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

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

Combination of CK20 and Ki-67 Immunostaining Analysis Predicts Recurrence, Progression, and Cancer-Specific Survival in pT1 Urothelial Bladder Cancer - Bertz, Simone; Otto, Wolfgang; Denzinger, Stefan; Wieland, Wolf F.; Burger, Maximilian; Stoehr, Robert; Link, Stefan; Hofstaedter, Ferdinand; Hartmann, Arndt (European Urology, 2014)
The prognostic value of CK20, Ki-67, and p53 has been investigated for non-muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers.To evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers.Data from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected.Adjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4-8 wk. A total of 76 patients underwent cystectomy.We conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS).At a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44-24.15; p=0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45-5.43, p=0.002). Ki-67 (HR: 3.83; 95% CI, 1.59-9.26; p=0.003), and CK20 (HR: 8.44; 95% CI,1.16-61.34; p=0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p=0.026), PFS (p=0.003), and CSS (p<0.001) in tumours with a high proliferation index and abnormal CK20 expression. A retrospective study design was the major limitation of this study.Our present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas.
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Combination of GP88 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Is an Independent Prognostic Factor for Bladder Cancer Patients - Eckstein, Markus; Lieb, Verena; Jung, Rudolf; Sikic, Danijel; Weigelt, Katrin; Stöhr, Robert; Geppert, Carol-Immanuel; Weyerer, Veronika; Bertz, Simone; Serrero, Ginette; Yue, Binbin; Hartmann, Arndt; et al. (Cells, 2021)
Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox's regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.
CRIS-Team WoS Importer:2021-08-06

Combination of growth pattern and tumor regression identifies a high-risk group in neoadjuvant treated rectal cancer patients - Jeßberger, Jonas; Erlenbach-Wuensch, Katharina; Posselt, Rebecca; Haderlein, Marlen; Agaimy, Abbas; Fietkau, Rainer; Hartmann, Arndt; Distel, Luitpold (Journal of Digestive Diseases, 2017)
To analyze the prognostic effect of E-cadherin expression, the growth pattern of the tumor and the regression grade in a rectal cancer cohort treated with neoadjuvant radiochemotherapy (RCT).A total of 223 patients with rectal cancer treated with neoadjuvant RCT followed by surgery were included. Altogether 88 biopsies prior to RCT and 213 tumor resections in an average of 55 days post-RCT were investigated. Protein expression of E-cadherin and tumor growth pattern (solid glandular vs single-cell pattern) was assessed by staining tissue microarrays. The regression grade at the invasion front was determined according to the Dworak scale.There was a significant decrease of E-cadherin expression (P = 0.002) and a significant increased single-cell growth (P < 0.001) at the invasion front in tumor samples after RCT compared with primary biopsies of the tumor. A low E-cadherin expression in the biopsy was related to a longer metastasis-free survival (P = 0.033) and tumor-specific survival (P = 0.030). Post-RCT single-cell growth at the tumor invasion front was a prognostic factor for longer tumor-specific survival (P = 0.021). A combination of growth pattern and the Dworak regression grade was an independent prognostic parameter for tumor-specific survival (P = 0.015).Loss of E-cadherin protein expression in the pretreatment biopsy of rectal cancer is associated with fewer metastases and improved survival. Furthermore, the growth pattern in the post-RCT resection specimen has a prognostic value for survival. A combination of growth pattern and tumor regression score (the RegPat score) showed the highest discriminatory power to identify high-risk patients.
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Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor - Haller, Florian; Zhang, Jitao David; Moskalev, Evgeny; Braun, Alexander; Otto, Claudia; Geddert, Helene; Riazalhosseini, Yasser; Ward, Aoife; Balwierz, Aleksandra; Schaefer, Inga-Marie; Cameron, Silke; Ghadimi, B. Michael; et al. (International Journal of Cancer, 2015)
Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category.
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Combined miR-486 and GP88 (Progranulin) Serum Levels Are Suggested as Supportive Biomarkers for Therapy Decision in Elderly Prostate Cancer Patients - Fichte, Alexander; Neumann, Anna-Dorothea; Weigelt, Katrin; Guzman, Juan; Jansen, Thilo; Keinert, Julia; Serrero, Ginette; Yue, Binbin; Stöhr, Robert; Greither, Thomas; Hartmann, Arndt; Wullich, Bernd; et al. (Life, 2022)
Our study aimed to assess the applicability of miR-486 in combination with soluble GP88 protein as a diagnostic and/or predictive biomarker for prostate cancer (PCa) patients. miR-486 and GP88 levels in serum samples from 136 patients undergoing MRI-guided biopsy of the prostate were assessed by qRT–PCR and ELISA, respectively. Of these, 86 patients received a histologically confirmed diagnosis of PCa. Neither marker showed an association with the diagnosis of cancer. PCa patients were separated based on (i) treatment into patients with active surveillance or patients with any type of curative treatment and (ii) age into elderly (>68 years) patients and younger patients (≤68 years). In elderly patients (N = 41) with the intention of curative treatment at optimized cut-off values, significantly higher GP88 levels (p = 0.018) and lower miR-486 levels (p = 0.014) were observed. The total PSA level and ISUP biopsy grade were used in a baseline model for predicting definitive therapy. The baseline model exhibited an area under the curve (AUC) of 0.783 (p = 0.005). The addition of the serum biomarkers miR-486 and GP88 to the baseline model yielded an improved model with an AUC of 0.808 (p = 0.002). Altogether, combined miR-486 and GP88 serum levels are associated with and are therefore suggested as supportive biomarkers for therapy decisions, particularly in elderly PCa patients.
CRIS-Team Scopus Importer:2022-06-03
Keywords: age; miRNAs; predictive biomarker; progranulin; prostate cancer; serum level

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

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

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

Comparative genomic hybridization shows complex genomic changes of plasmacytoid urothelial carcinoma - Keck, Bastian; Elhnann, Christina; Stoehr, Robert; Weigelt, Katrin; Goebell, Peter; Kunath, Frank; Taubert, Helge; Hartmann, Arndt; Wullich, Bernd; Wach, Sven (Urologic Oncology-Seminars and Original Investigations, 2014)
To describe genomic imbalances in plasmacytoid urothelial carcinoma (PUC), which is a rare and aggressive variant of urothelial carcinoma (UC).In total, 25 formalin-fixed paraffin-embedded PUCs were analyzed by metaphase comparative genomic hybridization. Genomic imbalances were considered to be characteristic if they were detected in >= 20% of the cases. Chromosome regions deviating by >= 3 standard deviations from the average chromosome profile were scored as chromosomal gains or losses. Copy-number variations (CNVs) of CDH1 (16q 22.1), SNAI1 (20q 13.1), CCND1 (11q13.3), ERBB2 (17q12), and FOXO3 (6q21) were validated using quantitative polymerase chain reaction.Chromosomal aberrations were detected in every PUC analyzed, and the average number of aberrations was 10.24 (ranging from 1-15). Characteristic aberrations were gains on 1q (48%), 3p (20%), 6p (32%), 11q (72%), 15q (36%), 16q (44%), 17p (76%), 17q (88%), and 20q (88%) and losses on 2q (24%) 4p (36%), 4q (84%), 5q (44%), 6q (68%), 13q (20%), and Xq (52%). polymerase chain reaction-based analysis of CNV for CCND1 (11q13) showed a deletion in 73% of the cases. CDH1 (16q22) was deleted in 72% and amplified in 5%. ERBB2 (17q12) displayed remarkably few copy-number alterations, with only 14% showing an amplification. SNAI1 (20q13) showed reduced gene copy numbers in 59.1% of the cases, whereas no copy-number gains were detected. FOXO3 (6q21) exhibited the lowest number of copy-number alterations, with 9% of all cases showing an amplification.In PUCs, the frequency of aneuploidy and the complexity of genomic changes per tumor are greater than those described in conventional UC. The aberrations described in PUC involve the same regions that are associated with aggressive biological behavior in conventional UC. Gains on 11q, 17q, 17p, and 20q and losses on 4q and 6q affect most PUCs and seem to harbor important chromosomal regions for PUC carcinogenesis. Large-scale deletions on chromosome 9 were not detected. CNV analysis indicates heterozygous deletion of CDH1 as one underlying mechanism of loss of membranous E-cadherin in PUC. Loss of CCND1 and SNAI1 is a common molecular feature and could contribute to the aggressive biological behavior of PUC.
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Comparative genomic profiling of glandular bladder tumours - Maurer, Angela; Ortiz-Bruechle, Nadina; Guricova, Karolina; Rose, Michael; Morsch, Ronja; Garczyk, Stefan; Stöhr, Robert; Bertz, Simone; Golz, Reinhard; Reis, Henning; Bremmer, Felix; Zimpfer, Annette; et al. (Virchows Archiv, 2020)
Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.
CRIS-Team WoS Importer:2020-04-07

