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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Fatal Encephalitis Associated with Borna Disease Virus 1 - Korn, Klaus; Coras, Roland; Bobinger, Tobias; Herzog, Sibylle M.; Lücking, Hannes; Stoehr, Roland; Huttner, Hagen; Hartmann, Arndt; Enßer, Armin (New England Journal of Medicine, 2018)
EVALuna2:34851

Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman - Olmes, David G.; Agaimy, Abbas; Kloska, Stephan; Linker, Ralf (BMJ Case Reports, 2014)
An 80-year-old woman presented with weight loss, fatigue, dizziness and a brain stem lesion. Extensive work-up revealed lymphomatoid granulomatosis (LYG) with primary clinical manifestation in the central nervous system (CNS), a rare Epstein-Barr virus-driven multisystem lymphoproliferative disorder, to be causative for the symptoms. Immunochemotherapy consisting of rituximab and temozolomide was started, but the disease progressed and the patient subsequently died. Histology, diagnostic criteria, differential diagnosis and treatment options for LYG with CNS involvement are discussed. This case demonstrates that LYG with CNS involvement may necessitate more aggressive treatment approaches than combination therapy with rituximab and temozolomide.
EVALuna2:6736

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

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

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

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

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

Fibroblast growth factor receptor-1 as a potential therapeutic target in sinonasal cancer - Schroeck, Andreas; Goeke, Friederike; Wagner, Patrick; Bode, Maike; Franzen, Alina; Huss, Sebastian; Agaimy, Abbas; Ihrler, Stephan; Kirsten, Robert; Kristiansen, Glen; Bootz, Friedrich; Lengerke, Claudia; et al. (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2014)
Despite multimodal treatment, sinonasal malignancies have an unfavorable prognosis. The purpose of this study was to elucidate if these tumors harbor amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, which has recently been identified as a potential therapeutic target in squamous cell lung cancer.One hundred twelve primary tumors (including squamous cell carcinoma [SCC], carcinoma associated with an inverted papilloma, sinonasal undifferentiated carcinoma [SNUC], adenocarcinoma, adenoid cystic carcinoma [ACC], esthesioneuroblastoma, and 9 corresponding lymph node metastases) were assessed by fluorescence in situ hybridization (FISH) for FGFR1 copy number status. Human papillomavirus (HPV) status was assessed by p16 immunohistochemical as a surrogate marker.FGFR1 amplification was found in subsets of sinonasal SCCs (20%), carcinomas associated with an inverted papilloma (33%), and SNUCs (5%). In all cases, metastatic tumor samples shared the same FGFR1 amplification status as the corresponding primary tumor tissue. None of the FGFR1-amplified tumors expressed p16.FGFR1 amplification represents a potential molecular target in a subset of patients with sinonasal cancer. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1253-1257, 2014.
EVALuna2:6681

Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup - Baldia, Philipp H.; Maurer, Angela; Heide, Timon; Rose, Michael; Stoehr, Robert; Hartmann, Arndt; Williams, Sarah V.; Knowles, Margaret A.; Knuechel, Ruth; Gaisa, Nadine T. (Oncotarget, 2016)
Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p < 0.001), and unfavourable clinical outcome (p = 0.001). Our findings are consistent with the results of the TCGA data set for the "squamous-like" subtype of bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA "squamous-like" subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies.
EVALuna2:6882

Fibroblast growth factor receptor (FGFR) gene amplifications are rare events in bladder cancer - Fischbach, Anna; Rogler, Anja; Erber, Ramona; Stoehr, Robert; Poulsom, Richard; Heidenreich, Axel; Schneevoigt, Birte-Swantje; Hauke, Sven; Hartmann, Arndt; Knüchel, Ruth; Veeck, Jürgen; Gaisa, Nadine T. (Histopathology, 2015)
Activating point mutations and protein overexpression of fibroblast growth factor receptors (FGFRs), especially FGFR3, are frequent events in bladder cancer. Little is known about gene amplifications, therefore we characterized amplification of FGFR1-3 by fluorescence in-situ hybridization (FISH).Tumours of 153 patients (n = 65 pTa low-grade, n = 15 pTa high-grade, n = 37 pT1, n = 20 pT2, n = 10 pT3, n = 6 pT4) were analysed by FISH for FGFR1-3 copy numbers and screened for FGFR3 mutations and immunohistochemical protein expression. Amplifications of FGFR1 were found in 1.6% (two of 122), FGFR2 in 0.8% (one of 121) and FGFR3 in 3.4% (five of 145). All amplifications were high-level amplifications, not overlapping with polysomy. Amplifications were found in papillary/papillary-invasive tumour parts, and predominantly in tumours with enhanced Ki67 index (>10%), aberrant CK20 expression, and low p53 expression. All FGFR3-amplified samples showed concomitant FGFR3 mutations and FGFR3 protein overexpression. FGFR amplifications were not associated significantly with gender, age, grade or stage in statistical analyses.FGFR amplifications are rare events in bladder cancer, with FGFR3 amplification being the most prevalent (3.4% of cases). Concomitant FGFR3 mutations and protein overexpression indicate that FGFR3-mediated signalling in these tumours would probably be highly active. This patient subgroup may be particularly suited to FGFR-targeted pharmacotherapy.
EVALuna2:6703

Filtration based assessment of CTCs and CellSearch® based assessment are both powerful predictors of prognosis for metastatic breast cancer patients - Hübner, Hanna; Fasching, Peter; Gumbrecht, Walter; Jud, Sebastian; Rauh, Claudia; Matzas, Mark; Paulicka, Peter; Friedrich, Katja; Lux, Michael P.; Volz, Bernhard; Gaß, Paul; Häberle, Lothar; et al. (BMC Cancer, 2018)
The assessment of circulating tumor cells (CTCs) has been shown to enable monitoring of treatment response and early detection of metastatic breast cancer (MBC) recurrence. The aim of this study was to compare a well-established CTC detection method based on immunomagnetic isolation with a new, filtration-based platform.In this prospective study, two 7.5 ml blood draws were obtained from 60 MBC patients and CTC enumeration was assessed using both the CellSearch® and the newly developed filtration-based platform. We analyzed the correlation of CTC-positivity between both methods and their ability to predict prognosis. Overall survival (OS) was calculated and Kaplan-Meier curves were estimated with thresholds of >=1 and >=5 detected CTCs.The CTC positivity rate of the CellSearch® system was 56.7% and of the filtration-based platform 66.7%. There was a high correlation of CTC enumeration obtained with both methods. The OS for patients without detected CTCs, regardless of the method used, was significantly higher compared to patients with one or more CTCs (p < 0.001). The median OS of patients with no CTCs vs. >= 1 CTC assessed by CellSearch® was 1.83 years (95% CI: 1.63-2.02) vs. 0.74 years (95% CI: 0.51-1.52). If CTCs were detected by the filtration-based method the median OS times were 1.88 years (95% CI: 1.74-2.03) vs. 0.59 years (95% CI: 0.38-0.80).The newly established EpCAM independently filtration-based system is a suitable method to determine CTC counts for MBC patients. Our study confirms CTCs as being strong predictors of prognosis in our population of MBC patients.
EVALuna2:51529

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression - Nitz, U.; Gluz, O.; Huober, J.; Kreipe, H. H.; Kates, R. E.; Hartmann, Arndt; Erber, Ramona; Scholz, M.; Lisboa, B.; Mohrmann, S.; Moebus, V.; Augustin, D.; et al. (Annals of Oncology, 2014)
Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only.A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors.Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (>= 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01).EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.ClinicalTrials.gov, NCT02115204.
EVALuna2:6696

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression (vol 25, pg 1551, 2014) - Nitz, U.; Gluz, O.; Huober, J.; Kreipe, H. H.; Kates, R. E.; Hartmann, Arndt; Erber, Ramona; Moustafa, Z.; Scholz, M.; Lisboa, B.; Mohrmann, S.; Moebus, V.; et al. (Annals of Oncology, 2017)
EVALuna2:34898

Fine needle aspiration cytology of lymph nodes in breast cancer follow-up is a feasible alternative to watchful waiting and to histology - Hammon, Matthias; Dankerl, Peter; Janka, Rolf Matthias; Wachter, David; Hartmann, Arndt; Schulz-Wendtland, Rüdiger; Uder, Michael; Wenkel, Evelyn (BMC Women's Health, 2015)
Early detection of loco-regional breast cancer recurrence improves patients' overall survival, as treatment can be initiated or active treatment can be changed. If a suspicious lymph node is diagnosed during a follow-up exam, surgical excision is often performed. The aim of this study was to evaluate the diagnostic performance of the minor invasive ultrasound-guided fine-needle aspiration cytology (FNAC) in sonomorphologically suspicious lymph nodes in breast cancer follow-up.Between April 2010 and November 2012, we performed ultrasound-guided FNAC in 38 sonographically suspicious lymph nodes of 37 breast cancer follow-up patients. Cytological specimens were evaluated if the sample material was sufficient for diagnosis and if they contained cancer cells. Patients with negative cytology were followed up clinically and sonographically. To evaluate the diagnostic performance we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for physical examination, the different sonomorphological malignancy criteria and FNAC.In 36/38 (94.7 %) lymph nodes, the pathologist had enough material to establish a final diagnosis; in 2/38 (5.3 %) lymph nodes, the probe material was non-evaluable during cytology, these 2 were excluded from further statistical evaluation. Cytology revealed malignancy in 21 lymph nodes and showed no evidence for malignancy in 15 lymph nodes. There was no evidence for malignant disease in follow-up exams in the 15 cytologically benign lymph nodes with an average follow-up time of 3 years. The diagnostic performances of physical examination and FNAC were: Sensitivity 52/100 %, specificity 88/100 %, PPV 85/100 %, NPV 60/100 %, respectively.Our preliminary results show that FNAC is a safe and fast diagnostic approach for the evaluation of suspicious lymph nodes in the follow-up of patients with breast cancer and, thus, together with follow-up represents a feasible alternative to surgery.
EVALuna2:6744

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

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

Flat intraurothelial lesions of the urinary bladder-do hyperplasia, dysplasia, and atypia of unknown significance need to exist as diagnostic entities? and how to handle in routine clinical practice - Paner, Gladell P.; Smith, Steven C.; Hartmann, Arndt; Agarwal, Piyush K.; Comperat, Eva; Amin, Mahul B. (Modern Pathology, 2022)
Classification of the putative flat preneoplastic and neoplastic lesions of the urothelium with features subthreshold for urothelial carcinoma in situ remains a challenging, indeed, vexing problem in diagnostic surgical pathology. This area, subtending lesions including flat urothelial hyperplasia, urothelial dysplasia, and atypia of unknown significance, has struggled under evolving classifications, changing criteria, and limited clinical actionability, all confounded by the recognized lack of diagnostic reproducibility. Herein, we review the state of the literature around these lesions, reviewing contemporary criteria and definitions, assessing the arguments in favor and against of retaining hyperplasia, dysplasia, and atypia of unknown significance as diagnostic entities. We clarify the intent of the original definitions for dysplasia as a lesion felt to be clearly neoplastic but with morphologic features that fall short of the threshold of urothelial carcinoma in situ. While several pathologists, including some experts in the field, conflate the term dysplasia with urothelial atypia of unknown significance, the latter is defined as a descriptive diagnosis term to express diagnostic uncertainty of a lesion of whether it is clearly reactive or neoplastic. Both molecular studies and clinical needs are considered, as we outline our approach on diagnosing each of these lesions in clinical practice. Recommendations are made to guide consistency and interoperability in future scholarship, and the place of these lesions in context of evolving trends in the field is considered.
CRIS-Team WoS Importer:2022-05-06

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group - Hettmer, Simone; Dachy, Guillaume; Seitz, Guido; Agaimy, Abbas; Duncan, Catriona; Jongmans, Marjolijn; Hirsch, Steffen; Kventsel, Iris; Kordes, Uwe; De Krijger, Ronald R.; Metzler, Markus; Michaeli, Orli; et al. (Familial Cancer, 2020)
Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary and multifocal IM lesions. PDGFRB variants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRB germline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Genetic counseling; Infantile myofibromatosis; PDGFRB variants; Surveillance

Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer. - Grampp, Steffen; Platt, James L.; Lauer, Victoria; Salama, Rafik; Kranz, Franziska; Neumann, Viviana K.; Wach, Sven; Stoehr, Christine; Hartmann, Arndt; Eckardt, Kai-Uwe; Ratcliffe, Peter John; Mole, David R.; et al. (Nature Communications, 2016)
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade - Purrington, Kristen S.; Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; et al. (Human Molecular Genetics, 2014)
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
EVALuna2:6629

Genetic variations in estrogen and progesterone pathway genes in preeclampsia patients and controls in Bavaria - Pretscher, Jutta; Rübner, Matthias; Ekici, Arif Bülent; Rödl, Melanie; Hübner, Hanna; Schwitulla, Judith; Titzmann, Adriana; Hartwig, Charlotte; Beckmann, Matthias; Fasching, Peter; Schneider, Michael; Schwenke, Eva (Archives of Gynecology and Obstetrics, 2020)
Purpose: Hypertensive pregnancy disorders and preeclampsia are major causes of maternal and fetal morbidity and mortality worldwide. Many different organs are involved in the diseases’ clinical phenotype. The underlying mechanism is still unknown, with a possible genetic component. This case–control study investigated effects on the risk of preeclampsia of genetic variations (single nucleotide polymorphisms, SNPs) in the estrogen and progesterone pathway genes. Methods: The study included 167 patients with preeclampsia and 115 healthy controls from the “Franconian Maternal Health Evaluation Studies” (FRAMES). All patients completed an epidemiological questionnaire, data from which were correlated with prospective data on pregnancy and labor. DNA was isolated from blood samples and genotyping was done by PCR. Variants in the aromatase gene CYP19A1 (rs10046, rs4646), progesterone receptor gene (rs1042838, rs10895068), and estrogen receptor-α gene (rs488133) were examined, and the genotype distribution in the two groups was analyzed statistically. Results: A significant difference in the distribution frequency of genotypes between preeclampsia patients and controls was identified in one of the five SNPs. For rs10895068 in the progesterone receptor gene, genotype G/A was significantly more frequent among cases than controls (P = 0.023). No significant differences between the two cohorts were found in the other SNPs. Conclusions: This study showed a significant association between only one SNP in the progesterone receptor and preeclampsia. Other studies have also noted genetic aspects of preeclampsia. The underlying mechanism and causal relationship are not yet known, and further research is needed to explain the extent of genetic variations and the causal relationship in preeclampsia.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Genetic marker; Preeclampsia; Pregnancy; Single nucleotide polymorphism (SNP)

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants - Jin, Ying; Andersen, Genevieve; Yorgov, Daniel; Ferrara, Tracey M.; Ben, Songtao; Brownson, Kelly M.; Holland, Paulene J.; Birlea, Stanca A.; Siebert, Janet; Hartmann, Arndt; Lienert, Anne-Marie; Van Geel, Nanja; et al. (Nature Genetics, 2016)
Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.
EVALuna2:19619

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer - Purrington, Kristen S.; Slager, Susan; Eccles, Diana; Yannoukakos, Drakoulis; Fasching, Peter A.; Miron, Penelope; Carpenter, Jane; Chang-Claude, Jenny; Martin, Nicholas G.; Montgomery, Grant W.; Kristensen, Vessela; Anton-Culver, Hoda; et al. (Carcinogenesis, 2014)
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
EVALuna2:6530

Genomic aberrations of MDM2, MDM4, FGFR1 and FGFR3 are associated with poor outcome in patients with salivary gland cancer - Ach, Tobias; Schwarz-Furlan, Stephan; Ach, Stephanie; Agaimy, Abbas; Gerken, Michael; Rohrmeier, Christian; Zenk, Johannes; Iro, Heinrich; Brockhoff, Gero; Ettl, Tobias (Journal of Oral Pathology & Medicine, 2016)
Fibroblast growth factor receptor 1 and 3 (FGFR1, FGFR3) impact on tissue homoeostasis, embryonic development and carcinogenesis. Murine double minute protein 4 (MDM4) and mouse double minute 2 homologue (MDM2) are regulators of p53-protein and may be the origin of an apoptosis overpowering cascade. A collective of 266 carcinomas of salivary glands were investigated for MDM2, MDM4, FGFR1 and FGFR3 aberrations by fluorescence in situ hybridization (FISH). The results were matched with clinicopathological parameters and with expression of PTEN and p53. MDM2 gene amplification (n = 9) and chromosomal aberrations (trisomy, n = 47; high polysomy, n = 7) are linked to high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.001), advanced tumour size (P = 0.013) and stage (P < 0.001), gender (P = 0.002) and age (P = 0.001). MDM4 gene amplification (n = 19) and chromosomal aberrations (trisomy, n = 34; high polysomy, n = 31) are correlated to high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.008), advanced tumour size (P = 0.039), stage (P = 0.004) and loss of PTEN (P < 0.001). Only, high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.036) and advanced tumour stage (P = 0.025) are associated with FGFR3 amplification (n = 1) or chromosomal aberrations (low polysomy, n = 61; high polysomy, n = 55) but not with MDM4 alterations. FGFR1 amplifications (n = 5) and chromosomal aberrations (trisomy, n = 38; high polysomy, n = 30) are associated with high-grade malignancy (P < 0.001), advanced tumour size (P = 0.026) and stage (P = 0.004), gender (P = 0.016) and age (P = 0.023). Aberrations of MDM2, MDM4, FGFR1 and FGFR3 correlate with aggressive tumour growth and nodal metastasis. MDM2 (P < 0.001), MDM4 (P = 0.005) and FGFR3 (P = 0.006) alterations are associated with worse overall survival of patients with salivary gland cancer.
EVALuna2:6776

Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma - Krumbholz, Manuela; Hellberg, Julia; Steif, Benedikt; Bäuerle, Tobias; Gillmann, Clarissa; Fritscher, Torsten; Agaimy, Abbas; Frey, Benjamin; Juengert, Joerg; Wardelmann, Eva; Hartmann, Wolfgang; Juergens, Heribert; et al. (Clinical Cancer Research, 2016)
The application of the tumor-specific genomic fusion sequence as noninvasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated.EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic EWSR1-FLI1 copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. EWSR1 fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared with tumor volumes calculated from MRI or CT imaging studies.Kinetics of EWSR1 fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell-free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development.Genomic fusion sequences represent promising noninvasive biomarkers for improved therapy monitoring in EwS. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response. Clin Cancer Res; 22(17); 4356-65. ©2016 AACR.
EVALuna2:6851

Genotype, Clinical Course, and Therapeutic Decision Making in 76 Infants with Severe Generalized Junctional Epidermolysis Bullosa - Hammersen, Johanna; Has, Cristina; Naumann-Bartsch, Nora; Stachel, Daniel; Kiritsi, Dimitra; Söder, Stephan; Tardieu, Mathilde; Metzler, Markus; Bruckner-Tuderman, Leena; Schneider, Holm (Journal of Investigative Dermatology, 2016)
Severe generalized junctional epidermolysis bullosa, a lethal hereditary blistering disorder, is usually treated by palliative care. Allogeneic stem cell transplantation (SCT) has been proposed as a therapeutic approach, yet without clinical evidence. Decision making was evaluated retrospectively in 76 patients with severe generalized junctional epidermolysis bullosa born in the years 2000-2015. The diagnosis was based on the absence of laminin-332 in skin biopsies. With an incidence of 1 of 150,000, severe generalized junctional epidermolysis bullosa occurred more often than published previously. Eleven as yet unreported mutations in the laminin-332 genes were detected. Although patients homozygous for the LAMB3 mutation c.1903C>T lived longer than the others, life expectancy was greatly diminished (10.8 vs. 4.6 months). Most patients failed to thrive. In two patients with initially normal weight gain, the decision for SCT from haploidentical bone marrow or peripheral blood was made. Despite transiently increasing skin erosions, the clinical status of both subjects stabilized for several weeks after SCT, but finally deteriorated. Graft cells, but no laminin-332, were detected in skin biopsies. The patients died 96 and 129 days after SCT, respectively, one of them after receiving additional skin grafts. Treatment of severe generalized junctional epidermolysis bullosa by SCT is a last-ditch attempt still lacking proof of efficacy.
EVALuna2:6828

Glial glycine transporter 1 function is essential for early postnatal survival but dispensable in adult mice - Papadopoulos, Thomas; Eulenburg, Volker; Retiounskaia, Marina; Papadopoulos, Theofilos; Gomeza, Jesus; Betz, Heinrich (Glia, 2010)
The glycine transporter 1 (GlyT1) is expressed in astrocytes and selected neurons of the mammalian CNS. In newborn mice, GlyT1 is crucial for efficient termination of glycine-mediated inhibitory neurotransmission. Furthermore, GlyT1 has been implicated in the regulation of excitatory N-methyl-D-asparate (NMDA) receptors. To evaluate whether glial and neuronal GlyT1 have distinct roles at inhibitory synapses, we inactivated the GlyT1 gene cell type-specifically using mice carrying floxed GlyT1 alleles GlyT1((+)/+)). GlyT1((+)/(+)) mice expressing Cre recombinase in glial cells developed severe neuromotor deficits during the first postnatal week, which mimicked the phenotype of conventional GlyT1 knock-out mice and are consistent with glycinergic over-inhibition. In contrast, Cre-mediated inactivation of the GlyT1 gene in neuronal cells did not result in detectable motor impairment. Notably, some animals deficient for glial GlyT1 survived the first postnatal week and did not develop neuromotor deficits throughout adulthood, although GlyT1 expression was efficiently reduced. Thus, glial GlyT1 is critical for the regulation of glycine levels at inhibitory synapses only during early postnatal life.

Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone - Lutsik, Pavlo; Baude, Annika; Mancarella, Daniela; Öz, Simin; Kühn, Alexander; Toth, Reka; Hey, Joschka; Toprak, Umut H.; Lim, Jinyeong; Nguyen, Viet Ha; Jiang, Chao; Mayakonda, Anand; et al. (Nature Communications, 2020)
The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.
CRIS-Team Scopus Importer:2020-11-06

Glomustumor am Finger – eine seltene, aber schmerzhafte handchirurgische Entität - Promny, Dominik; Horch, Raymund E.; Agaimy, Abbas; Hauck, Theresa (Handchirurgie, Mikrochirurgie, Plastische Chirurgie, 2020)
CRIS-Team WoS Importer:2020-07-10

Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma - Gähler, Alexander; Trufa, Denis; Chiriac, Mircea-Teodor; Tausche, Patrick; Hohenberger, Katja; Brunst, Ann-Kathrin; Rauh, Manfred; Geppert, Carol-Immanuel; Rieker, Ralf; Krammer, Susanne; Leberle, Anna; Neurath, Markus; et al. (Frontiers in Oncology, 2022)
BackgroundLung cancer is the second common cancer type in western countries and has a high mortality. During the development and progression of the tumor, the nutrients in its environment play a central role. The tumor cells depend crucially on glucose metabolism and uptake. Tumor cell metabolism is dominated by the Warburg effect, where tumor cells produce large amounts of lactate from pyruvate under aerobic conditions. We thus reasoned that, reducing carbohydrates in the diet might support anti-tumoral effects of current immunotherapy and additionally target tumor immune escape. ObjectivesThe link between reducing carbohydrates to improve current immunotherapy is not clear. We thus aimed at analyzing the effects of different glucose levels on the tumor development, progression and the anti-tumoral immune response. MethodsWe correlated the clinical parameters of our LUAD cohort with different metabolic markers. Additionally, we performed cell culture experiments with A549 tumor cell line under different glucose levels. Lastly, we investigated the effect of low and high carbohydrate diet in an experimental murine model of lung cancer on the tumor progression and different immune subsets. ResultsHere we found a positive correlation between the body mass index (BMI), blood glucose levels, reduced overall survival (OS) and the expression of Insulin-like growth factor-1 receptor (IGF1R) in the lung tumoral region of patients with lung adenocarcinoma (LUAD). Furthermore, increasing extracellular glucose induced IGF1R expression in A549 LUAD cells. Functional studies in a murine model of LUAD demonstrated that, glucose restricted diet resulted in decreased tumor load in vivo. This finding was associated with increased presence of lung infiltrating cytotoxic CD8+ T effector memory (TEM), tissue resident memory T (TRM) and natural killer cells as well as reduced IGFR mRNA expression, suggesting that glucose restriction regulates lung immunity in the tumor microenvironment. ConclusionsThese results indicate that, glucose restricted diet improves lung immune responses of the host and suppresses tumor growth in experimental lung adenocarcinoma. As glucose levels in LUAD patients were negatively correlated to postoperative survival rates, glucose-restricted diet emerges as therapeutic avenue for patients with LUAD.
CRIS-Team WoS Importer:2022-05-27

Gpr126 (Adgrg6) is expressed in cell types known to be exposed to mechanical stimuli - Musa, Gentian; Cazorla-Vázquez, Salvador; van Amerongen, Machteld J.; Stemmler, Marc; Eckstein, Markus; Hartmann, Arndt; Braun, Thomas; Brabletz, Thomas; Engel, Felix (Annals of the New York Academy of Sciences, 2019)
GPR126 (ADGRG6) is an adhesion G protein–coupled receptor that plays an important role in a variety of tissues/organs, such as heart, sciatic nerve, cartilage, and ear. Moreover, GPR126 (ADGRG6) mutations are associated with human diseases, like adolescent idiopathic scoliosis, lung disease, bladder cancer, and intellectual disability. Despite its clinical importance, it remains elusive how GPR126 is activated and mediates signal transduction and what cellular processes depend on GPR126 signaling. Here, we generated a lacZ reporter mouse line to determine endogenous Gpr126 (Adgrg6) expression in a cell type-specific manner during embryonic development, at postnatal day 5 and in adult animals. Our results confirm Gpr126 expression data previously obtained utilizing antibodies and in situ hybridization in embryonic heart and sciatic nerve. In addition, we provide data with cellular resolution for previously described RT-PCR–based data, including lung and bladder. Moreover, new Gpr126-expressing tissues and cell types were identified, such as ureter and acinar secretory cells. Collectively, our data demonstrate that the newly generated lacZ reporter mouse is a suitable model to study Gpr126 expression during development and adulthood, provide detailed insight into Gpr126 expression at the cellular level, and reveal that all identified Gpr126-expressing cells are known to be exposed to mechanical stimuli.
CRIS-Team Scopus Importer:2019-06-28
Keywords: ADGRG6; chondrocytes; endothelium; epithelium

Grading of head and neck neoplasms - Agaimy, Abbas; Weichert, W. (Pathologe, 2016)
Tumors of the head and neck form a heterogeneous group of benign and malignant neoplasms with significant differences in biological behavior and therapeutic strategies. Squamous cell carcinomas (SCC) of the larynx, pharynx and oral cavity represent the most frequent and, thus, clinically most important malignant neoplasms in this anatomical region. Similar to other neoplasms, grading of head and neck malignancies is based on evaluation of the tumor histology usually including both architectural and cytological features; however, the current consensus grading for head and neck SCC is of limited prognostic and therapeutic value and the reproducibility is low. Therefore, novel grading criteria have been proposed that are based on additional parameters, such as the type of tumor growth pattern at the invasive front (so-called tumor budding). These novel algorithms, however, have not yet been officially endorsed into guidelines. Salivary gland (SG) neoplasms, although less frequent, constitute a second important pathologically and clinically complex group of tumors at this location. In contrast to SCC, grading of these tumors is of high clinical importance. Based on the large variety of carcinoma entities of the SG, both entity-specific (e. g. mucoepidermoid carcinoma) algorithms but also algorithms, which are solely based on the recognition of a specific carcinoma variant with subsequent automatic assignment of the tumor grade (e. g. acinic cell carcinoma and salivary duct carcinoma) are in use. In the sinonasal tract, grading is important for non-intestinal type adenocarcinoma and esthesioneuroblastoma. In this article the most important grading schemes and criteria for head and neck malignancies are presented and their prognostic and therapeutic implications are discussed.
EVALuna2:6825

Granulation tissue-like spindle cell (sarcomatoid) carcinoma of the head and neck: a deceptively bland-looking underdiagnosed malignancy - Franchi, Alessandro; Agaimy, Abbas (Virchows Archiv, 2024)
The diagnosis of head and neck spindle cell squamous carcinoma (SC-SCC) is often challenging. Lesions with a prominent inflammatory infiltrate and reactive vessels may have a granulation tissue-like appearance, therefore being difficult to distinguish from reactive lesions, like contact ulcers, post-intubation granulomas, inflammatory pseudotumors, or benign vascular lesions. In this study, we analyzed the clinicopathological features of a series of 17 head and neck SC-SCC with granulation tissue-like appearance. All patients, but two, were males, ranging in age between 57 and 80 years. The larynx was the most frequently affected site (n = 12), followed by the tongue (n = 4). One tumor was hypopharyngeal. Most consult cases were submitted with benign suggestion or because of unexpected recurrences of granulation tissue polyps. Histologically, all lesions consisted of an ulcerated polypoid proliferation of moderately to markedly atypical spindle cells, with a minor component of conventional invasive or in situ squamous carcinoma. At least one cytokeratin cocktail was positive in 13 cases. The staining was limited to a few neoplastic cells in most cases. Positivity for p63, p40, and cytokeratins 5/6 was detected only in the conventional squamous cell carcinoma component, when present. ALK1 was negative in all cases. Sixteen cases were tested for p53 and all showed aberrant expression (12 diffusely positive and 4 of null-phenotype). The diagnosis of granulation tissue-like SC-SCC is challenging due to the close clinical and histological overlap with several benign conditions. Since the expression of epithelial markers is limited, the use of an immunohistochemical panel including p53 is recommended.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Granulation tissue; Head and neck; Immunohistochemistry; Sarcomatoid carcinoma; Spindle cell squamous cell carcinoma

Growth Arrest-Specific 6 in Chromophobe Renal Cell Carcinoma - Mikuteit, Marie; Zschäbitz, Stefanie; Erlmeier, Maximilian; Autenrieth, Michael; Weichert, Wilko; Hartmann, Arndt; Steffens, Sandra; Erlmeier, Franziska (Oncology, 2022)
BACKGROUND: Overexpression of tumor-associated growth arrest-specific protein 6 (Gas6) is found in many tumor entities. The prognostic value of Gas6 in renal cell carcinoma (RCC), especially in non-clear cell RCC, is still unclear. AIM: The aim of the study was to evaluate the prognostic impact of Gas6 expression in a large cohort of patients with chromophobe RCC (chRCC). MATERIAL AND METHODS: Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for Gas6 expression by immunohistochemistry. RESULTS: Eighty-one chRCC patients were eligible for analysis; of these, 24 (29.6%) patients were positive for Gas6. No significant associations were found for Gas6 expression and clinical attributes in patients with chRCC. The Kaplan-Meier analysis revealed no differences in 5-year overall survival for Gas6- compared to Gas6+ (89.6% vs. 100.0%; p = 0.288) tumors. CONCLUSION: In chRCC, Gas6 expression is not associated with survival and other parameters of aggressiveness. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Chromophobe histology; Growth arrest-specific protein 6; Renal cell carcinoma; Survival

Harmonization and Standardization of Panel-Based Tumor Mutational Burden Measurement: Real-World Results and Recommendations of the Quality in Pathology Study - Stenzinger, Albrecht; Endris, Volker; Budczies, Jan; Merkelbach-Bruse, Sabine; Kazdal, Daniel; Dietmaier, Wolfgang; Pfarr, Nicole; Siebolts, Udo; Hummel, Michael; Herold, Sylvia; Andreas, Johanna; Zoche, Martin; et al. (Journal of Thoracic Oncology, 2020)
Introduction: Tumor mutational burden (TMB) is a quantitative assessment of the number of somatic mutations within a tumor genome. Immunotherapy benefit has been associated with TMB assessed by whole-exome sequencing (wesTMB) and gene panel sequencing (psTMB). The initiatives of Quality in Pathology (QuIP) and Friends of Cancer Research have jointly addressed the need for harmonization among TMB testing options in tissues. This QuIP study identifies critical sources of variation in psTMB assessment. Methods: A total of 20 samples from three tumor types (lung adenocarcinoma, head and neck squamous cell carcinoma, and colon adenocarcinoma) with available WES data were analyzed for psTMB using six panels across 15 testing centers. Interlaboratory and interplatform variation, including agreement on variant calling and TMB classification, were investigated. Bridging factors to transform psTMB to wesTMB values were empirically derived. The impact of germline filtering was evaluated. Results: Sixteen samples had low interlaboratory and interpanel psTMB variation, with 87.7% of pairwise comparisons revealing a Spearman's ρ greater than 0.6. A wesTMB cut point of 199 missense mutations projected to psTMB cut points between 7.8 and 12.6 mutations per megabase pair; the corresponding psTMB and wesTMB classifications agreed in 74.9% of cases. For three-tier classification with cut points of 100 and 300 mutations, agreement was observed in 76.7%, weak misclassification in 21.8%, and strong misclassification in 1.5% of cases. Confounders of psTMB estimation included fixation artifacts, DNA input, sequencing depth, genome coverage, and variant allele frequency cut points. Conclusions: This study provides real-world evidence that all evaluated panels can be used to estimate TMB in a routine diagnostic setting and identifies important parameters for reliable tissue TMB assessment that require careful control. As complex or composite biomarkers beyond TMB are likely playing an increasing role in therapy prediction, the efforts by QuIP and Friends of Cancer Research also delineate a general framework and blueprint for the evaluation of such assays.
CRIS-Team Scopus Importer:2020-04-24
Keywords: Gene panel; Immuno-oncology; Lung cancer; Quality assurance; Sequencing; TMB; Tumor mutational burden

Harmonization and standardization of panel-based tumour mutational burden (TMB) measurement: Real-world results and recommendations of the QuIP study - Stenzinger, A.; Endris, V.; Budczies, J.; Merkelbach-Bruse, S.; Dietmaier, W.; Siebolts, U.; Maas, J.; Merino, D. M.; Stewart, M.; Allen, J.; Glimm, H.; Thiemann, M.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2020-01-28

Harnblase: Tumorvorstufen und nichtinvasive Karzinome - Lange, Fabienne; Hartmann, Arndt; Eckstein, Markus (Die Pathologie, 2024)
Background: In recent years, our understanding of the genesis and development of urothelial carcinomas (UC) has expanded considerably thanks to advancing molecular classifications. These advances have led to significant changes in the 5th edition of the WHO classification of tumors of the urinary tract and male genitalia. The new findings allow both the introduction of modern diagnostic approaches and a return to proven methods in the evaluation of precursor lesions and non-invasive carcinomas. Aims: This article is intended to provide a summarized overview of the various precursor lesions and pathways of urothelial carcinoma. Results and discussion: The changes and clarifications in the 5th edition of the WHO classification reflect the progress made in the molecular and morphological characterization of urothelial carcinomas. These adjustments provide an improved basis for diagnosis and treatment and emphasize the importance of differentiated molecular profiles for the classification and treatment of UC. Despite all this, conventional histology remains the gold standard for the diagnosis and classification of non-invasive carcinomas and precursor lesions.
CRIS-Team Scopus Importer:2024-11-22
Keywords: Carcinoma in situ; Immunohistochemistry; Papillary carcinoma; Prognosis; Transitional cell carcinoma

Hattori-Zyste – eine seltene Läsion im posterioren Mediastinum - Elsner, Felix; Khamitov, Koblandy; Hinsen, Maximilian; Sirbu, Horia; Hartmann, Arndt (Die Pathologie, 2024)
CRIS-Team Scopus Importer:2024-05-24

HCCs lacking arterial phase hyperenhancement (APHE) on contrast-enhanced ultrasound (CEUS) - a diagnostic challenge. Findings from the prospective multicenter DEGUM CEUS HCC trial - Strobel, Deike; Agaimy, Abbas; Jesper, Daniel; Zundler, Sebastian; Schellhaas, Barbara (Ultraschall in der Medizin, 2023)
Objectives Hepatocellular carcinoma (HCC) upon contrast-enhanced ultrasound (CEUS) typically shows arterial phase hyperenhancement (APHE), followed by late (> 60 seconds) and mild contrast washout (WO). Although APHE is considered as the hallmark of HCC, it can be absent in some HCCs. Thus, we explored which sonomorphological and histopathological features of HCC are associated with a lack of APHE upon CEUS.Methods Focal liver lesions in high-risk patients for HCC were assessed with CEUS following a standardized protocol in a prospective multi-center real-life setting. CEUS patterns in HCC were assessed, and tumour and patient characteristics were compared for HCCs with and without APHE.Results 316 patients with HCC were recruited (cirrhosis, 76.9%). APHE occurred in 271/316 HCCs (85.8%). A lack of APHE was associated with portal vein thrombosis, tumour infiltration of the liver vessels (p<0.001), larger size, multilocularity, and higher depth location upon ultrasound (p<0.01). Histological grading did not differ between HCCs with and without APHE (p=0.39). Histopathological features of HCCs without APHE included cirrhotic stromal reaction, marked tumour cell steatosis and absence of the typical surrounding dilated sinusoidal vascular channels.Conclusion Correlation with histopathological findings support the fact that HCCs with a lack of APHE in CEUS are a heterogeneous group. The examiner has to be aware that particularly HCCs with portal vein thrombosis or macro-invasion of the liver vessels may lack APHE.
CRIS-Team WoS Importer:2023-04-21

Head and Neck Kaposi Sarcoma: Clinicopathological Analysis of 11 Cases - Agaimy, Abbas; Müller, Sarina Katrin; Harrer, Thomas; Bauer, Sebastian; Thompson, Lester D. R. (Head and Neck Pathology, 2018)
Kaposi sarcoma (KS) of the head and neck area is uncommon with limited published case series. Our routine and consultation files were reviewed for histologically and immunohistochemically proven KS affecting any cutaneous or mucosal head and neck site. Ten males and one female aged 42-78 years (median, 51 years; mean, 52 years) were retrieved. Eight patients were HIV-positive and three were HIV-negative. The affected sites were skin (n = 5), oral/oropharyngeal mucosa (n = 5), and lymph nodes (n = 3) in variable combination. The ear (pinna and external auditory canal) was affected in two cases; both were HIV-negative. Multifocal non-head and neck KS was reported in 50% of patients. At last follow-up (12-94 months; median, 46 months), most of patients were either KS-free (n = 8) or had ongoing remission under systemic maintenance therapy (n = 2). One patient was alive with KS (poor compliance). Histopathological evaluation showed classical features of KS. One case was predominantly sarcomatoid with prominent inflammation mimicking undifferentiated sarcoma. Immunohistochemistry showed consistent expression of CD31, CD34, ERG, D2-40 and HHV8 in all cases. This is one of the few series devoted to head and neck KS showing high prevalence of HIV-positivity, but also unusual presentations in HIV-negative patients with primary origin in the skin of the ear and the auditory canal. KS should be included in the differential diagnosis of difficult-to-classify spindle cell lesions at this uncommon location.
EVALuna2:207378

Head and neck neoplasms : News from the WHO classification of 2017 - Agaimy, Abbas; Hartmann, Arndt (Pathologe, 2018)
EVALuna2:34261

[Head and neck pathology-new WHO classification]. - Ihrler, Stephan; Agaimy, Abbas (Die Pathologie, 2023)
EVALuna2:540023

Healing of the epithelial barrier in the ileum is superior to endoscopic and histologic remission for predicting major adverse outcomes in ulcerative colitis - Rath, Timo; Atreya, Raja; Bodenschatz, Julia; Uter, Wolfgang; Geppert, Carol-Immanuel; Vitali, Francesco; Zundler, Sebastian; Waldner, Maximilian; Hartmann, Arndt; Neurath, Markus (Frontiers in Medicine, 2023)
Background: Achieving endoscopic remission is a key therapeutic goal in patients with ulcerative colitis (UC) that is associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of endoscopic and/or histologic remission against ileal barrier healing for predicting long-term disease behavior in a large cohort of UC patients in clinical remission. Methods: At baseline, UC patients in clinical remission underwent ileocolonoscopy with assessment of ileal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity and ileal barrier healing were scored using validated scores. During subsequent follow-up (FU), patients were closely monitored for clinical disease activity and occurrence of major adverse outcomes (MAO) defined as the following: disease relapse; UC-related hospitalization; UC-related surgery; necessity for initiation or dose escalation of systemic steroids, immunosuppressants, small molecules or biological therapy. Results: Of the 73 UC patients included, 67% experienced MAO during a mean FU of 25 months. The probability of MAO-free survival was significantly higher in UC patients with endoscopic and/or histologic remission compared to patients with endoscopically and/or histologically active disease. Ileal barrier healing on endomicroscopy was highly accurate for predicting the further course of UC and outcompeted endoscopic and histologic remission for predicting MAO-free survival. Conclusion: Ileal barrier healing in clinically remittent UC patients can accurately predict future MAO development and is superior in its predictive capabilities than endoscopic and histologic remission. Ileal barrier healing therefore represents a novel and superior surrogate parameter for stratification of UC patients according to their risk for development of complicated disease behavior. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT05157750, identifier NCT05157750.
CRIS-Team Scopus Importer:2023-11-03
Keywords: endoscopy; histology; inflammatory bowel diseases; intestinal barrier; ulcerative colitis

Hearing restoration with cochlear implants after translabyrinthine vestibular schwannoma resection - Bohr, Christopher; Müller, Susanna; Hornung, Joachim; Hoppe, Ulrich; Iro, Heinrich (HNO, 2017)
BACKGROUND: Hearing restoration after translabyrinthine vestibular schwannoma resection is a challenge. Because the cochlea can begin to ossify a few months after cochlear or labyrinthine injury, the time interval for cochlear implant surgery is limited. To avoid complete ossification and to prolong the time interval until cochlear implantation, it is possible to insert a placeholder (depth gauge) into the cochlea and perform the cochlear implant surgery at a later time point (two-stage approach). OBJECTIVE: The aim of this retrospective case series was to present the outcomes after restoration of hearing with cochlea implants in six patients and to evaluate the use of the depth gauge in practice. METHODS: The hearing outcome of all patients with (n = 3) and without (n = 3) insertion of a depth gauge was measured with the Freiburg monosyllabic test without background noise at 65 dB. The first measurement was performed prior to the translabyrinthine vestibular schwannoma resection, the last measurement was performed up to 48 months after cochlear implantation. RESULTS: All 6 patients reached 22.5 ± 36.57% prior to vestibular schwannoma resection and 41.3 ± 26% 12 months after cochlear implantation. The understanding values of the patients with a depth gauge were 25.8 ± 16% after 12 months which is below the values of the other patients with 56.6 ± 25.0%. No severe intraoperative or postoperative complications occurred in any patient. CONCLUSION: The two-stage approach for cochlear implantation with depth gauge insertion following labrynthine incision and intact nerve appears to represent a very promising and safe variation for hearing restoration. Intensified research on this approach seems to be justified and necessary.
EVALuna2:33160

Helicobacter infection and gastric adenoma - Bertz, Simone; Angeloni, Miriam; Drgac, Jan; Falkeis, Christina; Lang-Schwarz, Corinna; Sterlacci, William; Veits, Lothar; Hartmann, Arndt; Vieth, Michael (Microorganisms, 2021)
Background: We aimed to provide insight into the actual frequencies of gastric adenoma types and their association with gastritis status and associated mucosal changes with a focus on Helicobacter infection and the operative link on gastritis assessment (OLGA)/operative link on gastric intestinal metaplasia assessment (OLGIM) staging. Methods: From the archive of the Institute of Pathology in Bayreuth, we collected a consecutive series of 1058 gastric adenomas diagnosed between 1987 and 2017. Clinicopathological parameters retrieved from diagnostic reports included adenoma type and localization, associated mucosal changes in antrum and corpus (i.e., type of gastritis, the extent of intestinal metaplasia and atrophy), gender, date of birth, and date of diagnosis. Results: Intestinal-type adenoma was the most frequent adenoma (89.1%), followed by foveolar-type adenoma (4.3%), pyloric gland adenoma (3.4%), adenomas associated with hereditary tumor syndromes (2.8%), and oxyntic gland adenoma (0.4%). Adenomas were found in the background of Helicobacter pylori (H. pylori) gastritis in 23.9%, Ex-H. pylori gastritis in 36.0%, autoimmune gastritis in 24.8%, chemical reactive gastritis in 7.4%, and others in 0.1%. More than 70% of patients with gastric adenomas had low-risk stages in OLGA and OLGIM. Conclusions: We found a higher frequency of foveolar-type adenoma than anticipated from the literature. It needs to be questioned whether OLGA/OLGIM staging can be applied to all patients.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Autoimmune; Familial adenomatosis coli; Foveolar-type adenoma; Gastric adenoma; Gastritis; Helicobacter; Intestinal tubular adenoma; Oxyntic gland adenoma; Pyloric gland adenoma

