TY - JOUR A1 - Stock, Benjamin A1 - Möckel, Sigrid A1 - Zander, Christine A1 - Heinsen, Helmut A1 - Bohnert, Simone A1 - Bohnert, Michael T1 - „Black esophagus“ – zwei Obduktionsfälle mit infektiöser Beteiligung JF - Rechtsmedizin N2 - „Black esophagus“ oder „akute Ösophagusnekrose“ (AÖN) ist eine seltene Erkrankung, die sich makroskopisch durch eine zirkumferente Schwarzverfärbung der Ösophagusmukosa mit abruptem Ende am gastroösophagealen Übergang auszeichnet. Die genaue Pathogenese ist unbekannt; es werden multifaktorielle Einflüsse wie z. B. Säurereflux, Ischämie und verringerte Schutzmechanismen der Mukosa als mögliche Ursachen diskutiert. Vorgestellt werden 2 Obduktionsfälle, die typische Befunde einer AÖN aufwiesen. Zusätzlich hatten Fall 1 eine Candida-Infektion und Fall 2 eine Appendizitis, sodass eine infektiöse Genese in beiden Fällen eine Rolle gespielt haben könnte. N2 - Black esophagus, also known as acute esophageal necrosis, is a rare disease characterized by a circumferential black discoloration of the esophageal mucosa with an abrupt stop at the gastroesophageal junction. The exact pathogenesis is unknown, but multifactorial influences, such as acid reflux, ischemia and reduced protective mechanisms of the mucosa are discussed as possible causes. Two autopsy cases are presented with typical signs of a black esophagus. The first case showed an infection with Candida albicans, the second one died of appendicitis, so in both cases an infectious genesis might have played a role. T2 - Black esophagus—Two autopsy cases with infectious involvement KW - Histopathologie KW - Blinddarmentzündung KW - Speiseröhre KW - Nekrose KW - Schleimhaut KW - Candida KW - Akute Ösophagusnekrose KW - Schleimhaut-Ulzera KW - Appendizitis KW - acute esophageal necrosis KW - histopathology KW - mucosal ulcers KW - appendicitis KW - Candida Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325022 SN - 0937-9819 VL - 33 IS - 3 ER - TY - JOUR A1 - Löb, Sanja A1 - Linsmeier, Eva A1 - Herbert, Saskia-Laureen A1 - Schlaiß, Tanja A1 - Kiesel, Matthias A1 - Wischhusen, Jörg A1 - Salmen, Jessica A1 - Kranke, Peter A1 - Quenzer, Anne A1 - Kurz, Florian A1 - Weiss, Claire A1 - Gerhard-Hartmann, Elena A1 - Wöckel, Achim A1 - Diessner, Joachim T1 - Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important. KW - breast cancer KW - HER2 conversion KW - HER2-low KW - trastuzumab deruxtecan KW - HER2 targeted therapy KW - trastuzumab Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324068 VL - 149 IS - 8 ER - TY - JOUR A1 - Schulmeyer, Carla E. A1 - Fasching, Peter A. A1 - Häberle, Lothar A1 - Meyer, Julia A1 - Schneider, Michael A1 - Wachter, David A1 - Ruebner, Matthias A1 - Pöschke, Patrik A1 - Beckmann, Matthias W. A1 - Hartmann, Arndt A1 - Erber, Ramona A1 - Gass, Paul T1 - Expression of the immunohistochemical markers CK5, CD117, and EGFR in molecular subtypes of breast cancer correlated with prognosis JF - Diagnostics N2 - Molecular-based subclassifications of breast cancer are important for identifying treatment options and stratifying the prognosis in breast cancer. This study aimed to assess the prognosis relative to disease-free survival (DFS) and overall survival (OS) in patients with triple-negative breast cancer (TNBC) and other subtypes, using a biomarker panel including cytokeratin 5 (CK5), cluster of differentiation 117 (CD117), and epidermal growth factor receptor (EGFR). This cohort–case study included histologically confirmed breast carcinomas as cohort arm. From a total of 894 patients, 572 patients with early breast cancer, sufficient clinical data, and archived tumor tissue were included. Using the immunohistochemical markers CK5, CD117, and EGFR, two subgroups were formed: one with all three biomarkers negative (TBN) and one with at least one of those three biomarkers positive (non-TBN). There were significant differences between the two biomarker subgroups (TBN versus non-TBN) in TNBC for DFS (p = 0.04) and OS (p = 0.02), with higher survival rates (DFS and OS) in the non-TBN subgroup. In this study, we found the non-TBN subgroup of TNBC lesions with at least one positive biomarker of CK5, CD117, and/or EGFR, to be associated with longer DFS and OS. KW - early breast cancer KW - therapy KW - prognosis KW - CK5 KW - CD117 KW - EGFR KW - triple-negative breast cancer Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304987 SN - 2075-4418 VL - 13 IS - 3 ER - TY - JOUR A1 - Stefanakis, Mona A1 - Bassler, Miriam