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing - Hart, Martin; Nolte, Elke; Wach, Sven; Szczyrba, Jaroslaw; Taubert, Helge; Rau, Tilman; Hartmann, Arndt; Graesser, Friedrich A.; Wullich, Bernd (Molecular Cancer Research, 2014)
MicroRNAs (miRNA) posttranscriptionally regulate gene expression and are important in tumorigenesis. Previous deep sequencing identified the miRNA profile of prostate carcinoma versus nonmalignant prostate tissue. Here, we generated miRNA expression profiles of prostate carcinoma by deep sequencing, with increasing tumor stage relative to corresponding nonmalignant and healthy prostate tissue, and detected clearly changed miRNA expression patterns. The miRNA profiles of the healthy and nonmalignant tissues were consistent with our previous findings, indicating a high fidelity of the method employed. In the tumors, quantitative real-time PCR (qRT-PCR) analysis of 40 paired samples of prostate carcinoma versus normal tissue revealed significant upregulation of miR-20a, miR-148a, miR-200b, and miR-375 and downregulation of miR-143 and miR-145. Hereby, miR-375 increased from normal to organ-confined tumors (pT2 pN0), slightly decreased in tumors with extracapsular growth (pT3 pN0), but was then expressed again at higher levels in lymph node metastasizing (pN1) tumors. The sequencing data for miR-375 were confirmed by Northern blotting and qRT-PCR. The regulation for other selected miRNAs could, however, not be confirmed by qRT-PCR in individual tumor stages. MiR-200b, in addition to miR-200c and miR-375 reduced the expression of SEC23A. Interestingly, miR-375, found by sequencing in pT2 upregulated by us and others in tumor versus normal tissue, and miR-15a, found by sequencing in pT2 and pT3 and in the metastasizing tumors, target the phosphatases PHLPP1 and PHLPP2, respectively. PHLPP1 and PHLPP2 dephosphorylate members of the AKT family of signal transducers, thereby inhibiting cell growth. Coexpression of miR-15a and miR-375 resulted in downregulation of PHLPP1/2 and strongly increased prostate carcinoma cell growth. Implications: These genomic data reveal relevant miRNAs in prostate cancer that may have biomarker and therapeutic potential. Mol Cancer Res; 12(2); 250-63. ©2013 AACR.
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Comparison of Intrinsic PAM50 Gene Expression Analysis and Immunohistochemical Subtypes of Salivary Duct Carcinoma - Erber, Ramona; Stoehr, Robert; Haller, Florian; Haderlein, Marlen; Hartmann, Arndt; Agaimy, Abbas (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Comparison of PD-L1 mRNA Expression Measured with the CheckPoint Typer® Assay with PD-L1 Protein Expression Assessed with Immunohistochemistry in Non-small Cell Lung Cancer - Erber, Ramona; Stoehr, Robert; Herlein, Stefanie; Giedl, Claudia; Rieker, Ralf; Fuchs, Florian; Ficker, Joachim H.; Hartmann, Arndt; Veltrup, Elke; Wirtz, Ralph M.; Brueckl, Wolfgang M. (Anticancer Research, 2017)
Immunohistochemical (IHC) assessment of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has become important since the development of anti-PD-1/-PD-L1 directed drugs. Various PD-L1 antibodies and cut-offs have been used in different trials to predict response to these drugs, thus comparison of those studies is difficult. We compared PD-L1 mRNA expression measured by RT-qPCR with PD-L1 protein expression evaluated by IHC. Moreover, we investigated the impact of different tumour tissue acquisition methods on the reliability of PD-L1 measurement techniques.NSCLC cases (N=22), including n=9 mediastinal lymph node biopsies acquired by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and n=5 metastases, were evaluated prospectively for PD-L1 protein on tumor cells (TC) and immune cells (IC) using E1L3N and 28-8 antibodies and PD-L1 mRNA using the CheckPoint TYPER® assay.In primary NSCLC tissues, agreement between PD-L1 mRNA and TC staining using the 28-8 antibody was excellent (?=0.85, p=0.0002). Comparing both PD-L1 antibodies against each other showed a kappa value of 0.58 (p=0.0106). In EBUS-TBNA, PD-L1 mRNA correlated perfectly with the 28-8 antibody (?=1.0, p=0.0023). PD-L1 mRNA levels significantly differed when comparing 28-8 TC staining of tumours >49% with 1-49% and 0% (p=0.0040; p=0.0081, respectively). In metastatic lesions, differences between PD-L1 mRNA and IHC became apparent (?=0.2, p=0.2525).Testing of PD-L1 mRNA and 28-8 IHC showed an excellent agreement in NSCLC samples including mediastinal lymph node biopsies. Since PD-L1 expression in >50% TC detected by 28-8 IHC can be reliably detected by RT-qPCR, quantitative PD-L1 mRNA determination should be considered as an alternative to IHC as there is no interobserver variability in RNA results.
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Comparison of PD-L1 mRNA expression measured with the CheckPointTyper(R) assay with PD-L1 protein expression assessed with immunohistochemistry (IHC) in lung cancer (NSCLC) - Erber, Ramona; Stoehr, R.; Herlein, S.; Fuchs, F.; Veltrup, Elke; Wirtz, Ralph; Hartmann, Arndt (2017)
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Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial - Gluz, O.; Liedtke, C.; Huober, J.; Peyro-Saint-Paul, H.; Kates, R. E.; Kreipe, H. H.; Hartmann, Arndt; Pelz, E.; Erber, Ramona; Mohrmann, S.; Moebus, V.; Augustin, D.; et al. (Annals of Oncology, 2016)
Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC).In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459).Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 >=20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients.In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone.The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.
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Comparison of the prognostic value of lymph node yield, lymph node ratio, and number of lymph node metastases in patients with oral squamous cell carcinoma - Struckmeier, Ann-Kristin; Buchbender, Mayte; Lutz, Rainer; Agaimy, Abbas; Kesting, Marco Rainer (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2024)
Background: The aim of this study was to assess the prognostic significance of lymph node yield (LNY), lymph node ratio (LNR), and the number of lymph node metastases (LNMs) in patients affected by oral squamous cell carcinoma (OSCC). Methods: The study included patients who underwent surgical treatment for primary OSCC. Receiver operating characteristic curves were generated to determine the optimal threshold values. Kaplan–Meier curves were employed, along with the log-rank test, for the analysis of survival. To compare the performance in terms of model fit, we computed Akaike's information criterion (AIC). Results: This study enrolled 429 patients. Prognostic thresholds were determined at 22 for LNY, 6.6% for LNR, and 3 for the number of LNMs. The log-rank test revealed a significant improvement in both overall survival and progression-free survival for patients with a LNR of ≤6.6% or a number of LNMs of ≤3 (p < 0.05). Interestingly, LNY did not demonstrate prognostic significance. The AIC analyses indicated that the number of LNMs is a superior prognostic indicator compared to LNY and LNR. Conclusions: Incorporating LNR or the number of LNMs into the TNM classification has the potential to improve the prognostic value, as in other types of cancers. Particularly, the inclusion of the number of LNMs should be contemplated for future N staging.
CRIS-Team Scopus Importer:2024-05-13
Keywords: lymph node; lymph node ratio; lymph node yield; metastasis; neck dissection; oral squamous cell carcinoma

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

Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces - Chen, Qian; Manzke, Melanie; Hartmann, Andrea; Büttner, Maike; Amann, Kerstin Ute; Pauly, Diana; Wiesener, Michael; Skerka, Christine; Zipfel, Peter F. (Journal of the American Society of Nephrology, 2016)
C3 glomerulopathy (C3G) is a severe kidney disease for which no specific therapy exists. The causes of C3G are heterogeneous, and defective complement regulation is often linked to C3G pathogenesis. Copy number variations in the complement factor H-related (CFHR) gene cluster on chromosome 1q32 and CFHR5 mutant proteins associate with this disease. Here, we identified CFHR5 as a pattern recognition protein that binds to damaged human endothelial cell surfaces and to properdin, the human complement activator. We found the two N-terminal short consensus repeat domains of CFHR5 contact properdin and mediate dimer formation. These properdin-binding segments are duplicated in two mutant CFHR5 proteins, CFHR2-CFHR5Hyb from German patients with C3G and CFHR5Dup from Cypriot patients with C3G. Each of these mutated proteins assembled into large multimeric complexes and, compared to CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local complement activation. This enhanced surface binding and properdin recruitment was further evidenced in the mesangia of a transplanted and explanted kidney from a German patient with a CFHR2-CFHR5Hyb protein. Enhanced properdin staining correlated with local complement activation with C3b and C5b-9 deposition on the mesangial cell surface in vitro This gain of function in complement activation for two disease-associated CFHR5 mutants describes a new disease mechanism of C3G, which is relevant for defining appropriate treatment options for this disorder.
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Complement factor H-related hybrid protein deregulates complement in dense deposit disease - Chen, Qian; Wiesener, Michael; Eberhardt, Hannes U.; Hartmann, Andrea; Uzonyi, Barbara; Kirschfink, Michael; Amann, Kerstin Ute; Büttner, Maike; Goodship, Tim; Hugo, Christian; Skerka, Christine; Zipfel, Peter F. (Journal of Clinical Investigation, 2014)
The renal disorder C3 glomerulopathy with dense deposit disease (C3G-DDD) pattern results from complement dysfunction and primarily affects children and young adults. There is no effective treatment, and patients often progress to end-stage renal failure. A small fraction of C3G-DDD cases linked to factor H or C3 gene mutations as well as autoantibodies have been reported. Here, we examined an index family with 2 patients with C3G-DDD and identified a chromosomal deletion in the complement factor H-related (CFHR) gene cluster. This deletion resulted in expression of a hybrid CFHR2-CFHR5 plasma protein. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H-mediated convertase decay. One patient was refractory to plasma replacement and exchange therapy, as evidenced by the hybrid protein quickly returning to pretreatment plasma levels. Subsequently, complement inhibitors were tested on serum from the patient for their ability to block activity of CFHR2-CFHR5. Soluble CR1 restored defective C3 convertase regulation; however, neither eculizumab nor tagged compstatin had any effect. Our findings provide insight into the importance of CFHR proteins for C3 convertase regulation and identify a genetic variation in the CFHR gene cluster that promotes C3G-DDD. Monitoring copy number and sequence variations in the CFHR gene cluster in C3G-DDD and kidney patients with C3G-DDD variations will help guide treatment strategies.
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Comprehensive genomic characterization of early-stage bladder cancer - Prip, Frederik; Lamy, Philippe; Lindskrog, Sia Viborg; Strandgaard, Trine; Nordentoft, Iver; Birkenkamp-Demtröder, Karin; Birkbak, Nicolai Juul; Kristjánsdóttir, Nanna; Kjær, Asbjørn; Andreasen, Tine G.; Ahrenfeldt, Johanne; Pedersen, Jakob Skou; et al. (Nature Genetics, 2025)
Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification.
CRIS-Team Scopus Importer:2025-01-31

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

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

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

Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations - Kraus, Cornelia; Rau, Tilman; Lux, Philipp; Erlenbach-Wuensch, Katharina; Loehr, Sabine; Krumbiegel, Mandy; Thiel, Christian; Stoehr, Robert; Agaimy, Abbas; Croner, Roland S.; Stürzl, Michael; Hohenberger, Werner; et al. (International Journal of Cancer, 2015)
Germline mutation testing in patients with colorectal cancer (CRC) is offered only to a subset of patients with a clinical presentation or tumor histology suggestive of familial CRC syndromes, probably underestimating familial CRC predisposition. The aim of our study was to determine whether unbiased screening of newly diagnosed CRC cases with next generation sequencing (NGS) increases the overall detection rate of germline mutations. We analyzed 152 consecutive CRC patients for germline mutations in 18 CRC-associated genes using NGS. All patients were also evaluated for Bethesda criteria and all tumors were investigated for microsatellite instability, immunohistochemistry for mismatch repair proteins and the BRAF*V600E somatic mutation. NGS based sequencing identified 27 variants in 9 genes in 23 out of 152 patients studied (18%). Three of them were already reported as pathogenic and 12 were class 3 germline variants with an uncertain prediction of pathogenicity. Only 1 of these patients fulfilled Bethesda criteria and had a microsatellite instable tumor and an MLH1 germline mutation. The others would have been missed with current approaches: 2 with a MSH6 premature termination mutation and 12 uncertain, potentially pathogenic class 3 variants in APC, MLH1, MSH2, MSH6, MSH3 and MLH3. The higher NGS mutation detection rate compared with current testing strategies based on clinicopathological criteria is probably due to the large genetic heterogeneity and overlapping clinical presentation of the various CRC syndromes. It can also identify apparently nonpenetrant germline mutations complicating the clinical management of the patients and their families.
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Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma - Hedegaard, Jakob; Lamy, Philippe; Nordentoft, Iver; Algaba, Ferran; Hoyer, Soren; Ulhoi, Benedicte Parm; Vang, Soren; Reinert, Thomas; Hermann, Gregers G.; Mogensen, Karin; Thomsen, Mathilde Borg Houlberg; Nielsen, Morten Muhlig; et al. (Cancer Cell, 2016)
Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
EVALuna2:6801

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

Concealed complete response in melanoma patients under therapy with immune checkpoint inhibitors: two case reports - Schliep, Stefan; Agaimy, Abbas; Kiesewetter, Franklin; Schuler, Gerold; Heinzerling, Lucie; Cavallaro, Alexander Josef (Journal for ImmunoTherapy of Cancer, 2018)
BACKGROUND: The assessment of tumor size by RECIST using CT scans and MRIs is considered to be standard of care for staging cancer patients. Despite radiologic evidence of widespread disease, we document for the first time that patients were completely free of viable tumor. CASE PRESENTATION: Two patients with metastatic melanoma were treated with immune checkpoint inhibitors (ipilimumab/ nivolumab) and progressive metastases were detected on CT-scans performed shortly before histologic examinations. In both patients histologic assessment revealed a complete response with necrotic and scarred lesions free of tumor. One of the patients had started immunotherapy 20 months before with an initial partial response. CONCLUSIONS: This phenomenon of a concealed complete response can lead to overtreatment or unnecessary change in treatment. Thus, it is essential to raise awareness for it. Correct identification of responders to immune checkpoint inhibitor therapy is crucial to spare patients immune-mediated side effects and unnecessary as well as expensive treatment. Regression of metastases without decline in size, in these cases manifesting as complete responses, are probably more common than expected and identified to date. Until such responses can be readily identified by new imaging techniques, we recommend liberal biopsies for histologic assessment of progressive metastases in patients during and/or after immune checkpoint inhibitor therapy.
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Concordance Rate of Colposcopy in Detecting Cervical Intraepithelial Lesions - Stübs, Frederik; Dietl, Anna; Behrens, Annika; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Mehlhorn, Grit; Schulmeyer, Carla; Gaß, Paul; Koch, Martin C. (Diagnostics, 2022)
Background: The purpose of this research is to estimate the rate of concordance, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of colposcopy for high-grade squamous lesions and carcinomas (HSIL+). Methods: We conducted a retrospective study of colposcopies performed in the certified Dysplasia Unit in Erlangen between January 2015 and May 2022 (7.5 years). The colposcopic findings were correlated with biopsies obtained during examinations or surgery. Cases without histology were excluded. The primary outcome was the rate of concordance between the colposcopic and histological findings in relation to the type of transformation zone (TZ), examiner's level of experience and age of the patients. Results: A total of 4778 colposcopies in 4001 women were analyzed. The rates of concordance for CIN I/LSIL, CIN II/HSIL, CIN III/HSIL, and carcinoma were 43.4%, 59.5%, 78.5%, and 53.9%, respectively. The rate of concordance was lowest for TZ3 and highest for colposcopists with more than 10 years' experience. Conclusions: Colposcopy is an important, feasible, and effective method. Careful work-up needs to be performed for women with TZ3 who are over 35 years old, as they are at the highest risk of being misdiagnosed. The highest concordance for detecting HSIL+ was seen for colposcopists with >10 years' experience.
CRIS-Team WoS Importer:2022-11-11

