (Frontiers in Immunology, 2023)
Purpose: Medication-related osteonecrosis occurs exclusively in the jaw bones. However, the exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) and the unique predisposition of the jaw bones have not been elucidated, making its treatment a challenge. Recent evidence indicates that macrophages might play a pivotal role in MRONJ pathogenesis. The aim of the present study was to compare the macrophage populations between the craniofacial and extracranial skeleton and to investigate the changes induced by zoledronate (Zol) application and surgical interventions. Materials and methods: An in vivo experiment was performed. 120 wistar rats were randomized to 4 groups (G1, G2, G3, G4). G1 served as an untreated control group. G2 and G4 received Zol injections for 8 weeks. Afterwards, the right lower molar of the animals from G3 and G4 was extracted and the right tibia osteotomized followed by osteosynthesis. Tissue samples were taken from the extraction socket and the tibia fracture at fixed time points. Immunohistochemistry was conducted to determine the labeling indexes of CD68+ and CD163+ macrophages. Results: Comparing the mandible and the tibia, we observed a significantly higher number of macrophages and a heightened pro-inflammatory environment in the mandible compared to the tibia. Tooth extraction caused an increase of the overall number of macrophages and a shift toward a more pro-inflammatory microenvironment in the mandible. Zol application amplified this effect. Conclusion: Our results indicate fundamental immunological differences between the jaw bone and the tibia, which might be a reason for the unique predisposition for MRONJ in the jaw bones. The more pro-inflammatory environment after Zol application and tooth extraction might contribute to the pathogenesis of MRONJ. Targeting macrophages might represent an attractive strategy to prevent MRONJ and improve therapy. In addition, our results support the hypothesis of an anti-tumoral and anti-metastatic effect induced by BPs. However, further studies are needed to delineate the mechanisms and specify the contributions of the various macrophage phenotypes.
CRIS-Team Scopus Importer:2023-06-30
Keywords: bisphosphonate; macrophage; MRONJ; osteonecrosis; tooth extraction

Alternative Splicing in Mechanically Stretched Podocytes as a Model of Glomerular Hypertension - Mattias, Francescapaola; Tsoy, Olga; Hammer, Elke; Gress, Alexander; Simm, Stefan; Lio, Chit Tong; Ameling, Sabine; Amann, Kerstin Ute; Dreher, Leonie; Wenzel, Ulrich; Kacprowski, Tim; List, Markus; et al. (Journal of the American Society of Nephrology, 2025)
Background: Alterations in pre-mRNA splicing are crucial to the pathophysiology of various diseases. However, the effects of alternative splicing of mRNA on podocytes in hypertensive nephropathy are still unknown. The Sys-CARE project aimed to identify alternative splicing events involved in the development and progression of glomerular hypertension. Methods: Murine podocytes were exposed to mechanical stretch, after which proteins and mRNA were analyzed by proteomics, RNA sequencing and several bioinformatic alternative splicing tools. Results: Using transcriptomic and proteomic analysis, we identified significant changes in gene expression and protein abundance due to mechanical stretch. RNA-Seq identified over 3,000 alternative spliced genes after mechanical stretch, including all types of alternative splicing events. Among these, 17 genes exhibited an alternative splicing event across four different splicing analysis tools. From this group, we focused on Myl6, a component of the myosin protein complex, and Shroom3, an actin-binding protein essential for podocyte function. We identified two Shroom3 isoforms with significant expression changes under mechanical stretch, which was validated by qRT-PCR and in situ hybridization. Additionally, we observed an expression switch of two Myl6 isoforms after mechanical stretch, accompanied by an alteration in the C-terminal amino acid sequence. Conclusions: A comprehensive RNA-Seq analysis of mechanically stretched podocytes identified novel potential podocyte-specific biomarkers and highlighted significant alternative splicing events, notably in the mRNA of Shroom3 and Myl6.
CRIS-Team Scopus Importer:2025-06-06

Alternative splicing of pericentrin contributes to cell cycle control in cardiomyocytes - Steinfeldt, Jakob; Becker, Robert; Vergarajauregui, Silvia; Engel, Felix (Journal of Cardiovascular Development and Disease, 2021)
Induction of cardiomyocyte proliferation is a promising option to regenerate the heart. Thus, it is important to elucidate mechanisms that contribute to the cell cycle arrest of mammalian cardiomyocytes. Here, we assessed the contribution of the pericentrin (Pcnt) S isoform to cell cycle arrest in postnatal cardiomyocytes. Immunofluorescence staining of Pcnt isoforms combined with SiRNA-mediated depletion indicates that Pcnt S preferentially localizes to the nuclear envelope, while the Pcnt B isoform is enriched at centrosomes. This is further supported by the localization of ectopically expressed FLAG-tagged Pcnt S and Pcnt B in postnatal cardiomyocytes. Analysis of centriole configuration upon Pcnt depletion revealed that Pcnt B but not Pcnt S is required for centriole cohesion. Importantly, ectopic expression of Pcnt S induced centriole splitting in a heterologous system, ARPE-19 cells, and was sufficient to impair DNA synthesis in C2C12 myoblasts. Moreover, Pcnt S depletion enhanced serum-induced cell cycle re-entry in postnatal cardiomyocytes. Analysis of mitosis, binucleation rate, and cell number suggests that Pcnt S depletion enhances serum-induced progression of postnatal cardiomyocytes through the cell cycle resulting in cell division. Collectively, our data indicate that alternative splicing of Pcnt contributes to the establishment of cardiomyocyte cell cycle arrest shortly after birth.
CRIS-Team Scopus Importer:2021-09-10
Keywords: Cardiomyocyte; Cell cycle; Centriole splitting; Centrosome; Heart regeneration; Non-centrosomal microtubule organizing center; Pericentrin

Ameloblastic Fibrosarcoma: Clinicopathological and Molecular Analysis of 7 Cases Highlighting Frequent BRAF and Rare NRAS Mutations - Agaimy, Abbas; Skalova, Alena; Franchi, Alessandro; Alshagroud, Rana; Stoehr, Robert; Baumhoer, Daniel; Bauer, Sebastian (MODERN PATHOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-23

Ameloblastic fibrosarcoma: clinicopathological and molecular analysis of seven cases highlighting frequent BRAF and occasional NRAS mutations - Agaimy, Abbas; Skalova, Alena; Franchi, Alessandro; Alshagroud, Rana; Gill, Anthony J.; Stoehr, Robert; Baumhoer, Daniel; Bauer, Sebastian (Histopathology, 2020)
Aims: Ameloblastic fibrosarcoma (AFS) is an aggressive odontogenic neoplasm featuring malignant mesenchymal stroma in addition to an ameloblastic epithelial component, and is hence considered to be the malignant counterpart of ameloblastic fibroma (AF). AFS is exceedingly rare, with <110 cases having been reported so far. Although BRAF mutations are recognised driver mutations in ameloblastoma, the molecular pathogenesis of AFS remains elusive. Methods and results: We herein describe seven AFSs that were analysed, for the first time, for mutations in the BRAF–NRAS pathway. The patients were four females and three males aged 23–57 years (median, 26 years). Three tumours developed after one or multiple recurrences of AF (4–20 years after initial diagnosis), two showed transition from AF-like bland areas, and two developed de novo. All patients were treated with surgery; adjuvant chemotherapy was given to one patient. At the last follow-up, five patients were alive and well (19–344 months). The remainder were lost to follow-up. Histological examination showed variable sarcomatous overgrowth with varying degrees of atypia and increased mitotic activity. The epithelial component varied greatly according to the degree of sarcomatous overgrowth. Molecular testing revealed BRAF V600E mutations in five cases and NRAS p.Gln61Lys mutation in one case. One tumour was wild-type. Conclusion: To our knowledge, this is the first study on BRAF/NRAS mutations in AFS. Given the activity of RAF and MEK inhibitors across different cancers harbouring V600E mutations, our data strongly suggest that all AFS cases should be genetically tested, and that targeted treatment approaches for this extremely rare sarcoma subtype should be clinically investigated.
CRIS-Team Scopus Importer:2020-04-28
Keywords: ameloblastic fibroma; ameloblastic fibrosarcoma; BRAF; molecular pathogenesis; NRAS; targeted therapy

A method for the graphical modeling of relative temporal constraints - Mate, Sebastian; Bürkle, Thomas; Kapsner, Lorenz; Toddenroth, Dennis; Kampf, Marvin; Sedlmayr, Martin; Castellanos, Ixchel; Prokosch, Hans-Ulrich; Kraus, Stefan (Journal of Biomedical Informatics, 2019)
Searching for patient cohorts in electronic patient data often requires the definition of temporal constraints between the selection criteria. However, beyond a certain degree of temporal complexity, the non-graphical, form-based approaches implemented in current translational research platforms may be limited when modeling such constraints. In our opinion, there is a need for an easily accessible and implementable, fully graphical method for creating temporal queries. We aim to respond to this challenge with a new graphical notation. Based on Allen's time interval algebra, it allows for modeling temporal queries by arranging simple horizontal bars depicting symbolic time intervals. To make our approach applicable to complex temporal patterns, we apply two extensions: with duration intervals, we enable the inference about relative temporal distances between patient events, and with time interval modifiers, we support counting and excluding patient events, as well as constraining numeric values. We describe how to generate database queries from this notation. We provide a prototypical implementation, consisting of a temporal query modeling frontend and an experimental backend that connects to an i2b2 system. We evaluate our modeling approach on the MIMIC-III database to demonstrate that it can be used for modeling typical temporal phenotyping queries. Data availability statement The source code (licensed under the GNU General Public License v3.0) is available on GitHub (https://github.com/sebmate/AllenGUI and https://github.com/sebmate/AllenSPARQL). Also supplied are the development i2b2 dataset (with the 13 artificial patients) and the SQL scripts to populate the i2b2 system with the MIMIC-III data. Please note that the software is of prototypical character and provided “as is”, without any warranties.
CRIS-Team Scopus Importer:2019-11-15
Keywords: Data integration; Data retrieval; Patient cohort identification; Phenotyping; Phenotyping algorithms; Temporal queries

AMIGO2 characterizes cancer-associated fibroblasts in metastatic colon cancer and induces the release of paracrine active tumorigenic secretomes - Yong, Yong-song; Demmler, Richard; Zohud, Bisan; Fang, Qi; Zhang, Tong; Zhou, Yonghua; Petter, Katja; Flierl, Christian; Gass, Tobias; Geppert, Carol-Immanuel; Merkel, Susanne; Schellerer, Vera; et al. (Journal of Pathology, 2024)
Secretomes of cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC) contribute to malignancy. Detailed knowledge is available on the components and functions of CAF secretomes. Little is known about the regulation of CAF secretomes. Here, we searched for receptor-like membrane-bound molecules in CAFs, which may regulate the production and release of tumor-activating secretomes. The adhesion molecule with Ig-like domain 2 (AMIGO2) was significantly upregulated in cultivated CAFs compared to normal tissue-associated fibroblasts (NAFs), and this was confirmed in patient-derived tissues. AMIGO2 expression was low or absent in healthy colon, significantly increased in fibroblasts of primary CRC, and highest in the stromal tissues of CRC-derived liver metastases. AMIGO2 expression in CAFs correlated with a higher T-category, increased lymph node metastasis, progressed tumor stages and was associated with reduced survival in different cohorts of CRC patients. Interestingly, AMIGO2 expression was induced by transforming growth factor-β and higher in female patients, who exhibit a more aggressive disease course. In functional studies, conditioned media of NAFs with experimentally induced AMIGO2 overexpression enhanced proliferation and migration of different CRC tumor cells, while siRNA-mediated inhibition of AMIGO2 in CAFs attenuated these effects. Accordingly, therapeutic inhibition of the receptor-like AMIGO2 protein in CRC CAFs could prevent tumorigenic secretomes in CRC. © 2024 The Author(s). 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:2024-11-22
Keywords: cancer-associated fibroblasts; colorectal cancer; secretion; secretomes; tumor microenvironment

A multicenter comparison of PD-L1 protein and mRNA expression in urothelial bladder cancer by immunohistochemistry and RT-qPCR (Checkpoint-Typer(C)): A round robin test by the BRIDGE-Consortium Germany - Eckstein, Markus; Wirtz, R.; Pfannstil, C.; Wach, S.; Stoehr, R.; Breyer, J.; Erlmeier, F.; Guenes, C.; Nitschke, K.; Weichert, W.; Otto, W.; Keck, Bastian; et al. (2018)
EVALuna2:34065

A multicenter round robin test of PD-L1 expression assessment in urothelial bladder cancer by immunohistochemistry and RT-qPCR with emphasis on prognosis prediction after radical cystectomy - Eckstein, Markus; Wirtz, Ralph M.; Pfannstil, Carolin; Wach, Sven; Stoehr, Robert; Breyer, Johannes; Erlmeier, Franziska; Günes, Cagatay; Nitschke, Katja; Weichert, Wilko; Otto, Wolfgang; Keck, Bastian; et al. (Oncotarget, 2018)
Background: Immunohistochemical PD-L1 assessment is currently used to identify responders towards checkpoint inhibitors although it is limited by inter-observer effects. Here, we conducted a multi-center round robin test to prove the possibility of assessing the PD-L1 status by gene expression to avoid inter-observer effects. Patients and methods: Gene expression of PD-L1 was analyzed in a total of 294 samples (14 cases non-muscle invasive and muscle-invasive bladder cancer; MIBC) in seven centers by a RT-qPCR kit and compared with immunohistochemical scoring of three pathologists (DAKO, 22c3). Both assays were compared towards prognosis prediction in a cohort of 88 patients with MIBC. Results: PD-L1 gene expression revealed very high inter center correlation (centrally extracted RNA: r = 0.68-0.98, p ≤ 0.0076; locally extracted RNA: r = 0.81-0.98, p ≤ 0.0014). IHC Inter-observer concordance was moderate to substantial for immune cells (IC), fair for combined IC/ tumor cell (TC) (IC: κ = 0.50-0.61; IC + TC: κ = 0.50), and fair for TC scoring (κ = 0.26-0.35). Gene expression assessment resulted in more positive cases (9/14 cases positive vs. 6/14 cases [IHC]) which could be validated in the independent cohort. Positive mRNA status was associated with significantly better overall and disease-specific survival (5-year OS: 50% vs. 26%, p = 0.0042, HR = 0.48; 5 year DSS: 65% vs. 40%, p = 0.012, HR = 0.49). The 1% IHC IC cut-off also revealed significant better OS (5 year OS: 58% vs. 31%, p = 0.036, HR = 0.62). Conclusion: Gene expression showed very high inter-center agreement. Gene expression assessment also resulted in more positive cases and revealed better prognosis prediction. PD-L1 mRNA expression seems to be a reproducible and robust tool for PD-L1 assessment.
EVALuna2:34268

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression - Jackson, Carolyn C.; Best, Lucy; Lorenzo, Lazaro; Casanova, Jean-Laurent; Wacker, Jochen; Bertz, Simone; Agaimy, Abbas; Harrer, Thomas (Journal of Clinical Immunology, 2016)
Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients' intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.
EVALuna2:6762

A mutation within the SH2 domain of slp-76 regulates the tissue distribution and cytokine production of iNKT cells in mice - Danzer, Claudia Agnes; Koller, Anna; Baier, Julia; Arnold, Harald; Giessler, Claudia; Opoka, Robert; Schmidt, Stephanie; Willers, Maike; Mihai, Sidonia; Parsch, Hans; Wirtz, Stefan; Daniel, Christoph; et al. (European Journal of Immunology, 2016)
TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76(ace/ace) mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP(-/-) iNKT cells, slp-76(ace/ace) iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP(-/-) mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76(ace/ace) mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.
EVALuna2:2050

Amyloid fibril structure from the vascular variant of systemic AA amyloidosis - Banerjee, Sambhasan; Baur, Julian; Daniel, Christoph; Pfeiffer, Peter Benedikt; Hitzenberger, Manuel; Kuhn, Lukas; Wiese, Sebastian; Bijzet, Johan; Haupt, Christian; Amann, Kerstin Ute; Zacharias, Martin; Hazenberg, Bouke P.C.; et al. (Nature Communications, 2022)
Systemic AA amyloidosis is a debilitating protein misfolding disease in humans and animals. In humans, it occurs in two variants that are called ‘vascular’ and ‘glomerular’, depending on the main amyloid deposition site in the kidneys. Using cryo electron microscopy, we here show the amyloid fibril structure underlying the vascular disease variant. Fibrils purified from the tissue of such patients are mainly left-hand twisted and contain two non-equal stacks of fibril proteins. They contrast in these properties to the fibrils from the glomerular disease variant which are right-hand twisted and consist of two structurally equal stacks of fibril proteins. Our data demonstrate that the different disease variants in systemic AA amyloidosis are associated with different fibril morphologies.
CRIS-Team Scopus Importer:2022-12-02

Analysis of androgen receptor mRNA expression in urothelial carcinoma of the bladder - Sikic, D.; Wirtz, R.; Wach, S.; Dyrskjot, L.; Erben, P.; Bolenz, C.; Breyer, J.; Otto, W.; Hoadley, K.; Lerner, S.; Eckstein, Markus; Hartmann, Arndt; et al. (2018)
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Analysis of CXCL9, PD1 and PD-L1 mRNA in stage T1 non-muscle invasive bladder cancer and their association with prognosis - Kubon, Jennifer; Sikic, Danijel; Eckstein, Markus; Weyerer, Veronika; Stöhr, Robert; Neumann, Angela; Keck, Bastian; Wullich, Bernd; Hartmann, Arndt; Wirtz, Ralph M.; Taubert, Helge; Wach, Sven (Cancers, 2020)
Non-muscle invasive bladder cancer (NMIBC), which is characterized by a recurrence rate of approximately 30% and very long treatment times, remains a major unresolved problem for patients and the health care system. The immunological interplay between tumor cells and the immune environment is important for tumor development. Therefore, we analyzed the mRNA of three immune markers, CXCL9, PD1 and PD-L1, in NMIBC by qRT-PCR. The results were subsequently correlated with clinicopathological parameters and prognostic data. Altogether, as expected, higher age was an independent prognostic factor for overall survival (OS) and disease-specific survival (DSS), but not for recurrence-free survival (RFS). Lower CXCL9 mRNA was observed in multivariate Cox’s regression analysis to be an independent prognostic parameter for reduced OS (relative risk; RR = 2.08; p = 0.049), DSS (RR = 4.49; p = 0.006) and RFS (RR = 2.69; p = 0.005). In addition, PD-L1 mRNA was an independent prognostic factor for DSS (RR = 5.02; p = 0.042) and RFS (RR = 2.07; p = 0.044). Moreover, in univariate Cox’s regression analysis, the stratification of patients revealed that low CXCL9 or low PD1 mRNA was associated with reduced RFS in the younger patient group (≤71 years), but not in the older patient group (>71 years). In addition, low CXCL9 or low PD-L1 was associated with shorter RFS in patients with higher tumor cell proliferation and in patients without instillation therapy. In conclusion, the characterization of mRNA levels of immune markers differentiates NIMBC patients with respect to prognosis.
CRIS-Team Scopus Importer:2020-10-09
Keywords: CXCL9; PD-L1; PD1; Prognosis; Stage T1 NMIBC

