Bericht der AG Molekularpathologie: Zusammenfassung der Mitgliederversammlung im Rahmen der 96. Jahrestagung der DGP in Berlin - Dietmaier, W.; Arens, N.; Haller, Florian (Pathologe, 2012)
CRIS-Team Scopus Importer:2025-03-24

Bericht der Arbeitsgemeinschaft Gynäko- und Mammapathologie der Deutschen Gesellschaft für Pathologie - Burandt, Eike; Erber, Ramona (Die Pathologie, 2023)
CRIS-Team Scopus Importer:2023-12-01

Bericht zur Late-Breaking Session Pathologie und COVID-19 - Boor, P.; Hartmann, Arndt (Pathologe, 2020)
This paper briefly summarizes the late-breaking session “Pathology and COVID-19” that took place at the virtual congress of the German Society of Pathology on June 6, 2020. The lectures tackled a broad variety of aspects, including the German Registry for COVID-19 autopsies (DeRegCOVID), the detection methods of SARS-CoV‑2 in pathological material, the typical lung findings in severe COVID-19 cases, the distinct (micro)vascular changes and the cardiac and gastrointestinal involvement in COVID-19. In summary, in this first scientific meeting in German pathology on the COVID-19 pandemic, it became clear that pathologists in Germany, Austria and Switzerland have reacted very quickly to the pandemic and have established an autopsy program that has led to medically highly relevant findings.
CRIS-Team Scopus Importer:2020-12-25
Keywords: Autopsy registry; Detection methods; Diffuse alveolar damage; SARS-CoV‑2; Thrombi

beta(2)-m - a Trigger for NLRP3 Inflammasome Activation within Macrophages Promoting Multiple Myeloma Cell Proliferation - Hofbauer, Daniel; Mougiakakos, Dimitrios; Büttner-Herold, Maike; Neumann, Frank; Nolting, Jens; Bisht, Savita; Zeiser, Robert; Hamarsheh, Shaima'A; Ricagno, Stefano; Zaiss, Mario; Eberhardt, Martin; Böttcher, Martin; et al. (BLOOD, 2019)
CRIS-Team WoS Importer:2021-10-18

Beta-HCG elevation as first sign of a malignant somatic transformation of a non-seminomatous germ cell tumor - Peuser, Moritz; Hartmann, Arndt; Schmidt, Daniela; Mackensen, Andreas; Meidenbauer, Norbert (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

Beyond PD‐L1—Identification of Further Potential Therapeutic Targets in Oral Cancer - Weber, Manuel; Lutz, Rainer; Olmos, Manuel; Glajzer, Jacek; Baran, Christoph; Nobis, Christopher-Philipp; Möst, Tobias; Eckstein, Markus; Kesting, Marco Rainer; Ries, Jutta (Cancers, 2022)
Background: The involvement of immune cell infiltration and immune regulation in the progression of oral squamous cell carcinoma (OSCC) is shown. Anti‐PD‐1 therapy is approved for the treatment of advanced OSCC cases, but not all patients respond to immune checkpoint inhibi-tors. Hence, further targets for therapeutic approaches are needed. The number of identified cellular receptors with immune checkpoint function is constantly increasing. This study aimed to perform a comparative analysis of a large number of immune checkpoints in OSCC in order to identify possible targets for therapeutic application. Materials and Methods: A NanoString mRNA analysis was performed to assess the expression levels of 21 immune regulatory checkpoint molecules in OSCC tissue (n = 98) and healthy oral mucosa (NOM; n = 41). The expression rates were compared between the two groups, and their association with prognostic parameters was determined. Additionally, relevant correlations between the expression levels of different checkpoints were examined. Results: In OSCC tissue, significantly increased expression of CD115, CD163, CD68, CD86, CD96, GITRL, CD28 and PD‐L1 was detected. Additionally, a marginally significant increase in CD8 expression was observed. BTLA and PD‐1 levels were substantially increased, but the differential expression was not statistically significant. The expression of CD137L was significantly downregulated in OSCC compared to NOM. Correlations between immune checkpoint expression levels were demonstrated, and some occurred specifically in OSCC tissue. Conclusions: The upregulation of inhibitory receptors and ligands and the downregulation of activators could contribute to reduced effector T‐cell function and could induce local immunosuppression in OSCC. Increased expression of activating actors of the immune system could be explained by the increased infiltration of mye-loid cells and T‐cells in OSCC tissue. The analysis contributes to the understanding of immune es-cape in OSCC and reveals potential targets for oral cancer immunotherapy.
CRIS-Team Scopus Importer:2022-04-15
Keywords: head and neck cancer; HNSCC; immune checkpoints; immunotherapy; macro-phage; MDSC; OSCC; T‐cell

Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation - Schwarz, Hannah; Popp, Bernt; Airik, Rannar; Torabi Sarijalo, Nasrin; Knaup, Karl; Stoeckert, Johanna; Wiech, Thorsten; Amann, Kerstin Ute; Wiesmann da Silva Reis, André; Schiffer, Mario; Schueler, Markus; Wiesener, Michael (Human Molecular Genetics, 2022)
Nephronophthisis-related ciliopathies (NPHP-RC) comprises a group of inherited kidney diseases, caused by mutations in genes encoding proteins localizing to primary cilia. NPHP-RC represents one of the most frequent monogenic causes of renal failure within the first three decades of life, but its molecular disease mechanisms remain unclear. Here, we identified biallelic ANKS6 mutations in two affected siblings with late-onset chronic kidney disease by whole-exome sequencing. We employed patient-derived fibroblasts generating an in vitro model to study the precise biological impact of distinct human ANKS6 mutations, completed by immunohistochemistry studies on renal biopsy samples. Functional studies using patient-derived cells showed an impaired integrity of the ciliary inversin compartment with reduced cilia length. Further analyses demonstrated that ANKS6 deficiency leads to a dysregulation of Hippo-signaling through nuclear yes-associated protein (YAP) imbalance and disrupted ciliary localization of YAP. In addition, an altered transcriptional activity of canonical Wnt target genes and altered expression of non-phosphorylated (active) beta-catenin and phosphorylated glycogen synthase kinase 3 beta were observed. Upon ciliation, ANKS6 deficiency revealed a deranged subcellular localization and expression of components of the endocytic recycling compartment. Our results demonstrate that ANKS6 plays a key role in regulating the Hippo pathway, and ANKS6 deficiency is linked to dysregulation of signaling pathways. Our study provides molecular clues in understanding pathophysiological mechanisms of NPHP-RC and may offer new therapeutic targets.
CRIS-Team WoS Importer:2022-05-13

Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition - Knaup, Karl; Hackenbeck, Thomas; Popp, Bernt; Stoeckert, Johanna; Wenzel, Andrea; Büttner-Herold, Maike; Pfister, Frederick; Schüler, Markus; Seven, Didem; May, Annette M.; Halbritter, Jan; Gröne, Hermann Josef; et al. (Journal of the American Society of Nephrology, 2018)
BACKGROUND: Providing the correct diagnosis for patients with tubulointerstitial kidney disease and secondary degenerative disorders, such as hypertension, remains a challenge. The autosomal dominant tubulointerstitial kidney disease (ADTKD) subtype caused by MUC1 mutations (ADTKD-MUC1) is particularly difficult to diagnose, because the mutational hotspot is a complex repeat domain, inaccessible with routine sequencing techniques. Here, we further evaluated SNaPshot minisequencing as a technique for diagnosing ADTKD-MUC1 and assessed immunodetection of the disease-associated mucin 1 frameshift protein (MUC1-fs) as a nongenetic technique. METHODS: We re-evaluated detection of MUC1 mutations by targeted repeat enrichment and SNaPshot minisequencing by haplotype reconstruction via microsatellite analysis in three independent ADTKD-MUC1 families. Additionally, we generated rabbit polyclonal antibodies against MUC1-fs and evaluated immunodetection of wild-type and mutated allele products in human kidney biopsy specimens. RESULTS: The detection of MUC1 mutations by SNaPshot minisequencing was robust. Immunostaining with our MUC1-fs antibodies and an MUC1 antibody showed that both proteins are readily detectable in human ADTKD-MUC1 kidneys, with mucin 1 localized to the apical membrane and MUC1-fs abundantly distributed throughout the cytoplasm. Notably, immunohistochemical analysis of MUC1-fs expression in clinical kidney samples facilitated reliable prediction of the disease status of individual patients. CONCLUSIONS: Diagnosing ADTKD-MUC1 by molecular genetics is possible, but it is technically demanding and labor intensive. However, immunohistochemistry on kidney biopsy specimens is feasible for nongenetic diagnosis of ADTKD-MUC1 and therefore, a valid method to select families for further diagnostics. Our data are compatible with the hypothesis that specific molecular effects of MUC1-fs underlie the pathogenesis of this disease.
EVALuna2:34428

BiasCorrector: Fast and accurate correction of all types of experimental biases in quantitative DNA methylation data derived by different technologies - Kapsner, Lorenz; Zavgorodnij, Mikhail G.; Majorova, Svetlana P.; Hotz-Wagenblatt, Agnes; Kolychev, Oleg V.; Lebedev, Igor N.; Hoheisel, Jörg D.; Hartmann, Arndt; Bauer, Andrea; Mate, Sebastian; Prokosch, Hans-Ulrich; Haller, Florian; et al. (International Journal of Cancer, 2021)
Quantification of DNA methylation in neoplastic cells is crucial both from mechanistic and diagnostic perspectives. However, such measurements are prone to different experimental biases. Polymerase chain reaction (PCR) bias results in an unequal recovery of methylated and unmethylated alleles at the sample preparation step. Post-PCR biases get introduced additionally by the readout processes. Correcting the biases is more practicable than optimising experimental conditions, as demonstrated previously. However, utilisation of our earlier developed algorithm strongly necessitates automation. Here, we present two R packages: rBiasCorrection, the core algorithms to correct biases; and BiasCorrector, its web-based graphical user interface frontend. The software detects and analyses experimental biases in calibration DNA samples at a single base resolution by using cubic polynomial and hyperbolic regression. The correction coefficients from the best regression type are employed to compensate for the bias. Three common technologies—bisulphite pyrosequencing, next-generation sequencing and oligonucleotide microarrays—were used to comprehensively test BiasCorrector. We demonstrate the accuracy of BiasCorrector's performance and reveal technology-specific PCR- and post-PCR biases. BiasCorrector effectively eliminates biases regardless of their nature, locus, the number of interrogated methylation sites and the detection method, thus representing a user-friendly tool for producing accurate epigenetic results.
CRIS-Team Scopus Importer:2021-06-04
Keywords: BiasCorrector; cancer; DNA methylation; PCR-bias; post-PCR bias

Bilateral Orbital IgG4-Related Disease with Systemic and Corneal Involvement Showing an Excellent Response to Steroid and Rituximab Therapy: Report of a Case with 11 Years Follow-Up - Berta, Agnes I.; Agaimy, Abbas; Braun, Joachim M.; Manger, Bernhard; Kruse, Friedrich Eduard; Holbach, Leonard (Orbit, 2015)
IgG4-related disease is a newly recognized fibro-inflammatory condition. The purpose of this report is to present a patient with 11 years of follow-up, who revealed characteristic features of IgG4-related disease with systemic, orbital and corneal involvement and showed a favorable response to steroids and rituximab treatment.
EVALuna2:6708

Bi-nucleation of podocytes is uniformly accompanied by foot processes widening in renal disease - Muehldorfer, Johanna; Pfister, Eva; Buettner-Herold, Maike; Klewer, Monika; Amann, Kerstin Ute; Daniel, Christoph (Nephrology Dialysis Transplantation, 2017)
Podocytes are terminally differentiated glomerular cells expressing a highly complex architecture and lacking the ability to proliferate. However, during renal injury or stress these cells can re-enter into the cell cycle but fail to divide. As a consequence, bi- and multi-nucleated podocytes can be identified in renal biopsies from patients with various kidney diseases. It is still unclear whether the occurrence of such cells is dependent on or correlates with renal damage and if bi- or multi-nucleation results in ultrastructural alterations such as e.g. foot process effacement. Therefore, we investigated the frequency, correlation with clinical parameters and morphological consequences of podocyte bi- or multi-nucleation in a cohort of 377 patients suffering from different renal diseases.Renal biopsies from patients with minimal change disease (MCD; n = 93), IgA-glomerulonephritis (IgA-GN, n = 95), lupus nephritis (LN; n = 90) and diabetic nephropathy (DN; n = 99) were investigated for the occurrence of bi-nucleated or multi-nucleated podocytes using semi-thin sections and light-microscopy at 1000× magnification. The frequency of bi-nucleation and multi-nucleation in podocytes was correlated with clinical parameters and markers of renal injury. In addition, ultrastructural morphological features associated with podocyte bi- or multi-nucleation were analysed by scanning transmission electron microscopy at various magnifications.Ultrastructural analysis of podocyte nuclear morphology revealed a broad spectrum of nuclear appearances. Therefore, podocytes were classified in cells with mono-nucleated, lobulated, potential bi-nucleated, symmetrically bi-nucleated, asymmetrically bi-nucleated and multi-nucleated nuclear morphology. In 65-80% of all investigated glomeruli only mono-nuclear podocytes were identified. The highest frequency of bi-nucleated podocytes was found in patients with IgA-GN (18.6%) and the lowest in patients with DN (5.6%). The proportion of bi-nucleated podocytes with asymmetric nuclear morphology was about 50% of all bi-nucleated podocytes and independent of the underlying renal disease. In addition, ultrastructural analysis by electron microscopy showed significant widening of foot processes in bi-nucleated compared with mono-nucleated podocytes. Interestingly, foot process width of podocytes with lobulated nuclei was also significantly increased compared with podocytes with normal mono-nuclear morphology. Furthermore, podocyte density per glomerular area was significantly lower in glomeruli with bi-nucleated podocytes. Due to the relatively low frequency of bi- and multi-nucleated podocytes, correlations with clinical parameters were weak and dependent on renal disease.The frequency of bi-nucleated podocytes was highest in IgA-GN but can also be observed in all investigated renal diseases. In podocytes with altered nuclear morphology particularly in bi- and multi-nucleated podocytes ultrastructural analysis of podocytes revealed significant widening of foot processes as a potential maladaptive structural consequence.
EVALuna2:25559

Biofabrication of 3D Alginate-Based Hydrogel for Cancer Research: Comparison of Cell Spreading, Viability, and Adhesion Characteristics of Colorectal HCT116 Tumor Cells - Ivanovska, Jelena; Zehnder, Tobias; Lennert, Pablo; Sarker, Bapi; Boccaccini, Aldo R.; Hartmann, Arndt; Schneider-Stock, Regine; Detsch, Rainer (Tissue Engineering - Part C: Methods, 2016)
Hydrogels are an important class of biomaterials as they could mimic the extracellular matrix (ECM). Among the naturally occurring biopolymers, alginate and gelatin are extensively used for many biomedical applications. For developing biofabrication constructs as three-dimensional (3D) cell culture models, realistic imaging of cell spreading and proliferation inside the hydrogels represents a major challenge. Therefore, we aimed to establish a system that can mimic the structural architecture, composition, and biological functions of the ECM for cancer research approaches. For this, we compared the cell behavior of human colon cancer HCT116 cells in two biofabricated hydrogels as follows: pure alginate and cross-linked alginate-gelatin (ADA-GEL) matrixes. Our data indicate that cells from the ADA-GEL matrix showed highest proliferation and cellular networks through the material. Analyzing the mRNA expression of several integrins of cells cultured inside of the matrix, we showed that mRNA expression of integrin subunits differed based on the cell focal adhesion characteristics. Furthermore, we showed that recultured ADA-GEL immobilized cells do not differ from parental HCT116 cells regarding migration and proliferation capabilities. Comparing adhesion and other phenotypic characteristics of HCT116 tumor cells, we suggest that ADA-GEL hydrogel is a more suitable 3D system than pure alginate and seems to optimally mimic the physiological behavior of the tumor microenvironment. For the first time, we present a functional 3D hydrogel construct for colon cancer cells, which are supporting their physiological cell attachment, spreading, and viability. We strongly believe that it will be applicable as a suitable in vitro 3D tumor model to study different aspects of tumor cell behavior.
EVALuna2:6830

Biofunctionalization of ADA-GEL Hydrogels Based on the Degree of Cross-Linking and Polymer Concentration Improves Angiogenesis - Heltmann-Meyer, Stefanie; Detsch, Rainer; Hazur, Jonas; Kling, Lasse; Pechmann, Sabrina; Kolan, Rajkumar Reddy; Osterloh, Justus; Boccaccini, Aldo R.; Christiansen, Silke; Geppert, Carol-Immanuel; Arkudas, Andreas; Horch, Raymund E.; et al. (Advanced Healthcare Materials, 2025)
The creation of bioartificial tissues is a promising option for the reconstruction of large-volume defects. The vascularization of tissue engineering constructs, as well as the material properties of the carrier matrix, are important factors for successful clinical application. In this regard, hydrogels are promising biomaterials, providing an extracellular matrix-like milieu that enables the possibility of cell transplantation and de novo tissue formation. Furthermore, biofunctionalization allows for a certain fine-tuning of angiogenic properties. This study aims to investigate vascularization and tissue formation of highly cross-linked alginate dialdehyde (ADA) and gelatin (GEL). This highly cross-linked network is created using a dural cross-linking mechanism combining ionic (Ca2+ ions) and enzymatic (human transglutaminase (hTG)) cross-linking, resulting in reduced swelling and moderate degradation rates. Vascularization of the ADA-GEL-hTG constructs is induced surgically using arteriovenous (AV) loops. Biocompatibility, tissue formation, and vascularization are analyzed by histology and X-ray microscopy. After only 2 weeks, vascularization of the ADA-GEL-hTG constructs is already present. After 4 weeks, both de novo tissue formation and vascularization of the ADA-GEL-hTG matrix increase. In conclusion, ADA-GEL-hTG-based hydrogels are shown to be promising scaffold materials for tissue engineering applications.
CRIS-Team Scopus Importer:2025-04-01
Keywords: ADA-GEL; angiogenesis; biofunctionalization; hydrogel; tissue engineering

BIOHYBRID HYDROGEL WITH ENHANCED ELECTROCONDUCTIVITY ADVANCES MATURATION OF HIPSC-DERIVED CARDIOMYOCYTES - Roshanbinfar, Kaveh; Engel, Felix (TISSUE ENGINEERING PART A, 2022)
CRIS-Team WoS Importer:2022-08-12

Biological predictors of radiosensitivity in head and neck squamous cell carcinoma - Fiedler, Mathias; Weber, Florian; Hautmann, Matthias G.; Haubner, Frank; Reichert, Torsten E.; Klingelhoeffer, Christoph; Schreml, Stephan; Meier, Johannes K.; Hartmann, Arndt; Ettl, Tobias (Clinical Oral Investigations, 2018)
OBJECTIVES: The aim of this study is to investigate the influence of prognostic biomarkers on radiosensitivity and survival of advanced head and neck squamous cell carcinomas treated by primary (chemo)radiation. MATERIAL AND METHODS: The clinicopathological data and immunohistochemical staining of p16, c-Met, survivin, PD-1, and PD-L1 of 82 primarily (chemo)irradiated patients with head and neck squamous cell carcinoma were analyzed. Associations with local and locoregional radiation response, overall survival (OS), disease-free (DFS), and disease-specific survival (DSS) were assessed. RESULTS: Complete tumor response was associated with increased patient age (p = 0.007), N0-status (p = 0.022), M0-status (p = 0.007), and p16-positivity (p = 0.022). High PD-L1 was associated with M0-status (p = 0.026) and indicated tumor response to irradiation (p = 0.057); survivin expression showed higher rates of response failure (p = 0.073). Low PD-1 was associated with increased T-stage (p = 0.029) and local recurrence (p = 0.014). High PD-1 was strongly correlated with PD-L1-positive tumor infiltrating lymphocytes (p < 0.001). Low PD-L1 showed a significant correlation with high c-Met expression (p = 0.01). Significant predictors for unfavorable univariate survival were incomplete tumor response (DSS, p < 0.001), single radiotherapy (DSS, p = 0.002), M1-status (DSS, p < 0.001), decreased radiation dose (DSS, p = 0.014), high survivin (DSS, p = 0.045), and high c-Met (OS, p < 0.05). Survivin and c-Met also showed prognostic significance in multivariate survival analysis. CONCLUSIONS: P16 and PD-L1 indicate radiosensitivity, whereas survivin and c-Met implicate radioresistance in primarily (chemo)irradiated head and neck squamous cell carcinomas. The role of the PD-1/PD-L1 immune checkpoints in radiation response and survival merits further investigation. CLINICAL RELEVANCE: The findings may improve patient-specific therapy according to individual tumor characteristics.
EVALuna2:34265

Biological Therapy of NSAID Intolerance and Food Allergy with Eggs of Pig WhipwormTrichiuris suis (TSO) in combination with Antiallergic Drugs - Heinrich, Johanna; Hotfiel, Katharina; Rieker, Ralf; Finzel, Stefanie; Goj, Detlef; Raithel, Martin (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

Biomarkers of precancerous colorectal cancer stages identified by transcriptome profiling - Siskova, Anna; Vymetalkova, Veronika; Vodicka, Pavel; Ferrero, Giulio; Naccarati, Alessio; Hampel, Chuanpit; Schneider-Stock, Regine (CANCER RESEARCH, 2022)
CRIS-Team WoS Importer:2023-04-07

Biomarkers of Response to Anti-NECTIN4 Antibody-Drug Conjugate Enfortumab Vedotin in Urothelial Cancer - Klümper, Niklas; Eckstein, Markus (European Urology Focus, 2024)
Initial studies indicated that NECTIN4 expression is widespread in metastatic urothelial cancer (mUC), which led to approval of the anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) for unselected patients with mUC. However, the recent literature suggests that there has been overestimation of membranous NECTIN4 expression in UC, which is a prerequisite for EV binding. It is well established from the development of Her2-targeting ADCs that treatment response is strongly dependent on membranous expression level of the relevant target antigen. In this context, it has been demonstrated that membranous NECTIN4 expression correlates with EV responses and outcomes. Another promising biomarker could be NECTIN4 copy number alteration, a genomic alteration that occurs in approximately 25% of mUC cases, which is associated with strong membranous NECTIN4 expression. Patients with NECTIN4 amplification exhibit an objective response rate of >90% to EV monotherapy and long-term survival. Given the heterogeneous expression of NECTIN4 in UC, future biomarker research is essential for the development of biomarker-driven mUC treatment strategies to further improve outcomes for patients with mUC. Patient summary: We reviewed current evidence on biomarkers for predicting response to enfortumab vedotin (EV) treatment for metastatic urinary tract cancer (mUC). Studies to date have shown that patients with high levels of the protein NECTIN4 on their cancer cells respond well to EV. This information has the potential to guide future treatment strategies for mUC.
CRIS-Team Scopus Importer:2024-04-26
Keywords: Antibody-drug conjugates; Enfortumab vedotin; NECTIN4; Urothelial carcinoma

Biomarker-stratified first-line treatment of right-sided metastatic colon cancer with interdisciplinary collaboration in the IVOPAK II trial - Vitali, Francesco; Merkel, Susanne; Schubart, Christoph; Schmid, Axel; Eckstein, Markus; Stöhr, Robert; Kersting, Stephan; Hartmann, Arndt; Grützmann, Robert; Wein, Axel (Anti-Cancer Drugs, 2024)
Patients with right-sided metastatic colon carcinoma have a significantly worse prognosis than those with left-sided colorectal cancer (CRC), regardless of treatment. The aim of the prospective IVOPAK II study was to implement an interdisciplinary guideline-conform personalized CRC palliative therapy of metastatic colorectal carcinoma and to improve the overall survival (OS) by multidisciplinary approach via secondary metastatic resection. We present the efficacy data of first-line treatment and the benefit of interdisciplinary collaboration of right-sided metastatic colon carcinoma patients: n = 25. RAS mutation: n = 20 (80%): received systemic first-line treatment: FOLFIRI plus bevacizumab. All-RAS-wildtype: n = 5 (20%): received systemic first-line treatment: FOLFIRI plus cetuximab. Last date evaluation: 31 January 2024. Median age: 59.6 years (range 42-71), men/women: 14/11. Eastern Cooperative Oncology Group (ECOG) index: 0/1/2 : 11/10/4. Evaluable for response: n = 25. Complete response: n = 0, partial response: n = 14 (56%), stable disease: n = 8 (32%), progressive disease: n = 3 (12%), early tumor shrinkage: n = 13 (52%), estimates progression-free survival: 13 months (95% CI 8-17 months), estimated OS: 48 months (95% CI 25-71 months), median follow-up: 26 months (1-61 months), no evidence of disease: n = 4 (16%). A chemotherapy doublette regimen with FOLFIRI plus a biological as first-line treatment shows promising efficacy and secondary metastatic resection after interdisciplinary discussion was associated with a survival benefit in right-sided metastatic colon carcinoma.
CRIS-Team Scopus Importer:2024-08-16
Keywords: biomarker guided first; line treatment; right; secondary metastatic resection; sided metastatic colon carcinoma

Biomimetic Organic-Inorganic Nanocomposite Scaffolds to Regenerate Cranial Bone Defects in a Rat Animal Model - Moosavifar, Mirjavad; Parsaei, Houman; Hosseini, Seyedjamal; Mirmontazeri, Seyed Mohammad; Ahadi, Reza; Ahadian, Samad; Engel, Felix; Roshanbinfar, Kaveh (ACS Biomaterials Science and Engineering, 2022)
While bone regenerates itself after an injury, a critical bone defect requires external interventions. Engineering approaches to restore bone provide a temporary scaffold to support the damage and provide beneficial biological cues for bone repair. Biomimetically generated scaffolds replicate the naturally occurring phenomena in bone regeneration. In this study, a gelatin-calcium phosphate nanocomposite was synthesized by an efficient and cost-effective double-diffusion biomimetic approach. Calcium and phosphate ions are impregnated in the gelatin, mimicking the natural bone mineralization process. Glutaraldehyde from 0.5 to 2 w/v% was used for gelatin cross-linking and mechanical properties of the scaffold, and its biological support for rat bone marrow mesenchymal stromal cells was analyzed. Analysis of scanning electron microscopy images of the nanocomposite scaffolds and Fourier transform infrared (FTIR) and X-ray diffraction (XRD) characterizations of these scaffolds confirmed precipitation of calcium phosphates in the gelatin. Moreover, lysozyme degradation assay showed that scaffold degradation reversely correlates with the concentration of the cross-linking agent. Increased glutaraldehyde concentrations enhanced the mechanical properties of the scaffolds, bringing them closer to those of cancellous bone. Rat bone marrow mesenchymal stromal cells maintained their viability on these scaffolds compared to standard cell culture plates. In addition, these cells showed differentiation into bone lineage as evaluated from alkaline phosphatase activity up to 21 days and Alizarin red staining of the cells over 28 days. Eventually, scaffolds were implanted in a cranial defect in a rat animal model with a 5 mm diameter. Bone regeneration was studied over 90 days. Analysis of histological sections of the injury and computer tomography images revealed that nanocomposite scaffolds cross-linked with 1% w/v glutaraldehyde provide the maximum bone regeneration after 90 days. Collectively, our data show that nanocomposite scaffolds developed here provide effective regeneration for extensive bone defects in vivo.
CRIS-Team Scopus Importer:2022-04-15
Keywords: biomimetic scaffold; bone tissue engineering; gelatin-calcium phosphate; nanocomposite graft

Biphasic papillary renal cell carcinoma is a rare morphological variant with frequent multifocality: a study of 28 cases - Trpkov, Kiril; Athanazio, Daniel; Magi-Galluzzi, Cristina; Yilmaz, Helene; Clouston, David; Agaimy, Abbas; Williamson, Sean R.; Brimo, Fadi; Lopez, Jose I.; Ulamec, Monika; Rioux-Leclercq, Nathalie; Kassem, Maysoun; et al. (Histopathology, 2018)
AIMS: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC. METHODS AND RESULTS: We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39-86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34βE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes). CONCLUSIONS: Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal.
EVALuna2:34260

Biphasic Squamoid Alveolar Renal Cell Carcinoma: A Distinctive Subtype of Papillary Renal Cell Carcinoma? - Hes, Ondrej; Condom Mundo, Enric; Peckova, Kvetoslava; Lopez, Jose I.; Martinek, Petr; Vanecek, Tomas; Falconieri, Giovanni; Agaimy, Abbas; Davidson, Whitney; Petersson, Fredrik; Bulimbasic, Stela; Damjanov, Ivan; et al. (American Journal of Surgical Pathology, 2016)
Biphasic squamoid alveolar renal cell carcinoma (BSARCC) has been recently described as a distinct neoplasm. Twenty-one cases from 12 institutions were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization. Tumors were removed from 11 male and 10 female patients, whose age ranged from 53 to 79 years. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9/21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. aCGH (confirmed by fluorescence in situ hybridization) in 5 analyzable cases revealed multiple numerical chromosomal changes including gains of chromosomes 7 and 17 in all cases. These changes were further disclosed in 6 additional cases, which were unsuitable for aCGH. We conclude that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All BSARCCs expressed CK7, EMA, vimentin, and cyclin D1. Antibody to cyclin D1 showed a unique and previously not recognized pattern of immunohistochemical staining. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to papillary RCC. Some BSARCCs were clinically aggressive, but their prognosis could not be predicted from currently available data. Present microscopic, immunohistochemical, and molecular genetic data strongly support the view that BSARCC is a distinctive and peculiar morphologic variant of papillary RCC.
EVALuna2:6773

Bispecific T cell engager therapy for refractory rheumatoid arthritis - Bucci, Laura; Hagen, Melanie; Rothe, Tobias; Raimondo, Maria Gabriella; Fagni, Filippo; Tur, Carlo; Wirsching, Andreas; Wacker, Jochen; Wilhelm, Artur; Auger, Jean-Philippe; Pachowsky, Milena; Eckstein, Markus; et al. (Nature Medicine, 2024)
Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function. Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells. Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.
CRIS-Team Scopus Importer:2024-05-03

BKPYV-SPECIFIC T CELLS REDUCE VIRAL LOAD IN A PRIMARY TUBULAR CELL MODEL - Wasielewski, E.; Lippler, Susanne; Knaup, Karl; Gary, Regina; Aigner, Michael; Kremer, Anna-Lena; Pfister, Felix; Amann, Kerstin Ute; Schiffer, Mario; Mackensen, Andreas; Wiesener, Michael (TRANSPLANT INTERNATIONAL, 2021)
CRIS-Team WoS Importer:2021-10-15

Bladder tumor subtype commitment occurs in carcinoma in-situ driven by key signaling pathways including ECM remodeling - Wullweber, Adrian; Strick, Reiner; Lange, Fabienne; Sikic, Danijel; Taubert, Helge; Wach, Sven; Wullich, Bernd; Bertz, Simone; Weyerer, Veronika; Stöhr, Robert; Breyer, J.; Burger, M.; et al. (EUROPEAN UROLOGY, 2021)
CRIS-Team WoS Importer:2021-08-20

Bladder Tumor Subtype Commitment Occurs in Carcinoma In Situ Driven by Key Signaling Pathways Including ECM Remodeling - Wullweber, Adrian; Strick, Reiner; Lange, Fabienne; Sikic, Danijel; Taubert, Helge; Wach, Sven; Wullich, Bernd; Bertz, Simone; Weyerer, Veronika; Stöhr, Robert; Breyer, Johannes; Burger, Maximilian; et al. (Cancer Research, 2021)
Basal and luminal subtypes of invasive bladder tumors have significant prognostic and predictive impacts for patients. However, it remains unclear whether tumor subtype commitment occurs in noninvasive urothelial lesions or in carcinoma in situ (CIS) and which gene pathways are important for bladder tumor progression. To understand the timing of this commitment, we used gene expression and protein analysis to create a global overview of 36 separate tissues excised from a whole bladder encompassing urothelium, noninvasive urothelial lesions, CIS, and invasive carcinomas. Additionally investigated were matched CIS, noninvasive urothelial lesions, and muscle-invasive bladder cancers (MIBC) from 22 patients. The final stage of subtype commitment to either a luminal or basal MIBC occurred at the CIS transition. For all tissues combined, hierarchical clustering of subtype gene expression revealed three subtypes: "luminal," "basal," and a "luminal p53-/extracellular matrix (ECM)-like" phenotype of ECM-related genes enriched in tumor-associated urothelium, noninvasive urothelial lesions, and CIS, but rarely invasive, carcinomas. A separate cohort of normal urothelium from noncancer patients showed significantly lower expression of ECM-related genes compared with tumor-associated urothelium, noninvasive urothelial lesions, and CIS. A PanCancer Progression Panel of 681 genes unveiled pathways specific for the luminal p53-/ECM-like cluster, for example, ECM remodeling, angiogenesis, epithelial-to-mesenchymal transition, cellular discohesion, cell motility involved in tumor progression, and cell proliferation and oncogenic ERBB2/ERBB3 signaling for invasive carcinomas. In conclusion, this study provides insights into bladder cancer subtype commitment and associated signaling pathways, which could help predict therapy response and enhance our understanding of therapy resistance.
CRIS-Team WoS Importer:2021-04-09

Blockade of the CD47/SIRPα checkpoint axis potentiates the macrophage-mediated antitumor efficacy of tafasitamab. - Biedermann, Alexander; Patra-Kneuer, Maria; Mougiakakos, Dimitrios; Büttner-Herold, Maike; Mangelberger-Eberl, Doris; Berges, Johannes; Kellner, Christian; Altmeyer, Sarah; Bittenbring, Jörg Thomas; Augsberger, Christian; Ilieva-Babinsky, Kristina; Haskamp, Stefan; et al. (Haematologica, 2024)
Macrophages are one of the key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD19 antibody tafasitamab, approved in combination with lenalidomide for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, antibody-dependent cellular phagocytosis (ADCP) in the tumor microenvironment can be counteracted by increased expression of the inhibitory receptor SIRPα on macrophages and its ligand, the immune checkpoint molecule CD47, on tumor cells. The aim of this study was to investigate the impact of the CD47-SIRPα axis on tafasitamab- mediated phagocytosis and explore the potential of anti-CD47 blockade to enhance its antitumor activity. Elevated expression of both SIRPα and CD47 was observed in DLBCL patient-derived lymph node biopsies compared to healthy control lymph nodes. CRISPR-mediated CD47 overexpression affected tafasitamab-mediated ADCP in vitro and increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab against DLBCL cell lines. A combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro-generated macrophages. Importantly, tafasitamab-mediated phagocytosis was elevated in combination with CD47 blockade using primary DLBCL cells and patient-derived lymphoma-associated macrophages in an autologous setting. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination treatment. Finally, combined treatment of tafasitamab and an anti-CD47 antibody resulted in enhanced tumor volume reduction and survival benefit in lymphoma xenograft mouse models. These findings provide evidence that CD47 blockade can enhance the phagocytic potential of tumor-targeting immunotherapies such as tafasitamab and suggest that there is value in exploring the combination in the clinic.
EVALuna2:569373

Blocking of angiotensin II is more than blocking of transforming growth factor-β - Daniel, Christoph (Kidney International, 2008)
Fibrosis is a common feature of chronic kidney diseases that is mediated by matrix-producing myofibroblasts. One potential origin of myofibroblasts is epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. Transforming growth factor-β (TGF-β) is a key factor inducing EMT. Carvajal et al. demonstrate that angiotensin II induces EMT by classical stimulation of TGF-β and also by a TGF-β-independent pathway, both signaling via Smad molecules. Therefore, blockade of angiotensin II is more than lowering of blood pressure and inhibition of TGF-β stimulation.
Created from Fastlane, Scopus look-up