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

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

Construction and analysis of tissue microarrays in the era of digital pathology: a pilot study targeting CDX1 and CDX2 in a colon cancer cohort of 612 patients - Nolte, Sarah; Zlobec, Inti; Lugli, Alessandro; Hohenberger, Werner; Croner, Roland; Merkel, Susanne; Hartmann, Arndt; Geppert, Carol-Immanuel; Rau, Tilman (Journal of Pathology: Clinical Research, 2017)
CDX1 and CDX2 are possibly predictive biomarkers in colorectal cancer. We combined digitally-guided (next generation) TMA construction (ngTMA) and the utility of digital image analysis (DIA) to assess accuracy, tumour heterogeneity and the selective impact of different combined intensity-percentage levels on prognosis.CDX1 and CDX2 immunohistochemistry was performed on ngTMAs covering normal tissue, tumour centre and invasive front. The percentages of all epithelial cells per staining intensity per core were analysed digitally. Beyond classical prognosis analysis following REMARK guidelines, we investigated pre-analytical conditions, three different types of heterogeneity (mosaic-like, targeted and haphazard) and influences on cohort segregation and patient selection. The ngTMA-DIA approach produced robust biomarker data with infrequent core loss and excellent on-target punching. The detailed assessment of tumour heterogeneity could - except for a certain diffuse mosaic-like heterogeneity - exclude differences between the invasive front and tumour centre, as well as detect haphazard clonal heterogeneous elements. Moreover, lower CDX1 and CDX2 counts correlated with mucinous histology, higher TNM stage, higher tumour grade and worse survival (p < 0.01, all). Different protein expression intensity levels shared comparable prognostic power and a great overlap in patient selection. The combination of ngTMA with DIA enhances accuracy and controls for biomarker analysis. Beyond the confirmation of CDX1 and CDX2 as prognostically relevant markers in CRC, this study highlights the greater robustness of CDX2 in comparison to CDX1. For the assessment of CDX2 protein loss, cut-points as percentage data of complete protein loss can be deduced as a recommendation.
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Contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression - Hartmann, Philipp; Trufa, Denis; Hohenberger, Katja; Tausche, Patrick; Trump, Sonja; Mittler, Susanne; Geppert, Carol-Immanuel; Rieker, Ralf; Schieweck, Oliver; Sirbu, Horia; Hartmann, Arndt; Neurath-Finotto, Susetta (Scientific Reports, 2023)
Neoplasms of the lungs are the leading cause of cancer incidence and mortality worldwide. Although immunotherapy has increased the overall survival of patients with lung cancer, there is the need to improve this treatment. At this regard, blood lipid levels are thought to be linked to cancer risk and thus a preventive intervention through regulation of the nutrition of patients with lung cancer is gaining much attention. In this study, we therefore asked about the contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression. We measured different serum lipids and analyzed cholesterol synthesis enzymes 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and acetyl-coenzyme A cholesterol acetyltransferase 1 (ACAT1) as well as the cholesterol cellular export protein ATP-binding cassette (ABC) A-1 mRNA by quantitative PCR (qPCR) in the control and tumoral regions of post-surgery lung tissues to analyze the accumulation of cholesterol in cancer cells in a cohort of patients with lung adenocarcinoma (LUAD). We found that triglycerides in serum directly correlated with the body mass index (BMI) in patients with LUAD. By contrast, we found that high-density lipoprotein (HDL) cholesterol inversely correlated with the BMI, C-reactive protein (CRP) and overall survival and total cholesterol inversely correlated with the tumor diameter, serum CRP and overall survival in these LUAD patients. Functionally, the role of cholesterol is indispensable for the growth and development of normal animal cells where it is tightly regulated. Excess of cellular cholesterol regulated by HMGCR is converted to cholesteryl esters by the enzyme ACAT1 and exported extracellularly by the cholesterol transporter ABCA1. Here we found HMGCR and ACAT1 upregulated and ABCA1 downregulated in the lung's tumoral region of our LUAD cohort, indicating cholesterol dysregulated cellular export in lung tumor cells.
CRIS-Team Scopus Importer:2023-04-21

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

Correction to: Anatomical locations in the oral cavity where surgical resections of oral squamous cell carcinomas are associated with a close or positive margin—a retrospective study (Clinical Oral Investigations, (2018), 22, 4, (1625-1630), 10.1007/s00784-018-2424-z) - Kerker, Florian; Adler, Werner; Brunner, Kathrin; Möst, Tobias; Wurm, Matthias; Nkenke, Emeka; Neukam, Friedrich Wilhelm; von Wilmowsky, Cornelius (Clinical Oral Investigations, 2019)
The following note was inadvertently omitted from the published paper: This work was performed in (partial) fulfillment of the requirements for the first author’s obtaining the degree Dr. med. dent.
CRIS-Team Scopus Importer:2019-05-02

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

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

Correction to: EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers (Modern Pathology, (2021), 34, 4, (770-785), 10.1038/s41379-020-00684-8) - Michal, Michael; Rubin, Brian P.; Agaimy, Abbas; Kosemehmetoglu, Kemal; Rudzinski, Erin R.; Linos, Konstantinos; John, Ivy; Gatalica, Zoran; Davis, Jessica L.; Liu, Yajuan J.; McKenney, Jesse K.; Billings, Steven D.; et al. (Modern Pathology, 2021)
The original version of this article unfortunately contained a mistake in an author name. Zarifa Yusifli was stated as Zerife Yusufli. We apologize for the mistake. The original article has been corrected.
CRIS-Team Scopus Importer:2021-06-18

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

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

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

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

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

Correlation of Hif1a expression of primary oral squamous cell carcinomas with histomorphologic parameters and macrophage polarization - Wehrhan, Falk; Möbius, Patrick; Amann, Kerstin Ute; Geppert, Carol-Immanuel; Preidl, Raimund; Ries, Jutta; Neukam, Friedrich Wilhelm; Weber, Manuel (2018)
EVALuna2:34066

Correlation of histological and macroscopic findings in peritoneal endometriosis - Strehl, Johanna; Hackl, Janina; Wachter, David; Klingsiek, Peter; Burghaus, Stefanie; Renner, Stefan; Fasching, Peter; Hartmann, Arndt; Beckmann, Matthias (International Journal of Clinical and Experimental Pathology, 2014)
In the last two decades, a color based concept of disease activity in peritoneal endometriosis has been in use in the clinical context, with red lesions being considered active and black or white lesions being interpreted as less active or dormant.Our aim was to analyze 4 main color categories of peritoneal endometriosis (black, white, red and brown) in one single patient group using histomorphological and immunohistochemical methods.65 endometriosis lesions (30 black, 17 white, 11 brown, 7 red) were resected from 47 premenopausal, nulliparous women which had not received exogenous hormones for at least six months prior to the operation. Specimen workup, histomorphological analysis and immunohistochemical analysis were performed in a standardized manner.The color categories showed a broad overlap in proliferative activity and hormone receptor expression. Differences were found in lesion morphology. Adjacent stromal reaction in particular showed a marked increase from red through brown and black to white lesions. Differences were also seen in gland pattern and gland content.Lesion colors in peritoneal endometriosis seem to be determined by gland content and a varying adjacent stromal reaction and more likely reflect an aging process than different levels of disease activity.
EVALuna2:6566

Correlation of RANK and RANKL with mammographic density in primary breast cancer patients - Wunderle, Marius; Heindl, Felix; Behrens, Annika; Häberle, Lothar; Hack, Carolin; Heusinger, Katharina; Hübner, Hanna; Gaß, Paul; Rübner, Matthias; Schulz-Wendtland, Rüdiger; Erber, Ramona; Hartmann, Arndt; et al. (Archives of Gynecology and Obstetrics, 2024)
Purpose: The receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) have been shown to promote proliferation of the breast and breast carcinogenesis. The objective of this analysis was to investigate whether tumor-specific RANK and RANKL expression in patients with primary breast cancer is associated with high percentage mammographic density (PMD), which is a known breast cancer risk factor. Methods: Immunohistochemical staining of RANK and RANKL was performed in tissue microarrays (TMAs) from primary breast cancer samples of the Bavarian Breast Cancer Cases and Controls (BBCC) study. For RANK and RANKL expression, histochemical scores (H scores) with a cut-off value of > 0 vs 0 were established. PMD was measured in the contralateral, non-diseased breast. Linear regression models with PMD as outcome were calculated using common predictors of PMD (age at breast cancer diagnosis, body mass index (BMI) and parity) and RANK and RANKL H scores. Additionally, Spearman rank correlations (ρ) between PMD and RANK and RANKL H score were performed. Results: In the final cohort of 412 patients, breast cancer-specific RANK and RANKL expression was not associated with PMD (P = 0.68). There was no correlation between PMD and RANK H score (Spearman’s ρ = 0.01, P = 0.87) or RANKL H score (Spearman’s ρ = 0.04, P = 0.41). RANK expression was highest in triple-negative tumors, followed by HER2-positive, luminal B-like and luminal A-like tumors, while no subtype-specific expression of RANKL was found. Conclusion: Results do not provide evidence for an association of RANK and RANKL expression in primary breast cancer with PMD.
CRIS-Team Scopus Importer:2024-06-14
Keywords: Breast cancer; Immunohistochemistry; Mammographic density; RANK expression; RANKL expression

Corrigendum: Complement activation via the lectin and alternative pathway in patients with severe COVID-19(Front. Immunol., (2022), 13, (835156), 10.3389/fimmu.2022.835156) - Niederreiter, Janina; Eck, Christine; Ries, Tajana; Hartmann, Arndt; Märkl, Bruno; Büttner-Herold, Maike; Amann, Kerstin Ute; Daniel, Christoph (Frontiers in Immunology, 2023)
In the published article, information in the Acknowledgments was mistakenly not included in the publication. A correction has been made to Acknowledgments:
CRIS-Team Scopus Importer:2023-10-20
Keywords: autopsy; complement deposition; COVID-19; kidney; lectin pathway; lung

Corrigendum to "Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes" [European Urology Oncology (2023)]. - Eckstein, Markus; Matek, Christian; Wagner, Paul; Erber, Ramona; Büttner-Herold, Maike; Wild, Peter J.; Taubert, Helge; Wach, Sven; Sikic, Danijel; Wullich, Bernd; Geppert, Carol-Immanuel; Compérat, Eva M.; et al. (European Urology Oncology, 2023)
EVALuna2:542094

Co-staining of microRNAs and their target proteins by miRNA in situ hybridization and immunohistofluorescence on prostate cancer tissue microarrays - Eckstein, Markus; Sailer, Verena; Nielsen, Boye Schnack; Wittenberg, Thomas; Wiesmann, Veit; Lieb, Verena; Nolte, Elke; Hartmann, Arndt; Kristiansen, Glen; Wernert, Nicolas; Wullich, Bernd; Taubert, Helge; et al. (Laboratory Investigation, 2019)
The co-expression of miRNAs and their target proteins was studied on tissue microarrays from different prostate cancer (PCa) patients. PCa of primary Gleason pattern 4 (GP4), lymph node metastases of GP4, distant metastases, and normal tissue from the transitional and peripheral zones were co-stained by fluorescent miRNA in situ hybridization (miRisH) and protein immunohistofluorescence (IHF). The miRNAs and corresponding target proteins include the pairs miR-145/ERG, miR-143/uPAR, and miR-375/SEC23A. The fluorescence-stained and scanned tissue microarrays (TMAs) were evaluated by experienced uropathologists. The pair miR-145/ERG showed an exclusive staining for miR-145 in the nuclei of stromal cells, both in tumor and normal tissue, and for ERG in the cytoplasm with/without co-expression in the nucleus of tumor cells. The pair miR-143/uPAR revealed a clear distinction between miR-143 in the nuclei of stromal cells and uPAR staining in the cytoplasm of tumor cells. Metastases (lymph node and distant) however, showed tumor cells with cytoplasmic staining for miR-143/uPAR. In normal tissues, beside the nuclei of the stroma cells, gland cells could also express miR-143 and uPAR in the cytoplasm. miR-375 showed particular staining in the nucleoli of GP4 and metastatic samples, suggesting that nucleoli play a special role in sequestering proteins and miRNAs. Combined miRisH/IHF allows for the study of miRNA expression patterns and their target proteins at the single-cell level.
CRIS-Team Scopus Importer:2019-06-28