Analysis of Intraoperative Frozen Pancreatic Resection Margin and Prediction of Postoperative Pancreatic Fistula Risk During Pancreatoduodenectomy - Brunner, Maximilian; Kovacevic, Jasna; Krautz, Christian; Merkel, Susanne; Hartmann, Arndt; Grützmann, Robert; Haller, Florian; Weber, Georg (Journal of the American College of Surgeons, 2022)
BACKGROUND: Pancreatic duct diameter and pancreatic texture are important predictive factors for a postoperative pancreatic fistula (POPF) and are assessed intraoperatively by the surgeon. However, surgical evaluation is arbitrary and difficult to objectify, especially in minimally invasive approaches in pancreatic surgery. STUDY DESIGN: We conducted a retrospective analysis of 275 patients that underwent pancreatoduodenectomy from 2012 to 2019 at our institution. Pancreatic duct diameter and pancreatic fibrosis were assessed by histopathologic examination of the pancreatic resection margin using intraoperative frozen sections and correlated with the occurrence of POPF and clinically relevant POPF (CR-POPF). RESULTS: The POPF and CR-POPF rates were 27% and 19%, respectively. Univariate analysis indicated that the indication for surgery, the surgically determined pancreatic duct diameter, and pancreatic texture, as well as the histopathologically determined pancreatic duct diameter and pancreatic fibrosis were significant predictive factors for POPF and CR-POPF. A multivariate analysis revealed histopathologically determined pancreatic duct diameter and pancreatic fibrosis as independent risk factors for POPF (OR [odds ratio] 2.3 [1.1 to 4.5], p = 0.022 and OR 2.4 [1.1 to 5.1], p = 0.023, respectively) and CR-POPF (OR 2.2 [1.1 to 4.8], p = 0.037 and OR 2.6 [1.1 to 6.1], p = 0.036). CONCLUSIONS: Histopathologically determined pancreatic duct diameter and pancreatic fibrosis are quantitatively measurable independent risk factors for POPF and CR-POPF. An intraoperative objective histopathologic evaluation of these parameters using frozen sections could support the surgical assessment of the pancreatic duct diameter and the pancreatic texture.
CRIS-Team Scopus Importer:2022-04-29

Analysis of the prognostic relevance of sex-steroid hormonal receptor mRNA expression in muscle-invasive urothelial carcinoma of the urinary bladder - Erben, Philipp; Sikic, Danijel; Wirtz, Ralph M.; Martini, Thomas; Weis, Cleo-Aron; Breyer, Johannes; Otto, Wolfgang; Keck, Bastian; Hartmann, Arndt; Bolenz, Christian (Virchows Archiv, 2019)
Muscle-invasive urothelial carcinoma of the urinary bladder (UCB) often recurs following radical cystectomy (RC). An altered expression of sex-steroid hormone receptors has been associated with oncological outcomes of UCB and may represent therapeutic targets. Here the expression of different hormone receptors was measured on mRNA levels in patients treated by RC and associated with outcomes. Androgen receptor (AR), estrogen receptor 1 (ESR1), and progesterone receptor (PGR) mRNA expression was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in RC samples of 87 patients with a median age of 66 (39-88) years. Univariate and multivariate analyses were performed to test associations with pathological and clinical characteristics as well as recurrence-free (RFS) and disease-specific survival (DSS). AR mRNA expression was lower in comparison with ESR1 and PGR expression (p<0.0001). In univariate analysis, high expression levels of AR were associated with reduced RFS (HR 2.8, p=0.015) and DSS (HR 2.8, p=0.010). High AR mRNA expression and a positive lymph node status were independent predictors for reduced RFS (HR 2.5, p=0.0049) and DSS (HR 3.4, p=0.009). In patients with low AR mRNA expression, an increased ESR1 and PGR mRNA expression were associated with reduced RFS and DSS. High expression levels of AR are significantly associated with adverse outcome in patients with muscle-invasive UCB following RC. ESR1 and PGR expression status can further stratify patients with low AR expression into subgroups with significantly reduced RFS and DSS. Therapeutic targeting of AR may influence outcomes in patients with UCB.
CRIS-Team WoS Importer:2019-02-21

Analytical and inter-observer comparability of 4 clinically developed programmed death-ligand 1 (PD-L1) immunohistochemistry assays in advanced clear cell renal cell carcinoma (CCRCC) - Sommer, Ulrich; Eckstein, Markus; Ammann, Johannes; Braunschweig, Till; Macher-Goeppinger, Stephan; Schwamborn, Kristina; Hieke-Schulz, Stefanie; Wullich, Bernd; Wirth, Manfred; Roth, Wilfried; Knuechel, Ruth; Weichert, Wilko; et al. (CANCER RESEARCH, 2019)
CRIS-Team WoS Importer:2019-10-22

Anamnese, pathologische Originalbefunde, Therapie bezogene Parameter und Krankheitsverlauf: retrospektive Analyse von klinisch basierten Faktoren für die Prognose des tumorspezifischen Überlebens von 378 Patienten mit pT1-Harnblasenkarzinom - Breyer, J.; Otto, Wolfgang; Hartmann, Arndt; Bumes, B.; Bruendl, J.; Gierth, M.; Bertz, Simone; Denzinger, Stefan; Burger, M.; Lausenmeyer, E. M. (Aktuelle Urologie, 2015)
Urothelial carcinoma of the bladder (UBC) at stage pT1 is a heterogenous disease. Established criteria for prognosis prediction are not suitable for every patient. Choosing the right therapeutic strategy for the individual patient thus remains a challenge. The aim of the present study was to identify clinical parameters regarding cancer-specific survival (CSS) in patients with pT1 UBC.A retrospective analysis of clinical parameters of all patients with a pT1 UBC between 1989 and 2012 from a single centre was performed. Treatment consisted of transurethral resection, second resection followed by initially bladder sparing treatment. Anamnestic data, histopathological reports and clinical course were assessed with CSS being defined as primary endpoint. Kaplan-Meier analysis, uni- and multivariate analysis were performed using SPSS (Version 22, IBM).378 patients (78% male, median age 72 years) were included, median follow-up was 35 months. Pathological stage pT1G3 (66 vs. 91%, p<0.001), lack of instillation therapy (66 vs. 83%, p<0.001), presence of a second malignoma (41 vs. 77%, p=0,004), diagnosis after 2000 (75 vs. 76%, p=0,018) and tumour progress (42 vs. 85%, p<0.001) were associated with a worse CSS in univariate and Kaplan-Meier analysis. Multivariate analysis revealed the presence of a second malignoma (HR 2.267; CI 95% 1.143-4.497, p=0.019), pathological stage pT1G3 at initial diagnosis (HR 4.567; CI 95% 2.040-10.22, p<0.001) and tumour progress (HR 3.742; CI 95% 1.544-9.069, p=0.003) as independent negative predictors of CSS. Instillation therapy was a prognostic factor for improved CSS (HR 0.368; CI 95% 0.212-0.638, p<0.001).The present study identified the presence of a second malignoma, pathological stage pT1G3 and tumour progress as negative predictive factors for CSS. Maintenance instillation therapy after reresection was associated with an improved CSS.
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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 - Kerker, Florian; Adler, Werner; Brunner, Kathrin; Moest, Tobias; Wurm, Matthias; Nkenke, Emeka; Neukam, Friedrich Wilhelm; von Wilmowsky, Cornelius (Clinical Oral Investigations, 2018)
OBJECTIVES: This study aimed to identify anatomical areas where resections of oral squamous cell carcinomas (OSCC) are significantly associated with close or positive margins. MATERIALS AND METHODS: This retrospective study included 330 patients with a primary OSCC from 2010 to 2015. Patient and tumour data were categorised into three groups by R-status (R0 [clear], ≥ 5 mm, 185 patients [56.06%]; R1 [positive], < 1 mm, 24 patients [7.27%]; and R0 [close], 1-5 mm, 121 patients [36.67%]). RESULTS: Areas where resections were significantly associated with close or positive margins were the hard palate (p < 0.001), buccal mucosa (p = 0.03), floor of the mouth (p = 0.004), lower alveolar ridge (p = 0.01), retromolar triangle (p = 0.005), and dorsal tongue (p = 0.02). CONCLUSIONS: Anatomical areas were identified in the oral cavity where it is challenging to resect OSCCs with an adequate safety margin. CLINICAL RELEVANCE: These results may enable surgeons to achieve a postulated safe distance during tumour resection, leading to a survival benefit for patients.
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ANCA-positive IgA nephropathy in a patient with ANA-positive long-standing rheumatoid arthritis and type 1 diabetes. - Krasselt, Marco; Halbritter, Jan; Amann, Kerstin Ute; Baerwald, Christoph G.; Seifert, Olga (Clinical and Experimental Rheumatology, 2020)
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ANCA-positive IgA nephropathy in a patient with ANA-positive long-standing rheumatoid arthritis and type 1 diabetes - Krasselt, Marco; Halbritter, Jan; Amann, Kerstin Ute; Baerwald, Christoph; Seifert, Olga (Clinical and Experimental Rheumatology, 2020)
CRIS-Team Scopus Importer:2020-06-05

ANCA-positive vasculitis as a secondary autoimmune disease after autologous stem cell transplantation for systemic sclerosis: a case report - Schmalzing, M; Amann, Kerstin Ute; Tony, H-P (Clinical and Experimental Rheumatology, 2014)
Autologous stem cell transplantation (SCT) is increasingly used to treat autoimmune diseases (AD), in particular systemic sclerosis (SSc). Secondary autoimmune diseases are a known complication after autologous stem cell transplantations for any cause. A 43-year-old man had received an autologous stem cell transplantation for an aggressive diffuse cutaneous SSc. After mobilisation with cyclophosphamide and Granulocyte-Colony-Stimulating Factor stem cells were CD34-selected. The patient received a conditioning regimen with cyclophosphamide and Antithymocyte globulin. He had an excellent response with the modified Rodnan Skin Score decreasing from 34 to 3. One year and 4 months after SCT mild erythrocyturia without acanthocytes and proteinuria were seen for the first time on routine urinalysis. During the following year erythrocyturia increased to 131 erythrocytes /?l and protein excretion to 628 mg/g creatinine. At that time, acanthocytes of 25% finally could be detected. Due to the clearly nephritic constellation in urinalysis a renal biopsy was performed, which revealed mild global and focal-segmental sclerosing and focal-segmental proliferative glomerulonephritis without any signs of a IgA-nephropathy. The result was compatible with a renal manifestation of a small-vessel vasculitis. During the following laboratory workup ANCA of a perinuclear pattern with specificity for myeloperoxidase in high titers could be detected. Therefore the diagnosis of a p-ANCA-positive glomerulonephritis was established. As treatment, the patient received Rituximab, which turned out to be effective. We provide the first report of a patient who developed a p-ANCA-associated vasculitis after autologous stem cell transplantation for an autoimmune disease, namely systemic sclerosis.
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Androgen Receptor mRNA Expression in Urothelial Carcinoma of the Bladder: A Retrospective Analysis of Two Independent Cohorts - Sikic, Danijel; Wirtz, Ralph M.; Wach, Sven; Dyrskjot, Lars; Erben, Philipp; Bolenz, Christian; Breyer, Johannes; Otte, Wolfgang; Hoadley, Katherine A.; Lerner, Seth P.; Eckstein, Markus; Hartmann, Arndt; et al. (Translational Oncology, 2019)
INTRODUCTION: Gender-specific differences have led to the androgen receptor (AR) being considered a possible factor in the pathophysiology of urothelial carcinoma of the bladder (UCB), but the exact role remains unclear. MATERIALS AND METHODS: The association of AR mRNA expression with clinicopathological features was retrospectively analyzed in two previously described cohorts. The first cohort consisted of 41 patients with all stages of UCB treated at Aarhus University Hospital, Denmark. The second cohort consisted of 323 patients with muscle-invasive bladder cancer (MIBC) accumulated by the Cancer Genome Atlas (TCGA) Research Network. RESULTS: AR mRNA expression is significantly higher in non-muscle-invasive bladder cancer (NMIBC) when compared to MIBC (P = .0004), with no relevant changes within the different stages of MIBC. AR mRNA expression was significantly associated with TCGA molecular subtypes (P < .0001). In the total cohort, there was no association between AR expression and gender (P = .23). When analyzed separately, females showed a significantly worse disease-free (P = .03) and overall survival (P = .02) when expressing AR mRNA above median level, while the same was not observed for men. Multivariable Cox's regression analyses revealed AR mRNA expression to be an independent prognostic marker for disease-free survival in women (P = .007). CONCLUSIONS: AR mRNA expression is significantly higher in NMIBC than in MIBC, while high AR mRNA expression is associated with worse survival in females with MIBC. Further studies need to investigate the gender-specific role of AR in UCB.
CRIS-Team WoS Importer:2019-03-22

An Empirical Survey on the Adaption of Neoadjuvant Chemotherapy in Bladder Cancer - Reike, Moritz J.; Reicherz, Alina; Tully, Karl H.; Bahlburg, Henning; Maas, Moritz; Bach, Peter; Klümper, Niklas; Eckstein, Markus; Hartmann, Arndt; Breyer, Johannes; Erben, Philipp; Bolenz, Christian; et al. (Urologia Internationalis, 2024)
Introduction: The aim of the study was to determine the adaption of neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) in Germany, Austria, and Switzerland and especially underlying reasons for potential low adherence to guidelines. Methods: We conducted a non-validated survey among 336 urologic departments in Germany, Austria, and Switzerland. RedCap questionnaires were electronically distributed and included 23 items concerning the general NAC administration standards and guideline compliance in patient counseling regarding the actual treatment. Results: The return rate of the questionnaire was 19.1% (63/336). Although 45 departments (71.4%) claim to perform NAC as the standard of care, only 49% of eligible patients actually receive NAC. An advanced disease stage (>cT3) and a high tumor volume were mentioned to support the application of NAC, whereas 35% of responders worry about deterioration of patients preoperative status due to NAC. Furthermore, 26.7% of respondents are concerned about the low extent of survival benefit. Conclusion: Application of NAC in eligible MIBC patients in Germany, Austria, and Switzerland remains low. Although the majority of urologic departments discuss NAC and acknowledge the need for intensified treatment in advanced disease stages, not all eligible patients will actually receive NAC before radical cystectomy.
CRIS-Team Scopus Importer:2024-06-07
Keywords: Bladder cancer; Empirical study; Germany; Neoadjuvant chemotherapy; Radical cystectomy

Angioleiomyoma of the Sinonasal Tract: Analysis of 16 Cases and Review of the Literature - Agaimy, Abbas; Michal, Michael; Thompson, Lester D.R.; Michal, Michal (Head and Neck Pathology, 2015)
Angioleiomyoma (ALM; synonyms: angiomyoma, vascular leiomyoma) is an uncommon benign tumor of skin and subcutaneous tissue. Most arise in the extremities (90 %). Head and neck ALMs are uncommon ( 10 % of all ALMs) and those arising beneath the sinonasal tract mucosa are very rare (<1 %) with 38 cases reported so far. We herein analyzed 16 cases identified from our routine and consultation files. Patients included seven females and nine males aged 25-82 years (mean 58; median 62). Symptoms were intermittent nasal obstruction, sinusitis, recurrent epistaxis, and a slow-growing mass. Fifteen lesions originated within different regions of the nasal cavity and one lesion was detected incidentally in an ethmoid sinus sample. Size range was 6-25 mm (mean 11). Histologically, all lesions were well circumscribed but non-encapsulated and most (12/16) were of the compact solid type superficially mimicking conventional leiomyoma but contained numerous compressed muscular veins. The remainder were of venous (2) and cavernous (2) type. Variable amounts of mature fat were observed in four cases (25 %). Atypia, necrosis, and mitotic activity were absent. Immunohistochemistry showed consistent expression of smooth muscle actin (12/12), h-caldesmon (9/9), muscle-specific actin (4/4), variable expression of desmin (11/14) and CD56 (4/6), and absence of HMB45 expression (0/11). The covering mucosa was ulcerated in 6 cases and showed squamous metaplasia in one case. There were no recurrences after local excision. Submucosal sinonasal ALMs are rare benign tumors similar to their reported cutaneous counterparts with frequent adipocytic differentiation. They should be distinguished from renal-type angiomyolipoma. Simple excision is curative.
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Angiosarcoma arising in association with vascular Dacron grafts and orthopedic joint prostheses: clinicopathologic, immunohistochemical, and molecular study - Agaimy, Abbas; Ben-Izhak, Ofer; Lorey, Thomas; Scharpf, Marcus; Rubin, Brian P. (Annals of Diagnostic Pathology, 2016)
Angiosarcoma may rarely arise near an inert foreign body material including vascular grafts and metal joint prostheses. Sixteen such cases have been reported since 1972 but mostly in the radiologic or surgical literature without detailed histologic or molecular analyses. We herein describe the clinicopathologic and molecular features of 2 new cases and reanalyzed 3 previously reported cases of angiosarcoma that developed in association with Dacron grafts for vascular repair (n=3) or related to orthopedic metal prostheses for joint replacement (n=2). All patients were men aged 50 to 84 years (median, 71 years). Mean time to development of angiosarcoma was 9years (range, 4.6-17 years). Symptoms were recurrent bleeding/loosening of prosthesis for suspected infection (in the joint prosthesis cases) and fatigue, weight loss, and abdominal symptoms in the Dacron-associated cases. Four patients died of disease within 1 to 24 months (mean, 8 months). One patient was alive after radical surgery, radiochemotherapy, and embolization of pulmonary metastases (17months). Histologically, all tumors were high-grade epithelioid neoplasms with a predominant solid growth pattern and variable vasoformation. All tumors expressed CD31, ERG, FLI-1, and variably pancytokeratin (diffuse in 3 cases), but none expressed D2-40, MDM2, or CDK4. Fluorescence in situ hybridization analysis revealed no MDM2 or CDK4 alterations. MYC was expressed in all cases, but only 1 case was MYC amplified by fluorescence in situ hybridization. Angiosarcomas are exceedingly rare fatal complications of long-standing metal and Dacron prostheses. Awareness of their morphology and frequent cytokeratin expression is necessary to avoid misdiagnosis as metastatic carcinoma. Limited awareness of their existence explains delayed clinical diagnosis in most of cases. Absence of MDM2/CDK4 alterations underlines their distinction from intimal-type sarcomas.
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Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy - Naschberger, Elisabeth; Croner, Roland S.; Merkel, Susanne; Dimmler, Arno; Tripal, Philipp; Amann, Kerstin Ute; Kremmer, Elisabeth; Brueckl, Wolfgang M.; Papadopoulos, Thomas; Hohenadl, Christine; Hohenberger, Werner; Stürzl, Michael (International Journal of Cancer, 2008)
Angiogenesis and inflammation are the 2 major stroma reactions in colorectal carcinoma (CRC). Guanylate binding protein-1 (GBP-1) is a key mediator of angiostatic effects of inflammation. Therefore, we hypothesized that GBP-1 may be a biomarker of intrinsic angiostasis associated with an improved outcome in CRC patients. GBP-1 was strongly expressed in endothelial cells and immune cells in the desmoplastic stroma of 32% of CRC as determined by immunohistochemical investigation of 388 sporadic CRC. Cancer-related 5-year survival was highly significant (p < 0.001) increased (16.2%) in patients with GBP-1-positive CRC. Multivariate analysis showed that GBP-1 is an independent prognostic factor indicating a reduction of the relative risk of cancer-related death by the half (p = 0.032). A comparative transcriptome analysis (22,215 probe sets) of GBP-1-positive (n = 12) and -negative (n = 12) tumors showed that particularly IFN-γ-induced genes including the major antiangiogenic chemokines CXCL9, CXCL10 and CXCL11 were coexpressed with GBP-1. Altogether our findings indicated that GBP-1 may be a novel biomarker and an active component of a Th-1-like angiostatic immune reaction in CRC. This reaction may affect patient's response to antiangiogenic therapy and the identification of such tumors may provide a novel criterion for patient selection. Moreover, the induction of a Th-1-like angiostatic immune reaction may be a promising approach for the clinical treatment of CRC. © 2008 Wiley-Liss, Inc.
Created from Fastlane, Scopus look-up
Keywords: Angiogenesis; Colorectal carcinoma; Guanylate binding protein-1; Inflammation; Interferon-γ