Helicobacter pylori Employs a Unique Basolateral Type IV Secretion Mechanism for CagA Delivery - Tegtmeyer, Nicole; Wessler, Silja; Necchi, Vittorio; Rohde, Manfred; Harrer, Aileen; Rau, Tilman; Asche, Isabell; Böhm, Manja; Loessner, Holger; Figueiredo, Ceu; Naumann, Michael; Palmisano, Ralf; et al. (Cell Host & Microbe, 2017)
The Helicobacter pylori (Hp) type IV secretion system (T4SS) forms needle-like pili, whose binding to the integrin-?1 receptor results in injection of the CagA oncoprotein. However, the apical surface of epithelial cells is exposed to Hp, whereas integrins are basolateral receptors. Hence, the mechanism of CagA delivery into polarized gastric epithelial cells remains enigmatic. Here, we demonstrate that T4SS pilus formation during infection of polarized cells occurs predominantly at basolateral membranes, and not at apical sites. Hp accomplishes this by secreting another bacterial protein, the serine protease HtrA, which opens cell-to-cell junctions through cleaving epithelial junctional proteins including occludin, claudin-8, and E-cadherin. Using a genetic system expressing a peptide inhibitor, we demonstrate that HtrA activity is necessary for paracellular transmigration of Hp across polarized cell monolayers to reach basolateral membranes and inject CagA. The contribution of this unique signaling cascade to Hp pathogenesis is discussed.
EVALuna2:6906

Hepatocyte differentiation markers in adenocarcinoma of the prostate: hepatocyte paraffin 1 but not arginase-1 is specifically expressed in a subset of prostatic adenocarcinoma - Giedl, Josef; Buettner-Herold, Maike; Wach, Sven; Wullich, Bernd; Hartmann, Arndt; Agaimy, Abbas (Human Pathology, 2016)
Prostate adenocarcinoma and hepatocellular carcinoma (HCC) are common cancer types. Both may present with bone metastases, and both are known to be CK7/CK20 negative. Thus, diagnosis of less well-differentiated tumors at metastatic sites essentially relies on immunohistochemical confirmation. However, insufficient data exist on the expression status of the main 2 hepatocyte markers hepatocyte paraffin 1 (HepPar-1) and arginase-1 (Arg-1) in prostatic adenocarcinoma. We screened 557 prostate carcinoma cases for expression of these 2 markers using tissue microarrays. Sixty-four of 557 (11.5%) cases showed highly variable expression of HepPar-1 in 1% to 75% of tumor cells with a characteristically strong granular "mitochondrial" pattern. Only 13 cases (2.3%) expressed HepPar-1 in greater than 10% of the tumor cells. No correlation was seen with Gleason grade. On the other hand, 19 (3.4%) of 557 cases showed variable nonspecific cytoplasmic expression of Arg-1 distinct from the specific combined nucleocytoplasmic staining seen in normal liver and in HCC. Specifically, this Arg-1 pattern was seen only using one antibody lot and not another suggesting cross-reactivity. Only a single case showed specific nucleocytoplasmic expression of Arg-1 in the tumor cells. In conclusion, specific granular cytoplasmic staining for HepPar-1 is frequent in prostatic adenocarcinomas (11.5%) but usually focal and limited to less than 5% of tumor cells. This should not be misinterpreted as evidence of HCC, particularly in solid-pattern neoplasms. On the other hand, specific Arg-1 expression is very rare (0.18%), highlighting the value of Arg-1 in distinguishing HepPar-1-positive prostatic carcinoma from HCC at metastatic sites or in cases of liver metastasis from prostate carcinoma.
EVALuna2:6774

HER2 and TOP2A amplification in a hospital-based cohort of breast cancer patients: associations with patient and tumor characteristics - Fasching, Peter A.; Weihbrecht, Sebastian; Haeberle, Lothar; Gasparyan, Armen; Villalobos, Ivonne E.; Ma, Yanling; Ekici, Arif Bülent; Wachter, David; Hartmann, Arndt; Beckmann, Matthias; Slamon, Dennis J.; Press, Michael F. (Breast Cancer Research and Treatment, 2014)
Gene amplification is an important factor for altered gene expression in breast cancers. TOP2A-amplification often occurs concomitantly with HER2 amplification, and it has been suggested to be predictive for the response to anthracycline chemotherapy. This study assessed the correlation between HER2 status and TOP2A co-amplification, the possible association of TOP2A single-nucleotide polymorphisms with the frequency of this co-amplification as well as confirmation of association with outcome. HER2 and TOP2A amplification were analyzed in a tissue microarray from a clinical cohort study. Additionally, a common genetic variant (rs13695) in the TOP2A gene was genotyped in germline DNA. HER2 gene amplification was compared with HER2-IHC findings assessed during clinical routine work, and the association between all the biomarkers analyzed and the clinical outcome was determined. As an exploratory aim, rs13695 genotypes were compared with TOP2A amplification status. HER2 amplification was seen in 101 of 628 (16.1 %) and TOP2A amplification in 32 (5.1 %) cancers. No TOP2A amplification occurred without HER2 co-amplification. HER2 amplification was found in 8, 13.6, and 55.1 % of patients with HER2-IHC 0/1+, 2+, and 3+ tumors, respectively. HER2-IHC was not associated with an effect on the prognosis, but HER2-FISH was. There was an association between the rs13695 genotype and TOP2A amplification status (P = 0.03). Although there was a significant correlation between HER2 status determined by IHC and HER2 by FISH, only HER2 gene amplification status by FISH was correlated with outcome indicating greater utility for FISH in routine clinical settings.
EVALuna2:6613

Hereditary colorectal cancer : An update on genetics and entities in terms of differential diagnosis - Rau, T. T.; Dawson, H.; Hartmann, Arndt; Rueschoff, J. (Pathologe, 2017)
The pathologist can contribute to recognizing hereditary causes of colorectal cancer via morphology. By identifying so-called index patients, it is possible to take preventive measures in affected families. The precise definition of the clinical presentation and the histopathological phenotype help to narrow the spectrum of expected genetic alterations. Novelties within Lynch syndrome include the recognition of EPCAM as a fifth gene locus, as well as the newly defined Lynch-like syndrome with evidence of somatic mismatch repair (MMR) mutations. With regard to polyposis-associated syndromes, the spectrum of polyps, whether serrated, hamartomatous or classic adenoma, is of crucial importance. The resulting differential diagnosis includes (attenuated) familial adenomatous polyposis ([a]FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis (PPAP), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome and juvenile polyposis, each with a specific genetic background.
EVALuna2:6878

Hereditary leiomyomatosis and renal cell cancer syndrome: A novel mutation in the FH gene - Tsagoudis, Konstantinos; Magiera-Lappann, Isabella; Haverkamp, Thomas; Drebber, Uta; Agaimy, Abbas; Tantcheva-Po'Or, Iliana (Journal of Dermatology, 2018)
EVALuna2:207216

Hereditary renal tumors: More common than expected? - Agaimy, Abbas; Hartmann, Arndt (Pathologe, 2016)
Renal cell carcinomas are associated with hereditary tumor syndromes in approximately 5 % of cases. In patients with a hereditary predisposition, tumors show an earlier age of onset, often with a multicentric and bilateral manifestation. While some patients with renal cell carcinoma can be classified into well-characterized kidney cancer syndromes others have a genetic background which is still poorly understood. Most of the specific tumor syndromes are associated with a histopathologically distinct renal cell tumor phenotype. The recognition of patients with hereditary renal cell carcinoma and the identification of individual family members with a higher risk of development of renal tumors is important for early tumor detection and treatment. This manuscript reviews the clinical pathological and molecular findings of hereditary renal cell carcinoma syndromes.
EVALuna2:6783

Hereditary SWI/SNF complex deficiency syndromes - Agaimy, Abbas; Foulkes, William D. (Seminars in Diagnostic Pathology, 2018)
The SWItch Sucrose non-fermentable (SWI/SNF) complex is a highly conserved multi-subunit complex of proteins encoded by numerous genes mapped to different chromosomal regions. The complex regulates the process of chromatin remodelling and hence plays a central role in the epigenetic regulation of gene expression, cell proliferation and differentiation. During the last three decades, the SWI/SNF complex has been increasingly recognized as a central molecular event driving the initiation and/or progression of several benign and malignant neoplasms of different anatomic origin and having diverse histomorphological appearance. Atypical teratoid/rhabdoid tumors (AT/RT) and renal/extrarenal malignant rhabdoid tumors of childhood, epithelioid sarcoma and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) represent the most commonly recognized SWI/SNF-driven neoplasms Approximately one-third of pediatric malignant rhabdoid tumors are linked to germline SWI/SNF alterations (SMARCB1/INI1, rarely SMARCA4) resulting in occasional familial clustering of these highly aggressive malignancies (so-called rhabdoid tumor predisposition syndrome, RTPS, types 1 and 2, respectively). However, more recently, inherited SWI/SNF-deficiency has been linked to several benign syndromic tumors including a subset of familial schwannomatosis (linked to SMARCB1) and multiple meningiomas (linked to SMARCE1) as well as others. Beyond neoplasms, several congenital developmental functional disorders such as Coffin-Siris syndrome and intellectual disability are now known to be SWI/SNF-related. The latter are essentially not associated with SWI/SNF-driven neoplasms, although at least anecdotal cases have documented concurrence of both neoplastic and developmental disorders. This review summarizes the most important SWI/SNF-driven diseases with a main focus on neoplasms.
EVALuna2:34878

Heterogeneity-analysis of molecular subtypes of muscle-invasive bladder cancer and their precursor lesions in multiregion mapped whole-organ bladders - Weyerer, Veronika; Lange, Fabienne; Wullweber, Adrian; Stöhr, Robert; Bertz, Simone; Wach, S.; Taubert, Helge; Wullich, Bernd; Sikic, Danijel; Strissel, Pamela; Strick, Reiner; Hartmann, Arndt; et al. (UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS, 2020)
CRIS-Team WoS Importer:2021-01-15

HIF activation protects from acute kidney injury - Weidemann, Alexander; Bernhardt, Wanja M.; Klanke, Bernd; Daniel, Christoph; Buchholz, Björn; Campean, Valentina; Amann, Kerstin Ute; Warnecke, Christina; Wiesener, Michael Sean; Eckardt, Kai-Uwe; Willam, Carsten (Journal of the American Society of Nephrology, 2008)
The contribution of hypoxia to cisplatin-induced renal tubular injury is controversial. Because the hypoxia-inducible factor (HIF) pathway is a master regulator of adaptation to hypoxia, we measured the effects of cisplatin on HIF accumulation in vitro and in vivo, and tested whether hypoxic preconditioning is protective against cisplatin-induced injury. We found that cisplatin did not stabilize HIF-1 alpha protein in vitro or in vivo under normoxic conditions. However, hypoxic preconditioning of cisplatin-treated proximal tubular cells in culture reduced apoptosis in an HIF-1 alpha-dependent fashion and increased cell proliferation as measured by BrdU incorporation. In vivo, rats preconditioned with carbon monoxide before cisplatin administration had significantly better renal function than rats kept in normoxic conditions throughout. Moreover, the histomorphological extent of renal damage and tubular apoptosis was reduced by the preconditional treatment. Therefore, development of pharmacologic agents to induce renal HIF might provide a new approach to ameliorate cisplatin-induced nephrotoxicity.

High androgen receptor mrna expression is associated with improved outcome in patients with high-risk non-muscle-invasive bladder cancer - Sikic, Danijel; Taubert, Helge; Wirtz, Ralph M.; Breyer, Johannes; Eckstein, Markus; Weyerer, Veronika; Kubon, Jennifer; Erben, Philipp; Bolenz, Christian; Burger, Maximilian; Hartmann, Arndt; Wullich, Bernd; et al. (Life, 2021)
The role of the androgen receptor (AR) in non-muscle-invasive bladder cancer (NMIBC) remains controversial. We retrospectively analyzed the mRNA expression of AR using RT-qPCR in 95 patients with high-risk NMIBC treated with a bladder-sparing approach and correlated AR with clinical data and recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). The mRNA expression of AR and KRT5, i.e., the basal-like subtype, was strongly correlated (rs = 0.456; p < 0.001). AR (p = 0.053) and KRT5 (p = 0.029) mRNA expression was negatively correlated with tumor grade. Kaplan–Meier analyses indicated significantly prolonged CSS (p = 0.020) and OS (p = 0.015) and a trend towards longer RFS (p = 0.051) in patients with high AR expression. High KRT5 expression was associated with significantly longer RFS (p = 0.033), CSS (p = 0.029) and OS (p = 0.030), while high KRT20 expression was associated with reduced RFS (p = 0.042). In multivariable analysis, none of the molecular markers was an independent prognostic factor. When performing a substratification with regard to molecular markers and clinicopathological parameters, high AR expression showed improved OS in patients with high KRT20 mRNA expression (p = 0.041). Women showed significantly longer OS in cases with high AR expression (p = 0.011). High AR was associated with significantly improved CSS in males (p = 0.044) and patients with instillation therapy (p = 0.040), while OS was improved regardless of instillation therapy. Younger patients with high AR expression had significantly improved RFS (p = 0.021), CSS (p = 0.014) and OS (p = 0.007). RFS was also improved in patients with high AR and low expression of either KRT5 (p = 0.003) or KRT20 (p = 0.014), but not in patients with high expression of KRT5 or KRT20. In conclusion, high AR mRNA expression is correlated with KRT5 mRNA expression and is associated with an improved outcome in high-risk NMIBC.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Androgen receptor; Bladder cancer; KRT20; KRT5; MRNA; NMIBC; PCR

High Androgen Receptor mRNA Expression Is Independently Associated with Prolonged Cancer-Specific and Recurrence-Free Survival in Stage T1 Bladder Cancer - Sikic, Danijel; Breyer, Johannes; Hartmann, Arndt; Burger, Maximilian; Erben, Philipp; Denzinger, Stefan; Eckstein, Markus; Stohr, Robert; Wach, Sven; Wullich, Bernd; Keck, Bastian; Wirtz, Ralph M.; et al. (Translational Oncology, 2017)
High-risk non-muscle-invasive bladder cancer (NMIBC) remains challenging given the high probability of progression. Given that the androgen receptor (AR) has been discussed as a possible factor in the development and progression of bladder cancer, we investigated the predictive value of AR in stage pT1 NMIBC.We retrospectively analyzed the clinical data and AR mRNA expression in 296 patients with stage pT1 NMIBC who underwent a transurethral resection of the bladder. The mRNA expression of the AR transcript variants 1 (AR1) and 2 (AR2) was measured by reverse transcription quantitative real-time polymerase chain reaction. AR expression was also correlated to KRT5 and KRT20 mRNA expression.Kaplan-Meier analysis indicated that high AR1 mRNA expression >=35.47 is associated with statistically significant better recurrence-free survival (RFS) (P=.0007), progression-free survival (PFS) (P=.0420), and cancer-specific survival (CSS) (P=.0050). Multivariate Cox regression analysis revealed that high AR1 mRNA expression is an independent prognostic marker for RFS (P=.0029) and CSS (P=.0119). Spearman rank correlation revealed a significant positive association between mRNA expression of AR1 and KRT5 (rs: 0.3171, P<.0001) as well as a negative association with multifocal tumors (rs: 0.1478, P<.0109). No association was noted between AR1 expression and tumor grade, concomitant CIS, gender, tumor size, and KRT20 in patients with stage T1 NMIBC.AR mRNA expression can predict RFS and CSS in patients with stage T1 NMIBC. Further studies are necessary to refine the relevance of AR mRNA expression compared with immunohistochemically detectable AR expression.
EVALuna2:6884

High CDKN2A/p16 and Low FGFR3 Expression Predict Progressive Potential of Stage pT1 Urothelial Bladder Carcinoma - Breyer, Johannes; Wirtz, Ralph M.; Erben, Philipp; Worst, Thomas S.; Stoehr, Robert; Eckstein, Markus; Bertz, Simone; Sikic, Danijel; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt; Otto, Wolfgang (Clinical Genitourinary Cancer, 2018)
BACKGROUND: A recent study on the comprehensive genomic profile of advanced urothelial bladder cancer (UBC) showed cyclin-dependent kinase inhibitor 2A (CDKN2A) and fibroblast growth factor receptor 3 (FGFR3) as the most often clinically relevant genomic alterations. Therefore, the prognostic role of FGFR3 and CDKN2A/p16 for pT1 UBC was studied. PATIENTS AND METHODS: Clinical data and formalin-fixed paraffin-embedded tissues of pT1 UBC treated with an organ-preserving approach was analyzed retrospectively. Total RNA was isolated using commercial RNA extraction kits and mRNA expression of CDKN2A/p16 and FGFR3 was measured using single step reverse transcription quantitative real time polymerase chain reaction using RNA-specific TaqMan assays. RESULTS: Data from 296 patients (79.4% male; median age: 72 years) could be used for the final evaluation. Spearman correlation revealed a statistically significant negative correlation between mRNA expression of CDKN2A/p16 and FGFR3. There was a positive correlation between CDKN2A/p16 and G3 tumors (ρ = 0.1875; P = .0012) and associated carcinoma in situ (ρ = 0.1703, P = .0033) and a negative correlation between FGFR3 and these factors (ρ = -0.2791, P < .0001 and ρ = -0.2182, P = .0002). High CDKN2A/p16 expression (≥38.04) and low FGFR3 expression (<39.14) were statistically significantly associated with worse progression-free survival (PFS; P = .0194 and P = .0089). Multivariate Cox regression analysis could identify patients with low FGFR3 and high CDKN2A/p16 expression (log rank (LR) χ2 = 10.69; P = .0048) as well as tumor size ≥3 cm (LR χ2 = 6.03; P = .0141) as independent predictors for PFS. CONCLUSION: High expression of CDKN2A/p16 and low expression of FGFR3 show a correlation with established prognostic features for non-muscle-invasive bladder cancer and can predict progression of stage pT1 UBC.
EVALuna2:33956

High coexpression of CCL2 and CX3CL1 is gender-specifically associated with good prognosis in soft tissue sarcoma patients - Kehlen, Astrid; Greither, Thomas; Wach, Sven; Nolte, Elke; Kappler, Matthias; Bache, Matthias; Holzhausen, Hans-Juergen; Lautenschlaeger, Christine; Goebel, Steffen; Wuerl, Peter; Immel, Uta-Dorothee; Agaimy, Abbas; et al. (International Journal of Cancer, 2014)
Chemokines are involved in both the negative and positive regulation of inflammatory processes, angiogenesis and cancer/cancer stem cell proliferation as well as the chemoattraction of tumor cells to metastatic sites. The aim of this study was to measure the mRNA expression levels of three chemokines, CCL2, CCL7 and CX3CL1, in soft tissue sarcomas (STSs) and to assess the correlations between these levels as well as their correlations with clinicopathological data and the disease-specific survival of STS patients. The mRNA levels of CCL2, CCL7 and CX3CL1 were analyzed in tumor tissues from 126 STS patients using qPCR. Low mRNA expression of CCL2 and CX3CL1 was significantly correlated with a worse prognosis (RR = 1.98; p = 0.019 and RR = 2.10; p = 0.014; multivariate Cox's regression analysis). A combined low expression of CCL2 and CX3CL1 was associated with a significantly increased risk of tumor-related death as compared to patients with high expression levels of both chemokines (RR = 3.08; p = 0.003). A gender-specific multivariate analysis revealed that female STS patients with low CX3CL1 mRNA expression had a 3.46-fold increased risk of death (p = 0.004). Low expression of both CCL2 and CX3CL1 mRNAs resulted in an additive 5.37-fold increased risk of tumor-related death (p = 0.003) as compared to those with high expression of both parameters in female patients. In conclusion, this is the first study to show a significant correlation between combined low expression of CCL2 and CX3CL1 and a poor prognosis for STS patients, particularly in female patients.
EVALuna2:6682

High expression of ERBB2 is an independent risk factor for reduced recurrence-free survival in patients with stage T1 non-muscle-invasive bladder cancer - Sikic, Danijel; Eckstein, Markus; Weyerer, Veronika; Kubon, Jennifer; Breyer, Johannes; Roghmann, Florian; Kunath, Frank; Keck, Bastian; Erben, Philipp; Hartmann, Arndt; Wirtz, Ralph M.; Wullich, Bernd; et al. (Urologic Oncology-Seminars and Original Investigations, 2021)
Introduction: Molecular markers associated with breast cancer are assumed to be associated with outcome in non-muscle-invasive bladder cancer (NMIBC). Materials and methods: We retrospectively investigated the association of the mRNA expression of estrogen receptor 1 (ESR1) and 2 (ESR2), progesterone receptor (PGR), MKI67, and HER2 (ERBB2) with recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) in 80 patients with stage T1 NMIBC. Results: High expression of ESR2 (P = 0.003), ERBB2 (P < 0.001), and MKI67 (P = 0.029) was associated with shorter RFS. Only high ERBB2 was an independent prognostic factor for reduced RFS (HR = 2.98; P = 0.009). When sub stratifying the cohort, high ESR2 was associated with reduced RFS (P < 0.001), CSS (P = 0.037) and OS (P = 0.006) in patients without instillation therapy. High ESR2 was associated with reduced CSS (P = 0.018) and OS (P = 0.029) in females and with shorter RFS in both sexes (males: P = 0.035; females: P = 0.010). Patients with high ERBB2 showed reduced CSS (P = 0.011) and OS (P = 0.042) in females and reduced CSS (P = 0.012) in those without instillation, while RFS was significantly reduced irrespective of sex or instillation. Conclusion: High mRNA expression of ERBB2 is an independent predictor of reduced RFS in patients with stage T1 NMIBC. High ERBB2 and ESR2 are associated with reduced outcomes, especially in females and patients without instillation therapy.
CRIS-Team Scopus Importer:2021-08-06
Keywords: ERBB2; Estrogen receptor; HER2; Non-muscle-invasive bladder cancer; Urothelial carcinoma