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

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

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

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

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

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

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

CXCL12 promotes glycolytic reprogramming in acute myeloid leukemia cells via the CXCR4/mTOR axis - Braun, Michael; Qorraj, M.; Büttner, Maike; Klein, F. A.; Saul, D.; Aigner, M.; Huber, W.; Mackensen, Andreas; Jitschin, R.; Mougiakakos, Dimitrios (Leukemia, 2016)
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CXCR2 expression on neutrophil granulocytes in peripheral tumor is associated with shorter survival in oral squamous cell carcinoma - Spörl, Silvia; Erber, Ramona; Gerken, M.; Wittenberg, M.; Fischer, R.; Taxis, J.; Hartmann, Arndt; Geppert, Carol-Immanuel; Mamilos, A.; Mackensen, Andreas; Reichert, T.; Spanier, G.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

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

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

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

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

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

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

DAPK and cytoskeleton-associated functions - Ivanovska, Jelena; Mahadevan, Vijayalakshmi; Schneider-Stock, Regine (Apoptosis, 2014)
Death-associated protein kinase (DAPK) undergoes activation in response to various death stimuli, and they have been associated with an increase in DAPK catalytic activity. One of the most prominent features of DAPK-induced cell death is the effect on the cytoskeleton, including loss of matrix attachment, and membrane blebbing. One known cytoskeletal-associated substrate of DAPK is the myosin-II light chain, phosphorylated by DAPK on Ser(19), thus stabilizing actin stress fibres. Moreover, paxillin, a component of focal adhesions, was found to be localized in close proximity to the tips of the DAPK-positive filaments, indicating that stress fibres containing DAPK extend to focal contacts. Forced expression of DAPK in multiple cell types results in morphological changes such as cell rounding, membrane blebbing, shrinking and detachment. During directed migration, DAPK functions as a potent inhibitor of cell polarization, as evidenced by its perturbation of the formation of static protrusion at the leading edge. Furthermore, DAPK inhibits random migration by suppressing directional persistence. One of the studies considered DAPK as an anoikis inducer. Others showed that DAP-kinase inhibits the activities of cell surface integrins by converting them into an inactive conformation. Biochemical experiments have established the DAPK binding to Syntaxin1 and its subsequent phosphorylation at Ser(188) in a Ca(2+) dependent manner. This phosphorylation event has been shown to decrease the binding of Syntaxin to MUNC18-1, a protein critically involved in synaptic vesicle docking. Here, we have investigated the structural interactions that modulate DAPK phosphorylation with Syntaxin and its functional role in binding to the MUNC18-1 to regulate vesicle docking. This review will summarize our current knowledge of the role of DAPK on cytoskeleton reorganization and report the mechanisms that regulate these changes.
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DAPK-HSF1 interaction as a positive-feedback mechanism stimulating TNF-induced apoptosis in colorectal cancer cells - Benderska, Natalya; Ivanovska, Jelena; Rau, Tilman; Schulze-Luehrmann, Jan; Mohan, Suma; Chakilam, Saritha; Gandesiri, Muktheshwar; Ziesche, Elisabeth; Fischer, Thomas; Söder, Stephan; Agaimy, Abbas; Distel, Luitpold; et al. (Journal of Cell Science, 2014)
Death-associated protein kinase (DAPK) is a serine-threonine kinase with tumor suppressor function. Previously, we demonstrated that tumor necrosis factor (TNF) induced DAPK-mediated apoptosis in colorectal cancer. However, the protein-protein interaction network associated with TNF-DAPK signaling still remains unclear. We identified HSF1 as a new DAPK phosphorylation target in response to low concentrations of TNF and verified a physical interaction between DAPK and HSF1 both in vitro and in vivo. We show that HSF1 binds to the DAPK promoter. Transient overexpression of HSF1 protein led to an increase in DAPK mRNA level and consequently to an increase in the amount of apoptosis. By contrast, treatment with a DAPK-specific inhibitor as well as DAPK knockdown abolished the phosphorylation of HSF1 at Ser230 (pHSF1(Ser230)). Furthermore, translational studies demonstrated a positive correlation between DAPK and pHSF1(Ser230) protein expression in human colorectal carcinoma tissues. Taken together, our data define a novel link between DAPK and HSF1 and highlight a positive-feedback loop in DAPK regulation under mild inflammatory stress conditions in colorectal tumors. For the first time, we show that under TNF the pro-survival HSF1 protein can be redirected to a pro-apoptotic program.
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DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells - Ivanovska, Jelena; Zlobec, Inti; Forster, Stefan; Karamitopoulou, Eva; Dawson, Heather; Koelzer, Viktor Hendrik; Agaimy, Abbas; Garreis, Fabian; Söder, Stephan; Laqua, William; Lugli, Alessandro; Hartmann, Arndt; et al. (Oncotarget, 2015)
Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation.
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Darbepoetin alpha reduces oxidative stress and chronic inflammation in atherosclerotic lesions of apo e deficient mice in experimental renal failure - Arend, Nicole; Hilgers, Karl Friedrich; Campean, Valentina; Karpe, Britta; Cordasic, Nada; Klanke, Bernd; Amann, Kerstin Ute (PLoS ONE, 2014)
Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction.Apo E knockout mice underwent unilateral (Unx, n = 20) or subtotal (Snx, n = 26) nephrectomy or sham operation (Sham, n = 16). Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta.Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters.Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment elevated serum urea. Elevation of hematocrit might be a favorable effect in anemic Snx animals but a thrombogenic risk in Sham animals.
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Das muskelinvasive und metastasierte Urothelkarzinom der Harnblase: Aktueller Stand histopathologischer, molekularer und immunologischer Prognose- und Prädiktionsfaktoren - Bertz, Simone; Bahlinger, Veronika; Lange, Fabienne; Hartmann, Arndt; Eckstein, Markus (Die Pathologie, 2024)
Background: Muscle-invasive and metastatic urothelial carcinoma (UC) represents a heterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. Aims: This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Results and discussion: Muscle-invasive and metastatic UC exhibits a wide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.
CRIS-Team Scopus Importer:2024-08-16
Keywords: B7-H1 antigen; Disease progression; Immunotherapy; Molecular pathology; Transitional cell carcinoma

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

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

Death-associated kinase (DAPK): a cancer "gene chameleon" - Schneider-Stock, Regine (Apoptosis, 2014)
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Death-associated protein kinase: A molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review) - Steinmann, Sara; Scheibe, Kristina; Erlenbach-Wuensch, Katharina; Neufert, Clemens; Schneider-Stock, Regine (International Journal of Oncology, 2015)
The cytoskeleton-associated serine/threonine kinase death-associated protein kinase (DAPK) has been described as a cancer gene chameleon with functional antagonistic duality in a cell type and context specific manner. The broad range of interaction partners and substrates link DAPK to inflammatory processes especially in the gut. Herein we summarize our knowledge on the role of DAPK in different cell types that play a role under inflammatory conditions in the gut. Besides some promising experimental data suggesting DAPK as an interesting drug target in inflammatory bowel disease there are many open questions regarding direct evidence for a role of DAPK in intestinal inflammation.
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Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases with Literature Review and Proposal of Diagnostic Criteria - Agaimy, Abbas; Stöhr, Robert; Hornung, Annkathrin; Popp, Judith; Erdmann, Michael; Heinzerling, Lucie; Hartmann, Arndt (American Journal of Surgical Pathology, 2021)
Dedifferentiated melanoma (DM) and undifferentiated melanoma (UM) is defined as a primary or metastatic melanoma showing transition between conventional and undifferentiated components (DM) or lacking histologic and immunophenotypic features of melanoma altogether (UM). The latter is impossible to verify as melanoma by conventional diagnostic tools alone. We herein describe our experience with 35 unpublished cases to expand on their morphologic, phenotypic, and genotypic spectrum, along with a review of 50 previously reported cases (total: 85) to establish the diagnostic criteria. By definition, the dedifferentiated/undifferentiated component lacked expression of 5 routinely used melanoma markers (S100, SOX10, Melan-A, HMB45, Pan-melanoma). Initial diagnoses (known in 66 cases) were undifferentiated/unclassified pleomorphic sarcoma (n=30), unclassified epithelioid malignancy (n=7), pleomorphic rhabdomyosarcoma (n=5), other specific sarcoma types (n=6), poorly differentiated carcinoma (n=2), collision tumor (n=2), atypical fibroxanthoma (n=2), and reactive osteochondromatous lesion (n=1). In only 11 cases (16.6%) was a diagnosis of melanoma considered. Three main categories were identified: The largest group (n=56) comprised patients with a history of verified previous melanoma who presented with metastatic DM or UM. Axillary or inguinal lymph nodes, soft tissue, bone, and lung were mainly affected. A melanoma-compatible mutation was detected in 35 of 48 (73%) evaluable cases: BRAF (n=20; 40.8%), and NRAS (n=15; 30.6%). The second group (n=15) had clinicopathologic features similar to group 1, but a melanoma history was lacking. Axillary lymph nodes (n=6) was the major site in this group followed by the lung, soft tissue, and multiple site involvement. For this group, NRAS mutation was much more frequent (n=9; 60%) than BRAF (n=3; 20%) and NF1 (n=1; 6.6%). The third category (n=14) comprised primary DM (12) or UM (2). A melanoma-compatible mutation was detected in only 7 cases: BRAF (n=2), NF1 (n=2), NRAS (n=2), and KIT exon 11 (n=1). This extended follow-up study highlights the high phenotypic plasticity of DM/UM and indicates significant underrecognition of this aggressive disease among general surgical pathologists. The major clues to the diagnosis of DM and UM are: (1) presence of minimal differentiated clone in DM, (2) earlier history of melanoma, (3) undifferentiated histology that does not fit any defined entity, (4) locations at sites that are unusual for undifferentiated/unclassified pleomorphic sarcoma (axilla, inguinal, neck, digestive system, etc.), (5) unusual multifocal disease typical of melanoma spread, (6) detection of a melanoma-compatible gene mutation, and (7) absence of another genuine primary (eg, anaplastic carcinoma) in other organs.
CRIS-Team Scopus Importer:2021-02-05
Keywords: BRAF; chondrosarcoma; dedifferentiated melanoma; giant cell tumor; KIT; NRAS; osteosarcoma; pleomorphic sarcoma; rhabdomyosarcoma; undifferentiated melanoma