Angiotensin II type 1a receptor-deficient mice develop angiotensin II-induced oxidative stress and DNA damage without blood pressure increase - Zimnol, Anna; Amann, Kerstin Ute; Mandel, Philipp; Hartmann, Christina; Schupp, Nicole (American Journal of Physiology-Renal Physiology, 2017)
Hypertensive patients have an increased risk to develop kidney cancer. We have shown in vivo, that besides elevating blood pressure, angiotensin II causes DNA damage dose-dependently. Here, the role of blood pressure in the formation of DNA damage is studied. Mice lacking one of the two murine angiotensin II type 1 receptor (AT1R) subtypes, AT1aR, were equipped with osmotic minipumps, delivering angiotensin II during 28 days. Parameters of oxidative stress and DNA damage of kidneys and hearts of AT1aR-knockout mice were compared to wildtype (C57BL/6) mice receiving angiotensin II, and additionally, to wildtype (WT) mice treated with candesartan, an antagonist of both AT1R-subtypes. In WT mice, angiotensin II induced hypertension, reduced kidney function and led to a significant formation of reactive oxygen species (ROS). Furthermore, genomic damage was markedly increased in this group. All these responses to angiotensin II could be attenuated by concurrent administration of candesartan. In AT1aR-deficient mice treated with angiotensin II, systolic pressure was not increased, and renal function was not affected. However, angiotensin II still led to an increase of ROS in kidneys and hearts of these animals. Additionally, genomic damage in the form of double-strand breaks, was significantly induced in kidneys of AT1aR-deficient mice. Our results show that angiotensin II induced ROS production and DNA damage even without the presence of AT1aR and independently of blood pressure changes.
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An Immunoregulatory Role of Interleukin-3 in Allergic Asthma - Krammer, Susanne; Yang, Zuqin; Zimmermann, Theodor; Xepapadaki, Paraskevi; Geppert, Carol-Immanuel; Papadopoulos, Nikolaos G.; Finotto, Susetta (Frontiers in Immunology, 2022)
Background: Allergic asthma is a chronic airway inflammatory disease associated with airway mucus hyper-production. ILC2 cells, which express the Th2 transcription factor GATA3, have been associated with allergic asthma. The cytokine IL-3 is known to support eosinophil, basophil and mucosal mast cell differentiation and survival; however, its role on T regulatory cells as well as on lung ILC2 and in pediatric asthma needs further investigation. Objectives: To investigate the role of IL-3 in preschool children and to explore its therapeutic role in experimental asthma. Methods: In a cohort of preschool children with and without asthma, we analyzed the secretion of IL-3 in nasopharyngeal fluid (NPF) and IL-3 receptor (R) alpha chain mRNA expression in peripheral blood mononuclear cells (PBMCs). In a murine model of allergic asthma, we analyzed the phenotype of wild-type untreated and rIL-3 intranasally treated asthmatic mice. Results: IL-3 was found downregulated in the nasopharyngeal fluid of children with partially controlled asthma, as compared to control children. Moreover, IL-3 was found induced in phytohemagglutinin (PHA)-stimulated PBMCs from children with asthma and treated with steroids. Finally, IL-3 in NPF directly correlated with the anti-inflammatory molecule sST2 in steroid-treated asthmatic children. Intranasal rIL-3 delivery in vivo during the challenge phase decreased airway mucus production and inflammatory eosinophils. Moreover, rIL-3 given during the challenge phase, reduced lung ST2intGATA3+ILC2, accompanied by an induction of T regulatory cells in the airways. Conclusions: IL-3 was found associated with steroid-resolved asthma. Moreover, treatment with rIL-3 resulted in amelioration of airway eosinophilia and mucus production, two main pathophysiological conditions associated with asthma in a murine model of allergic asthma. Thus, rIL-3 opens new strategies for immunotherapy of this disease.
CRIS-Team Scopus Importer:2022-03-25
Keywords: allergic asthma; eosinophils; IL-3; ILC2s; T regulatory cells

An Innovative Arteriovenous (AV) Loop Breast Cancer Model Tailored for Cancer Research - An, Ran; Strissel, Pamela; Al-Abboodi, Majida; Robering, Jan Willem; Reakasame, Supachai; Eckstein, Markus; Peddi, Ajay; Hauck, Theresa; Bäuerle, Tobias; Boccaccini, Aldo R.; Youssef, Almoatazbellah; Sun, Jiaming; et al. (Bioengineering, 2022)
Animal models are important tools to investigate the pathogenesis and develop treatment strategies for breast cancer in humans. In this study, we developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone. We examined the in vivo effects of various matrices on the growth of breast cancer cells by imaging and immunohistochemistry evaluation. Our findings clearly demonstrate that vascularized breast cancer microtissues could be engineered and recapitulate the in vivo situation and tumor-stromal interaction within an isolated environment in an in vivo organism. Alginate–fibrin hybrid matrices were considered as a highly powerful material for breast tumor engineering based on its stability and biocompatibility. We propose that the novel tumor model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors.
CRIS-Team Scopus Importer:2022-07-15
Keywords: animal model; arteriovenous loop; breast cancer

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer - Lindskrog, Sia Viborg; Prip, Frederik; Lamy, Philippe; Taber, Ann; Groeneveld, Clarice S.; Birkenkamp-Demtröder, Karin; Jensen, Jørgen Bjerggaard; Strandgaard, Trine; Nordentoft, Iver; Christensen, Emil; Sokac, Mateo; Birkbak, Nicolai J.; et al. (Nature Communications, 2021)
The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
CRIS-Team Scopus Importer:2021-04-30

An introduction to the WHO 5th edition 2022 classification of testicular tumours - Berney, Daniel M.; Cree, Ian; Rao, Vishal; Moch, Holger; Srigley, John R.; Tsuzuki, Toyonori; Amin, Mahul B.; Comperat, Eva M.; Hartmann, Arndt; Menon, Santosh; Netto, George J.; Rubin, Mark A.; et al. (Histopathology, 2022)
The 5th edition of the World Health Organisation Blue Book was published recently and includes a comprehensive update on testicular tumours. This builds upon the work of the 4th edition, retaining its structure and main nomenclature, including the use of the term ‘germ cell neoplasia in situ’ (GCNIS) for the pre-invasive lesion of most germ cell tumours and division from those not derived from GCNIS. While there have been important developments in understanding the molecular underpinnings of testicular cancer, this updated classification paradigm and approach remains rooted in morphology. Nomenclature changes include replacement of the term ‘primitive neuroectodermal tumour’ by ‘embryonic neuroectodermal tumour’ based on the non-specificity of the former term and to separate these tumours clearly from Ewing sarcoma. Seminoma is placed in a germinoma family of tumours emphasising relation to those tumours at other sites. Criteria for the diagnosis of ‘teratoma with somatic transformation’ have been modified to not include variable field size assessments. The word ‘carcinoid’ has been changed to ‘neuroendocrine tumour’, with most examples in the testis now classified as ‘prepubertal type testicular neuroendocrine tumour’. For sex cord-stromal tumours, the use of mitotic counts per high-power field has been changed to per mm2 for malignancy assessments, and the new entities, ‘signet ring stromal tumour’ and ‘myoid gonadal stromal tumour’, are defined. Well-differentiated papillary mesothelial tumour has now been defined as tumour type with a favourable prognosis. Sertoliform cystadenoma has been removed as an entity from testicular adnexal tumours and placed with Sertoli cell tumours.
CRIS-Team Scopus Importer:2022-07-08
Keywords: classification; Germ Cell Tumour; teratoma; testis; WHO

An investigation of the diagnostic, predictive, and prognostic impacts of three colonic biopsy grading systems for acute graft versus host disease - Kreft, Andreas; Hippe, Katrin; Wagner-Drouet, Eva Maria; Ries, Isabelle; Kandulski, Arne; Büttner-Herold, Maike; Neumann, Helmut; Weber, Daniela; Holler, Ernst; Schindeldecker, Mario (PLoS ONE, 2021)
Acute graft versus host disease (aGvHD) is an important, life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). To investigate the value of multiple simultaneous colon biopsies in improving diagnostic accuracy in patients with aGvHD, we retrospectively analyzed 157 patients after alloHSCT. The biopsies were evaluated individually using three established histological grading systems (Lerner, Sale, and Melson). The maximum, minimum, median, and mean histological aGvHD grades were calculated for each patient, and the results were correlated with the Glucksberg grade of clinical manifestation of GvHD, steroid therapy status, and outcome. We found that multiple colon biopsies enhanced diagnostic sensitivity. Moreover, higher histological grades correlated with steroid therapy initiation and refractoriness; the latter particularly occurred when advanced damage was present in all samples and healthy colon mucosa was reduced or absent. On multivariate analysis, the minimal Lerner and Glucksberg grades for intestinal aGvHD were significantly associated with steroid treatment failure. Ninety-nine patients died. The median survival was 285 days after the biopsies were taken. Fifteen patients died from relapse of their underling disorder and 84 from other causes, mostly infection (53 patients) and GvHD (14 patients). Multivariate analysis revealed a significant association between none-relapse mortality and the mean Lerner grade, minimum Melson grade, Glucksberg organ stage, and platelet counts. Thus, we found the Lerner system to be superior to the other grading methods in most instances and histologic evaluation of multiple simultaneously obtained biopsies from the colon to result in a higher diagnostic yield, which helps plan systemic steroid treatment while predicting treatment response and outcome.
CRIS-Team Scopus Importer:2021-09-10

Anisometric cell lipoma: Insight from a case series and review of the literature on adipocytic neoplasms in survivors of retinoblastoma suggest a role for RB1 loss and possible relationship to fat-predominant ("fat-only") spindle cell lipoma - Agaimy, Abbas (Annals of Diagnostic Pathology, 2017)
The term "anisometric cell lipoma" (ACL) has been proposed recently by Evans for a lipoma variant characterized by striking variation in size and shape of adipocytes but little or no cytological atypia. One patient with multiple ACL had a history of retinoblastoma. The current study analyzed six patients with ACL (4 males and two females aged 34 to 87years; median, 58); all seen in consultation. Five patients presented with solitary and one with multiple subcutaneous masses measuring 5 to 9cm (median, 7.5cm). Affected sites were upper arm (3), shoulder (2), neck (1), trunk (1) and chest wall (1). Surgical excision was the treatment in all cases. No recurrence was recorded at last follow-up (1-17months). Submitted diagnoses were atypical lipomatous tumor (n=3), lipoma with regressive changes (n=1) and unclassified lipomatous neoplasm (n=2). In all cases, the striking variation in size of adipocytes was mentioned as the most or sole worrisome feature justifying external consultation. Histology was similar in all cases. All fulfilled the features reported by Evans as stated above and lacked any conventional spindle cell lipoma-like areas. Multi-vacuolated (lipoblast-like) cells were seen in three cases. MDM2/CDK4 were negative by immunohistochemistry and MDM2 amplification was absent by FISH in all cases. RB1 immunoexpression was lost in 5/5 cases. Rb1 FISH analysis revealed copy number aberrations in 3 of 4 cases (heterozygous deletions in two cases and homozygous deletion in one). In conclusion, ACL shares similar clinicopathological, demographic and molecular features as spindle cell lipoma suggesting related diseases. In the light of the available literature on adipocytic neoplasms in retinoblastoma survivors (>30 patients with multiple lipomas following retinoblastoma reported), it is probably that retinoblastoma-associated lipomas belong to the ACL category. Thus, it seems that Somatic RB1 loss probably drives sporadic ACL in a comparable way to post-retinoblastoma lipomas which were shown to be driven by LOH of the RB1 wild-type allele.
EVALuna2:6889

Anln and tle2 in muscle invasive bladder cancer: A functional and clinical evaluation based on in silico and in vitro data - Wu, Sheng; Nitschke, Katja; Heinkele, Jakob; Weis, Cleo Aron; Worst, Thomas Stefan; Eckstein, Markus; Porubsky, Stefan; Erben, Philipp (Cancers, 2019)
Anilin actin binding protein (ANLN) and transducing-like enhancer protein 2 (TLE2) are associated with cancer patient survival and progression. The impact of their gene expression on progression-free survival (PFS) of patients with muscle invasive bladder cancer (MIBC) treated with radical cystectomy (RC) and subtype association has not yet been investigated. qRT-PCR was used to measure the transcript levels of ANLN and TLE2 in the Mannheim cohort, and validated in silico by The Cancer Genome Atlas (TCGA) cohort. Uni-and multivariate Cox regression analyses identified predictors for disease-specific survival (DSS) and overall survival (OS). In the Mannheim cohort, tumors with high ANLN expression were associated with lower OS and DSS, while high TLE2 expression was associated with a favorable OS. The TCGA cohort confirmed that high ANLN and low TLE2 expression was associated with shorter OS and disease-free survival (DFS). In both cohorts, multivariate analyses showed ANLN and TLE2 expression as independent outcome predictors. Furthermore, ANLN was more highly expressed in cell lines and patients with the basal subtype, while TLE2 expression was higher in cell lines and patients with the luminal subtype. ANLN and TLE2 are promising biomarkers for individualized bladder cancer therapy including cancer subclassification and informed MIBC prognosis.
CRIS-Team Scopus Importer:2019-11-29
Keywords: Biomarker; Molecular subtype; Muscle invasive bladder cancer; Prognosis

Annual meeting of the German Prostate Cancer Consortium: Updates to circulating tumor cells, "liquid biopsy" and the role of the androgen receptor - Taubert, Helge; Becker, Christoph; Fuessel, Susanne; Seitz, Gerhard; Thelen, Paul; Wullich, Bernd (Urologe, 2016)
EVALuna2:16346

An ongoing, randomized phase II study of Nivolumab plus Ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST) - Ahrens, M.; Escudier, B.; Haanen, J. B. A. G.; Boleti, E.; Goupil, Gross M.; Grimm, M. O.; Negrier, S.; Barthelemy, P.; Gravis, G.; Ivany, P.; Bedke, J.; Castellano, D.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

A noninvasive diagnostic approach to retrospective donor HLA typing in kidney transplant patients using urine - Bach, Christian; Knaup, Karl; Herrmann, Markus; Krumbiegel, Mandy; Pfister, Frederick; Büttner-Herold, Maike; Steffen, Martin; Zecher, Daniel; Lopau, Kai; Schneider, Karen; Dieterle, Anne; Amann, Kerstin Ute; et al. (Transplant International, 2021)
Antibody-mediated rejection (AMR) is a major obstacle to long-term kidney transplantation. AMR is mostly caused by donor specific HLA antibodies, which can arise before or any time after transplantation. Incomplete donor HLA typing and unavailability of donor DNA regularly preclude the assessment of donor-specificity of circulating anti-HLA antibodies. In our centre, this problem arises in approximately 20% of all post-transplant HLA-antibody assessments. We demonstrate that this diagnostic challenge can be resolved by establishing donor renal tubular cell cultures from recipient´s urine as a source of high-quality donor DNA. DNA was then verified for genetic origin and purity by fluorescence in situ hybridization and short tandem repeat analysis. Two representative cases highlight the diagnostic value of this approach which is corroborated by analysis of ten additional patients. The latter were randomly sampled from routine clinical care patients with available donor DNA as controls. In all 12 cases, we were able to perform full HLA typing of the respective donors confirmed by cross-comparison to results from the stored 10 donor DNAs. We propose that this noninvasive diagnostic approach for HLA typing in kidney transplant patients is valuable to determine donor specificity of HLA antibodies, which is important in clinical assessment of suspected AMR.
CRIS-Team Scopus Importer:2021-06-25
Keywords: antibody-mediated rejection; HLA typing; HLA-antibody post-transplantation; rejection

A novel grading approach predicts worse outcomes in stage pT1 non-muscle-invasive bladder cancer - Haas, Maximilian; Engelmann, Simon U.; Mayr, Roman; Gossler, Christopher; Pickl, Christoph; Kälble, Sebastian; Yang, Yushan; Otto, Wolfgang; Hartmann, Valerie; Burger, Maximilian; Hartmann, Arndt; Breyer, Johannes; et al. (Bju International, 2024)
Objective: To develop a prognostically relevant scoring system for stage pT1 non-muscle-invasive bladder cancer (NMIBC) incorporating tumour budding, growth pattern and invasion pattern because the World Health Organisation grading system shows limited prognostic value in such patients. Patients and Methods: The tissue specimens and clinical data of 113 patients with stage pT1 NMIBC who underwent transurethral resection of bladder tumour were retrospectively investigated. Tumour budding, and growth and invasion patterns were evaluated and categorised into two grade groups (GGs). GGs and other clinical and histopathological variables were investigated regarding recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) using univariable and multivariable Cox regression analyses. Results: The integration of two tumour budding groups, two growth patterns, and two invasion patterns yielded an unfavourable GG (n = 28; 24.7%) that had a high impact on oncological outcomes. The unfavourable GG was identified as an independent RFS and OS predictor (P = 0.004 and P = 0.046, respectively) and linked to worse PFS (P = 0.001) and CSS (P = 0.001), irrespective of the European Association of Urology risk group. The unfavourable GG was associated with higher rates of BCG-unresponsive tumours (P = 0.006). Study limitations include the retrospective, single-centre design, diverse therapies and small cohort. Conclusions: We present a morphology-based grading system for stage pT1 NMIBC that correlates with disease aggressiveness and oncological patient outcomes. It therefore identifies a highest risk group of stage pT1 NMIBC patients, who should be followed up more intensively or receive immediate radical cystectomy. The grading incorporates objective variables assessable on haematoxylin and eosin slides and immunohistochemistry, enabling an easy-to-use low-cost approach that is applicable in daily routine. Further studies are needed to validate and confirm these results.
CRIS-Team Scopus Importer:2024-03-15
Keywords: bladder cancer; EMT; grade group; NMIBC; tumour budding

A Novel Grading System Based on Tumor Budding and Cell Nest Size Is a Strong Predictor of Patient Outcome in Esophageal Squamous Cell Carcinoma - Jesinghaus, Moritz; Boxberg, Melanie; Konukiewitz, Bjoern; Slotta-Huspenina, Julia; Schlitter, Anna M.; Steiger, Katja; Specht, Katja; Wieczorek, Kathrin; Warth, Arne; Schmidt, Thomas; Hartmann, Arndt; Demir, Ihsan E.; et al. (American Journal of Surgical Pathology, 2017)
The determination of prognosis in patients with esophageal squamous cell carcinoma (ESCC) is primarily based on staging according to the TNM-classification, whereas conventional grading is of minor clinical importance because of its deficiencies in prognostic patient stratification. Recently, a novel, highly prognostic grading scheme based on budding activity and cell nest size has been proposed for squamous cell carcinoma (SCC) of both pulmonary as well as oral origin. In order to investigate the utility and transferability of this approach to ESCC, we evaluated budding activity and cell nest size, as well as other histomorphologic characteristics, in a cohort of 135 primarily resected tumors and correlated the results with clinicopathologic and outcome parameters. High budding activity and small cell nest size showed a strong association with reduced overall, disease-specific, and disease-free survival (P<0.001, respectively) in ESCC. The combination of both markers in a 3-step grading system showed excellent prognostic separation of well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) carcinomas (P<0.001). The hazard ratio for disease-free survival in multivariate analysis under inclusion of stage was 2.97 for G2 and 5.42 for G3 ESCC (P<0.001). World Health Organization-based grading had no prognostic impact. Taken together, our data prove the value of tumor budding and cell nest size as excellent outcome predictors in ESCC and validate the utility of a previously established grading scheme proposed for oral and pulmonary SCC in this tumor entity. Ultimately, these combined efforts may result in a universal grading system for SCC regardless of the site of origin.
EVALuna2:6868

A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia - Wohlfart, Sigrun; Söder, Stephan; Smahi, Asma; Schneider, Holm (American Journal of Medical Genetics Part A, 2016)
Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-?B signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-?B signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition.
EVALuna2:6777