High-grade histology as predictor of early distant metastases and decreased disease-free survival in salivary gland cancer irrespective of tumor subtype - Haderlein, Marlen; Scherl, Claudia; Semrau, Sabine; Lettmaier, Sebastian; Uter, Wolfgang; Neukam, Friedrich Wilhelm; Iro, Heinrich; Agaimy, Abbas; Fietkau, Rainer (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2016)
The purpose of this study was to evaluate risk factors that influence overall survival (OS)/disease-free survival (DFS)/locoregional recurrence-free survival (LRFS), and distant metastases-free survival (DMFS) in patients with high-risk primary salivary gland carcinoma who underwent surgery and postoperative (chemo)radiotherapy with curative intention.We reviewed data of 63 patients with high-risk primary salivary gland carcinoma in a retrospective single-center audit.At a median follow-up of 31 months (range, 5-145 months), cumulative OS and DFS were 91.7%, 77.6%, and 62.9%, and 82.1%, 65.6%, and 57.7%, respectively, after 1, 2, and 5 years. LRFS and DMFS were 92%, 86%, and 86%, and 83.4%, 70.4%, and 62.3% after 1, 2, and 5 years, respectively. Of all patient-related, tumor-related, and treatment-related factors, high-grade histology (G3) was the only factor in univariate and multivariate analysis that was predictive for a shorter DMFS (low/intermediate vs high-grade: 100%, 100%, and 89.4% vs 72.9%, 54.3%, and 42.8% after 1, 2, and 5 years, respectively) and a shorter DFS (low/intermediate vs high-grade: 100%, 90%, and 84.4% vs 71.2%, 50.1%, and 39.4% after 1, 2, and 5 years, respectively) and OS (low/intermediate vs high-grade: 100%, 100%, and 86.5% vs 86.5%, 63.2%, and 46.5% after 1, 2, and 5 years, respectively).High-grade tumor histology is a highly significant predictor of a shorter DMFS, OS, and DFS in salivary gland carcinoma, irrespective of histological subtype. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2041-E2048, 2016.
EVALuna2:5539

High-grade myoepithelial carcinoma can show histologically undifferentiated/anaplastic features - Mok, Yingting; Agaimy, Abbas; Wang, Shi; Kuick, Chik Hong; Chang, Kenneth Tou En; Petersson, Fredrik (Annals of Diagnostic Pathology, 2018)
High grade malignant tumors with a poorly-/un-differentiated morphology pose significant diagnostic challenges. Increasingly, the use of adjunct immunohistochemical and molecular tests to characterize and delineate the histopathologic phenotype of these tumors has become necessary, particularly in head and neck tumors. Recently, several entities with a poorly-/un-differentiated light microscopic morphology have been defined based on specific immunohistochemical and genetic characteristics. We herein describe two cases of high-grade myoepithelial carcinoma, one occurring in the submandibular gland and the other occurring in the left nasal cavity, both showing undifferentiated histological and anaplastic cytomorphological features. This led to very broad differential diagnostic considerations and the diagnosis was only established after extensive immunohistochemical studies. Molecular testing for HPV was negative in both cases. Gene fusion analysis using a targeted sequencing assay (Archer® FusionPlex® system) did not identify fusions involving PLAG1, HMGA2, EWSR1 or ALK genes in either case. The submandibular tumor showed an aggressive clinical course, with diffuse pulmonary metastases at presentation, whilst the nasal cavity tumor showed only localized disease. Awareness of a subcategory of high-grade myoepithelial carcinomas with undifferentiated light microscopical features is of significant importance in antibody selection for immunohistochemical investigation of poorly-/undifferentiated malignant tumors in the head and neck region. This histological variant of myoepithelial carcinoma adds to the growing list of differential diagnoses in this diagnostically complex and multifaceted field.
EVALuna2:34887

High-grade salivary gland cancer: is surgery followed by radiotherapy an adequate treatment to reach tumor control? Results from a tertiary referral centre focussing on incidence and management of distant metastases - Freitag, Viola; Lettmaier, Sebastian; Semrau, Sabine; Hecht, Markus; Mantsopoulos, Konstantinos; Müller-Hübner, Sarina Katrin Ursel; Traxdorf, Maximilian; Iro, Heinrich; Agaimy, Abbas; Fietkau, Rainer; Haderlein, Marlen (European Archives of Oto-Rhino-Laryngology, 2021)
Purpose: Salivary Gland cancer (SGC) is a rare and heterogenous group of tumors. Standard therapeutic options achieve high local but poor distant control rates, especially in high-grade SGC. The aim of this monocentric study was to evaluate patterns of recurrence and its treatment options (local ablative vs. systemic) in a homogenously treated patient population with high-grade SGC after surgery and radio(chemo)therapy. Methods: Monocentric, retrospective study of patients with newly diagnosed high-grade salivary gland cancer. We retrospectively reviewed clinical reports from 69 patients with high-grade salivary gland cancer in a single-center audit. Survival rates were calculated using the Kaplan–Meier method and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox regression analysis). Results: The median time of follow-up was 31 months. After 5 years, the cumulative overall survival was 65.2%, cumulative incidence of local recurrence was 7.2%, whereas the cumulative incidence of distant metastases was 43.5% after 5 years. 30 of 69 patients developed distant metastases during the time of follow-up, especially patients with adenoid cystic carcinoma, salivary duct carcinoma, adenocarcinoma NOS and acinic cell carcinoma with high-grade transformation. The most common type of therapy therefore was chemotherapy (50%). 85.7% of patients with local ablative therapy of distant metastases show disease progression during follow-up afterwards. Conclusion: With surgery and radio-chemotherapy, a high rate of loco-regional control is reached, but over 40% of patients develop distant metastases in the further follow-up which usually present a diffuse pattern involving in a diffuse metastases. Therefore, in the future, intensified interdisciplinary combination therapies even in the first-line treatment in certain subtypes of high-grade SGC should be investigated.
CRIS-Team Scopus Importer:2021-09-10
Keywords: Chemotherapy; Distant metastases; High-grade; Radiotherapy; Salivary gland cancer

High-grade Transformation/Dedifferentiation in Salivary Gland Carcinomas: Occurrence Across Subtypes and Clinical Significance - Skalova, Alena; Leivo, Ilmo; Hellquist, Henrik; Agaimy, Abbas; Simpson, Roderick H.W.; Stenman, Göran; Vander Poorten, Vincent; Bishop, Justin A.; Franchi, Alessandro; Hernandez-Prera, Juan C.; Slouka, David; Willems, Stefan M.; et al. (Advances in Anatomic Pathology, 2021)
High-grade transformation (HGT) or dedifferentiation has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, secretory carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous adenocarcinoma, low-grade mucoepidermoid carcinoma, and hyalinizing clear cell carcinoma. High-grade (HG) transformed tumors are composed of a conventional low-grade component characterized by specific microscopic and immunohistochemical features for the given entity, intermingled with or juxtaposed to areas of HG morphology. This is usually either poorly differentiated adenocarcinoma, carcinoma not otherwise specified, or undifferentiated carcinoma, in which the original line of differentiation is lost. The HG component is composed of solid nests of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli, and abundant cytoplasm. Frequent mitoses and extensive necrosis may be present. The Ki-67 labeling index is consistently higher in the HG component. The molecular genetic mechanisms responsible for HGT of salivary gland carcinomas are largely unknown, though p53 inactivation and human epidermal growth factor receptor 2 overexpression and/or gene amplification have been demonstrated in the HG component in a few examples, the frequency varies for each histologic type. Salivary gland carcinomas with HGT are more aggressive than conventional carcinomas, with a higher local recurrence rate and a poorer prognosis. They have a high propensity for cervical lymph node metastasis suggesting a need for a wider resection and neck dissection. HGT of salivary gland carcinoma can occur either at initial presentation or less commonly at the time of recurrence, sometimes following postoperative radiotherapy. The potential for HGT in almost any type of salivary gland carcinoma warrants a thorough sampling of all salivary gland malignancies to prevent oversight of a HG component.
CRIS-Team Scopus Importer:2021-04-19

High interobserver variability of PTEN immunohistochemistry defining PTEN status in low- to intermediate-risk prostate cancer: results of the first German ring trial - Hommerding, Oliver; Bernhardt, Marit; Kreft, Tobias; Scherping, Anna; Abbas, Mahmoud; Baretton, Gustavo; Bräsen, Jan Hinrich; Breyer, Johannes; Darr, Christopher; Dressler, Franz Friedrich; Ellinger, Jörg; Erber, Ramona; et al. (Virchows Archiv, 2024)
The prognostication of individual disease trajectory and selection of optimal therapy in patients with localized, low-grade prostate cancer often presents significant difficulty. The phosphatase and tensin homolog on chromosome 10 (PTEN) has emerged as a potential novel biomarker in this clinical context, based on its demonstrated prognostic significance in multiple retrospective studies. Incorporation into standard clinical practice necessitates exceptional diagnostic accuracy, and PTEN’s binary readout—retention or loss—suggests its suitability as a biomarker. This multi-institutional ring trial aimed to validate the diagnostic precision of PTEN immunohistochemistry in localized, low- to intermediate-risk prostate cancer, across ten university pathology institutes in Germany. The trial incorporated 90 cases of patients diagnosed with acinar adenocarcinoma of the prostate of grade groups 1 (n = 8, 8.9%) and 2 (n = 82, 91.1%) post-radical prostatectomy. Remarkably, the interpretation of PTEN immunohistochemistry displayed substantial variation (12.5–51.2% PTEN loss rates) within an identical cohort of prostate cancer. Fluorescence in situ hybridization analysis demonstrated PTEN hemizygous deletions in 5.5% (5/90) of cases. All cases with hemizygous deletions presented a distinct loss of PTEN expression by immunohistochemistry and were unanimously identified as PTEN loss by all participants (sensitivity 100%). However, negative (loss) immunohistochemistry was relatively non-specific for an underlying genomic deletion. Improved inter-observer agreement was observed in a subsequent ring trial. Finally, we identify S473-pAKT immunohistochemistry as a useful marker in equivocal cases. In summary, this multi-institutional ring trial illustrates surprisingly heterogeneous outcomes in defining PTEN status by immunohistochemistry.
CRIS-Team Scopus Importer:2025-02-04
Keywords: Active surveillance; AKT; Prognostic biomarker; Prostate cancer; PTEN

High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients - Breyer, Johannes; Wirtz, Ralph M.; Otto, Wolfgang; Erben, Philipp; Worst, Thomas S.; Stoehr, Robert; Eckstein, Markus; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt (Cancer Immunology, Immunotherapy, 2018)
INTRODUCTION AND OBJECTIVES: Checkpoint inhibition has emerged as new therapeutic option in muscle-invasive bladder cancer. The objective of the present study was to evaluate the prognostic role of PD1 and PDL1 expression in non-muscle-invasive bladder cancer (NMIBC) and establish an objective measuring method using RNA quantification. MATERIALS AND METHODS: We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder. mRNA expression of PD1, PDL1 and CD3 was measured by single step RT-qPCR and correlated to clinicopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS) and carcinoma-specific survival (CSS). RESULTS: We have analyzed 334 patients with NMIBC at stage pT1 for mRNA analysis. Data from 296 patients (79% male, median age: 72 years) could be used. Spearman correlation revealed significant associations between mRNA expressions of PD1/PDL1 (ρ: 0.6024, p < 0.0001), CD3/PDL1 (ρ: 0.5728, p < 0.0001) and CD3/PD1 (ρ: 0.7005, p < 0.0001). Kaplan-Meier analysis revealed that high PDL1 mRNA expression (≥ 33.83) is a favorable prognostic factor with regard to better RFS (p = 0.0018), PFS (p = 0.021) and CSS (p = 0.012). Multivariate Cox-regression analysis proved PDL1 expression to be an independent prognosticator for RFS [HR 0.48 (0.31-0.72), p = 0.0005], PFS [HR 0.45 (0.24-0.80), p = 0.0059] and CSS [HR 0.31 (0.13-0.67), p = 0.0021]. CONCLUSION: High mRNA expression of PDL1 predicts improved RFS, PFS and CSS of pT1 NMIBC. Following prospective validation, this objective measurement of PD-L1 might help stratify patients with NMIBC for immunotherapy and identify patients who might benefit from early cystectomy.
EVALuna:33789

High proliferation rate and TNM stage but not histomorphological subtype are independent prognostic markers for overall survival in papillary renal cell carcinoma - Polifka, Iris; Agaimy, Abbas; Herrmann, Edwin; Spath, Verena; Trojan, Lutz; Stoeckle, Michael; Becker, Frank; Stroebel, Philipp; Muelfing, Christian; Schrader, Andres J.; Barth, Peter; Staehler, Michael; et al. (Human Pathology, 2019)
Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/Intemational Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. chi(2)-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2. (C) 2018 Elsevier Inc. All rights reserved.
CRIS-Team WoS Importer:2019-03-06

High stroma T-cell infiltration is associated with better survival in stage pT1 bladder cancer - Hülsen, Sabine; Lippolis, Eleonora; Ferrazzi, Fulvia; Otto, Wolfgang; Distel, Luitpold; Fietkau, Rainer; Denzinger, Stefan; Breyer, Johannes; Burger, Maximilian; Bertz, Simone; Eckstein, Markus; Ebner, Annette; et al. (International Journal of Molecular Sciences, 2020)
Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3+ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3+ and CD8+ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased antitumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3+ (not CD8+) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients’ risk and therefore, to optimize patients’ management and follow-up examination as well as possible therapies.
CRIS-Team Scopus Importer:2020-11-20
Keywords: CD8; Immunoscore; Progression; PT1 bladder cancer; Survival; Tumor-infiltrating lymphocytes (TILs); CD3

Histiocyte-rich rhabdomyoblastic tumor: rhabdomyosarcoma, rhabdomyoma, or rhabdomyoblastic tumor of uncertain malignant potential? A histologically distinctive rhabdomyoblastic tumor in search of a place in the classification of skeletal muscle neoplasms - Martinez, Anthony P.; Fritchie, Karen J.; Weiss, Sharon W.; Agaimy, Abbas; Haller, Florian; Huang, Hsuan-Ying; Lee, Seungjae; Bahrami, Armita; Folpe, Andrew L. (Modern Pathology, 2019)
Skeletal muscle tumors are traditionally classified as rhabdomyoma or rhabdomyosarcoma. We have identified an unusual adult rhabdomyoblastic tumor not clearly corresponding to a previously described variant of rhabdomyoma or rhabdomyosarcoma, characterized by a very striking proliferation of non-neoplastic histiocytes, obscuring the underlying tumor. Ten cases were identified in nine males and one female with a median age of 43 years (range 23-69 years). Tumors involved the deep soft tissues of the trunk (N = 4), lower limbs (N = 4), and neck (N = 2). Tumors were well-circumscribed, nodular masses, frequently surrounded by a fibrous capsule containing lymphoid aggregates and sometimes calcifications. Numerous foamy macrophages, multinucleated Touton-type giant cells, and sheets/fascicles of smaller, often spindled macrophages largely obscured the underlying desmin, MyoD1, and myogenin-positive rhabdomyoblastic tumor. Cases were wild type for MYOD1 and no other mutations or rearrangements characteristic of a known subtype of rhabdomyoma or rhabdomyosarcoma were identified. Two of four cases successfully analyzed using a next-generation sequencing panel of 170 common cancer-related genes harbored inactivating NF1 mutations. Next-generation sequencing showed no gene fusions. Clinical follow (nine patients; median 9 months; mean 23 months; range 3-124 months) showed all patients received wide excision; four patients also received adjuvant radiotherapy and none received chemotherapy. At the time of last follow-up, all patients were alive and without disease; no local recurrences or distant metastases occurred. We hypothesize that these unusual tumors represent rhabdomyoblastic tumors of uncertain malignant potential. Possibly over time they should be relegated to a new category of skeletal muscle tumors of intermediate (borderline) malignancy.
CRIS-Team WoS Importer:2019-03-15

Histiocytosis With Raisinoid Nuclei: A Unifying Concept for Lesions Reported Under Different Names as Nodular Mesothelial/Histiocytic Hyperplasia, Mesothelial/Monocytic Incidental Cardiac Excrescences, Intralymphatic Histiocytosis, and Others: A Report of - Michal, Michael; Kazakov, Dmitry V.; Dundr, Pavel; Peckova, Kvetoslava; Agaimy, Abbas; Kutzner, Heinz; Havlicek, Frantisek; Daum, Ondrej; Dubova, Magdalena; Michal, Michal (American Journal of Surgical Pathology, 2016)
We report 50 cases of peculiar histiocytic proliferations occurring in diverse body sites that currently bear various names, including nodular mesothelial/histiocytic hyperplasia, nodular histiocytic aggregates, mesothelial/monocytic incidental cardiac excrescences, reactive eosinophilic pleuritis, histioeosinophilic granuloma of the thymus, and intralymphatic histiocytosis. They can sometimes cause considerable differential diagnostic difficulties by resembling a metastatic carcinoma or Langerhans cell histiocytosis. Several previous publications have established a link between some of these conditions, suggesting that these are merely variations within a histopathologic spectrum, affecting different organs and bearing different names based on a particular location. However, no publication has ever comprehensively addressed all of these lesions together in one study in an attempt to explain and discuss their striking analogy. Having studied a large series of cases we provide evidence that all these lesions share the same morphologic, immunohistochemical, and pathogenetic properties, thus they all represent the same pathologic process and should be referred to as such. Taking into account their typical nuclear features we propose a collective term "histiocytosis with raisinoid nuclei" for this spectrum of conditions.
EVALuna2:6822

Histological, immunohistological and molecular characteristics of intraductal precursor of carcinoma ex pleomorphic adenoma support a multistep carcinogenic process - Ihrler, Stephan; Guntinas-Lichius, Orlando; Agaimy, Abbas; Wolf, Agnes; Mollenhauer, Martin (Virchows Archiv, 2017)
In recent years, multistep carcinogenesis of carcinoma ex pleomorphic adenoma (CEPA) has been identified, starting with intraductal neoplasia within pre-existent pleomorphic adenoma (PA). However, as yet there is no consensus regarding clinical relevance and appropriate terminology of precursor lesions in CEPA. We therefore decided to investigate precursor lesions, especially intraductal carcinoma, in a series of 85 cases of CEPA. Intraductal carcinoma confined by benign myoepithelial cells was found in 60 cases and mostly exhibited high-grade cellular atypia, increased cellular proliferation and frequent genetic alterations (TP53, Her2-neu, androgen receptor). Intraductal carcinoma was absent only in the myoepithelial type of CEPA. In 26 cases, purely intraductal CEPA with extensive intraductal expansion was found. This suggests that there is a long period of intraductal growth before extraductal intracapsular infiltration of the PA. We identified two different histomorphological types of intraductal carcinoma, which we call 'clinging' and 'solid' types. In summary, combined histological, immunohistological and molecular data strongly support multistep carcinogenesis starting with intraductal carcinoma for all non-myoepithelial types of CEPA. The clinical significance of our finding of two histomorphological types of intraductal carcinoma (clinging and solid) is not yet clear. Intraductal carcinoma, intracapsular invasive CEPA and minor extracapsular invasive CEPA (up to about 6 mm) all show favourable prognosis and together comprise half of the cases in our study.
EVALuna2:6864

Histologische Subtypen des Nierenzellkarzinoms: Übersicht und neue Entwicklungen - Polifka, Iris; Agaimy, Abbas; Moch, H.; Hartmann, Arndt (Pathologe, 2021)
Background: The classification of renal cell carcinoma (RCC) has changed remarkably in recent years. Objectives: This is a short overview of the classification of RCC, focusing on new developments. Materials and Methods: A literature search was performed resulting in an overview of the classification of RCC. Emerging entities were discussed in detail. Results: Apart from the RCC subtypes in the WHO classification of 2016, several emerging entities came up over the last few years that are characterized by typical morphology, immunophenotype, and especially specific genetic alterations. Conclusion: Precise classification of RCC is the key to better prognostic assessment with potential tumor-specific therapy and plays an important role in the recognition of possible association with hereditary tumor syndromes.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Fumarate hydratase; Genetic predisposition to disease; Immunophenotyping; Prognosis; Succinatdehydrogenase B (SDHB)

Histology of Luminal Breast Cancer - Erber, Ramona; Hartmann, Arndt (Breast Care, 2020)
Background: Invasive breast cancer (IBC) can be categorized into prognostic and predictive molecular subtypes (including luminal breast cancer) using gene expression profiling. Luminal IBC comprises a variety of histological subtypes with varying clinical and pathological features. Summary: IBC of no special subtype is the most common histological subtype in general and likewise within luminal IBC. Classical invasive lobular breast cancer, typically clustering into luminal subgroup, is characterized by discohesive growth and loss of E-cadherin expression. Infrequent, morphologically distinct luminal IBC subtypes are tubular, invasive cribriform, mucinous, and invasive micropapillary carcinomas. Breast carcinoma with apocrine differentiation, with characteristic expression of androgen receptor (AR), often clusters into the luminal AR category. Rarely, neuroendocrine neoplasms of the breast can be seen. IBC of the male breast usually matches with the luminal subtype. Key Messages: Independently from histological subtypes, invasive breast cancer (IBC) can be divided into molecular subtypes based on mRNA gene expression levels. Using this molecular subtyping, risk scores based on gene expression profiling (established for hormone receptor-positive, HER2-negative IBC), grading, and Ki-67 index, prognosis of patients with luminal breast cancer and response to chemotherapy can be predicted. In routine diagnostics, the expression of estrogen receptor (ER) and progesterone receptor (PR), HER2 status, and the proliferation rate (Ki-67) are used to determine a surrogate (molecular-like) subtype. Within luminal(-like) IBC, no special subtype and invasive lobular breast carcinoma are the most common histological subtypes. Other rare histological subtypes (e.g., tubular carcinoma) should be recognized due to their distinct clinical and pathological features.
CRIS-Team Scopus Importer:2020-07-31