Dedifferentiated liposarcoma composed predominantly of rhabdoid/epithelioid cells: a frequently misdiagnosed highly aggressive variant - Agaimy, Abbas; Michal, Michael; Hadravsky, Ladislav; Michal, Michal (Human Pathology, 2018)
Dedifferentiated liposarcoma is one of the most common sarcoma types in adults with a predilection for the retroperitoneum. We have recently encountered 6 cases of DDL composed predominantly of rounded, rhabdoid or epithelioid cells mimicking rhabdoid melanoma, epithelioid rhabdomyosarcoma or undifferentiated carcinoma. Patients were 5 males and one female aged 64 to 81 years (median, 68). Tumors originated in the retroperitoneum (n = 5; 3 in the psoas muscle) and deep soft tissue of the thigh (n = 1). All 3 patients with follow-up died of metastatic disease within 4 to 8 months. Preoperative biopsy diagnoses never suggested dedifferentiated liposarcoma as a possibility; instead carcinoma, rhabdomyosarcoma and lymphoma were on top of suggestions. Five resected tumors were composed predominantly (70%-100%) of anaplastic rounded to oval rhabdoid cells with prominent central nucleoli and paranuclear rhabdoid inclusions. Bi- and multinucleation was a constant feature. The background stroma showed variable myxoid changes and minor mixed inflammatory cells. Two cases showed homologous dedifferentiation and another had sclerosing spindle cell nodule but a well-differentiated lipomatous component was not seen in any. One biopsied case showed solely monotonous small round blue cells with scattered rhabdoid cells. Immunohistochemistry showed expression of MDM2 (6/6), CDK4 (5/6), pancytokeratin AE/1 AE3 (4/6) and diffusely desmin and myogenin (2/6). All cases showed high-level co-amplification of MDM2/CDK4 by in situ hybridization. The SWI/SNF complex components (SMARCB1, SMARCA2, SMARCA4, ARID1A and PBRM1) were intact in all cases. This highly aggressive liposarcoma variant needs to be distinguished from a variety of neoplasms including undifferentiated carcinoma, melanoma, lymphoma, rhabdomyosarcoma and others. (C) 2018 Elsevier Inc. All rights reserved.
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Deep hypothermic circulatory arrest or tepid regional cerebral perfusion: impact on haemodynamics and myocardial integrity in a randomized experimental trial - Kellermann, Stephanie; Janssen, Carina; Münch, Frank; Koch, Anna Maria; Schneider-Stock, Regine; Cesnjevar, Robert; Rueffer, Andre (Interactive Cardiovascular and Thoracic Surgery, 2017)
OBJECTIVES: Organ protective management during aortic arch surgery comprises deep hypothermic (18°C) circulatory arrest (DHCA), or moderate hypothermia (28°C/ 'tepid') with regional cerebral perfusion (TRCP). The aim of this experimental study was to evaluate the effect of distinct organ protective management on hemodynamic performance and myocardial integrity. METHODS: Ten male piglets were randomized to group DHCA (n = 5) or TRCP (n = 5) group and operated on cardiopulmonary bypass (CPB) with 60 min of aortic cross-clamping. Blood gas analysis was performed throughout the experiment. Haemodynamic assessment was performed using a thermodilution technique before and after CPB. Myocardial biopsies were taken 2 h after CPB and evaluated using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling assay and western blot analysis. RESULTS: At reperfusion, levels of central venous saturation were significantly higher (P = 0.016) and levels of lactate significantly lower (P = 0.029) in the DHCA group. After CPB, thermodilution measurements revealed higher stroke volume and lower peripheral resistance in the TRCP group (P = 0.012 and 0.037). At the end of the experiment, no significant differences regarding laboratory and haemodynamic parameters were evident. All specimens showed enrichment of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling-positive cells exclusively at the left ventricular subendocardium with no difference between groups and equal concentrations of cyclo-oxygenase-2. CONCLUSIONS: TRCP is associated with decreased peripheral resistance and higher stroke volume immediately after CPB. However, this beneficial effect is contrasted by signs of lower body hypoperfusion, which is expressed by lower central venous saturations and higher lactate levels. Distinct strategies of organ protection did not seem to affect apoptotic/necrotic and inflammatory changes in the left ventricular myocardium.
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Deep learning-based classification of blue light cystoscopy imaging during transurethral resection of bladder tumors - Ali, Nairveen; Bolenz, Christian; Todenhöfer, Tilman; Stenzel, Arnulf; Deetmar, Peer; Kriegmair, Martin; Knoll, Thomas; Porubsky, Stefan; Hartmann, Arndt; Popp, Jürgen; Kriegmair, Maximilian C.; Bocklitz, Thomas (Scientific Reports, 2021)
Bladder cancer is one of the top 10 frequently occurring cancers and leads to most cancer deaths worldwide. Recently, blue light (BL) cystoscopy-based photodynamic diagnosis was introduced as a unique technology to enhance the detection of bladder cancer, particularly for the detection of flat and small lesions. Here, we aim to demonstrate a BL image-based artificial intelligence (AI) diagnostic platform using 216 BL images, that were acquired in four different urological departments and pathologically identified with respect to cancer malignancy, invasiveness, and grading. Thereafter, four pre-trained convolution neural networks were utilized to predict image malignancy, invasiveness, and grading. The results indicated that the classification sensitivity and specificity of malignant lesions are 95.77% and 87.84%, while the mean sensitivity and mean specificity of tumor invasiveness are 88% and 96.56%, respectively. This small multicenter clinical study clearly shows the potential of AI based classification of BL images allowing for better treatment decisions and potentially higher detection rates.
CRIS-Team Scopus Importer:2021-06-11

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

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

Defective autophagosome formation in p53-null colorectal cancer reinforces crocin-induced apoptosis - Amin, Amr; Bajbouj, Khuloud; Koch, Anna Maria; Gandesiri, Muktheshwar; Schneider-Stock, Regine (International Journal of Molecular Sciences, 2015)
Crocin, a bioactive molecule of saffron, inhibited proliferation of both HCT116 wild-type and HCT116 p53(-/-) cell lines at a concentration of 10 mM. Flow cytometric analysis of cell cycle distribution revealed that there was an accumulation of HCT116 wild-type cells in G1 (55.9%, 56.1%) compared to the control (30.4%) after 24 and 48 h of crocin treatment, respectively. However, crocin induced only mild G2 arrest in HCT116 p53(-/-) after 24 h. Crocin induced inefficient autophagy in HCT116 p53(-/-) cells, where crocin induced the formation of LC3-II, which was combined with a decrease in the protein levels of Beclin 1 and Atg7 and no clear p62 degradation. Autophagosome formation was not detected in HCT116 p53(-/-) after crocin treatment predicting a nonfunctional autophagosome formation. There was a significant increase of p62 after treating the cells with Bafilomycin A1 (Baf) and crocin compared to crocin exposure alone. Annexin V staining showed that Baf-pretreatment enhanced the induction of apoptosis in HCT116 wild-type cells. Baf-exposed HCT116 p53(-/-) cells did not, however, show any enhancement of apoptosis induction despite an increase in the DNA damage-sensor accumulation, ?H2AX indicating that crocin induced an autophagy-independent classical programmed cell death.
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Defined morphological criteria allow reliable diagnosis of colorectal serrated polyps and predict polyp genetics - Rau, Tilman; Agaimy, Abbas; Gehoff, Anastasia; Geppert, Carol-Immanuel; Jung, Klaus; Knobloch, Katharina; Langner, Cord; Lugli, Alessandro; Groenbus-Lurkin, Irene; Nagtegaal, Iris D.; Rueschoff, Josef; Saegert, Xavier; et al. (Virchows Archiv, 2014)
Criteria for the diagnosis of serrated colorectal lesions (hyperplastic polyp, sessile serrated adenoma without or with dysplasia–which we called mixed polyp–and traditional serrated adenoma) for which consensus has been reached should be validated for applicability in daily practice in terms of inter-observer reproducibility and their association with clinical features and (epi)genetic events. A study set was created from a consecutive series of colorectal polyps (n = 1,926) by selecting all sessile serrated adenomas, traditional serrated adenomas and mixed polyps. We added consecutive series of hyperplastic polyps, classical adenomas and normal mucosa samples for a total of 200 specimens. With this series, we conducted an inter-observer study, encompassing ten pathologists with gastrointestinal pathology experience from five European countries, in three rounds in which all cases were microscopically evaluated. An assessment of single morphological criteria was included, and these were correlated with clinical parameters and the mutation status of KRAS, BRAF and PIK3CA and the methylation status of MLH1. Gender, age and localisation were significantly associated with certain types of lesions. Kappa statistics revealed moderate to good inter-observer agreement for polyp classification (? = 0.56 to 0.63), but for single criteria, this varied considerably (? = 0.06 to 0.82). BRAF mutations were frequently found in hyperplastic polyps (86 %, 62/72) and sessile serrated adenomas (80 %, 41/51). KRAS mutations occurred more frequently in traditional serrated adenomas (78 %, 7/9) and less so in classical adenomas (20 %, 10/51). Single morphological criteria for sessile serrated adenomas showed significant correlation with BRAF mutation (all p <= 0.001), and those for classical adenomas or traditional serrated adenoma correlated significantly with KRAS mutation (all p < 0.001). Therefore, single well-defined morphological criteria are predictive for genetic alterations in colorectal polyps.
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Defining Ewing and Ewing-like small round cell tumors (SRCT): The need for molecular techniques in their categorization and differential diagnosis. A study of 200 cases - Machado, Isidro; Navarro, Lara; Pellin, Antonio; Navarro, Samuel; Agaimy, Abbas; Tardio, Juan C.; Karseladze, Apollon; Petrov, Semyon; Scotlandi, Katia; Picci, Piero; Llombart-Bosch, Antonio (Annals of Diagnostic Pathology, 2016)
Differentiation of Ewing sarcoma family of tumors (ESFT) and Ewing-like tumors remains problematic. Certain ESFT with morphological and immunohistochemical (IHC) profiles lack the EWSR1-ETS transcript. To improve diagnostic accuracy we investigated the presence of several specific transcripts in 200 small round cell tumors (SRCT) displaying ESFT morphology and immunophenotype in which EWSR1 FISH analysis was non-informative or negative.200 tumors (formalin-fixed, paraffin-embedded) were analyzed by RT-PCR. All tumors were tested for EWSR1-ETS, EWSR1/WT1, PAX3/7-FOX01 or SYT/SSX transcripts, and the negative tumors were subsequently analyzed for CIC/DUX4, BCOR/CCNB3 and CIC/FOX04 transcripts.133 (66.5%) ESFT displayed one of the above EWSR1-ETS translocations. Three cases (1.5%) revealed the SYT-SSX transcript for Synovial sarcoma, and one (0.5%) a EWSR1-WT1 transcript for Desmoplastic Small Round Cell tumor. The CIC-DUX4 translocation was found in six Ewing-like tumors (3%) with CD99 positivity. The BCOR-CCNB3 gene fusion was observed in 5 tumors (2.5%) displaying round or spindle cells with strong CCNB3 IHC expression in 3 tumors. Moreover, RT-PCR failed to detect any gene fusion transcripts in 19 tumors (9.5%) and were considered "undifferentiated small round cell sarcoma" (SRCS). Molecular biology results were non-informative in 33 SRCTs (16.5%) due to RNA degradation through inadequate fixation and/or decalcification.Our analysis of 200 SRCTs confirms the molecular heterogeneity of neoplasms with ESFT morphology and highlight that molecular studies with RT-PCR including new emerging gene fusion transcripts are mandatory for the diagnosis when EWSR1 FISH is negative or non-informative. The incidence of CIC-DUX4, BCOR-CCNB3 and CIC-FOX04 transcripts was relatively low. A small group of Ewing-like sarcomas or undifferentiated SRCS remains unclassified. Adopting appropriate tissue fixation and processing protocols is important to avoid degradation of fixed/embedded tissue when no frozen tumor is available.
EVALuna2:6748

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Different Diagnostic Methods for Identification of FGFR Alteration in Advanced Urothelial Carcinomas: Proficiency Results Based on Multiple RNA Extraction Kits and Mutation Detection Methods - Weyerer, Veronika; Stoehr, Robert; Juette, Hendrik; Wirtz, Ralph; Eckstein, Markus; Roghmann, Florian; Breyer, Johannes; Porubsky, Stefan; Sikic, Danijel; Bolenz, Christian; Kriegmair, Maximilian; Hartmann, Arndt; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Efficacy of anti-PD(L)1 treatment in patients with metastatic urothelial cancer based on mRNA- and protein- based PD-L1 determination: Results from the multicentric, retrospective FOsMIC trial - Jarczyk, J.; Wirtz, R.; Roghmann, F.; Juette, H.; Kriegmair, M. C.; Worst, T. S.; Sikic, D.; Wach, S.; Taubert, Helge; Wullich, Bernd; Weyerer, Veronika; Stöhr, Robert; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Efficacy of neoadjuvant pertuzumab in addition to chemotherapy and trastuzumab in routine clinical treatment of patients with primary breast cancer: a multicentric analysis - Fasching, Peter; Hartkopf, Andreas D.; Gaß, Paul; Häberle, Lothar; Akpolat-Basci, Leyla; Hein, Alexander; Volz, Bernhard; Taran, Florin-Andrei; Nabieva, Naiba; Pott, Birgit; Overkamp, Friedrich; Einarson, Hanna; et al. (Breast Cancer Research and Treatment, 2019)
PurposeNeoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials.MethodsIn a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors.ResultspCR with complete disappearance of all tumor cells was seen in 30.2% (n=58) of patients treated with CTX/TZM and in 52.8% (n=57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49-4.02). Mastectomy rates were not influenced by the therapy.ConclusionsThe results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.
CRIS-Team WoS Importer:2019-03-15

EGFR Mutation Testing Using Liquid Biopsy Technology for Patients with Advanced EGFR-Mutant NSCLC - Seitz, Jan; Moskalev, Evgeny; Fuchs, Florian; Haller, Florian; Hartmann, Arndt (2018)
EVALuna2:34073

Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) in Penile Squamous Cell Carcinoma-No Evidence for a Role in Carcinogenesis. - Fiegl, August; Wendler, Olaf; Giedl, Josef; Gaisa, Nadine T.; Richter, Georg; Campean, Valentina; Burger, Maximilian; Simmer, Femke; Nagtegaal, Iris; Wullich, Bernd; Bertz, Simone; Hartmann, Arndt; et al. (Current Oncology, 2024)
Penile squamous cell carcinoma (pSCC) is a rare malignancy with a global incidence ranging from 0.1 to 0.7 per 100,000 males. Prognosis is generally favorable for localized tumors, but metastatic pSCC remains challenging, with low survival rates. The role of novel biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI), in predicting the response to immune checkpoint inhibitors (ICIs) has been investigated in various cancers. However, MSI has not been observed in pSCC, limiting immunotherapy options for this patient subgroup. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are a distinct form of genomic instability associated with deficient MSH3 expression, which has been proposed as a potential biomarker in several cancers. This study investigates EMAST and MSH3 expression in a cohort of 78 pSCC cases using PCR, fragment analysis and immunohistochemistry. For the detection of EMAST, the stability of five microsatellite markers (D9S242, D20S82, MYCL1, D8S321 and D20S85) was analyzed. None of the cases showed an instability. As for MSH3 immunohistochemistry, all analyzable cases showed retained MSH3 expression. These results strongly suggest that neither EMAST nor MSH3 deficiency is involved in the carcinogenesis of pSCC and do not represent reliable predictive biomarkers in this entity. Furthermore, these findings are in full agreement with our previous study showing a very low frequency of MSI and further support the thesis that EMAST and MSI are strongly interconnected forms of genomic instability. Further research is needed to explore novel therapeutic targets and predictive biomarkers for immunotherapy in this patient population.
EVALuna2:578801

Emerging Entities and New Diagnostic Markers for Head and Neck Soft Tissue and Bone Tumors - Franchi, Alessandro; Thompson, Lester D.R.; Hernandez-Prera, Juan C.; Agaimy, Abbas; Williams, Michelle D.; Mikkelsen, Lauge H.; Bishop, Justin A.; Willems, Stefan M.; Hellquist, Henrik; Ferlito, Alfio (Advances in Anatomic Pathology, 2021)
Bone and soft tissue tumors of the head and neck are relatively uncommon tumors that often represent a diagnostic challenge because of the wide range of entities that must be considered in the differential diagnosis. Over the past few years, classification of bone and soft tissue tumors has evolved primarily because of substantial contributions from molecular genetics, with the identification of new markers that are increasingly used to complement histopathologic findings in the routine diagnostic workup. This review focuses on the recently described mesenchymal tumors that preferentially involve the head and neck region, with a focus on the most relevant novel immunohistochemical and molecular findings, including gene fusions and mutations, that can help in the diagnosis and in the assessment of clinical behavior.
CRIS-Team Scopus Importer:2021-04-19

EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells - Lindner, Pablo; Paul, Sushmita; Eckstein, Markus; Hampel, Chuanpit; Muenzner, Julienne K.; Erlenbach-Wuensch, Katharina; Ahmed, Husayn P.; Mahadevan, Vijayalakshmi; Brabletz, Thomas; Hartmann, Arndt; Vera, Julio; Schneider-Stock, Regine (Cell Death & Disease, 2020)
Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial–mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.
CRIS-Team Scopus Importer:2020-03-20

En-bloc resection of bladder tumours (ERBT): current and future perspectives - Struck, J. P.; Kramer, M. W.; Merseburger, A. S.; Hartmann, Arndt; Herrmann, T. R. W. (Aktuelle Urologie, 2017)
Limitations inherent in the conventional transurethral resection of bladder tumours, the standard approach for diagnosis and treatment of bladder cancer, are well known: staging errors due to insufficient resection depth as well as intravesical tumour fragmentation, both of which make histopathological evaluation difficult. The purpose of this review is to present recent clinical data on the en-bloc resection of bladder tumours (ERBT), which has been demonstrated to offer a high potential to overcome these limitations. The recent findings show that ERBT provides a good resection quality with varying detection rates for tunica muscularis, which is a surrogate marker for resection quality regarding muscle-invasive tumours. ERBT can be performed using all energy sources. Available data show no relevant difference with regard to perioperative morbidity compared with cTURB. No conclusions can be drawn regarding the impact of ERBT on recurrence as the data are partly controversial. This has to be defined by further studies.
EVALuna2:6865

Endocytoscopy for assessing histologic inflammation in ulcerative colitis: development and prospective validation of the ELECT (ErLangen Endocytoscopy in ColiTis) score (with videos) - Vitali, Francesco; Morgenstern, Nadine; Eckstein, Markus; Atreya, Raja; Waldner, Maximilian; Hartmann, Arndt; Neurath, Markus; Rath, Timo (Gastrointestinal Endoscopy, 2022)
Background and Aims: Apart from endoscopic healing as an established treatment goal in patients with inflammatory bowel disease (IBD), histologic remission is an emerging endpoint that might even better predict disease outcome, especially in ulcerative colitis (UC). Within this study, we aimed to evaluate whether endocytoscopy (EC) as an in vivo contact microscopy technology can accurately assess histologic inflammation and predict the further course of disease in UC patients. Methods: Initially, a new and intuitive EC score reflecting the entire spectrum of microscopic disease activity in UC was consensually developed. Subsequently, this score was independently validated in 46 patients with UC who underwent close-meshed follow-up during which major adverse outcomes (MAOs; defined as disease flare, IBD-related hospitalization, IBD-related surgery, necessity for initiation or escalation therapy) were recorded. Results of EC grading of inflammatory activity were compared against 2 validated histologic scores in UC. Diagnostic performance of endoscopic remission under white-light endoscopy (Mayo Endoscopic Score and Ulcerative Colitis Endoscopic Index of Severity), EC, and histology were compared for the prediction of MAOs. Results: Endocytoscopic assessment of inflammatory activity in UC based on the newly developed ErLangen Endocytoscopy in ColiTis score showed strong correlation with histopathologic scoring (Robarts Histopathology Index, r = .70; Nancy Histologic Index, r = .73) and was superior to white-light endoscopy for grading of microscopic disease activity, with a sensitivity of 88%, specificity of 95.2%, and area under the curve of .916. Furthermore, EC exhibited a high interobserver agreement for in vivo grading of microscopic inflammation and was comparably accurate as histopathology for forecasting the occurrence of MAOs in UC. Conclusions: Endocytoscopic grading of inflammatory activity along a newly developed scoring system enabled real-time histology in UC patients and better predicted clinical outcome in UC patients than endoscopic remission.
CRIS-Team Scopus Importer:2022-12-16

Endogenous Retroviral-K Envelope Is a Novel Tumor Antigen and Prognostic Indicator of Renal Cell Carcinoma - Weyerer, Veronika; Strissel, Pamela; Stohr, Christine; Eckstein, Markus; Wach, Sven; Taubert, Helge; Brandl, Lisa; Geppert, Carol-Immanuel; Wullich, Bernd; Cynis, Holger; Beckmann, Matthias; Seliger, Barbara; et al. (Frontiers in Oncology, 2021)
Renal cell carcinoma (RCC) is one of the ten most common cancers for men and women with an approximate 75% overall 5-year survival. Sixteen histological tumor subtypes exist and the most common are papillary, chromophobe and clear cell renal cell carcinoma (ccRCC) representing 85% of all RCC. Although epigenetically silenced, endogenous retroviral (ERV) genes become activated in tumors and function to ignite immune responses. Research has intensified to understand ERV protein function and their role as tumor antigens and targets for cancer (immune) therapy. ERV-K env is overexpressed and implicated as a therapeutic target for breast cancer, however studies in RCC are limited. In this investigation a human RCC tissue microarray (TMA) (n=374) predominantly consisting of the most common histological tumor subtypes was hybridized with an ERV-K env antibody and correlated with patient clinical data. TMA results showed the highest amount of ERV-K env protein expression and the strongest significant membrane expression in ccRCC versus other RCC subtypes. High ERV-K env total protein expression of all tumor subtypes significantly correlated with low tumor grading and a longer disease specific survival using multivariable analyses. Cell proliferation and invasion were assayed using the kidney cell lines HEK293 with wild-type p53 and a ccRCC cell line MZ1257RC mutated for p53. Transfecting these cell lines with a codon optimized ERV-K113 env overexpressing CMV vector was performed with or without 5'-Aza-2'-deoxycytidine (Aza) treatment to sustain promoter de-methylation. MZ1257RC showed induction of ERV-K113 expression and significantly increased both proliferation and invasion in the presence or absence of Aza. HEK293 cells demonstrated a restriction of ERV-K113 env expression and invasion with no changes in proliferation in the absence of Aza. However, in the presence of Aza despite increased ERV-K113 env expression, an inhibition of HEK293 proliferation and a further restriction of invasion was found. This study supports ERV-K env as a single prognostic indicator for better survival of RCC, which we propose represents a new tumor antigen. In addition, ERV-K env significantly regulates proliferation and invasion depending on p53 status and Aza treatment.
CRIS-Team WoS Importer:2021-05-14
Keywords: tumor antigen; renal cell carcinoma; patient prognosis; p53; ERV-K; invasion; azacytidine; endogenous retrovirus

Endometrial Dating Method Detects Individual Maturation Sequences During the Secretory Phase - Alfer, Joachim; Fattahi, Amir; Bleisinger, Nathalie; Krieg, JÜrgen; Behrens, Rolf; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Classen-Linke, Irmgard; Popovici, Roxana M. (In Vivo, 2020)
BACKGROUND/AIM: This study assessed whether a new immunohistochemical dating method allows precise endometrial dating allowing optimal timing for embryo transfer. PATIENTS AND METHODS: A novel method was used for endometrial dating, with parameters including menstrual cycle days, Noyes histological criteria, along with immunohistochemical expression pattern of estrogen and progesterone receptors and proliferation marker Ki-67. Endometrial maturation was analyzed on days +5 to +10 after ovulation or progesterone administration in 217 biopsies from 151 subfertile patients during the secretory phase. RESULTS: Endometrial maturation varied individually, occurring 1.68±1.67 days late. Comparison of histological maturation with clinical days after ovulation showed a delay of about 2 days. CONCLUSION: Endometrial maturation requires 8 days, rather than the expected 6 days, to reach the histological mid-secretory phase. This is not a delay and is also seen in fertile patients. The new analysis method used is superior to that using Noyes criteria alone and provides a better basis for determining conditions for optimal timing of embryo transfers.
CRIS-Team Scopus Importer:2020-07-17
Keywords: Endometrial dating; endometrial receptivity; estrogen receptor; progesterone receptor; window of implantation

Endometrial delay is found to be part of a normal individual dynamic transformation process - Alfer, Joachim; Popovici, Roxana M.; Fattahi, Amir; Krieg, Juergen; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Bleisinger, Nathalie (Archives of Gynecology and Obstetrics, 2021)
Purpose: Limited information is clinically available concerning endometrial receptivity; assessing endometrial transformation status is therefore an urgent topic in assisted reproductive technology. This study aimed to investigate individual endometrial transformation rates during the secretory phase in subfertile patients using personal endometrial transformation analysis. Methods: Monitoring was carried out during the secretory phase to obtain endometrial receptivity profiles. For the investigation, two endometrial biopsies were taken within one menstrual cycle. The extended endometrial dating was based on the Noyes criteria, combined with immunohistochemical analyses of hormone receptors and proliferation marker Ki-67. Biopsies were taken mainly at days ovulation (OV, n = 76)/hormone replacement therapy (HRT, n = 58) + 5 and + 10. Results: The results of the two biopsies were correlated with the clinically expected day of the cycle and showed temporal delays or hypercompensations, diverging from the expected cycle days by 0.5–5 days. In comparison with the first biopsies, the transformation rate in the second biopsies showed compensation, augmented delay, or constant transformation in 48.69, 22.37, and 28.94% of cases for ovulation in natural cycles and 56.89, 25.85, and 17.26% for HRT cycles, respectively. Conclusion: The study revealed an individually dynamic transformation process of the endometrium, with the ability to compensate or enlarge an initial “delay”, which is now identified as a normal individual transformation process during the secretory phase. This information is of great importance for the scientific investigation of dynamic changes in endometrial tissue, as well as for the timing of embryo transfers.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Delay; Endometrium; Maturation; Receptivity