A novel molecular signature identifies mixed subtypes in renal cell carcinoma with poor prognosis and independent response to immunotherapy - Buettner, Florian A.; Winter, Stefan; Stuehler, Viktoria; Rausch, Steffen; Hennenlotter, Joerg; Füssel, Susanne; Zastrow, Stefan; Meinhardt, Matthias; Toma, Marieta; Jeronimo, Carmen; Henrique, Rui; Miranda-Goncalves, Vera; et al. (Genome Medicine, 2022)
Background: Renal cell carcinoma (RCC) is a heterogeneous disease comprising histologically defined subtypes. For therapy selection, precise subtype identification and individualized prognosis are mandatory, but currently limited. Our aim was to refine subtyping and outcome prediction across main subtypes, assuming that a tumor is composed of molecular features present in distinct pathological subtypes.
CRIS-Team WoS Importer:2022-09-23

A novel urinary proteomics classifier for non-invasive evaluation of interstitial fibrosis and tubular atrophy in chronic kidney disease - Catanese, Lorenzo; Siwy, Justyna; Mavrogeorgis, Emmanouil; Amann, Kerstin Ute; Mischak, Harald; Beige, Joachim; Rupprecht, Harald (Proteomes, 2021)
Non-invasive urinary peptide biomarkers are able to detect and predict chronic kidney disease (CKD). Moreover, specific urinary peptides enable discrimination of different CKD etiologies and offer an interesting alternative to invasive kidney biopsy, which cannot always be performed. The aim of this study was to define a urinary peptide classifier using mass spectrometry technology to predict the degree of renal interstitial fibrosis and tubular atrophy (IFTA) in CKD patients. The urinary peptide profiles of 435 patients enrolled in this study were analyzed using capillary electrophoresis coupled with mass spectrometry (CE-MS). Urine samples were collected on the day of the diagnostic kidney biopsy. The proteomics data were divided into a training (n = 200) and a test (n = 235) cohort. The fibrosis group was defined as IFTA ≥ 15% and no fibrosis as IFTA < 10%. Statistical comparison of the mass spectrometry data enabled identification of 29 urinary peptides with differential occurrence in samples with and without fibrosis. Several collagen fragments and peptide fragments of fetuinA and others were combined into a peptidomic classifier. The classifier separated fibrosis from non-fibrosis patients in an independent test set (n = 186) with area under the curve (AUC) of 0.84 (95% CI: 0.779 to 0.889). A significant correlation of IFTA and FPP_BH29 scores could be observed Rho = 0.5, p < 0.0001. We identified a peptidomic classifier for renal fibrosis containing 29 peptide fragments corresponding to 13 different proteins. Urinary proteomics analysis can serve as a noninvasive tool to evaluate the degree of renal fibrosis, in contrast to kidney biopsy, which allows repeated measurements during the disease course.
CRIS-Team Scopus Importer:2021-08-06
Keywords: Biomarkers; Fibrosis; IFTA; Peptides; Urine

Anthocyanins Prevent Colorectal Cancer Development in a Mouse Model - Lippert, Elisabeth; Ruemmele, Petra; Obermeier, Florian; Goelder, Stefan; Kunst, Claudia; Rogler, Gerhard; Dunger, Nadja; Messmann, Helmut; Hartmann, Arndt; Endlicher, Esther (Digestion, 2017)
Colorectal cancer is the main leading cause of cancer-related deaths worldwide. Present data suggest that plant-derived anthocyanins have anti-inflammatory and chemopreventive properties. This study was aimed at evaluating the effect of an anthocyanin-rich extract from bilberries on colorectal tumour development and growth in the administration of azoxymethan (AOM)/dextran sodium sulfate (DSS) mouse model.Colonic carcinogenesis was induced by AOM and DSS 3 or 5%, respectively, in 50 female Balb/c mice. Mice received either normal food (controls) or a diet containing either 10 or 1% anthocyanin-rich bilberry extract. Colonoscopy took place at week 4 and 9 after initiation of carcinogenesis. After termination at week 9, colon samples were analysed macroscopically and microscopically.Mice receiving 10% anthocyanins showed significantly (p < 0.004) less reduced colon length (12.1 cm [8.5-14.4 cm]) as compared to controls (11.2 cm [9.8-12.3]) indicating less inflammation. Mice fed with 10% anthocyanin-rich extract revealed significantly less mean tumour numbers (n = 1.2) compared to control (n = 14) and anthocyanin 1% treated mice (n = 10.6, p < 0.001).Anthocyanins prevented the formation and growth of colorectal cancer in AOM/DSS-treated Balb/c mice. Further studies should investigate the mechanisms of how anthocyanins influence the development of colorectal cancer.
EVALuna2:6869

Anti-angiogenic therapy in head and neck squamous cell carcinoma - current limitations and future directions - Nieberle, Felix; Spoerl, Steffen; Głuszko, Alicja; Taxis, Juergen; Spanier, Gerrit; Erber, Ramona; Spörl, Silvia; Szczepański, Mirosław J.; Beckhove, Philipp; Reichert, Torsten E.; Whiteside, Theresa L.; Ludwig, Nils (Vessel Plus, 2024)
Angiogenesis, the formation of new blood vessels, plays a crucial role in the progression and metastasis of various cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCCs are characterized by altered levels of angiogenesis-related factors, including the overexpression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as the dysregulation of angiogenesis inhibitors. Together, these factors drive the formation of new blood vessels within the tumor microenvironment and are considered therapeutic targets in HNSCC. Although preclinical studies are promising, challenges have emerged in the clinical use of anti-angiogenic agents in the clinic, including treatment-related toxicities and the development of resistance to therapy. There is an unmet need for further research to elucidate the molecular pathways involved in HNSCC angiogenesis, identify novel therapeutic targets, and discover predictive biomarkers to improve patient selection.
CRIS-Team Scopus Importer:2024-07-19
Keywords: antiangiogenic therapy; Head and neck squamous cell carcinoma; HNSCC; oral squamous cell carcinoma; OSCC; tumor angiogenesis

Anti-BAFF treatment interferes with humoral responses in a model of renal transplantation in rats - Steines, Louisa; Poth, Helen; Schuster, Antonia; Geissler, Edward K.; Amann, Kerstin Ute; Banas, Bernhard; Bergler, Tobias (Transplantation, 2019)
BACKGROUND: B cell activating factor (BAFF) is associated with donor-specific antibodies (DSA) and poorer outcomes after renal transplantation (RTx). We examined the effects of anti-BAFF treatment on B cells, expression of costimulatory molecules and cytokines, germinal centers (GCs) and DSA formation in a RTx model in rats. METHODS: Anti-BAFF antibody was injected on days 3, 17, 31 and 45 after allogeneic RTx. Rats received reduced dose cyclosporine A (CsA) for 28 or 56 days to allow chronic rejection and DSA formation. Leukocytes, B cell subsets and DSA were measured using flow cytometry; expression of cytokines and costimulatory molecules was measured by qRT-PCR, and GCs and T follicular helper (TfH) were assessed using immunohistochemistry. Rejection was evaluated by a nephropathologist. RESULTS: Anti-BAFF treatment reduced the frequency of B cells in allografts and spleen. Naïve B cells were strongly reduced by anti-BAFF treatment in all compartments. mRNA expression of IL-6 and the costimulatory molecules CD40 and ICOS ligand was significantly reduced in anti-BAFF-treated rats. GCs were smaller and plasmablast/plasma cell numbers lower in anti-BAFF-treated rats, which was reflected by less DSA in certain IgG subclasses. CONCLUSIONS: Anti-BAFF treatment interferes with humoral responses at multiple levels in this model of allogeneic RTx.
EVALuna2:205573

Anti-DNA-IgM Favors the Detection of NET-Associated Extracellular DNA - Wang, Han; Stehr, Antonia; Singh, Jeeshan; Zlatar, Leticija; Hartmann, Arndt; Evert, Katja; Naschberger, Elisabeth; Von Stillfried, Saskia; Boor, Peter; Munoz, Luis Enrique; Knopf, Jasmin; Stürzl, Michael; et al. (International Journal of Molecular Sciences, 2023)
During inflammatory responses, neutrophils enter the sites of attack where they execute various defense mechanisms. They (I) phagocytose microorganisms, (II) degranulate to release cytokines, (III) recruit various immune cells by cell-type specific chemokines, (IV) secrete anti-microbials including lactoferrin, lysozyme, defensins and reactive oxygen species, and (V) release DNA as neutrophil extracellular traps (NETs). The latter originates from mitochondria as well as from decondensed nuclei. This is easily detected in cultured cells by staining of DNA with specific dyes. However, in tissues sections the very high fluorescence signals emitted from the condensed nuclear DNA hamper the detection of the widespread, extranuclear DNA of the NETs. In contrast, when we employ anti-DNA-IgM antibodies, they are unable to penetrate deep into the tightly packed DNA of the nucleus, and we observe a robust signal for the extended DNA patches of the NETs. To validate anti-DNA-IgM, we additionally stained the sections for the NET-markers histone H2B, myeloperoxidase, citrullinated histone H3, and neutrophil elastase. Altogether, we have described a fast one-step procedure for the detection of NETs in tissue sections, which provides new perspectives to characterize neutrophil-associated immune reactions in disease.
CRIS-Team Scopus Importer:2023-03-10
Keywords: anti-DNA-IgM; extracellular DNA; NETs

Anti-TNF alpha/azathioprine therapy modulates the Natural killer cell compartment in pediatric inflammatory bowel disease - Knieling, Ferdinand; Schnell, Alexander; Allabauer, I.; Schwarz, B.; Rechenauer, Tobias; Kaspar, S.; Siebenlist, G.; Rueckel, A.; Hartmann, Arndt; Wahlbuhl-Becker, Mandy; Hoerning, A. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis - Lankes, Katharina; Hundorfean, Gheorghe; Harrer, Thomas; Pommer, Ansgar J.; Agaimy, Abbas; Angelovska, Irena; Tajmir-Riahi, Azadeh; Göhl, Jonas; Schuler, Gerold; Neurath, Markus; Hohenberger, Werner; Heinzerling, Lucie (OncoImmunology, 2016)
Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
EVALuna2:2063

An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) - Kasper, B.; Baumgarten, C.; Garcia, J.; Bonvalot, S.; Haas, R.; Haller, F.; Hohenberger, P.; Penel, N.; Messiou, C.; Van Der Graaf, W. T.; Gronchi, A. (Annals of Oncology, 2017)
Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals' AND patients' expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.
EVALuna2:6898

A partial epithelial-mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction - Pastorino, Gil; Sheraj, Ilir; Hübner, Kerstin; Ferrero, Giulio; Kunze, Philipp; Hartmann, Arndt; Hampel, Chuanpit; Husnugil, Hepsen Hazal; Maiuthed, Arnatchai; Gebhart, Florian; Schlattmann, Fynn; Gulec Taskiran, Aliye Ezgi; et al. (Journal of Pathology, 2024)
Partial epithelial-mesenchymal transition (p-EMT) has recently been identified as a hybrid state consisting of cells with both epithelial and mesenchymal characteristics and is associated with the migration, metastasis, and chemoresistance of cancer cells. Here, we describe the induction of p-EMT in starved colorectal cancer (CRC) cells and identify a p-EMT gene signature that can predict prognosis. Functional characterisation of starvation-induced p-EMT in HCT116, DLD1, and HT29 cells showed changes in proliferation, morphology, and drug sensitivity, supported by in vivo studies using the chorioallantoic membrane model. An EMT-specific quantitative polymerase chain reaction (qPCR) array was used to screen for deregulated genes, leading to the establishment of an in silico gene signature that was correlated with poor disease-free survival in CRC patients along with the CRC consensus molecular subtype CMS4. Among the significantly deregulated p-EMT genes, a triple-gene signature consisting of SERPINE1, SOX10, and epidermal growth factor receptor (EGFR) was identified. Starvation-induced p-EMT was characterised by increased migratory potential and chemoresistance, as well as E-cadherin processing and internalisation. Both gene signature and E-cadherin alterations could be reversed by the proteasomal inhibitor MG132. Spatially resolving EGFR expression with high-resolution immunofluorescence imaging identified a proliferation stop in starved CRC cells caused by EGFR internalisation. In conclusion, we have gained insight into a previously undiscovered EMT mechanism that may become relevant when tumour cells are under nutrient stress, as seen in early stages of metastasis. Targeting this process of tumour cell dissemination might help to prevent EMT and overcome drug resistance. © 2024 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:2024-01-26
Keywords: consensus molecular subtype 4; E-cadherin processing; EGFR internalisation; intermediate EMT; partial EMT; prognosis; proteasome; starvation

A Pleomorphic Puzzle: Heterogeneous Pulmonary Vascular Occlusions in Patients with COVID-19 - Singh, Jeeshan; Herrmann, Irmgard; Mahajan, Aparna; Schauer, Christine; Shan, Xiaomei; Hartmann, Arndt; Rieker, Ralf; Evert, Katja; Falkeis, Christina; Naschberger, Elisabeth; von Stillfried, Saskia; Boor, Peter; et al. (International Journal of Molecular Sciences, 2022)
Vascular occlusions in patients with coronavirus diseases 2019 (COVID-19) have been frequently reported in severe outcomes mainly due to a dysregulation of neutrophils mediating neutrophil extracellular trap (NET) formation. Lung specimens from patients with COVID-19 have previously shown a dynamic morphology, categorized into three types of pleomorphic occurrence based on histological findings in this study. These vascular occlusions in lung specimens were also detected using native endogenous fluorescence or NEF in a label-free method. The three types of vascular occlusions exhibit morphology of DNA rich neutrophil elastase (NE) poor (type I), NE rich DNA poor (type II), and DNA and NE rich (type III) cohort of eleven patients with six males and five females. Age and gender have been presented in this study as influencing variables linking the occurrence of several occlusions with pleomorphic contents within a patient specimen and amongst them. This study reports the categorization of pleomorphic occlusions in patients with COVID-19 and the detection of these occlusions in a label-free method utilizing NEF.
CRIS-Team Scopus Importer:2022-12-23
Keywords: age; COVID-19; gender; immunothrombosis; native endogenous fluorescence; occlusions; pleomorphism; SARS-CoV-2

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results - Wein, Axel; Stöhr, Robert; Kersting, Stephan; Siebler, Jürgen; Merkel, Susanne; Busse, Daniel; Wolff, Kerstin; Ostermeier, Nicola; Neufert, Clemens; Vitali, Francesco; Eckstein, Markus; Roth, Jan-Peter; et al. (Oncology, 2021)
Objective: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. Patients and Methods: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. Results: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. Conclusion: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.
CRIS-Team WoS Importer:2021-11-05

Application of Stem Cells Shows Antiinflammatory Effect in an Irradiated Random Pattern Flap Model - Müller-Seubert, Wibke; Fuchs, Lena; Horch, Raymund E.; Distel, Luitpold; Frey, Benjamin; Renno, Isabell; Erber, Ramona; Arkudas, Andreas (Journal of Personalized Medicine, 2024)
Background: In reconstructive surgery, local flaps might develop tissue necrosis or partial flap loss especially after previous irradiation, which may be necessary in many tumor entities. The application of stem cells seems promising to improve flap perfusion and might be a possible solution to optimize flap survival. Methods: Twenty rats received harvesting of bilateral random pattern fasciocutaneous flaps. The right flaps received 20 Gy ionizing radiation 4 weeks prior to the surgery, while the left flaps served as the non-irradiated control. After flap harvest, four different stem cell mixtures (5 × 106 ASC, ASC-HUVEC, MSC, MSC-HUVEC) were applied under both right and left flaps using 1 mL fibrin glue as the delivery vehicle. Flap size and its necrotic area were examined clinically. Two weeks after the surgery, HE staining and immunohistochemical staining for CD68 and ERG, as well as PCR analysis (Interleukin 6, HIF-1α and VEGF), were performed. Results: Application of ASCs, ASCs-HUVECs and MSCs resulted in a lower number of CD68-stained cells compared to the no cell group. The expression of Hif1α was higher in the ASC group compared to those in the MSC and previously treated no cell groups. Treatment with MSCs and MSCs-HUVECs prevented shrinking of the flaps in this series. Conclusion: Application of ASCs, MSCs and ASCs-HUVECs was shown to have an antiinflammatory effect. Treatment with MSCs and MSCs-HUVECs can prevent early shrinking of the flaps.
CRIS-Team Scopus Importer:2024-07-05
Keywords: ASC; HUVEC; irradiation; MSC; random pattern flaps

A prediction model for pathological complete response after neoadjuvant chemotherapy of HER2-negative breast cancer patients - Häberle, Lothar; Erber, Ramona; Gaß, Paul; Hein, Alexander; Jud, Sebastian; Langemann, Hanna; Rauh, C.; Hack, Caroline; Schulz-Wendtland, Rüdiger; Hartmann, Arndt; Beckmann, Matthias; Lux, Michael P.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

A preliminary analysis of renal infiltrating cells in acute tubular injury induced by water treated with high fluoride and high hardness in rat model - Perera, Thanusha; Ranasinghe, Shirani; Alles, Neil; Daniel, Christoph; Waduge, Roshitha (Research Journal of Biotechnology, 2021)
The impact of water containing high fluoride and high hardness on kidneys of rats was investigated. Control and test water sample with high fluoride and hardness were collected from Kandy and Mihinthale regions respectively. Twelve rats were divided into 2 control and 2 test groups. One set of control and test group received normal and test water for 60 days and the other set of control and test group received same water treatment for 90 days. Rats treated with test water for 60 days were observed loss of brush border in less than 25% of tubular cells and in 90 days associated with loss of brush border in more than 25% of tubule cells resulting in acute tubular injury compared to control group. Immunohistochemical staining revealed the strong infiltration of CD3 T-cells and CD68 macrophages in test group for 90 days.
CRIS-Team WoS Importer:2021-04-02

A prospective, open-label, multicenter, randomized phase II trial: Sequential therapy with BEvacizumab, RAd001 (Everolimus) and AxiTinib in metastatic renal cell carcinoma (mRCC) (BERAT study of the IAG-N) - Hilser, Thomas; Gruenwald, Viktor; Bergmann, Lothar; Goebell, Peter; Strauss, Arne; Meiler, Johannes; Hartmann, Arndt; Ivanyi, Philipp; Bedke, Jens (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

A Prospectivly Randomized Phase-II Trial of Axitinib versus Everolimus as Second-Line Therapy in Metastatic Renal Cell Carcinoma (BERAT Study) - Grünwald, Viktor; Hilser, Thomas; Meiler, Johannes; Goebell, Peter; Ivanyi, Philipp; Strauss, Arne; Hartmann, Arndt; Bedke, Jens; Bergmann, Lothar (Oncology Research and Treatment, 2022)
Introduction: Inhibition of neo-angiogenesis is a cornerstone of medical treatment in metastatic renal cell carcinoma (mRCC). While 1st line therapies were previously dominated by inhibitors of the vascular endothelial growth factor axis, 2nd line options were less clearly defined. We investigated the role of everolimus (EVE) or a tyrosine kinase inhibitor (TKI) in 2nd line treatment of mRCC patients. Methods: Key inclusion criteria were measurable mRCC, ECOG 0-1, IMDC risk: good or intermediate and adequate organ function. Patients who progressed on or were intolerant to bevacizumab + interferon were subject for randomization between TKI and EVE treatment. Cross-over occurred at time of progression during 2nd line treatment. Improvement of 2nd line progression-free survival (PFS) rate (PFR) at 6 months from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, objective response rate (ORR), overall survival (OS), safety, and patient reported outcomes. Results: In 2012-2015, a total of 22 patients were included. The study was stopped for poor accrual. Ten patients (46%) were randomized to receive 2nd line treatment with EVE (n = 5) or axitinib (n = 4)/sunitinib (n = 1). ECOG 0 was recorded in 20% (EVE) and 60% (TKI). Severe adverse events occurred in approx. 60% in each arm. ORR was 1/5 (20%) for TKI and 0/5 (0%) for EVE. PFR at 6 months was 20% in each arm. Median PFS was 3.7 months (EVE) and 2.2 months (TKI) (hazard ratio [HR] 1.0 [95% confidence interval [CI]: 0.26-3.85]). The OS was comparable between arms HR 1.12 (95% CI: 0.27-4.61). Conclusion: The rapid change of the treatment landscape, the limited use of bevacizumab and interferon in 1st line and the duration of 1st line treatment jeopardized BERAT trial recruitment. The small number of patients is a major limitation of our trial. Our observation indicated the poor prognosis in progressive patients and the limited efficacy of TKI or mTOR inhibitors in 2nd line treatment.
CRIS-Team Scopus Importer:2022-06-10
Keywords: Axitinib; Bevacizumab; Everolimus; Interferon alpha; Metastatic renal cell carcinoma

Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome - Bohnert, Bernhard N.; Menacher, Martina; Janessa, Andrea; Woern, Matthias; Schork, Anja; Daiminger, Sophie; Kalbacher, Hubert; Haering, Hans-Ulrich; Daniel, Christoph; Amann, Kerstin Ute; Sure, Florian; Bertog, Marko; et al. (Kidney International, 2018)
Volume retention in nephrotic syndrome has been linked to activation of the epithelial sodium channel (ENaC) by proteolysis of its ?-subunit following urinary excretion of serine proteases such as plasmin. Here we tested whether pharmacological inhibition of urinary serine protease activity might protect from ENaC activation and volume retention in nephrotic syndrome. Urine from both nephrotic mice (induced by doxorubicin injection) and nephrotic patients exhibited high aprotinin-sensitive serine protease activity. Treatment of nephrotic mice with the serine protease inhibitor aprotinin by means of subcutaneous sustained-release pellets normalized urinary serine protease activity and prevented sodium retention, as did treatment with the ENaC inhibitor amiloride. In the kidney cortex from nephrotic mice, immunofluorescence revealed increased apical ?-ENaC staining, normalized by aprotinin treatment. In Xenopus laevis oocytes heterologously expressing murine ENaC, aprotinin had no direct inhibitory effect on channel activity but prevented proteolytic channel activation. Thus, our study shows that volume retention in experimental nephrotic syndrome is related to proteolytic ENaC activation by proteasuria and can be prevented by treatment with aprotinin. Hence, inhibition of urinary serine protease activity might become a therapeutic approach to treat patients with nephrotic-range proteinuri
EVALuna2:25560

Aquaporin 3 Expression Loss in Urothelial Carcinoma: Association with Tumor Invasion Depth, but not with Grading? - Breyer, Johannes; Otto, Wolfgang; Burger, Maximilian; Hartmann, Arndt; Rubenwolf, Peter C. (Bladder Cancer, 2017)
We have previously provided molecular evidence of expression of aquaporin 3 (AQP3) in normal human urothelium and in UBC of various stages. Whereas former studies demonstrated that loss of AQP3 was associated with invasive and high-grade disease and worse progression-free and cancer-specific survival, this report investigates the expression of AQP3 in associated CIS. Contrary to what we had expected, all CIS specimens were shown to exhibit strong AQP3 expression, suggesting loss of AQP3 in UBC is primarily associated with the ability of tumor cells for invasion but not with grading as sign of dedifferentiation.
EVALuna2:34251

A randomised phase II study of Nivolumab plus Ipilimumab versus Standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST) - Ahrens, M.; Scheich, S.; Goekbuget, N.; Boleti, E.; Gruenwald, V.; Escudier, B.; Goebell, Peter; Gschwend, J.; Hartmann, Arndt; Miller, K.; Burkholder, I.; Schmidinger, M.; et al. (2018)
EVALuna2:35902

A Randomized Phase IIa Trial with Temsirolimus versus Sunitinib in Advanced Non-Clear Cell Renal Cell Carcinoma: An Intergroup Study of the CESAR Central European Society for Anticancer Drug Research-EWIV and the Interdisciplinary Working Group on Renal Cell Cancer (IAGN) of the German Cancer Society - Bergmann, Lothar; Grünwald, Viktor; Maute, Luise; Grimm, Marc Oliver; Weikert, Steffen; Schleicher, Jan; Klotz, Theodor; Greiner, Jochen; Flörcken, Anne; Hartmann, Arndt; Gauler, Thomas (Oncology Research and Treatment, 2020)
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65-4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
CRIS-Team Scopus Importer:2020-07-10

A Randomized Phase II Study of Nivolumab Plus Ipilimumab Versus Standard of Care in Previously Untreated and Advanced Non-Clear Cell Renal Cell Carcinoma (Suniforecast) - Ahrens, Marit; Escudier, Bernard; Boleti, Ekaterini; Grimm, Marc-Oliver; Goupir, Marine Gross; Barthelemy, Pilippe; Gravis, Gwenaelle; Bedekes, Jens; Ivanyi, Philipp; Panic, Andrej; Zschaebitz, Stefanie; Neyrieru, Sylvie; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

A randomized phase II trial of ipilimumab and nivolumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNNIFORECAST) - Ahrens, M.; Escudier, B.; Haanen, J.; Gross-Goupil, M.; Boleti, E.; Gravis, G.; Grimm, M. -O.; Negrier, S.; Bedke, J.; Barthelemy, P.; Castellano, D.; Mellado, B.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

A rare case of Epstein-Barr virus-associated hepatosplenic smooth muscle tumors after kidney transplantation - Pircher, C.; Schneeberger, Stefan; Boesmueller, C.; Agaimy, Abbas; Zoller, Heinz; Bale, Reto; Henninger, B.; Mayer, G.; Neuwirt, Hannes (Transplant Infectious Disease, 2018)
A 27-year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein-Barr virus (EBV)-associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors.
EVALuna2:205474

Architectural crypt distortions in ulcerative colitis: Time for reappraisal - Rubio, Carlos A.; Lang-Schwarz, Corinna; Vieth, Michael (Journal of Gastroenterology and Hepatology, 2024)
Chronic mucosal inflammation and architectural crypt distortions (ACD) are essential for the histologic diagnosis of ulcerative colitis (UC). ACD in UC has been defined as irregularly arranged, dilated, branched, and shortened crypts with inequality of inter-crypt distance. However, neither the diagnostic sections' crypt phenotype nor the cutting mode have been considered. In this regard, previous studies showed that most diagnostic biopsies in UC are fortuitously crosscut at laboratories. In this communication, we review the crypt phenotypes that are included in the ACD in UC notion: crypts in asymmetric branching, crypt rings in tandem, crypts with lateral buds, face-to-face “kissing crypts,” crypts-in-crypts, laterally orientated crypts in anthemia fold domains, and crypts with irregular shape and size in innominate groves domains. The awareness that disparate crypt phenotypes may participate in the ACD notion may open new vistas in the interpretation of crypt distortions in crosscut diagnostic sections in UC. The present findings will permit endoscopists and clinicians to better understand the narrative of ACD in the pathological diagnosis.
CRIS-Team Scopus Importer:2024-11-15
Keywords: Anthemial crypts; crypt distortions; innominate grooves crypts; ulcerative colitis

ARE PROTEINS OF THE DEGRANULATION MACHINERY REQUIRED FOR RUBELLA VIRUS CONTROL IN THE SKIN? - Ehl, Stephan; Heizmann, Miriam; Maier, Sarah Lena; Speckmann, Carsten; Tesi, Bianca; Khurana, Claudia; Naumann-Bartsch, Nora; Agaimy, Abbas; Huzly, Daniela; Bryceson, Yenan T.; Schmitt-Graeff, Annette; Lehmberg, Kai (PEDIATRIC BLOOD & CANCER, 2019)
CRIS-Team WoS Importer:2020-02-21

Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome - Baier, Julia; Gänsbauer, Maximilian; Giessler, Claudia; Arnold, Harald; Muske, Mercedes; Schleicher, Ulrike; Lukassen, Sören; Ekici, Arif Bülent; Rauh, Manfred; Daniel, Christoph; Hartmann, Arndt; Schmid, Benjamin; et al. (Journal of Clinical Investigation, 2020)
Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from experimental colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells and an accumulation of intraluminal polyamines that promote epithelial healing. The pro-resolving effect of Arg1-deletion was reduced by an L-arginine-free diet, but rescued by simultaneous deletion of other L-arginine-metabolizing enzymes such as Arg2 or Nos2, demonstrating that protection from colitis requires L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wild-type recipients ameliorated intestinal inflammation while transfers from wild-type littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of L-arginine as well as altered intestinal microbiota and metabolic products account for the accelerated resolution from colitis in the absence of Arg1. Consequently, the metabolism of L-arginine may serve as target for clinical intervention in IBD patients.<br

Artificial intelligence in kidney transplant pathology Künstliche Intelligenz in der Nierentransplantationspathologie - Bülow, Roman David; Lan, Yu Chia; Amann, Kerstin Ute; Boor, Peter (Die Pathologie, 2024)
Background: Artificial intelligence (AI) systems have showed promising results in digital pathology, including digital nephropathology and specifically also kidney transplant pathology. Aim: Summarize the current state of research and limitations in the field of AI in kidney transplant pathology diagnostics and provide a future outlook. Materials and methods: Literature search in PubMed and Web of Science using the search terms “deep learning”, “transplant”, and “kidney”. Based on these results and studies cited in the identified literature, a selection was made of studies that have a histopathological focus and use AI to improve kidney transplant diagnostics. Results and Conclusion: Many studies have already made important contributions, particularly to the automation of the quantification of some histopathological lesions in nephropathology. This likely can be extended to automatically quantify all relevant lesions for a kidney transplant, such as Banff lesions. Important limitations and challenges exist in the collection of representative data sets and the updates of Banff classification, making large-scale studies challenging. The already positive study results make future AI support in kidney transplant pathology appear likely.
CRIS-Team Scopus Importer:2024-05-03
Keywords: Computer assistance; Datenintegration; Deep learning; Histomorphometry; Kidney transplantation

Assessing viability of extracorporeal preserved muscle transplants using external field stimulation: a novel tool to improve methods prolonging bridge-to-transplantation time. - Taeger, Christian; Friedrich, Oliver; Dragu, Adrian; Weigand, Annika; Hobe, Frieder; Drechsler, Caroline; Geppert, Carol-Immanuel; Arkudas, Andreas; Münch, Frank; Buchholz, Rainer; Pollmann, Charlotte; Schramm, Axel; et al. (Scientific Reports, 2015)
Preventing ischemia-related cell damage is a priority when preserving tissue for transplantation. Perfusion protocols have been established for a variety of applications and proven to be superior to procedures used in clinical routine. Extracorporeal perfusion of muscle tissue though cumbersome is highly desirable since it is highly susceptible to ischemia-related damage. To show the efficacy of different perfusion protocols external field stimulation can be used to immediately visualize improvement or deterioration of the tissue during active and running perfusion protocols. This method has been used to show the superiority of extracorporeal perfusion using porcine rectus abdominis muscles perfused with heparinized saline solution. Perfused muscles showed statistically significant higher ability to exert force compared to nonperfused ones. These findings can be confirmed using Annexin V as marker for cell damage, perfusion of muscle tissue limits damage significantly compared to nonperfused tissue. The combination of extracorporeal perfusion and external field stimulation may improve organ conservation research.

Assessment and Risk Prediction of Chronic Kidney Disease and Kidney Fibrosis Using Non-Invasive Biomarkers. - Rupprecht, Harald; Catanese, Lorenzo; Amann, Kerstin Ute; Hengel, Felicitas E.; Huber, Tobias B.; Latosinska, Agnieszka; Lindenmeyer, Maja T.; Mischak, Harald; Siwy, Justyna; Wendt, Ralph; Beige, Joachim (International Journal of Molecular Sciences, 2024)
Effective management of chronic kidney disease (CKD), a major health problem worldwide, requires accurate and timely diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for evaluating specific aspects of CKD have been proposed in the literature, many of which are based on a small number of samples. Based on the evidence presented in relevant studies, a comprehensive overview of the different biomarkers applicable for clinical implementation is lacking. This review aims to compile information on the non-invasive diagnostic, prognostic, and predictive biomarkers currently available for the management of CKD and provide guidance on the application of these biomarkers. We specifically focus on biomarkers that have demonstrated added value in prospective studies or those based on prospectively collected samples including at least 100 subjects. Published data demonstrate that several valid non-invasive biomarkers of potential value in the management of CKD are currently available.
EVALuna2:566232

Assessment of a fully-automated diagnostic AI software in prostate MRI: Clinical evaluation and histopathological correlation - Bayerl, Nadine; Adams, Lisa C.; Cavallaro, Alexander Josef; Bäuerle, Tobias; Schlicht, Michael; Wullich, Bernd; Hartmann, Arndt; Uder, Michael; Ellmann, Stephan (European Journal of Radiology, 2024)
Objective: This study aims to evaluate the diagnostic performance of a commercial, fully-automated, artificial intelligence (AI) driven software tool in identifying and grading prostate lesions in prostate MRI, using histopathological findings as the reference standard, while contextualizing its performance within the framework of PI-RADS v2.1 criteria. Material and methods: This retrospective study analyzed 123 patients who underwent multiparametric prostate MRI followed by systematic and targeted biopsies. MRI protocols adhered to international guidelines and included T2-weighted, diffusion-weighted, T1-weighted, and dynamic contrast-enhanced imaging. The AI software tool mdprostate was integrated into the Picture Archiving and Communication System to automatically segment the prostate, calculate prostate volume, and classify lesions according to PI-RADS scores using biparametric T2-weighted and diffusion-weighted imaging. Histopathological analysis of biopsy cores served as the reference standard. Diagnostic performance metrics including sensitivity, specificity, positive and negative predictive value (PPV, NPV), and area under the ROC curve (AUC) were calculated. Results: mdprostate demonstrated 100 % sensitivity at a PI-RADS ≥ 2 cutoff, effectively ruling out both clinically significant and non-significant prostate cancers for lesions remaining below this threshold. For detecting clinically significant prostate cancer (csPCa) using a PI-RADS ≥ 4 cutoff, mdprostate achieved a sensitivity of 85.5 % and a specificity of 63.2 %. The AUC for detecting cancers of any grade was 0.803. The performance metrics of mdprostate were comparable to those reported in two meta-analyses of PI-RADS v2.1, with no significant differences in sensitivity and specificity (p > 0.05). Conclusion: The evaluated AI tool demonstrated high diagnostic performance in identifying and grading prostate lesions, with results comparable to those reported in meta-analyses of expert readers using PI-RADS v2.1. Its ability to standardize evaluations and potentially reduce variability underscores its potential as a valuable adjunct in the prostate cancer diagnostic pathway. The high accuracy of mdprostate, particularly in ruling out prostate cancers, highlights its clinical utility by reducing workload and enhancing patient outcomes.
CRIS-Team Scopus Importer:2024-11-15
Keywords: Artificial intelligence; Clinical evaluation; Diagnostic performance; PI-RADS; Prostate cancer; Prostate MRI

Assessment of myocardial fibrosis in patients with systemic sclerosis using [Ga-68]Ga-FAPI-04-PET-CT - Treutlein, Christoph; Distler, Jörg; Tascilar, Koray; Chenguiti Fakhouri, Sara; Györfi, Andrea-Hermina; Atzinger, Armin; Matei, Alexandru-Emil; Dees, Clara; Büttner-Herold, Maike; Kuwert, Torsten; Prante, Olaf; Bäuerle, Tobias; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2022)
Purpose Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize (68)Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([Ga-68]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF.Methods In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [Ga-68]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated.Results [Ga-68]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [Ga-68]Ga-FAPI-04-positive regions confirmed the accumulation of FAP(+) fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [Ga-68]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [Ga-68]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [Ga-68]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage.Conclusions We present first in-human evidence that [Ga-68]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.
CRIS-Team WoS Importer:2023-02-10

Assessment of PD-L1 Status in Urothelial Cancer - Bahlinger, Veronika; Hartmann, Arndt; Eckstein, Markus (Urothelial Carcinoma - Methods and Protocols, 2023)
Since 2016, the immunotherapeutic agents targeting PD-1 and PD-L1 are an integral part in first-line and second-line treatment of advanced or metastatic urothelial cancer. By PD-1 and PD-L1 inhibition with these drugs, the immune system is supposed to regain the capacity to actively kill cancer cells. Meanwhile, PD-L1 assessment is prescribed for patients not being eligible for platinum-based chemotherapy in first-line settings in metastatic disease (for monotherapy with atezolizumab or pembrolizumab) and for patients who are intended to receive adjuvant nivolumab treatment following radical cystectomy. Several challenges which are highlighted in this chapter affect PD-L1 testing in daily routine including availability of representative tissue materials, inter-observer variability, and different available PD-L1 immunohistochemistry assays with different analytical properties.
CRIS-Team Scopus Importer:2023-07-21
Keywords: Distinct algorithms; PD-L1 assessment; Urothelial carcinoma

Assessment of prognostic and predictive value of FGFR alterations (FGFRa) in a real-world cohort of patients (pts) with high-risk pT1 non-muscle-invasive bladder cancer (NMIBC) - Breyer, J.; Monga, M.; Mayr, R.; Otto, W.; Burger, M.; Eckstein, Markus; Stöhr, Robert; Erben, P.; Bolenz, C.; Eidt, S.; Sundaram, R.; Baig, M.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30

Assessment of the additional clinical potential of X-ray dark-field imaging for breast cancer in a preclinical setup - Emons, J.; Fasching, Peter; Wunderle, M.; Heindl, F.; Rieger, Jens; Horn, Florian; Pelzer, Georg; Ritter, André; Weber, Thomas; Radicke, M.; Polifka, Iris; Wachter, David Lukas; et al. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Assessment of the additional clinical potential of X-ray dark-field imaging for breast cancer in a preclinical setup - Emons, Julius; Fasching, Peter; Wunderle, Marius; Heindl, Felix; Rieger, Jens; Horn, Florian; Pelzer, Georg; Ritter, André; Weber, Thomas; Radicke, Marcus; Polifka, Iris; Wachter, David; et al. (Therapeutic Advances in Medical Oncology, 2020)
Background: Mammography can identify calcifications up to 50–100 μm in size as a surrogate parameter for breast cancer or ductal carcinoma in situ (DCIS). Microcalcifications measuring <50 µm are also associated with breast cancer or DCIS and are frequently not detected on mammography, although they can be detected with dark-field imaging. This study examined whether additional breast examination using X-ray dark-field imaging can increase the detection rate of calcifications. Advances in knowledge: (1) evaluation of additional modality of breast imaging; (2) specific evaluation of breast calcifications. Implications for patient care: the addition of X-ray dark-field imaging to conventional mammography could detect additional calcifications. Methods: Talbot–Lau X-ray phase–contrast imaging and X-ray dark-field imaging were used to acquire images of breast specimens. The radiation dosage with the technique is comparable with conventional mammography. Three X-ray gratings with periods of 5–10 µm between the X-ray tube and the flat-panel detector provide three different images in a single sequence: the conventional attenuation image, differential phase image, and dark-field image. The images were read by radiologists. Radiological findings were marked and examined pathologically. The results were described in a descriptive manner. Results: A total of 81 breast specimens were investigated with the two methods; 199 significant structures were processed pathologically, consisting of 123 benign and 76 malignant lesions (DCIS or invasive breast cancer). X-ray dark-field imaging identified 15 additional histologically confirmed carcinoma lesions that were visible but not declared suspicious on digital mammography alone. Another four malignant lesions that were not visible on mammography were exclusively detected with X-ray dark-field imaging. Conclusions: Adding X-ray dark-field imaging to digital mammography increases the detection rate for breast cancer and DCIS associated lesions with micrometer-sized calcifications. The use of X-ray dark-field imaging may be able to provide more accurate and detailed radiological classification of suspicious breast lesions. Adding X-ray dark-field imaging to mammography may be able to increase the detection rate and improve preoperative planning in deciding between mastectomy or breast-conserving therapy, particularly in patients with invasive lobular breast cancer.
CRIS-Team Scopus Importer:2020-09-25
Keywords: breast cancer; interferometry; mammography; microcalcifications