Histomorphologisch definierte Nierenzellkarzinome 2025: Aktuelle WHO-Klassifikation und sich abzeichnende zukünftige Subtypen - Stöhr, Christine; Fiegl, August; Bercebal, C.; Agaimy, Abbas; Hartmann, Arndt (Die Pathologie, 2025)
BACKGROUND: The latest edition of the WHO classification of urinary and male genital tumours was published in 2022. The revision was based on the newest scientific literature. This article summarizes the updated recommendations regarding the classification of histomorphologically defined tumours. RESULTS AND CONCLUSIONS: The current edition of the WHO classification made some adjustments on the classification of histomorphologically defined tumour types. Papillary renal cell carcinoma is no longer categorized into two subtypes. Also, the new classification recognized the benign nature of clear cell papillary tumours, which are no longer regarded as carcinomas. Finally, several emerging renal tumours were introduced.
EVALuna2:585361

Histopathological comparison of pleomorphic adenomas of the parotid and submandibular gland - Mantsopoulos, Konstantinos; Sievert, Matti; Iro, Ann Kristin; Müller, Susanna; Koch, Michael; Schapher, Mirco; Agaimy, Abbas; Iro, Heinrich (Oral Diseases, 2021)
Objective: The aim of this study was to investigate and compare the histopathological findings in pleomorphic adenomas (PA) of the parotid and submandibular gland with emphasis on the histological subtype and capsular characteristics. Materials and Methods: The histopathological specimens of all patients with PAs of the parotid and submandibular gland between 2000 and 2020 were re-examined by an experienced head and neck pathologist. Patients without representative slides allowing evaluation of the whole periphery of the PA were excluded from our study sample. Results: Nine hundred and thirty-four patients formed our study sample (327 men, 607 women, male-to-female ratio: 0.53:1). Eight hundred and forty-four cases had a PA in the parotid gland and the remaining 90 in the submandibular gland. Our comparative analysis showed that submandibular PAs are characterized by the consistent presence of an intact anatomical capsule, infrequent occurrence of pseudopodia and satellite nodules, and a low proportion of the high-risk myxoid subtype. Conclusion: Our study highlights significant differences between PAs of the parotid and submandibular glands in their histopathological characteristics. Their differences likely underlie the favorable surgical outcome observed in PAs of the submandibular glands and may explain the propensity of PAs of the parotid glands for local recurrences.
CRIS-Team Scopus Importer:2021-04-16
Keywords: capsule; parotid gland; pleomorphic adenoma; satellite nodules; submandibular gland

Histopathology of Parotid Pleomorphic Adenomas: A "Pleomorphic Approach" to a Demanding Lesion - Mantsopoulos, Konstantinos; Thimsen, Vivian; Gostian, Antoniu-Oreste; Müller, Sarina Katrin; Sievert, Matti; Iro, Ann-Kristin; Agaimy, Abbas; Iro, Heinrich (Laryngoscope, 2021)
Objectives/Hypothesis The aim of this study was to identify potential associations between epidemiologic, morphologic, and histopathologic features in pleomorphic adenomas (PAs) of the parotid gland in order to extract information about the natural course and biologic behavior of these lesions on the basis of a single-center series of 845 cases within a period of 15 years. Study Design Retrospective study in a tertiary academic center. Methods For this study, an experienced head and neck pathologist critically re-evaluated the histological slides of the pathological specimens of all patients who underwent a parotidectomy for PA of the parotid gland between 2006 and 2020. Results A total of 845 cases made up our study sample. Our analysis showed a statistically significant association of the histologic subtype with younger age (P = .001) and maximal diameter (P = .044), with the hypocellular type being encountered more often in younger patients and in smaller lesions. The same subtype was significantly associated with an incomplete capsule (P = .001), pseudopodia (P = .006), and satellite nodules (P = .001). An incomplete capsule was associated with the presence of pseudopodia (P = .001) and satellite nodules (P = .001). Conclusion It seems that various histologic subtypes have different capsule-producing properties. Apparently, over the course of time, tumor material builds a finger-like projection still inside the capsule, separates itself from the parenchyma with fibrous tissue still remaining enclosed within the capsule (pseudopodium), slowly penetrates the capsule (incomplete capsule), and leaves the main lesion taking a part of the capsule with it (satellite nodules). Laryngoscope, 2021
CRIS-Team WoS Importer:2021-07-16

HLA-E expression and its clinical relevance in human renal cell carcinoma - Seliger, Barbara; Jasinski-Bergner, Simon; Quandt, Dagmar; Stoehr, Christine; Bukur, Juergen; Wach, Sven; Legal, Wolfgang; Taubert, Helge; Wullich, Bernd; Hartmann, Arndt (Oncotarget, 2016)
The non-classical human leukocyte antigen E (HLA-E) expression is frequently overexpressed in tumor diseases, transplants and virus-infected cells and represents an immunomodulatory molecule by binding to the receptors CD94/NKG2A, -B and -C on NK and T cells. Due to its immune suppressive features HLA-E expression might represent an important mechanism of tumors to escape immune surveillance. While an aberrant expression of the non-classical HLA-G antigen in human renal cell carcinoma (RCC) has been demonstrated to be associated with a worse outcome of patients and reduced sensitivity to immune effector cell-mediated cytotoxicity, the expression and function of HLA-E has not yet been analyzed in this tumor entity. Higher levels of HLA-E transcripts were detected in all RCC cell lines and tumor lesions, which were tested in comparison to normal kidney epithelium. Immunohistochemical staining of a tissue microarray (TMA) using the HLA-E-specific monoclonal antibody TFL-033 recognizing the cytoplasmic HLA-E ?-chain as monomer revealed a heterogeneous HLA-E expression in RCC lesions with the highest frequency in chromophobe RCC when compared to other RCC subtypes. HLA-E expression did not correlate with the frequency of CD3+, CD4+, CD8+ and FoxP3+ immune cell infiltrations, but showed an inverse correlation with infiltrating CD56+ cells. In contrast to HLA-G, HLA-E expression in RCCs was not statistically significant associated with a decreased disease specific survival. These data suggest that HLA-E overexpression frequently occurs in RCC and correlates with reduced immunogenicity.
EVALuna2:6816

HLA-G and HLA-F protein isoform expression in breast cancer patients receiving neoadjuvant treatment - Würfel, Franziska; Hübner, Hanna; Häberle, Lothar; Gaß, Paul; Hein, Alexander; Jud, Sebastian; Hack, Carolin; Wunderle, Marius; Schulz-Wendtland, Rüdiger; Erber, Ramona; Hartmann, Arndt; Ekici, Arif Bülent; et al. (Scientific Reports, 2020)
The immunosuppressive human leukocyte antigens HLA-G and HLA-F are expressed on trophoblast and malignant cells. Four membrane-bound and three soluble HLA-G protein isoforms have been described, which have different immunosuppressive potentials. HLA-F has three transcript variants, resulting in three different protein isoforms. The aim of this study was to evaluate the prognostic and predictive value of HLA-G and HLA-F protein isoform expression patterns in patients with breast cancer. Core biopsies were taken at diagnosis in patients with HER2+ (n = 28), luminal B-like (n = 49) and triple-negative (n = 38) breast cancers who received neoadjuvant chemotherapy. Expression levels of HLA-F and -G were correlated with the pathological complete response (pCR). Protein expression was determined by Western blot analysis, using two antibodies for each HLA, specific for different isoforms. The protein expression of HLA isoforms did not significantly differ between breast cancer subtypes. However, some initial indications were found for an association between the soluble HLA-G6 protein isoform and pCR in HER2+ breast cancer. The study provides preliminary evidence for the evaluation of HLA-G isoform expression, in particular HLA-G6, as a possible new marker for pCR in HER2+ breast cancer.
CRIS-Team Scopus Importer:2020-10-02

HLA-G expression associates with immune evasion muscle-invasive urothelial cancer and drives prognostic relevance - Branz, Annalena; Matek, Christian; Lange, Fabienne; Bahlinger, Veronika; Klümper, Niklas; Hölzel, Michael; Strissel, Pamela; Strick, Reiner; Sikic, Danijel; Wach, Sven; Taubert, Helge; Wullich, Bernd; et al. (Frontiers in Immunology, 2024)
Introduction: Urothelial bladder cancer is frequent and exhibits diverse prognoses influenced by molecular subtypes, urothelial subtype histology, and immune microenvironments. HLA-G, known for immune regulation, displays significant membranous expression in tumor tissues. Methods: We studied the protein expression of Human Leucocyte Antigen G (HLA-G) in 241 Muscle-Invasive Bladder Cancer (MIBC) patients, elucidating its potential clinical and biological significance. Protein expression levels were evaluated and correlated with molecular subtypes, histological characteristics, immune microenvironment markers, and survival outcomes. Results: High HLA-G expression associates with poor overall survival (OS) and diseasespecific survival (DSS), independent of clinicopathological parameters. HLA-G expression varies among molecular subtypes and Urothelial Subtype Histology, e.g., elevated expression levels in basal/squamous MIBC and those with sarcomatoid differentiation. Notably, HLA-G is increased in MIBC with an immune evasive microenvironment (high PD-L1 tumor cell expression, NK cell depletion, granzyme B (GZMB)/CD8 ratio reduction, MHC class I (MHCI) expression reduction) that are characterized by immunosuppressive features and poor prognosis. Furthermore, HLA-G correlates with elevated levels of other immune checkpoint proteins (TIGIT, LAG3, CTLA-4), indicating its role in immune evasion. Discussion: Our findings underscore HLA-G’s role as a potential prognostic marker and interesting immunotherapeutic target in MIBC. Its impact on immune evasion mechanisms and broad expression, coupled with associations withpoor survival and distinct tumor phenotypes, positions HLA-G as a promising protein for further exploration in developing targeted immunotherapies for MIBC patients.
CRIS-Team Scopus Importer:2024-11-15
Keywords: HLA-G; immune checkpoints; immune evasion; immune microenvironment; urothelial cancer

HMGA1/HMGA2 Gene Rearrangements and HMGA1/HMGA2 Protein Overexpression in Spindle Cell/Pleomorphic Lipomas (SPL) - Michalova, Kvetoslava; Steiner, Petr; Grossmann, Petr; Suster, Saul; Agaimy, Abbas; Kazakov, Dmitry; Michal, Michal; Michal, Michael (MODERN PATHOLOGY, 2020)
CRIS-Team WoS Importer:2020-03-24

HMGA2-WIF1 Rearrangements Characterize a Distinctive Subset of Salivary Pleomorphic Adenomas With Prominent Trabecular (Canalicular Adenoma-like) Morphology - Agaimy, Abbas; Ihrler, Stephan; Baneckova, Martina; Martineau, Valerie Costes; Mantsopoulos, Konstantinos; Hartmann, Arndt; Iro, Heinrich; Stöhr, Robert; Skalova, Alena (American Journal of Surgical Pathology, 2022)
Most of salivary gland neoplasms (benign and malignant) are characterized by recurrent gene fusions. Pleomorphic adenoma (PA), the most frequent salivary gland tumor, is driven by chromosomal rearrangements involving PLAG1 mapped to 8q12 and HMGA2 mapped to 12q13-15 in most cases. Multiple fusion partners have been identified including CTNNB1, FGFR1, LIFR, CHCHD7 and TCEA for PLAG1 fusions and NFIB, WIF1 and FHIT for HMGA2 fusions. To date, no data exist on the morphology of the few reported HMGA2-WIF1-rearranged PAs. We present 28 major salivary gland adenomas displaying distinctive trabecular and canalicular morphology associated with recurrent genotype. Patients were 15 females and 13 males aged 43 to 87 (median: 65). All tumors originated from the parotid. Their size range was 1 to 4 cm (mean: 2.3). Histologically, all tumors showed elongated or columnar cells arranged into bilayered to multilayered communicating and branching strands and trabeculae in a manner similar to canalicular adenoma of minor salivary glands or trabecular myoepithelioma with variable solid confluent intercalated duct-like areas. Fifteen tumors were exclusively canalicular/trabecular while 13 had intermingled or well-demarcated conventional (chondromyxoid) PA component comprising 5 to >50% of the tumor. The monomorphic areas expressed uniformly CK7 (28/28), vimentin (21/21), S100 (24/24), SOX10 (16/17) and variably p63 (8/21) and mammaglobin (6/16) but were negative with p40 (0/24), smooth muscle actin (0/24) and MUC4 (0/16). Targeted RNA sequencing revealed HMGA2 fusions in 14/16 (87%) assessable cases. Fusion partner was WIF1 (12), RPSAP52 (1) and HELB (1). Separate testing of the 2 components in 1 hybrid tumor showed same HMGA2/WIF1 fusion. HMGA2 immunohistochemistry was homogeneously positive in all cases including the 2 fusion-negative cases. A control cohort of 12 genuine canalicular adenomas revealed no HMGA2 fusions (0/4) and lacked HMGA2 immunoreactivity (0/12). This study highlights a distinctive variant in the spectrum of PA characterized by prominent trabecular and canalicular adenoma-like morphology. Our data confirm that canalicular adenomas in major salivary glands (either monomorphic or part of hybrid tumors) are distinct from canalicular adenoma of minor salivary glands. Their uniform genotype irrespective of presence or absence of a conventional PA component argues for classifying those tumors lacking a conventional PA component as "monomorphic variants of PA" rather than canalicular/basal cell adenomas, intercalated duct adenoma, trabecular myoepithelioma or true hybrid tumors.
CRIS-Team WoS Importer:2022-01-21

Homozygous G/G variant of SNP309 in the human MDM2 gene is associated with earlier tumor onset in Caucasian female renal cell carcinoma patients - Stoehr, Christine; Stoehr, R.; Wenners, A.; Hartmann, Arndt; Bertz, Simone; Spath, V.; Walter, B.; Junker, K.; Moch, H.; Hinze, R.; Denzinger, S.; Bond, E. E.; et al. (Oncogenesis, 2016)
Human mouse double minute 2 (Mdm2) plays an essential role in the regulation of the tumor suppressor p53. The G/G variant of SNP309 was shown to increase Mdm2 mRNA/protein expression and to be associated with an increased risk and earlier onset of different cancers in Asian populations. However, the frequency and impact of these G/G variants have not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). When separating all females into two groups at their median age (68 years), 7 and 1 patients with the G/G variant and 9 and 13 patients with the T/T variant were noted in these age groups (P=0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was investigated, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P=0.039 and 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP309 G/G genotype showed significantly earlier tumor onset than patients with the wild-type T/T genotype.
EVALuna2:6760

Hormone replacement therapy and prognosis in ovarian cancer patients - Hein, Alexander; Thiel, Falk; Bayer, Christian M.; Fasching, Peter; Häberle, Lothar; Lux, Michael P.; Renner, Stefan; Jud, Sebastian; Schrauder, Michael G.; Müller, Andreas; Wachter, David; Strehl, Johanna; et al. (European Journal of Cancer Prevention, 2013)
Estrogen exposure has at least a moderate effect on the risk for ovarian cancer, and antiestrogen therapy may be helpful in treating the disease. It is known from breast cancer that previous hormone replacement therapy (HRT) may influence the molecular profile and prognostic behavior of these tumors. The aim of this study was therefore to investigate the influence of previous HRT on the prognosis in a cohort of patients with invasive epithelial ovarian cancer. Among 547 patients who were treated for ovarian malignancies at a single institution from 1995 to 2008, a total of 244 postmenopausal patients with epithelial cancer and under the age of 75 were identified for whom information about HRT before the onset of the disease was available. HRT was correlated with tumor and patient characteristics. Analyses of overall survival and progression-free survival were carried out using Cox proportional hazards models. Age, tumor stage, and resection status correlated significantly with HRT in the univariate analysis. Patients with previous HRT were more likely to have a lower stage, to be younger, and to have optimal debulking. With regard to survival, HRT had a positive effect on overall survival, specifically in the subgroup of patients with optimal debulking. No correlation was seen in relation to progression-free survival. Sex hormone exposure through HRT may influence the behavior of ovarian cancers after the onset of the disease. This study supports the hypothesis that ovarian cancer is a hormonally influenced tumor. © 2012 Lippincott Williams & Wilkins.
CRIS-Team Scopus Importer:2021-07-19
Keywords: estrogen; hormone replacement therapy; ovarian cancer; pathogenesis; prognosis

Hormone Therapy and its Effect on the Prognosis in Breast Cancer Patients - Rauh, C.; Schuetz, F.; Rack, B.; Stickeler, E.; Klar, M.; Orlowska-Volk, M.; Windfuhr-Blum, M.; Heil, J.; Rom, J.; Sohn, C.; Andergassen, U.; Jueckstock, J.; et al. (Geburtshilfe und Frauenheilkunde, 2015)
Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.
EVALuna2:6745

How Much Liver Tissue Is Required for Sufficient Histological Staging in Patients with Primary Biliary Cholangitis? - Vetter, Marcel; Kremer, Andreas; Agaimy, Abbas; Pfeifer, Lukas; Neurath, Markus; Zopf, Steffen; Siebler, Jürgen (Digestion, 2020)
Introduction: Histological alterations in primary biliary cholangitis (PBC) are heterogeneously distributed throughout the liver. Thus, the quality of histological staging is probably dependent on the available amount of liver tissue. The goals of this study were to test this hypothesis and to define biopsy conditions for obtaining sufficient tissue. Methods: In this retrospective analysis, we investigated 34 patient cases who fulfilled the criteria of the European Association for the Study of the Liver (EASL) for PBC and underwent a mini-laparoscopic liver biopsy between 2011 and 2018 using 16 or 18G needles. For histological assessment of fibrosis, we used the Ishak score, and the amount of tissue was measured by the number of portal fields. Histological staging was compared with the macroscopic mini-laparoscopic fibrosis score (MLFS), and non-invasive liver stiffness measurements using acoustic radiation force impulse (ARFI) imaging and the FIB-4 score. Results: Biopsy was successful in 33 of 34 patients (97%). Fibrosis assessment by MLFS and ARFI correlated strongly with each other (r = 0.7088, p = 0.000017). However, the correlation of both methods with the histological staging was weaker (MLFS vs. histology: r = 0.4231, p = 0.0142; ARFI vs. histology: r = 0.3564, p = 0.0577). The correlation of ARFI and MLFS with the histological staging was better in the subgroup of biopsies with at least 10 portal fields (= SG≥10PF) (MLFS vs. histology: r = 0.6369, p = 0.006; ARFI vs. histology: r = 0.7538, p = 0.0012). FIB-4 correlated weakly with the histological staging, which was statistically not significant (all samples: r = 0.2693, p = 0.1296; SG≥10PF: r = 0.2244, p = 0.3866). The number of portal fields correlated well with the length of the samples (r = 0.6436, p = 0.00012). The probability to attain at least 10 portal fields depended on the needle diameter and number of samples (1 × 16G or 18G [n = 10]: 30.0%; 2 × 18G [n = 15]: 53.3%; 2 × 16G [n = 5]: 100%; p = 0.0414). Conclusion: ARFI and MLFS are probably well suited for the assessment of liver fibrosis in patients with PBC. A minimum of 10 portal fields could improve the histological assessment in PBC and can probably be achieved by obtaining two 16G biopsies.
CRIS-Team Scopus Importer:2020-06-19

HPV16-L1-specific antibody response is associated with clinical remission of high-risk HPV-positive early dysplastic lesions - Mehlhorn, Grit; Hautmann, Simone K.; Koch, Martin; Strehl, Johanna D.; Hartmann, Arndt; Hilfrich, Ralf; Beckmann, Matthias; Griesser, Henrik (Anticancer Research, 2014)
The present study was aimed at clarifying if use of a rapid human papillomavirus type 16 L1-specific antibody test could be used to improve clinical management of high-risk HPV-positive low-grade squamous intraepithelial lesion (LSIL)/high-grade squamous intraepithelial lesion (HSIL).The study was nested within a prospective study of 801 patients with early dysplastic high-risk HPV-positive lesions to examine the prognostic significance of HPV-L1 protein detection. Serum samples of 87 patients were tested with a rapid HPV16-L1-specific antibody test. The results were correlated with the clinical outcome during 66 months of follow-up.A combined analysis of the 22 antibody-positive women showed that 17 were also L1 protein-positive, and 5 were L1 capsid protein-negative. An HPV-specific immune competence strongly correlates with clinical remission of low-grade squamous intraepithelial lesion (76.6%). For L1 antigen and HPV16-L1 antibody double-positive women, the risk of progression to cervical intraepithelial neoplasia grade 3 was low (5.8%).The rapid anti-HPV16-L1 test could be a promising tool to improve risk assessment and appropriate clinical management of high-risk HPV-positive early dysplastic lesions.
EVALuna2:6623

HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo - Safavi, Setareh; Jarnum, Sofia; Vannas, Christoffer; Udhane, Sameer; Jonasson, Emma; Tomic, Tajana Tesan; Grundevik, Pernilla; Fagman, Henrik; Hansson, Magnus; Kalender, Zeynep; Jauhiainen, Alexandra; Dolatabadi, Soheila; et al. (Oncotarget, 2016)
Myxoid sarcoma (MLS) is one of the most common types of malignant soft tissue tumors. MLS is characterized by the FUS-DDIT3 or EWSR1-DDIT3 fusion oncogenes that encode abnormal transcription factors. The receptor tyrosine kinase (RTK) encoding RET was previously identified as a putative downstream target gene to FUS-DDIT3 and here we show that cultured MLS cells expressed phosphorylated RET together with its ligand Persephin. Treatment with RET specific kinase inhibitor Vandetanib failed to reduce RET phosphorylation and inhibit cell growth, suggesting that other RTKs may phosphorylate RET. A screening pointed out EGFR and ERBB3 as the strongest expressed phosphorylated RTKs in MLS cells. We show that ERBB3 formed nuclear and cytoplasmic complexes with RET and both RTKs were previously reported to form complexes with EGFR. The formation of RTK hetero complexes could explain the observed Vandetanib resistence in MLS. EGFR and ERBB3 are clients of HSP90 that help complex formation and RTK activation. Treatment of cultured MLS cells with HSP90 inhibitor 17-DMAG, caused loss of RET and ERBB3 phosphorylation and lead to rapid cell death. Treatment of MLS xenograft carrying Nude mice resulted in massive necrosis, rupture of capillaries and hemorrhages in tumor tissues. We conclude that complex formation between RET and other RTKs may cause RTK inhibitor resistance. HSP90 inhibitors can overcome this resistance and are thus promising drugs for treatment of MLS/RCLS.
EVALuna2:33955

Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma - Steinmann, Sara; Gali-Muhtasib, Hala; Hübner, Kerstin; Al-Halabi, Racha; Abou Merhi, Raghida; Aman, Pierre; Agaimy, Abbas; Haller, Florian; Schneider-Stock, Regine (Cancer Letters, 2015)
Liposarcoma is one of the most common soft tissue sarcomas in adults. Recognized histological subtypes include well differentiated/dedifferentiated liposarcoma (WD/DDLS), myxoid liposarcoma (MLS) and pleomorphic liposarcoma. Currently, there are no proper subtype-specific treatments due to the genetic, histological and clinical heterogeneity of the liposarcoma subentities. In the past decade, the rising understanding of the various genetic and molecular aberrations in liposarcoma led to the development of novel alternative therapeutic strategies. One such therapy is the inhibition of the heat shock protein 90 (Hsp90) which is overexpressed in liposarcomas. In this study, we dissect the functional role of a novel potent Hsp90 inhibitor NVP-AUY922 (AUY922) in different cell lines of myxoid (MLS402, MLS1765) and undifferentiated (SW872) liposarcomas. We show that compared with 17-AAG treatment, lower concentrations of AUY922 achieve markedly cytotoxic effects on tumor cell viability. Combination treatment of AUY922 (20 nM) with Doxorubicin (300 nM) yielded a further reduction in cell viability in comparison to Doxorubicin alone. In vivo, we document an inhibition of tumor growth after AUY922 treatment. Further analyses revealed that Hsp90-inhibition induces apoptotic cell death and cell cycle arrest. In addition, we report striking perturbations of subtype-specific pattern in Raf/MEK/ERK and PI3K signaling after AUY922 application. In conclusion, our results provide evidence that Hsp90-inhibition by AUY922 may be a promising alternative therapeutic strategy for myxoid liposarcoma patients.
EVALuna2:6717

Huge coronary artery fistula to the pulmonary artery - Strecker, Thomas; Nooh, Ehab; Weyand, Michael; Agaimy, Abbas (Journal of Cardiac Surgery, 2019)
CRIS-Team Scopus Importer:2019-05-07

Huge lipomatous tumor in the adductor muscle - Zonnur, S.; Falkeis, C.; Ondang, G.; Weiner, M.; Maier, H.; Agaimy, Abbas (Pathologe, 2015)
Deep-seated lipomatous tumors of the peripheral soft tissue of the extremities are uncommon. The majority represent atypical lipomatous tumors or well-differentiated liposarcomas. On rare occasions benign adipocytic tumors, such as hibernoma may present as huge, deep-lying subfascial masses. As a consequence of the deep location and usually heterogeneous signal intensities in imaging, they are particularly at risk to be misinterpreted as liposarcomas on clinical grounds. Furthermore, the rarity and thus limited familiarity with the morphological appearance and spectrum still represent a pitfall for the histopathological assessment.
EVALuna2:6720

Human CD22-transgenic, primary murine lymphoma challenges immunotherapies in organ-specific tumor microenvironments - Gsottberger, Franziska; Brandl, Carolin; Wendland, Kerstin; Petkovic, Srdjan; Emmerich, Charlotte; Erber, Ramona; Geppert, Carol-Immanuel; Hartmann, Arndt; Mackensen, Andreas; Nitschke, Lars; Müller, Fabian (International Journal of Molecular Sciences, 2021)
Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a myc-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22+ lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22+ lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22+ lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.
CRIS-Team Scopus Importer:2021-10-08
Keywords: CD22; Checkpoint molecule; Immunotoxin; Lymphoma microenvironment; MDSCs; Mouse model; Myc-driven lymphoma; Myeloid derived suppressor cells; PD-L1; Tumor microenvironment

Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, Jil; Lehmann, Christian; Heger, Lukas; Eissing, Nathalie; Baranska, Anna; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (Science immunology, 2016)
In mice, conventional and plasmacytoid dendritic cells (DCs) derive from separate hematopoietic precursors before they migrate to peripheral tissues. Moreover, two classes of conventional DCs (cDC1 and cDC2 DCs) and one class of plasmacytoid DCs (pDCs) have been shown to be transcriptionally and functionally distinct entities. In humans, these three DC subtypes can be identified using the cell surface markers CD1c (cDC2), CD141 (cDC1), and CD303 (pDCs), albeit it remains elusive whether DC functionality is mainly determined by ontogeny or the tissue microenvironment. By phenotypic and transcriptional profiling of these three DC subtypes in different human tissues derived from a large number of human individuals, we demonstrate that DC subpopulations in organs of the lymphohematopoietic system (spleen, thymus, and blood) are strongly defined by ontogeny rather than by signals from the microenvironment. In contrast, DC subsets derived from human lung or skin differed substantially, strongly arguing that DCs react toward modulatory signals from tissue microenvironments. Collectively, the data obtained in this study may serve as a major resource to guide further studies into human DC biology during homeostasis and inflammatio
EVALuna2:6852

Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, J.; Lehmann, C. H. K.; Heger, Lukas; Eissing, N.; Baranska, A.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (2017)
EVALuna2:33137

Human papilloma virus genotype distribution in women with premalignant or malignant lesions of the uterine cervix - Stübs, Frederik; Gaß, Paul; Dietl, Anna; Schulmeyer, Carla; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Koch, Martin (Archives of Gynecology and Obstetrics, 2021)
Objective: Cervical cancer is caused by persistent infection with high-risk human papillomavirus (hrHPV). Cytology-based national screening programs have reduced the incidence and mortality of cervical cancer. Different hrHPV subtypes have different carcinogenic potentials. This study evaluated the distribution of different types of hrHPV relative to age in cervical cancer and its precursor lesions. Methods: HPV testing was performed between November 2018 and February 2020 using the Abbott RealTime high-risk HPV assay on an Abbott m2000sp instrument. This assay separately detects HPV-16, HPV-18, and a pool of 12 additional hrHPV types (HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, and -68). Results: The study included 652 women with HPV samples and biopsies of the cervix or histology samples obtained during surgery. In all, 30.8% (95% CI, 27.3–34.6%) were HPV-negative. Among HPV-positive women, HPV-16, HPV-18, and “HPV other” types were found in 33.5, 4.4, and 49.4%, respectively. Cervical intraepithelial neoplasia (CIN) 3/high-grade squamous intraepithelial lesions (HSILs) in women ≤ 34 years were positive for HPV-16 in 54.5% of cases and in those ≥ 35 years in 45.4% of cases. Among women with cervical cancer, 75.8% were infected with HPV-16 or had coinfection with HPV-16 and “HPV other”. Conclusions: HPV-16 is the most common type of hrHPV in HSIL + lesions. It is more common in women diagnosed with CIN 3/HSIL who are aged ≤ 35 and is decreasing with age. Therefore, women age ≥ 35 with persistent infection with this type of hrHPV need careful surveillance, as they are at high risk of progression to cervical cancer.
CRIS-Team Scopus Importer:2021-02-19
Keywords: Age-distribtuion of HPV; Cervical cancer; Colposcopy; HPV-distribution; HSIL

Human Papillomavirus (HPV) Prevalence in Nasal and Antrochoanal Polyps and Association with Clinical Data - Knör, Mareike; Tziridis, Konstantin; Agaimy, Abbas; Zenk, Johannes; Wendler, Olaf (PLoS ONE, 2015)
The pathogenesis of sinonasal polyposis remains unclear, in spite of several investigative approaches. Antrochoanal polyps, a subgroup of sinonasal polyposis along with allergic- and chronic-inflammatory nasal polyps, mostly originate from the maxillary sinus and develop as a unilateral, pedunculated mass towards the nasopharynx. The human papillomavirus (HPV) is discussed as a possible causative and influencing factor in development and progression of sinonasal polyposis. This study aims to elucidate HPV frequency in nasal polyps and antrochoanal polyps.Genomic DNA from 257 tissue specimens (166 nasal polyps, 39 antrochoanal polyps and 52 nasal turbinates) was subjected to three different established HPV- polymerase chain reaction assays, testing for 37 low- and high-risk HPV. In addition, immunohistochemical analyses for HPV16 were carried out, as well as immunohistochemistry and western blots of p16, a biomarker for HPV induced cancer.HPV-DNA was detected in 53.8% of antrochoanal polyps, 15.1% of nasal polyps, and 5.8% of nasal turbinates. HPV16 was the predominant type with a detection rate of 76% in nasal polyps and 62% in antrochoanal polyps. Immunohistochemically, HPV positive tissues stained positive for HPV16 antigens and p16 in epithelial cell layers. No significant p16 overexpression was traceable in antrochoanal polyps, nasal polyps and nasal turbinates by western blot. There was no correlation of HPV-status with sex, age, smoking, alcohol consumption or allergic background.The present study shows a significant frequency of high-risk type HPV16 in antrochoanal polyps. Absence of oncogenic transformation or correlation of the HPV-status with clinical data suggests a latent superinfection, possibly because of anatomical proximity to the oropharynx.
EVALuna2:6739

Hydroxyethyl starch solution for extracorporeal tissue perfusion - Taeger, Christian; Friedrich, Oliver; Drechsler, Caroline; Weigand, Annika; Hobe, Frieder; Geppert, Carol-Immanuel; Münch, Frank; Birkholz, Torsten; Buchholz, Rainer; Horch, Raymund E.; Präbst, Konstantin; Buchholz, Rainer (Clinical hemorheology and microcirculation, 2016)
In the field of free flap transfer in reconstructive surgery, the trans- or replanted tissue always undergoes cell damage during ischemia to a more or less strong extent. In previous studies we already showed that conserving muscle transplants by means of extracorporeal perfusion over a period of 6 hours by using a crystalloid solution for perfusion. However, we observed significant edema formation. In this study we aimed at reducing the edema formation by using an iso-oncotic colloid as perfusion solution. This way we want to evaluate a possible new application of hydroxyl-ethyl starch in an extracorporeal setup to exploit potential benefits of the colloid.Examined parameters include the muscles' functionality with external field stimulation, histological examination and edema formation. Perfused muscles showed a statistically significant higher ability to exert force compared to nonperfused ones. These findings can be confirmed using Annexin V as marker for cell damage, perfusion of muscle tissue limits damage significantly compared to nonperfused tissue. Substituting the electrolyte perfusion solution with a colloidal one shows the tendency to reduce the edema formation but without statistical significance.

Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma - Hübner, Hanna; Strick, Reiner; Wachter, David Lukas; Kehl, Sven; Strissel, Pamela; Schneider-Stock, Regine; Rascher, Wolfgang; Horn, L. C.; Beckmann, Matthias; Rübner, Matthias; Fahlbusch, F. B.; Hartner, Andrea (Journal of Experimental & Clinical Cancer Research, 2017)
BACKGROUND: Human placental development resembles tumorigenesis, due to the invasive and fusogenic potential of trophoblasts. However, these features are tightly controlled in trophoblasts. Disturbance of this spatial and temporal regulation is thought to contribute to the rare formation of choriocarcinomas. Promoter hypermethylation and loss of the tumor suppressor Retinoic acid receptor responder 1 (RARRES1) were shown to contribute to cancer progression. Our study investigated the epigenetic and transcriptional regulation of RARRES1 in healthy human placenta in comparison to choriocarcinoma cell lines and cases. METHODS: Three choriocarcinoma cell lines (Jeg-3, JAR and BeWo) were treated with three different retinoic acid derivates (Am580, Tazarotene and all-trans retinoic acid) and 5-aza-2'-deoxycytidine. We analyzed RARRES1 promoter methylation by pyrosequencing and performed realtime-PCR quantification to determine RARRES1 expression in placental tissue and trophoblastic cell lines. Additionally, RARRES1 was stained in healthy placentas and in biopsies of choriocarcinoma cases (n = 10) as well as the first trimester trophoblast cell line Swan71 by immunofluorescence and immunohistochemistry. RESULTS: In the choriocarcinoma cell lines, RARRES1 expression could not be induced by sole retinoic acid treatment. Stimulation with 5-aza-2'-deoxycytidine significantly induced RARRES1 expression, which then could be further increased with Am580, Tazarotene and all-trans retinoic acid. In comparison to healthy placenta, choriocarcinoma cell lines showed a hypermethylation of the RARRES1 promoter, which correlated with a reduced RARRES1 expression. In concordance, RARRES1 protein expression was lost in choriocarcinoma tissue. Additionally, in the trophoblastic cell line Swan71, we found a significant induction of RARRES1 expression with increased cell density, during mitosis and in syncytial knots. CONCLUSIONS: Our findings showed that RARRES1 expression is absent in choriocarcinoma due to promoter methylation. Based on our analysis, we hypothesize that RARRES1 might exert tumor suppressive functions in multiple cellular processes (e.g. cell cycle regulation, adhesion, invasion and apoptosis).
EVALuna2:33950

Hypoxia drives glucose transporter 3 expression through hypoxia-inducible transcription factor (HIF)-mediated induction of the long noncoding RNA NICI - Lauer, Victoria; Grampp, Steffen; Platt, James; Lafleur, Veronique; Lombardi, Olivia; Choudhry, Hani; Kranz, Franziska; Hartmann, Arndt; Wullich, Bernd; Yamamoto, Atsushi; Coleman, Mathew L.; Ratcliffe, Peter John; et al. (Journal of Biological Chemistry, 2020)
Hypoxia-inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long noncoding transcripts with unknown function. We used pan-genomic HIF-binding and transcriptomic data to identify a novel long noncoding RNA Noncoding Intergenic Co-Induced transcript (NICI) on chromosome 12p13.31 which is regulated by hypoxia via HIF-1 promoter-binding in multiple cell types. CRISPR/Cas9-mediated deletion of the hypoxia-response element revealed co-regulation of NICI and the neighboring protein-coding gene, solute carrier family 2 member 3 (SLC2A3) which encodes the high-affinity glucose transporter 3 (GLUT3). Knockdown or knockout of NICI attenuated hypoxic induction of SLC2A3, indicating a direct regulatory role of NICI in SLC2A3 expression, which was further evidenced by CRISPR/Cas9-VPR-mediated activation of NICI expression. We also demonstrate that regulation of SLC2A3 is mediated through transcriptional activation rather than posttranscriptional mechanisms because knockout of NICI leads to reduced recruitment of RNA polymerase 2 to the SLC2A3 promoter. Consistent with this we observe NICI-dependent regulation of glucose consumption and cell proliferation. Furthermore, NICI expression is regulated by the von Hippel-Lindau (VHL) tumor suppressor and is highly expressed in clear cell renal cell carcinoma (ccRCC), where SLC2A3 expression is associated with patient prognosis, implying an important role for the HIF/NICI/SLC2A3 axis in this malignancy.
CRIS-Team Scopus Importer:2020-04-07
Keywords: ChIP; ChIP-sequencing (ChIP-Seq); glucose transport; GLUT3; hypoxia; hypoxia-inducible factor (HIF); long noncoding RNA (long ncRNA; lncRNA)

Identification and characterization of a GLMN splice site variant in a family with glomuvenous malformations - Skowronek, Dariush; Hebebrand, Moritz; Erber, Ramona; Agaimy, Abbas; Zweier, Christiane; Felbor, Ute; Rath, Matthias (European Journal of Dermatology, 2020)
CRIS-Team Scopus Importer:2020-06-26

Identification and characterization of a GLMN splice site variant in a three-generation-family with glomuvenous malformations - Skowronek, D.; Hebebrand, Moritz; Erber, Ramona; Agaimy, Abbas; Zweier, Christiane; Felbor, U.; Rath, M. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2020)
CRIS-Team WoS Importer:2021-01-22

Identification and characterization of the specific murine NK cell subset supporting graft-versus-leukemia- and reducing graft-versus-host-effects - Meinhardt, Kathrin; Kroeger, Irena; Bauer, Ruth; Ganss, Franziska; Ovsiy, Ilja; Rothamer, Johanna; Büttner, Maike; Atreya, Imke; Waldner, Maximilian; Bittrich, Max; Lehmann, Christian; Rieger, Michael A.; et al. (OncoImmunology, 2015)
Clinical studies investigating the impact of natural killer (NK) cells in allogeneic hematopoietic stem cell transplantation settings have yielded promising results. However, NK cells are a functionally and phenotypically heterogeneous population. Therefore, we addressed the functional relevance of specific NK cell subsets distinguished by expression of CD117, CD27 and CD11b surface markers in graft-versus-leukemia (GVL)-reaction and graft-versus-host-disease (GVHD). Our results clearly demonstrate that the subset of c-Kit(-)CD27(-)CD11b(+) NK cells expressed multiple cytotoxic pathway genes and provided optimal graft-versus-leukemia-effects, while significantly reducing T cell proliferation induced by allogeneic dendritic cells. Furthermore, these NK cells migrated to inflamed intestinal tissues where graft-versus-host-colitis was efficiently mitigated. For the first time, we identified the c-Kit(-)CD27(-)CD11b(+) NK cell population as the specific effector NK cell subset capable of significantly diminishing GVHD in fully mismatched bone marrow transplantation settings. In conclusion, the subset of c-Kit(-)CD27(-)CD11b(+) NK cells not only supports GVL, but also plays a unique role in the protection against GVHD by migrating to the peripheral GVHD target organs where they exert efficient immunoregulatory activities. These new insights demonstrate the importance of selecting the optimal NK cell subset for cellular immunotherapy following allogeneic hematopoietic stem cell transplantation.
EVALuna2:1965

Identification and diagnostic performance of a small RNA within the PCA3 and BMCC1 gene locus that potentially targets mRNA - Drayton, Ross M.; Rehman, Ishtiaq; Clarke, Raymond; Zhao, Zhongming; Pang, Karl; Miah, Saiful; Stoehr, Robert; Hartmann, Arndt; Blizard, Sheila; Lavin, Martin; Bryant, Helen E.; Martens-Uzunova, Elena S.; et al. (Cancer Epidemiology Biomarkers & Prevention, 2015)
PCA3 is a long noncoding RNA (lncRNA) with unknown function, upregulated in prostate cancer. LncRNAs may be processed into smaller active species. We hypothesized this for PCA3.We computed feasible RNA hairpins within the BMCC1 gene (encompassing PCA3) and searched a prostate transcriptome for these. We measured expression using qRT-PCR in three cohorts of prostate cancer tissues (n = 60), exfoliated urinary cells (n = 484 with cancer and n = 166 controls), and in cell lines (n = 22). We used in silico predictions and RNA knockup to identify potential mRNA targets of short transcribed RNAs.We predicted 13 hairpins, of which PCA3-shRNA2 was most abundant within the prostate transcriptome. PCA3-shRNA2 is located within intron 1 of PCA3 and appears regulated by androgens. Expression of PCA3-shRNA2 was upregulated in malignant prostatic tissues, exfoliated urinary cells from men with prostate cancer (13-273 fold change; t test P < 0.003), and closely correlated to PCA3 expression (r = 0.84-0.93; P < 0.001). Urinary PCA3-shRNA2 (C-index, 0.75-0.81) and PCA3 (C-index, 0.78) could predict the presence of cancer in most men. PCA3-shRNA2 knockup altered the expression of predicted target mRNAs, including COPS2, SOX11, WDR48, TEAD1, and Noggin. PCA3-shRNA2 expression was negatively correlated with COPS2 in patient samples (r = -0.32; P < 0.001).We identified a short RNA within PCA3, whose expression is correlated to PCA3, which may target mRNAs implicated in prostate biology.This short RNA is stable ex vivo, suggesting a role as a robust biomarker. We identify cytoplasmic enrichment of this RNA and potential targeting of mRNAs implicated in prostate carcinogenesis.
EVALuna2:6667

Identification of DAPK as a scaffold protein for the LIMK/cofilin complex in TNF-induced apoptosis - Ivanovska, Jelena; Tregubova, Alexandra; Mahadevan, Vijayalakshmi; Chakilam, Saritha; Gandesiri, Muktheshwar; Benderska, Natalya; Ettle, Benjamin; Hartmann, Arndt; Söder, Stephan; Ziesche, Elisabeth; Fischer, Thomas; Lautscham, Lena; et al. (International Journal of Biochemistry and Cell Biology, 2013)
The role of cytoskeleton-associated proteins during TNF-induced apoptosis is not fully understood. A potential candidate kinase that might connect TNF signalling to actin reorganization is the death-associated protein kinase (DAPK). To identify new DAPK interaction partners in TNF-induced apoptosis, we performed a peptide array screen. We show that TNF-treatment enhanced the phosphorylation of LIMK at threonine508 and its downstream target cofilin at serine3 (p-cofilin(Ser3)). Modulation of DAPK activity and expression by DAPK inhibitor treatment, siRNA knockdown, and overexpression affected the phosphorylation of both proteins. We propose a 3D structural model where DAPK functions as a scaffold for the LIMK/cofilin complex and triggers a closer interaction of both proteins under TNF stimulation. Upon TNF a striking redistribution of LIMK, DAPK, and cofilin to the perinuclear compartment was observed. The pro-apoptotic DAPK/LIMK/cofilin multiprotein complex was abrogated in detached cells, indicating that its signaling was no longer needed if cells committed to apoptosis. P-cofilin(Ser3) was strongly accumulated in cells with condensed chromatin, pronounced membrane blebs and Annexin V up-regulation. From studying different cofilin(Ser3) mutants we suggest that p-cofilin(Ser3) is an indicator of TNF-induced apoptosis. Collectively, our findings identify a novel molecular cytoskeleton-associated mechanism in TNF-induced DAPK-dependent apoptosis.