Blocking the CD47-Sirpa Axis Enhances Tafasitamab-Mediated Phagocytosis - Biedermann, Alexander; Mangelberger-Eberl, Doris; Mougiakakos, Dimitrios; Büttner-Herold, Maike; Flamann, Cindy; Kellner, Christian; Altmeyer, Sarah; Bittenbring, Joerg; Augsberger, Christian; Patra-Kneuer, Maria; Landgraf, Karin; Ilieva-Babinsky, Kristina; et al. (BLOOD, 2022)
CRIS-Team WoS Importer:2023-03-17

Blood group-specific apheresis in combination with daratumumab as a rescue therapy of acute antibody-mediated rejection in a case of ABO- and human leukocyte antigen-incompatible kidney transplantation - Süsal, Can C.; Kraft, Leonie; Ender, Andrea; Süsal, Caner; Schwenger, Amelie; Amann, Kerstin Ute; Böhmig, Georg A.; Schwenger, Vedat (SAGE Open Medical Case Reports, 2023)
We report a case of antibody-mediated rejection treated with the human CD38 monoclonal antibody daratumumab in a 58-year-old female patient with end-stage kidney disease due to autosomal dominant polycystic kidney disease who received an ABO- and human leukocyte antigen antibody-incompatible living donor kidney transplant. The patient experienced an episode of severe antibody-mediated rejection within the first week of transplantation. Blood-group-antibody selective immunoadsorption in combination with administration of four doses of daratumumab (each 1800 mg s.c.) led to a persistent decrease of ABO- and more interestingly donor-specific human leukocyte antigen antibody reactivity and resulted in clinical and histopathological remission with full recovery of graft function, which has remained stable until post-transplant day 212. This case illustrates the potential of targeting CD38 in antibody-mediated rejection.
CRIS-Team Scopus Importer:2023-11-24
Keywords: antibody-mediated rejection; blood-group incompatibility; Case report; daratumumab; HLA incompatibility; kidney transplantation; living-donor transplantation; rejection therapy

BLU-285-the breakthrough in treatment of patients with aggressive systemic mastocytosis and gastrointestinal stromal tumor - Schneider-Stock, Regine (Annals of Translational Medicine, 2018)
EVALuna2:205470

Blunted transcriptional response to skeletal muscle ischemia in rats with chronic kidney disease: potential role for impaired ischemia-induced angiogenesis - Heiß, Rafael; Fahlbusch, Fabian B.; Jacobi, Johannes; Daniel, Christoph; Ekici, Arif Bülent; Cordasic, Nada; Amann, Kerstin Ute; Hilgers, Karl Friedrich; Hartner, Andrea (Physiological Genomics, 2017)
Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Previous studies indicated an impairment of ischemia-induced angiogenesis in skeletal muscle of rats with CKD. We performed a systematic comparison of early gene expression in response to ischemia in rats with or without CKD to identify potential molecular mechanisms underlying impaired angiogenesis in CKD. CKD was induced in male rats by 5/6 nephrectomy (SNX); control rats were sham operated (sham). Eight weeks later, ischemia of the right limb was induced by ligation and resection of the femoral artery. Rats were sacrificed 24 hours after the onset of ischemia, and RNA was extracted from the musculus soleus of the ischemic and the nonischemic hindlimb. To identify differentially expressed transcripts, RNA was analyzed employing Affymetrix GeneChip Rat Genome 230 2.0 Arrays. RT-PCR analysis of selected genes was performed to validate observed changes. Hindlimb ischemia up-regulated 239 genes in CKD and 299 genes in control rats (66% overlap) whereas only a few genes were down-regulated (14 in CKD and 34 in controls), compared with the non-ischemic limb of the same animals. Comparison between the ischemic limbs of CKD and controls revealed down-regulation of 65 genes in CKD; 37 of these genes were also among the ischemia-induced genes in controls. Analysis of functional groups (other than angiogenesis) pointed to genes involved in leukocyte recruitment and fatty acid metabolism. Transcript expression profiling points to a relatively small number of differentially expressed genes which may underlie the impaired post-ischemic angiogenesis in CKD.
EVALuna2:3946

Bone Tissue Engineering Under Xenogeneic-Free Conditions in a Large Animal Model as a Basis for Early Clinical Applicability - Weigand, Annika; Beier, Justus; Schmid, Rafael; Knorr, Thomas; Kilian, David; Goetzl, Rebekka; Gerber, Thomas; Horch, Raymund E.; Boos, Anja (Tissue Engineering: Parts A, B, and C, 2017)
For decades, researchers have been developing a range of promising strategies in bone tissue engineering with the aim of producing a significant clinical benefit over existing therapies. However, a major problem concerns the traditional use of xenogeneic substances for the expansion of cells, which complicates direct clinical transfer. The study's aim was to establish a totally autologous sheep model as a basis for further preclinical studies and future clinical application. Ovine mesenchymal stromal cells (MSC) were cultivated in different concentrations (0%, 2%, 5%, 10%, and 25%) of either autologous serum (AS) or fetal calf serum (FCS). With an increase of serum concentration, enhanced metabolic activity and proliferation could be observed. There were minor differences between MSC cultivated in AS or FCS, comparing gene and protein expression of osteogenic and stem cell markers, morphology, and osteogenic differentiation. MSC implanted subcutaneously in the sheep model, together with a nanostructured bone substitute, either in stable block or moldable putty form, induced similar vascularization and remodeling of the bone substitute irrespective of cultivation of MSC in AS or FCS and osteogenic differentiation. The bone substitute in block form together with MSC proved particularly advantageous in the induction of ectopic bone formation compared to the cell-free control and putty form. It could be demonstrated that AS is suitable for replacement of FCS for cultivation of ovine MSC for bone tissue engineering purposes. Substantial progress has been made in the development of a strictly xenogeneic-free preclinical animal model to bring future clinical application of bone tissue engineering strategies within reach.
EVALuna2:32847

BRAF mutation testing in melanoma: results from a German observational multicenter study - Hartmann, Arndt; Schirmacher, Peter; Sterlacci, William; Koch, Winfried; Liesenfeld, David B.; Schif, Birgit; Garbe, Claus (Virchows Archiv, 2019)
Quality control of BRAF mutation testing methods used in routine practice is crucial for optimal treatment selection. In this prospective study, we assessed the impact of patient/sample characteristics on BRAF mutation testing results in patients with melanoma, during clinical practice. Data were collected on routine testing practices and documented mutation status in patients with melanoma stages IIIB, IIIC, or IV across 28 diagnostic pathology centers in Germany. Patient/sample data collected included: patient age, location of primary melanoma and metastases, origin of sample, melanoma subtype, and quality of tissue. Statistical influence of patient/sample characteristics on BRAF mutation rate was assessed using multiple logistic regression analyses and statistical models developed to predict the probability of BRAF mutations for individual patient cohorts. Data/samples from 642 patients with melanoma were analyzed. BRAF mutations were documented in 241/642 patients (37.5%). The primary statistical model to predict BRAF mutation rates included: age (continuous), origin of sample, method of mutation analysis, and quality of tissue. Analyses of post hoc collected data identified major deviations between documented mutation rates included in this study vs. routinely recorded mutation rates for three centers. When samples from these centers were excluded, the influence of testing method was no longer statistically significant. The final model included patient age, origin of sample (including metastasis location), and quality of tissue. Once validated in an independent population, this type of model could allow pathology centers to compare the performance of their testing methods with what would be expected based on patient, tumor, and sample characteristics.
EVALuna2:52992

Brain and breast cancer cells with pten loss of function reveal enhanced durotaxis and rhob dependent amoeboid migration utilizing 3d scaffolds and aligned microfiber tracts - Wieland, Annalena; Strissel, Pamela; Schorle, Hannah; Bakirci, Ezgi; Janzen, Dieter; Beckmann, Matthias; Eckstein, Markus; Dalton, Paul D.; Strick, Reiner (Cancers, 2021)
Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy.
CRIS-Team Scopus Importer:2021-10-29
Keywords: 3D microfiber; 3D tumor model; Amoeboid cell migration; Brain cancer; Breast cancer; Durotaxis; PTEN; RHO; ROCK; Topotaxis

Branchioma: immunohistochemical and molecular genetic study of 23 cases highlighting frequent loss of retinoblastoma 1 immunoexpression - Bradová, Martina; Thompson, Lester D.R.; Hyrcza, Martin; Vaněček, Tomáš; Grossman, Petr; Michal, Michael; Hájková, Veronika; Taheri, Touraj; Rupp, Niels; Suster, David; Lakhani, Sunil; Nikolov, Dimitar Hadži; et al. (Virchows Archiv, 2023)
Branchioma is an uncommon benign neoplasm with an adult male predominance, typically occurring in the lower neck region. Different names have been used for this entity in the past (ectopic hamartomatous thymoma, branchial anlage mixed tumor, thymic anlage tumor, biphenotypic branchioma), but currently, the term branchioma has been widely accepted. Branchioma is composed of endodermal and mesodermal lineage derivatives, in particular epithelial islands, spindle cells, and mature adipose tissue without preexistent thymic tissue or evidence of thymic differentiation. Twenty-three branchiomas were evaluated morphologically. Eighteen cases with sufficient tissue were assessed by immunohistochemistry, next-generation sequencing (NGS) using the Illumina Oncology TS500 panel, and fluorescence in situ hybridization (FISH) using an RB1 dual-color probe. All cases showed a biphasic morphology of epithelial and spindle cells with intermingled fatty tissue. Carcinoma arising in branchioma was detected in three cases. The neoplastic cells showed strong AE1/3 immunolabeling (100%), while the spindle cells expressed CD34, p63, and SMA (100%); AR was detected in 40–100% of nuclei (mean, 47%) in 14 cases. Rb1 showed nuclear loss in ≥ 95% of neoplastic cells in 16 cases (89%), while two cases revealed retained expression in 10–20% of tumor cell nuclei. NGS revealed a variable spectrum of likely pathogenic variants (n = 5) or variants of unknown clinical significance (n = 6). Loss of Rb1 was detected by FISH in two cases. Recent developments support branchioma as a true neoplasm, most likely derived from the rudimental embryological structures of endoderm and mesoderm. Frequent Rb1 loss by immunohistochemistry and heterozygous deletion by FISH is a real pitfall and potential confusion with other Rb1-deficient head and neck neoplasms (i.e., spindle cell lipoma), especially in small biopsy specimens.
CRIS-Team Scopus Importer:2023-11-24
Keywords: And neck; Branchioma; CD34; Ectopic hamartomatous thymoma; Head; RET; Retinoblastoma 1

Branchioma with a nested/organoid morphology: molecular profiling of a distinctive potentially misleading variant and reappraisal of potential relationship to CD34-positive/Rb1-deficient tumors of the neck. - Baněčková, Martina; Michal, Michael; Vaněček, Tomáš; Grossman, Petr; Nikolov, Dimitar Hadži; Včelák, Radek; Žalud, Radim; Michal, Michal; Agaimy, Abbas (Virchows Archiv, 2023)
Branchioma (previously called ectopic hamartomatous thymoma, branchial anlage mixed tumor, or thymic anlage tumor) is a rare lower neck lesion with an adult male predominance and an uncertain histogenesis. Except for 4 cases, all branchiomas described in the literature were benign. Recently, HRAS mutation was detected in one case, but still little is known about the molecular genetic background of this rare entity. We herein report the histological, immunohistochemical, and molecular genetic analysis of a branchioma with a nested/organoid (neuroendocrine-like) morphology in a 78-year-old man. Histology revealed classical branchioma areas merging with nested/organoid cellular component lacking conventional features of malignancy. Immunohistochemistry was positive for high-molecular-weight cytokeratins. CD34 was expressed in the spindle cell component. Moreover, the tumor cells showed near-complete loss of retinoblastoma (RB1) expression (<1% of cells positive). All neuroendocrine markers (synaptophysin, chromogranin, and INSM1) were negative. Next-generation sequencing (TSO500 Panel) revealed 5 pathogenic/likely pathogenic mutations including 1 mutation in KRAS and 2 different mutations in each of MSH6 and PTEN. FISH and DNA sequencing were negative for RB1 gene alterations. To our knowledge, this is the first report of a branchioma showing misleading nested/organoid morphology and the first report on Rb1 immunodeficiency in this entity, in addition to multiple gene mutations revealed by NGS.
EVALuna2:540021

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients - Wunderle, Marius; Gaß, Paul; Häberle, Lothar; Flesch, Vivien M.; Rauh, Claudia; Bani, Mayada; Hack, Carolin; Schrauder, Michael G.; Jud, Sebastian; Emons, Julius; Erber, Ramona; Ekici, Arif Bülent; et al. (Breast Cancer Research and Treatment, 2018)
PURPOSE: BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy. METHODS: Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival. RESULTS: Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as "ypT0; ypN0" was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26-4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status. CONCLUSIONS: BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.
EVALuna2:34606

Breast cancer risk - From genetics to molecular understanding of pathogenesis - Fasching, Peter; Ekici, Arif Bülent; Wachter, David Lukas; Hein, Alexander; Bayer, Christian M.; Häberle, Lothar; Löhberg, Christian; Schneider, Michael; Jud, Sebastian; Heusinger, K.; Rübner, Matthias; Rauh, Claudia; et al. (Geburtshilfe und Frauenheilkunde, 2013)
Several advancements over the last decade have triggered the developments in the field of breast cancer risk research. One of them is the availability of the human genome sequence along with cheap genotyping possibilities. Another is the globalization of research, which has led to the growth of research collaboration into large international consortia that facilitate the pooling of clinical and genotype data of hundreds of thousands of patients and healthy control individuals. This review concerns with the recent developments in breast cancer risk research and focuses on the discovery of new genetic breast cancer risk factors and their meaning in the context of established non-genetic risk factors. Finally the clinical application is highly dependent on the accuracy of breast cancer risk prediction models, not only for all breast cancer patients, but also for molecular subtypes, preferably for those which are associated with an unfavorable prognosis. Recently risk prediction incorporates all possible risk factors, which include epidemiological risk factors, mammographic density and genetic risk factors. © Georg Thieme Verlag KG Stuttgart• New York•.
CRIS-Team Scopus Importer:2021-07-19
Keywords: BRCA; breast cancer risk; gene-environment interaction; genetic risk factors; prediction models

Breast cancer risk - Genes, environment and clinics Mammakarzinomrisiko - Gene, Umwelt und Klinik - Fasching, Peter; Ekici, Arif Bülent; Adamietz, B. R.; Wachter, David Lukas; Hein, Alexander; Bayer, Christian M.; Häberle, Lothar; Löhberg, Christian; Jud, Sebastian; Heusinger, K.; Rübner, Matthias; Rauh, Claudia; et al. (Geburtshilfe und Frauenheilkunde, 2011)
The information available about breast cancer risk factors has increased dramatically during the last 10 years. In particular, studies of low-penetrance genes and mammographic density have improved our understanding of breast cancer risk. In addition, initial steps have been taken in investigating interactions between genes and environmental factors. This review concerns with actual data on this topic. Several genome-wide association studies (GWASs) with a casecontrol design, as well as large-scale validation studies, have identified and validated more than a dozen single nucleotide polymorphisms (SNPs) associated with breast cancer risk. They are located not only in or close to genes known to be involved in cancer pathogenesis, but also in genes not previously associated with breast cancer pathogenesis, or may even not be related to any genes. SNPs have also been identified that alter the lifetime risk in BRCA mutation carriers. With regard to nongenetic risk factors, studies of postmenopausal hormone replacement therapy (HRT) have revealed important information on how to weigh up the risks and benefits of HRT. Mammographic density (MD) has become an accepted and important breast cancer risk factor. Lifestyle and nutritional considerations have become an integral part of most studies of breast cancer risk, and some improvements have been made in this field as well. More than 10 years after the publication of the first breast cancer prevention studies with tamoxifen, other substances such as raloxifene and aromatase inhibitors have been investigated and have also been shown to have preventive potential. Finally, mammographic screening systems have been implemented in most Western countries during the last decade. These may be developed further by including more individualized methods of predicting the patients breast cancer risk. © Georg Thieme Verlag KG Stuttgart - New York.
CRIS-Team Scopus Importer:2021-07-19
Keywords: BRCA (breast cancer antigen); breast; breast feeding; CAM (Complementary and Alternative medicine); cancer registry; estrogen receptor

Breast MRI at Very Short TE (minTE): Image Analysis of minTE Sequences on Non-Fat-Saturated, Subtracted T1-Weighted Images - Wenkel, Evelyn; Janka, Rolf Matthias; Geppert, Christian; Kämmerer, Nadine; Hartmann, Arndt; Uder, Michael; Hammon, Matthias; Brand, Michael (Röfo-Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren, 2017)
Purpose The aim was to evaluate a minimum echo time (minTE) protocol for breast magnetic resonance imaging (MRI) in patients with breast lesions compared to a standard TE (nTE) time protocol. Methods Breasts of 144 women were examined with a 1.5 Tesla MRI scanner. Additionally to the standard gradient-echo sequence with nTE (4.8 ms), a variant with minimum TE (1.2 ms) was used in an interleaved fashion which leads to a better temporal resolution and should reduce the scan time by approximately 50 %. Lesion sizes were measured and the signal-to-noise ratio (SNR) as well as the contrast-to-noise ratio (CNR) were calculated. Subjective confidence was evaluated using a 3-point scale before looking at the nTE sequences (1 = very sure that I can identify a lesion and classify it, 2 = quite sure that I can identify a lesion and classify it, 3 = definitely want to see nTE for final assessment) and the subjective image quality of all examinations was evaluated using a four-grade scale (1 = sharp, 2 = slight blur, 3 = moderate blur and 4 = severe blur/not evaluable) for lesion and skin sharpness. Lesion morphology and contrast enhancement were also evaluated. Results With minTE sequences, no lesion was rated with "definitely want to see nTE sequences for final assessment". The difference of the longitudinal and transverse diameter did not differ significantly (p > 0.05). With minTE, lesions and skin were rated to be significantly more blurry (p < 0.01 for lesions and p < 0.05 for skin). There was no difference between both sequences with respect to SNR, CNR, lesion morphology, contrast enhancement and detection of multifocal disease. Conclusion Dynamic breast MRI with a minTE protocol is feasible without a major loss of information (SNR, CNR, lesion morphology, contrast enhancement and lesion sizes) and the temporal resolution can be increased by a factor of 2 using minTE sequences. Key points · Increase of temporal resolution for a better in-flow curve.. · Dynamic breast MRI with a shorter TE time is possible without relevant loss of information.. · Possible decrease of the overall scan time.. Citation Format · Wenkel E, Janka R, Geppert C et al. Breast MRI at Very Short TE (minTE): Image Analysis of minTE Sequences on Non-Fat-Saturated, Subtracted T1-Weighted Images. Fortschr Röntgenstr 2017; 189: 137 - 145.
EVALuna2:6843

Breast Tumor Analysis Using Shifted-Excitation Raman Difference Spectroscopy (SERDS) - Gebrekidan, Medhanie; Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Emons, Julius; Beckmann, Matthias; Bräuer, Andreas (Technology in Cancer Research & Treatment, 2018)
We used a shifted-excitation Raman difference spectroscopy method for the ex vivo classification of resected and formalin-fixed breast tissue samples as normal (healthy) tissue, fibroadenoma, or invasive carcinoma. We analyzed 8 tissue samples containing invasive carcinoma that were surrounded by normal tissue and 3 tissue samples with fibroadenoma only. We made various measurement sites on various tissue samples, in total 240 measurements for each type of tissue. Although the acquired raw spectra contain enough information to clearly differentiate between normal and tumor (fibroadenoma and invasive carcinoma) tissue, the differentiation between fibroadenoma and invasive carcinoma was possible only after the shifted-excitation Raman difference spectroscopy isolation of pure Raman spectra from the heavily fluorescence interfered raw spectra. We used 784 and 785 nm as excitation wavelengths for the shifted-excitation Raman difference spectroscopy method. The differences in the obtained pure Raman spectra are assigned to the different chemical compositions of normal breast tissue, fibroadenoma, and invasive breast carcinoma. Principal component analysis and linear discriminant analysis showed excellent classification results in the Raman shift range between 1000 and 1800 cm-1. Invasive breast carcinoma was identified with 99.15% sensitivity, and the absence of invasive carcinoma was identified with 90.40% specificity. Tumor tissue in tumor-containing tissue was identified with 100% sensitivity, and the absence of tumor in no-tumor containing tissue was identified with 100% specificity. As gold standard for the determination of the sensitivity and the specificity, we considered the conventional histopathological classification. In summary, shifted-excitation Raman difference spectroscopy could be potentially very useful to support histopathological diagnosis in breast pathology.
EVALuna2:34855

Breast Tumor Cell Survival and Morphology in a Brain-like Extracellular Matrix Depends on Matrix Composition and Mechanical Properties - Türker, Esra; Andrade Mier, Mateo S.; Faber, Jessica; Padilla Padilla, Selma J.; Murenu, Nicoletta; Stahlhut, Philipp; Lang, Gregor; Lamberger, Zan; Weigelt, Jeanette; Schaefer, Natascha; Tessmar, Jörg; Strissel, Pamela; et al. (Advanced Biology, 2024)
Triple-negative breast cancer (TNBC) is the most invasive type of breast cancer with high risk of brain metastasis. To better understand interactions between breast tumors with the brain extracellular matrix (ECM), a 3D cell culture model is implemented using a thiolated hyaluronic acid (HA-SH) based hydrogel. The latter is used as HA represents a major component of brain ECM. Melt-electrowritten (MEW) scaffolds of box- and triangular-shaped polycaprolactone (PCL) micro-fibers for hydrogel reinforcement are utilized. Two different molecular weight HA-SH materials (230 and 420 kDa) are used with elastic moduli of 148 ± 34 Pa (soft) and 1274 ± 440 Pa (stiff). Both hydrogels demonstrate similar porosities. The different molecular weight of HA-SH, however, significantly changes mechanical properties, e.g., stiffness, nonlinearity, and hysteresis. The breast tumor cell line MDA-MB-231 forms mainly multicellular aggregates in both HA-SH hydrogels but sustains high viability (75%). Supplementation of HA-SH hydrogels with ECM components does not affect gene expression but improves cell viability and impacts cellular distribution and morphology. The presence of other brain cell types further support numerous cell–cell interactions with tumor cells. In summary, the present 3D cell culture model represents a novel tool establishing a disease cell culture model in a systematic way.
CRIS-Team Scopus Importer:2024-07-19
Keywords: breast tumor cells; co-cultures; hyaluronic acid; Matrigel; PCL scaffolds

BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin-implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates - Wehrhan, Falk; Amann, Kerstin Ute; Moebius, Patrick; Weber, Manuel; Preidl, Raimund; Ries, Jutta; Stockmann, Philipp (Clinical Oral Investigations, 2015)
Site-specific suppression of bone remodelling has been implicated in bisphosphonate-(BP)-related osteonecrosis of the jaws (BRONJ). Due to the origin of jaw bone from cranial neural crest, osseous differentiation is regulated specifically by the antagonizing BMP-2-downstream-transcription factors Msx-1 and Dlx-5. Osteopontin has been implicated in bone remodelling and angiogenesis. The osteoblast and osteoclast progenitor proliferation mediating Msx-1 has been demonstrated to be suppressed in BRONJ. In vitro BPs were shown to increase Dlx-5 and to suppress osteopontin expression. This study targeted Dlx-5 and osteopontin in BRONJ-related and BP-exposed jaw bone compared with healthy jaw bone samples at protein- and messenger RNA (mRNA) level, since increased Dlx-5 and suppressed osteopontin might account for impaired bone turnover in BRONJ.Fifteen BRONJ-exposed, 15 BP-exposed and 20 healthy jaw bone samples were processed for real-time reverse transcription polymerase chain reaction (RT-PCR) and for immunohistochemistry. Targeting Dlx-5, osteopontin and glyceraldehyde 3-phosphate dehydrogenase mRNA was extracted, quantified by the LabChip-method, followed by quantitative RT-PCR. For immunohistochemistry, an autostaining-based alkaline phosphatase antialkaline phosphatase (APAPP) staining kit was used. Semiquantitative assessment was performed measuring the ratio of stained cells/total number of cells (labelling index, Bonferroni adjustment).The labelling index was significant decreased for osteopontin (p < 0.017) and significantly increased for Dlx-5 (p < 0.021) in BRONJ samples. In BRONJ specimens, a significant fivefold decrease in gene expression for osteopontin (p < 0.015) and a significant eightfold increase in Dlx-5 expression (p < 0.012) were found.BRONJ-related suppression of bone turnover is consistent with increased Dlx-5 expression and with suppression of osteopontin. The BP-related impaired BMP-2-Msx-1-Dlx-5 axis might explain the jaw bone specific alteration by BP.The findings of this study help to explain the restriction of RONJ to craniofacial bones. BRONJ might serve as a model of disease elucidating the specific signal transduction of neural crest cell-derived bone structures in health and disease.
EVALuna2:24383

Brown bowel syndrome: a rare complication in diseases associated with long-standing malabsorption - Albrecht, Heinz; Hagel, Alexander; De Rossi, Thomas; Rau, Tilman; Kirchner, Thomas; Neurath, Markus; Raithel, Martin (Digestion, 2014)
Longtime chronic malabsorption may among other things cause a lack of liposoluble vitamins. Vitamin E deficiency can lead to formation of lipofuscin aggregates. Its deficiency is also associated with an increased lipofuscinosis of the bowel, i.e. brown bowel syndrome.Systematic research via Medline on brown bowel syndrome, lipofuscinosis, and vitamin E deficiency was performed. We combined our own clinical experience and a review of the literature for this paper. Its goal is to inform about the possible consequences of severe malabsorption and brown bowel syndrome.Systematic data about the occurrence of severe malabsorption and brown bowel syndrome are rare. Only about 27 scientific reports can be found on this subject. Brown bowel syndrome is found mostly in conjunction with vitamin E deficiency and lipofuscinosis of the bowel. The clinical findings are caused by both malabsorption and lipofuscinosis. Case reports show a therapeutic effect of vitamin E.Vitamin deficiency caused by longtime chronic malabsorption can lead to the development of brown bowel syndrome, which is seen as the expression of lipofuscinosis of the bowel, and can cause further clinical disorders. Patients with malabsorption should therefore be monitored regarding their vitamin E levels.
EVALuna2:1837

Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome - Kroeller, Sarah; Wissuwa, Bianka; Dennhardt, Sophie; Krieg, Nadine; Thiemermann, Christoph; Daniel, Christoph; Amann, Kerstin Ute; Gunzer, Florian; Coldewey, Sina M. (Frontiers in Immunology, 2023)
Hemolytic-uremic syndrome (HUS) can occur as a complication of an infection with Shiga-toxin (Stx)-producing Escherichia coli. Patients typically present with acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia. There is evidence that Stx-induced renal damage propagates a pro-inflammatory response. To date, therapy is limited to organ-supportive strategies. Bruton’s tyrosine kinase (BTK) plays a pivotal role in recruitment and function of immune cells and its inhibition was recently shown to improve renal function in experimental sepsis and lupus nephritis. We hypothesized that attenuating the evoked immune response by BTK-inhibitors (BTKi) ameliorates outcome in HUS. We investigated the effect of daily oral administration of the BTKi ibrutinib (30 mg/kg) and acalabrutinib (3 mg/kg) in mice with Stx-induced HUS at day 7. After BTKi administration, we observed attenuated disease progression in mice with HUS. These findings were associated with less BTK and downstream phospholipase-C-gamma-2 activation in the spleen and, subsequently, a reduced renal invasion of BTK-positive cells including neutrophils. Only ibrutinib treatment diminished renal invasion of macrophages, improved acute kidney injury and dysfunction (plasma levels of NGAL and urea) and reduced hemolysis (plasma levels of bilirubin and LDH activity). In conclusion, we report here for the first time that BTK inhibition attenuates the course of disease in murine HUS. We suggest that the observed reduction of renal immune cell invasion contributes – at least in part – to this effect. Further translational studies are needed to evaluate BTK as a potential target for HUS therapy to overcome currently limited treatment options.
CRIS-Team Scopus Importer:2023-03-24
Keywords: acalabrutinib; acute kidney injury; animal model; Bruton’s tyrosine kinase; hemolytic-uremic syndrome; ibrutinib; inflammation

Built to Last? Reproducibility and Reusability of Deep Learning Algorithms in Computational Pathology. - Wagner, Sophia J.; Matek, Christian; Shetab Boushehri, Sayedali; Boxberg, Melanie; Lamm, Lorenz; Sadafi, Ario; Winter, Dominik J.E.; Marr, Carsten; Peng, Tingying (Modern Pathology, 2024)
Recent progress in computational pathology has been driven by deep learning. While code and data availability are essential to reproduce findings from preceding publications, ensuring a deep learning model's reusability is more challenging. For that, the codebase should be well-documented and easy to integrate into existing workflows and models should be robust toward noise and generalizable toward data from different sources. Strikingly, only a few computational pathology algorithms have been reused by other researchers so far, let alone employed in a clinical setting. To assess the current state of reproducibility and reusability of computational pathology algorithms, we evaluated peer-reviewed articles available in PubMed, published between January 2019 and March 2021, in 5 use cases: stain normalization; tissue type segmentation; evaluation of cell-level features; genetic alteration prediction; and inference of grading, staging, and prognostic information. We compiled criteria for data and code availability and statistical result analysis and assessed them in 160 publications. We found that only one-quarter (41 of 160 publications) made code publicly available. Among these 41 studies, three-quarters (30 of 41) analyzed their results statistically, half of them (20 of 41) released their trained model weights, and approximately a third (16 of 41) used an independent cohort for evaluation. Our review is intended for both pathologists interested in deep learning and researchers applying algorithms to computational pathology challenges. We provide a detailed overview of publications with published code in the field, list reusable data handling tools, and provide criteria for reproducibility and reusability.
EVALuna2:546414

Calbindin D28k-Immunoreactivity in Human Enteric Neurons - Zetzmann, Katharina; Strehl, Johanna; Geppert, Carol-Immanuel; Kürten, Stefanie; Jabari, Samir; Brehmer, Axel (International Journal of Molecular Sciences, 2018)
Calbindin (CALB) is well established as immunohistochemical marker for intrinsic primary afferent neurons in the guinea pig gut. Its expression by numerous human enteric neurons has been demonstrated but little is known about particular types of neurons immunoreactive for CALB. Here we investigated small and large intestinal wholemount sets of 26 tumor patients in order to evaluate (1) the proportion of CALB⁺ neurons in the total neuron population, (2) the colocalization of CALB with calretinin (CALR), somatostatin (SOM) and vasoactive intestinal peptide (VIP) and (3) the morphology of CALB+ neurons. CALB+ neurons represented a minority of myenteric neurons (small intestine: 31%; large intestine: 25%) and the majority of submucosal neurons (between 72 and 95%). In the submucosa, most CALB⁺ neurons co-stained for CALR and VIP (between 69 and 80%) or for SOM (between 20 and 3%). In the myenteric plexus, 85% of CALB+ neurons did not co-stain with the other markers investigated. An unequivocal correlation between CALB reactivity and neuronal morphology was found for myenteric type III neurons in the small intestine: uniaxonal neurons with long, slender and branched dendrites were generally positive for CALB. Since also other neurons displayed occasional CALB reactivity, this protein is not suited as an exclusive marker for type III neurons.
EVALuna2:34063

Calcification in Salivary Gland Cancer Mimicking Sialolithiasis-A Diagnostic Pitfall on Imaging: Report of Two Cases and Brief Review of the Literature - Thimsen, Vivian; Fauck, Vanessa; Wiesmüller, Marco; Agaimy, Abbas; Schapher, Mirco; Iro, Heinrich; Koch, Michael; Mantsopoulos, Konstantinos (Journal of Clinical Medicine, 2022)
Objectives: Sialolithiasis is the most common cause of calcifications detected with ultrasound in patients with chronic inflammatory symptoms and swellings of the salivary glands. Other differential diagnoses of calcifications are extremely rare and mostly benign. Methods: Case report and literature review. Results: Two rare cases of malignant parotid gland tumors with calcifications in a localization typical for sialolithiasis, which were mistaken for salivary calculi based on image findings, are presented. Conclusions: This report intends to highlight the pitfalls in the imaging of parotid gland diseases. Even if malignant tumors of the parotid gland with calcifications are extremely rare, in ambiguous cases, differential diagnoses should be considered carefully. A high suspicion index of the need for further diagnostics in cases with calcifications is practical and could include missing periprandial symptoms, no obstruction signs in the proximal duct, and missing evidence of sialolithiasis in sialendoscopy.
CRIS-Team WoS Importer:2022-07-08

Calcified Amorphous Tumor and Granulomatosis with Polyangiitis—Case Report and Systematic Review of the Literature - Suleiman, Mathieu; Agaimy, Abbas; Dewald, Oliver; Kaemmerer-Suleiman, Ann-Sophie; Mellert, Fritz; Weyand, Michael; Harig, Frank (Journal of Clinical Medicine, 2025)
Background: Calcified amorphous tumor (CAT) is a rare, mostly incidental tumor-like cardiac lesion of unknown histogenesis. Current imaging modalities do not differentiate between CAT and other masses. As it can be a source for embolization, surgical excision of CAT is mandatory. CAT in patients with Granulomatosis with polyangiitis (GPA) is exceedingly rare. Methods: This systematic literature review was prompted by the case of a CAT in a patient with GPA. The search of all types of studies in two databases (PubMed and Scopus) was conducted through November 2024 to identify the relevant studies. Results: Nine studies were included describing cases of patients being diagnosed with GPA and a cardiac mass. All included patients had a histopathological examination of the either biopsied or surgically resected mass. Only one case reported a CAT. In our case, the patient was diagnosed with GPA through a kidney biopsy, whereas a cardiac mass in the right atrium was diagnosed by echocardiography during evaluation for possible kidney transplantation. One year later a progression was observed, and the mass was resected. The histopathological examination revealed a CAT. The patient could be successfully discharged in a good clinical condition. Conclusions: This systematic literature search and case report highlight the importance of regular echocardiographic examination in patients with GPA. Moreover, surgical excision is crucial for the diagnosis and for further therapy planning, regardless of whether the mass is neoplastic or not.
CRIS-Team Scopus Importer:2025-01-31
Keywords: calcified amorphous tumors; cardiac mass; CAT; granulomatosis with polyangiitis (GPA); Wegener’s granulomatosis

Calcium supplementation of bioinks reduces shear stress-induced cell damage during bioprinting - Fischer, Lena; Nosratlo, Mojtaba; Hast, Katharina; Karakaya, Emine; Ströhlein, Nadi; Esser, Tilman; Gerum, Richard; Richter, Sebastian; Engel, Felix; Detsch, Rainer; Fabry, Ben; Thievessen, Ingo (Biofabrication, 2022)
During bioprinting, cells are suspended in a viscous bioink and extruded under pressure through small diameter printing needles. The combination of high pressure and small needle diameter exposes cells to considerable shear stress, which can lead to cell damage and death. Approaches to monitor and control shear stress-induced cell damage are currently not well established. To visualize the effects of printing-induced shear stress on plasma membrane integrity, we add FM 1-43 to the bioink, a styryl dye that becomes fluorescent when bound to lipid membranes, such as the cellular plasma membrane. Upon plasma membrane disruption, the dye enters the cell and also stains intracellular membranes. Extrusion of alginate-suspended NIH/3T3 cells through a 200 mu m printing needle led to an increased FM 1-43 incorporation at high pressure, demonstrating that typical shear stresses during bioprinting can transiently damage the plasma membrane. Cell imaging in a microfluidic channel confirmed that FM 1-43 incorporation is caused by cell strain. Notably, high printing pressure also impaired cell survival in bioprinting experiments. Using cell types of different stiffnesses, we find that shear stress-induced cell strain, FM 1-43 incorporation and cell death were reduced in stiffer compared to softer cell types and demonstrate that cell damage and death correlate with shear stress-induced cell deformation. Importantly, supplementation of the suspension medium with physiological concentrations of CaCl2 greatly reduced shear stress-induced cell damage and death but not cell deformation. As the sudden influx of calcium ions is known to induce rapid cellular vesicle exocytosis and subsequent actin polymerization in the cell cortex, we hypothesize that calcium supplementation facilitates the rapid resealing of plasma membrane damage sites. We recommend that bioinks should be routinely supplemented with physiological concentrations of calcium ions to reduce shear stress-induced cell damage and death during extrusion bioprinting.
CRIS-Team WoS Importer:2022-08-26