Assessment of the risk of malignancy in Bethesda III thyroid nodules: a comprehensive review - Rao, Karthik Nagaraja; Randolph, Gregory W.; Lopez, Fernando; Zafereo, Mark; Coca-Pelaz, Andrés; Piazza, Cesare; Dange, Prajwal; Rodrigo, Juan Pablo; Stenman, Göran; de Keizer, Bart; Nixon, Iain; Sinha, Shriyash; et al. (Endocrine, 2024)
The increasing prevalence of thyroid cancer emphasizes the need for a thorough assessment of risk of malignancy in Bethesda III nodules. Various methods ranging commercial platforms of molecular genetic testing (including Afirma® GEC, Afirma® GSC, ThyroSeq® V3, RosettaGX®, ThyGeNEXT®/ThyraMIR®, ThyroidPRINT®) to radionuclide scans and ultrasonography have been investigated to provide a more nuanced comprehension of risk estimation. The integration of molecular studies and imaging techniques into clinical practice may provide clinicians with improved and personalized risk assessment. This integrated approach we feel may enable clinicians to carefully tailor interventions, thereby minimizing the likelihood of unnecessary thyroid surgeries and overall crafting the optimal treatment. By aligning with the evolving landscape of personalized healthcare, this comprehensive strategy ensures a patient-centric approach to thyroid nodule and thyroid cancer management.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Artificial intelligence; Bethesda system; Molecular testing; Risk assessment; Thyroid neoplasms

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 - Schmidkonz, Christian; Krumbholz, Manuela; Atzinger, Armin; Cordes, Michael; Goetz, Theresa Ida; Prante, Olaf; Ritt, Philipp; Schaefer, Christiane; Agaimy, Abbas; Hartmann, Wolfgang; Rössig, Claudia; Fröhlich, Birgit; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2019)
Purpose: The purpose of this study was to perform a prospective integrated analysis of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS). Methods: A total of 20 patients with histologically confirmed EwS underwent multiple 18F-FDG-PET/CT, performed at the time of each patient’s initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 18F-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels. Results: Twenty patients underwent a total of 87 18F-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen κ = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8–104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive 18F-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%. Conclusion: The combination of 18F-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.
CRIS-Team Scopus Importer:2019-12-27
Keywords: Circulating tumor DNA; Ewing sarcoma; Pediatric oncology; Treatment response

Association between breast cancer risk factors and molecular type in postmenopausal patients with hormone receptor-positive early breast cancer - Wunderle, Marius; Pretscher, Jutta; Brucker, Sara Y.; Volz, Bernhard; Hartmann, Arndt; Fießler, Cornelia; Hein, Alexander; Häberle, Lothar; Jud, Sebastian; Lux, Michael P.; Janni, Wolfgang; Löhberg, Christian; et al. (Breast Cancer Research and Treatment, 2019)
PurposeEvidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients.MethodsThe prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test.ResultsIn a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively).ConclusionsThis analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.
CRIS-Team WoS Importer:2019-03-29

Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: Results from a population-based case-control study - Maass, Matthias; Faller, Gerhard; Gesslein, Markus; Neureiter, Daniel; Neundörfer, Bernhard; Craiovan, Benjamin; Beck, Georg; Kolominsky-Rabas, Peter; Heuschmann, Peter U. (2001)
Background and Purpose - Helicobacter pylori and Chlamydia pneumoniae have been associated epidemiologically and pathogenetically with coronary atherosclerosis. However, population-based data on chronic infection and stroke are lacking. Therefore, we investigated the association of both bacterial pathogens and ischemic stroke subtypes in a population-based case-control study. Methods - Patients with first ischemic stroke in the population-based Erlangen Stroke Project were collected as cases. Neighborhood controls were drawn from the study population, matched for age, sex, and place of residence. IgG antibodies to H pylori were measured by enzyme immunoassay, and IgG antibodies to C pneumoniae were measured by microimmunofluorescence technique. Conditional logistic regression was used. Analyses were stratified for etiologic stroke subtypes according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results - A total of 145 case and 260 control subjects were included. Chronic H pylori infection was associated with a higher risk of stroke caused by small-artery occlusion (adjusted odds ratio, 3.31; 95% CI, 1.15 to 9.56) and a lower risk of cardioembolic stroke (adjusted odds ratio, 0.21; 95% CI, 0.06 to 0.71). Overall, elevated H pylori as well as elevated C pneumoniae antibodies were not associated with ischemic stroke. Conclusions - Our population-based study does not provide evidence of any strong association between the immune response to C pneumoniae as a marker of prior infection and ischemic stroke. Further studies are required to reveal the role of chronic H pylori infection as an independent risk factor for the subgroup small-artery occlusion.
Created from Fastlane, Scopus look-up
Keywords: Chlamydia pneumoniae; Helicobacter pylori; Seroepidemiologic studies; Stroke

Association between mammographic density and pregnancies relative to age and BMI: a breast cancer case-only analysis - Hack, Carolin; Emons, Julius; Jud, Sebastian; Heusinger, Katharina; Adler, Werner; Gaß, Paul; Haeberle, Lothar; Heindl, Felix; Hein, Alexander; Schulz-Wendtland, Rüdiger; Uder, Michael; Hartmann, Arndt; et al. (Breast Cancer Research and Treatment, 2017)
Percentage mammographic density (PMD) is a major risk factor for breast cancer (BC). It is strongly associated with body mass index (BMI) and age, which are themselves risk factors for breast cancer. This analysis investigated the association between the number of full-term pregnancies and PMD in different subgroups relative to age and BMI.Patients were identified in the breast cancer database of the University Breast Center for Franconia. A total of 2410 patients were identified, for whom information on parity, age, and BMI, and a mammogram from the time of first diagnosis were available for assessing PMD. Linear regression analyses were conducted to investigate the influence on PMD of the number of full-term pregnancies (FTPs), age, BMI, and interaction terms between them.As in previous studies, age, number of FTPs, and BMI were found to be associated with PMD in the expected direction. However, including the respective interaction terms improved the prediction of PMD even further. Specifically, the association between PMD and the number of FTPs differed in young patients under the age of 45 (mean decrease of 0.37 PMD units per pregnancy) from the association in older age groups (mean decrease between 2.29 and 2.39 PMD units). BMI did not alter the association between PMD and the number of FTPs.The effect of pregnancies on mammographic density does not appear to become apparent before the age of menopause. The mechanism that drives the effect of pregnancies on mammographic density appears to be counter-regulated by other influences on mammographic density in younger patients.
EVALuna2:14710

Association of Blood Donor-derived Cell-free DNA Levels with Banff Scores and Histopathological Lesions in Kidney Allograft Biopsies: Results from an Observational Study - Akifova, Aylin; Budde, Klemens; Choi, Mira; Amann, Kerstin Ute; Büttner-Herold, Maike; Oellerich, Michael; Beck, Julia; Bornemann-Kolatzki, Kirsten; Schütz, Ekkehard; Bachmann, Friederike; Halleck, Fabian; Schrezenmeier, Eva V.; et al. (Transplantation Direct, 2025)
Background. Donor-derived cell-free DNA (dd-cfDNA) is an emerging biomarker of kidney allograft injury, mainly investigated in the context of rejection. However, the dd-cfDNA dynamics in other graft pathologies merit further investigation. Methods. In this single-center observational study, we prospectively collected dd-cfDNA at indication biopsies. To evaluate the association between dd-cfDNA and different histological patterns, we correlated absolute and relative dd-cfDNA (thresholds of 50 copies/mL and 0.5%, respectively) with the Banff 2022 lesion scores and the assigned diagnoses. Results. We examined 151 dd-cfDNA paired biopsies in 131 kidney transplant recipients and found significantly higher absolute dd-cfDNA levels in antibody-mediated rejection (n, median, IQR: 45, 63 copies/mL, 42-89), microvascular inflammation (MVI) without donor-specific antibodies or C4d-deposition (6, 102 copies/mL, 61-134), mixed rejection (8, 140 copies/mL, 77-171), and BK virus-Associated nephropathy (6, 213 copies/mL, 83-298) compared with glomerulonephritis (20, 12 copies/mL, 8-18), calcineurin toxicity (19, 10 copies/mL, 7-16), interstitial fibrosis/tubular atrophy (12, 10 copies/mL, 9-16) and normal histology (6, 9 copies/mL, 7-16). In the multivariable analysis, absolute and relative dd-cfDNA correlated with the peritubular capillaritis (ptc), glomerulitis (g), and tubulitis (t) scores. In the receiver operating characteristic analysis, absolute dd-cfDNA showed best discrimination for MVI of any cause (area under the curve [AUC] 0.88, sensitivity 0.71, specificity 0.86, positive predictive value [PPV] 0.76, negative predictive value [NPV] 0.82), followed by antibody-mediated rejection including mixed rejection (AUC 0.85, sensitivity 0.72, specificity 0.83, PPV 0.69, NPV 0.84), and overall rejection (AUC 0.83, sensitivity 0.66, specificity 0.85, PPV 0.76, NPV 0.77). T cell-mediated rejection was only detectable by dd-cfDNA when associated with vascular lesions. Conclusions. Altogether, we conclude that dd-cfDNA-release is not limited to rejection-related injury phenotypes and is mainly driven by MVI in kidney allografts.
CRIS-Team Scopus Importer:2025-05-02

Association of Cardiac MRI–derived Aortic Stiffness with Early Stages and Progression of Heart Failure with Preserved Ejection Fraction - Schulz, Alexander; Schellinger, Isabel N.; Backhaus, Sören J.; Adler, Ansgar S.; Lange, Torben; Evertz, Ruben; Kowallick, Johannes T.; Hoffmann, Annett; Matek, Christian; Tsao, Philip S.; Hasenfuß, Gerd; Raaz, Uwe; et al. (Radiology: Cardiothoracic Imaging, 2024)
Purpose: To investigate if aortic stiffening as detected with cardiac MRI is an early phenomenon in the development and progression of heart failure with preserved ejection fraction (HFpEF). Materials and Methods: Both clinical and preclinical studies were performed. The clinical study was a secondary analysis of the prospective HFpEF stress trial (August 2017 through September 2019) and included 48 participants (median age, 69 years [range, 65–73 years]; 33 female, 15 male) with noncardiac dyspnea (NCD, n = 21), overt HFpEF at rest (pulmonary capillary wedge pressure [PCWP] ≥ 15 mm Hg, n = 14), and masked HFpEF at rest diagnosed during exercise stress (PCWP ≥ 25 mm Hg, n = 13) according to right heart catheterization. Additionally, all participants underwent echocardiography and cardiac MRI at rest and during exercise stress. Aortic pulse wave velocity (PWV) was calculated. The mechanistic preclinical study characterized cardiac function and structure in transgenic mice with induced arterial stiffness (Runx2-smTg mice). Statistical analyses comprised nonparametric and parametric comparisons, Spearman correlations, and logistic regression models. Results: Participants with HFpEF showed increased PWV (NCD vs masked HFpEF: 7.0 m/sec [IQR: 5.0–9.5 m/sec] vs 10.0 m/sec [IQR: 8.0–13.4 m/sec], P = .005; NCD vs overt HFpEF: 7.0 m/sec [IQR: 5.0–9.5 m/sec] vs 11.0 m/sec [IQR: 7.5–12.0 m/sec], P = .01). Increased PWV correlated with higher PCWP (P = .006), left atrial and left ventricular long-axis strain (all P < .02), and N-terminal pro–brain natriuretic peptide levels (P < .001). Participants with overt HFpEF had higher levels of myocardial fibrosis, as demonstrated by increased native T1 times (1199 msec [IQR: 1169–1228 msec] vs 1234 msec [IQR: 1208–1255 msec], P = .009). Aortic stiffness was independently associated with HFpEF on multivariable analyses (odds ratio, 1.31; P = .049). Runx2-smTG mice exhibited an “HFpEF” phenotype compared with wild-type controls, with preserved left ventricular fractional shortening but an early and late diastolic mitral annulus velocity less than 1 (mean, 0.67 ± 0.39 [standard error of the mean] vs 1.45 ± 0.47; P = .004), increased myocardial collagen deposition (mean, 11% ± 1 vs 2% ± 1; P < .001), and increased brain natriuretic peptide levels (mean, 171 pg/mL ± 23 vs 101 pg/mL ± 10; P < .001). Conclusion: This study provides translational evidence that increased arterial stiffness might be associated with development and progression of HFpEF and may facilitate its early detection.
CRIS-Team Scopus Importer:2024-09-20
Keywords: Animal Studies; Aorta; Cardiac; Heart; MR Functional Imaging; MR Imaging

Association of donor hypertension and recipient renal function in living donor kidney transplantation: A single-center retrospective study - Dienemann, Thomas; Schellenberg, Jana; Heller, Katharina; Daniel, Christoph; Amann, Kerstin Ute; Hilgers, Karl Friedrich; Schiffer, Mario; Weidemann, Alexander (Clinical Transplantation, 2019)
Transplant centers now accept living donors with well-controlled hypertension. Little is known whether hypertension in living donors affects recipient's kidney function. We aimed to examine potential differences in kidneys from hypertensive donors compared to normotensive donors with respect to renal function over 36 months and histologic findings at transplantation (T0) and 12 months after transplantation (T1). Retrospective single-center analysis of 174 living donor-recipient pairs (age > 18; transplantation date 1/2008-3/2016). Hypertension in donors was defined as being on antihypertensive medication. All biopsies were assessed by the same blinded, experienced renal pathologist. Biopsies were scored for glomerulosclerosis, IFTA, and arteriosclerosis. Regression models were used to examine the relationship of donor hypertension with renal function and histologic changes. Hypertensive donors were significantly older than normotensive donors. Chronic changes such as tubular atrophy and atherosclerosis were more evident in kidneys from hypertensive donors at T0 as well as T1. Donor hypertension was independently associated with histologic changes at T0 and T1 but not with renal function over the follow period. Despite more pronounced histologic changes in kidneys from hypertensive living donors, these grafts exhibited a similar functional outcome. However, they subsequently might be at a greater risk and warrant thorough follow-up care.
CRIS-Team WoS Importer:2019-09-27

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment - Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Keeman, Renske; Canisius, Sander; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Auer, Paul L.; Augustinsson, Annelie; Freeman, Laura E. Beane; et al. (BREAST CANCER RES, 2021)
Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
CRIS-Team WoS Importer:2021-09-03

Association of KRT20 and KRT5 with response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer - Roghmann, Florian; Reike, Moritz; Wirtz, Ralph; Kriegmair, Maximilian; Erben, Philipp; Tully, Karl; Weyerer, Veronika; Eckstein, Markus; Hartmann, Arndt; Wezel, Felix; Bolenz, Christian; Tannapfel, Andrea; et al. (JOURNAL OF CLINICAL ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-05-22

Association of molecular subtypes with breast cancer risk factors: a case-only analysis - Rauh, Claudia; Gaß, Paul; Heusinger, Katharina; Haeberle, Lothar; Jud, Sebastian; Hein, Alexander; Löhberg, Christian; Lux, Michael P.; Wachter, David; Heimrich, Jutta; Strehl, Johanna D.; Haller, Florian; et al. (European Journal of Cancer Prevention, 2015)
As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case-case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients' charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern.
EVALuna2:5482

Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial - Kitz, Julia; Fokas, Emmanouil; Beissbarth, Tim; Stroebel, Philipp; Wittekind, Christian; Hartmann, Arndt; Rueschoff, Josef; Papadopoulos, Thomas; Roesler, Elisabeth; Ortloff-Kittredge, Peter; Kania, Ulrich; Schlitt, Hans; et al. (JAMA Surgery, 2018)
Importance: Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.. Objective: In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Design, Setting, and Participants: The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010. Interventions: Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy. Main Outcomes and Measures: The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model. Results: Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002). Conclusions and Relevance: This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.
EVALuna2:34814

Association of tissue mRNA and serum antigen levels of members of the urokinase-type plasminogen activator system with clinical and prognostic parameters in prostate cancer - Al-Janabi, Omar; Taubert, Helge; Lohse-Fischer, Andrea; Froehner, Michael; Wach, Sven; Stoehr, Robert; Keck, Bastian; Burger, Max; Wieland, Wolf; Erdmann, Kati; Wirth, Manfred P.; Wullich, Bernd; et al. (BioMed Research International, 2014)
The objective was to determine the mRNA expression and protein levels of uPA system components in tissue specimens and serum samples, respectively, from prostate cancer (PCa) patients and to assess their association with clinicopathological parameters and overall survival (OS). The mRNA expression levels of uPA, its receptor (uPAR), and its inhibitor type 1 (PAI-1) were analyzed in corresponding malignant and adjacent nonmalignant tissue specimens from 132 PCa patients by quantitative PCR. Preoperative serum samples from 81 PCa patients were analyzed for antigen levels of uPA system members by ELISA. RNA levels of uPA system components displayed significant correlations with each other in the tumor tissues. A significantly decreased uPA mRNA expression in PCa compared to the corresponding nonmalignant tissue was detected. High uPA mRNA level was significantly associated with a high Gleason score. Elevated concentration of soluble uPAR (suPAR) in serum was significantly associated with a poor OS of PCa patients (P = 0.022). PCa patients with high suPAR levels have a significantly higher risk of death (multivariate Cox's regression analysis; HR = 7.12, P = 0.027). The association of high suPAR levels with poor survival of PCa patients suggests a prognostic impact of suPAR levels in serum of cancer patients.
EVALuna2:6625

Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression, and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts - Bahlinger, Veronika; Branz, Annalena; Strissel, Pamela; Strick, Reiner; Lange, Fabienne; Geppert, Carol-Immanuel; Klümper, Niklas; Hölzel, Michael; Wach, Sven; Taubert, Helge; Sikic, Danijel; Wullich, Bernd; et al. (Histopathology, 2024)
Aims: Treatment options for advanced urothelial carcinoma (aUC) rapidly evolved: besides immunomodulative therapeutic options and inhibitors targeting Fibroblast growth factor receptor (FGFR) alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved. However, little is known about the associations of specific aUC properties and the surface target expression of TROP2 and NECTIN-4. Our aim was to characterize associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 protein and gene expression with morphomolecular and clinicopathological characteristics of aUC in two large independent cohorts. Methods and results: The TCGA BLCA (n = 405) and the CCC-EMN (n = 247) cohorts were retrospectively analysed. TROP2/TACSTD2 and NECTIN-4/NECTIN-4 are highly expressed at the protein and transcript level in aUC, and their expression status did not correlate with patient survival in both cohorts. NECTIN-4/NECTIN-4 expression was higher in luminal tumours and reduced in squamous aUCs. NECTIN-4 was negative in 10.6% of samples, and 18.4% of samples had low expression (H-score <15). The TROP2 negativity rate amounted to 6.5%. TACSTD2 and NECTIN-4 expression was reduced in neuroendocrine-like and/or protein-based double-negative tumours. TROP2- and NECTIN-4-negative tumours included one sarcomatoid and four neuroendocrine aUC. FGFR3 alterations and PD-L1 expression on tumour and immune cells did not associate with TROP2 or NECTIN-4 expression. Conclusions: TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression, thus representing a suitable target for ADC treatment in the majority of aUC. The expression loss was associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC.
CRIS-Team Scopus Importer:2024-01-19
Keywords: Advanced urothelial carcinoma; membranous expression; NECTIN-4/NECTIN-4; TACSTD2/TROP2; treatment options