Identification of Disparities in Personalized Cancer Care—A Joint Approach of the German WERA Consortium - Lüke, Florian; Haller, Florian; Utpatel, Kirsten; Krebs, Markus; Meidenbauer, Norbert; Scheiter, Alexander; Spörl, Silvia; Heudobler, Daniel; Sparrer, Daniela; Kaiser, Ulrich; Keil, Felix; Schubart, Christoph; et al. (Cancers, 2022)
(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.
CRIS-Team Scopus Importer:2022-11-04
Keywords: cancer care; MTB; outcomes research; outreach; patient access; precision oncology; real world data

Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA - Schmidt, Thomas P.; Perna, Anna M.; Fugmann, Tim; Böhm, Manja; Hiss, Jan; Haller, Sarah; Goetz, Camilla; Tegtmeyer, Nicole; Hoy, Benjamin; Rau, Tilman; Neri, Dario; Backert, Steffen; et al. (Scientific Reports, 2016)
The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori (H. pylori) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions.
EVALuna2:6912

Identification of miRNA-mRNA Modules in Colorectal Cancer Using Rough Hypercuboid Based Supervised Clustering - Paul, Sushmita; Lakatos, Petra; Hartmann, Arndt; Schneider-Stock, Regine; Vera, Julio (Scientific Reports, 2017)
Differences in the expression profiles of miRNAs and mRNAs have been reported in colorectal cancer. Nevertheless, information on important miRNA-mRNA regulatory modules in colorectal cancer is still lacking. In this regard, this study presents an application of the RH-SAC algorithm on miRNA and mRNA expression data for identification of potential miRNA-mRNA modules. First, a set of miRNA rules was generated using the RH-SAC algorithm. The mRNA targets of the selected miRNAs were identified using the miRTarBase database. Next, the expression values of target mRNAs were used to generate mRNA rules using the RH-SAC. Then all miRNA-mRNA rules have been integrated for generating networks. The RH-SAC algorithm unlike other existing methods selects a group of co-expressed miRNAs and mRNAs that are also differentially expressed. In total 17 miRNAs and 141 mRNAs were selected. The enrichment analysis of selected mRNAs revealed that our method selected mRNAs that are significantly associated with colorectal cancer. We identified novel miRNA/mRNA interactions in colorectal cancer. Through experiment, we could confirm that one of our discovered miRNAs, hsa-miR-93-5p, was significantly up-regulated in 75.8% CRC in comparison to their corresponding non-tumor samples. It could have the potential to examine colorectal cancer subtype specific unique miRNA/mRNA interactions.
EVALuna2:6844

Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma - Jasinski-Bergner, Simon; Reches, Adi; Stoehr, Christine; Massa, Chiara; Gonschorek, Evamaria; Huettelmaier, Stefan; Braun, Juliane; Wach, Sven; Wullich, Bernd; Spath, Verena; Wang, Ena; Marincola, Francesco M.; et al. (Oncotarget, 2016)
The non-classical human leukocyte antigen G (HLA-G) is expressed at a high frequency in renal cell carcinoma (RCC) and is associated with a higher tumor grade and a poor clinical outcome. This might be caused by the HLA-G-mediated inhibition of the cytotoxicity of T and NK cells. Therefore a selective targeting of HLA-G might represent a powerful strategy to enhance the immunogenicity of RCC lesions. Recent studies identified a number of HLA-G-regulating microRNAs (miRs) and demonstrated an inverse expression of some of these miRs with HLA-G in RCC in vitro and in vivo. However, it was postulated that further miRs might exist contributing to the tightly controlled selective HLA-G expression.By application of a miR enrichment assay (miTRAP) in combination with in silico profiling two novel HLA-G-regulatory miRs, miR-548q and miR-628-5p, were identified. Direct interactions of both miRs with the 3' untranslated region of HLA-G were confirmed with luciferase reporter gene assays. In addition, qPCR analyses and immunohistochemical staining revealed an inverse, expression of miR-628-5p, but not of miR-548q to the HLA-G protein in primary RCC lesions and cell lines. Stable overexpression of miR-548q and miR-628-5p caused a downregulation of HLA-G mRNA and protein. This leads in case of miR-548q to an enhanced NK cell-mediated HLA-G-dependent cytotoxicity, which could be reverted by ILT2 blockade suggesting a control of the immune effector cell activity at least by this miR. The identification of two novel HLA-G-regulatory miRs extends the number of HLA-G-relevant miRs tuning the HLA-G expression and might serve as future therapeutic targets.
EVALuna2:6802

Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis - Croner, Roland S.; Sevim, Muezeyyen; Metodiev, Metodi V.; Jo, Peter; Ghadimi, Michael; Schellerer, Vera; Brunner, Michaela; Geppert, Carol-Immanuel; Rau, Tilman; Stürzl, Michael; Naschberger, Elisabeth; Matzel, Klaus E.; et al. (International Journal of Molecular Sciences, 2016)
Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%-15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients' informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL(TM)) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort.
EVALuna2:6749

Identifying fibroblast growth factor receptor genetic alterations using RNA-based assays in patients with metastatic or locally advanced, surgically unresectable, urothelial carcinoma who may benefit from erdafitinib treatment - Wang, Songbai; Burgess, Mike; Major, Christopher; English, Alistair; Sweeney, Maranna; Hartmann, Arndt (Journal of Pathology: Clinical Research, 2020)
Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor received accelerated approval from the US Food and Drug Administration (FDA) for locally advanced or metastatic urothelial carcinoma (mUC) in adult patients with specific FGFR3/2 genetic alterations who progressed during or after >= 1 line of prior platinum-containing chemotherapy (PCC), including within 12 months of neoadjuvant or adjuvant PCC. Concordance between the clinical trial assay (CTA) used in a phase 2 study and QIAGEN's therascreen (R) FGFR kit (a two-step, multiplex, real-time, RT-PCR assay), the FDA-approved companion diagnostic (CDx) with erdafitinib, was evaluated in this bridging study. Study samples included 100 CTA-confirmed FGFR-positive samples from 100 erdafitinib-treated mUC patients, plus 200 CTA-confirmed FGFR-negative samples from the phase 2 study. The primary objective was met if the lower bound of 95% CI of objective response rate (ORR) in CDx-confirmed patients with FGFR alterations was >25%. Demographics were similar between the bridging study and CTA-screened patients. In total, 292 of 300 samples (97.3%) with valid CDx results showed high analytical concordance versus CTA (percent agreement [95% CI]: positive percent agreement, 87.2 [79.0; 92.5]; negative percent agreement, 97.0 [93.5; 98.6]; overall percent agreement, 93.8 [90.5; 96.1]). Investigator-assessed ORR in the 81 CDx-identified, erdafitinib-treated patients who tested positive for both assays was 45.7% (95% CI: 35.3%; 56.5%) versus 40.4% (95% CI: 30.7%; 50.1%) for CTA and met the criteria for primary objective. High ORR and clinical concordance to CTA suggest that QIAGEN's CDx can reliably select mUC patients who would potentially benefit from erdafitinib treatment.
CRIS-Team WoS Importer:2020-05-02

Identifying the Molecular Mechanisms Contributing to Progression, Metastasis, and Death in Low-grade Non–muscle-invasive Bladder Cancer: A Case Report - Weiß, Sarah; Hallmann, Steffen; Koch, Stefan; Eidt, Sebastian; Stöhr, Robert; Veltrup, Elke; Roggisch, Jenny; Wirtz, Ralph M.; Ecke, Thorsten H. (European Urology Open Science, 2021)
Transitional cell carcinoma of the bladder is a common malignancy with an estimated 549 393 new cases occurring in 2018 alone. Both non–muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) show high recurrence and progression rates, and therefore impose a great burden on patients and health care systems. Current risk stratification and therapy strategies are predominantly based on clinical and histopathological findings for tumor stage and grade. The chemoresistance and metastasis of low-grade tumors suggest an incomplete understanding of disease mechanisms, despite numerous studies on differentiating molecular subtypes of bladder cancer to identify tumor drivers and potential therapeutic targets. We present a highly unusual course for a low-grade bladder tumor leading to metastasis and death, for which we used postmortem histopathological and molecular analyses to evaluate targetable alterations in key signaling pathways driving the underlying tumor biology.
CRIS-Team Scopus Importer:2021-03-26
Keywords: Death; ERBB2; FGFR3; KRT20; Luminal subtype; Metastasis; Non–muscle-invasive bladder cancer

IDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies Forty Molecularly Homogenous and Histologically Variable Cases With Favorable Outcome - Gloss, Stefanie; Jurmeister, Philipp; Thieme, Anne; Schmid, Simone; Cai, Wei Y.; Serrette, Rene N.; Perner, Sven; Ribbat-Idel, Julika; Pagenstecher, Axel; Blaeker, Hendrik; Keber, Ursula; Stadelmann, Christine; et al. (American Journal of Surgical Pathology, 2021)
IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses.
CRIS-Team WoS Importer:2021-08-27

Idiopathic Mast Cell Activation Syndrome With Associated Salicylate Intolerance - Rechenauer, Tobias; Raithel, Martin; Goetze, Thomas; Siebenlist, Gregor; Rueckel, Aline; Baenkler, Hanns-Wolf; Hartmann, Arndt; Haller, Florian; Hoerning, Andre (Frontiers in Pediatrics, 2018)
Idiopathic mast cell activation syndrome can be a rare cause for chronic abdominal pain in children. It remains a diagnosis by exclusion that can be particularly challenging due to the vast variety of possible clinical manifestations. We present a 13-year-old boy who suffered from a multitude of unspecific complaints over a long period of time. In this case, an assessment of mast cell-derived metabolites and immunohistochemical analysis of bioptic specimen was worthwhile. After ruling out, primary (oncologic) and secondary causes for mast cell activation, pharmacologic treatment adapted to the patient's salicylate intolerance resulted in a major relief of symptoms.
EVALuna2:34101

IDKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells - Bley, Isabelle Ariane; Zwick, Anabel; Hans, Muriel Charlotte; Thieser, Katrin; Wagner, Viktoria; Ludwig, Nicole; Khalmurzaev, Oybek; Matveev, Vsevolod Borisovich; Loertzer, Philine; Pryalukhin, Alexey; Hartmann, Arndt; Geppert, Carol-Immanuel; et al. (Translational Oncology, 2022)
Penile squamous cell cancer (PSCC) is the most frequent penile malignant disease. Infections with human papillomaviruses (HPV) are a major etiologic driver of PSCC. However, the molecular details of the underlying carcinogenesis are understudied because of rare clinical specimens and missing cell lines. Here, we investigated if the expression of high-risk HPV16 oncogenes causes an augmentation of the Wnt pathway using unique HPV-positive penile cancer (PeCa) cell lines in monolayer and organotypic 3D raft cultures as well as tissue micro arrays containing clinical tissue specimens. The HPV oncoproteins enhanced the expression of Leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and the HPV-positive PeCa cells expressed a signature of Wnt target and stemness-associated genes. However, the notable lack of nuclear β-catenin in vitro and in situ raised the question if the enhanced expression of Wnt pathway factors is tantamount to an active Wnt signaling. Subsequent TOP-flash reporter assays revealed Wnt signaling as absent and not inducible by respective Wnt ligands in PeCa cell lines. The HPV-positive PeCa cells and especially HPV-positive PeCa specimens of the tumor core expressed the Wnt antagonist and negative feedback-regulator Dickkopf1 (DKK1). Subsequent neutralization experiments using PeCa cell line-conditioned media demonstrated that DKK1 is capable to impair ligand-induced Wnt signaling. While gene expression analyses suggested an augmented and active canonical Wnt pathway, the respective signaling was inhibited due to the endogenous expression of the antagonist DKK1. Subsequent TMA stainings indicated Dkk1 as linked with HPV-positivity and metastatic disease progression in PeCa suggesting potential as a prognostic marker.
CRIS-Team Scopus Importer:2021-11-19
Keywords: Dickkopf1; HPV; Penile cancer; Stemness; Wnt pathway; β-catenin

IFN-γ-driven intratumoral microenvironment exhibits superior prognostic effect compared with an IFN-α-driven microenvironment in patients with colon carcinoma - Grenz, Sandra; Naschberger, Elisabeth; Merkel, Susanne; Britzen-Laurent, Nathalie; Schaal, Ute; Konrad, Andreas; Aigner, Michael; Rau, Tilman; Hartmann, Arndt; Croner, Roland S.; Hohenberger, Werner; Stürzl, Michael (American Journal of Pathology, 2013)
Interferon (IFN)-α and IFN-γ are cytokines with potent immunomodulating and anti-tumor activities. It is unknown which of the two IFNs may be more potent in the regulation of an anti-tumorigenic response in colorectal carcinoma or whether both cytokines cooperate. We, therefore, established human myxovirus resistance protein A and human guanylate-binding protein-1 as markers for the differential detection of IFN-α- and IFN-γ-driven tumor micromilieus, respectively. In vitro studies with different cultures of tumor cells from colorectal carcinoma and stroma cells showed that the expression of myxovirus resistance protein A was exclusively induced by IFN-α, whereas guanylate-binding protein-1 was strongly induced by IFN-γ and only weakly by IFN-α. This expression pattern was used to distinguish cell activation caused by the two cytokines in a clinical cohort of patients with colon carcinoma (n = 378). Patients with primary tumors expressing only guanylate-binding protein-1 exhibited the highest cancer-specific 5-year survival (94.0%, P = 0.006) compared with those expressing both factors (90.3%, P = 0.006), myxovirus resistance protein A alone (83.5%, P = 0.096), or none (72.8%). Our study describes a successful proof-of-principle approach that complex cytokine interaction networks can be dissected in human tissues and demonstrates that an IFN-γ-driven tumor microenvironment exhibits a superior prognostic effect compared with an IFN-α-driven tumor microenvironment in colon carcinoma. © 2013 American Society for Investigative Pathology.
Created from Fastlane, Scopus look-up

IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption - Langer, Victoria; Vivi, Eugenia; Regensburger, Daniela; Winkler, Thomas; Waldner, Maximilian; Rath, Timo; Schmid, Benjamin; Skottke, Lisa; Lee, Somin; Jeon, Noo Li; Wohlfahrt, Thomas; Kramer, Viktoria; et al. (Journal of Clinical Investigation, 2019)
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.

IgG4 immune response in Churg-Strauss syndrome - Vaglio, Augusto; Strehl, Johanna D.; Manger, Bernhard; Maritati, Federica; Alberici, Federico; Beyer, Christian; Rech, Jürgen; Rech, Juergen; Sinico, Renato A.; Bonatti, Francesco; Battistelli, Luisita; Distler, Jörg; et al. (Annals of the Rheumatic Diseases, 2012)
Objective: T-helper type 2 responses are crucial in Churg-Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients. Methods: The authors included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels. Tissue infiltration by IgG4 plasma cells was assessed in nine patients with CSS, 10 with GPA, 22 with chronic sinusitis (11 with and 11 without eosinophilia). Results: IgG4 levels were markedly higher in active CSS patients than in controls (p<0.001 vs all control groups). Serum IgG4 correlated with the number of disease manifestations (r=0.52, p=0.01) and the Birmingham vasculitis activity score (r=0.64, p=0.001). Longitudinal analysis in 12 CSS cases showed that both the IgG4 level and IgG4/IgG ratio dropped during disease remission (p=3×10 -5 and p=6×10 -4, respectively). Tissue analysis did not show an increased IgG4 plasma cell infiltration in CSS biopsies compared with control groups. Conclusions: Serum IgG4 levels are markedly elevated in active CSS and correlate with the number of organ manifestations and disease activity.
CRIS-Team Scopus Importer:2021-02-03

IgG4-related disease: an update on pathology and diagnostic criteria with a focus on salivary gland manifestations - Czarnywojtek, Agata; Agaimy, Abbas; Pietrończyk, Krzysztof; Nixon, Iain J.; Vander Poorten, Vincent; Mäkitie, Antti A.; Zafereo, Mark; Florek, Ewa; Sawicka-Gutaj, Nadia; Ruchała, Marek; Ferlito, Alfio (Virchows Archiv, 2024)
Immunoglobulin G4-related disease (IgG4-RD) is a multi-organ disorder characterized by a highly variable clinical presentation depending on the affected organ/s, extent of tumefactive fibroinflammatory lesions, and associated functional impairment. The disease pursues a chronic, relapsing, often asymptomatic course and hence may pose a significant diagnostic challenge. Diagnostic delay can lead to progressive fibrosis and irreversible organ damage resulting into significant morbidity and even mortality. Given its broad clinical spectrum, physicians of all specialties may be the first clinicians facing this diagnostic challenge. Outside the pancreatobiliary system, the head and neck represents the major site of IgG4-RD with variable organ-specific diffuse or mass-forming lesions. In up to 75% of cases, elevated serum IgG4 levels are observed, but this figure possibly underestimates the fraction of seronegative cases, as the disease manifestations may present metachronously with significant intervals. Together with negative serology, this can lead to misdiagnosis of seronegative cases. A standardized nomenclature and diagnostic criteria for IgG4-RD were established in 2012 and revised in 2020 facilitating scientific research and expanding the range of diseases associated with IgG4 abnormalities. In addition to orbital pseudotumor, dacryoadenitis, Riedel thyroiditis, sinonasal manifestations, and rare miscellaneous conditions, IgG4-related sialadenitis is one of the most frequent presentations in the head and neck region. However, controversy still exists regarding the relationship between sialadenitis and IgG4-RD. This review focuses on the clinicopathological features of IgG4-related sialadenitis and its contemporary diagnostic criteria.
CRIS-Team Scopus Importer:2024-02-16
Keywords: Clinical picture; IgG4-related disease; IgG4-related sialadenitis/dacryoadenitis; Pathogenesis of IgG4-RD; Treatment

IgG4-related fasciitis - Morf, Harriet; Roemer, Frank; Agaimy, Abbas; Schett, Georg; Manger, Bernhard (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-02-18

IgG4-related pseudotumours: a series of 12 cases and a review of the literature - Maccagno, Andrea; Grosser, Bianca; Füzesi, László; Konukiewitz, Björn; Vlasenko, Dmytro; Weckermann, Dorothea; Raab, Stephan; Zenk, Johannes; Agaimy, Abbas; Märkl, Bruno (Pathology, 2022)
IgG4-related pseudotumours (IgG4-RPT) represent a distinctive manifestation in the broad spectrum of IgG4-related diseases (IgG4-RD). Due to their wide morphology and rarity, IgG4-RPTs represent a diagnostic challenge in the differential between reactive lesions and a fibrous soft tissue tumours. Thus, our aim was to characterise our cases and review the literature, focusing on the macroscopic and microscopic features of the lesions. In this paper, we summarise the possible presentations and histomorphological features of IgG4-RPT based on data collected from the literature and from cases at our institute and provide an overview of the pathogenesis and histological characteristics based on the knowledge accumulated in recent years. We collected surgical cases with a diagnosis of IgG4-RPT over the period 2013–2020 at two centres and analysed their macroscopic, histological, and immunohistochemical profiles. Furthermore, we performed a literature research in the MEDLINE and EBSCO databases regarding case reports and studies with the explicit diagnosis of IgG4-RPT. Our cases consist of nine men and three women, with an average age of 60±14 years, representing about 0.05% of the lesions evaluated at the two departments. The involved sites include the kidney, lung, gallbladder, pterygopalatine fossa, spleen, tongue, mediastinum, and submandibular gland. Grossly, nine lesions showed sharp margins. On histological examination, all the lesions showed an abundant inflammatory infiltrate with lymphocytes and IgG4-positive plasma cells as well as characteristic fibroblastic storiform proliferation. The literature search revealed 266 cases and similar histomorphological features in 23 locations. In 30 of these cases (11%), IgG4-RPTs were multifocal. IgG4-RPT are exceedingly rare lesions, which makes them challenging to diagnose. They can affect different sites, and the histomorphological presentation may differ.
CRIS-Team Scopus Importer:2022-03-11
Keywords: autoimmune; IgG4-related; pseudotumour

IgG4-related sclerosing thyroiditis (Riedel-Struma): a review of clinicopathological features and management - Czarnywojtek, Agata; Pietronczyk, Krzysztof; Thompson, Lester D. R.; Triantafyllou, Asterios; Florek, Ewa; Sawicka-Gutaj, Nadia; Ruchala, Marek; Plazinska, Maria Teresa; Nixon, Iain J.; Shaha, Ashok R.; Zafereo, Mark; Randolph, Gregory William; et al. (Virchows Archiv, 2023)
We present a thorough review of the literature on Riedel thyroiditis (RT) with emphasis on aetiology, diagnosis and management, using the PubMed, Sinomed, and China National Knowledge Infrastructure databases. Although the exact aetiology of RT remains obscure, the histopathological features are consistent with a localized form of IgG(4)-related systemic disease (IgG(4)-RSD). Nevertheless, IgG4-RSD as a systemic fibroinflammatory disorder per se rarely affects the thyroid in the context of multiorgan manifestations. The initial diagnosis of RT is based on clinical history and imaging, but confirmation by histopathological examination is mandatory. In contrast to the historical surgical approach, glucocorticosteroid therapy is currently considered first line therapy, in line with the RT currently being viewed as a manifestation of, or analogous to, IgG4-RSD. For disease relapse, immunomodulatory agents (azathioprine, methotrexate, rituximab) can be used.
CRIS-Team WoS Importer:2023-06-02

IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice - Erhardt, Annette Lydia; Biburger, Markus; Papadopoulos, Thomas; Tiegs, Gisa (Hepatology, 2007)
The liver appears to play an important role in immunological tolerance, for example, during allo-transplantation. We investigated tolerance mechanisms in the model of concanavalin A (ConA)-induced immune-mediated liver injury in mice. We found that a single injection of a sublethal ConA dose to C57BL/6 mice induced tolerance toward ConA-induced liver damage within 8 days. This tolerogenic state was characterized by suppression of the typical Th1 response in this model and increased IL-10 production. Tolerance induction was fully reversible in IL-10 mice and after blockade of IL-10 responses by anti-IL10R antibody. Co-cultures of CD4CD25 regulatory T cells (Ts) and CD4CD25 responder cells revealed T from ConA-tolerant mice being more effective in suppressing polyclonal T cell responses than T from control mice. Moreover, T from tolerant but not from control mice were able to augment in vitro IL-10 expression. Depletion by anti-CD25 monoclonal antibody (MAb) indicated a functional role of Ts in ConA tolerance in vivo. Cell depletion studies revealed Ts and Kupffer cells (KC) to be crucial for IL-10 expression in ConA tolerance. Studies with CD1d mice lacking natural killer T (NKT) cells disclosed these cells as irrelevant for the tolerogenic effect. Finally, cellular immune therapy with CD4 CD25 cells prevented ConA-induced liver injury, with higher protection by T from ConA-tolerized mice. Conclusion: The immunosuppressive cytokine IL-10 is crucial for tolerance induction in ConA hepatitis and is mainly expressed by CD4CD25 T and KC. Moreover, Ts exhibit therapeutic potential against immune-mediated liver injury. Copyright © 2007 by the American Association for the Study of Liver Diseases.

IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling - Chiriac, Mircea-Teodor; Hracsko, Zsuzsanna; Günther, Claudia; Gonzalez Acera, Miguel; Atreya, Raja; Stolzer, Iris; Wittner, Leonie; Dressel, Anja; Schickedanz, Laura; Gámez Belmonte, Maria de los Reyes; Erkert, Lena; Hundorfean, Gheorghe; et al. (Gut, 2023)
Objective: We sought to investigate the role of interleukin (IL)-20 in IBD and experimental colitis. Design: Experimental colitis was induced in mice deficient in components of the IL-20 and signal transducer and activator of transcription (STAT)2 signalling pathways. In vivo imaging, high-resolution mini-endoscopy and histology were used to assess intestinal inflammation. We further used RNA-sequencing (RNA-Seq), RNAScope and Gene Ontology analysis, western blot analysis and co-immunoprecipitation, confocal microscopy and intestinal epithelial cell (IEC)-derived three-dimensional organoids to investigate the underlying molecular mechanisms. Results were validated using samples from patients with IBD and non-IBD control subjects by a combination of RNA-Seq, organoids and immunostainings. Results: In IBD, IL20 levels were induced during remission and were significantly higher in antitumour necrosis factor responders versus non-responders. IL-20RA and IL-20RB were present on IECs from patients with IBD and IL-20-induced STAT3 and suppressed interferon (IFN)-STAT2 signalling in these cells. In IBD, experimental dextran sulfate sodium (DSS)-induced colitis and mucosal healing, IECs were the main producers of IL-20. Compared with wildtype controls, Il20-/-, Il20ra-/- and Il20rb-/- mice were more susceptible to experimental DSS-induced colitis. IL-20 deficiency was associated with increased IFN/STAT2 activity in mice and IFN/STAT2-induced necroptotic cell death in IEC-derived organoids could be markedly blocked by IL-20. Moreover, newly generated Stat2ΔIEC mice, lacking STAT2 in IECs, were less susceptible to experimental colitis compared with wildtype controls and the administration of IL-20 suppressed colitis activity in wildtype animals. Conclusion: IL-20 controls colitis and mucosal healing by interfering with the IFN/STAT2 death signalling pathway in IECs. These results indicate new directions for suppressing gut inflammation by modulating IL-20-controlled STAT2 signals.
CRIS-Team Scopus Importer:2023-11-17
Keywords: experimental colitis; inflammatory bowel disease; interferon; interleukins; signal transduction

IL-23 is centrally involved in mediating molecular resistance to anti-TNF therapy in Crohn's disease patients - Schmitt, H.; Billmeier, Ulrike; Dieterich, Walburga; Rath, T.; Sonnewald, Sophia; Reid, Stephen; Hirschmann, S.; Hildner, Kai; Waldner, Maximilian; Mudter, J.; Hartmann, Arndt; Grützmann, Robert; et al. (2018)
EVALuna2:34077

IL-9 and its receptor are predominantly involved in the pathogenesis of UC - Nalleweg, Nancy; Chiriac, Mircea Teodor; Podstawa, Eva; Lehmann, Christian; Rau, Tilman; Atreya, Raja; Krauss, Ekaterina; Hundorfean, Gheorghe; Fichtner-Feigl, Stefan; Hartmann, Arndt; Becker, Christoph; Mudter, Jonas (Gut, 2015)
Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far.We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing.IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments.Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.
EVALuna2:1839

Imaging, histopathological degree of degeneration and clinical findings – Do these correlate in patients with temporomandibular joint disorders - Eckstein, Fabian; Wurm, Matthias; Eckstein, Markus; Wiesmüller, Marco; Müller, Magdalena; Jehn, Philipp; Söder, Stephan; Schlittenbauer, Tilo (Journal of Stomatology, Oral and Maxillofacial Surgery, 2021)
The gold standard for temporomandibular joint imaging is magnetic resonance imaging, although there are still pathological findings that cannot be seen in MRI but in surgery and the subsequent histological analysis only. The main goal of this investigation was to validate the MRI score used by histopathological findings as well as clinical findings. In this retrospective study 39 patients were included; 38 of which underwent unilateral and 1 underwent bilateral discectomy. MRI findings were graded according to the score by Wurm. Histopathological analysis was performed in hematoxylin-eosin staining and graded in accordance with the scores by Krenn and by Leonardi. For valuation of preoperative pain values of the temporomandibular joint operated on the numeric rating scale was utilized. Correlations were verified by Spearman-Rho. The MRI scores on average showed significantly lower scores for the discs of the operated temporomandibular joint than for the discs of the non-operated side(p<.01). No significant correlations between MRI findings, histopathological findings and pain intensities could be observed. Thus unsuspicious morphology of the TMJ and the articular disc in MRI is no guarantee for the absence of cartilage-degeneration. Further investigations utilizing T2 cartilage mapping could possibly show better correlations between the temporomandibular joint's degree of degeneration and imaging results.
CRIS-Team Scopus Importer:2021-06-11
Keywords: CMD; Temporomandibular joint; Temporomandibular joint imaging; Temporomandibular joint pathology; Temporomandibular joint surgery; TMD

Immune Cell-Associated Protein Expression Helps to Predict Survival in Muscle-Invasive Urothelial Bladder Cancer Patients after Radical Cystectomy and Optional Adjuvant Chemotherapy - Taubert, Helge; Eckstein, Markus; Epple, Elena; Jung, Rudolf; Weigelt, Katrin; Lieb, Verena; Sikic, Danijel; Stöhr, Robert; Geppert, Carol-Immanuel; Weyerer, Veronika; Bertz, Simone; Kehlen, Astrid; et al. (Cells, 2021)
Bladder cancer (BCa) is the tenth most commonly diagnosed malignant cancer worldwide. Although adjuvant chemotherapy following radical cystectomy is a common therapy for muscle invasive bladder cancer patients, no applicable biomarkers exist to predict which patients will benefit from chemotherapy. In this study, we examined three immune cell markers, the chemokine CC motif ligand 2 (CCL2), the pan macrophage marker cluster of differentiation 68 (CD68) and the M2 macrophage marker cluster of differentiation 163 (CD163), using immunohistochemistry to determine their predictive value for the chemotherapy response in different nodal stage (pN0 vs. pN1 + 2) and tumor stage subgroups (pT2 vs. pT3 + 4). The prognosis was studied in terms of the overall survival (OS), disease-specific survival (DSS), and recurrence-free-survival (RFS) in 168 muscle invasive BCa patients. Chemotherapy was associated with a poorer prognosis in patients with a higher expression of the immune markers CCL2 (RFS), CD68 (DSS and RFS), and CD163 (DSS and RFS) in the N0 group and with poorer survival in patients with a higher expression of the immune markers CCL2 (OS, DSS, and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS, DSS, and RFS) in the pT2 group when compared with treatments without chemotherapy. In contrast, chemotherapy was associated with a better prognosis in patients with a low expression of the immune markers CCL2 (DSS and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS) in the N1 + 2 group. In addition, chemotherapy was associated with improved survival in patients with a low expression of the immune marker CD68 (OS and DSS) and there was a trend for a better prognosis in patients with a low expression of CD163 (OS) in the pT3 + 4 group compared to patients not treated with chemotherapy. Interestingly, CD68 appeared to be the most applicable immune marker to stratify patients by the outcome of chemotherapy in the nodal stage and tumor stage groups. Overall, we suggest that, in addition to the clinical factors of tumor stage and nodal stage, it is also meaningful to consider the abundance of immune cells, such as macrophages, to better predict the response to chemotherapy for BCa patients after radical treatment.
CRIS-Team Scopus Importer:2021-02-12
Keywords: bladder cancer; CCL2; CD163; CD68; chemotherapy; immune cells; nodal stage; tumor stage

Immune Cell Gene Expression Signature is Associated with Improved Outcome in Muscle-Invasive Urothelial Bladder Cancer Patients Treated with Radical Cystectomy - Eckstein, Markus; Strissel, Pamela; Strick, Reiner; Weyerer, Veronika; Wirtz, Ralph M.; Pfannstiel, Carolin; Wullweber, Adrian; Lange, Fabienne; Erben, Philipp; Stöhr, Robert; Bertz, Simone; Geppert, Carol-Immanuel; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Immunoglobulin G4 (IgG4)-related disease of the stomach – a challenging differential diagnosis in suspected gastric cancer - Probst, Andreas; Schaller, Tina; Sommer, Florian; Geissler, Bernd; Agaimy, Abbas; Messmann, Helmut; Märkl, Bruno (Zeitschrift für Gastroenterologie, 2019)
BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) can involve different organs and is diagnosed by a combination of clinicopathological features, including storiform fibrosclerosis infiltrated by numerous IgG4-positive plasma cells that frequently forms tumor-like lesions with or without associated obliterative phlebitis. Involvement of the stomach is rare and can occur as part of a multiorgan involvement of IgG4-RD or as isolated gastric involvement. CASE REPORT: We report 2 female patients with therapy-refractory gastric ulcers associated with gastric wall thickening and lymphadenopathy that were highly suggestive of gastric cancer or lymphoma. Biopsies failed to confirm a diagnosis, and IgG4-RD was diagnosed only after surgical resection in both patients. The previous literature on gastric IgG4-RD is summarized and shows different characteristics in patients with multiorgan IgG4-RD and isolated gastric IgG4-RD. As reported for autoimmune pancreatitis type 1, patients with multiorgan IgG4-RD are mainly elderly men with frequently elevated serum IgG4 concentrations. In contrast, isolated gastric IgG4-RD predominantly affects female patients with normal serum IgG4 levels. Surgical resection is commonly performed due to the clinical suspicion of malignancy and the absence of findings indicative of IgG4-RD on biopsy. Today, diagnosis is confirmed histopathologically only after resection. CONCLUSION: IgG4-RD should be taken into account when gastric malignancy is suspected endoscopically or radiologically and biopsies fail to confirm the presence of a malignancy (especially subepithelial tumors or refractory gastric ulcers). Serum IgG4 concentrations are insufficient to confirm localized gastric IgG4-RD. Diagnostic workups need to be improved to avoid unnecessary surgical resections with the attendant potential morbidity and mortality.
CRIS-Team Scopus Importer:2019-11-26

Immunohistochemical analysis of sex hormone receptors in squamous changes of the urothelium. - Seitz, Julia; Hoegel, Josef; Eckstein, Markus; Lieb, Verena; Wullich, Bernd; Hartmann, Arndt; Rieker, Ralf (International Journal of Clinical and Experimental Pathology, 2022)
OBJECTIVE: Squamous cell transformation of the urinary bladder urothelium has various causes, symptoms, and few treatment options. The aim of this study was to analyze and compare the expression of sex hormone receptors in non-keratinized and keratinized squamous metaplasia (NKSM, KSM), squamous cell carcinoma (SCC), and healthy urothelium with regard to possible therapeutic approaches. METHODS: Biopsies from 26 patients with urothelial NKSM, KSM, and SCC were analyzed retrospectively. Tissue microarrays (TMA) of formalin-fixed paraffin-embedded (FFPE) bladder biopsies were stained with hematoxylin and eosin followed by immunohistochemical analysis with specific antibodies against estrogen, progesterone, and androgen receptors (ER, PR, AR) and assessment using the immunoreactive score. Statistical evaluations included the Wilcoxon signed-rank test and the Wilcoxon rank-sum test in the form of permutation tests. RESULTS: Of the 15 women and 11 men included in this explorative study, 17 had metaplasia: 15 (six men, nine women) had NKSM and two KSM (both men). A total of nine patients (three men, six women) had keratinized SCC or urothelial carcinoma with squamous differentiation. The comparison between normal urothelial cells and metaplasia showed a significantly stronger expression in the metaplastic tissue (P=0.0374). The invasive carcinoma showed significantly less PR than the extracellular matrix of the healthy urothelium (P=0.0026). Expression of AR was nearly absent in healthy and metaplastic urothelium. CONCLUSION: There appears to be an association between squamous metaplasia of the bladder mucosa and sex steroid hormone receptor expression, especially estrogen receptors. Topical hormone therapy should be considered.
EVALuna2:512116

Immunohistochemical analysis of sex hormone receptors in squamous changes of the urothelium - Seitz, Julia; Hogel, Josef; Eckstein, Markus; Lieb, Verena; Wullich, Bernd; Hartmann, Arndt; Rieker, Ralf (International Journal of Clinical and Experimental Pathology, 2022)
Objective: Squamous cell transformation of the urinary bladder urothelium has various causes, symptoms, and few treatment options. The aim of this study was to analyze and compare the expression of sex hormone receptors in non-keratinized and keratinized squamous metaplasia (NKSM, KSM), squamous cell carcinoma (SCC), and healthy urothelium with regard to possible therapeutic approaches. Methods: Biopsies from 26 patients with urothelial NKSM, KSM, and SCC were analyzed retrospectively. Tissue microarrays (TMA) of formalin-fixed paraffinembedded (FFPE) bladder biopsies were stained with hematoxylin and eosin followed by immunohistochemical analysis with specific antibodies against estrogen, progesterone, and androgen receptors (ER, PR, AR) and assessment using the immunoreactive score. Statistical evaluations included the Wilcoxon signed-rank test and the Wilcoxon rank-sum test in the form of permutation tests. Results: Of the 15 women and 11 men included in this explorative study, 17 had metaplasia: 15 (six men, nine women) had NKSM and two KSM (both men). A total of nine patients (three men, six women) had keratinized SCC or urothelial carcinoma with squamous differentiation. The comparison between normal urothelial cells and metaplasia showed a significantly stronger expression in the metaplastic tissue (P=0.0374). The invasive carcinoma showed significantly less PR than the extracellular matrix of the healthy urothelium (P=0.0026). Expression of AR was nearly absent in healthy and metaplastic urothelium. Conclusion: There appears to be an association between squamous metaplasia of the bladder mucosa and sex steroid hormone receptor expression, especially estrogen receptors. Topical hormone therapy should be considered.
CRIS-Team WoS Importer:2022-09-30

Immunohistochemical and molecular characterizations in urothelial carcinoma of bladder in patients less than 45 years - Weyerer, Veronika; Schneckenpointner, Roland; Filbeck, Thomas; Burger, Maximilian; Hofstaedter, Ferdinand; Wild, Peter J.; Fine, Samson W.; Humphrey, Peter A.; Dehner, Louis P.; Amin, Mahul B.; Rueschoff, Josef; Boltze, Carsten; et al. (Journal of Cancer, 2017)
Bladder tumours in early-onset patients are rare and seem to exhibit unique clinicopathological features. Only few studies have investigated somatic alterations in this specific age of onset group and evidence is accumulating of a distinct molecular behaviour of early-onset bladder tumours. We collected the largest cohort of early-onset tumours of patients 45 years old or younger and aimed to test genomic alterations typically found in bladder cancer. Tumours of 118 early-onset patients were compared with a consecutive group of 113 cases. Immunohistochemistry of TP53, CK20 and Ki-67 was carried out. Molecular analysis was conducted to test for loss of heterozygosity of chromosome 9 and 17, as well as TP53 and FGFR3 mutations. Fisher´s exact and chi-squared test were appropriately used. No differences in grade/stage characteristics were observed. Overexpressed TP53 was differentially distributed between the two groups. TP53 nuclear accumulation was significantly more frequent in early-onset papillomas, PUNLMPs and pTa low-grade tumours compared to the consecutive cohort (p=0.005). Moreover, chromosome 9 deletions (29.5% vs. 44.6%) and FGFR3 mutations (34.5% vs. 63.7%) were less often detected in early-onset patients (p=0.05 and p<0.0001). By comparing the largest cohort of early-onset bladder cancer patients with an unselected group, we demonstrated that the typical molecular features are not independent of age at diagnosis. Our study supports the hypothesis of a distinct biological behaviour in early-onset tumours.
EVALuna2:6841

Immunohistochemical expression of IMP3 and p53 in inflammatory lesions and neoplastic lesions of the gastric mucosa - Strehl, Johanna D.; Hoegel, Josef; Hornicek, Ines; Hartmann, Arndt; Riener, Marc-Oliver (International Journal of Clinical and Experimental Pathology, 2014)
Expression of the oncofetal protein insulin like growth factor II messenger ribonucleic acid binding protein 3 (IMP3) has been shown to differentiate between benign and malignant lesions in several tissues. Our aim was to assess the immunohistochemical expression of IMP3 in inflammatory and neoplastic lesions of the gastric mucosa and to determine whether IMP3, alone or in combination with p53, could be used for identifying neoplasia of the gastric mucosa.IMP3 and p53 immunohistochemistry was performed on 57 cases of gastritis, 28 cases of dysplasia of the gastric mucosa and 63 cases of gastric carcinomas. Focal IMP3 positivity was detected in 86% of non-neoplastic lesions of the gastric mucosa. Using a simple product score (PS), 96% of non-neoplastic lesions of the gastric mucosa were assessed as IMP3(PS) negative. None of the low-grade dysplasia but 83% of high-grade dysplasia were IMP3(PS) positive. Gastric carcinomas showed IMP3(PS) positivity in 65%. Adding p53 to the diagnostic panel increased sensitivity significantly.High-grade dysplasia and gastric carcinomas can be distinguished from low-grade dysplasia and inflammatory lesions of the gastric mucosa with a high specificity and good sensitivity using a combination of the immunohistochemical markers IMP3 and p53.
EVALuna2:6602

Immunohistochemical expression of the hepatocyte growth factor in chromophobe renal cell carcinoma - Erlmeier, Maximilian; Mikuteit, Marie; Zschaebitz, Stefanie; Autenrieth, Michael; Weichert, Wilko; Hartmann, Arndt; Steffens, Sandra; Erlmeier, Franziska (BMC Urology, 2023)
Background: The prognostic value of Hepatocyte growth factor (HGF) in non-clear cell renal cell carcinoma (RCC) is still unclear. The aim of this study is to evaluate the prognostic impact of HGF expression in a large cohort of chromophobe RCC (chRCC). Methods: Patients who underwent renal surgery due to chRCC were recruited. Clinical data was retrospectively evaluated. Tumor specimen were analyzed for HGF expression by immunohistochemistry. Results: 81 chRCC patients were eligible for analysis, thereof 37 (45.7%) patients were positive for HGF. No significant associations were found for HGF expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis revealed no differences in 5-year overall survival (OS) for patients with HGF− compared to HGF+ tumors (95.0% versus 90.9%; p = 0.410). Conclusions: In chRCC HGF expression is not associated with parameters of aggressiveness or survival.
CRIS-Team Scopus Importer:2023-05-26
Keywords: Chromophobe histology; HGF; Renal Cell Carcinoma; Survival

Immunohistochemical panel for the diagnosis of Hirschsprung's disease using antibodies to MAP2, calretinin, GLUT1 and S100 - Bachmann, Leonhard; Besendörfer, Manuel; Carbon, Roman; Lux, Philipp; Agaimy, Abbas; Hartmann, Arndt; Rau, Tilman (Histopathology, 2015)
The diagnosis of Hirschsprung's disease is currently based on the identification of aganglionosis and the presence of an increase in acetylcholinesterase-positive hypertrophic nerve fibres in the large bowel submucosa. However, acetylcholinesterase staining is laborious and requires a skilled technician. The aim of this study was to identify a method for diagnosing Hirschsprung's disease reliably using an immunohistochemical panel of recently proposed markers.Sixty-nine specimens from 37 patients were evaluated. MAP2 and calretinin antibodies were shown to stain ganglia reliably in the submucosal and myenteric plexuses of normal tissue. By contrast, reduced staining of ganglia was observed in patients with Hirschsprung's disease. Staining for GLUT1 and S100 was used to evaluate the number and thickness of nerve fibres. Gain of GLUT1 and S100 expression was in contrast to the loss of calretinin and MAP2. Hypertrophic submucosal nerve fibres in Hirschsprung's disease develop a perineurium with a ring-like GLUT1 staining pattern similar in size and intensity to that observed in deeper subserosal tissue.The diagnosis of Hirschsprung's disease using immunohistochemical panels could be as accurate as with conventional frozen section techniques. In particular, the use of a combination of markers for ganglia and hypertrophic nerve fibres highlighting a prominent perineurium in Hirschsprung's disease could be an alternative method.
EVALuna2:6718

Immunohistochemical TP53 expression in atypical fibroxanthoma and their mimics - Erber, Ramona; Hartmann, Arndt; Agaimy, Abbas (VIRCHOWS ARCHIV, 2019)
CRIS-Team WoS Importer:2019-09-27