Can clinicopathological parameters predict for lymph node metastases in ypT0-2 rectal carcinoma? Results of the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 phase 3 trials - Von Den Gruen, Jens Mueller; Hartmann, Arndt; Fietkau, Rainer; Ghadimi, Michael; Liersch, Torsten; Hohenberger, Werner; Weitz, Jurgen; Sauer, Rolf; Wittekind, Christian; Stroebel, Philipp; Roedel, Claus; Fokas, Emmanouil (Radiotherapy and Oncology, 2018)
BACKGROUND: The advent of less radical surgical approaches has generated concern about leaving locoregional lymph node metastases (LNM) unresected that could lead to adverse outcome. We examined the prognostic role of clinicopathological factors for ypN-positivity in patients with ypT0-2 rectal carcinoma treated within the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 randomized phase 3 trials. METHODS: The correlation of clinicopathological factors with ypN-status (ypN0 vs ypN1/2) was examined in n = 776 patients with ypT0-2 rectal carcinoma after preoperative CRT and total mesorectal excision surgery using Pearson's Chi-squared test for categorical variables and Kruskal-Wallis' test for continuous variables. Multivariable analysis was performed using binary logistic regression to identify independent prognosticators for ypN-positivity. RESULTS: Residual LNM (ypN+) were found in 6%, 20.8% and 21.4% of patients with ypT0, ypT1 and ypT2 carcinomas, respectively. Independent prognosticators for LNM were advanced ypT category (p = 0.002) and lymphatic invasion (p = 0.020). In a separate multivariable analysis performed upon exclusion of ypT-category due to multicollinearity with residual tumor diameter (RTD), lymphatic invasion (p = 0.015) and RTD ≥10 mm (p = 0.005) demonstrated strong correlation with LNM. CONCLUSION: Advanced ypT-stage, lymphatic invasion and RTD ≥10 mm were prognostic factors for LNM in patients ypT0-2 rectal carcinoma treated with CRT and surgery within both phase 3 trials. The high incidence of LNM in the ypT1-2 group needs to be taken into consideration in the context of oncological safety and indicate that LE should be advocated with great caution in this patient subgroup. The prognostic pathological factor identified here could help guide decision of LE vs TME after standard CRT.
EVALuna2:34854

Can Gene Expression Analysis in Zero-Time Biopsies Predict Kidney Transplant Rejection? - Vonbrunn, Eva; Angeloni, Miriam; Büttner-Herold, Maike; Müller-Deile, Janina; Heller, Katharina M.; Bleich, Erik; Söllner, Stefan; Amann, Kerstin Ute; Ferrazzi, Fulvia; Daniel, Christoph (Frontiers in Medicine, 2022)
Zero-time biopsies are taken to determine the quality of the donor organ at the time of transplantation. Histological analyses alone have so far not been able to identify parameters that allow the prediction of subsequent rejection episodes or graft survival. This study investigated whether gene expression analyses of zero-time biopsies might support this prediction. Using a well-characterized cohort of 26 zero-time biopsies from renal transplant patients that include 4 living donor (LD) and 22 deceased donor (DD) biopsies that later developed no rejection (Ctrl, n = 7), delayed graft function (DGF, n = 4), cellular (T-cell mediated rejection; TCMR, n = 8), or antibody-mediated rejection (ABMR, n = 7), we analyzed gene expression profiles for different types of subsequent renal transplant complication. To this end, RNA was isolated from formalin-fixed, paraffin-embedded (FFPE) sections and gene expression profiles were quantified. Results were correlated with transplant data and B-cell, and plasma cell infiltration was assessed by immunofluorescence microscopy. Both principal component analysis and clustering analysis of gene expression data revealed marked separation between LDs and DDs. Differential expression analysis identified 185 significant differentially expressed genes (adjusted p < 0.05). The expression of 68% of these genes significantly correlated with cold ischemia time (CIT). Furthermore, immunoglobulins were differentially expressed in zero-time biopsies from transplants later developing rejection (TCMR + ABMR) compared to non-rejected (Ctrl + DGF) transplants. In addition, immunoglobulin expression did not correlate with CIT but was increased in transplants with previous acute renal failure (ARF). In conclusion, gene expression profiles in zero-time biopsies derived from LDs are markedly different from those of DDs. Pre-transplant ARF increased immunoglobulin expression, which might be involved in triggering later rejection events. However, these findings must be confirmed in larger cohorts and the role of early immunoglobulin upregulation in zero-biopsies needs further clarification.
CRIS-Team Scopus Importer:2022-04-29
Keywords: inflammation; kidney transplantation; mRNA expression; outcome; zero-time biopsy

Can local excision be safely recommended in patients with ypT0-2 rectal cancer after chemoradiotherapy? Clinicopathological results of the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 randomized phase 3 trials - Von Den Gruen, Mueller J.; Hartmann, Arndt; Fietkau, Rainer; Ghadimi, M.; Liersch, T.; Stroebel, P.; Sauer, Rolf; Roedel, C.; Fokas, E. (2018)
EVALuna2:36508

Cap polyposis in children: case report and literature review - Brunner, Maximilian; Agaimy, Abbas; Atreya, Raja; Grützmann, Robert; Matzel, Klaus E. (International Journal of Colorectal Disease, 2019)
PURPOSE: Cap polyposis is a benign disease of the colon, characterized by inflammatory polyps with a "cap" of inflammatory granulation tissue. Its prevalence is very low, especially in children. METHODS AND RESULTS: A 16-year-old girl presented with frequent bowel movements with mucous discharge and bloody stool, leading to the initial suspicion of chronic inflammatory bowel disease. Results of further investigation by endoscopy and histological examination were consistent with a diagnosis of cap polyposis. Treatment with systemic steroids resulted in symptom improvement. CONCLUSION: A review of the literature shows that cap polyposis can occur at any age, including childhood, with a slight predilection for the male gender. Rectal bleeding and rectal polyps are consistent features in all reported cases. Other typical symptoms include constipation, diarrhea, and abdominal pain. Symptoms may be very similar to those of chronic inflammatory bowel disease, the most important differential diagnosis. The cause of cap polyposis is still unclear, and specific therapy has not as yet been established. Conservative therapeutic measures should be preferred, especially in children.
EVALuna2:52991

Carbon nanotube doped pericardial matrix derived electroconductive biohybrid hydrogel for cardiac tissue engineering - Roshanbinfar, Kaveh; Mohammadi, Zahra; Sheikh-Mahdi Mesgar, Abdorreza; Dehghan, Mohammad Mehdi; Oommen, Oommen P.; Hilborn, Jöns; Engel, Felix (Biomaterials Science, 2019)
Cardiovascular diseases represent a major socio-economic burden. In recent years, considerable effort has been invested in optimizing cell delivery strategies to advance cell transplantation therapies to restore heart function for example after an infarct. A particular issue is that the implantation of cells using a non-electroconductive matrix potentially causes arrhythmia. Here, we demonstrate that our hydrazide-functionalized nanotubes-pericardial matrix-derived electroconductive biohybrid hydrogel provides a suitable environment for maturation of human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. hiPSC-derived cardiomyocytes exhibited an improved contraction amplitude (>500%) on conductive hydrogels compared to cells cultured on Matrigel®. This was accompanied by increased cellular alignment, enhanced connexin 43 expression, and improved sarcomere organization suggesting maturation of the hiPSC-derived cardiomyocytes. Sarcomeric length of these cells increased from 1.3 to 1.7 μm. Moreover, 3D cell-laden engineered tissues exhibited enhanced calcium handling as well as positive response to external electrical and pharmaceutical stimulation. Collectively, our data indicate that our biohybrid hydrogels consisting of solubilized nanostructured pericardial matrix and electroconductive positively charged hydrazide-conjugated carbon nanotubes provide a promising material for stem cell-based cardiac tissue engineering.
CRIS-Team Scopus Importer:2019-09-03

Carborane-Based Analogues of 5-Lipoxygenase Inhibitors Co-inhibit Heat Shock Protein 90 in HCT116 Cells - Kuhnert, Robert; Sarosi, Menyhart-Botond; George, Sven; Loennecke, Peter; Hofmann, Bettina; Steinhilber, Dieter; Steinmann, Sara; Schneider-Stock, Regine; Murganic, Blagoje; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela; Hey-Hawkins, Evamarie (ChemMedChem, 2019)
5-Lipoxygenase converts arachidonic acid into leukotrienes, which are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. Herein we report the syntheses of several carborane-based inhibitors of the 5-lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity toward several melanoma and colon cancer cell lines. For the colon cancer cell line HCT116, the co-inhibition of heat shock protein 90 was observed.
EVALuna2:205466

Cardiac injury of the newborn mammalian heart accelerates cardiomyocyte terminal differentiation - Zebrowski, David; Jensen, Charlotte H.; Becker, Robert; Ferrazzi, Fulvia; Baun, Christina; Hvidsten, Svend; Sheikh, Soren P.; Polizzotti, Brian D.; Andersen, Ditte C.; Engel, Felix (Scientific Reports, 2017)
After birth cardiomyocytes undergo terminal differentiation, characterized by binucleation and centrosome disassembly, rendering the heart unable to regenerate. Yet, it has been suggested that newborn mammals regenerate their hearts after apical resection by cardiomyocyte proliferation. Thus, we tested the hypothesis that apical resection either inhibits, delays, or reverses cardiomyocyte centrosome disassembly and binucleation. Our data show that apical resection rather transiently accelerates centrosome disassembly as well as the rate of binucleation. Consistent with the nearly 2-fold increased rate of binucleation there was a nearly 2-fold increase in the number of cardiomyocytes in mitosis indicating that the majority of injury-induced cardiomyocyte cell cycle activity results in binucleation, not proliferation. Concurrently, cardiomyocytes undergoing cytokinesis from embryonic hearts exhibited midbody formation consistent with successful abscission, whereas those from 3 day-old cardiomyocytes after apical resection exhibited midbody formation consistent with abscission failure. Lastly, injured hearts failed to fully regenerate as evidenced by persistent scarring and reduced wall motion. Collectively, these data suggest that should a regenerative program exist in the newborn mammalian heart, it is quickly curtailed by developmental mechanisms that render cardiomyocytes post-mitotic.
EVALuna2:9380

Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression - Leone, Marina; Musa, Gentian; Engel, Felix (Cardiovascular Research, 2018)
Aims After birth mammalian cardiomyocytes initiate a last cell cycle which results in binucleation due to cytokinesis failure. Despite its importance for cardiac regenerative therapies, this process is poorly understood. Here, we aimed at a better understanding of the difference between cardiomyocyte proliferation and binucleation and providing a new tool to distinguish these two processes.Methods and results Monitoring of cell division by time-lapse imaging revealed that rat cardiomyocyte binucleation stems from a failure to properly ingress the cleavage furrow. Astral microtubule required for actomyosin ring anchorage and thus furrow ingression were not symmetrically distributed at the periphery of the equatorial region during anaphase in binucleating cardiomyocytes. Consequently, RhoA, the master regulator of actomyosin ring formation and constriction, non-muscle myosin IIB, a central component of the actomyosin ring, as well as IQGAP3 were abnormally localized during cytokinesis. In agreement with improper furrow ingression, binucleation in vitro and in vivo was associated with a failure of RhoA and IQGAP3 to localize to the stembody of the midbody.Conclusion Taken together, these results indicate that naturally occurring cytokinesis failure in primary cardiomyocytes is due to an aberrant mitotic microtubule apparatus resulting in inefficient anchorage of the actomyosin ring to the plasma cell membrane. Thus, cardiomyocyte binucleation and division can be discriminated by the analysis of RhoA as well as IQGAP3 localization.
Keywords: IQGAP3; RhoA; Actomyosin ring; Cardiomyocytes; Microtubules

Cardiomyocyte Cell-Cycle Activity during Preadolescence - Soonpaa, Mark H.; Zebrowski, David; Platt, Colin; Rosenzweig, Anthony; Engel, Felix; Field, Loren J. (Cell, 2015)
EVALuna2:25501

Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations - Leone, Marina; Magadum, Ajit; Engel, Felix (American Journal of Physiology-Heart and Circulatory Physiology, 2015)
The newt and the zebrafish have the ability to regenerate many of their tissues and organs including the heart. Thus, a major goal in experimental medicine is to elucidate the molecular mechanisms underlying the regenerative capacity of these species. A wide variety of experiments have demonstrated that naturally occurring heart regeneration relies on cardiomyocyte proliferation. Thus, major efforts have been invested to induce proliferation of mammalian cardiomyocytes in order to improve cardiac function after injury or to protect the heart from further functional deterioration. In this review, we describe and analyze methods currently used to evaluate cardiomyocyte proliferation. In addition, we summarize the literature on naturally occurring heart regeneration. Our analysis highlights that newt and zebrafish heart regeneration relies on factors that are also utilized in cardiomyocyte proliferation during mammalian fetal development. Most of these factors have, however, failed to induce adult mammalian cardiomyocyte proliferation. Finally, our analysis of mammalian neonatal heart regeneration indicates experiments that could resolve conflicting results in the literature, such as binucleation assays and clonal analysis. Collectively, cardiac regeneration based on cardiomyocyte proliferation is a promising approach for improving adult human cardiac function after injury, but it is important to elucidate the mechanisms arresting mammalian cardiomyocyte proliferation after birth and to utilize better assays to determine formation of new muscle mass.
EVALuna2:25502

Cardiovascular changes in the NZB/W F1 mouse model of lupus nephritis - Böhme, Romy; Daniel, Christoph; Ferrazzi, Fulvia; Angeloni, Miriam; Ekici, Arif Bülent; Winkler, Thomas; Hilgers, Karl Friedrich; Wellmann, Ute; Voll, Reinhard E.; Amann, Kerstin Ute (Frontiers in Cardiovascular Medicine, 2023)
Background: Patients with systemic lupus erythematosus (SLE), an autoimmune disease, have a higher risk of cardiovascular (CV) disease and death. In addition, up to 40%–50% of SLE patients develop lupus nephritis (LN) and chronic kidney disease, which is an additional CV risk factor. Thus, the individual contributions of LN and other SLE-specific factors to CV events are unclear. Methods: In this study, we investigated the effect of LN on the development of CV changes using the female NZBxNZW F1 (NZB/W) mouse model of lupus-like disease, with female NZW mice as controls. Standard serologic, morphologic, immunohistologic, and molecular analyses were performed. In a separate group of NZB/W mice, systolic blood pressure (BP) was measured during the course of the disease using tail plethysmography. Results: Our data show marked CV changes in NZB/W mice, i.e., increased heart weight, hypertrophy of the left ventricle (LV) and septum, and increased wall thickness of the intramyocardial arteries and the aorta, which correlated with the progression of renal damage, but not with the age of the mice. In addition, systolic BP was increased in NZB/W mice only when kidney damage progressed and proteinuria was present. Pathway analysis based on gene expression data revealed a significant upregulation of the response to interferon beta in NZB/W mice with moderate kidney injury compared with NZB mice. Furthermore, IFI202b and IL-6 mRNA expression is correlated with CV changes. Multiple linear regression analysis demonstrated serum urea as a surrogate marker of kidney function and IFI202b expression as an independent predictor for LV wall thickness. In addition, deposition of complement factors CFD and C3c in hearts from NZB/W mice was seen, which correlated with the severity of kidney disease. Conclusions: Thus, we postulate that the pathogenesis of CV disease in SLE is affected by renal impairment, i.e., LN, but it can also be partly influenced by lupus-specific cardiac expression of pro-inflammatory factors and complement deposition.
CRIS-Team Scopus Importer:2023-08-18
Keywords: autoimmune disease; cardiovascular disease; IL-15; interferon-related; renal disease; systemic lupus erythematosus

Case History Report: Immediate Rehabilitation with a Prefabricated Fibula Flap Following Removal of a Locally Aggressive Maxillary Tumor - Nkenke, Emeka; Agaimy, Abbas; Vairaktaris, Elefterios; Lell, Michael; von Wilmowsky, Cornelius; Eitner, Stephan (International Journal of Prosthodontics, 2016)
The present clinical case history report describes an interdisciplinary treatment protocol that combines maxillary tumor resection with immediate reconstruction to achieve functional rehabilitation. A fibula flap that received four dental implants and a split-thickness graft epithelial layer was prefabricated for a 31-year-old man. The flap was designed so that it could be adapted to fit in different extents of tumor resection. Resection and immediate reconstruction were successfully performed 6 weeks after flap prefabrication, with the final bar-retained dental prosthesis delivered 4 weeks later.
EVALuna2:6763

Case Report: IBD-like colitis following CAR T cell therapy for diffuse large B cell lymphoma - Zundler, Sebastian; Vitali, Francesco; Kharboutli, Soraya; Völkl, Simon; Polifka, Iris; Mackensen, Andreas; Atreya, Raja; Neurath, Markus; Mougiakakos, Dimitrios (Frontiers in Oncology, 2023)
Chimeric antigen receptor (CAR) T cell therapy has become a new mainstay in the treatment of several hematologic malignancies, but the spectrum of associated complications is still incompletely defined. Here, we report the case of a 70-year-old female patient treated with tisagenlecleucel for diffuse large B cell lymphoma (DLBCL), who developed chronic diarrhea with characteristics of inflammatory bowel disease (IBD)-like colitis. CAR T cells were substantially enriched in the colon lamina propria and other diagnoses were ruled out. Thus, we conclude that IBD-like colitis in this patient was associated to CAR T cell therapy and needs to be considered as a rare potential complication.
CRIS-Team Scopus Importer:2023-06-16
Keywords: CAR T cells; case report; diffuse large B cell lymphoma; inflammatory bowel disease (IBD); tisagenlecleucel

Case report: Immunovirotherapy as a novel add-on treatment in a patient with thoracic NUT carcinoma - Kloker, Linus D.; Calukovic, Branko; Benzler, Katrin; Golf, Alexander; Böhm, Sebastian; Günther, Sven; Horger, Marius; Haas, Simone; Berchtold, Susanne; Beil, Julia; Carter, Mary E.; Ganzenmueller, Tina; et al. (Frontiers in Oncology, 2022)
NUT carcinoma (NC) is a rare and extremely aggressive form of cancer, usually presenting with intrathoracic or neck manifestations in adolescents and young adults. With no established standard therapy regimen and a median overall survival of only 6.5 months, there is a huge need for innovative treatment options. As NC is genetically driven by a single aberrant fusion oncoprotein, it is generally characterized by a low tumor mutational burden, thus making it immunologically cold and insusceptible to conventional immunotherapy. Recently, we have demonstrated that oncolytic viruses (OVs) are able to specifically infect and lyse NC cells, thereby turning an immunologically cold tumor microenvironment into a hot one. Here, we report an intensive multimodal treatment approach employing for the first time an OV (talimogene laherparepvec (T-VEC); IMLYGIC®) together with the immune checkpoint inhibitor pembrolizumab as an add-on to a basic NC therapy (cytostatic chemotherapy, radiation therapy, epigenetic therapy) in a patient suffering from a large thoracic NC tumor which exhibits an aberrant, unique BRD3:NUTM1 fusion. This case demonstrates for the first time the feasibility of this innovative add-on immunovirotherapy regimen with a profound, repetitive and durable replication of T-VEC that is instrumental in achieving tumor stabilization and improvement in the patient´s quality of life. Further, a previously unknown BRD3:NUTM1 fusion gene was discovered that lacks the extraterminal domain of BRD3.
CRIS-Team Scopus Importer:2022-11-25
Keywords: BRD3; chemotherapy; immunotherapy; NUT carcinoma; NUTM1; T-VEC; virotherapy

Case report: Patient specific combination of surgery and immunotherapy in advanced squamous cell carcinoma of the head and neck – a case series and review of literature - Olmos, Manuel; Lutz, Rainer; Büntemeyer, Tjark-Ole; Glajzer, Jacek; Nobis, Christopher-Philipp; Ries, Jutta; Möst, Tobias; Eckstein, Markus; Hecht, Markus; Gostian, Antoniu-Oreste; Erdmann, Michael; Foerster, Yannick; et al. (Frontiers in Immunology, 2022)
Background: Prognosis of patients with recurrent or metastatic head and neck cancer is generally poor. Adjuvant immunotherapy (IT) featuring immune checkpoint inhibition (ICI) is standard of care in advanced stage head and neck squamous cell carcinoma (HNSCC) and cutaneous squamous cell carcinoma (CSCC). ICI response rates in CSCC are described as higher than in HNSCC. IT is constantly shifting into earlier disease stages which confronts the surgeon with immunotherapeutically pre-treated patients. It is therefore becoming increasingly difficult to assess which patients with symptomatic tumor disease and a lack of curative surgical option might benefit from salvage surgery. Case presentations: The following 6 cases describe therapeutic decision-making regarding ICI and (salvage) surgery in patients with advanced stage HNSCC or CSCC. Cases A and B focus on neoadjuvant ICI followed by salvage surgery. In Cases C and D salvage surgery was performed after short-term stabilization with partial response to ICI. The last two cases (Cases E and F) address the surgical approach after failure of ICI. All cases are discussed in the context of the current study landscape and with focus on individual decision-making. For better understanding, a timetable of the clinical course is given for each case. Conclusions: ICI is rapidly expanding its frontiers into the neoadjuvant setting, frequently confronting the surgeon with heavily pretreated patients. Salvage surgery is a viable therapeutic concept despite the rise of systemic treatment options. Decision-making on surgical intervention in case of a salvage surgery remains an individual choice. For neoadjuvant ICI monitoring regarding pathological tumor response or tumor necrosis rate, we suggest correlation between the initial biopsy and the definite tumor resectate in order to increase its significance as a surrogate marker. Scheduling of neoadjuvant ICI should be further investigated, as recent studies indicate better outcomes with shorter time frames.
CRIS-Team Scopus Importer:2022-11-25
Keywords: anti-PD 1; checkpoint inhibition; CSCC; HNSCC; immunotherapy; neoadjuvant; OSCC; salvage surgery

Case Report: Pediatric Renal Sarcoidosis and Prognostic Factors in Reviewed Cases - Klaus, Richard; Jansson, Annette Friederike; Griese, Matthias; Seeman, Tomas; Amann, Kerstin Ute; Lange-Sperandio, Bärbel (Frontiers in Pediatrics, 2021)
Background: Pediatric sarcoidosis is a complex inflammatory disorder with multisystemic manifestations. Kidney involvement in children is rare, and prognostic factors are unknown. Case Report and Methods: We report the case of a 16-year-old girl with multiorgan sarcoidosis and renal involvement. The patient presented with tubulointerstitial nephritis, acute kidney injury (AKI), chest CT disseminated noduli, granulomatous iridocyclitis, giant-cell sialadenitis, and arthralgia. The kidney biopsy revealed non-granulomatous interstitial nephritis. Treatment consisted of initial high-dose methylprednisolone pulse followed by oral prednisolone and methotrexate. Full remission was achieved. In addition, we performed a literature review using PubMed and analyzed data on pediatric renal sarcoidosis cases. Results: We identified 36 cases of pediatric sarcoidosis with renal involvement on presentation and data on the end-of-follow-up glomerular filtration rate (GFR). The data from the literature review showed that renal involvement was slightly more prevalent in males (60%). AKI was present in most of the described patients (84%). Oral prednisolone was used in 35 of 36 cases; in more severe cases, other immunosuppressants were used. We newly identified renal concentration impairment and granulomatous interstitial nephritis as factors with a clear trend toward GFR loss at the end of follow-up, emphasizing the importance of kidney biopsy in symptomatic patients. In contrast, higher GFR at presentation and hypercalcemia were rather favorable factors. According to the identified predictive factors, our patient has a good prognosis and is in remission. Conclusion: The factors indicating a trend toward an unfavorable renal outcome in pediatric sarcoidosis are renal concentration impairment and granulomatous interstitial nephritis at presentation, while a higher GFR is beneficial.
CRIS-Team Scopus Importer:2021-10-08
Keywords: acute kidney injury; case report; prognostic factor analysis; sarcoidosis; tubulointerstitial nephritis

Case report: upper arm metastasis of an oral squamous cell carcinoma - Wurm, Matthias; Nkenke, Emeka; Neukam, Friedrich Wilhelm; Moest, Tobias; Lutz, Rainer; Wehrhan, Falk; Brunner, Kathrin; Mitsimponas, Konstantinos; Schlechtweg, Philipp; von Wilmowsky, Cornelius (BMC Oral Health, 2015)
The Oral Squamous Cell Carcinoma (OSCC) frequently metastasizes lymphogenously. Haematogenous dissemination is less common. This report describes a rare case of a metastatic OSCC of the floor of the mouth to the patients' left upper arm. To our knowledge this is the first of such case described in the literature.Twelve months after R0 tumor resection surgery, including microvascular reconstruction of the lower jaw followed by adjuvant radiotherapy, the patient was admitted for osteosynthesis plates removal. During clinical examination a tumor located at his left upper arm was detected. According to the patient the tumor has demonstrated rapid growth. Macroscopic appearance and conventional imaging led to the differential diagnosis of an abscess. MR-imaging could not differentiate between a tumor of soft tissue origin and a metastasis. A biopsy was taken and the pathological examination confirmed the diagnosis of an OSCC metastasis. The postoperative interdisciplinary tumor board recommended radiation therapy.Due to the fact that patients with regional lymph node metastases have a higher probability to develop distant metastasis a more detailed screening might be considered - especially when hemangiosis carcinomatosa was histologically or macroscopically found.
EVALuna2:6693

Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis - Günther, Claudia; Martini, Eva; Amann, Kerstin Ute; Weigmann, Benno; Neumann, Helmut; Waldner, Maximilian; Tenzer, Stefan; Neurath, Markus; Becker, Christoph; et al. (Nature, 2011)
Dysfunction of the intestinal epithelium is believed to result in the excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease, an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria adjacent to the epithelium. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn's disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death.

CCL2 expression in tumor cells and tumor-infiltrating immune cells shows divergent prognostic potential for bladder cancer patients depending on lymph node stage - Eckstein, Markus; Epple, Elena; Jung, Rudolf; Weigelt, Katrin; Lieb, Verena; Sikic, Danijel; Stöhr, Robert; Geppert, Carol-Immanuel; Weyerer, Veronika; Bertz, Simone; Kehlen, Astrid; Hartmann, Arndt; et al. (Cancers, 2020)
Bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide. Although there are several well-established molecular and immunological classifications, markers for tumor cells and immune cells that are associated with prognosis are still needed. The chemokine CC motif ligand 2 (CCL2) could be such a marker. We analyzed the expression of CCL2 by immunohistochemistry (IHC) in 168 muscle invasive BCa samples using a tissue microarray. Application of a single cut-off for the staining status of tumor cells (TCs; positive vs. negative) and immune cells (ICs; ≤6% of ICs vs. >6% of ICs) revealed 57 cases (33.9%) and 70 cases (41.7%) with CCL2-positive TCs or ICs, respectively. IHC results were correlated with clinicopathological and survival data. Positive CCL2 staining in TCs was associated with shorter overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) (p = 0.004, p = 0.036, and p = 0.047; log rank test) and appeared to be an independent prognostic factor for OS (RR = 1.70; p = 0.007; multivariate Cox’s regression analysis). In contrast, positive CCL2 staining in the ICs was associated with longer OS, DSS, and RFS (p = 0.032, p = 0.001, and p = 0.001; log rank test) and appeared to be an independent prognostic factor for DSS (RR = 1.77; p = 0.031; multivariate Cox’s regression analysis). Most interestingly, after separating the patients according to their lymph node status (N0 vs. N1+2), CCL2 staining in the ICs was differentially associated with prognosis. In the N0 group, CCL2 positivity in the ICs was a positive independent prognostic factor for OS (RR = 1.99; p = 0.014), DSS (RR = 3.17; p = 0.002), and RFS (RR = 3.10; p = 0.002), whereas in the N1+2 group, CCL2 positivity was a negative independent factor for OS (RR = 3.44; p = 0.019)) and RFS (RR = 4.47; p = 0.010; all multivariate Cox’s regression analyses). In summary, CCL2 positivity in TCs is a negative prognostic factor for OS, and CCL2 can mark ICs that are differentially associated with prognosis depending on the nodal stage of BCa patients. Therefore, CCL2 staining of TCs and ICs is suggested as a prognostic biomarker for BCa patients.
CRIS-Team Scopus Importer:2020-06-02
Keywords: Bladder cancer; CCL2; Immune cells; Lymph node stage; Prognosis; Tumor cells

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study - Kang, Eun Young; Weir, Ashley; Meagher, Nicola S.; Farrington, Kyo; Nelson, Gregg S.; Ghatage, Prafull; Lee, Cheng Han; Riggan, Marjorie J.; Bolithon, Adelyn; Popovic, Gordana; Leung, Betty; Tang, Katrina; et al. (Cancer, 2023)
Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p =.034, and HR, 1.18; 95% CI, 1.05-1.32, p =.015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p =.033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p =.58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
CRIS-Team Scopus Importer:2023-02-17
Keywords: CCNE1 amplification; cyclin E1 expression; high-grade serous carcinoma; ovarian cancer; prognosis

CCR3 deficiency shifts adaptive to innate-driven immunity in asthma - Krammer, Susanne; Yang, Zuqin; Mitländer, Hannah; Grund, Janina; Geppert, Carol-Immanuel; Rieker, Ralf; Zirlik, Sabine; Finotto, Susetta (Journal of Allergy and Clinical Immunology: Global, 2025)
Background: Because of repeated contact with airborne allergens, patients suffering from allergic asthma experience acute asthma attacks, characterized by shortness of breath, chest tightness, and coughing. The underlying immune response is highly complex and involves various immune cells. Chemokines play a pivotal role in the appropriate relocation of these diverse immune cells, ensuring their directed migration to the site of inflammation, their survival, and their effector functions. In the context of allergic asthma, the chemokine receptor CCR3 is crucially involved in TH2-mediated airway inflammation by recruiting eosinophils and other immune cells to the site of inflammation. However, more recent studies demonstrate its presence also on mast cells, macrophages, T cells, and dendritic cells. Objective: We sought to investigate the role of CCR3 in different immune cell types during asthma pathogenesis. Methods: Human peripheral blood cells collected from healthy controls and asthmatic individuals were analyzed for CCR3 expression. A murine model of asthma was used to compare wild-type and CCR3-deficient mice in the context of airway inflammation. Results: In a human cohort of asthmatic patients, CCR3 mRNA expression was found induced in PBMCs and positively correlated with decreased lung function and blood eosinophilia. In a murine model of disease, CCR3 was found to be important for the establishment of eosinophilic inflammation. Moreover, CCR3-deficient mice showed impaired cytokine release, resulting in an innate-like mast cell and neutrophil-mediated lung inflammation and reduced TH2-orchestrated eosinophil-driven asthma. In the absence of CCR3, CD8 T cells underwent phenotypic changes, inhibiting the development of migratory effector memory CD8 T-cell subsets. Conclusions: Taken together, this work demonstrates the functional involvement of CCR3 in both innate and adaptive immune cells in the lung during asthma pathogenesis.
CRIS-Team Scopus Importer:2025-03-14
Keywords: asthma; CD8; Chemokines; eosinophils; neutrophils

CD101 inhibits the expansion of colitogenic T cells - Schey, Regina; Dornhoff, H.; Baier, J. L. C.; Purtak, M.; Opoka, R.; Koller, A. K.; Atreya, Raja; Rau, Tilman; Daniel, Christoph; Amann, Kerstin Ute; Bogdan, Christian; Mattner, Jochen (Mucosal Immunology, 2016)
CD101 exerts negative-costimulatory effects in vitro, but its function in vivo remains poorly defined. CD101 is abundantly expressed on lymphoid and myeloid cells in intestinal tissues, but absent from naïve splenic T cells. Here, we assessed the impact of CD101 on the course of inflammatory bowel disease (IBD). Using a T-cell transfer model of chronic colitis, we found that in recipients of naïve T cells from CD101(+/+) donors up to 30% of the recovered lymphocytes expressed CD101, correlating with an increased interleukin (IL)-2-mediated FoxP3 expression. Transfer of CD101(-/-) T cells caused more severe colitis and was associated with an expansion of IL-17-producing T cells and an enhanced expression of IL-2R?/? independently of FoxP3. The co-transfer of naïve and regulatory T cells (Treg) protected most effectively from colitis, when both donor and recipient mice expressed CD101. Although the expression of CD101 on T cells was sufficient for Treg-function and the inhibition of T-cell proliferation, sustained IL-10 production required additional CD101 expression by myeloid cells. Finally, in patients with IBD a reduced CD101 expression on peripheral and intestinal monocytes and CD4(+) T cells correlated with enhanced IL-17 production and disease activity. Thus, CD101 deficiency is a novel marker for progressive colitis and potential target for therapeutic intervention.
EVALuna2:2051

CD107a+ (LAMP-1) Cytotoxic CD8+ T-Cells in Lupus Nephritis Patients - Wiechmann, Anika; Wilde, Benjamin; Tyczynski, Bartosz; Amann, Kerstin Ute; Abdulahad, Wayel H.; Kribben, Andreas; Lang, Karl Sebastian; Witzke, Oliver; Dolff, Sebastian (Frontiers in Medicine, 2021)
Cytotoxic CD8+ T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8+ T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients (n = 31) and healthy controls (n = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8+ and C107a+ cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a+ on CD8+ T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ± 18.5% vs. 47.9 ± 15.0%, p = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a+CD8+ T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a+CD8+ T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a+ was significantly correlated with proteinuria. These results demonstrate that CD8+ T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a+CD8+ suggests a role in the pathogenesis of lupus nephritis.
CRIS-Team Scopus Importer:2021-04-16
Keywords: CD107a; cytotoxic T-cells; LAMP-1; lupus nephritis; SLE

CD161a-positive natural killer (NK) cells and α-smooth muscle actin-positive myofibroblasts were upregulated by extrarenal DPP4 in a rat model of acute renal rejection - Schmid, Franziska; Mayer, Carolin; Büttner-Herold, Maike; von Hörsten, Stephan; Amann, Kerstin Ute; Daniel, Christoph (Diabetes Research and Clinical Practice, 2021)
Aims: Systemic inhibition of dipeptidyl peptidase 4 (DPP4) showed a protective effect in several transplant models. Here we assessed the specific role of extrarenal DPP4 in renal transplant rejection. Methods: Kidneys from wildtype (wt) F344 rats were either transplanted in wt Dark Agouti or congenic rats not expressing DPP4. The remaining, not transplanted donor kidney served as healthy controls. To investigate early inflammatory events rats were sacrificed 3 days after transplantation and kidneys were evaluated for inflammatory cells, capillary rarefaction, proliferation, apoptosis and myofibroblasts by immunohistochemistry. Results: Capillary ERG-1-positive endothelial cells were significantly more abundant in renal cortex when transplanted into DPP4 deficient compared to wt recipients. In contrast, TGF-ß and myofibroblasts were reduced by more than 25% in kidneys transplanted into DPP4 deficient compared to wt recipients. Numbers of CD161a-positive NK-cells were significantly lower in allografts in DPP4 deficient compared to wt recipients. Numbers of all other investigated immune cells were not affected by the lack of extrarenal DPP4. Conclusion: In early transplant rejection extrarenal DPP4 is involved in the recruitment of NK-cells and early fibrosis. Beneficial effects were less pronounced than reported for systemic DPP4 inhibition, indicating that renal DPP4 is an important player in transplantation-mediated injury.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Extrarenal DPP4; Fibrosis; Inflammation; Renal transplantation