A Standard Mammography Unit - Standard 3D Ultrasound Probe Fusion Prototype: First Results - Schulz-Wendtland, Rüdiger; Jud, Sebastian; Fasching, Peter; Hartmann, Arndt; Radicke, Marcus; Rauh, Claudia; Uder, Michael; Wunderle, Marius; Gaß, Paul; Langemann, Hanna; Beckmann, Matthias; Emons, Julius (Geburtshilfe und Frauenheilkunde, 2017)
The combination of different imaging modalities through the use of fusion devices promises significant diagnostic improvement for breast pathology. The aim of this study was to evaluate image quality and clinical feasibility of a prototype fusion device (fusion prototype) constructed from a standard tomosynthesis mammography unit and a standard 3D ultrasound probe using a new method of breast compression.Imaging was performed on 5 mastectomy specimens from patients with confirmed DCIS or invasive carcinoma (BI-RADS ((TM)) 6). For the preclinical fusion prototype an ABVS system ultrasound probe from an Acuson S2000 was integrated into a MAMMOMAT Inspiration (both Siemens Healthcare Ltd) and, with the aid of a newly developed compression plate, digital mammogram and automated 3D ultrasound images were obtained.The quality of digital mammogram images produced by the fusion prototype was comparable to those produced using conventional compression. The newly developed compression plate did not influence the applied x-ray dose. The method was not more labour intensive or time-consuming than conventional mammography. From the technical perspective, fusion of the two modalities was achievable.In this study, using only a few mastectomy specimens, the fusion of an automated 3D ultrasound machine with a standard mammography unit delivered images of comparable quality to conventional mammography. The device allows simultaneous ultrasound - the second important imaging modality in complementary breast diagnostics - without increasing examination time or requiring additional staff.
EVALuna2:6849

Asymmetric Omphalopagus in a Triplet after In Vitro Fertilization: A Rare Case of Conjoined Twinning - Jabari, Samir; Carbon, Roman; Besendörfer, Manuel; Hartmann, Arndt; Rompel, Oliver; Hoerning, Andre; Söder, Stephan (Case Reports in Pediatrics, 2018)
Introduction: Asymmetric omphalopagus is a rare situation of conjoined twinning, in which a grossly defective twin is attached to the thorax and upper abdomen of the main twin. We describe a case of an asymmetric omphalopagus accompanied by a normal triplet after assisted reproductive technology (ART) and tried to further characterize the all aspects of the conjoined twins. Case Presentation: Perioperative diagnostic imaging was carried out followed by an autopsy to evaluate all aspects of the parasite accompanied by histological, immunohistochemical, and molecular biological evaluation. The parasite had well-developed lower extremities as well as upper extremities with a cleft hand syndrome. The sex was nondeterminable, but DNA fingerprinting revealed that both parasite and autosite are monozygotic, so are females. There was no sign of any axial skeleton or central nervous system. We found a rudimentary rectum with a nonpervious anus, a kidney, ureter, urinary bladder, and a blind-ending urethra. The blood supply of the parasite was connected to the vessel system of the autosite. Conclusions: To our knowledge, only two cases of parasitic omphalopagus after ART have been described to date. Altogether, 52 cases have been reported, and in most of them, the parasites were successfully separated.
EVALuna2:34614

ATF2 loss promotes 5-FU resistance in colon cancer cells via activation of the ATR-Chk1 damage response pathway - Yang, Hao; Hübner, Kerstin; Hampel, Chuanpit; Erlenbach-Wünsch, Katharina; Selvamani, Selva Babu; Shukla, Vikas; Geppert, Carol-Immanuel; Hartmann, Arndt; Mahadevan, Vijayalakshmi; Schneider-Stock, Regine (BMC Cancer, 2023)
Background: The role of ATF2 in colon cancer (CC) is controversial. Recently, we reported that low ATF2 expression is characteristic of highly invasive tumors, suggesting that ATF2 might also be involved in therapy resistance. 5-Fluorouracil (5-FU) is the best-known chemotherapeutic drug for CC, but drug resistance affects its curative effect. To date, the role of ATF2 in the 5-FU response remains elusive. Methods/Results: For our study, we had available HCT116 cells (wild-type p53) and HT29 colon tumor cells (mutant p53) and their corresponding CRISPR‒Cas9-generated ATF2-KO clones. We observed that loss of ATF2 triggered dose- and time-dependent 5-FU resistance in HCT116 cells by activating the DNA damage response (DDR) pathway with high p-ATRThr1989 and p-Chk1Ser317 levels accompanied by an increase in the DNA damage marker γ-H2AX in vitro and in vivo using the chicken chorioallantoic membrane (CAM) model. Chk1 inhibitor studies causally displayed the link between DDR and drug resistance. There were contradictory findings in HT29 ATF2-KO cells upon 5-FU exposure with low p-Chk1Ser317 levels, strong apoptosis induction, but no effects on DNA damage. In ATF2-silenced HCT116 p53−/− cells, 5-FU did not activate the DDR pathway. Co-immunoprecipitation and proximity ligation assays revealed that upon 5-FU treatment, ATF2 binds to ATR to prevent Chk1 phosphorylation. Indeed, in silico modelling showed reduced ATR-Chk1 binding when ATF2 was docked into the complex. Conclusions: We demonstrated a novel ATF2 scaffold function involved in the DDR pathway. ATF2-negative cells are highly resistant due to effective ATR/Chk1 DNA damage repair. Mutant p53 seems to overwrite the tumor suppressor function of ATF2.
CRIS-Team Scopus Importer:2023-06-30
Keywords: ATR kinase; CAM model; DDR; DNA repair; γ-H2AX

ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2 - Hübner, Kerstin; Erlenbach-Wünsch, Katharina; Prochazka, Jan; Sheraj, Ilir; Hampel, Chuanpit; Mrazkova, Blanka; Michalcikova, Tereza; Tureckova, Jolana; Iatsiuk, Veronika; Weissmann, Anne; Ferrazzi, Fulvia; Kunze, Philipp; et al. (Cellular and Molecular Life Sciences, 2022)
In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2(KO)/TROP2(high) status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2(low)/TROP2(high) expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.
CRIS-Team WoS Importer:2022-07-29

A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer - Stubendorff, Beatrice; Wilhelm, Kerstin; Posselt, Kathleen; Catto, James; Hartmann, Arndt; Bertz, Simone; Fuessel, Susanne; Novotny, Vladimir; Toma, Marieta; Gajda, Mieczyslaw; Lehmann, Jan; Wunderlich, Heiko; et al. (Journal of Cancer Research and Clinical Oncology, 2019)
PurposeIn this study, we aimed to identify a DNA methylation pattern suitable for prognosis assessment of muscle-invasive bladder cancer and to investigate metastasis-associated processes regulated by DNA methylation.MethodsGenome-wide methylation analysis was performed on 23 muscle-invasive bladder tumors by microarray analysis. Validation was performed by the qAMP technique in two different patient cohorts (n=32 and n=100). mRNA expression was analyzed in 12 samples. Protein expression was determined using tissue microarrays of 291 patients. Bladder cancer cell lines T24 and 253JB-V were used for functional analyses.ResultsMicroarray analyses revealed KISS1R, SEPT9 and CSAD as putative biomarkers with hypermethylation in node-positive tumors. The combination of the three genes predicted the metastatic risk with sensitivity of 73% and specificity of 71% in cohort 1, and sensitivity of 82% and specificity of 54% in cohort 2. mRNA expression differences were detected for KISS1R (p=0.04). Protein expression of KISS1R was significantly reduced (p<0.001). Knockdown of SEPT9v3 resulted in increased cell migration by 28% (p=0.04) and increased invasion by 22% (p=0.004). KISS1R overexpression resulted in decreased cell migration (25%, p=0.1).ConclusionsWe identified a methylation marker panel suitable to differentiate between patients with positive and negative lymph nodes at time of cystectomy. This enables a risk assessment for patients who potentially benefit from extended lymph node resection as well as from neoadjuvant chemotherapy and could improve the survival rates. Furthermore, we examined the impact of putative markers on tumor behavior. Hence, KISS1R and SEPT9 could represent a starting point for the development of novel therapy approaches.
CRIS-Team WoS Importer:2019-04-12

AT II Receptor Blockade and Renal Denervation: Different Interventions with Comparable Renal Effects? - Rodionova, Kristina; Hindermann, Martin; Hilgers, Karl Friedrich; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Ditting, Tilmann (Kidney & Blood Pressure Research, 2021)
Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. Conclusion: The prominent function of increased RSNA - retaining salt and water - could no longer be observed after renal Ang II receptor blockade in CHF rats.
CRIS-Team WoS Importer:2021-06-11
Keywords: Renal sympathetic innervation; Angiotensin II; Congestive heart failure; Renal nerve ablation; Renal function

A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity - Vargas, Juan Gamboa; Wagner, Jennifer; Shaikh, Haroon; Lang, Isabell; Medler, Juliane; Anany, Mohamed; Steinfatt, Tim; Mosca, Josefina Pena; Haack, Stephanie; Dahlhoff, Julia; Büttner-Herold, Maike; Graf, Carolin; et al. (Frontiers in Immunology, 2022)
Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity. MethodsSingle-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fc gamma-receptors (Fc gamma Rs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems. ResultsSTAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD. ConclusionsNewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.
CRIS-Team WoS Importer:2022-07-08

A TNM-Immune (TNM-I) classification staging system for predicting survival in colon cancer in a multicenter international SITC study - Mlecnik, B.; Bifulco, C.; Marliot, F.; Lugli, A.; Nagtegaal, I.; Hartmann, Arndt; Van Den Eynde, M.; Roehrl, M.; Ohashi, P.; Zavadova, E.; Torigoe, T.; Patel, P.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-08-28

A toolbox for functional analysis and the systematic identification of diagnostic and prognostic gene expression signatures combining meta-analysis and machine learning - Vey, Johannes; Kapsner, Lorenz; Fuchs, Maximilian; Unberath, Philipp; Veronesi, Giulia; Kunz, Meik (Cancers, 2019)
The identification of biomarker signatures is important for cancer diagnosis and prognosis. However, the detection of clinical reliable signatures is influenced by limited data availability, which may restrict statistical power. Moreover, methods for integration of large sample cohorts and signature identification are limited. We present a step-by-step computational protocol for functional gene expression analysis and the identification of diagnostic and prognostic signatures by combining meta-analysis with machine learning and survival analysis. The novelty of the toolbox lies in its all-in-one functionality, generic design, and modularity. It is exemplified for lung cancer, including a comprehensive evaluation using different validation strategies. However, the protocol is not restricted to specific disease types and can therefore be used by a broad community. The accompanying R package vignette runs in 1 h and describes the workflow in detail for use by researchers with limited bioinformatics training.
CRIS-Team Scopus Importer:2019-11-22
Keywords: Bioinformatics tool; Biomarker signature; Functional analysis; Gene expression analysis; Machine learning; Meta-analysis; R package; Survival analysis

A tribute to Prof. Ondrej Hes, MD, PhD (1968-2022) - Alaghehbandan, Reza; Agaimy, Abbas; Ali, Leila; Alvarado-Cabrero, Isabel; Amin, Mahul B.; Boudova, Ludmila; Calio, Anna; Comperat, Eva M.; Damjanov, Ivan; Daum, Ondrej; Farcas, Mihaela; Gatalica, Zoran; et al. (Modern Pathology, 2022)
CRIS-Team Scopus Importer:2022-12-30

Attenuated lipotoxicity and apoptosis is linked to exogenous and endogenous augmenter of liver regeneration by different pathways - Weiss, Thomas S.; Lupke, Madeleine; Ibrahim, Sara; Buechler, Christa; Lorenz, Julia; Ruemmele, Petra; Hofmann, Ute; Melter, Michael; Dayoub, Rania (PLoS ONE, 2017)
Nonalcoholic fatty liver disease (NAFLD) covers a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Free fatty acids (FFA) induce steatosis and lipo-toxicity and correlate with severity of NAFLD. In this study we aimed to investigate the role of exogenous and endogenous ALR (augmenter of liver regeneration) for FFA induced ER (endoplasmatic reticulum) -stress and lipoapoptosis. Primary human hepatocytes or hepatoma cells either treated with recombinant human ALR (rhALR, 15kDa) or expressing short form ALR (sfALR, 15kDa) were incubated with palmitic acid (PA) and analyzed for lipo-toxicity, -apoptosis, activation of ER-stress response pathways, triacylglycerides (TAG), mRNA and protein expression of lipid metabolizing genes. Both, exogenous rhALR and cytosolic sfALR reduced PA induced caspase 3 activity and Bax protein expression and therefore lipotoxicity. Endogenous sfALR but not rhALR treatment lowered TAG levels, diminished activation of ER-stress mediators C-Jun N-terminal kinase (JNK), X-box binding protein-1 (XBP1) and proapoptotic transcription factor C/EBP-homologous protein (CHOP), and reduced death receptor 5 protein expression. Cellular ALR exerts its lipid lowering and anti-apoptotic actions by enhancing FABP1, which binds toxic FFA, increasing mitochondrial ?-oxidation by elevating the mitochondrial FFA transporter CPT1?, and decreasing ELOVL6, which delivers toxic FFA metabolites. We found reduced hepatic mRNA levels of ALR in a high fat diet mouse model, and of ALR and FOXA2, a transcription factor inducing ALR expression, in human steatotic as well as NASH liver samples, which may explain increased lipid deposition and reduced ?-oxidation in NASH patients. Present study shows that exogenous and endogenous ALR reduce PA induced lipoapoptosis. Furthermore, cytosolic sfALR changes mRNA and protein expression of genes regulating lipid metabolism, reduces ER-stress finally impeding progression of NASH.
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Atypical Fibroxanthoma - Histological Diagnosis, Immunohistochemical Markers and Concepts of Therapy - Koch, Michael; Freundl, Anne J.; Agaimy, Abbas; Kiesewetter, Franklin; Kuenzel, Julian; Cicha, Iwona; Alexiou, Christoph (Anticancer Research, 2015)
Atypical fibroxanthoma (AFX) is an uncommon, rapidly growing cutaneous neoplasm of uncertain histogenesis. Thus far, there are no guidelines for diagnosis and therapy of this tumor.We included 18 patients with 21 AFX, and 2,912 patients with a total of 2,939 AFX cited in the literature between 1962 and 2014.In our cohort, excision with safety margin was performed in 100% of primary tumors. Local recurrences were observed in 25% of primary tumors and parotid metastases in 5%. Ten-year disease-specific survival was 100%. The literature research yielded 280 relevant publications. Over 90% of the reported cases were negative for cytokeratins, S100, desmin and human melanoma black 45 (HMB-45). Recurrent AFX was reported in 7.6% and metastasizing AFX in 2.75% cases. No significant differences in the recurrence and survival rates following wide local excision versus Mohs microsurgery were observed. Twenty-year disease-specific survival rate was 97.8%.A well-selected panel of immunohistochemical markers is necessary to establish AFX diagnosis with sufficient certainty. Adequately treated, AFX has an excellent prognosis, but long-term follow-up is recommended due to the potential for aggressive behavior.
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A urinary metabolite constellation to detect acute rejection in kidney allografts - Banas, Miriam C.; Neumann, Sindy; Pagel, Philipp; Putz, Franz Josef; Krämer, Bernhard K.; Böhmig, Georg A.; Eiglsperger, Johannes; Schiffer, Eric; Ruemmele, Petra; Banas, Bernhard (EBioMedicine, 2019)
Background: To validate a novel method for post-transplant surveillance to detect kidney allograft rejection via a characteristic constellation of the urine metabolites alanine, citrate, lactate, and urea investigated by nuclear magnetic resonance (NMR) spectroscopy a first prospective, observational study was performed. Methods: Within the UMBRELLA study 986 urine specimens were collected from 109 consecutively enrolled renal transplant recipients, and metabolite constellations were analyzed. A metabolite rejection score was calculated and compared to histopathological results of corresponding indication and protocol allograft biopsies (n = 206). Findings: The metabolite constellation was found to be a useful biomarker to non-invasively detect acute allograft rejection (AUC = 0.75; 95% confidence interval (CI) 0.68–0.83; based on 46 cases and 520 control samples). Combined analysis of the metabolite rejection score and the estimated glomerular filtration rate (eGFR) at the time of urine sampling further improved the overall test performance significantly (AUC = 0.84; 95% CI 0.76–0.91; based on 42 cases and 468 controls). Regarding the time course analysis in patients without rejection episodes the test results remained well below a diagnostic threshold associated with high risk of acute rejection. In other cases, a marked increase above this threshold indicated acute allograft rejection already six to ten days before diagnostic renal biopsies were performed. Interpretation: A combination of an NMR-based urine metabolite analysis and eGFR is promising as a non-invasive test for post-transplant surveillance and to support decision making whether renal allografts need histopathological evaluation.
CRIS-Team Scopus Importer:2019-10-29
Keywords: Biomarker; Kidney transplant rejection; NMR-spectroscopy; Non-invasive test; Urinary metabolites

A URINARY METABOLITE CONSTELLATION TO DETECT ACUTE REJECTION IN KIDNEY ALLOGRAFTS - Banas, Miriam; Neumann, Sindy; Pagel, Philipp; Putz, Franz Josef; Kraemer, Bernhard K.; Ruemmele, Petra; Eiglsperger, Johannes; Schiffer, Eric; Banas, Bernhard (Transplant International, 2019)
CRIS-Team WoS Importer:2019-11-08

Author Correction: CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression (Scientific Reports, (2023), 13, 1, (73), 10.1038/s41598-022-26579-z) - Saponaro, Miriam; Flottmann, Sina; Eckstein, Markus; Hommerding, Oliver; Klümper, Niklas; Corvino, Dillon; Hosni, Sana; Schmidt, Anja; Mönig, Nicolas; Schmidt, Doris; Ellinger, Jörg; Toma, Marieta; et al. (Scientific Reports, 2023)
Tables 1 and 2 in the original version of this Article presented redundant for the research information. To increase their readability, data in both Tables was summarized. The original Article has been corrected.
CRIS-Team Scopus Importer:2023-03-03

Author Correction: Non-professional phagocytosis: a general feature of normal tissue cells (Scientific Reports, (2019), 9, 1, (11875), 10.1038/s41598-019-48370-3) - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2020)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2020-06-16

Author Correction: Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis (Scientific Reports, (2021), 11, 1, (4577), 10.1038/s41598-021-83883-w) - Müller-Deile, Janina; Sarau, George; Kotb, Ahmed M.; Jaremenko, Christian; Rolle-Kampczyk, Ulrike E.; Daniel, Christoph; Kalkhof, Stefan; Christiansen, Silke H.; Schiffer, Mario (Scientific Reports, 2021)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2021-06-04

Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With Ipilimumab - Uslu, Ugur; Agaimy, Abbas; Hundorfean, Gheorghe; Harrer, Thomas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2015)
Ipilimumab, a humanized CTLA-4 antibody, improves overall survival in patients with metastatic melanoma. However, immune-related adverse effects occur in about 65% of ipilimumab-treated patients and have to be adequately managed. A 55-year-old patient developed grade 3 autoimmune colitis 7 weeks after initiation of ipilimumab treatment and subsequently hepatitis with grade 3 elevation of transaminases and ?-glutamyl transferase. Colitis manifested with up to 18 watery and bloody stools per day and severe attacks of abdominal pain. After exclusion of infectious causes, immunosuppression with corticosteroids was initiated. Because of recurrent abdominal pain, spontaneous perforation of the colon had to be excluded. Elevated liver function tests (grade 3 CTCAE) occurred and differential diagnosis included immune-mediated, toxic, and viral hepatitis. It is interesting to note that, not an immune-mediated but a cytomegalovirus-induced hepatitis was diagnosed by serum blood tests and liver biopsy and was subsequently successfully treated. Careful elaboration of the patient under immunotherapy was essential as further immunosuppression mandatory for autoimmune hepatitis would have worsened the viral hepatitis. In conclusion, cytomegalovirus reactivation should be included in the differential in patients under immunotherapy with checkpoint inhibitors and has to be considered as a cause for morbidity.
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Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis - Voskens, Caroline; Stoica, Diane; Rosenberg, Marita; Vitali, Francesco; Zundler, Sebastian; Ganslmayer, Marion; Knott, Heike; Wiesinger, Manuel; Wunder, Jutta; Kummer, Mirko; Siegmund, Britta; Schnoy, Elisabeth; et al. (Gut, 2022)
Objective Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.
CRIS-Team WoS Importer:2022-04-29

Automatic Detection of Tumor Buds in Pan-Cytokeratin Stained Colorectal Cancer Sections by a Hybrid Image Analysis Approach - Bergler, Matthias; Benz, Michaela; Rauber, David; Hartmann, David; Kötter, Malte; Eckstein, Markus; Schneider-Stock, Regine; Hartmann, Arndt; Merkel, Susanne; Bruns, Volker; Wittenberg, Thomas; Geppert, Carol-Immanuel (Digital Pathology, 2019)
This contribution introduces a novel approach to the automatic detection of tumor buds in a digitalized pan-cytokeratin stained colorectal cancer slide. Tumor buds are representing an invasive pattern and are frequently investigated as a new diagnostic factor for measuring the aggressiveness of colorectal cancer. However, counting the number of buds under the microscope in a high power field by eyeballing is a strenuous, lengthy and error-prone task, whereas an automated solution could save time for the pathologists and enhance reproducibility. We propose a new hybrid method that consists of two steps. First possible tumor bud candidates are detected using a chain of classical image processing methods. Afterwards a convolutional deep neural network is applied to filter and reduce the number of false positive candidates detected in the first step. By comparing the automatically detected buds with a gold standard created by manual annotations, we gain a score of 0.977 for precision and 0.934 for sensitivity in our test sets on over 8.000 tumor buds.