Endometriosis as a risk factor for ovarian or endometrial cancer - results of a hospital-based case-control study - Burghaus, Stefanie; Haeberle, Lothar; Schrauder, Michael G.; Heusinger, Katharina; Thiel, Falk; Hein, Alexander; Wachter, David; Strehl, Johanna; Hartmann, Arndt; Ekici, Arif Bülent; Renner, Stefan; Beckmann, Matthias; et al. (BMC Cancer, 2015)
No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer.In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use.Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41).This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis.
EVALuna2:6731

Endoscopic therapy of Zenker's diverticulum using a novel endoscopic scissor - the Clutch Cutter device - Neumann, Helmut; Loeffler, Silke; Rieger, Stefanie; Kretschmer, Claudia; Naegel, Andreas (Endoscopy, 2015)
EVALuna2:2014

Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma - Kachler, Katerina; Bailer, Maximilian; Heim, Lisanne; Schumacher, Fabian; Reichel, Martin; Holzinger, Corinna D.; Trump, Sonja; Mittler, Susanne; Monti, Juliana; Trufa, Denis; Rieker, Ralf; Hartmann, Arndt; et al. (Cancer Research, 2017)
The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. ©2017 AACR.
EVALuna2:4034

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease - Arndt, Stephanie; Wacker, Eva; Dorn, Christoph; Koch, Andreas; Saugspier, Michael; Thasler, Wolfgang E.; Hartmann, Arndt; Bosserhoff, Anja Katrin; Hellerbrand, Claus (Gut, 2015)
Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease.BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6(-/-)) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets.BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6(-/-) compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6(-/-) mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs.Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy.
EVALuna2:4714

Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands - Haller, Florian; Bieg, Matthias; Will, Rainer; Koerner, Cindy; Weichenhan, Dieter; Bott, Alexander; Ishaque, Naveed; Lutsik, Pavlo; Moskalev, Evgeny; Müller, Susanna; Baehr, Marion; Woerner, Angelika; et al. (Nature Communications, 2019)
The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC.
EVALuna2:35381

Eosinophiles solide und zystisches Nierenzellkarzinom (ESC-NZK) - Hartmann, Arndt; Agaimy, Abbas (Pathologe, 2021)
Despite its descriptive name, eosinophilic, solid, and cystic renal cell carcinoma (ESC-RCC) represents a distinctive epithelial renal tumor entity defined by characteristic clinicopathological and molecular features. ESC-RCC occurs predominantly in women and is characterized in the majority of cases by sporadic (somatic) TSC mutations. A small subset of cases, however, affects patients with TSC germline mutations (tuberous sclerosis syndrome). TSC mutations have therefore been shown to be pathogenetic in this type of tumor. Most tumors present as small (pT1) well circumscribed but not encapsulated lesions with variable macrocystic spaces on their cut surface. Immunohistochemically, their CD117−/CK7−/CK20+ profile is characteristic. Although the tumor cell nuclei of the ESC-RCC occasionally correspond to ISUP/WHO grade 2–3, these tumors are essentially indolent with aggressive cases being only rarely observed. Single case reports have documented effective treatment of aggressive cases with mTOR inhibitors. ESC-RCC needs to be distinguished from a variety of eosinophilic RCC types with secondary cystic changes including cystic SDH-deficient RCC, the recently proposed eosinophilic vacuolated tumor (EVT; also mTOR-related), oncocytoma, and low-grade oncocytic tumor (LOT). The generally indolent behavior and frequent TSC/mTOR alterations in ESC-RCC, EVT, and some LOTs raise the question of whether these lesions represent independent tumor entities or are merely morphological variants on the spectrum of eosinophilic low-grade TSC/mTOR-related neoplasms.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Eosinophilic renal tumors; Human mTOR protein; Kidney neoplasms; TOR serine-threonine kinases; Tuberous sclerosis

Eosinophilic cystitis mimicking bladder cancer—considerations on the management based upon a case report and a review of the literature - Schmitz-Draeger, Bernd J.; Skutetzki, Andreas; Rieker, Ralf J.; Schwab, Siegfried A.; Stöhr, Robert; Bismarck, Ekkehardt; Savov, Orlin; Ebert, Thomas; Benderska-Soeder, Natalya; Hartmann, Arndt (Virchows Archiv, 2021)
The hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and infiltration of various organs with eosinophils. Eosinophilic cystitis (EC), mimicking bladder cancer clinically but also in ultrasound and in radiographic imaging, is one potential manifestation of the HES occurring in adults as well as in children. This case report describes the course of disease in a 57-year-old male presenting with severe gait disorders and symptoms of a low compliance bladder caused by a large retropubic tumor. After extensive urine and serologic examination and histologic confirmation of EC the patient was subjected to medical treatment with cetirizine and prednisolone for 5 weeks. While gait disorders rapidly resolved, micturition normalized only 10 months after initiation of therapy. Based upon this course the authors recommend patience and reluctance concerning radical surgical intervention in EC.• Genetic alterations (e.g., BRAF mutations) may predispose for the disease
CRIS-Team Scopus Importer:2021-03-05
Keywords: Bladder tumor; Eosinophilic cystitis; Hypereosinophilic syndrome; Inflammatory pseudotumor

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases - Mihaela, Farcas; Zoran, Gatalica; Kiril, Trpkov; Jeffrey, Swensen; Ming, Zhou; Reza, Alaghehbandan; Williamson, Sean R.; Cristina, Magi-Galluzzi; Gill, Anthony J.; Maria, Tretiakova; Lopez, Jose; Delia, Perez Montiel; et al. (Modern Pathology, 2021)
A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.
CRIS-Team WoS Importer:2021-09-24

Epidemiology and survival of HPV-related tonsillar carcinoma - Psychogios, Georgios; Alexiou, Christoph; Agaimy, Abbas; Brunner, Kathrin; Koch, Michael; Mantsopoulos, Konstantinos; Tomppert, Andrea; Iro, Heinrich (Cancer Medicine, 2014)
The aim of this study was to determine the proportion of human papilloma virus (HPV)-positive cases in tonsillar carcinomas and investigate its development over the last decade. Further aim was to show the oncologic results in accord to HPV status and various treatment modalities. A retrospective study was conducted between 2000 and 2012 and included 275 patients treated for tonsillar carcinoma. P16 immunohistochemistry was used as a surrogate marker for HPV-associated carcinogenesis. A total of 101 (36.7%) patients proved to be p16 positive and 174 p16 negative. 80.2% of the p16-positive cases presented with T1-2 tumor. Of the early-stage patients, 79% of the p16-positive and 52.3% of the p16-negative presented with lymph node metastases. The percentage of p16-positive patients increased from 23.2% in the period 2005-2007 to 58.6% in the period 2010-2012 in the whole population and from 30.9% to 76.9% in T1-2 carcinomas. Early T-category p16-positive carcinomas had significantly better disease-specific survival (92.4% vs. 75.5%, P = 0.007) and overall survival (OS, 79.6% vs. 54.3%, P < 0.001) compared to p16-negative tumors. This study showed an increase in the percentage of p16-positive patients in tonsillar carcinoma from 23.2% in the years between 2005 and 2007 to 58.6% between 2010 and 2012. The majority (80.2%) of p16-positive patients presented with early T-category tumor but most of these (79.0%) had also lymph node metastases. Nevertheless, p16-positive patients had excellent oncologic results after surgery and adjuvant radiotherapy and could be considered for de-escalation of treatment.
EVALuna2:6679

Epigenetic inactivation of ITIH5 promotes bladder cancer progression and predicts early relapse of pT1 high-grade urothelial tumours - Rose, Michael; Gaisa, Nadine T.; Antony, Pia; Fiedler, David; Heidenreich, Axel; Otto, Wolfgang; Denzinger, Stefan; Bertz, Simone; Hartmann, Arndt; Karl, Alexander; Knüchel, Ruth; Dahl, Edgar (Carcinogenesis, 2014)
Inter-?-trypsin inhibitor heavy chain 5 (ITIH5) has been associated with tumour suppression in various cancers. However, its putative role in bladder cancer is completely unknown. Therefore, we initiated a study analysing ITIH5 expression as well as its prognostic and functional impact on human urothelial cancers (UCs). Expression analysis showed a clear down-regulation of ITIH5 mRNA in 61% (n = 45) of UCs, especially in muscle-invasive tumours (P < 0.001). ITIH5 loss in UCs was further evident on protein level (65.5%, n = 55) as detected by immunohistochemistry. DNA methylation analysis demonstrated tumour-specific ITIH5 promoter methylation in 50% of papillary none-invasive pTa (n = 30) and 68% of invasive (n = 28) UCs. Aberrant ITIH5 promoter methylation in bladder tumours was tightly linked (P < 0.001) with loss of ITIH5 mRNA expression, which was furthermore functionally confirmed by demethylation analysis in cell lines. Pyrosequencing analysis revealed that ITIH5 promoter hypermethylation was closely associated with progressive bladder cancers. Subsequently, a large cohort (n = 120) of clinically challenging pT1 high-grade UC was analysed for ITIH5 expression. Of clinical significance, we found an association between loss of ITIH5 expression and unfavourable prognosis of UC patients without distant metastasis at first diagnosis (recurrence-free survival; hazard ratio: 4.35, P = 0.048). Functionally, ITIH5 re-expression in human RT112 bladder cancer cells led to both suppression of cell migration and inhibition of colony spreading. Hence, we provide evidence that down-regulation of ITIH5 by aberrant DNA hypermethylation may provoke invasive phenotypes in human bladder cancer. Moreover, ITIH5 protein might become a prognostic biomarker for relapse risk stratification in high-grade UC patients.
EVALuna2:6568

Epigenetic Regulation of CD133 in Gastrointestinal Stromal Tumors - Geddert, Helene; Braun, Alexander; Kayser, Claudia; Dimmler, Arno; Faller, Gerhard; Agaimy, Abbas; Haller, Florian; Moskalev, Evgeny (American Journal of Clinical Pathology, 2017)
This study ascertained the regulation of the stem cell marker CD133 and its potential applicability for prognostication of gastrointestinal stromal tumors (GISTs).A total of 95 resected GISTs were included in the study. CD133 protein expression was assessed immunohistochemically on tissue microarrays. Methylation percentage was quantified by pyrosequencing. Gene expression in cell lines GIST48b and GIST882 upon treatment with DNA demethylation agent 5-aza-2'-deoxycytidine was analyzed by quantitative polymerase chain reaction.The expression of hypermethylated CD133 could be reactivated in the GIST cell line upon hypomethylation with the drug. Similarly, in patient material, CD133 methylation percentage correlated inversely with the protein expression and reflected tumor size with hypermethylation in small (<2 cm) tumors and virtually no methylation in large (>10 cm) GISTs. The gene's methylation percentage and expression level were clearly specific to anatomic sites and distinct driver mutations. KIT -mutant gastric GISTs exhibited significantly lower methylation degrees and concomitant high CD133 protein abundance compared with KIT -mutant GISTs from the small intestine. CD133 hypermethylation was documented in PDGFRA -mutant gastric GISTs along with low CD133 expression compared with KIT -mutant gastric GISTs. High CD133 expression was a prognosticator of shorter disease-free survival in all patients. In a subgroup of KIT -mutant gastric GISTs, low CD133 methylation degree was correlated with a shorter disease-free survival.Our results strongly suggest epigenetic regulation of CD133 expression by promoter methylation in GISTs. Pending further validation studies, high abundance of the protein can serve as a marker for malignant GISTs.
EVALuna2:6853

Epigenetic regulation of p21cip1/waf1 in human cancer - Ocker, Matthias; Al Bitar, Samar; Monteiro, Ana; Gali-Muhtasib, Hala; Schneider-Stock, Regine (Cancers, 2019)
p21cip1/waf1 is a central regulator of cell cycle control and survival. While mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. These mechanisms include promoter hypermethylation as well as additional pathways such as histone acetylation or methylation. The epigenetic regulators include writers, such as DNA methyltransferases (DNMTs); histone acetyltransferases (HATs) and histone lysine methyltransferases; erasers, such as histone deacetylases (HDACs); histone lysine demethylases [e.g., the Lysine Demethylase (KDM) family]; DNA hydroxylases; readers, such as the methyl-CpG-binding proteins (MBPs); and bromodomain-containing proteins, including the bromo-and extraterminal domain (BET) family. We further discuss the roles that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play in the epigenetic control of p21cip1/waf1 expression and its function in human cancers.
CRIS-Team Scopus Importer:2019-10-22
Keywords: DNA methylation; Epigenetic eraser; Epigenetic reader; Epigenetic writer; Histone acetylation; Histone methylation; LncRNA; MiRNA; P21