CD163+ M2c-like macrophages predominate in renal biopsies from patients with lupus nephritis - Olmes, Gregor; Buettner-Herold, Maike; Ferrazzi, Fulvia; Distel, Luitpold; Amann, Kerstin Ute; Daniel, Christoph (Arthritis Research & Therapy, 2015)
The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters.Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II-V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test.The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ISN/RPS class V. In all ISN/RPS classes we detected more M2c-like CD163+/CD68+ than M2a-like CD206+/CD68+ cells, while M1-macrophages played only a minor role. Cluster analysis using macrophage subtype numbers in different renal compartments revealed three main clusters showing cluster 1 dominated by class V. Clusters 2 and 3 were dominated by lupus class IV indicating that this class can be further differentiated by its macrophage population. The number of tubulointerstitial FoxP3+ cells correlated with all investigated macrophage subtypes showing the strongest association to numbers of M2a-like macrophages. Kidney function, as assessed by serum creatinine and serum urea, correlated positively with the number of total CD68+, M2a-like and M2c-like macrophages in the tubulointerstitium. In addition, total CD68+ and M2c-like macrophage numbers highly correlated with Austin activity score. Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.M2-like macrophages are the dominant subpopulation in human lupus nephritis and particularly, M2a subpopulations were associated with disease progression, but their role in disease progression remains unclear.
EVALuna2:9308

CD19-CAR T-cell therapy induces deep tissue depletion of B cells - Tur, Carlo; Eckstein, Markus; Velden, Joachim; Rauber, Simon; Bergmann, Christina; Auth, Janina; Bucci, Laura; Corte, Giulia; Hagen, Melanie; Wirsching, Andreas; Grieshaber Bouyer, Ricardo; Reis, Petra; et al. (Annals of the Rheumatic Diseases, 2024)
Objectives CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo. Methods Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages. Results Sequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19+ and CD20+ B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells. Discussion This study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy.
CRIS-Team Scopus Importer:2024-09-27
Keywords: Autoimmune Diseases; B-Lymphocytes; Rituximab; Ultrasonography

CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series - Auth, Janina; Müller, Fabian; Völkl, Simon; Bayerl, Nadine; Distler, Jörg H.W.; Tur, Carlo; Raimondo, Maria Gabriella; Chenguiti Fakhouri, Sara; Atzinger, Armin; Coppers, Birte; Eckstein, Markus; Liphardt, Anna-Maria; et al. (The Lancet Rheumatology, 2024)
Background: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown remarkable outcomes in patients with systemic lupus erythematosus. The effects of CD19-targeting CAR T cells on organ manifestations in patients with systemic sclerosis have yet to be characterised. B cells have a central role in the pathogenesis of systemic sclerosis. We present a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis. Methods: Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited at the Department of Internal Medicine 3, University Hospital Erlangen (Erlangen, Germany) to receive CD19-targeting CAR T-cell treatment (1 × 106 CAR T cells per kg bodyweight). Events were predefined by progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension, or initiation of new immunosuppressive or antifibrotic therapy. Event-free time or treatment intensification after study entry was the primary outcome. Key secondary outcomes included changes in the modified Rodnan Skin Score (mRSS), imaging (a component of the assessment of lung fibrosis), laboratory assessments, patient-reported outcomes, and a modified version of the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline, 3 months, 6 months, 9 months, and 12 months. Findings: Between April 20, 2022, and Nov 8, 2023, six patients with severe diffuse systemic sclerosis (median age 42 years [IQR 36–53]; four men and two women; all White European) were recruited and received CD19-targeted CAR T-cell therapy. The median follow-up time was 487 days (IQR 342–585). No events occurred within the observational period. Probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100–100) at 6 months. Median mRSS decreased by 31% (IQR 29–38), corresponding to a median of 8 points (IQR 7–13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3–4) due to reduction of ground-glass opacities while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18–275) at the latest observational timepoint. Interpretation: We provide the first evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis. Funding: Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN-Foundation Erlangen, IZKF Erlangen, and Bundesministerium für Bildung und Forschung.
CRIS-Team Scopus Importer:2024-12-13

CD22 x Siglec-G Double-Deficient Mice Have Massively Increased B1 Cell Numbers and Develop Systemic Autoimmunity - Jellusova, Julia; Wellmann, Ute; Amann, Kerstin Ute; Winkler, Thomas; Nitschke, Lars (Journal of Immunology, 2010)
CD22 and Siglec-G are inhibitory coreceptors for BCR-mediated signaling. Although CD22-deficient mice show increased calcium signaling in their conventional B2 cells and a quite normal B cell maturation, Siglec-G-deficient mice have increased calcium mobilization just in B1 cells and show a large expansion of the 131 cell population. Neither CD22-deficient, nor Siglec-G-deficient mice on a pure C57BL/6 or BALB/c background, respectively, develop autoimmunity. Using Siglec-G X CD22 double-deficient mice, we addressed whether Siglec-G and CD22 have redundant functions. Siglec-G X CD22 double-deficient mice show elevated calcium responses in both B1 cells and B2 cells, increased serum IgM levels and an enlarged population of B1 cells. The enlargement of 131 cell numbers is even higher than in Siglecg(-/-) mice. This expansion seems to happen at the expense of B2 cells, which are reduced in absolute cell numbers, but show an activated phenotype. Furthermore, Siglec-G X CD22 double-deficient mice show a diminished immune response to both thymus-dependent and thymus-independent type 11 Ags. In contrast, B cells from Siglec-G X CD22 double-deficient mice exhibit a hyperproliferative response to stimulation with several TLR ligands. Aged Siglec-G X CD22 double-deficient mice spontaneously develop anti-DNA and antinuclear autoantibodies. These resulted in a moderate form of immune complex glomerulonephritis. These results show that Siglec-G and CD22 have partly compensatory functions and together are crucial in maintaining the B cell tolerance. The Journal of Immunology, 2010, 184: 3618-3627.

CD24 targeting with NK-CAR immunotherapy in testis, prostate, renal and (luminal-type) bladder cancer and identification of direct CD24 interaction partners - Söhngen, Christian; Thomas, David J.; Skowron, Margaretha A.; Bremmer, Felix; Eckstein, Markus; Stefanski, Anja; Driessen, Marc D.; Wakileh, Gamal A.; Stühler, Kai; Altevogt, Peter; Theodorescu, Dan; Klapdor, Rüdiger; et al. (Febs Journal, 2023)
Alternative therapeutic options targeting urologic malignancies, such as germ cell tumours, as well as urothelial, renal and prostate carcinomas, are still urgently needed. The membrane protein CD24 represents a promising immunotherapeutical approach. The present study aimed to decipher the molecular function of CD24 in vitro and evaluate the cytotoxic capacity of a third-generation natural killer (NK) cell chimeric antigen receptor (CAR) against CD24 in urologic tumour cell lines. Up to 20 urologic tumour cell lines and several non-malignant control cells were included. XTT viability assays and annexin V/propidium iodide flow cytometry analyses were performed to measure cell viability and apoptosis rates, respectively. Co-immunoprecipitation followed by mass spectrometry analyses identified direct interaction partners of CD24. Luciferase reporter assays were used to functionally validate transactivation of CD24 expression by SOX2. N- and O-glycosylation of CD24 were evaluated by enzymatic digestion and mass spectrometry. The study demonstrates that SOX2 transactivates CD24 expression in embryonal carcinoma cells. In cells of different urological origins, CD24 interacted with proteins involved in cell adhesion, ATP binding, phosphoprotein binding and post-translational modifications, such as histone acetylation and ubiquitination. Treatment of urological tumour cells with NK-CD24-CAR cells resulted in a decreased cell viability and apoptosis induction specifically in CD24+ tumour cells. Limitations of the study include the in vitro setting, which still has to be confirmed in vivo. In conclusion, we show that CD24 is a promising novel target for immune therapeutic approaches targeting urologic malignancies.
CRIS-Team Scopus Importer:2023-07-07
Keywords: CD24; immunotherapy; testicular germ cell tumour; urologic malignancies

CD8+and Regulatory T cells Differentiate Tumor Immune Phenotypes and Predict Survival in Locally Advanced Head and Neck Cancer - Echarti, Alessia; Hecht, Markus; Büttner-Herold, Maike; Haderlein, Marlen; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (Cancers, 2019)
Background: The tumor immune status "inflamed", "immune excluded", and "desert" might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy were analyzed. A double staining of CD8+ cytotoxic T cells (CTL) and FoxP3+ (Treg) was performed and the cell density was evaluated in the intraepithelial and stromal compartment of the tumor. Results: The classification of tumors as "immune desert" when stromal CTL were <= 50 cells/mm(2), "inflamed" when intraepithelial CTL were > 500 cells/mm(2), and as "excluded" when neither of these definitions met these cut off values allowed the best discrimination regarding overall survival. These groups had median OS periods of 37, 61, and 85 months, respectively. In "immune desert" and "immune excluded" tumors high Treg tended to worsen OS, but in "inflamed" tumors high Treg clearly improved OS. Conclusions: We propose that, in locally advanced HNSCC, the tumor immune state "inflamed", "immune excluded", and "immune desert" can be defined by intraepithelial and stromal CTL. Tregs can further subdivide these groups. The opposing effects of Tregs in the different groups might be the reason for the inconsistency of Tregs prognostic values published earlier.
CRIS-Team WoS Importer:2019-10-25

CD8+ Cytotoxic Immune Infiltrate in Non-Muscle Invasive Bladder Cancer: A Standardized Methodology to Study Association with Clinico-Pathological Features and Prognosis - Masson-Lecomte, Alexandra; Maille, Pascale; Pineda, Silvia; Soyeux, Pascale; Sagrera, Ana; Rava, Marta; Lopez De Maturana, Evangelina; Marquez, Mirari; Tardon, Adonina; Carrato, Alfredo; Kogevinas, Manolis; De La Taille, Alexandre; et al. (Bladder Cancer, 2019)
Background: Major interest lies in the evaluation of immune infiltrate in bladder cancer. CD8+ cytotoxic lymphocytes are key effectors of adaptive immune response. Objectives: The aims of the study were to set up a standardized methodology for CD8+ lymphocytes estimation in NMIBC and investigate how intra-tumoral heterogeneity influences CD8+ immune infiltrate. Methods: We considered 995 NMIBC included in the Spanish Bladder Cancer (SBC)/EPICURO Study. Duplicate 0.6mm TMA spots and paired full sections (FS) for 50 selected cases were double stained with anti-pan cytokeratin antibody and anti-CD8 antibody. Slides were digitalized and CD8+ cells were automatically counted after tissue recognition (tumor vs stroma). Spatial heterogeneity was assessed and a resampling strategy was applied to estimate the proper number of 0.6mm TMA spots providing an adequate CD8+ cell estimate. Association between CD8+ count and expression of urothelial differentiation markers was estimated. Cox regression models were performed to assess association between CD8+ cell count and risk of recurrence and progression. Results: Microscopic examination of full sections showed spatial heterogeneity for CD8+ infiltrates. Simulation analyses demonstrated that 5 TMA regions provided a correct sampling of tumor and stromal compartments in Ta while 2 and 6 TMA regions were necessary in T1, respectively. CD8+ cells infiltration was associated with stage, regardless of the histological compartment analyzed (median CD8+/mm2 were 25/mm2 and 129/mm2 in tumor and stroma respectively in Ta and 111/mm2 and 344/mm2 in T1; p-value=0.006). CD8+ infiltration in tumor compartment was significantly associated with low FGFR3 expression. CD8+/mm2 count in the tumor compartment was not associated with prognosis. Conclusion: Differences identified between Ta and T1 tumours supported the hypothesis that rigorous efforts should be placed in proper study design. These results provide a new framework to investigate microenvironment complexity in bladder cancer.
CRIS-Team Scopus Importer:2019-09-03
Keywords: CD8; methodology; prognosis; Urothelial carcinoma

CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression - 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)
The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP1 is highly expressed in advanced UC, which significantly correlates with shorter overall survival. Importantly, the basal/squamous UC subtype showed significantly enriched CDCP1 at the mRNA and protein levels. The functional role of CDCP1 overexpression was assessed taking advantage of ex vivo organoids derived from the CDCP1pcLSL/+ transgenic mouse model. Furthermore, CDCP1 knockout UC cell lines were generated using CRISPR/Cas9 technology. Interestingly, CDCP1 overexpression significantly induced the activation of MAPK/ERK pathways in ex vivo organoids and increased their proliferation. Similarly, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK/ERK pathway activity reduction. Our results highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role, suggesting that targeting CDCP1 could be a rational therapeutic strategy for the treatment of advanced UC.
CRIS-Team Scopus Importer:2023-01-13

CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer - Zeng, Siyuan; Lan, Bin; Ren, Xiaofan; Zhang, Shuman; Schreyer, Daniel; Eckstein, Markus; Yang, Hai; Britzen-Laurent, Nathalie; Dahl, Andreas; Mukhopadhyay, Debabrata; Chang, David; Kutschick, Isabella; et al. (Journal of Experimental & Clinical Cancer Research, 2022)
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Although combined treatment with gemcitabine and albumin-bound paclitaxel has improved the prognosis of PDAC, both intrinsic and acquired chemoresistance remain as severe hurtles towards improved prognosis. Thus, new therapeutic targets and innovative strategies are urgently needed. Methods: In this study, we used the KPC mouse model-derived PDAC cell line TB32047 to perform kinome-wide CRISPR-Cas9 loss-of-function screening. Next-generation sequencing and MAGeCK-VISPR analysis were performed to identify candidate genes. We then conducted cell viability, clonogenic, and apoptosis assays and evaluated the synergistic therapeutic effects of cyclin-dependent kinase 7 (CDK7) depletion or inhibition with gemcitabine (GEM) and paclitaxel (PTX) in a murine orthotopic pancreatic cancer model. For mechanistic studies, we performed genome enrichment analysis (GSEA) and Western blotting to identify and verify the pathways that render PDAC sensitive to GEM/PTX therapy. Results: We identified several cell cycle checkpoint kinases and DNA damage-related kinases as targets for overcoming chemoresistance. Among them, CDK7 ranked highly in both screenings. We demonstrated that both gene knockout and pharmacological inhibition of CDK7 by THZ1 result in cell cycle arrest, apoptosis induction, and DNA damage at least predominantly through the STAT3-MCL1-CHK1 axis. Furthermore, THZ1 synergized with GEM and PTX in vitro and in vivo, resulting in enhanced antitumor effects. Conclusions: Our findings support the application of CRISPR-Cas9 screening in identifying novel therapeutic targets and suggest new strategies for overcoming chemoresistance in pancreatic cancer.
CRIS-Team Scopus Importer:2022-08-19
Keywords: CDK7; CRISPR-Cas9; FOLFIRINOX; Gemcitabine; Paclitaxel; THZ1

CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making - Worst, Thomas S.; Weis, Cleo-Aron; Stoehr, Robert; Bertz, Simone; Eckstein, Markus; Otto, Wolfgang; Breyer, Johannes; Hartmann, Arndt; Bolenz, Christian; Wirtz, Ralph M.; Erben, Philipp (Scientific Reports, 2018)
Deletions of the cell cycle control gene CDKN2A are described as progression markers of non-muscle invasive bladder cancer and to be associated with fibroblast growth factor 3 (FGFR3) mutations. The prognostic role of CDKN2A RNA expression in muscle invasive bladder cancer (MIBC) is under discussion. In 80 MIBC patients (m/f 60/20) who underwent radical cystectomy the expression of CDKN2A and FGFR3 was examined with qRT-PCR (test cohort). The MDA cohort (n = 57) and the TCGA cohort (n = 365) served for validation. The expression of drug target genes and TCGA molecular subtypes was correlated with CDKN2A expression. In the test cohort CDKN2Ahigh patients (n = 8; 10.0%) had a significantly shorter recurrence-free (p = 0.018) and disease-specific (p = 0.006) survival compared to the rest of the cohort. A similar stratification was seen in the validation cohorts (CDKN2Ahigh: n = 7, 12.3%, p = 0.001; n = 46, 12.6%, p = 0.011). In the TCGA cohort these patients had a comparably low expression of drug target genes. The expression of CDKN2A significantly differed among TGCA molecular subtypes. 71.7% of CDKN2Ahigh were TCGA basal squamous tumours but also show divergent molecular features compared to this group. In summary CDKN2A RNA expression-based risk stratification of MIBC allows the identification of a CDKN2Ahigh poor prognosis group with low expression of drug target genes.
EVALuna2:34853

Cell cycle re-entry sensitizes podocytes to injury induced death - Hagen, Manuel; Pfister, Eva; Kosel, Andrea; Shankland, Stuart; Pippin, Jeffrey; Amann, Kerstin Ute; Daniel, Christoph (Cell Cycle, 2016)
Podocytes are terminally differentiated renal cells, lacking the ability to regenerate by proliferation. However, during renal injury, podocytes re-enter into the cell cycle but fail to divide. Earlier studies suggested that re-entry into cell cycle results in loss of podocytes, but a direct evidence for this is lacking. Therefore, we established an in vitro model to test the consequences of re-entry into the cell cycle on podocyte survival. A mouse immortalized podocyte cell line was differentiated to non-permissive podocytes and stimulated with e.g. growth factors. Stimulated cells were analyzed for mRNA-expression or stained for cell cycle analysis using flow cytometry and immunocytofluorescence microscopy. After stimulation to re-entry into cell cycle, podocytes were stressed with puromycin aminonucleoside (PAN) and analyzed for survival. During permissive stage more than 40% of immortalized podocytes were in the S-phase. In contrast, S-phase in non-permissive differentiated podocytes was reduced to 5%. Treatment with b-FGF dose dependently induced re-entry into cell cycle increasing the number of podocytes in the S-phase to 10.7% at an optimal bFGF dosage of 10 ng/ml. Forty eight hours after stimulation with bFGF the number of bi-nucleated podocytes significantly increased. A secondary injury stimulus significantly reduced podocyte survival preferentially in bi-nucleated podocytes In conclusion, stimulation of podocytes using bFGF was able to induce re-entry of podocytes into the cell cycle and to sensitize the cells for cell death by secondary injuries. Therefore, this model is appropriate for testing new podocyte protective substances that can be used for therapy.
EVALuna:32169

Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients - Lieb, Verena; Abdulrahman, Amer; Weigelt, Katrin; Hauch, Siegfried; Gombert, Michael; Guzman, Juan; Bellut, Laura; Goebell, Peter; Stöhr, Robert; Hartmann, Arndt; Wullich, Bernd; Taubert, Helge; et al. (Cells, 2022)
In the present study, we further analyzed the data obtained in our previous study, where we investigated the cell-free DNA (cfDNA) of 34 progressive prostate cancer patients via targeted sequencing. Here, we studied the occurrence and prognostic impact of sequence variants according to their clinical pathological significance (CPS) or their functional impact (FI) in 23 DNA damage repair (DDR) genes with a focus on the ATM serine/threonine kinase gene (ATM). All patients had at least one DDR gene with a CPS or FI variant. Kaplan-Meier analysis indicated that the group with a higher number of CPS variants in DDR genes had a shorter time to treatment change (TTC) compared to the group with a lower number of CPS variants (p = 0.038). Analysis of each DDR gene revealed that CPS variants in the ATM gene and FI variants in the nibrin (NBN) gene showed a shorter TTC (p = 0.034 and p = 0.042). In addition, patients with CPS variants in the ATM gene had shorter overall survival (OS; p = 0.022) and disease-specific survival (DSS; p = 0.010) than patients without these variants. Interestingly, patients with CPS variants in seven DDR genes possessed a better OS (p = 0.008) and DSS (p = 0.009), and patients with FI variants in four DDR genes showed a better OS (p = 0.007) and DSS (p = 0.008). Together, these findings demonstrated that the analysis of cfDNA for gene variants in DDR genes provides prognostic information that may be helpful for future temporal and targeted treatment decisions for advanced PCa patients.
CRIS-Team Scopus Importer:2022-12-02
Keywords: ATM; cfDNA; DDR genes; NBN; prognosis; prostate cancer; sequence variants

Cell-free dna variant sequencing using plasma and ar-v7 testing of circulating tumor cells in prostate cancer patients - Lieb, Verena; Bellut, Laura; Abdulrahman, Amer; Weigelt, Katrin; Hauch, Siegfried; Gombert, Michael; Guzman, Juan; Goebell, Peter; Stöhr, Robert; Hartmann, Arndt; Wullich, Bernd; Taubert, Helge; et al. (Cells, 2021)
Prostate cancer (PCa) is the second most common malignant cancer and is a major cause of morbidity and mortality among men worldwide. There is still an urgent need for biomarkers applicable for diagnosis, prognosis, therapy prediction, or therapy monitoring in PCa. Liquid biopsies, including cell-free DNA (cfDNA) and circulating tumor cells (CTCs), are a valuable source for studying such biomarkers and are minimally invasive. In our study, we investigated the cfDNA of 34 progressive PCa patients, via targeted sequencing, for sequence variants and for the occurrence of CTCs, with a focus on androgen receptor splice variant 7 (AR-V7)-positive CTCs. The cfDNA content was associated with overall survival (OS; p = 0.014), disease-specific survival (DSS; p = 0.004), and time to treatment change (TTC; p = 0.001). Moreover, when considering all sequence variants grouped by their functional impact and allele frequency, a significant association with TTC (p = 0.017) was observed. When investigating only pathogenic or likely pathogenic gene variants, variants of the BRCA1 gene (p = 0.029) and the AR ligand-binding domain (p = 0.050) were associated with a shorter TTC. Likewise, the presence of CTCs was associated with a shorter TTC (p = 0.031). The presence of AR-V7-positive CTCs was associated with TTC (p < 0.001) in Kaplan–Meier analysis. Interestingly, all patients with AR-V7-positive CTCs also carried TP53 point mutations. Altogether, analysis of cfDNA and CTCs can provide complementary information that may support temporal and targeted treatment decisions and may elucidate the optimal choice within the variety of therapy options for advanced PCa patients.
CRIS-Team Scopus Importer:2021-11-26
Keywords: CfDNA; CTCs; Prognosis; prostate cancer; Sequence variants

Cell-in-cell phenomenon: leukocyte engulfment by non-tumorigenic cells and cancer cell lines - Bauer, Mareike; Hader, Michael; Hecht, Markus; Büttner-Herold, Maike; Fietkau, Rainer; Distel, Luitpold (BMC Molecular and Cell Biology, 2021)
Background Research on cell-in-cell (CIC) phenomena, including entosis, emperipolesis and cannibalism, and their biological implications has increased in recent years. Homotypic and heterotypic engulfment of various target cells by numerous types of host cells has been studied in vitro and in tissue sections. This work has identified proteins involved in the mechanism and uncovered evidence for CIC as a potential histopathologic predictive and prognostic marker in cancer. Our experimental study focused on non-professional phagocytosis of leukocytes. Results We studied the engulfment of peripheral blood mononuclear cells isolated from healthy donors by counting CIC structures. Two non-tumorigenic cell lines (BEAS-2B, SBLF-9) and two tumour cell lines (BxPC3, ICNI) served as host cells. Immune cells were live-stained and either directly co-incubated or treated with irradiation or with conventional or microwave hyperthermia. Prior to co-incubation, we determined leukocyte viability for each batch via Annexin V-FITC/propidium iodide staining. All host cells engulfed their targets, with uptake rates ranging from 1.0% +/- 0.5% in BxPC3 to 8.1% +/- 5.0% in BEAS-2B. Engulfment rates of the cancer cell lines BxPC3 and ICNI (1.6% +/- 0.2%) were similar to those of the primary fibroblasts SBLF-9 (1.4% +/- 0.2%). We found a significant negative correlation between leukocyte viability and cell-in-cell formation rates. The engulfment rate rose when we increased the dose of radiotherapy and prolonged the impact time. Further, microwave hyperthermia induced higher leukocyte uptake than conventional hyperthermia. Using fluorescent immunocytochemistry to descriptively study the proteins involved, we detected ring-like formations of diverse proteins around the leukocytes, consisting, among others, of alpha-tubulin, integrin, myosin, F-actin, and vinculin. These results suggest the involvement of actomyosin contraction, cell-cell adhesion, and the alpha-tubulin cytoskeleton in the engulfment process. Conclusions Both non-tumorigenic and cancer cells can form heterotypic CIC structures by engulfing leukocytes. Decreased viability and changes caused by microwave and X-ray irradiation trigger non-professional phagocytosis.
CRIS-Team WoS Importer:2021-08-13

Cell-In-Cell Structures in Early Breast Cancer Are Prognostically Valuable - Bauer, Mareike; Hildebrand, Laura; Rosahl, Marie-Charlotte; Erber, Ramona; Schnellhardt, Sören; Büttner-Herold, Maike; Putz, Florian; Ott, Oliver; Hack, Carolin; Fietkau, Rainer; Distel, Luitpold (Cells, 2023)
Cell-in-cell (CIC) structures in breast cancer have so far been studied in a small inhomogeneous patient population, suggesting the prognostic importance of CIC. In the present study, we focused on CIC in early hormone-sensitive breast cancer. With in vitro co-culture experiments, we compared the homotypic phagocytic capacity of two breast cancer cell lines to that of primary human fibroblasts. Afterward, we studied 601 tissue specimens from 147 patients participating in an institutional accelerated partial breast irradiation (APBI) phase II trial. Both breast cancer cell lines performed non-professional phagocytosis at a higher rate than primary human fibroblasts. In this study cohort, 93.2% of the patients had T1 tumours, and 6.8% had T2 tumours. CIC was found in 61.2% of the patients, with a CIC rate ranging from <1/mm2 to 556.5/mm2 with a mean of 30.9/mm2 ± 68.4/mm2. CIC structures were prognostically favourable for local recurrence-free survival and disease-free survival. Regarding metastasis-free survival, CIC-positive patients had an unfavourable prognosis. Subgroup analysis indicated a correlation between a high proliferation index and high CIC rates. CIC had the highest prognostic value in young breast cancer patients (p = 0.004). With this study, we provide further evidence of CIC as a prognostic marker in breast cancer.
CRIS-Team Scopus Importer:2023-01-20
Keywords: accelerated partial breast irradiation; breast cancer; cell-in-cell; ionizing radiation; non-professional phagocytosis; radiotherapy

Cell-to-cell distances between tumor-infiltrating inflammatory cells have the potential to distinguish functionally active from suppressed inflammatory cells - Nagl, Sandra; Haas, M.; Lahmer, Godehard; Buettner-Herold, M.; Grabenbauer, Gerhard; Fietkau, Rainer; Distel, Luitpold (OncoImmunology, 2016)
Beyond their mere presence, the distribution pattern of inflammatory cells is of special interest. Our hypothesis was that random distribution may be a clear indicator of being non-functional as a consequence of lack of interaction. Here, we have assessed the implication of cell-to-cell distances among inflammatory cells in anal squamous cell carcinoma and a possible association with survival data. Thirty-eight patients suffering from anal carcinoma were studied using tissue microarrays, double staining immunohistochemistry, whole slide scanning and image analysis software. Therapy consisted of concurrent radiochemotherapy. Numbers of stromal and intraepithelial tumor-infiltrating inflammatory cells (TIC) and the distances between cells were quantified. Double-staining of FoxP3(+) cells with either CD8(+), CD1a(+) or CD20(+) cells was performed. Measured cell-to-cell distances were compared to computer simulated cell-to-cell distances leading to the assumption of non-randomly distributed and therefore functional immune cells. Intraepithelial CD1a(+) and CD20(+) cells were randomly distributed and therefore regarded as non-functional. In contrary, stromal CD20(+) cells had a non-random distribution pattern. A non-random distance between CD20(+) and FoxP3(+) cells was associated with a clearly unfavorable outcome. Measured distances between FoxP3(+) cells were distinctly shorter than expected and indicate a functional active state of the regulatory T cells (Treg). Analysis of cell-to-cell distances between TIC has the potential to distinguish between suppressed non-functional and functionally active inflammatory cells. We conclude that in this tumor model most of the CD1a(+) cells are non-functional as are the intraepithelial CD20(+) cells, while stromal CD20(+) cells and FoxP3(+) cells are functional cells.
EVALuna2:18358

Cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways by CD101 - Wrage, Marius; Holland, Tim; Nüse, Björn; Kaltwasser, Johanna; Fröhlich, Jessica; Arnold, Harald; Gießler, Claudia; Flamann, Cindy; Bruns, Heiko; Berges, Johannes; Daniel, Christoph; Hoffmann, Markus; et al. (Mucosal Immunology, 2024)
T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101−/− mice, animals with a regulatory T cell-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101−/− x interferon-g−/− mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.
CRIS-Team Scopus Importer:2024-07-19

Cellular density and variability in laryngeal and pharyngeal squamous cell carcinoma using confocal laser endomicroscopy - Sievert, Matti; Aubreville, M.; Eckstein, Markus; Mantsopoulos, Konstantinos; Koch, Matthias; Gostian, Antoniu-Oreste; Müller, Sarina Katrin; Iro, Heinrich; Goncalves, M. (European Review for Medical and Pharmacological Sciences, 2023)
OBJECTIVE: Confocal laser endomicroscopy (CLE) allows the visualization of epithelium in a thousand-fold magnification. This study analyzes the architectural differences at the cellular level of the mucosa and squamous cell carcinoma (SCC). PATIENTS AND METHODS: A total of 60 CLE sequences recorded in 5 patients with SCC undergoing laryngectomy between October 2020 and February 2021 were analyzed. The corresponding histologic sample derived from H&E staining was assigned to each sequence, capturing CLE images of the tumor and healthy mucosa. In addition, the cellular structure analysis was performed to diagnose SCC by measuring the total number of cells and cell size in 60 sequences in a fixed field of view (FOV) with 240 μm in diameter (45,239 μm2). RESULTS: Out of 3,600 images, 1,620 (45%) showed benign mucosa and 1,980 (55%) SCC. The automated analysis yielded a difference in cell size, with healthy epithelial cells being 171.9±82.0 μm2 smaller than SCC cells, which were 246.3±171.9 μm2 and showed greater variability in size (p=0.037). In addition, due to the probe’s fixed FOV, there was a difference in cell count with a total of 188.7±38.3 and 124.8±38.6 cells in images of normal epithelium and SCC (p<0.001), respectively. Regarding cell density as a criterion for the differentiation of benign/malign, using a cut-off value of 145.5 cells/FOV, we obtained sensitivity and specificity of 88.0% and 71.9%, respectively. CONCLUSIONS: SCC reveals marked differences at a cellular level compared to the healthy epithelium. Our results further support the importance of this feature for identifying SCC during CLE imaging.
CRIS-Team Scopus Importer:2023-05-26
Keywords: Classification; Confocal laser endomicroscopy; Head and neck squamous cell carcinoma; Larynx; Optical biopsy; Pharynx

Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. - Günther, Claudia; Martini, Eva; He, Guiwei; Amann, Kerstin Ute; He, You-Wen; Neurath, Markus; Becker, Christoph; et al. (Gastroenterology, 2013)
The intestinal epithelium generates a barrier that protects mammals from potentially harmful intestinal contents, such as pathogenic bacteria. Dysregulation of epithelial cell death has been implicated in barrier dysfunction and in the pathogenesis of intestinal inflammation. We investigated mechanisms of cell-death regulation in the intestinal epithelium of mice. Conditional knockout mice (either inducible or permanent) with deletion of cellular FLICE-inhibitory protein (cFlip) or caspase-8 in the intestinal epithelium were analyzed by histology and high-resolution endoscopy. We assessed the effects of cFlip or caspase-8 deficiency on intestinal homeostasis. Expression of cFlip in the intestinal epithelium was required for constitutive activation of caspase-8 under steady-state conditions. Intestinal expression of cFlip was required for development; disruption of the gene encoding cFlip from the intestinal epithelium (cFlip(fl/fl) VillinCre(+) mice) resulted in embryonic lethality. When cFlip was deleted from the intestinal epithelium of adult mice (cFlip(iΔIEC) mice), the animals died within a few days from severe tissue destruction, epithelial cell death, and intestinal inflammation. Death of cFlip-depleted intestinal epithelial cells was regulated extrinsically and required the presence of death receptor ligands, such as tumor necrosis factor-α and CD95 ligand, but was independent of receptor-interacting protein 3. cFlip deficiency was associated with strong up-regulation of caspase-8 and caspase-3 activity and excessive apoptosis in intestinal crypts. cFlip is required for intestinal tissue homeostasis in mice. It controls the level of activation of caspase-8 to promote survival of intestinal epithelial cells. BACKGROUND & AIMS METHODS RESULTS CONCLUSIONS
Keywords: CASP8; CFLAR; Fadd; Fadd-Like Apoptosis Regulator; Fas-associated protein with death domain; IEC; NEMO; NF-κB essential modulator; Rip; TNF; TUNEL; cFLIP; cellular FLICE-like inhibitory protein; intestinal epithelial cell; receptor interacting protein; terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling; tumor necrosis factor

Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy - Nicolay, Jan P.; Thorn, Verena; Daniel, Christoph; Amann, Kerstin Ute; Siraskar, Balasaheb; Lang, Florian; Hillgruber, Carina; Goerge, Tobias; Hoffmann, Stefan; Gorzelanny, Christian; Huck, Volker; Mess, Christian; et al. (Scientific Reports, 2018)
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
EVALuna:34419

Cervical intraepithelial neoplasia grade 2/3: development during pregnancy and postpartum - Stübs, Frederik; Mergel, F.; Koch, M. C.; Dietl, Anna; Schulmeyer, Carla; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Gaß, Paul; Mehlhorn, G. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

Cervical intraepithelial neoplasia grade 3: development during pregnancy and postpartum - Stübs, Frederik; Mergel, Franziska; Koch, Martin; Dietl, Anna; Schulmeyer, Carla; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Gaß, Paul; Mehlhorn, Grit (Archives of Gynecology and Obstetrics, 2022)
Purpose: The aims of the present study were to evaluate the development of untreated cervical intraepithelial neoplasia (CIN) 3 during pregnancy and to assess persistence, progression, and regression rates postpartum to identify factors associated with regression. Methods: In a tertiary gynecology and obstetrics department, a total of 154 pregnant women with CIN 3 were treated in the dysplasia unit. The follow-up findings were analyzed retrospectively on the basis of histological, cytological, and human papillomavirus (HPV) testing of 154 pregnant women confirmed as having CIN 3 in colposcopically guided biopsies. Results: The rates of persistence, regression, and progression of CIN 3 in these women were 76.1%, 20% and 3.2%, respectively. Data for the delivery mode was available for 126 women. The rate of regression was almost twice as high with vaginal delivery as with cesarean section, at 27.4 vs. 15.2%, whereas the rate of progression was lower with vaginal delivery, at 2.7 vs. 6.5%. Conclusion: The rate of persistence of CIN observed in this study is comparable to that reported in other studies. The study provides strong evidence for greater regression among women who have vaginal deliveries. Careful work-up is recommended postpartum for this group of women in order to rule out persistent CIN 3 or invasive disease.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Cervical dysplasia; High-grade squamous intraepithelial lesion (HSIL); Mode of delivery; Pregnancy; Treatment