C. A1 - Walczuch, Tobias R. A1 - Gerhard-Hartmann, Elena A1 - Youssef, Almoatazbellah A1 - Scherzad, Agmal A1 - Stöth, Manuel Bernd A1 - Ostertag, Edwin A1 - Hagen, Rudolf A1 - Steinke, Maria R. A1 - Hackenberg, Stephan A1 - Brecht, Marc A1 - Meyer, Till Jasper T1 - The impact of tissue preparation on salivary gland tumors investigated by Fourier-transform infrared microspectroscopy JF - Journal of Clinical Medicine N2 - Due to the wide variety of benign and malignant salivary gland tumors, classification and malignant behavior determination based on histomorphological criteria can be difficult and sometimes impossible. Spectroscopical procedures can acquire molecular biological information without destroying the tissue within the measurement processes. Since several tissue preparation procedures exist, our study investigated the impact of these preparations on the chemical composition of healthy and tumorous salivary gland tissue by Fourier-transform infrared (FTIR) microspectroscopy. Sequential tissue cross-sections were prepared from native, formalin-fixed and formalin-fixed paraffin-embedded (FFPE) tissue and analyzed. The FFPE cross-sections were dewaxed and remeasured. By using principal component analysis (PCA) combined with a discriminant analysis (DA), robust models for the distinction of sample preparations were built individually for each parotid tissue type. As a result, the PCA-DA model evaluation showed a high similarity between native and formalin-fixed tissues based on their chemical composition. Thus, formalin-fixed tissues are highly representative of the native samples and facilitate a transfer from scientific laboratory analysis into the clinical routine due to their robust nature. Furthermore, the dewaxing of the cross-sections entails the loss of molecular information. Our study successfully demonstrated how FTIR microspectroscopy can be used as a powerful tool within existing clinical workflows. KW - formalin KW - fixation KW - tissue preparation KW - salivary gland neoplasia KW - FTIR spectroscopy KW - principal component analysis KW - discriminant analysis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304887 SN - 2077-0383 VL - 12 IS - 2 ER - TY - JOUR A1 - Marquardt, André A1 - Hartrampf, Philipp A1 - Kollmannsberger, Philip A1 - Solimando, Antonio G. A1 - Meierjohann, Svenja A1 - Kübler, Hubert A1 - Bargou, Ralf A1 - Schilling, Bastian A1 - Serfling, Sebastian E. A1 - Buck, Andreas A1 - Werner, Rudolf A. A1 - Lapa, Constantin A1 - Krebs, Markus T1 - Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures JF - Cancers N2 - (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets. KW - machine learning KW - tumor microenvironment KW - immune infiltration KW - angiogenesis KW - mRNA KW - miRNA KW - transcriptome Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305036 SN - 2072-6694 VL - 15 IS - 2 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Kessler, Almuth F. A1 - Feldheim, Julia J. A1 - Schmitt, Dominik A1 - Oster, Christoph A1 - Lazaridis, Lazaros A1 - Glas, Martin A1 - Ernestus, Ralf-Ingo A1 - Monoranu, Camelia M. A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - BRMS1 in gliomas — an expression analysis JF - Cancers N2 - The metastatic suppressor BRMS1 interacts with critical steps of the metastatic cascade in many cancer entities. As gliomas rarely metastasize, BRMS1 has mainly been neglected in glioma research. However, its interaction partners, such as NFκB, VEGF, or MMPs, are old acquaintances in neurooncology. The steps regulated by BRMS1, such as invasion, migration, and apoptosis, are commonly dysregulated in gliomas. Therefore, BRMS1 shows potential as a regulator of glioma behavior. By bioinformatic analysis, in addition to our cohort of 118 specimens, we determined BRMS1 mRNA and protein expression as well as its correlation with the clinical course in astrocytomas IDH mutant, CNS WHO grade 2/3, and glioblastoma IDH wild-type, CNS WHO grade 4. Interestingly, we found BRMS1 protein expression to be significantly decreased in the aforementioned gliomas, while BRMS1 mRNA appeared to be overexpressed throughout. This dysregulation was independent of patients’ characteristics or survival. The protein and mRNA expression differences cannot be finally explained at this stage. However, they suggest a post-transcriptional dysregulation that has been previously described in other cancer entities. Our analyses present the first data on BRMS1 expression in gliomas