A VERSATILE MODEL OF CARDIAC TISSUE FROM HIPSC-DERIVED CARDIOMYOCYTES WITHIN PERICARDIAL MATRIX HYDROGELS DOPED WITH HYDRAZIDE FUNCTIONALIZED MWCNTS FOR PHARMACEUTICAL SCREENING AND TISSUE ENGINEERING APPLICATIONS - Roshanbinfar, Kaveh; Oommen, Oommen Podiyan; Hilborn, Jons; Engel, Felix (TISSUE ENGINEERING PART A, 2022)
CRIS-Team WoS Importer:2022-08-12

A virtual chromoendoscopy artificial intelligence system to detect endoscopic and histologic activity/remission and predict clinical outcomes in ulcerative colitis - Iacucci, Marietta; Cannatelli, Rosanna; Parigi, Tommaso L.; Nardone, Olga M.; Tontini, Gian Eugenio; Labarile, Nunzia; Buda, Andrea; Rimondi, Alessandro; Bazarova, Alina; Bisschops, Raf; Del Amor, Rocio; Meseguer, Pablo; et al. (Endoscopy, 2022)
Background Endoscopic and histological remission (ER, HR) are therapeutic targets in ulcerative colitis (UC). Virtual chromoendoscopy (VCE) improves endoscopic assessment and the prediction of histology; however, interobserver variability limits standardized endoscopic assessment. We aimed to develop an artificial intelligence (AI) tool to distinguish ER/activity, and predict histology and risk of flare from white-light endoscopy (WLE) and VCE videos. Methods 1090 endoscopic videos (67 280 frames) from 283 patients were used to develop a convolutional neural network (CNN). UC endoscopic activity was graded by experts using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Paddington International virtual ChromoendoScopy ScOre (PICaSSO). The CNN was trained to distinguish ER/activity on endoscopy videos, and retrained to predict HR/activity, defined according to multiple indices, and predict outcome; CNN and human agreement was measured. Results The AI system detected ER (UCEIS = 1) in WLE videos with 72% sensitivity, 87% specificity, and an area under the receiver operating characteristic curve (AUROC) of 0.85; for detection of ER in VCE videos (PICaSSO = 3), the sensitivity was 79 %, specificity 95%, and the AUROC 0.94. The prediction of HR was similar between WLE and VCE videos (accuracies ranging from 80% to 85%). The model s stratification of risk of flare was similar to that of physician-assessed endoscopy scores. Conclusions Our system accurately distinguished ER/activity and predicted HR and clinical outcome from colonoscopy videos. This is the first computer model developed to detect inflammation/healing on VCE using the PICaSSO and the first computer tool to provide endoscopic, histologic, and clinical assessment.
CRIS-Team Scopus Importer:2024-12-16

Back to the roots - dermatology in ancient Egyptian medicine - Hartmann, Arndt (Journal der Deutschen Dermatologischen Gesellschaft, 2016)
Although ancient Greek and Roman medicine is generally considered the origin of European medicine, there is evidence in ancient Egyptian texts suggesting a precursor role of ancient Egyptian medicine in this regard. What did Greek and Roman physicians learn from their Egyptian counterparts? Of the medical papyri discovered to date, the largest and most significant - the Ebers papyrus and the Smith papyrus - originate from the beginning of the New Kingdom, however, they were - at least in part - already written during the Old Kingdom. Considering the times, the spectrum of diseases treated as well as the range of conservative and surgical treatment methods was truly astounding. Taking a medical history, performing a thorough manual examination, and assessing clinical findings constituted key components in establishing a diagnosis. Apart from hygienic aspects, skin and hair disorders, the treatment of acute and chronic wounds and injuries as well as cosmetic procedures took on an important role. Even back then, physicians sought to assess inflammatory processes with respect to their cardinal features, implement graded wound therapy, and treat diseases with allopathic drugs. The 'channel theory' prevalent at that time, in which the unimpeded flow of bodily fluids was considered a fundamental prerequisite for health, may likely be regarded as precursor of ancient Greek humoral pathology. The latter became the basis for the subsequently established theory of the four humors, and was thus essential for the entire field of medieval medicine.
EVALuna:33697

Banff 2022 pancreas transplantation multidisciplinary report: Refinement of guidelines for T cell–mediated rejection, antibody-mediated rejection and islet pathology. Assessment of duodenal cuff biopsies and noninvasive diagnostic methods - Drachenberg, Cinthia B.; Büttner-Herold, Maike; Aguiar, Pedro Ventura; Horsfield, Catherine; Mikhailov, Alexei V.; Papadimitriou, John C.; Seshan, Surya V.; Perosa, Marcelo; Boggi, Ugo; Uva, Pablo; Rickels, Michael; Grzyb, Krzyztof; et al. (American Journal of Transplantation, 2024)
The Banff pancreas working schema for diagnosis and grading of rejection is widely used for treatment guidance and risk stratification in centers that perform pancreas allograft biopsies. Since the last update, various studies have provided additional insight regarding the application of the schema and enhanced our understanding of additional clinicopathologic entities. This update aims to clarify terminology and lesion description for T cell–mediated and antibody-mediated allograft rejections, in both active and chronic forms. In addition, morphologic and immunohistochemical tools are described to help distinguish rejection from nonrejection pathologies. For the first time, a clinicopathologic approach to islet pathology in the early and late posttransplant periods is discussed. This update also includes a discussion and recommendations on the utilization of endoscopic duodenal donor cuff biopsies as surrogates for pancreas biopsies in various clinical settings. Finally, an analysis and recommendations on the use of donor-derived cell-free DNA for monitoring pancreas graft recipients are provided. This multidisciplinary effort assesses the current role of pancreas allograft biopsies and offers practical guidelines that can be helpful to pancreas transplant practitioners as well as experienced pathologists and pathologists in training.
CRIS-Team Scopus Importer:2024-03-15
Keywords: acute T cell–mediated rejection; antibody-mediated rejection; donor-specific antibody; mixed rejection; pancreas after kidney transplant; percutaneous pancreas biopsy; simultaneous pancreas kidney transplant; solitary pancreas transplant; whole pancreas transplantation

BAP1 Loss is a Useful Adjunct to Distinguish Malignant Mesothelioma Including the Adenomatoid-like Variant From Benign Adenomatoid Tumors - Erber, Ramona; Warth, Arne; Muley, Thomas; Hartmann, Arndt; Herpel, Esther; Agaimy, Abbas (Applied Immunohistochemistry & Molecular Morphology, 2020)
Malignant mesothelioma (MM) can show areas closely mimicking reactive mesothelial proliferations or recapitulating benign adenomatoid tumors (ATs) making distinction on occasion impossible on morphologic ground alone, particularly in limited biopsy material. Recently, loss of BAP1 by immunohistochemistry (IHC) has been suggested as a potential marker for identifying MM, but data is still limited. We studied 264 MM cases (257 using tissue microarrays; 7 on conventional slides) and 42 genital ATs for BAP1 immunohistochemical expression. Loss of BAP1 protein expression was observed in 119/211 of MM cases (56.4%). Taken by histologic type, 64.3% of biphasic, 55.4% of epithelioid, and 41.7% of sarcomatoid MM were BAP1-deficient. In contrast, all 42 ATs showed retained BAP1 immunoreactivity. Notably, all 4 MM cases with variable adenomatoid-like features were BAP1-deficient. Surface components of MM of the pleura showed concordant loss as the invasive tumor suggesting a potential role for BAP1 loss for recognizing so-called early mesothelioma. In conclusion, BAP1 loss demonstrated by IHC is seen in more than half of MM cases but none of ATs. Thus, BAP1 IHC represents a potential adjunct for distinguishing MM from benign mesothelial proliferations including in particular "MM with bland adenomatoid-like pattern versus benign ATs" on biopsy material and early mesothelioma with limited invasion.
CRIS-Team WoS Importer:2020-01-07

Basic nephropathology for pathologists—part 1: Kidney biopsy—inflammation and immune complexes Grundlagen der Nierenpathologie für Pathologen – Teil 1: Nierenbiopsie – Inflammation und Immunkomplexe - Büttner-Herold, Maike; Gaspert, Ariana; Amann, Kerstin Ute (Pathologe, 2022)
The assessment of kidney biopsies is mainly confined to specialized centres. However, sometimes a kidney biopsy is submitted to a general pathologist, and in addition peritumorous renal parenchyma in tumour nephrectomies can have concomitant non-neoplastic renal disease. Here we present a survey of inflammatory and immunologic changes in all renal compartments, which may in part indicate the need of prompt therapeutic intervention such as in vasculitis, glomerulonephritis and interstitial nephritis. It is important to take into account that renal involvement of vasculitis is mainly centred in glomeruli and only to a much lesser extent in arteries, and that the frequently observed interstitial inflammation very often is an epiphenomenon of another primary kidney disease and not an independent disease process. Typical renal patterns of injury are emphasised.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Biopsy; Differential diagnosis; Immune complexes; Inflammation; Microscopy

Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer - Punkenburg, Elise; Vogler, Tina; Büttner, Maike; Amann, Kerstin Ute; Waldner, Maximilian; Atreya, Raja; Abendroth, Benjamin; Mudter, Jonas; Merkel, Susanne; Gallmeier, Eike; Rose-John, Stefan; Neurath, Markus; et al. (Gut, 2016)
IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo.We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and ROR?t in patients with IBD and CRC.Batf but not retinoic acid-related orphan receptor ?t(ROR?t) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not ROR?t expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not ROR?t was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4(+) T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf(-/-) tumours lacked IL-17a(+)IL-23R(+)IL-6(+)CD4(+) T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4(+) T cells. Strikingly, Batf(-/-) tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor.Batf-dependent IL-23R(+)IL-6(+)CD4(+) Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R(+) T cells represent a potential future therapeutic target limiting CRC progression.
EVALuna2:2026

B-Cos Aligned Transformers Learn Human-Interpretable Features - Tran, Manuel; Lahiani, Amal; Dicente Cid, Yashin; Boxberg, Melanie; Lienemann, Peter; Matek, Christian; Wagner, Sophia J.; Theis, Fabian J.; Klaiman, Eldad; Peng, Tingying (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 2023)
Vision Transformers (ViTs) and Swin Transformers (Swin) are currently state-of-the-art in computational pathology. However, domain experts are still reluctant to use these models due to their lack of interpretability. This is not surprising, as critical decisions need to be transparent and understandable. The most common approach to understanding transformers is to visualize their attention. However, attention maps of ViTs are often fragmented, leading to unsatisfactory explanations. Here, we introduce a novel architecture called the B-cos Vision Transformer (BvT) that is designed to be more interpretable. It replaces all linear transformations with the B-cos transform to promote weight-input alignment. In a blinded study, medical experts clearly ranked BvTs above ViTs, suggesting that our network is better at capturing biomedically relevant structures. This is also true for the B-cos Swin Transformer (Bwin). Compared to the Swin Transformer, it even improves the F1-score by up to 4.7% on two public datasets.
CRIS-Team Scopus Importer:2023-11-03
Keywords: explainability; interpretability; self-attention; transformer

BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression? - Huth, Laura; Rose, Michael; Kloubert, Veronika; Winkens, Wiebke; Schlensog, Martin; Hartmann, Arndt; Knuechel, Ruth; Dahl, Edgar (PLoS ONE, 2014)
Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies.
EVALuna2:6675

BDNF: mRNA expression in urine cells of patients with chronic kidney disease and its role in kidney function - Endlich, Nicole; Lange, Tim; Kuhn, Jana; Klemm, Paul; Kotb, Ahmed M.; Siegerist, Florian; Kindt, Frances; Lindenmeyer, Maja T.; Cohen, Clemens D.; Kuss, Andreas W.; Nath, Neetika; Rettig, Rainer; et al. (Journal of Cellular and Molecular Medicine, 2018)
Podocyte loss and changes to the complex morphology are major causes of chronic kidney disease (CKD). As the incidence is continuously increasing over the last decades without sufficient treatment, it is important to find predicting biomarkers. Therefore, we measured urinary mRNA levels of podocyte genes NPHS1, NPHS2, PODXL and BDNF, KIM-1, CTSL by qRT-PCR of 120 CKD patients. We showed a strong correlation between BDNF and the kidney injury marker KIM-1, which were also correlated with NPHS1, suggesting podocytes as a contributing source. In human biopsies, BDNF was localized in the cell body and major processes of podocytes. In glomeruli of diabetic nephropathy patients, we found a strong BDNF signal in the remaining podocytes. An inhibition of the BDNF receptor TrkB resulted in enhanced podocyte dedifferentiation. The knockdown of the orthologue resulted in pericardial oedema formation and lowered viability of zebrafish larvae. We found an enlarged Bowman's space, dilated glomerular capillaries, podocyte loss and an impaired glomerular filtration. We demonstrated that BDNF is essential for glomerular development, morphology and function and the expression of BDNF and KIM-1 is highly correlated in urine cells of CKD patients. Therefore, BDNF mRNA in urine cells could serve as a potential CKD biomarker.
EVALuna2:156717

Bedeutung von HPV-Status und p16 für die Prognose des Peniskarzinoms - Mink, Jan Niklas; Khalmurzaev, Oybek; Pryalukhin, Alexey; Hölters, Sebastian; Geppert, Carol-Immanuel; Lohse, Stefan; Bende, Kristóf; Lobo, João; Henrique, Rui; Loertzer, Hagen; Steffens, Joachim; Jerónimo, Carmen; et al. (Aktuelle Urologie, 2023)
BACKGROUND: Penile cancer is a rare but often lethal tumour disease, especially in the metastatic stage. Most data on prognostic factors for penile cancer are based on small patient cohorts, and even meta-analyses are mostly limited in terms of patient numbers. There is a lack of sufficient parameters to predict the metastatic risk of these tumours. Furthermore, the role of the HPV status for the prognosis, and, in this regard, of p16INK4a is still unclear. MATERIAL AND METHODS: In this study, 236 patients from an international multicentre cohort were analysed with regard to histological subtypes, HPV and p16 status, and other clinical parameters. The HPV status was only graded as HPV-positive if HPV was detected by PCR and the p16 status defined by immunochemistry was positive. The statistical analysis was carried out using the Kaplan-Meier method as well as the log-rank test and a univariable and multivariable analysis using the Cox regression model. RESULTS: A positive HPV status was not a significant parameter for either metastasis-free (MFS), tumour-specific (CSS) or overall survival (OS). p16-positive tumours showed a significantly better MFS (p=0.026), which was also confirmed in the subgroup analysis of HPV-negative tumours (p=0.037) without differences in CSS or OS. In the usual type, there was also a trend towards an improved MFS, but without statistical significance (p=0.070). p16-positive tumours were associated with a highly significantly better MFS (hazard ratio 0.3; p=0.004) in the multivariable Cox regression, while patients with a pT1b tumour stage or advanced lymph node metastasis showed a significantly worse survival. In the multivariable analysis of HPV-negative tumours, p16 status was also confirmed as an independent predictor of MFS (Hazard ratio 0.2; p=0.007). CONCLUSION: HPV status alone seems to be lacking prognostic relevance. In contrast, p16 status was confirmed as an independent prognostic factor. Thus, the expression of p16INK4a is associated with a significantly better MFS. Especially in HPV-negative tumours, the p16 status should be evaluated with regard to the prognostic value and thus also with a view to the treatment decision.
CRIS-Team Scopus Importer:2023-08-11

Benchmarking whole exome sequencing in the German network for personalized medicine - Menzel, Michael; Martis-Thiele, Mihaela; Goldschmid, Hannah; Ott, Alexander; Romanovsky, Eva; Siemanowski-Hrach, Janna; Seillier, Lancelot; Brüchle, Nadina Ortiz; Maurer, Angela; Lehmann, Kjong Van; Begemann, Matthias; Elbracht, Miriam; et al. (European Journal of Cancer, 2024)
Introduction: Whole Exome Sequencing (WES) has emerged as an efficient tool in clinical cancer diagnostics to broaden the scope from panel-based diagnostics to screening of all genes and enabling robust determination of complex biomarkers in a single analysis. Methods: To assess concordance, six formalin-fixed paraffin-embedded (FFPE) tissue specimens and four commercial reference standards were analyzed by WES as matched tumor-normal DNA at 21 NGS centers in Germany, each employing local wet-lab and bioinformatics. Somatic and germline variants, copy-number alterations (CNAs), and complex biomarkers were investigated. Somatic variant calling was performed in 494 diagnostically relevant cancer genes. The raw data were collected and re-analyzed with a central bioinformatic pipeline to separate wet- and dry-lab variability. Results: The mean positive percentage agreement (PPA) of somatic variant calling was 76 % while the positive predictive value (PPV) was 89 % in relation to a consensus list of variants found by at least five centers. Variant filtering was identified as the main cause for divergent variant calls. Adjusting filter criteria and re-analysis increased the PPA to 88 % for all and 97 % for the clinically relevant variants. CNA calls were concordant for 82 % of genomic regions. Homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI) status were concordant for 94 %, 93 %, and 93 % of calls, respectively. Variability of CNAs and complex biomarkers did not decrease considerably after harmonization of the bioinformatic processing and was hence attributed mainly to wet-lab differences. Conclusion: Continuous optimization of bioinformatic workflows and participating in round robin tests are recommended.
CRIS-Team Scopus Importer:2024-09-27
Keywords: Clinical exome; Molecular pathology; Multi-centric inter-laboratory test; Precision oncology; Whole exome sequencing

Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases - Yin, Xiaoxue; Wei, Xiaoxia; Al Shamsi, Ruqaiya; Ali, Fatima S.; Al Kindi, Faiza; Zhang, Xingming; Liang, Jiayu; Pan, Xiuyi; Al Masqari, Mohammed; Zheng, Linmao; Zhou, Qiao; Agaimy, Abbas; et al. (Virchows Archiv, 2024)
Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5–2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.
CRIS-Team Scopus Importer:2024-05-17
Keywords: Fumarate hydratase-deficient leiomyoma; Hereditary genital cancer; HLRCC; Kidney; Lung; Multi-organ metastases

Bericht der AG Molekularpathologie-Jahrestagung DGP 2020 - Haller, Florian; Lassmann, S.; Siebolts, U. (Pathologe, 2020)
CRIS-Team Scopus Importer:2020-11-06

Bericht der AG Molekularpathologie – Virtuelle Pathologietage der DGP 2021 - Lassmann, Silke; Haller, Florian; Siebolts, Udo (Pathologe, 2021)
CRIS-Team Scopus Importer:2021-11-05