Cervical Lymph Node Metastases from Central Nervous System Tumors: A Systematic Review - Coca-Pelaz, Andres; Bishop, Justin A.; Zidar, Nina; Agaimy, Abbas; Mello Santiago Gebrim, Eloisa Maria; Mondin, Vanni; Cohen, Oded; Strojan, Primoz; Rinaldo, Alessandra; Shaha, Ashok R.; De Bree, Remco; Hamoir, Marc; et al. (Cancer Management and Research, 2022)
Introduction: Lymph node metastasis (LNM) from primary tumors of the central nervous system (CNS) is an infrequent condition, and classically it was thought that CNS tumors could not spread via the lymphatic route. Recent discoveries about this route of dissemination make its knowledge necessary for surgeons and pathologists to avoid delays in diagnosis and unnecessary treatments. The aim of this paper is to review the literature and to discuss the relevant pathogenetic mechanism and the cytologic features along with recommendations for surgical treatment of these cervical LNM. Materials and Methods: Using PRISMA guidelines, we conducted a systematic review of the literature published from 1944 to 2021, updating the comprehensive review published in 2010 by our group. Results: Our review includes data of 143 articles obtaining 174 patients with LNM from a primary CNS tumor. The mean age of the patients was 31.9 years (range, 0.1-87) and there were 61 females (35.1%) and 103 males (59.2%), and in 10 cases (5.7%) the gender was not specified. The more frequent sites of distant metastasis were bones (23%), lungs (11.5%) and non-cervical lymph nodes (11%). Conclusion: Cervical LNM from CNS tumors is infrequent. Pathologic diagnosis can be obtained by fine-needle aspiration cytology in most cases, giving surgeons the option to plan the appropriate surgical treatment. Given the poor prognosis of these cases, the most conservative possible cervical dissection is usually the treatment of choice.
CRIS-Team WoS Importer:2022-03-25

Challenging the prognostic impact of the new WHO and TNM classifications with special emphasis on HPV status in penile carcinoma - Hölters, Sebastian; Khalmurzaev, Oybek; Pryalukhin, Alexey; Loertzer, Philine; Janssen, Martin; Heinzelbecker, Julia; Ueberdiek, Stefan; Pfuhl, Thorsten; Smola, Sigrun; Agaimy, Abbas; Geppert, Carol-Immanuel; Loertzer, Hagen; et al. (Virchows Archiv, 2019)
The evidence concerning prognostic parameters for clinical decision-making in penile cancer is either weak or missing. We therefore analysed the prognostic value of the revised TNM and WHO classification systems on relapse and survival with special emphasis on HPV status. We collected clinical data and tissue samples of 121 patients from centres in Germany and Russia. HPV genotyping and p16INK4a immunostaining were performed. The histological subtype and TNM were reclassified by two experienced uropathologists. Survival analyses were performed by Kaplan-Meier estimator and log-rank test. Uni- and multivariable analyses were performed by Cox proportional hazard model and Fisher’s exact test for contingency analysis. HPV status was not found to be an independent prognostic factor. Histological subtypes differ in prognosis with the best outcome found in warty and the worst in basaloid carcinomas. Patients with pT1b defined by poor differentiation or lymphovascular invasion (LVI) had the shortest metastasis-free survival compared with pT1a (log-rank, p = 0.02). Lymph node metastasis and LVI were significantly associated with poor metastasis-free, cancer-specific and overall survival and could be identified as the only independent prognostic parameters. Prognostic value of TNM could not be improved using the 8th versus the 7th edition. In contrast to HPV status, histological subtypes are of prognostic value and should be an essential part of pathologic reports. The impact of the HPV status needs to be analysed in a subtype-specific manner. Parameters describing lymphatic dissemination have the highest impact on prognosis. Inclusion of tumour grade and LVI into a single T-category (pT1b) seems questionable.
CRIS-Team Scopus Importer:2019-08-06
Keywords: HPV; Prognosis; Squamous penile carcinoma

Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age - Roeder, Sebastian S.; Stefanska, Ania; Eng, Diana G.; Kaverina, Natalya; Sunseri, Maria W.; Mcnicholas, Bairbre A.; Rabinovitch, Peter; Engel, Felix; Daniel, Christoph; Amann, Kerstin Ute; Lichtnekert, Julia; Pippin, Jeffrey W.; et al. (American Journal of Physiology-Renal Physiology, 2015)
Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27-mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers ?-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E-cadherin and ?-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-?, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age.
EVALuna2:25490

Characteristic morphological changes in anti-VEGF therapy induced glomerular microangiopathy - Pfister, Frederick; Amann, Kerstin Ute; Daniel, Christoph; Klewer, Monika; Büttner, Anke; Büttner-Herold, Maike (Histopathology, 2018)
BACKGROUND: Thrombotic microangiopathy (TMA) is a microvascular pathology caused by several drugs used in cancer therapy. Agents targeting vascular endothelial growth factor (VEGF) have increasingly been used in therapy of advanced malignancies and have been found to induce renal TMA and proteinuria. However, histomorphological changes in human biopsies in this setting and the underlying mechanism are not yet fully understood. METHODS: Renal biopsies of 15 patients with anti-VEGF therapy (aVEGF) evaluated between 2013 and 2017 at a single centre were morphologically characterized using light microscopy, electron microscopy and immunohistochemistry (IgA, IgG, IgM, C1q, C3) and compared to cases with acute TMA caused by atypical haemolytic uramic syndrome or hypertension. Morphological overlap with immune-complex and cryoglobulinemic membranoproliferative glomerulonephritis, diabetic glomerulopathy and pre-emclapsia induced glomerulopathy were discussed. RESULTS: Segmental glomerular capillary microaneurysms and segmental hyalinosis were typical morphological features of aVEGF therapy induced glomerular microangiopathy, whereas fibrin or platelet thrombi or fragmented erythrocytes were rarely found or absent. aVEGF therapy associated microangiopathy was diffusely distributed in the glomeruli, spared pre-glomerular vessels, and showed morphological characteristics of chronic TMA. In individual cases, aVEGF therapy induced glomerular microangiopathy was accompanied by immune-complex glomerulonephritis. CONCLUSION: aVEGF therapy induced glomerular microangiopathy has a characteristic morphology and clinical presentation that helps to differentiate it from other causes of TMA. Awareness of these light microscopic findings allows identification of aVEGF therapy as a trigger of renal disease in critically ill cancer patients and therefore might help in deciding on further therapy. This article is protected by copyright. All rights reserved.
EVALuna2:34420

Characterization of esophageal inflammation in patients with achalasia. A retrospective immunohistochemical study - Döhla, Manuel; Leichauer, Katharina; Gockel, Ines; Niebisch, Stefan; Thieme, René; Lundell, Lars; Schumacher, Johannes; Becker, Jessica; Rieker, Ralf; Hartmann, Arndt; Veits, Lothar; Vieth, Michael (Human Pathology, 2019)
CRIS-Team Scopus Importer:2019-05-02
Keywords: Achalasia; Cytotoxic T cells; Esophagus; Inflammation; Regulatory T cells

Characterization of Glomerular Sox9+ Cells in Anti-Glomerular Basement Membrane Nephritis in the Rat - Prochnicki, Ania; Amann, Kerstin Ute; Wegner, Michael; Sock, Elisabeth; Pfister, Eva; Shankland, Stuart; Pippin, Jeffrey; Daniel, Christoph (American Journal of Pathology, 2018)
Mechanisms of glomerular crescent formation and podocyte repair processes are still unclear. Therefore, we investigated the expression of the transcription factor Sox9 as a potential marker of a subpopulation of parietal epithelial cells (PECs) with potential regenerative properties. Glomerular Sox9 expression was characterized in detail in a rat anti-glomerular basement membrane (GBM) nephritis model using immunofluorescence and confocal laser scanning microscopy. In healthy kidneys Sox9 is expressed in a subpopulation of PECs restricted to approximately 20% to 50% of PEC nuclei and was highly conserved in all investigated species. During rat anti-GBM nephritis the number of glomerular Sox9+ cells increased and was associated with proliferation activity. In nephritic glomeruli Sox9 expression was not restricted to Bowman's capsule lining but was also found on cells of the glomerular tuft. Nearly all Sox9+ cells also expressed the PEC marker Pax8, whereas endothelial cells, mesangial cells, macrophages, and T lymphocytes lacked Sox9 expression. At the margins of crescents Sox9+/Pax8+ cells additionally expressed podocyte markers. In contrast, in sclerotic lesions a minority of Sox9+/Pax8+ cells expressed the myofibroblast marker α-smooth muscle actin. In glomerular Sox9+ cells Jagged 1 was up-regulated. During anti-GBM nephritis Sox9+ PECs proliferate and migrate onto the glomerular tuft. Future studies are needed to confirm the origin of Sox9+ cells from PECs and differentiation in both podocytes and/or myofibroblasts.
EVALuna2:35393

Characterization of Molecular Subtypes of Paget Disease of the Breast Using Immunohistochemistry and In Situ Hybridization - Wachter, David; wachter, peter wolf; Fasching, Peter; Beckmann, Matthias; Hack, Carolin; Riener, Marc-Oliver; Hartmann, Arndt; Strehl, Johanna D. (Archives of Pathology & Laboratory Medicine, 2018)
CONTEXT: - Paget disease of the breast, in most cases, represents intraepidermal spread of ductal carcinoma in situ. Molecular subtypes of invasive carcinoma of the breast have prognostic and therapeutic significance and show characteristic distribution. Little is known about the distribution of molecular subtypes in Paget disease of the breast. OBJECTIVES: - To examine the distribution of molecular subtypes in Paget disease of the breast and to compare them to concurrent invasive carcinoma of the breast, if present. DESIGN: - We examined 48 cases of Paget disease of the breast with immunohistochemistry and antibodies against estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as HER2 chromogenic in situ hybridization, to classify the cases into molecular subtypes. Then, we compared the results to the molecular subtypes of associated, invasive carcinoma of the breast, if present. RESULTS: - The HER2 subtype was the most common found in Paget disease of the breast, followed by the luminal B subtype and 2 cases of the triple-negative subtype. The associated, invasive carcinoma cases were most often of the luminal B subtype, followed by the HER2 subtype and the triple-negative subtype. The molecular subtype of Paget disease and invasive carcinoma was congruent in most of the cases. CONCLUSIONS: - Molecular subtypes of invasive carcinoma of the breast can already be detected in Paget disease. The distribution of molecular subtypes of Paget disease and of Paget disease-associated, invasive carcinoma differs from invasive carcinoma without associated Paget disease, with the HER2 subtype overrepresented in Paget disease and associated, invasive carcinoma and the luminal and triple-negative subtypes underrepresented.
EVALuna2:34808

Characterization of PD-1 and PD-L1 Expression in Papillary Renal Cell Carcinoma: Results of a Large Multicenter Study - Erlmeier, Franziska; Steffens, Sandra; Stöhr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Ströbel, Philipp; Becker, Frank; Wülfing, Christian; Barth, Peter; Stöckle, Michael; et al. (Clinical Genitourinary Cancer, 2020)
Background: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) play a decisive role as prognostic markers in clear-cell renal cell carcinoma (RCC). To date, the role of PD-1/PD-L1 as a prognostic marker in papillary RCC (pRCC) remains scarce. Patients and Methods: Patients’ sample collection was a joint collaboration of the nationwide PANZAR consortium – a multicenter study. Medical history and tumor specimens were collected from 245 and 129 patients with pRCC types 1 and 2, respectively. Expression of PD-1 and PD-L1 was determined by immunohistochemistry in pRCC and tumor-infiltrating mononuclear cells. Results: Of 374 pRCC specimens, 204 type 1 and 97 type 2 were evaluable for PD-1 and PD-L1 expression analysis. In total, PD-1 and PD-L1 expression were found in 8 (4.9%) of 162 and 12 (7.2%) of 166 evaluable pRCC type 1 specimens. Comparably, PD-1 and PD-L1 expression were found in 2 (2.4%) of 83 and 5 (6.2%) of 81 evaluable pRCC type 2 specimens. Hardly any clinically relevant associations between PD-1 and PD-L1 positivity and clinicopathologic or clinical courses were observed, neither in pRCC type 1 nor type 2. Conclusion: The analysis of a large pRCC cohort from a multicenter consortium revealed no impact of PD-1/PD-L1 expression on prognosis in patients with pRCC with predominantly limited disease status, neither for type 1 nor type 2. However, the impact of PD-1 and PD-L1 in more advanced pRCC disease needs further elucidation. Understanding the impact of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression becomes increasingly important in renal cell carcinoma (RCC) owing to increasing therapeutic implications. However, little is known in non–clear-cell RCC about the relevance of those immune checkpoint surrogates. Here, we suggest that PD-1/PD-L1 expression in papillary RCC does not have prognostic impact, neither for type 1 nor type 2. However, in advanced disease, further evaluation according to PD-1/PD-L1 is warranted.
CRIS-Team Scopus Importer:2020-08-14
Keywords: Non-clear-cell-renal carcinoma; Papillary renal cell; PD-1; PD-L1; Renal cell carcinoma

Characterization of Proenkephalin-A as a potential biomarker for kidney damage in the murine and human kidney - Fuchs, M. A. A.; Schrankl, J.; Wagner, C.; Daniel, Christoph; Kurtz, A.; Broeker, K. A. -E. (ACTA PHYSIOLOGICA, 2022)
CRIS-Team WoS Importer:2022-10-07

Characterization of the expression and immunological impact of the transcriptional activator CREB in renal cell carcinoma - Friedrich, Michael; Stoehr, Christine; Jasinski-Bergner, Simon; Hartmann, Arndt; Wach, Sven; Wullich, Bernd; Steven, André; Seliger, Barbara (Journal of Translational Medicine, 2020)
Background: The non-classical human leukocyte antigen (HLA)-G is a strong immunomodulatory molecule. Under physiological conditions, HLA-G induces immunological tolerance in immune privileged tissues, while under pathophysiological situations it contributes to immune escape mechanisms. Therefore, HLA-G could act as a potential immune checkpoint for future anti-cancer immunotherapies. Recent data suggest an aberrant expression of the cAMP response element binding protein (CREB) in clear cell renal cell carcinoma (ccRCC), which is correlated with tumor grade and stage. Furthermore, preliminary reports demonstrated a connection of CREB as a control variable of HLA-G transcription due to CREB binding sites in the HLA-G promoter region. This study investigates the interaction between CREB and HLA-G in different renal cell carcinoma (RCC) subtypes and its correlation to clinical parameters. Methods: The direct interaction of CREB with the HLA-G promoter was investigated by chromatin immunoprecipitation in RCC cell systems. Furthermore, the expression of CREB and HLA-G was determined by immunohistochemistry using a tissue microarray (TMA) consisting of 453 RCC samples of distinct subtypes. Staining results were assessed for correlations to clinical parameters as well as to the composition of the immune cell infiltrate. Results: There exists a distinct expression pattern of HLA-G and CREB in the three main RCC subtypes. HLA-G and CREB expression were the lowest in chromophobe RCC lesions. However, the clinical relevance of CREB and HLA-G expression differed. Unlike HLA-G, high levels of CREB expression were positively associated to the overall survival of RCC patients. A slightly, but significantly elevated number of tumor infiltrating regulatory T cells was observed in tumors of high CREB expression. Whether this small increase is of clinical relevance has to be further investigated. Conclusions: An interaction of CREB with the HLA-G promoter could be validated in RCC cell lines. Thus, for the first time the expression of CREB and its interaction with the HLA-G in human RCCs has been shown, which might be of clinical relevance.
CRIS-Team Scopus Importer:2020-10-23
Keywords: CREB; HLA-G; Immune cell infiltration; Renal cell carcinoma

Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism - Fahkri, Hajar; Zhang, Bingbing; Fajol, Abul; Hernando, Nati; Elvira, Bernat; Mannheim, Julia G.; Pichler, Bernd J.; Daniel, Christoph; Amann, Kerstin Ute; Hirao, Atsushi; Haight, Jillian; Mak, Tak W.; et al. (Pflügers Archiv: European Journal of Physiology, 2015)
Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1?-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1?-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2 (-/-)) were compared to wild-type mice (chk2 (+/+)). Transcript levels of renal 25-hydroxyvitamin D 1?-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by ?CT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1?-hydroxylase as well as serum 1,25 (OH)2D3 and FGF23 levels were significantly lower in chk2 (-/-) mice compared to chk2 (+/+) mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher in chk2 (-/-) mice than in chk2 (+/+) mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25-hydroxyvitamin D 1?-hydroxylase expression thereby impacting on calcium and phosphate metabolism.
EVALuna2:25469

Chemoradiotherapy plus hyperthermia (CRTH) versus chemoradiotherapy (CRT) alone in neoadjuvant treatment of soft tissue sarcoma: tumor response, treatment toxicity and disease control - Willner, Alexander; Agaimy, Abbas; Fechner, Katja; Ott, Oliver; Denz, Axel; Weissmann, Thomas; Meidenbauer, Norbert; Höfler, Daniel; Gaipl, Udo; Frey, Benjamin; Schmidt, Manfred; Haller, Florian; et al. (International Journal of Hyperthermia, 2023)
Introduction: Neoadjuvant chemotherapy and radiotherapy for the management of soft tissue sarcomas (STS) are still preferably delivered sequentially, with or without concurrent hyperthermia. Concurrent delivery of chemo-, radio- and thermotherapy may produce synergistic effects and reduce chemotherapy-free intervals. The few available studies suggest that concurrent chemoradiation (CRT) has a greater local effect. Data on the efficacy and toxicity of adding hyperthermia to CRT (CRTH) are sparse. Materials and methods: A cohort of 101 patients with STS of the extremities and trunk who received CRT (n = 33) or CRTH (n = 68) before resection of macroscopic tumor (CRT: n = 19, CRTH: n = 49) or re-resection following a non-oncological resection, so called ‘whoops procedure’, (CRT: n = 14, CRTH: n = 19) were included in this retrospective study. CRT consisted of two cycles of doxorubicine (50 mg/m2 on d2) plus ifosfamide (1500 mg/m2 on d1-5, q28) plus radiation doses of up to 60 Gy. Hyperthermia was delivered in two sessions per week. Results: All patients received the minimum dose of 50 Gy. Median doses of ifosfamide and doxorubicin were comparable between CRT (75%/95%) and CRTH (78%/97%). The median number of hyperthermia sessions was seven. There were no differences in acute toxicities. Major wound complications occurred in 15% (CRT) vs. 25% (CRTH) (p = 0.19). In patients with macroscopic disease, the addition of hyperthermia resulted in a tendency toward improved remission: regression ≥90% occurred in 21/48 (CRTH) vs. 4/18 (CRT) patients (p = 0.197). With a median postoperative follow-up of 72 months, 6-year local control and overall survival rates for CRTH vs. CRT alone were 85 vs. 78% (p = 0.938) and 79 vs. 71% (p = 0.215). Conclusions: Both CRT and CRTH are well tolerated with an expected rate of wound complications. The results suggest that adding hyperthermia may improve tumor response.
CRIS-Team Scopus Importer:2023-09-01
Keywords: chemoradiotherapy; chemotherapy; hyperthermia; neoadjuvant; radiotherapy; Sarcoma; soft-tissue sarcoma; toxicity

CHIR99021 Promotes hiPSC-Derived Cardiomyocyte Proliferation in Engineered 3D Microtissues - Hesselbarth, Ramona; Esser, Tilman; Roshanbinfar, Kaveh; Schrüfer, Stefan; Schubert, Dirk W.; Engel, Felix (Advanced Healthcare Materials, 2021)
Cardiac tissue engineering is a promising strategy to generate human cardiac tissues for modeling cardiac diseases, screening for therapeutic drugs, and repairing the injured heart. Yet, several issues remain to be resolved including the generation of tissues with high cardiomyocyte density. Here, it is shown that the integration of the glycogen synthase kinase-3β inhibitor CHIR99021 in collagen I hydrogels promotes proliferation of human-induced pluripotent stem cell-derived (hiPSC) cardiomyocytes post-fabrication improving contractility of and calcium flow in engineered 3D cardiac microtissues. CHIR99021 has no effect on the gelation kinetics or the mechanical properties of collagen I hydrogels. Analysis of cell density and proliferation based on Ki-67 staining indicates that integration of CHIR99021 together with external CHIR99021 stimulation increases hiPSC-cardiomyocyte number by ≈2-fold within 7 d post-fabrication. Analysis of the contractility of engineered cardiac tissues after another 3 d in the absence of external CHIR99021 shows that CHIR99021-induced hiPSC-cardiomyocyte proliferation results in synchronized calcium flow, rhythmic beating, increased speed of contraction and contraction amplitude, and reduced peak-to-peak time. The CHIR99021-stimulated engineered cardiac microtissues exhibit spontaneous rhythmic contractions for at least 35 d. Collectively, the data demonstrate the potential of induced cardiomyocyte proliferation to enhance engineered cardiac microtissues by increasing cardiomyocyte density.
CRIS-Team Scopus Importer:2021-09-17
Keywords: cardiomyocytes; CHIR99021; heart; hiPSC; proliferation; tissue engineering

Chromophobes Nierenzellkarzinom – Diagnostik und Prognostik - Erlmeier, Franziska (Pathologe, 2019)
Chromophobe renal cell carcinoma is one of four malignant kidney tumor subtypes. Due to its morphological variance in clinical pathological routine diagnostics, this subtype can cause certain difficulties. The tumor can be mistaken for more aggressive or benign tumors. In both cases the consequences of misdiagnosis regarding treatment decisions can be serious. Due to the morphological variance of the tumor, it has not yet been possible to develop a generally accepted, prognostically convincing graduation scheme. The aim is to improve the quality of diagnostics and estimation of prognosis for this subtype of tumor in order to optimize patient care.
CRIS-Team Scopus Importer:2019-11-26
Keywords: B7-H1 antigen; Diagnostic errors; Prognosis; Proto-oncogene proteins c‑met; Renal cell carcinoma

Chromosomal aberrations in primary PDGFRA-mutated gastrointestinal stromal tumors - Schaefer, Inga-Marie; Delfs, Christian; Cameron, Silke; Gunawan, Bastian; Agaimy, Abbas; Ghadimi, B. Michael; Haller, Florian (Human Pathology, 2014)
Approximately 15% of gastrointestinal stromal tumors (GISTs) harbor mutations in the platelet-derived growth factor receptor ? (PDGFRA) gene. Chromosomal aberrations play a crucial role in tumor progression and correlate with clinical behavior. Imbalances, particularly in PDGFRA-mutated GISTs, have not yet been evaluated in larger series. We analyzed 53 PDGFRA-mutated GISTs (including 2 with corresponding metastases) for chromosomal imbalances by conventional comparative genomic hybridization and compared them with a historical collective of 122 KIT-mutated GISTs. PDGFRA exon 18 mutations (91% of cases) and exon 12 mutations (9% of cases) correlated significantly with gastric and intestinal sites, respectively. The most common aberrations were identical to those found in KIT-mutated GISTs, with -14q in 70%, -1p in 28%, and -22q in 17% of cases. Overall, there were significantly fewer chromosomal aberrations compared with KIT-mutated GISTs, with a mean of 2.8 (0.6 gains, 2.1 losses) aberrations per tumor. There was a statistically significant association of more than 5 chromosomal imbalances with intermediate/high-risk categories. Regarding specific chromosomal aberrations, -9p, -13q, and -22q correlated with intermediate/high risk, and -1p and +8q with poorer survival, although progression occurred in only 2 cases. Altogether, PDGFRA-mutated GISTs display the same chromosomal aberrations as KIT-mutated GISTs, although they have a lower degree of chromosomal instability in line with their generally favorable outcome.
EVALuna2:6492

Chronic hearing loss turns out being a calcified chondroid mesenchymal neoplasm with FN1::FGFR2 fusion - Bauerschmitz, Leonard; Agaimy, Abbas; Eckstein, Markus; Balk, Matthias; Iro, Heinrich; Schleder, Stephan; Schlaffer, Sven-Martin; Gostian, Antoniu-Oreste (European Archives of Oto-Rhino-Laryngology, 2024)
A 53 year old female presented with a six-year history of right-sided slow deterioration in hearing and a feeling of pressure in the right ear. The patient had not experienced any pain but reported some paresthesia of the right half of the tongue, whereas no further other cranial nerve deficits were evident. The otoscopy was unremarkable as well as the rest of the clinical ENT examination except for a slight asymptomatic swelling of the right cheek. Imaging findings showed an expansive tumor infiltrating and destroying the right lateral skull base. The tumor was partially composed of cystic/regressive lesions with high contrast media uptake. The tumor had high-signal intensity with water-sensitive sequences (T2w) and was hypointense on T1w images. We performed a tumor resection via a transparotideal-infratemporal approach. Histologically, the tumor was composed of granular variably calcified chondroid matrix with extensive regressive changes and granulation-like tissue reaction associated with calcinosis and crystal deposition. Molecular analysis of the tumor via the TruSight- RNA-Fusion panel detected a fusion involving FN1::FGFR2, consistent with “calcified chondroid mesenchymal neoplasm” (CCMN), a rare tumor entity recently defined by Liu et al 2021. In regular follow-up care no residual tumor has been detected in imaging studies (MRI and CT) within 2 years and 4 months. The biology and consequently the radio sensitivity cannot be defined precisely since long term results are missing due to the first description of this entity in 2021. As a consequence, surgical resection is recommended as the treatment of choice. Thorough clinical and radiological follow-up is mandatory as local recurrences are to be expected due to the infiltrative behavior. In case of a loco regional recurrence the fusion with FGFR2 may represent a therapeutic option for a targeted therapy on molecular level.
CRIS-Team Scopus Importer:2024-11-01
Keywords: Calcified chondroid mesenchymal neoplasm; Calcifying aponeurotic fibroma; CCMN; Chondrobastoma; Chondroma; Chondrosarcoma; Chordoma; FGF23; FGFR1; FGFR2; FN1; Ossifying fibromyxoid tumor; Phosphaturic mesenchymal tumors; PMT; Skull base tumor; TEK; Temporomandibular Joint; Tenosynovial giant cell tumor; TruSight-RNA-Fusion panel

Chronic Kidney Disease and Coronary Artery Disease: JACC State-of-the-Art Review - Sarnak, Mark J.; Amann, Kerstin Ute; Bangalore, Sripal; Cavalcante, João L.; Charytan, David M.; Craig, Jonathan C.; Gill, John S.; Hlatky, Mark A.; Jardine, Alan G.; Landmesser, Ulf; Newby, L. Kristin; Herzog, Charles A.; et al. (Journal of the American College of Cardiology, 2019)
Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage kidney disease and transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and priorities for research.
CRIS-Team Scopus Importer:2019-10-01
Keywords: acute coronary syndromes; calcification; chronic kidney disease; coronary artery disease; revascularization

Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference - Marwick, Thomas H.; Amann, Kerstin Ute; Bangalore, Sripal; Cavalcante, João L.; Charytan, David M.; Craig, Jonathan C.; Gill, John S.; Hlatky, Mark A.; Jardine, Alan G.; Landmesser, Ulf; Newby, L. Kristin; Herzog, Charles A.; et al. (Kidney International, 2019)
Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research.
CRIS-Team Scopus Importer:2019-09-24
Keywords: aortic stenosis; chronic kidney disease; end-stage kidney disease; mitral annular calcification; valvular heart disease

Chronic popliteal entrapment with calcified lesions results in an acute occlusion after blunt knee trauma in a 17-year-old soccer player - Regus, Susanne; Söder, Stephan; Janka, Rolf Matthias; Lang, Werner (Journal of Vascular Surgery, 2015)
EVALuna2:6687

Chronic recurrent multifocal osteomyelitis in association with pyoderma gangraenosum - Wurm, Matthias; Brecht, Ines; Lell, Michael; Brunner, Kathrin; Mitsimponas, Konstantinos Theodorou; Chada, Martin; Jahn, Julia; Neukam, Friedrich Wilhelm; von Wilmowsky, Cornelius (BMC Oral Health, 2016)
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare acquired inflammatory skeletal disorder of unknown origin. CRMO was first described by Gideon in 1972 and mainly affects children and young adults of female gender. The CRMO is part of the clinical picture of non-bacterial Osteomyelitis (NBO) and typically presents a relapsing recurring course with both remission and spontaneous exacerbation. CRMO is typically encountered in the limbs and the metaphysis of long bones in particular. Usually the clinical symptoms include painful swellings of the affected regions. This case report describes the rare case of a CRMO of the mandible in association with pyoderma gangraenosum.A 14-year old female caucasian patient, residing in the south of Germany, presented in the oncological outpatient clinic of our Department of Paediatrics and Adolescent Medicine in June 2014 complaining of increasing neck pain and progressive swelling at her left cheek ongoing for about 6 weeks. These symptoms had been occurring quarterly for 4 years, but had never been as pronounced. Blood biochemistry showed a moderately elevated CRP (35 mg/l) and a significantly increased blood sedimentation rate (BSR 48/120 mm). The panoramic radiograph, however, revealed a bone alteration in the left mandibular region. Further investigations confirmed the diagnosis of CRMO.The present case underlines the fact that rare diseases might occasionally present with even more rare symptoms. These occasions can obviously be considered to present a considerable diagnostic challenge.
EVALuna2:14591

Chronic renal insufficiency with hypercalcemia in a 60-year-old patient - Prechter, F.; Velden, J.; Mertz, A.; Messmann, H.; Goelder, S. (Internist, 2014)
A 60-year-old man developed stomach pains and early morning vomiting as well as fatigue over the last few months. Severe hypercalcemia was found in combination with a significantly reduced renal function. Laboratory tests as well as histological findings from the kidneys led to the working diagnosis of sarcoidosis with renal and possible osseous manifestations. After 14 days of oral medication with steroids the symptoms were significantly improved and renal parameters normalized.
EVALuna2:6747

CIDP, myasthenia gravis, and membranous glomerulonephritis - three autoimmune disorders in one patient: a case report - Bolz, Saskia; Totzeck, Andreas; Amann, Kerstin Ute; Stettner, Mark; Kleinschnitz, Christoph; Hagenacker, Tim (BMC Neurology, 2018)
BACKGROUND: We present a patient fulfilling the electrophysiological criteria for definite chronic inflammatory demyelinating polyneuropathy (CIDP), antibody-positive myasthenia gravis (MG), and membranous glomerulonephritis (MGN) confirmed by biopsy. To our knowledge, this is the first case of the concomitant appearance of these three autoimmune diseases in a single patient. CASE REPRESENTATION: A 42-year-old Caucasian male presented with rapidly progressive gait disturbance, distal weakness of the lower extremities, ascending hypoesthesia, impaired fine motor skills, and beginning cranial nerve palsy showing dysarthrophonia, facial paralysis, and eye movement abnormalities and was diagnosed as rapid onset (atypical) CIDP. After 3 months, the patient complained of increasing physical exhaustion, reduction of his walking distance, worsening of the residual dysphagia, and dysarthria with an inability to swallow. AChR antibodies (17.0 nmol/L, RF < 0.4) and titin antibodies were positive and repetitive nerve stimulation showed an abnormal decrement matching the criteria of myasthenia gravis. Over time the patient developed severe acute-on-chronic renal failure with high-grade proteinuria resulting in generalized edema followed by secondary hyperparathyroidism and dialysis-dependent renal failure. Renal biopsy confirmed beginning anti-phospholipase A2 receptor antibody membranous nephropathy. CONCLUSION: All three diseases are of autoimmune origin with distinctive immunopathogenetic mechanisms. The present case of CIDP, MG, and MGN occurring in one patient indicates a common underlying immune mechanism in these distinct conditions, including the involvement of autoantibodies and T cells.
EVALuna2:205570

Circulating micro-RNAs as potential blood-based markers for early stage breast cancer detection - Schrauder, Michael G.; Strick, Reiner; Schulz-Wendtland, Rüdiger; Strissel, Pamela; Kahmann, Laura; Loehberg, Christian R.; Lux, Michael P.; Jud, Sebastian; Hartmann, Arndt; Hein, Alexander; Bayer, Christian M.; Bani, Mayada; et al. (PLoS ONE, 2012)
Introduction: MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development. MiRNAs offer great potential as biomarkers for cancer detection due to their remarkable stability in blood and their characteristic expression in many different diseases. We investigated whether microarray-based miRNA profiling on whole blood could discriminate between early stage breast cancer patients and healthy controls. Methods: We performed microarray-based miRNA profiling on whole blood of 48 early stage breast cancer patients at diagnosis along with 57 healthy individuals as controls. This was followed by a real-time semi-quantitative Polymerase Chain Reaction (RT-qPCR) validation in a separate cohort of 24 early stage breast cancer patients from a breast cancer screening unit and 24 age matched controls using two differentially expressed miRNAs (miR-202, miR-718). Results: Using the significance level of p<0.05, we found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs and miRNA star sequences could be detected. A set of 240 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 78.8%, and a sensitivity of 92.5%, as well as an accuracy of 85.6%. Two miRNAs were validated by RT-qPCR in an independent cohort. The relative fold changes of the RT-qPCR validation were in line with the microarray data for both miRNAs, and statistically significant differences in miRNA-expression were found for miR-202. Conclusions: MiRNA profiling in whole blood has potential as a novel method for early stage breast cancer detection, but there are still challenges that need to be addressed to establish these new biomarkers in clinical use. © 2012 Schrauder et al.
CRIS-Team Scopus Importer:2021-07-19

Classification of three prognostically different groups of head and neck cancer patients based on their metabolic response to induction chemotherapy (IC-1) - Semrau, Sabine; Schmidt, Daniela; Hecht, Markus; Haderlein, Marlen; Kitzsteiner, Christian; Müller, Susanna; Traxdorf, Maximilian; Agaimy, Abbas; Iro, Heinrich; Kuwert, Torsten; Fietkau, Rainer (Oral Oncology, 2020)
Objectives: There exist no uniform decision criteria for conservative organ preservation treatments in head and neck cancer patients. Even with 18F-FDG-PET/CT after induction chemotherapy patient selection is challenging. This study correlated metabolic tumor response with treatment types and recurrence patterns. Materials and methods: Decrease in SUVmax in 18F-FDG-PET/CT was measured 21–28 days after IC-1 in 102 patients and correlated to cancer-specific endpoints. Results: Residual SUVmax (resSUVmax) values were uniformly distributed across five cut-off levels (0–0.2 vs. >0.2–0.4 vs. >0.4–0.6 vs. >0.6–0.8 vs. >0.8) containing 20%, 25% 25%, 15% and 15% of patients. Patients were stratified into three response categories according to residual SUVmax (Group A: 0–0.4 = high response Group B: >0.4–0.8 = moderate response, Group C > 0.8 = non-response), 5-year local control rates were 90.5% (Group A) vs. 78.9% (Group B; univariate p = 0.07, multivariate: HR: 3.6, p = 0.03) vs. 49.4% (Group C vs. B; univariate p = 0.04, multivariate: HR 5.5, p < 0.01). After IC-1, Group A received chemoradiotherapy (CRT) only. Group B received surgery plus either (chemo)radiotherapy (B_S + RT/CRT) or chemoradiotherapy (B_CRT), yielding local control rates of 100% and 74.2% (p = 0.11). Group C received surgery plus CRT or CRT alone; both achieved equally poor local control (p = 0.71). Group C had significantly worse distant metastasis-free survival and overall survival than Groups A and B (p < 0.05). Conclusion: Metabolic response after IC-1 differentiates HNC patients into three subgroups predicting local tumor control. Non-response was associated with a poor outcome.
CRIS-Team Scopus Importer:2019-12-03
Keywords: 18F-FDG PET/CT; Chemoradiation; Chemoselection; Head and neck cancer; Hypopharynx; Induction chemotherapy; Larynx; Metabolic response; Resection

Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas - Schaefer, Inga-Marie; Agaimy, Abbas; Fletcher, Christopher D. M.; Hornick, Jason L. (Modern Pathology, 2017)
Inactivation of SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex subunits is a feature shared by select carcinomas and sarcomas with epithelioid morphology and variable keratin expression, making the distinction between carcinoma and sarcoma challenging in some cases. The tight junction-associated protein claudin-4 is a marker of epithelial differentiation that is expressed in nearly all carcinomas. Claudin-4 expression has been reported in the glandular component of biphasic synovial sarcoma but has not been systematically evaluated in other sarcoma types. In this study we assessed claudin-4 expression in SWI/SNF complex-deficient neoplasms showing loss of SMARCB1 (INI1), SMARCA4 (BRG1), or ARID1A and other sarcomas with epithelioid morphology. Immunohistochemistry for claudin-4 was performed on 130 neoplasms, including 90 soft tissue tumors with epithelioid morphology and/or SMARCB1 deficiency (20 epithelioid sarcomas (10 conventional, 10 proximal-type); 10 epithelioid angiosarcomas; 10 epithelioid hemangioendotheliomas; 15 epithelioid malignant peripheral nerve sheath tumors; 10 malignant rhabdoid tumors; 15 myoepithelial carcinomas; 10 biphasic synovial sarcomas), 10 ovarian clear cell carcinomas, 10 ovarian small cell carcinomas of hypercalcemic type, and 20 SWI/SNF complex-deficient undifferentiated carcinomas (14 SMARCB1 deficient and 6 SMARCA4 deficient, including rhabdoid carcinomas of various sites and sinonasal carcinomas). Membranous expression of claudin-4 (>=5% of cells) was observed in all biphasic synovial sarcomas (epithelial component only), all ovarian clear cell carcinomas, and 16 (80%) SWI/SNF complex-deficient undifferentiated carcinomas. All other soft tissue tumors were negative for claudin-4, with the exception of two myoepithelial carcinomas and one malignant rhabdoid tumor. Interestingly, none of the ovarian small cell carcinomas of hypercalcemic type expressed claudin-4. In summary, expression of claudin-4 is highly specific for true epithelial differentiation and may be useful to distinguish SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas with epithelioid morphology. The lack of claudin-4 expression in ovarian small cell carcinomas of hypercalcemic type suggests that these tumors may be better regarded as sarcomas rather than carcinomas.
EVALuna2:6859

Clear cell myoepithelial carcinoma of salivary glands showing EWSR1 rearrangement: molecular analysis of 94 salivary gland carcinomas with prominent clear cell component - Skalova, Alena; Weinreb, Ilan; Hyrcza, Martin; Simpson, Roderick H. W.; Laco, Jan; Agaimy, Abbas; Vazmitel, Marina; Majewska, Hanna; Vanecek, Tomas; Talarcik, Peter; Manajlovic, Spomenka; Losito, Simona N.; et al. (American Journal of Surgical Pathology, 2015)
This study examines the presence of the EWSR1 rearrangement in a variety of clear cell salivary gland carcinomas with myoepithelial differentiation. A total of 94 salivary gland carcinomas with a prominent clear cell component included 51 cases of clear cell myoepithelial carcinomas de novo (CCMC), 21 cases of CCMCs ex pleomorphic adenoma (CCMCexPA), 11 cases of epithelial-myoepithelial carcinoma (EMC), 6 cases of EMC with solid clear cell overgrowth, and 5 cases of hyalinizing clear cell carcinoma of minor salivary glands. In addition, 10 cases of myoepithelial carcinomas devoid of clear cell change and 12 cases of benign myoepithelioma were included as well. All the tumors in this spectrum were reviewed, reclassified, and tested by fluorescence in situ hybridization (FISH) for the EWSR1 rearrangement using the Probe Vysis EWSR1 Break Apart FISH Probe Kit. The EWSR1 rearrangement was detected in 20 of 51 (39%) cases of CCMC, in 5 of 21 (24%) cases of CCMCexPA, in 1 of 11 (9%) cases of EMC, and in 4 of 5 (80%) cases of hyalinizing clear cell carcinoma. The 25 EWSR1-rearranged CCMCs and CCMCexPAs shared similar histomorphology. They were arranged in nodules composed of compact nests of large polyhedral cells with abundant clear cytoplasm. Necrosis, areas of squamous metaplasia, and hyalinization were frequent features. Immunohistochemically, the tumors expressed p63 (96%), cytokeratin CK14 (96%), and S100 protein (88%). MIB1 index varied from 10% to 100%, with most cases in the 20% to 40% range. Clinical follow-up information was available in 21 cases (84%) and ranged from 3 months to 15 years (mean 5.2 y); 4 patients were lost to follow-up. Ten patients are alive with no evidence of recurrent or metastatic disease in the follow-up period from 3 months to 15 years (mean 5 y), 3 patients are alive with recurrent and metastatic disease, and 8 died of disseminated cancer 9 months to 16 years after diagnosis (mean 6 y). Lymph node metastasis appeared in 5 patients within 5 months to 4 years after diagnosis (mean 22 mo), distant metastases were noted in 7 patients with invasion of orbit (2 cases), and in 1 case each metastasis to the neck soft tissues, liver, lungs, mediastinum, and thoracic vertebra was noted. We describe for the first time EWSR1 gene rearrangement in a subset of myoepithelial carcinomas arising in minor and major salivary glands. The EWSR1-rearranged CCMC represents a distinctive aggressive variant composed predominantly of clear cells with frequent necrosis. Most EWSR1-rearranged CCMCs of salivary glands are characterized by poor clinical outcomes.
EVALuna2:6713

CLEC10A Is a Specific Marker for Human CD1c+ Dendritic Cells and Enhances Their Toll-Like Receptor 7/8-Induced Cytokine Secretion - Heger, Lukas; Balk, Silke; Lühr, Jennifer; Heidkamp, Gordon Frederik; Lehmann, Christian; Hatscher, Lukas; Purbojo, Ariawan; Hartmann, Arndt; Garcia-Martin, Fayna; Nishimura, Shin-Ichiro; Cesnjevar, Robert; Nimmerjahn, Falk; et al. (Frontiers in Immunology, 2018)
Dendritic cells (DCs) are major players for the induction of immune responses. Apart from plasmacytoid DCs (pDCs), human DCs can be categorized into two types of conventional DCs: CD141+ DCs (cDC1) and CD1c+ DCs (cDC2). Defining uniquely expressed surface markers on human immune cells is not only important for the identification of DC subpopulations but also a prerequisite for harnessing the DC subset-specific potential in immunomodulatory approaches, such as antibody-mediated antigen targeting. Although others identified CLEC9A as a specific endocytic receptor for CD141+ DCs, such a receptor for CD1c+ DCs has not been discovered, yet. By performing transcriptomic and flow cytometric analyses on human DC subpopulations from different lymphohematopoietic tissues, we identified CLEC10A (CD301, macrophage galactose-type C-type lectin) as a specific marker for human CD1c+ DCs. We further demonstrate that CLEC10A rapidly internalizes into human CD1c+ DCs upon binding of a monoclonal antibody directed against CLEC10A. The binding of a CLEC10A-specific bivalent ligand (the MUC-1 peptide glycosylated with N-acetylgalactosamine) is limited to CD1c+ DCs and enhances the cytokine secretion (namely TNFα, IL-8, and IL-10) induced by TLR 7/8 stimulation. Thus, CLEC10A represents not only a candidate to better define CD1c+ DCs-due to its high endocytic potential-CLEC10A also exhibits an interesting candidate receptor for future antigen-targeting approaches.
EVALuna2:34257

Clinical Actionability of the Genomic Landscape of Metastatic Castration Resistant Prostate Cancer - Devlies, Wout; Eckstein, Markus; Cimadamore, Alessia; Devos, Gaetan; Moris, Lisa; Van Den Broeck, Thomas; Montironi, Rodolfo; Joniau, Steven; Claessens, Frank; Gevaert, Thomas (Cells, 2020)
The development of targeted therapies increases treatment options for metastatic castration resistant prostate cancer (mCRPC) patients. There is a need for strong predictive and prognostic signatures to guide physicians in treating mCRPC patients. In this review we unravel the possible actionability in the AR pathway, PI3K AKT signaling, and DNA repair pathways. Additionally, we make recommendations on biomarker trial design, and the clinical use of this new type of data.
CRIS-Team Scopus Importer:2020-12-18
Keywords: androgen receptor; biomarker; histology; mCRPC; prostate cancer; targeted therapies

Clinical and histopathological characterization of penile carcinomas with focus on HPV-status and histological subtype - Mink, Jan; Khalmurzaev, Oybek; Hoelters, Sebastian; Pryalukhin, Alexey; Heinzelbecker, Julia; Lohse, Stefan; Bende, Kristóf; Loertzer, Hagen; Steffens, Joachim; Jeronimo, Carmen; Wunderlich, Heiko; Bohle, Rainer; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium - Martins, Filipe Correia; Couturier, Dominique Laurent; Paterson, Anna; Karnezis, Anthony N.; Chow, Christine; Nazeran, Tayyebeh M.; Odunsi, Adekunle; Gentry-Maharaj, Aleksandra; Vrvilo, Aleksandra; Hein, Alexander; Talhouk, Aline; Osorio, Ana; et al. (British Journal of Cancer, 2020)
Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
CRIS-Team Scopus Importer:2020-06-26

Clinical and Surgical Evaluation of Sentinel Node Biopsy in Patients with Early-Stage Endometrial Cancer and Atypical Hyperplasia - Pöschke, Patrik; Gaß, Paul; Krückel, Annika; Keller, Katharina; Erber, Ramona; Hartmann, Arndt; Beckmann, Matthias; Emons, Julius (Geburtshilfe und Frauenheilkunde, 2024)
Introduction The medical and surgical treatment of endometrial cancer (EC) is evolving toward a more patient-centered and personalized approach. The role of laparoscopic sentinel node biopsy (SNB) for early-stage EC is unclear, and very few data are available for atypical endometrial hyperplasia (AEH). The present study investigated the effectiveness of SNB combined with laparoscopic hysterectomy in patients with early-stage EC and AEH. Patients and Methods This was a retrospective, single-center cohort study for the period from January 2018 to December 2023. A total of 102 patients with atypical hyperplasia (n = 20) and early-stage EC (n = 82) findings on diagnostic curettage underwent pelvic sentinel node biopsy during the final operation. Results Eleven patients (55%) who had initially been diagnosed with AEH were found to have EC in the final pathology report. No lymph node metastases were detected in patients who had initially been diagnosed with AEH; a 3.6% rate of positive SNBs was found in patients with EC. Changes in tumor grade occurred in 31.3% of the patients and changes in FIGO stage in 33%. Bilateral sentinel node (SN) mapping was successful in 94.1% of the patients. The postoperative outcomes were comparable to those of routine clinical practice without SNB. Conclusions SNB can be safely offered to patients who have precursor lesions and early-stage EC without notably extending surgical times or increasing postoperative morbidity. This approach can be considered and is safe for patients diagnosed with AEH, but it appears to have a rather small impact on these patients.
CRIS-Team Scopus Importer:2024-06-14
Keywords: atypical endometrial hyperplasia; endometrial cancer; indocyanine green; sentinel node biopsy; surgery

Clinical behavior of chromophobe renal cell carcinoma is less aggressive than that of clear cell renal cell carcinoma, independent of Fuhrman grade or tumor size - Steffens, Sandra; Roos, Frederik C.; Janssen, Martin; Becker, Frank; Steinestel, Julie; Abbas, Mahmoud; Steinestel, Konrad; Wegener, Gerd; Siemer, Stefan; Thueroff, Joachim W.; Hofmann, Rainer; Stoeckle, Michael; et al. (Virchows Archiv, 2014)
Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of RCC, after clear cell (ccRCC) and papillary RCC. Its lower incidence and frequent exclusion from clinical trials might be why chRCC characteristics have not been extensively studied. The aim of our study was to examine tumor characteristics and long-term prognosis of chRCC compared to ccRCC. We collected 4,210 evaluable patients subjected to surgery for chRCC (n = 176) or ccRCC (n = 4,034) at five centers in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm, and Marburg) between 1990 and 2010. Patients with chRCC were significantly younger (mean, 60.1 vs. 62.1 years) and tended to be more frequently female (43.8 vs. 36.5 %). Although Fuhrman grade and median tumor diameter were not significantly different, significantly fewer patients with chRCC than with ccRCC presented with high tumor stage or metastasis at diagnosis (18.5 vs. 43.8 %). Moreover, significantly more chRCC patients were treated with partial nephrectomy (41.5 vs. 26.2 %). Accordingly, 5-year cancer-specific survival (CSS) rates were 83.2 % for chRCC against 75.8 % for ccRCC patients (p = 0.014, log rank). However, in multivariate analysis, chromophobe subtype was not confirmed as a significant positive prognostic factor for RCC (HR 0.88, 95 % CI 0.63-1.24; p = 0.48 Cox regression). This is one of the largest studies to date showing that chRCC is associated with a significantly lower risk of locally invasive tumor growth and metastatic disease than ccRCC. We conclude that the clinical behavior of chRCC is less aggressive than that of ccRCC, independent of Fuhrman grade or tumor size.
EVALuna2:6677

Clinical Characteristics and Prognosis of HER2-0 and HER2-Low-Positive Breast Cancer Patients: Real-World Data from Patients Treated with Neoadjuvant Chemotherapy - Pöschke, Patrik; Fasching, Peter; Adler, Werner; Rübner, Matthias; Beckmann, Matthias; Hack, Carolin; Heindl, Felix; Hartmann, Arndt; Erber, Ramona; Gaß, Paul (Cancers, 2023)
In our study, we observed the long-term survival outcomes investigated for HER2-0 and HER2-low-positive breast cancer patients who received neoadjuvant chemotherapy. Between 1998 and 2020, 10,333 patients with primary breast cancer were treated, including 1373 patients with HER2-0 or HER2-low-positive disease with neoadjuvant chemotherapy. Descriptive analyses were performed, and logistic regression models and survival analyses were calculated for disease-free survival (DFS) and overall survival (OS). Among the 1373 patients, 930 (67.73%) had HER2-low-positive and 443 (32.27%) had HER2-0 tumors. Patients with HER2-0 tumors had a significantly better pathological complete response, 29.25% vs. 20.09%, and pathological complete response/in situ, 31.97% vs. 24.08%, than patients with HER2-low-positive tumors (p < 0.001; p = 0.003), regardless of the hormone receptor (HR) status. No statistically significant differences were observed for the HR-positive (p = 0.315; p = 0.43) or HR-negative subgroups (p = 0.573; p = 0.931). DFS and OS were significantly longer for HR-positive, HER2-low-positive patients (log-rank p = 0.02; p = 0.012). OS was significantly longer for HR-negative, HER2-0 patients (log-rank p = 0.032). No significant DFS differences were found for the HR-negative cohort (log-rank p = 0.232). For the overall cohort, no significant differences were noted between HER2-low-positive and HER2-0 patients, either for DFS (log-rank p = 0.220) or OS (log-rank p = 0.403). These results show different survival outcomes for HER2-0 and HER2-low-positive tumors relative to HR status. These different cohorts can be identified using standardized immunohistochemistry, even retrospectively.
CRIS-Team Scopus Importer:2023-10-20
Keywords: breast cancer; HER2; HER2-0; HER2-low-positive; neoadjuvant therapy; prognosis

Clinical Course of an Early Childhood-Onset Granulomatosis with Polyangiitis - Krasselt, Marco; Pierer, Matthias; Amann, Kerstin Ute; Bachmann, Anette; Lindner, Tom H. (Deutsche Medizinische Wochenschrift, 2017)
History A 26-year-old male patient presented with an eight-week history of unspecific symptoms such as weight loss and fever. Besides, he also suffered from haemoptysis, cough, and arthralgia. Since the age of twelve years, the patient has been treated for Wegner's granulomatosis. At the age of 20 years he received a kidney transplant which failed only four years later. Investigations The relapse we clinically suspected was confirmed by CT scan showing bilateral pulmonary manifestations. Moreover, we found highly positive antibodies against proteinase 3. Treatment and course After an induction therapy using Glucocorticoids and Rituximab, accompanied by plasmapheresis, the patient's clinical condition showed a marked improvement. We were able to discharge him continuing the treatment in an outpatient setting. Conclusion Childhood-onset GPA is a life-threatening disease and often characterized by recurring relapses as well as a significantly reduced quality of life for the patient.
EVALuna2:25540

Clinical Data Do Not Reliably Predict Duodenal Histology at Follow-up in Celiac Disease: A 13 Center Correlative Study - Patel, Natalie; Leffler, Daniel A.; Al-Toma, Abdulbaqi; Mulder, Chris J.; Elli, Luca; Gan, Geliang; Patil, Pallavi; Atsawarungruangkit, Amporn; Kuijpers, Karel C.; Del Gobbo, Alessandro; Goldsmith, Jeffrey; Hintze, Zach; et al. (American Journal of Surgical Pathology, 2024)
Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti-tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti-tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score (P<0.001) and IELs (P<0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.
CRIS-Team Scopus Importer:2024-02-02
Keywords: celiac disease; duodenum; intraepithelial lymphocytes; Marsh score; tissue transglutaminase

Clinical Implications of Basic Research: Exploring the Transformative Potential of Spatial 'Omics in Uro-oncology - Figiel, Sandy; Bates, Anthony; Braun, David A.; Eapen, Renu; Eckstein, Markus; Manley, Brandon J.; Milowsky, Matthew I.; Mitchell, Tom J.; Bryant, Richard J.; Sfakianos, John P.; Lamb, Alastair D. (European Urology, 2024)
New spatial molecular technologies are poised to transform our understanding and treatment of urological cancers. By mapping the spatial molecular architecture of tumours, these platforms uncover the complex heterogeneity within and around individual malignancies, offering novel insights into disease development, progression, diagnosis, and treatment. They enable tracking of clonal phylogenetics in situ and immune-cell interactions in the tumour microenvironment. A whole transcriptome/genome/proteome-level spatial analysis is hypothesis generating, particularly in the areas of risk stratification and precision medicine. Current challenges include reagent costs, harmonisation of protocols, and computational demands. Nonetheless, the evolving landscape of the technology and evolving machine learning applications have the potential to overcome these barriers, pushing towards a future of personalised cancer therapy, leveraging detailed spatial cellular and molecular data. Patient summary: Tumours are complex and contain many different components. Although we have been able to observe some of these differences visually under the microscope, until recently, we have not been able to observe the genetic changes that underpin cancer development. Scientists are now able to explore molecular/genetic differences using approaches such as “spatial transcriptomics” and “spatial proteomics”, which allow them to see genetic and cellular variation across a region of normal and cancerous tissue without destroying the tissue architecture. Currently, these technologies are limited by high associated costs, and a need for powerful and complex computational analysis workflows. Future advancements and results through these new technologies may assist patients and their doctors as they make decisions about treating their cancer.
CRIS-Team Scopus Importer:2024-09-13
Keywords: Genomics; Proteomics; Transcriptomics; Urological cancer

Clinically relevant molecular pathological diagnostics in breast cancer Klinisch relevante molekularpathologische Diagnostik beim Mammakarzinom - Rodepeter, Fiona R.; Teply-Szymanski, Julia; Romey, Marcel; Grass, Albert; Erber, Ramona; Lebeau, Annette; Mack, Elisabeth K.M.; Tarawneh, Thomas S.; Gremke, Niklas; Boekhoff, Jelena; Wündisch, Thomas; Wagner, Uwe; et al. (Die Pathologie, 2023)
In breast cancer, the current guideline for pathological workup includes recommendations for advanced molecular analysis of certain predictive molecular markers in addition to basic immunohistochemical diagnostics. These markers are determined depending on tumor stage, including sequencing techniques and immunohistochemical methods. This comprises the systematic investigation of molecular alterations such as PIK3CA or BRCA1,2 mutations, NTRK fusions, or microsatellite instability as a basis for targeted therapy. Further alterations, for example in the PI3K pathway, ESR1 alterations, or ERBB2 mutations, may also be relevant for individual therapy decisions especially in the context of resistant or relapsed disease. Thus, particularly in advanced stages, a more comprehensive molecular characterization of the tumor may reveal genetic alterations that act as tumor drivers and provide targets for personalized therapies. Due to the large number of potential molecular targets, NGS panel diagnostics are a suitable approach in this conjunction with immunohistochemical characterization and the individual clinical situation. Molecular based therapeutical strategies outside of entity-specific approvals should be discussed in an interdisciplinary team within the framework of a molecular tumor board.
CRIS-Team Scopus Importer:2023-01-20
Keywords: Biomarkers; Breast neoplasms; Diagnostic algorithm; Panel sequencing; Targeted therapy

Clinical performance of Immunoscore (R) in early colon cancer in the Asian population - Galon, J.; Kawakami, Y.; Torigoe, T.; Wang, Y.; Patel, P. S.; Vora, H.; Mlecnik, B.; Marliot, F.; Bifulco, C. B.; Lugli, A.; Nagtegaal, I. D.; Hartmann, Arndt; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Clinical Performance of QIAGEN Fibroblast Growth Factor Receptor (FGFR) Assay for the Detection of FGFR Alterations in Erdafitinib-Treated Patients with Metastatic or Locally Advanced, Surgically Unresectable, Urothelial Cancer - Major, C.; Wang, S.; Burgess, M.; English, A.; Sweeney, M.; Hartmann, Arndt (JOURNAL OF MOLECULAR DIAGNOSTICS, 2019)
CRIS-Team WoS Importer:2021-10-18

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study - Mlecnik, Bernhard; Torigoe, Toshihiko; Bindea, Gabriela; Popivanova, Boryana; Xu, Mingli; Fujita, Tomonobu; Hazama, Shoichi; Suzuki, Nobuaki; Nagano, Hiroaki; Okuno, Kiyotaka; Hirohashi, Yoshihiko; Furuhata, Tomohisa; et al. (Cancers, 2022)
BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I–III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10–4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.
CRIS-Team Scopus Importer:2022-10-07
Keywords: Asian; classification; colon cancer; immune response; Immunoscore; MSI; prognostic markers; risk stratification; T cell; tumor microenvironment

Clinical relevance of miR-mediated HLA-G regulation and the associated immune cell infiltration in renal cell carcinoma - Jasinski-Bergner, Simon; Stoehr, Christine; Bukur, Juergen; Massa, Chiara; Braun, Juliane; Huettelmaier, Stefan; Spath, Verena; Wartenberg, Roland; Legal, Wolfgang; Taubert, Helge; Wach, Sven; Wullich, Bernd; et al. (OncoImmunology, 2015)
In human tumors of distinct origin including renal cell carcinoma (RCC), the non-classical human leukocyte antigen G (HLA-G) is frequently expressed, thereby inhibiting the cytotoxic activity of T and natural killer (NK) cells. Recent studies demonstrated a strong post-transcriptional gene regulation of the HLA-G by miR-152, -148A, -148B and -133A. Standard methods were applied to characterize the expression and function of HLA-G, HLA-G-regulatory microRNAs (miRs) and the immune cell infiltration in 453 RCC lesions using a tissue microarray and five RCC cell lines linking these results to clinical parameters. Direct interactions with HLA-G regulatory miRs and the HLA-G 3' untranslated region (UTR) were detected and the affinities of these different miRs to the HLA-G 3'-UTR compared. qPCR analyses and immunohistochemical staining revealed an inverse expression of miR-148A and -133A with the HLA-G protein in situ and in vitro. Stable miR overexpression caused a downregulation of HLA-G protein enhancing the NK and LAK cell-mediated cytotoxicity in in vitro CD107a activation assays revealing a HLA-G-dependent cytotoxic activity of immune effector cells. A significant higher frequency of CD3(+)/CD8(+) T cell lymphocytes, but no differences in the activation markers CD69, CD25 or in the presence of CD56(+), FoxP3(+) and CD4(+) immune cells were detected in HLA-G(+) compared to HLA-G(-) RCC lesions. This could be associated with higher WHO grade, but not with a disease-specific survival. These data suggest a miR-mediated control of HLA-G expression in RCC, which is associated with a distinct pattern of immune cell infiltration.
EVALuna2:6743

Clinical utility of the S3-score for molecular prediction of outcome in non-metastatic and metastatic clear cell renal cell carcinoma - Buettner, Florian; Winter, Stefan; Rausch, Steffen; Hennenlotter, Joerg; Kruck, Stephan; Stenzl, Arnulf; Scharpf, Marcus; Fend, Falko; Agaimy, Abbas; Hartmann, Arndt; Bedke, Jens; Schwab, Matthias; et al. (BMC Medicine, 2018)
BACKGROUND: Stratification of cancer patients to identify those with worse prognosis is increasingly important. Through in silico analyses, we recently developed a gene expression-based prognostic score (S3-score) for clear cell renal cell carcinoma (ccRCC), using the cell type-specific expression of 97 genes within the human nephron. Herein, we verified the score using whole-transcriptome data of independent cohorts and extend its application for patients with metastatic disease receiving tyrosine kinase inhibitor treatment. Finally, we sought to improve the signature for clinical application using qRT-PCR. METHODS: A 97 gene-based S3-score (S397) was evaluated in a set of 52 primary non-metastatic and metastatic ccRCC patients as well as in 53 primary metastatic tumors of sunitinib-treated patients. Gene expression data of The Cancer Genome Atlas (n = 463) was used for platform transfer and development of a simplified qRT-PCR-based 15-gene S3-score (S315). This S315-score was validated in 108 metastatic and non-metastatic ccRCC patients and ccRCC-derived metastases including in part several regions from one metastasis. Univariate and multivariate Cox regression stratified by T, N, M, and G were performed with cancer-specific and progression-free survival as primary endpoints. RESULTS: The S397-score was significantly associated with cancer-specific survival (CSS) in 52 ccRCC patients (HR 2.9, 95% Cl 1.0-8.0, PLog-rank = 3.3 × 10-2) as well as progression-free survival in sunitinib-treated patients (2.1, 1.1-4.2, PLog-rank = 2.2 × 10-2). The qRT-PCR based S315-score performed similarly to the S397-score, and was significantly associated with CSS in our extended cohort of 108 patients (5.0, 2.1-11.7, PLog-rank = 5.1 × 10-5) including metastatic (9.3, 1.8-50.0, PLog-rank = 2.3 × 10-3) and non-metastatic patients (4.4, 1.2-16.3, PLog-rank = 1.6 × 10-2), even in multivariate Cox regression, including clinicopathological parameters (7.3, 2.5-21.5, PWald = 3.3 × 10-4). Matched primary tumors and metastases revealed similar S315-scores, thus allowing prediction of outcome from metastatic tissue. The molecular-based qRT-PCR S315-score significantly improved prediction of CSS by the established clinicopathological-based SSIGN score (P = 1.6 × 10-3). CONCLUSION: The S3-score offers a new clinical avenue for ccRCC risk stratification in the non-metastatic, metastatic, and sunitinib-treated setting.
EVALuna2:34608

Clinical utility of the simplified 15-gene S3-score for prediction of outcome in clear cell renal cell carcinoma - Buettner, F.; Winter, S.; Rausch, S.; Hennenlotter, J.; Kruck, S.; Stenzl, A.; Scharpf, M.; Fend, F.; Agaimy, Abbas; Hartmann, Arndt; Bedke, J.; Schwab, M.; et al. (NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2019)
CRIS-Team WoS Importer:2019-02-21

Clinicopathological, immunohistochemical, molecular-genetic and risk profiles of gastrointestinal stromal tumors in a cohort of Sudanese patients - Husain, Nazik Elmalaika; Osman, Ihsan Mohamed; Khalid, Ahmed; Satir, Ali Abdel; Stöhr, Robert; Agaimy, Abbas (African Health Sciences, 2023)
Background: Determining the risk of malignant behaviour and mutational status of gastrointestinal stromal tumours (GISTs) guide the management decision and allow optimal individualized patient treatment.Objectives: To determine clinicopathological, immunohistochemical (IHC), risk and KIT mutational findings of GISTs in Sudanese patients. Methods: Histological slides were reviewed, IHC for DOG-1 and CD117 performed and hotspot KIT mutations examined. The risk group was assigned using combined risk criteria.Results: 21 of the 36 patients (58.3%) were males (mean age, 54.83 +/- 12.57; range, 26-71). Abdominal pain and mass were the most frequent symptoms. Mean tumor size (+/- SD) was 11.6(+/- 5.82) cm. Either CD117, DOG1 or both were positive in all cases. Using risk criteria, 33.3% (n=12) were clinically malignant at presentation, 13.9% (n=5) high risk, 16.7% (n=6) intermediate, 27.8% (n=10) low risk and 2.8% (n=1) very low risk. Sixteen of 23 (70%) tested cases had KIT (14 exon 11 and two exon 9) mutations. Six tumors were wild type. Exon 11 deletions (p.I563-L576 del and p.V559-N566delinsD) significantly correlate with disease recurrence (p-value: 0.028). Conclusions: Sudanese patients with GIST tend to present late. Nearly half of them correspond to the malignant/high-risk category. The frequency of KIT mutations (79.31%) is in line with the literature.
CRIS-Team WoS Importer:2023-06-02
Keywords: Gastrointestinal stromal tumour; GIST; risk stratification; malignant behaviour; risk assessment; tumour rupture; metastasis; Imatinib; genotyping; KIT; DOG1

CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs - Jitschin, Regina; Braun, Martina; Büttner, Maike; Dettmer-Wilde, Katja; Bricks, Juliane; Berger, Jana; Eckart, Michael J.; Krause, Stefan; Oefner, Peter J.; Le Blanc, Katarina; Mackensen, Andreas; Mougiakakos, Dimitrios (Blood, 2014)
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population that shares certain characteristics including an aberrant myeloid phenotype and the ability to suppress T cells. MDSCs have been predominantly studied in malignant diseases and findings suggest involvement in tumor-associated immune suppression. Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence among adults. Immune defects occur already at early disease stages and impact the clinical course. We assessed presence, frequency, association to other immune parameters, and functional properties of circulating CD14(+) cells lacking HLA-DR expression (HLA-DR(lo)) in patients with untreated CLL. These monocytic cells represent one of the best-defined human MDSC subsets. Frequency of CD14(+)HLA-DR(lo) cells was significantly increased in CLL patients. Furthermore, MDSCs suppressed in vitro T-cell activation and induced suppressive regulatory T cells (TRegs). The MDSC-mediated modulation of T cells could be attributed to their increased indoleamine 2,3-dioxygenase (IDO) activity. CLL cells induced IDO(hi) MDSCs from healthy donor monocytes suggesting bidirectional crosstalk between CLL-cells, MDSCs, and TRegs. Overall, we identified a MDSC population that expands in CLL. The exact mechanisms responsible for such accumulation remain to be elucidated and it will be of interest to test whether antagonizing suppressive functions of CLL MDSCs could represent a mean for enhancing immune responses.
EVALuna2:25463

cMET: a prognostic marker in papillary renal cell carcinoma? - Erlmeier, Franziska; Bruecher, Benedict; Stoehr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Ströbel, Philipp; Becker, Frank; Wülfing, Christian; Barth, Peter; Stöckle, Michael; et al. (Human Pathology, 2022)
The tyrosine-protein kinase c-Met plays a decisive role in numerous cellular processes, as a proto-oncogene that supports aggressive tumor behavior. It is still unknown whether c-Met could be relevant for prognosis of papillary RCC (pRCC). Specimen collection was a collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from 197 and 110 patients with type 1 and 2 pRCC, respectively. Expression of cMET was determined by immunohistochemistry. In total, cMET staining was evaluable in of 97 of 197 type 1 and 63 of 110 type 2 pRCC cases. Five-year overall survival revealed no significant difference in dependence of cMET positivity (cMET− vs. cMET+: pRCC type 1: 84.8% vs. 80.3%, respectively [p = 0.303, log-rank]; type 2: 71.4% vs. 64.4%, respectively [p = 0.239, log-rank]). Interestingly, the subgroup analyses showed a significant difference for cMET expression in T stage and metastases of the pRCC type 2 (p = 0.014, p = 0.022, chi-square). The cMET-positive type 2 collective developed more metastases than the cMET-negative cohort (pRCC type 2 M+: cMET−: 2 [4.3%] vs. cMET+: 12 [19%]). cMET expression did not qualify as a prognostic marker in pRCC for overall survival.
CRIS-Team Scopus Importer:2022-02-04
Keywords: cMET; Outcome; Papillary renal cell carcinoma; Prognosis; Survival

c-Met in chromophobe renal cell carcinoma - Erlmeier, Franziska; Ivanyi, Philipp; Hartmann, Arndt; Autenrieth, Michael; Wiedemann, Max; Weichert, Wilko; Steffens, Sandra (Medical Oncology, 2017)
c-Met plays a role as a prognostic marker in clear cell renal cell carcinoma. In addition, recently the tyrosine kinase inhibitor cabozantinib targeting c-Met was approved for the treatment of advanced renal cell carcinoma (RCC). In contrast to clear cell RCC, little is known about c-Met expression patterns in rarer RCC subtypes. The aim of this study was to evaluate the prevalence, distribution and prognostic impact of c-Met expression on chromophobe (ch)RCC. Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for c-Met expression by immunohistochemistry. Expression data were associated with clinicopathological parameters including patient survival. Eighty-one chRCC patients were eligible for analysis. Twenty-four (29.6%) patients showed a high c-Met expression (c-Met(high), staining intensity higher than median). Our results showed an association between c-Met(high) expression and the existence of lymph node metastasis (p = 0.007). No further significant clinicopathological associations with c-Met were identified, also regarding c-Met expression and overall survival. In conclusion, to our knowledge this is the first study evaluating the prognostic impact of c-Met in a considerably large cohort of chRCC. High c-Met expression is associated with the occurrence of lymph node metastasis. This indicates that c-Met might be implicated into metastatic progression in chRCC.
EVALuna2:6842

c-MET Oncogene in Renal Cell Carcinomas - Erlmeier, F.; Weichert, W.; Autenrieth, M.; Ivanyi, P.; Hartmann, Arndt; Steffens, S. (Aktuelle Urologie, 2016)
c-Met plays a significant role in multiple cellular processes. Being encoded by a proto-oncogene, tyrosine kinase supports aggressive tumour behaviour such as tumour invasiveness and formation of metastases. For some subtypes of renal cell carcinoma studies have shown a association between c-Met expression and clinical outcome or prognosis. Therefore, c-Met represents a prognostic marker in renal cell carcinoma.Furthermore, c-MET will play a decisive role as a possible target for targeted therapies in the era of personalised medicine. Especially for RCC, the dual inhibition of VEGF and c-MET tyrosine kinase in cases of metastatic, treatment-resistant tumours is gaining clinical relevance. The role of c-Met has not been fully elucidated for all subtypes of renal cell carcinomas. The relevance of c-Met for the remaining subtypes of renal tumours has yet to be clarified.
EVALuna2:6923

Coding and Non-coding: Molecular Portrait of GIST and its Clinical Implication - Bure, I.; Haller, Florian; Zaletaev, D. V. (Current Molecular Medicine, 2018)
Gastrointestinal stromal tumours are the most common mesenchymal tumours of the gastrointestinal tract. Despite similar mutation pattern of activating mutations in KIT or PDGFRA receptors in 85% of cases, they demonstrate significantly heterogeneous clinical behaviour and pathological characteristics. This heterogeneity opens the question of the role of other factors and mechanisms of regulation in the development of GIST. Additional mutations in downstream effectors of GIST related signalling pathways or aberrant expression of non-coding RNAs may be additional contributing factors, the latter being increasingly recognized in carcinogenesis in general. Recently, a substantial progress has been achieved in understanding the functional roles of lncRNAs in GIST suggesting their potential employment as biomarkers and therapeutic targets in GIST. Moreover, some miRNAs have recently been found to be able to sensitize cells to imatinib, which could be an attractive option to overcome the resistance to the drug, which hampers the efficacy of GIST treatment. Therefore, the advantage can be taken of both coding and non-coding parts of the genome in order to significantly improve prognostication and help find personalized therapy for patients, depending on a subtype of GIST and personal characteristics.
EVALuna2:207062