that can provide a starting point for further investigations. KW - glioblastoma KW - metastasis KW - suppressor KW - behavior KW - mRNA KW - protein Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319225 SN - 2072-6694 VL - 15 IS - 11 ER - TY - JOUR A1 - Nickl, Vera A1 - Eck, Juliana A1 - Goedert, Nicolas A1 - Hübner, Julian A1 - Nerreter, Thomas A1 - Hagemann, Carsten A1 - Ernestus, Ralf-Ingo A1 - Schulz, Tim A1 - Nickl, Robert Carl A1 - Keßler, Almuth Friederike A1 - Löhr, Mario A1 - Rosenwald, Andreas A1 - Breun, Maria A1 - Monoranu, Camelia Maria T1 - Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma JF - Cancers N2 - While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future. KW - glioblastoma KW - organoids KW - slice culture KW - tumormicroenvironment Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319249 SN - 2072-6694 VL - 15 IS - 10 ER - TY - JOUR A1 - Böck, Julia A1 - Maurus, Katja A1 - Gerhard-Hartmann, Elena A1 - Brändlein, Stephanie A1 - Kurz, Katrin S. A1 - Ott, German A1 - Anagnostopoulos, Ioannis A1 - Rosenwald, Andreas A1 - Zamò, Alberto T1 - Targeted panel sequencing in the routine diagnosis of mature T- and NK-cell lymphomas BT - report of 128 cases from two German reference centers JF - Frontiers in Oncology N2 - Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97%) and could detect mutations in the majority (79%) of tested T-cell lymphoma samples. KW - T-cell lymphoma KW - panel-sequencing KW - NGS KW - diagnostics KW - mutation KW - FFPE Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-326478 SN - 2234-943X VL - 13 ER - TY - JOUR A1 - Kreß, Julia Katharina Charlotte A1 - Jessen, Christina A1 - Hufnagel, Anita A1 - Schmitz, Werner A1 - Da Xavier Silva, Thamara Nishida A1 - Ferreira Dos Santos, Ancély A1 - Mosteo, Laura A1 - Goding, Colin R. A1 - Friedmann Angeli, José Pedro A1 - Meierjohann, Svenja T1 - The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2 JF - Cell Reports N2 - Highlights • The integrated stress response leads to a general ATF4-dependent activation of NRF2 • ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization • An elevation of NRF2 transcript levels fosters this effect • NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply Summary The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease. KW - NRF2 KW - ATF4 KW - integrated stress response KW - CHAC1 KW - melanoma KW - SLC7A11 KW - GSH Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350312 VL - 42 IS - 7 ER - TY - JOUR A1 - Bassler, Miriam C. A1 - Knoblich, Mona A1 - Gerhard-Hartmann, Elena A1 - Mukherjee, Ashutosh A1 - Youssef, Almoatazbellah A1 - Hagen, Rudolf A1 - Haug, Lukas A1 - Goncalves, Miguel A1 - Scherzad, Agmal A1 - Stöth, Manuel A1 - Ostertag, Edwin A1 - Steinke, Maria A1 - Brecht, Marc A1 - Hackenberg, Stephan A1 - Meyer, Till Jasper T1 - Differentiation of salivary gland and salivary gland tumor tissue via Raman imaging combined with multivariate data analysis JF - Diagnostics N2 - Salivary gland tumors (SGTs) are a relevant, highly diverse subgroup of head and neck tumors whose entity determination can be difficult. Confocal Raman imaging in combination with multivariate data analysis may possibly support their correct classification. For the analysis of the translational potential of Raman imaging in SGT determination, a multi-stage evaluation process is necessary. By measuring a sample set of Warthin tumor, pleomorphic adenoma and non-tumor salivary gland tissue, Raman data were obtained and a thorough Raman band analysis was performed. This evaluation revealed highly overlapping Raman patterns with only minor spectral differences. Consequently, a principal component analysis (PCA) was calculated and further combined with a discriminant analysis (DA) to enable the best possible distinction. The PCA-DA model was characterized by accuracy, sensitivity, selectivity and precision values above 90% and validated by predicting model-unknown Raman spectra, of which 93% were classified correctly. Thus, we state our PCA-DA to be suitable for parotid tumor and non-salivary salivary gland tissue discrimination and prediction. For evaluation of the translational potential, further validation steps are necessary. KW - salivary gland tumor KW - confocal Raman imaging KW - principal component analysis KW - discriminant analysis KW - multivariate data analysis KW - molecular diagnostics Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-355558 SN - 2075-4418 VL - 14 IS - 1 ER -