Coding practice in national and regional kidney biopsy registries - Dendooven, Amélie; Peetermans, Han; Helbert, Mark; Nguyen, Tri Q.; Marcussen, Niels; Nagata, Michio; Gesualdo, Loreto; Perkowska-Ptasinska, Agnieszka; Capusa, Cristina; López-Gómez, Juan M.; Geddes, Colin; Abdul-Hamid, Myrurgia A.; et al. (BMC Nephrology, 2021)
Background: Kidney biopsy registries all over the world benefit research, teaching and health policy. Comparison, aggregation and exchange of data is however greatly dependent on how registration and coding of kidney biopsy diagnoses are performed. This paper gives an overview over kidney biopsy registries, explores how these registries code kidney disease and identifies needs for improvement of coding practice. Methods: A literature search was undertaken to identify biopsy registries for medical kidney diseases. These data were supplemented with information from personal contacts and from registry websites. A questionnaire was sent to all identified registries, investigating age of registries, scope, method of coding, possible mapping to international terminologies as well as self-reported problems and suggestions for improvement. Results: Sixteen regional or national kidney biopsy registries were identified, of which 11 were older than 10 years. Most registries were located either in Europe (10/16) or in Asia (4/16). Registries most often use a proprietary coding system (12/16). Only a few of these coding systems were mapped to SNOMED CT (1), older SNOMED versions (2) or ERA-EDTA PRD (3). Lack of maintenance and updates of the coding system was the most commonly reported problem. Conclusions: There were large gaps in the global coverage of kidney biopsy registries. Limited use of international coding systems among existing registries hampers interoperability and exchange of data. The study underlines that the use of a common and uniform coding system is necessary to fully realize the potential of kidney biopsy registries.
CRIS-Team Scopus Importer:2021-06-11
Keywords: Coding; Kidney biopsy registry; Nephropathology; Renal pathology; Systematic review

Coexistence of gastrointestinal stromal tumours (GIST) and malignant neoplasms of different origin: prognostic implications - Vassos, Nikolaos; Agaimy, Abbas; Hohenberger, Werner; Croner, Roland S. (International Journal of Surgery, 2014)
Over the past decade, several changes occurred in diagnostics, treatment and understanding of pathogenesis of gastrointestinal stromal tumours (GIST). However, their coexistence with other malignancies of different histogenetic origin remains a challenging issue.Patients diagnosed with GIST in a 10-years period were identified retrospectively and clinical history and findings thoroughly explored for the presence of associated other malignancies. Follow up data were obtained and analysed for prognostic impact of the concurrent malignancy and/or GIST.Thirty seven (27 males, 10 females) of 86 GIST-patients (43%) had another malignancy. Mean age was 70 years. Associated malignancies were gastrointestinal (n = 29; 69%), renal-/urological (n = 5; 12%), haematological (n = 4; 9.5%), cutaneous (n = 3; 7%) and thyroid (n = 1; 2.5%) in origin. Majority of GISTs occurred in stomach (65%) and small intestine (30.6%) and most (78%) were asymptomatic incidental findings during diagnostic or therapeutic procedures for associated malignancies. GIST size ranged from 0.1 cm to 9 cm (mean, 2.2 cm) and all of them had a low (<5/50 HPFs) or no mitotic activity. Thirty-one tumours (84%) were of no/very low/low risk and 6 were of intermediate risk. During follow-up (range 3-160 months, mean; 60 months), one patient suffered from distant metastases of GIST. Seven patients (19%) died of associated malignancies and three patients (8%) of other non-tumour-associated cause, but none died of GIST.Coexistence of GIST with other malignancies is higher than previously reported and should draw attention of clinicians towards these incidental findings. Prognosis in these patients is usually determined by other malignancy and not significantly influenced by GIST. Therefore treatment algorithms should be focused on prognostically relevant malignancy.
EVALuna2:6572

COL4A5-p.Gly624Asp is the Predominant Variant in Europe Associated With a Mild Alport Syndrome Phenotype - Krüger, Bastian M.; Jens, Annika; Neuhaus, Anna; Ćomić, Jasmina; Berutti, Riccardo; de Fallois, Jonathan; Petzold, Friederike; Münch, Johannes; Kowald, Jan; Lindner, Tom H.; Budde, Klemens; Brüning, Klara K.; et al. (Kidney International Reports, 2025)
Introduction: Pathogenic variants in COL4A3–5 are common causes of inherited kidney disease. The clinical presentation extends from classical Alport syndrome (AS) to focal segmental glomerulosclerosis (FSGS) without extrarenal manifestation. In this study, we aimed to assess the genetic and phenotypic spectrum, along with the associated natural histories, in a cohort of patients with AS from 3 tertiary centers in Central Europe. Methods: A total of 210 patients with disease causing variants in one of the COL4A3–5 genes were characterized and evaluated for genotype-phenotype correlations. In addition, 48 COL4A5-p.Gly624Asp carriers were analyzed for replication and pooled analysis. Results: COL4A5-p.Gly624Asp was by far the most common variant, accounting for 16% of all genetic diagnoses. These patients presented with overall milder renal phenotypes than patients with other COL4A5 missense variants and COL4A5 glycine-missense variants after age- and sex-matching. In patients lacking a wild-type allele (X-Linked AS [XLAS] males and autosomal recessive AS [ARAS]), histological AS was most frequently observed in kidney biopsies, and truncating variants were associated with increased disease severity. Conversely, in patients with a wild-type allele present (XLAS females and autosomal dominant AS [ADAS]), FSGS was more frequently observed. Predicted protein truncation was not inferior to missense alterations in terms of renal survival. Conclusion: The predominance of the European COL4A5 founder variant p.Gly624Asp allowed for the creation of the largest cohort of patients with an identical Alport variant to date, confirming the more favorable renal prognosis specific to this amino acid change. Allelic and gene dosage effects drive phenotypic differences and should be incorporated into future risk models.
CRIS-Team Scopus Importer:2025-04-01
Keywords: alport syndrome; chronic kidney disease; COL4A3; COL4A4; COL4A5; collagen type IV

Collagen Hydrogel Containing Polyethylenimine-Gold Nanoparticles for Drug Release and Enhanced Beating Properties of Engineered Cardiac Tissues - Roshanbinfar, Kaveh; Kolesnik-Gray, Maria; Angeloni, Miriam; Schrüfer, Stefan; Fiedler, Maren; Schubert, Dirk W.; Ferrazzi, Fulvia; Krstic, Vojislav; Engel, Felix (Advanced Healthcare Materials, 2023)
Cardiac tissue engineering is a promising strategy to prevent heart failure. However, several issues remain unsolved, including efficient electrical coupling and incorporating factors to enhance tissue maturation and vascularization. Herein, a biohybrid hydrogel that enhances beating properties of engineered cardiac tissues and allows drug release concurrently is developed. Gold nanoparticles (AuNPs) with different sizes (18–241 nm) and surface charges (33.9–55.4 mV) are synthesized by reducing gold (III) chloride trihydrate using branched polyethyleneimine (bPEI). These nanoparticles increase gel stiffness from ≈91 to ≈146 kPa, enhance electrical conductivity of collagen hydrogels from ≈40 to 49–68 mS cm−1, and allow slow and steady release of loaded drugs. Engineered cardiac tissues based on bPEI-AuNP-collagen hydrogels and either primary or human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes show enhanced beating properties. hiPSC-derived cardiomyocytes exhibit more aligned and wider sarcomeres in bPEI-AuNP-collagen hydrogels compared to collagen hydrogels. Furthermore, the presence of bPEI-AuNPs result in advanced electrical coupling evidenced by synchronous and homogenous calcium flux throughout the tissue. RNA-seq analyses are in agreement with these observations. Collectively, this data demonstrate the potential of bPEI-AuNP-collagen hydrogels to improve tissue engineering approaches to prevent heart failure and possibly treat diseases of other electrically sensitive tissues.
CRIS-Team Scopus Importer:2023-04-21
Keywords: collagen; gold nanoparticles; heart; tissue engineering

Collecting duct carcinoma versus renal medullary carcinoma: an appeal for nosologic and biological clarity - Amin, Mahul B.; Smith, Steven C.; Agaimy, Abbas; Argani, Pedram; Comperat, Eva Marie; Delahunt, Brett; Epstein, Jonathan I.; Eble, John N.; Grignon, David J.; Hartmann, Arndt; Hes, Ondrej; Hirsch, Michelle S.; et al. (American Journal of Surgical Pathology, 2014)
EVALuna2:6697

Collective forces of tumor spheroids in three-dimensional biopolymer networks - Mark, Christoph; Grundy, Thomas J.; Strissel, Pamela; Böhringer, David; Grummel, Nadine; Gerum, Richard; Steinwachs, Julian; Hack, Carolin; Beckmann, Matthias; Eckstein, Markus; Strick, Reiner; O'Neill, Geraldine M.; et al. (eLife, 2020)
We describe a method for quantifying the contractile forces that tumor spheroids collectively exert on highly nonlinear three-dimensional collagen networks. While three-dimensional traction force microscopy for single cells in a nonlinear matrix is computationally complex due to the variable cell shape, here we exploit the spherical symmetry of tumor spheroids to derive a scale-invariant relationship between spheroid contractility and the surrounding matrix deformations. This relationship allows us to directly translate the magnitude of matrix deformations to the total contractility of arbitrarily sized spheroids. We show that our method is accurate up to strains of 50% and remains valid even for irregularly shaped tissue samples when considering only the deformations in the far field. Finally, we demonstrate that collective forces of tumor spheroids reflect the contractility of individual cells for up to 1 hr after seeding, while collective forces on longer timescales are guided by mechanical feedback from the extracellular matrix.
CRIS-Team WoS Importer:2020-05-22

Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association - Kneis, Barbara; Wirtz, Stefan; Weber, Klaus; Denz, Axel; Gittler, Matthias; Geppert, Carol-Immanuel; Brunner, Maximilian; Krautz, Christian; Siebenhuener, Alexander Reinhard; Schierwagen, Robert; Tyc, Olaf; Agaimy, Abbas; et al. (International Journal of Molecular Sciences, 2023)
In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome-ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.
CRIS-Team Scopus Importer:2023-03-10
Keywords: colon cancer; gut microbiome; left-sided colon cancer; microbiome; right-sided colon cancer; tumor microbiome

Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature - Lasota, Jerzy; Chłopek, Małgorzata; Lamoureux, Jennifer; Christiansen, Jason; Kowalik, Artur; Wasąg, Bartosz; Felisiak-Gołąbek, Anna; Agaimy, Abbas; Biernat, Wojciech; Canzonieri, Vincenzo; Centonze, Giovanni; Chmielik, Ewa; et al. (American Journal of Surgical Pathology, 2020)
This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.
CRIS-Team Scopus Importer:2020-01-21

Colonic-type Adenocarcinoma of the Tongue and Oral Cavity (CATOC) - Agaimy, Abbas (Head and Neck Pathology, 2018)
EVALuna2:207225

Colony-stimulating factor-1: a potential biomarker for lupus nephritis - Menke, Julia; Amann, Kerstin Ute; Cavagna, Lorenzo; Blettner, Maria; Weinmann, Arndt; Schwarting, Andreas; Kelley, Vicki R. (Journal of the American Society of Nephrology, 2015)
A noninvasive means to predict the onset and recurrence of lupus nephritis (LN) before overt renal injury is needed to optimize and individualize treatment. Colony-stimulating factor-1 (CSF-1) is expressed by kidney tubules at the onset of LN, increases with disease progression, and spills into the circulation in lupus-prone mice. We tested the hypothesis that amplified expression of CSF-1 detected in the serum or urine correlates with intrarenal CSF-1 expression and histopathology (increased macrophage accumulation, activity indices) and clinical kidney disease activity and predicts the onset and recurrence of nephritis in patients with systemic lupus erythematosus (SLE). We found increased serum or urine CSF-1 levels in patients with cutaneous, serositis, and musculoskeletal disease; however, the increase in CSF-1 levels was far greater in LN. Moreover, an elevation in serum or urine CSF-1 levels correlated with increasing intrarenal CSF-1 expression and histopathology. By longitudinally tracking patients, we found that elevated serum CSF-1 heralded the initial onset of disease, and a rise in serum or urine CSF-1 predicted recurrences of LN before clinical evidence of glomerular dysfunction and conventional serologic measures, even in patients with other manifestations of SLE. These findings indicate that serial monitoring for a rise in serum or urine CSF-1 levels in patients with SLE reflects kidney histopathology and may predict renal disease activity and the onset and recurrence of LN more accurately than conventional laboratory measures.
EVALuna2:25483

Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature. - Lasota, Jerzy; Chlopek, Malgorzata; Wasag, Bartosz; Kowalik, Artur; Christiansen, Jason; Lamoureux, Jennifer; Kuzniacka, Alina; Felisiak-Golabek, Anna; Liu, Yalan; Reyes, Tiffany Ashley R.; Saha, Rishabh; Agaimy, Abbas; et al. (American Journal of Surgical Pathology, 2020)
This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.
EVALuna2:252946

Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells - Ndreshkjana, Benardina; Capci Karagöz, Aysun; Klein, Volker; Chanvorachote, Pithi; Muenzner, Julienne K.; Hübner, Kerstin; Steinmann, Sara; Erlenbach-Wuensch, Katharina; Geppert, Carol-Immanuel; Agaimy, Abbas; Ballout, Farah; El-Baba, Chirine; et al. (Cell Death & Disease, 2019)
Cancer stem cells (CSCs) residing in colorectal cancer tissues have tumorigenic capacity and contribute to chemotherapeutic resistance and disease relapse. It is well known that the survival of colorectal CSCs after 5-fluorouracil (5-FU)-based therapy leads to cancer recurrence. Thus CSCs represent a promising drug target. Here, we designed and synthesized novel hybrid molecules linking 5-FU with the plant-derived compound thymoquinone (TQ) and tested the potential of individual compounds and their combination to eliminate colorectal CSCs. Both, Combi and SARB hybrid showed augmented cytotoxicity against colorectal cancer cells, but were non-toxic to organoids prepared from healthy murine small intestine. NanoString analysis revealed a unique signature of deregulated gene expression in response to the combination of TQ and 5-FU (Combi) and SARB treatment. Importantly, two principle stem cell regulatory pathways WNT/ß-Catenin and PI3K/AKT were found to be downregulated after Combi and hybrid treatment. Furthermore, both treatments strikingly eliminated CD133+ CSC population, accompanying the depleted self-renewal capacity by eradicating long-term propagated 3D tumor cell spheres at sub-toxic doses. In vivo xenografts on chicken eggs of SARB-treated HCT116 cells showed a prominent nuclear ß-Catenin and E-cadherin staining. This was in line with the reduced transcriptional activity of ß-Catenin and diminished cell adhesion under SARB exposure. In contrast to 5-FU, both, Combi and SARB treatment effectively reduced the angiogenic capacity of the remaining resistant tumor cells. Taken together, combination or hybridization of single compounds target simultaneously a broader spectrum of oncogenic pathways leading to an effective eradication of colorectal cancer cells.
CRIS-Team Scopus Importer:2019-05-28

Combination of an ultrafast TWIST-VIBE Dixon sequence protocol and diffusion-weighted imaging into an accurate easily applicable classification tool for masses in breast MRI - Peter, Sandra C.; Wenkel, Evelyn; Weiland, Elisabeth; Dietzel, Matthias; Janka, Rolf Matthias; Hartmann, Arndt; Emons, Julius; Uder, Michael; Ellmann, Stephan (European Radiology, 2020)
Objectives: This study aimed to develop a tool for the classification of masses in breast MRI, based on ultrafast TWIST-VIBE Dixon (TVD) dynamic sequences combined with DWI. TVD sequences allow to abbreviate breast MRI protocols, but provide kinetic information only on the contrast wash-in, and because of the lack of the wash-out kinetics, their diagnostic value might be hampered. A special focus of this study was thus to maintain high diagnostic accuracy in lesion classification. Materials and methods: Sixty-one patients who received breast MRI between 02/2014 and 04/2015 were included, with 83 reported lesions (60 malignant). Our institute’s standard breast MRI protocol was complemented by an ultrafast TVD sequence. ADC and peak enhancement of the TVD sequences were integrated into a generalised linear model (GLM) for malignancy prediction. For comparison, a second GLM was calculated using ADC and conventional DCE curve type. The resulting GLMs were evaluated for standard diagnostic parameters. For easy application of the GLMs, nomograms were created. Results: The GLM based on peak enhancement of the TVD and ADC was as equally accurate as the GLM based on conventional DCE and ADC, with no significant differences (sensitivity, 93.3%/93.3%; specificity, 91.3%/87.0%; PPV, 96.6%/94.9%; NPV, 84.0%/83.3%; all, p ≥ 0.315). Conclusions: This study presents a method to integrate ultrafast TVD sequences into a breast MRI protocol, allowing a reduction of the examination time while maintaining diagnostic accuracy. A GLM based on the combination of TVD-derived peak enhancement and ADC provides high diagnostic accuracy, and can be easily applied using a nomogram. Key Points: • Ultrafast TWIST-VIBE Dixon sequence protocols in combination with diffusion-weighted imaging allow to shorten breast MRI examinations, while diagnostic accuracy is maintained. • Integrating peak enhancement from the TWIST-VIBE Dixon sequence and the apparent diffusion coefficient into a generalised linear model provides a comprehensible image evaluation approach. • This approach is further facilitated by nomograms.
CRIS-Team Scopus Importer:2020-02-11
Keywords: Breast cancer; Diagnostic imaging; Diffusion magnetic resonance imaging; Magnetic resonance imaging; Statistical model

Combination of CK20 and Ki-67 Immunostaining Analysis Predicts Recurrence, Progression, and Cancer-Specific Survival in pT1 Urothelial Bladder Cancer - Bertz, Simone; Otto, Wolfgang; Denzinger, Stefan; Wieland, Wolf F.; Burger, Maximilian; Stoehr, Robert; Link, Stefan; Hofstaedter, Ferdinand; Hartmann, Arndt (European Urology, 2014)
The prognostic value of CK20, Ki-67, and p53 has been investigated for non-muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers.To evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers.Data from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected.Adjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4-8 wk. A total of 76 patients underwent cystectomy.We conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS).At a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44-24.15; p=0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45-5.43, p=0.002). Ki-67 (HR: 3.83; 95% CI, 1.59-9.26; p=0.003), and CK20 (HR: 8.44; 95% CI,1.16-61.34; p=0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p=0.026), PFS (p=0.003), and CSS (p<0.001) in tumours with a high proliferation index and abnormal CK20 expression. A retrospective study design was the major limitation of this study.Our present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas.
EVALuna2:6465

Combination of GP88 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Is an Independent Prognostic Factor for Bladder Cancer Patients - Eckstein, Markus; Lieb, Verena; Jung, Rudolf; Sikic, Danijel; Weigelt, Katrin; Stöhr, Robert; Geppert, Carol-Immanuel; Weyerer, Veronika; Bertz, Simone; Serrero, Ginette; Yue, Binbin; Hartmann, Arndt; et al. (Cells, 2021)
Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox's regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.
CRIS-Team WoS Importer:2021-08-06

Combination of growth pattern and tumor regression identifies a high-risk group in neoadjuvant treated rectal cancer patients - Jeßberger, Jonas; Erlenbach-Wuensch, Katharina; Posselt, Rebecca; Haderlein, Marlen; Agaimy, Abbas; Fietkau, Rainer; Hartmann, Arndt; Distel, Luitpold (Journal of Digestive Diseases, 2017)
To analyze the prognostic effect of E-cadherin expression, the growth pattern of the tumor and the regression grade in a rectal cancer cohort treated with neoadjuvant radiochemotherapy (RCT).A total of 223 patients with rectal cancer treated with neoadjuvant RCT followed by surgery were included. Altogether 88 biopsies prior to RCT and 213 tumor resections in an average of 55 days post-RCT were investigated. Protein expression of E-cadherin and tumor growth pattern (solid glandular vs single-cell pattern) was assessed by staining tissue microarrays. The regression grade at the invasion front was determined according to the Dworak scale.There was a significant decrease of E-cadherin expression (P = 0.002) and a significant increased single-cell growth (P < 0.001) at the invasion front in tumor samples after RCT compared with primary biopsies of the tumor. A low E-cadherin expression in the biopsy was related to a longer metastasis-free survival (P = 0.033) and tumor-specific survival (P = 0.030). Post-RCT single-cell growth at the tumor invasion front was a prognostic factor for longer tumor-specific survival (P = 0.021). A combination of growth pattern and the Dworak regression grade was an independent prognostic parameter for tumor-specific survival (P = 0.015).Loss of E-cadherin protein expression in the pretreatment biopsy of rectal cancer is associated with fewer metastases and improved survival. Furthermore, the growth pattern in the post-RCT resection specimen has a prognostic value for survival. A combination of growth pattern and tumor regression score (the RegPat score) showed the highest discriminatory power to identify high-risk patients.
EVALuna2:6858

Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor - Haller, Florian; Zhang, Jitao David; Moskalev, Evgeny; Braun, Alexander; Otto, Claudia; Geddert, Helene; Riazalhosseini, Yasser; Ward, Aoife; Balwierz, Aleksandra; Schaefer, Inga-Marie; Cameron, Silke; Ghadimi, B. Michael; et al. (International Journal of Cancer, 2015)
Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category.
EVALuna2:6650

Combined miR-486 and GP88 (Progranulin) Serum Levels Are Suggested as Supportive Biomarkers for Therapy Decision in Elderly Prostate Cancer Patients - Fichte, Alexander; Neumann, Anna-Dorothea; Weigelt, Katrin; Guzman, Juan; Jansen, Thilo; Keinert, Julia; Serrero, Ginette; Yue, Binbin; Stöhr, Robert; Greither, Thomas; Hartmann, Arndt; Wullich, Bernd; et al. (Life, 2022)
Our study aimed to assess the applicability of miR-486 in combination with soluble GP88 protein as a diagnostic and/or predictive biomarker for prostate cancer (PCa) patients. miR-486 and GP88 levels in serum samples from 136 patients undergoing MRI-guided biopsy of the prostate were assessed by qRT–PCR and ELISA, respectively. Of these, 86 patients received a histologically confirmed diagnosis of PCa. Neither marker showed an association with the diagnosis of cancer. PCa patients were separated based on (i) treatment into patients with active surveillance or patients with any type of curative treatment and (ii) age into elderly (>68 years) patients and younger patients (≤68 years). In elderly patients (N = 41) with the intention of curative treatment at optimized cut-off values, significantly higher GP88 levels (p = 0.018) and lower miR-486 levels (p = 0.014) were observed. The total PSA level and ISUP biopsy grade were used in a baseline model for predicting definitive therapy. The baseline model exhibited an area under the curve (AUC) of 0.783 (p = 0.005). The addition of the serum biomarkers miR-486 and GP88 to the baseline model yielded an improved model with an AUC of 0.808 (p = 0.002). Altogether, combined miR-486 and GP88 serum levels are associated with and are therefore suggested as supportive biomarkers for therapy decisions, particularly in elderly PCa patients.
CRIS-Team Scopus Importer:2022-06-03
Keywords: age; miRNAs; predictive biomarker; progranulin; prostate cancer; serum level

Comparative analysis of human dendritic cell subpopulations in steady state and inflammation - Heger, Lukas; Heidkamp, Gordon Frederik; Lehmann, Christian; Eissing, N.; Söder, Stephan; Hartmann, Arndt; Zenk, J.; Alexiou, Christoph; Schuler, Gerold; Purbojo, Ariawan; Cesnjevar, Robert; Nimmerjahn, Falk; et al. (2017)
EVALuna2:33136

Comparative analysis of human dendritic cell subpopulations in steady state and inflammation - Heger, Lukas; Heidkamp, Gordon Frederik; Lehmann, Christian; Söder, Stephan; Hartmann, Arndt; Alexiou, Christoph; Schuler, Gerold; Purbojo, Ariawan; Cesnjevar, Robert; Nimmerjahn, Falk; Dudziak, Diana (2018)
EVALuna2:34382

Comparative Analysis of Inhibitory and Activating Immune Checkpoints PD-1, PD-L1, CD28, and CD86 in Non-Melanoma Skin Cancer - Winter, Linus; Ries, Jutta; Vogl, Christoph; Trumet, Leah; Geppert, Carol-Immanuel; Lutz, Rainer; Kesting, Marco Rainer; Weber, Manuel (Cells, 2024)
The establishment of immunotherapy applying immune checkpoint inhibitors (ICI) has provided an important new option for the treatment of solid malignant diseases. However, different tumor entities show dramatically different responses to this therapy. BCC responds worse to anti-PD-1 ICIs as compared to cSCC. Differential immune checkpoint expression could explain this discrepancy and, therefore, the aim of this study was to analyze activating and inhibitory immune checkpoints in cSCC and BCC tissues. Tissue microarrays of the invasive front as well as the tumor core of BCC and cSCC samples were used to evaluate PD-1, PD-L1, CD28, and CD86 expression and their topographic distribution profiles by chromogenic immunohistochemistry. QuPath was used to determine the labeling index. The expression of PD-1, PD-L1, and CD28 was significantly higher in both the tumor core and the invasive front of cSCC samples as compared to BCC (p < 0.001). In addition, the ratios of PD-L1/CD86 (p < 0.001) and CD28/CD86 (p < 0.001) were significantly higher in cSCC. The invasive front of both tumor entities showed higher expression levels of all immune markers compared to the tumor core in both tumor entities. The significantly higher expression of PD-1, PD-L1, and CD28 in cSCC, along with the predominance of the inhibitory ligand PD-L1 as compared to the activating CD86 in cSCC, provide a potential explanation for the better objective response rates to anti-PD-1 immunotherapy as compared to BCC. Furthermore, the predominant site of interaction between the immune system and the tumor was within the invasive front in both tumor types.
CRIS-Team Scopus Importer:2024-10-04
Keywords: BCC; CD28; CD86; cSCC; IHC; NMSC; PD-1; PD-L1; TMA; TME

Comparative analysis of tumour mutational burden (TMB) prediction methods and its association with determinants of the tumour immune microenvironment of urothelial bladder cancer (UBC) - Eckstein, Markus; Hartmann, Arndt; Strissel, Pamela; Strick, Reiner; Wach, S.; Taubert, Helge; Wullich, Bernd; Geppert, Carol-Immanuel; Weyerer, Veronika; Stöhr, Robert; Rübner, Matthias; Fasching, Peter; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Comparative genomic hybridization shows complex genomic changes of plasmacytoid urothelial carcinoma - Keck, Bastian; Elhnann, Christina; Stoehr, Robert; Weigelt, Katrin; Goebell, Peter; Kunath, Frank; Taubert, Helge; Hartmann, Arndt; Wullich, Bernd; Wach, Sven (Urologic Oncology-Seminars and Original Investigations, 2014)
To describe genomic imbalances in plasmacytoid urothelial carcinoma (PUC), which is a rare and aggressive variant of urothelial carcinoma (UC).In total, 25 formalin-fixed paraffin-embedded PUCs were analyzed by metaphase comparative genomic hybridization. Genomic imbalances were considered to be characteristic if they were detected in >= 20% of the cases. Chromosome regions deviating by >= 3 standard deviations from the average chromosome profile were scored as chromosomal gains or losses. Copy-number variations (CNVs) of CDH1 (16q 22.1), SNAI1 (20q 13.1), CCND1 (11q13.3), ERBB2 (17q12), and FOXO3 (6q21) were validated using quantitative polymerase chain reaction.Chromosomal aberrations were detected in every PUC analyzed, and the average number of aberrations was 10.24 (ranging from 1-15). Characteristic aberrations were gains on 1q (48%), 3p (20%), 6p (32%), 11q (72%), 15q (36%), 16q (44%), 17p (76%), 17q (88%), and 20q (88%) and losses on 2q (24%) 4p (36%), 4q (84%), 5q (44%), 6q (68%), 13q (20%), and Xq (52%). polymerase chain reaction-based analysis of CNV for CCND1 (11q13) showed a deletion in 73% of the cases. CDH1 (16q22) was deleted in 72% and amplified in 5%. ERBB2 (17q12) displayed remarkably few copy-number alterations, with only 14% showing an amplification. SNAI1 (20q13) showed reduced gene copy numbers in 59.1% of the cases, whereas no copy-number gains were detected. FOXO3 (6q21) exhibited the lowest number of copy-number alterations, with 9% of all cases showing an amplification.In PUCs, the frequency of aneuploidy and the complexity of genomic changes per tumor are greater than those described in conventional UC. The aberrations described in PUC involve the same regions that are associated with aggressive biological behavior in conventional UC. Gains on 11q, 17q, 17p, and 20q and losses on 4q and 6q affect most PUCs and seem to harbor important chromosomal regions for PUC carcinogenesis. Large-scale deletions on chromosome 9 were not detected. CNV analysis indicates heterozygous deletion of CDH1 as one underlying mechanism of loss of membranous E-cadherin in PUC. Loss of CCND1 and SNAI1 is a common molecular feature and could contribute to the aggressive biological behavior of PUC.
EVALuna2:6676

Comparative genomic profiling of glandular bladder tumours - Maurer, Angela; Ortiz-Bruechle, Nadina; Guricova, Karolina; Rose, Michael; Morsch, Ronja; Garczyk, Stefan; Stöhr, Robert; Bertz, Simone; Golz, Reinhard; Reis, Henning; Bremmer, Felix; Zimpfer, Annette; et al. (Virchows Archiv, 2020)
Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.
CRIS-Team WoS Importer:2020-04-07

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing - Hart, Martin; Nolte, Elke; Wach, Sven; Szczyrba, Jaroslaw; Taubert, Helge; Rau, Tilman; Hartmann, Arndt; Graesser, Friedrich A.; Wullich, Bernd (Molecular Cancer Research, 2014)
MicroRNAs (miRNA) posttranscriptionally regulate gene expression and are important in tumorigenesis. Previous deep sequencing identified the miRNA profile of prostate carcinoma versus nonmalignant prostate tissue. Here, we generated miRNA expression profiles of prostate carcinoma by deep sequencing, with increasing tumor stage relative to corresponding nonmalignant and healthy prostate tissue, and detected clearly changed miRNA expression patterns. The miRNA profiles of the healthy and nonmalignant tissues were consistent with our previous findings, indicating a high fidelity of the method employed. In the tumors, quantitative real-time PCR (qRT-PCR) analysis of 40 paired samples of prostate carcinoma versus normal tissue revealed significant upregulation of miR-20a, miR-148a, miR-200b, and miR-375 and downregulation of miR-143 and miR-145. Hereby, miR-375 increased from normal to organ-confined tumors (pT2 pN0), slightly decreased in tumors with extracapsular growth (pT3 pN0), but was then expressed again at higher levels in lymph node metastasizing (pN1) tumors. The sequencing data for miR-375 were confirmed by Northern blotting and qRT-PCR. The regulation for other selected miRNAs could, however, not be confirmed by qRT-PCR in individual tumor stages. MiR-200b, in addition to miR-200c and miR-375 reduced the expression of SEC23A. Interestingly, miR-375, found by sequencing in pT2 upregulated by us and others in tumor versus normal tissue, and miR-15a, found by sequencing in pT2 and pT3 and in the metastasizing tumors, target the phosphatases PHLPP1 and PHLPP2, respectively. PHLPP1 and PHLPP2 dephosphorylate members of the AKT family of signal transducers, thereby inhibiting cell growth. Coexpression of miR-15a and miR-375 resulted in downregulation of PHLPP1/2 and strongly increased prostate carcinoma cell growth. Implications: These genomic data reveal relevant miRNAs in prostate cancer that may have biomarker and therapeutic potential. Mol Cancer Res; 12(2); 250-63. ©2013 AACR.
EVALuna2:6552

Comparison of different normalization strategies for the analysis of glomerular microRNAs in IgA nephropathy - Bockmeyer, Clemens L.; Saeuberlich, Karen; Wittig, Juliane; Esser, Marc; Röder, Sebastian; Vester, Udo; Hoyer, Peter F.; Agustian, Putri A.; Zeuschner, Philip; Amann, Kerstin Ute; Daniel, Christoph; Becker, Jan U. (Scientific Reports, 2016)
Small nucleolar RNAs (snoRNAs) have been used for normalization in glomerular microRNA (miRNA) quantification without confirmation of validity. Our aim was to identify glomerular reference miRNAs in IgA nephropathy. We compared miRNAs in human paraffin-embedded renal biopsies from patients with cellular-crescentic IgA-GN (n = 5; crescentic IgA-GN) and non-crescentic IgA-GN (n = 5; IgA-GN) to mild interstitial nephritis without glomerular abnormalities (controls, n = 5). Laser-microdissected glomeruli were used for expression profiling of 762 miRNAs by low-density TaqMan arrays (cards A and B). The comparison of different normalization methods (GeNormPlus, NormFinder, global mean and snoRNAs) in crescentic IgA-GN, IgA-GN and controls yielded similar results. However, levels of significance and the range of relative expression differed. In median, two normalization methods demonstrated similar results. GeNormPlus and NormFinder gave different top ranked reference miRNAs. Stability ranking for snoRNAs varied between cards A and B. In conclusion, we suggest the geometric mean of the most stable reference miRNAs found in GeNormPlus (miR-26b-5p), NormFinder (miR-28-5p) and snoRNAs (RNU44) as reference. It should be considered that significant differences could be missed using one particular normalization method. As a starting point for glomerular miRNA studies in IgA nephropathy we provide a library of miRNAs.
EVALuna2:25525

Comparison of Intrinsic PAM50 Gene Expression Analysis and Immunohistochemical Subtypes of Salivary Duct Carcinoma - Erber, Ramona; Stoehr, Robert; Haller, Florian; Haderlein, Marlen; Hartmann, Arndt; Agaimy, Abbas (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Comparison of PD-L1 mRNA Expression Measured with the CheckPoint Typer® Assay with PD-L1 Protein Expression Assessed with Immunohistochemistry in Non-small Cell Lung Cancer - Erber, Ramona; Stoehr, Robert; Herlein, Stefanie; Giedl, Claudia; Rieker, Ralf; Fuchs, Florian; Ficker, Joachim H.; Hartmann, Arndt; Veltrup, Elke; Wirtz, Ralph M.; Brueckl, Wolfgang M. (Anticancer Research, 2017)
Immunohistochemical (IHC) assessment of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has become important since the development of anti-PD-1/-PD-L1 directed drugs. Various PD-L1 antibodies and cut-offs have been used in different trials to predict response to these drugs, thus comparison of those studies is difficult. We compared PD-L1 mRNA expression measured by RT-qPCR with PD-L1 protein expression evaluated by IHC. Moreover, we investigated the impact of different tumour tissue acquisition methods on the reliability of PD-L1 measurement techniques.NSCLC cases (N=22), including n=9 mediastinal lymph node biopsies acquired by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and n=5 metastases, were evaluated prospectively for PD-L1 protein on tumor cells (TC) and immune cells (IC) using E1L3N and 28-8 antibodies and PD-L1 mRNA using the CheckPoint TYPER® assay.In primary NSCLC tissues, agreement between PD-L1 mRNA and TC staining using the 28-8 antibody was excellent (?=0.85, p=0.0002). Comparing both PD-L1 antibodies against each other showed a kappa value of 0.58 (p=0.0106). In EBUS-TBNA, PD-L1 mRNA correlated perfectly with the 28-8 antibody (?=1.0, p=0.0023). PD-L1 mRNA levels significantly differed when comparing 28-8 TC staining of tumours >49% with 1-49% and 0% (p=0.0040; p=0.0081, respectively). In metastatic lesions, differences between PD-L1 mRNA and IHC became apparent (?=0.2, p=0.2525).Testing of PD-L1 mRNA and 28-8 IHC showed an excellent agreement in NSCLC samples including mediastinal lymph node biopsies. Since PD-L1 expression in >50% TC detected by 28-8 IHC can be reliably detected by RT-qPCR, quantitative PD-L1 mRNA determination should be considered as an alternative to IHC as there is no interobserver variability in RNA results.
EVALuna2:6916

Comparison of PD-L1 mRNA expression measured with the CheckPointTyper(R) assay with PD-L1 protein expression assessed with immunohistochemistry (IHC) in lung cancer (NSCLC) - Erber, Ramona; Stoehr, R.; Herlein, S.; Fuchs, F.; Veltrup, Elke; Wirtz, Ralph; Hartmann, Arndt (2017)
EVALuna2:34085

Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial - Gluz, O.; Liedtke, C.; Huober, J.; Peyro-Saint-Paul, H.; Kates, R. E.; Kreipe, H. H.; Hartmann, Arndt; Pelz, E.; Erber, Ramona; Mohrmann, S.; Moebus, V.; Augustin, D.; et al. (Annals of Oncology, 2016)
Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC).In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459).Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 >=20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients.In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone.The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.
EVALuna2:6775

Comparison of Sonography versus Digital Breast Tomosynthesis to Locate Intramammary Marker Clips - Schulz-Wendtland, Rüdiger; Dankerl, Peter; Dilbat, G.; Bani, Mayada; Fasching, Peter; Heusinger, K.; Lux, Michael P.; Löhberg, Christian; Jud, Sebastian; Rauh, C.; Bayer, C. M.; Beckmann, Matthias; et al. (Geburtshilfe und Frauenheilkunde, 2015)
Introduction: This study aimed to compare the accuracy of sonography versus digital breast tomosynthesis to locate intramammary marker clips placed under ultrasound guidance. Patients and Methods: Fifty patients with suspicion of breast cancer (lesion diameter less than 2 cm [cT1]) had ultrasound-guided core needle biopsy with placement of a marker clip in the center of the tumor. Intramammary marker clips were subsequently located with both sonography and digital breast tomosynthesis. Results: Sonography detected no dislocation of intrammammary marker clips in 42 of 50 patients (84 %); dislocation was reported in 8 patients (16 %) with a maximum dislocation of 7 mm along the x-, y- or z-axis. Digital breast tomosynthesis showed accurate placement without dislocation of the intramammary marker clip in 48 patients (96 %); 2 patients (4 %) had a maximum clip dislocation of 3 mm along the x-, y- or z-axis (p < 0.05). Conclusion: The use of digital breast tomosynthesis could improve the accuracy when locating intramammary marker clips compared to sonography and could, in future, be used to complement or even completely replace sonography.
EVALuna2:6724

Comparison of the 7th and revised 8th UICC editions (2020) for oral squamous cell carcinoma: How does the reclassification impact staging and survival? - Struckmeier, Ann-Kristin; Eichhorn, Philip; Agaimy, Abbas; Buchbender, Mayte; Möst, Tobias; Lutz, Rainer; Kesting, Marco Rainer (Virchows Archiv, 2024)
Since its introduction in 1968, the TNM (tumor, node, metastasis) classification established by the International Union Against Cancer has provided a consistent framework for staging of oral squamous cell carcinoma (OSCC). The introduction of the 8th edition in 2017 brought about significant modifications, encompassing the integration of depth of invasion (DOI) and extranodal extension (ENE) into the T and N classifications. Further, the UICC the criteria for the T3 and T4a categories were amended in 2020. This study aimed to evaluate the impact of reclassification on staging and, subsequently, the survival of patients with OSCC. Primary OSCCs from 391 patients were classified according to the 7th and revised 8th UICC editions (2020). Stage migration was assessed, and stage-specific progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan–Meier method. The log-rank test was used to compare the different stages. Cox-proportional hazard modeling was used to compare the two editions. Incorporating the DOI into the T classification resulted in an upstaging of 77 patients, constituting 19.69% of the cohort. In addition, 49 (12.53%) patients experienced an upstaging when considering ENE in the N classification. Consequently, 103 patients underwent upstaging in UICC staging, accounting for 21.74% of cases. Upstaging mainly occurred from stage III to IVA (26.92%) and from stage IVA to IVB (31.78%). Upon comparing the categories in survival analysis, significant differences in OS and PFS were especially observed between stage IVB and lower stages. When examining the hazard ratios, it became evident that UICC 8 stage IVB is burdened by a 5.59-fold greater risk of disease progression than stage I. Furthermore, UICC 8 stage IVB exhibits a 3.83 times higher likelihood of death than stage I disease. We demonstrated significant stage migration from the 7th to the revised 8th UICC edition. Overall, incorporating DOI and ENE into the T and N classifications represents a substantial clinical advancement, leading to a more accurate staging of OSCC patients. Both staging systems exhibited statistically significant discrimination between stages; however, the 8th UICC edition allowed for a more precise categorization of patients based on their prognosis and led to enhanced hazard discrimination, particularly within higher stages.
CRIS-Team Scopus Importer:2024-02-02
Keywords: Oral squamous cell carcinoma; Staging; TNM classification; UICC

Comparison of the prognostic value of lymph node yield, lymph node ratio, and number of lymph node metastases in patients with oral squamous cell carcinoma - Struckmeier, Ann-Kristin; Buchbender, Mayte; Lutz, Rainer; Agaimy, Abbas; Kesting, Marco Rainer (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2024)
Background: The aim of this study was to assess the prognostic significance of lymph node yield (LNY), lymph node ratio (LNR), and the number of lymph node metastases (LNMs) in patients affected by oral squamous cell carcinoma (OSCC). Methods: The study included patients who underwent surgical treatment for primary OSCC. Receiver operating characteristic curves were generated to determine the optimal threshold values. Kaplan–Meier curves were employed, along with the log-rank test, for the analysis of survival. To compare the performance in terms of model fit, we computed Akaike's information criterion (AIC). Results: This study enrolled 429 patients. Prognostic thresholds were determined at 22 for LNY, 6.6% for LNR, and 3 for the number of LNMs. The log-rank test revealed a significant improvement in both overall survival and progression-free survival for patients with a LNR of ≤6.6% or a number of LNMs of ≤3 (p < 0.05). Interestingly, LNY did not demonstrate prognostic significance. The AIC analyses indicated that the number of LNMs is a superior prognostic indicator compared to LNY and LNR. Conclusions: Incorporating LNR or the number of LNMs into the TNM classification has the potential to improve the prognostic value, as in other types of cancers. Particularly, the inclusion of the number of LNMs should be contemplated for future N staging.
CRIS-Team Scopus Importer:2024-05-13
Keywords: lymph node; lymph node ratio; lymph node yield; metastasis; neck dissection; oral squamous cell carcinoma

Complement 9 in amyloid deposits - Lux, Annelie; Gottwald, Juliane; Behrens, Hans-Michael; Daniel, Christoph; Amann, Kerstin Ute; Roecken, Christoph (Amyloid-Journal of Protein Folding Disorders, 2021)
Amyloidosis is a disease group caused by pathological aggregation and deposition of peptides in diverse tissue sites. Apart from the fibril protein, amyloid deposits frequently enclose non-fibrillar constituents. In routine diagnostics, we noticed the presence of complement 9 (C9) in amyloid. Based on this observation, we systematically explored the occurrence of C9 in amyloid. Apolipoprotein E (apoE), caspase 3 and complement 3 (C3) served as controls. From the Amyloid Registry Kiel, we retrieved 118 formalin-fixed and paraffin-embedded tissue samples, including eight different amyloid- and 18 different tissue types. The expression patterns were assessed immunohistochemically in relation to amyloid deposits. A literature search on proteomic data was performed. Amyloid deposits stained for C9 and apoE in 117 (99.2%) and 112 of 118 (94.9%) cases, respectively. A homogeneous immunostaining of the entire amyloid deposits was found in 75.4% (C9) and 61.9% (apoE) of the cases. Caspase 3 and C3 were present only in 22 (19.3%) of 114 and 20 (36%) of 55 assessable cases, respectively. Caspase 3 and C3 immunostaining rarely covered substantial areas of the amyloid deposits. The literature search on proteomic data confirmed the frequent detection of apoE and the occurrence of C9 and C3 in amyloid deposits. No data were found regarding caspase 3. Our findings demonstrate the ubiquitous, spatial and specific enrichment of C9 in amyloid deposits irrespective of amyloid-, organ- or tissue type. Our findings lend support to the hypothesis that amyloidosis might activate the complement cascade, which could lead to the formation of the membrane attack complex and cell death.
CRIS-Team WoS Importer:2021-06-11

Complement Activation in Kidneys of Patients With COVID-19 - Pfister, Frederick; Vonbrunn, Eva; Ries, Tajana; Jäck, Hans-Martin; Überla, Klaus; Lochnit, Günter; Sheriff, Ahmed; Herrmann, Martin; Büttner-Herold, Maike; Amann, Kerstin Ute; Daniel, Christoph (Frontiers in Immunology, 2021)
Most patients who became critically ill following infection with COVID-19 develop severe acute respiratory syndrome (SARS) attributed to a maladaptive or inadequate immune response. The complement system is an important component of the innate immune system that is involved in the opsonization of viruses but also in triggering further immune cell responses. Complement activation was seen in plasma adsorber material that clogged during the treatment of critically ill patients with COVID-19. Apart from the lung, the kidney is the second most common organ affected by COVID-19. Using immunohistochemistry for complement factors C1q, MASP-2, C3c, C3d, C4d, and C5b-9 we investigated the involvement of the complement system in six kidney biopsies with acute kidney failure in different clinical settings and three kidneys from autopsy material of patients with COVID-19. Renal tissue was analyzed for signs of renal injury by detection of thrombus formation using CD61, endothelial cell rarefaction using the marker E-26 transformation specific-related gene (ERG-) and proliferation using proliferating cell nuclear antigen (PCNA)-staining. SARS-CoV-2 was detected by in situ hybridization and immunohistochemistry. Biopsies from patients with hemolytic uremic syndrome (HUS, n = 5), severe acute tubular injury (ATI, n = 7), zero biopsies with disseminated intravascular coagulation (DIC, n = 7) and 1 year protocol biopsies from renal transplants (Ctrl, n = 7) served as controls. In the material clogging plasma adsorbers used for extracorporeal therapy of patients with COVID-19 C3 was the dominant protein but collectin 11 and MASP-2 were also identified. SARS-CoV-2 was sporadically present in varying numbers in some biopsies from patients with COVID-19. The highest frequency of CD61-positive platelets was found in peritubular capillaries and arteries of COVID-19 infected renal specimens as compared to all controls. Apart from COVID-19 specimens, MASP-2 was detected in glomeruli with DIC and ATI. In contrast, the classical pathway (i.e. C1q) was hardly seen in COVID-19 biopsies. Both C3 cleavage products C3c and C3d were strongly detected in renal arteries but also occurs in glomerular capillaries of COVID-19 biopsies, while tubular C3d was stronger than C3c in biopsies from COVID-19 patients. The membrane attack complex C5b-9, demonstrating terminal pathway activation, was predominantly deposited in COVID-19 biopsies in peritubular capillaries, renal arterioles, and tubular basement membrane with similar or even higher frequency compared to controls. In conclusion, various complement pathways were activated in COVID-19 kidneys, the lectin pathway mainly in peritubular capillaries and in part the classical pathway in renal arteries whereas the alternative pathway seem to be crucial for tubular complement activation. Therefore, activation of the complement system might be involved in the worsening of renal injury. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury.
CRIS-Team Scopus Importer:2021-03-05
Keywords: complement—immunological term; COVID-19; endothelial injury; kidney; lectin pathway activation

Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19 - Niederreiter, Janina; Eck, Christine; Ries, Tajana; Hartmann, Arndt; Märkl, Bruno; Büttner-Herold, Maike; Amann, Kerstin Ute; Daniel, Christoph (Frontiers in Immunology, 2022)
Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19 via the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred via the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19.
CRIS-Team Scopus Importer:2022-03-11
Keywords: autopsy; complement deposition; COVID-19; kidney; lectin pathway; lung

Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces - Chen, Qian; Manzke, Melanie; Hartmann, Andrea; Büttner, Maike; Amann, Kerstin Ute; Pauly, Diana; Wiesener, Michael; Skerka, Christine; Zipfel, Peter F. (Journal of the American Society of Nephrology, 2016)
C3 glomerulopathy (C3G) is a severe kidney disease for which no specific therapy exists. The causes of C3G are heterogeneous, and defective complement regulation is often linked to C3G pathogenesis. Copy number variations in the complement factor H-related (CFHR) gene cluster on chromosome 1q32 and CFHR5 mutant proteins associate with this disease. Here, we identified CFHR5 as a pattern recognition protein that binds to damaged human endothelial cell surfaces and to properdin, the human complement activator. We found the two N-terminal short consensus repeat domains of CFHR5 contact properdin and mediate dimer formation. These properdin-binding segments are duplicated in two mutant CFHR5 proteins, CFHR2-CFHR5Hyb from German patients with C3G and CFHR5Dup from Cypriot patients with C3G. Each of these mutated proteins assembled into large multimeric complexes and, compared to CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local complement activation. This enhanced surface binding and properdin recruitment was further evidenced in the mesangia of a transplanted and explanted kidney from a German patient with a CFHR2-CFHR5Hyb protein. Enhanced properdin staining correlated with local complement activation with C3b and C5b-9 deposition on the mesangial cell surface in vitro This gain of function in complement activation for two disease-associated CFHR5 mutants describes a new disease mechanism of C3G, which is relevant for defining appropriate treatment options for this disorder.
EVALuna2:3837

Complement factor H-related hybrid protein deregulates complement in dense deposit disease - Chen, Qian; Wiesener, Michael; Eberhardt, Hannes U.; Hartmann, Andrea; Uzonyi, Barbara; Kirschfink, Michael; Amann, Kerstin Ute; Büttner, Maike; Goodship, Tim; Hugo, Christian; Skerka, Christine; Zipfel, Peter F. (Journal of Clinical Investigation, 2014)
The renal disorder C3 glomerulopathy with dense deposit disease (C3G-DDD) pattern results from complement dysfunction and primarily affects children and young adults. There is no effective treatment, and patients often progress to end-stage renal failure. A small fraction of C3G-DDD cases linked to factor H or C3 gene mutations as well as autoantibodies have been reported. Here, we examined an index family with 2 patients with C3G-DDD and identified a chromosomal deletion in the complement factor H-related (CFHR) gene cluster. This deletion resulted in expression of a hybrid CFHR2-CFHR5 plasma protein. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H-mediated convertase decay. One patient was refractory to plasma replacement and exchange therapy, as evidenced by the hybrid protein quickly returning to pretreatment plasma levels. Subsequently, complement inhibitors were tested on serum from the patient for their ability to block activity of CFHR2-CFHR5. Soluble CR1 restored defective C3 convertase regulation; however, neither eculizumab nor tagged compstatin had any effect. Our findings provide insight into the importance of CFHR proteins for C3 convertase regulation and identify a genetic variation in the CFHR gene cluster that promotes C3G-DDD. Monitoring copy number and sequence variations in the CFHR gene cluster in C3G-DDD and kidney patients with C3G-DDD variations will help guide treatment strategies.
EVALuna2:3659

Complement Inhibition in Kidney Transplantation: Where Are We Now? - Vonbrunn, Eva; Büttner-Herold, Maike; Amann, Kerstin Ute; Daniel, Christoph (Biodrugs, 2022)
Kidney transplantation is a life-saving strategy for patients with end-stage renal disease. Although progress has been made in the field of transplantation medicine in recent decades in terms of surgical techniques and immunosuppression, long-term organ survival remains a challenge. Also, for reasons of organ shortage, there is an unmet need for new therapeutic approaches to improve the long-term survival of transplants. There is increasing evidence that the complement system plays a crucial role in various pathological events after transplantation, including ischemia/reperfusion injury as well as rejection episodes. The complement system is part of the innate immune system and plays a crucial role in the defense against pathogens but is also involved in tissue homeostasis. However, the tightly regulated complement system can become dysregulated or activated by non-infectious stimuli, then targeting the organism’s own cells and leading to inflammatory tissue damage that exacerbates injury. In this review, we will highlight the role of the complement system after transplantation and discuss ongoing and potential therapeutic approaches.
CRIS-Team Scopus Importer:2022-12-23

Complement in Renal Disease as a Potential Contributor to Arterial Hypertension - Fischer, Lisa-Maren; Fichte, Laura A.; Büttner-Herold, Maike; Ferrazzi, Fulvia; Amann, Kerstin Ute; Benz, Kerstin; Daniel, Christoph (Kidney & Blood Pressure Research, 2021)
Objective: Complement deposition is prevalent in kidney biopsies of patients with arterial hypertension and hypertensive nephropathy, but an association of hypertension and complement deposition or involvement of complement in the pathogenesis of hypertensive nephropathy has not been shown to date. Methods: In this study, we analyzed complement C1q and C3c deposition in a rat model of overload and hypertension by subtotal nephrectomy (SNX) and in archival human renal biopsies from 217 patients with known hypertension and 91 control patients with no history of hypertension using semiquantitative scoring of C1q and C3c immunohistochemistry and correlation with parameters of renal function. To address whether complement was only passively deposited or actively expressed by renal cells, C1q and C3 mRNA expression were additionally analyzed. Results: Glomerular C1q and C3c complement deposition were significantly higher in kidneys of hypertensive SNX rats and hypertensive compared to nonhypertensive patients. Mean arterial blood pressure (BP) in SNX rats correlated well with the amount of glomerular C1q and C3c deposition and with left ventricular weight, as an indirect parameter of high BP. Quantitative mRNA analysis showed that C3 was not only deposited but also actively produced by glomerular cells of hypertensive SNX rats and in human renal biopsies. Of note, in patients CKD-stage correlated significantly with the intensity of glomerular C3c staining, but not with that of C1q. Conclusion: Renal complement deposition correlated with experimental hypertension as well as the presence of hypertension in a variety of renal diseases. To answer the question, if and how exactly renal complement is causative for the pathogenesis of arterial hypertension in men, further studies are needed.
CRIS-Team WoS Importer:2021-06-11
Keywords: Kidney; Complement deposition; Hypertension; Renal disease

Complex reinnervation pattern after unilateral renal denervation in rats - Rodionova, Kristina; Fiedler, Christian; Günther, Franziska; Grouzmann, Eric; Neuhuber, Winfried; Fischer, Michael; Ott, Christian; Linz, Peter; Freisinger, Wolfgang; Heinlein, Sonja; Schmidt, Stefan; Schmieder, Roland; et al. (American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 2016)
Renal denervation (DNX) is a treatment for resistant arterial hypertension. Efferent sympathetic nerves regrow, but reinnervation by renal afferent nerves has only recently been shown in the renal pelvis of rats after unilateral DNX. We examined intrarenal perivascular afferent and sympathetic efferent nerves after unilateral surgical DNX. Tyrosine hydroxylase (TH), CGRP, and smooth muscle actin were identified in kidney sections from 12 Sprague-Dawley rats, to distinguish afferents, efferents, and vasculature. DNX kidneys and nondenervated kidneys were examined 1, 4, and 12 wk after DNX. Tissue levels of CGRP and norepinephrine (NE) were measured with ELISA and mass spectrometry, respectively. DNX decreased TH and CGRP labeling by 90% and 95%, respectively (P < 0.05) within 1 wk. After 12 wk TH and CGRP labeling returned to baseline with a shift toward afferent innervation (P < 0.05). Nondenervated kidneys showed a doubling of both labels within 12 wk (P < 0.05). CGRP content decreased by 72% [3.2 ± 0.3 vs. 0.9 ± 0.2 ng/gkidney; P < 0.05] and NA by 78% [1.1 ± 0.1 vs. 0.2 ± 0.1 pmol/mgkidney; P < 0.05] 1 wk after DNX. After 12 wk, CGRP, but not NE, content in DNX kidneys was fully recovered, with no changes in the nondenervated kidneys. The use of phenol in the DNX procedure did not influence this result. We found morphological reinnervation and transmitter recovery of afferents within 12 wk after DNX. Despite morphological evidence of sympathetic regrowth, NE content did not fully recover. These results suggest a long-term net surplus of afferent influence on the DNX kidney may be contributing to the blood pressure lowering effect of DNX.
EVALuna2:3840

Comprehensive genomic characterization of early-stage bladder cancer - Prip, Frederik; Lamy, Philippe; Lindskrog, Sia Viborg; Strandgaard, Trine; Nordentoft, Iver; Birkenkamp-Demtröder, Karin; Birkbak, Nicolai Juul; Kristjánsdóttir, Nanna; Kjær, Asbjørn; Andreasen, Tine G.; Ahrenfeldt, Johanne; Pedersen, Jakob Skou; et al. (Nature Genetics, 2025)
Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification.
CRIS-Team Scopus Importer:2025-01-31

Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas - Glueckstein, Marie-Isabelle; Dintner, Sebastian; Arndt, Tim Tobias; Vlasenko, Dmytro; Schenkirsch, Gerhard; Agaimy, Abbas; Mueller, Gernot; Maerkl, Bruno; Grosser, Bianca (Cancers, 2021)
Simple Summary This study aimed to investigate the clinical relevance of immunohistochemical expression of proteins of the SWI/SNF complex, SMARCA2, SMARCA4 SMARCB1, ARID1A, ARID1B, and PBRM1 in 477 adenocarcinomas of the stomach and gastroesophageal junction. Additionally, the tumors were classified immunohistochemically in analogy to The Cancer Genome Atlas (TCGA) classification. Overall, 32% of cases demonstrated aberrant expression of the SWI/SNF complex. SWI/SNF aberration emerged as an independent negative prognostic factor for overall survival in all patients and in genomically stable patients in analogy to TCGA. In conclusion, determination of SWI/SNF status could be suggested in routine diagnostics in genomically stable tumors to identify patients who might benefit from new therapeutic options. The SWI/SNF complex has important functions in the mobilization of nucleosomes and consequently influences gene expression. Numerous studies have demonstrated that mutations or deficiency of one or more subunits can have an oncogenic effect and influence the development, progression, and eventual therapy resistance of tumor diseases. Genes encoding subunits of the SWI/SNF complex are mutated in approximately 20% of all human tumors. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of immunohistochemical expression of proteins of the SWI/SNF complexes, SMARCA2, SMARCA4 SMARCB1, ARID1A, ARID1B, and PBRM1 in 477 adenocarcinomas of the stomach and gastroesophageal junction. Additionally, the tumors were classified immunohistochemically in analogy to The Cancer Genome Atlas (TCGA) classification. Overall, 32% of cases demonstrated aberrant expression of the SWI/SNF complex. Complete loss of SMARCA4 was detected in three cases (0.6%) and was associated with adverse clinical characteristics. SWI/SNF aberration emerged as an independent negative prognostic factor for overall survival in genomically stable patients in analogy to TCGA. In conclusion, determination of SWI/SNF status could be suggested in routine diagnostics in genomically stable tumors to identify patients who might benefit from new therapeutic options.
CRIS-Team WoS Importer:2021-08-20

Comprehensive Molecular Profiling of Sinonasal Teratocarcinosarcoma Identifies Recurrent SMARCA4 and Wnt/beta-catenin Pathway Mutations - Rooper, Lisa M.; Din, Nasir Ud; Gagan, Jeffrey; Thompson, Lester; Agaimy, Abbas; Bishop, Justin (MODERN PATHOLOGY, 2021)
CRIS-Team WoS Importer:2021-04-16

Comprehensive profile of platelet derived growth factor receptor alpha (PDGFRA) mutations in gastrointestinal stromal tumors - Khosroyani, Homma; Klug, Lillian R.; Town, Ajia; Lategahn, Jonas; Falkenhorst, Johanna; Grunewald, Susanne; Muhlenberg, Thomas; Ehrt, Christiane; Wardelmann, Eve; Hartmann, Wolfgang; Schildhaus, Hans-Ulrich; Jung, Sascha; et al. (CANCER RESEARCH, 2020)
CRIS-Team WoS Importer:2021-03-05

Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations - Kraus, Cornelia; Rau, Tilman; Lux, Philipp; Erlenbach-Wuensch, Katharina; Loehr, Sabine; Krumbiegel, Mandy; Thiel, Christian; Stoehr, Robert; Agaimy, Abbas; Croner, Roland S.; Stürzl, Michael; Hohenberger, Werner; et al. (International Journal of Cancer, 2015)
Germline mutation testing in patients with colorectal cancer (CRC) is offered only to a subset of patients with a clinical presentation or tumor histology suggestive of familial CRC syndromes, probably underestimating familial CRC predisposition. The aim of our study was to determine whether unbiased screening of newly diagnosed CRC cases with next generation sequencing (NGS) increases the overall detection rate of germline mutations. We analyzed 152 consecutive CRC patients for germline mutations in 18 CRC-associated genes using NGS. All patients were also evaluated for Bethesda criteria and all tumors were investigated for microsatellite instability, immunohistochemistry for mismatch repair proteins and the BRAF*V600E somatic mutation. NGS based sequencing identified 27 variants in 9 genes in 23 out of 152 patients studied (18%). Three of them were already reported as pathogenic and 12 were class 3 germline variants with an uncertain prediction of pathogenicity. Only 1 of these patients fulfilled Bethesda criteria and had a microsatellite instable tumor and an MLH1 germline mutation. The others would have been missed with current approaches: 2 with a MSH6 premature termination mutation and 12 uncertain, potentially pathogenic class 3 variants in APC, MLH1, MSH2, MSH6, MSH3 and MLH3. The higher NGS mutation detection rate compared with current testing strategies based on clinicopathological criteria is probably due to the large genetic heterogeneity and overlapping clinical presentation of the various CRC syndromes. It can also identify apparently nonpenetrant germline mutations complicating the clinical management of the patients and their families.
EVALuna2:6598

Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma - Hedegaard, Jakob; Lamy, Philippe; Nordentoft, Iver; Algaba, Ferran; Hoyer, Soren; Ulhoi, Benedicte Parm; Vang, Soren; Reinert, Thomas; Hermann, Gregers G.; Mogensen, Karin; Thomsen, Mathilde Borg Houlberg; Nielsen, Morten Muhlig; et al. (Cancer Cell, 2016)
Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
EVALuna2:6801

Computer-aided diagnosis in multiparametric mri of the prostate: An open-access online tool for lesion classification with high accuracy - Ellmann, Stephan; Schlicht, Michael; Dietzel, Matthias; Janka, Rolf Matthias; Hammon, Matthias; Saake, Marc; Ganslandt, Thomas; Hartmann, Arndt; Kunath, Frank; Wullich, Bernd; Uder, Michael; Bäuerle, Tobias (Cancers, 2020)
Computer-aided diagnosis (CADx) approaches could help to objectify reporting on prostate mpMRI, but their use in many cases is hampered due to common-built algorithms that are not publicly available. The aim of this study was to develop an open-access CADx algorithm with high accuracy for classification of suspicious lesions in mpMRI of the prostate. This retrospective study was approved by the local ethics commission, with waiver of informed consent. A total of 124 patients with 195 reported lesions were included. All patients received mpMRI of the prostate between 2014 and 2017, and transrectal ultrasound (TRUS)-guided and targeted biopsy within a time period of 30 days. Histopathology of the biopsy cores served as a standard of reference. Acquired imaging parameters included the size of the lesion, signal intensity (T2w images), diffusion restriction, prostate volume, and several dynamic parameters along with the clinical parameters patient age and serum PSA level. Inter-reader agreement of the imaging parameters was assessed by calculating intraclass correlation coefficients. The dataset was stratified into a train set and test set (156 and 39 lesions in 100 and 24 patients, respectively). Using the above parameters, a CADx based on an Extreme Gradient Boosting algorithm was developed on the train set, and tested on the test set. Performance optimization was focused on maximizing the area under the Receiver Operating Characteristic curve (ROCAUC). The algorithm was made publicly available on the internet. The CADx reached an ROCAUC of 0.908 during training, and 0.913 during testing (p = 0.93). Additionally, established rule-in and rule-out criteria allowed classifying 35.8% of the malignant and 49.4% of the benign lesions with error rates of <2%. All imaging parameters featured excellent inter-reader agreement. This study presents an open-access CADx for classification of suspicious lesions in mpMRI of the prostate with high accuracy. Applying the provided rule-in and rule-out criteria might facilitate to further stratify the management of patients at risk.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Artificial intelligence; Computer-aided diagnosis; Machine learning; Prostate cancer; Prostate mpMRI

Concealed complete response in melanoma patients under therapy with immune checkpoint inhibitors: two case reports - Schliep, Stefan; Agaimy, Abbas; Kiesewetter, Franklin; Schuler, Gerold; Heinzerling, Lucie; Cavallaro, Alexander Josef (Journal for ImmunoTherapy of Cancer, 2018)
BACKGROUND: The assessment of tumor size by RECIST using CT scans and MRIs is considered to be standard of care for staging cancer patients. Despite radiologic evidence of widespread disease, we document for the first time that patients were completely free of viable tumor. CASE PRESENTATION: Two patients with metastatic melanoma were treated with immune checkpoint inhibitors (ipilimumab/ nivolumab) and progressive metastases were detected on CT-scans performed shortly before histologic examinations. In both patients histologic assessment revealed a complete response with necrotic and scarred lesions free of tumor. One of the patients had started immunotherapy 20 months before with an initial partial response. CONCLUSIONS: This phenomenon of a concealed complete response can lead to overtreatment or unnecessary change in treatment. Thus, it is essential to raise awareness for it. Correct identification of responders to immune checkpoint inhibitor therapy is crucial to spare patients immune-mediated side effects and unnecessary as well as expensive treatment. Regression of metastases without decline in size, in these cases manifesting as complete responses, are probably more common than expected and identified to date. Until such responses can be readily identified by new imaging techniques, we recommend liberal biopsies for histologic assessment of progressive metastases in patients during and/or after immune checkpoint inhibitor therapy.
EVALuna2:34405

Concordance Rate of Colposcopy in Detecting Cervical Intraepithelial Lesions - Stübs, Frederik; Dietl, Anna; Behrens, Annika; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Mehlhorn, Grit; Schulmeyer, Carla; Gaß, Paul; Koch, Martin C. (Diagnostics, 2022)
Background: The purpose of this research is to estimate the rate of concordance, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of colposcopy for high-grade squamous lesions and carcinomas (HSIL+). Methods: We conducted a retrospective study of colposcopies performed in the certified Dysplasia Unit in Erlangen between January 2015 and May 2022 (7.5 years). The colposcopic findings were correlated with biopsies obtained during examinations or surgery. Cases without histology were excluded. The primary outcome was the rate of concordance between the colposcopic and histological findings in relation to the type of transformation zone (TZ), examiner's level of experience and age of the patients. Results: A total of 4778 colposcopies in 4001 women were analyzed. The rates of concordance for CIN I/LSIL, CIN II/HSIL, CIN III/HSIL, and carcinoma were 43.4%, 59.5%, 78.5%, and 53.9%, respectively. The rate of concordance was lowest for TZ3 and highest for colposcopists with more than 10 years' experience. Conclusions: Colposcopy is an important, feasible, and effective method. Careful work-up needs to be performed for women with TZ3 who are over 35 years old, as they are at the highest risk of being misdiagnosed. The highest concordance for detecting HSIL+ was seen for colposcopists with >10 years' experience.
CRIS-Team WoS Importer:2022-11-11

Concordance rate of vulvoscopic findings in detecting early vulvar neoplasia - Stuebs, Frederik A.; Mehlhorn, Grit; Gaß, Paul; Schulmeyer, Carla; Adler, Werner; Strehl, Johanna; Hartmann, Arndt; Beckmann, Matthias; Renner, Stefan; Koch, Martin (Gynecologic Oncology, 2020)
Purpose: Colposcopy-guided punch biopsy is a cornerstone method for diagnosing vulvar diseases. The aim of this study was to evaluate the concordance rate of clinical findings in vulvar diseases during examinations, in comparison with colposcopy-directed punch biopsy. We also developed a new classification to simplify the categorization of vulvoscopic findings. Methods: The concordance rate of the clinical findings was compared with the final histology results from punch biopsies. The data were collected between January 2014 and May 2017 at the Erlangen University Hospital. Results: A total of 482 colposcopy-directed punch biopsies of the vulva were obtained in 420 women. The overall concordance rate of the clinical findings in comparison with the histological vulvar punch-biopsy findings was 53.9% for all entities — benign lesions, lichen, low- and high-grade squamous intraepithelial lesions (LSIL/HSILs), and vulvar carcinoma. The concordance rate for detecting LSILs was 64.3% (45/70). The concordance rate for detecting HSILs was 62.3% and for Vulvar carcinoma 65.2%. Conclusions: Punch biopsy of suspicious lesions continues to be a cornerstone in diagnosing HSILs and carcinoma of the vulva. Careful work-up of the vulva is recommended when patients have symptoms such as pruritus or pain. The new classification is more specific for diagnosing lesions in the vulva.
CRIS-Team Scopus Importer:2020-03-06
Keywords: Colposcopy-directed punch biopsy; High-grade squamous intraepithelial lesion (HSIL); Vulvar cancer; Vulvar intraepithelial neoplasia (VIN)

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma - Saner, Flurina A.M.; Takahashi, Kazuaki; Budden, Timothy; Pandey, Ahwan; Ariyaratne, Dinuka; Zwimpfer, Tibor A.; Meagher, Nicola S.; Fereday, Sian; Twomey, Laura; Pishas, Kathleen I.; Hoang, Therese; Bolithon, Adelyn; et al. (Clinical Cancer Research, 2024)
PURPOSE: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
CRIS-Team Scopus Importer:2024-08-23

Confocal Laser Endomicroscopy for Diagnosing Malignant Pleural Effusions - Zirlik, Sabine; Hildner, Kai; Rieker, Ralf; Neurath, Markus; Fuchs, Florian; Vieth, Michael (Medical Science Monitor, 2018)
BACKGROUND Confocal laser endomicroscopy (CLE) enables "in vivo" microscopic tissue diagnosis based on tissue reflectance or tissue fluorescence upon application of fluorescence agents. The aim of the present study was to evaluate CLE as a new diagnostic approach for differentiation between malignant versus non-malignant pleural effusions. MATERIAL AND METHODS In 100 patients with pleural effusions, thoracentesis was performed. Cresyl violet and acriflavine were used as contrast agents for probe-based CLE of effusions. CLE video sequences were assessed by 4 independent investigators (2 experienced in this technique, 2 with only basic knowledge). In addition, all CLE samples were evaluated by an expert pathologist (p). Results were compared with conventional cytology of effusions and histology of cell blocks. RESULTS CLE reliably permitted identification of malignant cells in pleural effusions. Sensitivity for detection of malignant effusions was 87% (p: 87%) and 81% (p: 72%) for acriflavine and cresyl violet, respectively. With regard to specificity, acriflavine and cresyl violet yielded a mean value of 99% (p: 100%) and 92% (p: 100%). CONCLUSIONS In this pilot study, CLE permitted simple and rapid detection of malignant pleural effusions. Larger prospective studies are warranted to corroborate our findings.
EVALuna2:35147

Consensus definitions for glomerular lesions by light and electron microscopy: recommendations from a working group of the Renal Pathology Society - Haas, Mark; Seshan, Surya V.; Barisoni, Laura; Amann, Kerstin Ute; Bajema, Ingeborg M.; Becker, Jan Ulrich; Joh, Kensuke; Ljubanovic, Danica; Roberts, Ian S.D.; Roelofs, Joris J.; Sethi, Sanjeev; Zeng, Caihong; et al. (Kidney International, 2020)
Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have consortia of pathologists and nephrologists for the study of glomerular diseases, including correlation of pathologic findings with clinical features and outcomes. However, one important limitation faced by members of these consortia and other renal pathologists and nephrologists in both investigative work and routine practice remains a lack of uniformity and precision in clearly defining the morphologic lesions on which the scoring systems are based. In response to this issue, the Renal Pathology Society organized a working group to identify the most frequently identified glomerular lesions observed by light microscopy and electron microscopy, review the literature to capture the published definitions most often used for each, and determine consensus terms and definitions for each lesion in a series of online and in-person meetings. The defined lesions or abnormal findings are not specific for any individual disease or subset of diseases, but rather can be applied across the full spectrum of glomerular diseases and within the context of the different scoring systems used for evaluating and reporting these diseases. In addition to facilitating glomerular disease research, standardized terms and definitions should help harmonize reporting of medical kidney diseases worldwide and lead to more-precise diagnoses and improved patient care.
CRIS-Team Scopus Importer:2020-11-06
Keywords: electron microscopy; glomerulonephritis; glomerulus; kidney biopsy; renal pathology