Epigenetic regulation of the putative breast cancer metastasis suppressor gene SCN4B - Hilgers, L.; Hartmann, Arndt; Fasching, Peter; Villwock, S.; Moll, L.; Roger, S.; Knuechel-Clarke, R.; Steib, F.; Dahl, E. D. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

Epithelial-Myoepithelial Carcinoma: Frequent Morphologic and Molecular Evidence of Preexisting Pleomorphic Adenoma, Common HRAS Mutations in PLAG1-intact and HMGA2-intact Cases, and Occasional TP53, FBXW7, and SMARCB1 Alterations in High-grade Cases - El Hallani, Soufiane; Udager, Aaron M.; Bell, Diana; Fonseca, Isabel; Thompson, Lester D. R.; Assaad, Adel; Agaimy, Abbas; Luvison, Alyssa M.; Miller, Caitlyn; Seethala, Raja R.; Chiosea, Simion (American Journal of Surgical Pathology, 2018)
We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.
EVALuna2:34892

ERBB2/ ERBB3-mutated S100/ SOX10-positive unclassified high-grade uterine sarcoma: first detailed description of a novel entity - Agaimy, Abbas; Dermawan, Josephine K.; Haller, Florian; Semrau, Sabine; Meidenbauer, Norbert; Stöhr, Robert; Lax, Sigurd; Hartmann, Arndt; Zou, Ying S.; Xing, Deyin; Tögel, Lars; Gross, John M.; et al. (Virchows Archiv, 2024)
With the increasing use of innovative next generation sequencing (NGS) platforms in routine diagnostic and research settings, the genetic landscape of uterine sarcomas has been dynamically evolving during the last two decades. Notably, the majority of recently recognized genotypes in uterine sarcomas represent gene fusions, while recurrent oncogene mutations of diagnostic and/ or therapeutic value have been rare. Recently, a distinctive aggressive uterine sarcoma expressing S100 and SOX10, but otherwise lacking diagnostic morphological, immunophenotypic and molecular features of other uterine malignancies has been presented in a scientific abstract form (USCAP, 2023), but detailed description and delineation of the entity is still missing. We herein describe two high-grade unclassified uterine sarcomas characterized by spindle to round cell morphology and diffuse expression of S100 and SOX10, originating in the uterine body and cervix of 53- and 45-year-old women and carrying an ERBB3 (p.Glu928Gly) and an ERBB2 (p.Val777Leu) mutation, respectively. Both tumors harbored in addition genomic HER2 amplification, ATRX mutation and CDKN2A deletion. Methylation studies revealed a methylome most similar to MPNST-like tumors, but distinct from melanoma, MPNST, clear cell sarcoma, and endometrial stromal sarcoma. Case 1 died of progressive peritoneal metastases after multiple trials of chemotherapy 47 months after diagnosis. Case 2 is a recent case who presented with a cervical mass, which was biopsied. This study defines a novel heretofore unrecognized aggressive uterine sarcoma with unique phenotypic and genotypic features. Given the potential value of targeting HER2, recognizing this tumor type is mandatory for appropriate therapeutic strategies and for better future delineation of the entity.
CRIS-Team Scopus Importer:2024-09-06
Keywords: EGFR; Molecular profiling; nerve sheath tumor; Targeted therapy; Tyrosine kinase fusions; Undifferentiated uterine sarcoma

ERBB2 Expression as Potential Risk-Stratification for Early Cystectomy in Patients with pT1 Bladder Cancer and Concomitant Carcinoma in situ - Breyer, Johannes; Otto, Wolfgang; Wirtz, Ralph M.; Wullich, Bernd; Keck, Bastian; Erben, Philipp; Kriegmair, Maximilian C.; Stoehr, Robert; Eckstein, Markus; Laible, Mark; Schlombs, Kornelia; Eidt, Sebastian; et al. (Urologia Internationalis, 2017)
Background/Aims/Objectives: It is difficult to identify patients with a non-muscle-invasive bladder cancer (NMIBC) at stage pT1 with concomitant carcinoma in situ (Cis) who will benefit from an early cystectomy.We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues of patients with NMIBC. Messenger ribonucleic acid (mRNA) expression of progesterone receptor (PGR), estrogen receptor (ESR1), ERBB2, and marker of proliferation Ki-67 (MKI67) was measured by single-step reverse transcription quantitative real-time polymerase chain reaction using RNA-specific TaqMan assays. Relative gene expression was determined by the normalization of 2 reference genes (CALM2, B2M) using the 40 ??CT method and relative gene expression was correlated to the histopathological stage and oncological outcome.Of 302 patients with pT1 NMIBC in the initial transurethral resection of the bladder, 65 had a concomitant Cis. Elevated ERBB2 expression (>40.1) significantly correlated with progress in patients with and without concomitant Cis (p = 0.020 and p = 0.049, respectively). For the subgroup of pT1 with concomitant Cis, elevated ERBB2 expression significantly discriminated between a high-risk group of 55% progression-free survival (PFS) and a low-risk group of 90% PFS after a 5-year follow-up (p = 0.020). Cox-regression analysis revealed ERBB2 expression as the only independent prognostic factor for PFS (p = 0.0037).High mRNA expression of ERBB2 can identify patients with pT1 NMIBC with concomitant Cis, who have a high risk of progression and might benefit from an early cystectomy.
EVALuna2:6879

Erratum to: DAPK plays an important role in panobinostat-induced autophagy and commits cells to apoptosis under autophagy deficient conditions - Gandesiri, Muktheshwar; Chakilam, Saritha; Ivanovska, Jelena; Benderska, Natalya; Ocker, Matthias; Di Fazio, Pietro; Feoktistova, Maria; Gali-Muhtasib, Hala; Rave-Fraenk, Margret; Prante, Olaf; Christiansen, Hans; Leverkus, Martin; et al. (Apoptosis, 2016)
EVALuna2:6627

Erratum to 'Deep hypothermic circulatory arrest or tepid regional cerebral perfusion: impact on haemodynamics and myocardial integrity in a randomized experimental trial' [Interact CardioVasc Thorac Surg 2018;26:667-672] - Kellermann, Stephanie; Janssen, Carina; Muench, Frank; Koch, Anna Maria; Schneider-Stock, Regine; Cesnjevar, Robert; Rueffer, Andre (Interactive Cardiovascular and Thoracic Surgery, 2018)
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Erratum to: Eosinophilic, solid, and cystic renal cell carcinoma (ESC-RCC) (Der Pathologe, (2021), 42, 6, (565-570), 10.1007/s00292-021-00998-7) Erratum zu: Eosinophiles solide und zystisches Nierenzellkarzinom (ESC-NZK) (Der Pathologe, (2021), 42, 6, (565-570), 10.1007/s00292-021-00998-7) - Hartmann, Arndt; Agaimy, Abbas (Pathologe, 2021)
CRIS-Team Scopus Importer:2021-11-05

Erratum zu Mitteilungen der Deutschen Gesellschaft für Pathologie (Der Pathologe, (2021), 42, 3, (352-353), 10.1007/s00292-021-00931-y) - Joehrens, Korinna; Baretton, Gustavo; Schildhaus, Hans-Ulrich; Agaimy, Abbas; Scheel, Andreas; Schwammborn, Kristina; Laenger, Florian; Tiemann, Markus; Dietel, Manfred (Pathologe, 2021)
CRIS-Team Scopus Importer:2021-09-03

Erratum zu: Testung auf Mismatch-Reparatur-Defizienz und Mikrosatelliteninstabilität: Eine fokussierte Aktualisierung (Die Pathologie, (2023), 44, 5, (301-310), 10.1007/s00292-023-01209-1) - Rüschoff, Josef; Schildhaus, Hans-Ulrich; Rüschoff, Jan Hendrik; Jöhrens, Korinna; Bocker-Edmonston, Tina; Dietmaier, Wolfgang; Bläker, Hendrik; Baretton, Gustavo; Horst, David; Dietel, Manfred; Hartmann, Arndt; Klauschen, Frederick; et al. (Die Pathologie, 2023)
CRIS-Team Scopus Importer:2023-09-08

Escalation in mucus cystatin 2, pappalysin-A, and periostin levels over time predict need for recurrent surgery in chronic rhinosinusitis with nasal polyps - Müller, Sarina Katrin; Wendler, Olaf; Nocera, Angela; Grundtner, Philipp; Schlegel, Patrick; Agaimy, Abbas; Iro, Heinrich; Bleier, Benjamin S. (International Forum of Allergy and Rhinology, 2019)
Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is treated using oral/topical steroids and surgery. Despite maximal medical therapy, some patients remain recalcitrant. Mucus cystatin 2, pappalysin-A, and periostin can predict the presence of CRSwNP and correlate with disease severity. This study was designed to determine whether prospective sampling of these mucus proteins could predict medical failure and the need for revision surgery. Methods: This investigation was an institutional review board‒approved, prospective study of 66 patients with CRSwNP. All patients underwent surgery, administration of topical/oral steroids, and outpatient mucus sampling at 10 time-points over 2 years. Five proteins, including cystatin 2 (CST2), pappalysin-A (PAPP-A), and periostin (PST), were analyzed and correlated with subjective parameters (including scores on the 22-item Sino-Nasal Outcomes Test [SNOT-22]). Variables were then analyzed and compared between those requiring revision surgery within 2 years (n = 5) and those with stable disease (n = 61). Results: All patients demonstrated a significant decline in CST2, PAPP-A, and periostin after their initial surgery. The recalcitrant group demonstrated escalations in all proteins despite steroids, with levels higher than those of the stable group at 1 year (CST2: 258.1 ± 205.2 pg/mL vs 235.3 ± 275.7 pg/mL, p = 0.86; PAPP-A: 170.3 ± 150.4 pg/mL vs 74.6 ± 106.7 pg/mL, p < 0.05; periostin: 188.8 ± 192.4 ng/mL vs 54.5 ± 47.6 ng/mL, p < 0.001). Escalation in all proteins correlated significantly with worsening SNOT-22 score at each time-point (domain 1: 8.2 ± 1.3 vs 5.5 ± 1.1; p < 0.05). Conclusion: Early recurrences and medical recalcitrance in CRSwNP may be predicted noninvasively through the serial, prospective sampling of mucus CST2, PAPP-A, and periostin levels. These biosignatures may help to predict disease course and guide individualized therapy.
CRIS-Team Scopus Importer:2019-08-30
Keywords: biomarker; chronic rhinosinusitis; mucus; noninvasive; recurrence

ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC) - Breyer, Johannes; Wirtz, Ralph M.; Laible, Mark; Schlombs, Kornelia; Erben, Philipp; Kriegmair, Maximilian Christian; Stoehr, Robert; Eidt, Sebastian; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt; Otto, Wolfgang (Virchows Archiv, 2016)
Pathological staging and grading are crucial for risk assessment in non-muscle-invasive bladder cancer (NMIBC). Molecular grading might support pathological evaluation and minimize interobserver variability. In this study, the well-established breast cancer markers ESR1, PGR, ERBB2, and MKI67 were evaluated as potential molecular markers to support grading and staging in NMIBC. We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with NMIBC. Messenger RNA (mRNA) expression of the aforementioned markers was measured by single-step reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) using RNA-specific TaqMan assays. Relative gene expression was determined by normalization to two reference genes (CALM2 and B2M) using the 40(-??CT) method and correlated to histopathological stage and grade. Pathological assessment was performed by an experienced uropathologist. Statistical analysis was performed using the SAS software JMP 9.0.0 version and GraphPad Prism 5.04. Of 381 cases of NMIBC, samples of 100 pTa and 255 pT1 cases were included in the final study. Spearman rank correlation revealed significant correlations between grade and expression of MKI67 (r = 0.52, p < 0.0001), ESR1 (r = 0.25, p < 0.0001), and ERBB2 (r = 0.18, p = 0.0008). In Mann-Whitney tests, MKI67 was significantly different between all grades (p < 0.0001), while ESR1 (p = 0.0006) and ERBB2 (p = 0.027) were significantly different between G2 and G3. Higher expression of MKI67 (r = 0.49; p < 0.0001), ERBB2 (r = 0.22; p < 0.0001), and ESR1 (r = 0.18; p = 0.0009) mRNA was positively correlated with higher stage. MKI67 (p < 0.0001), ERBB2 (p = 0.0058), and PGR (p = 0.0007) were significantly different between pTa and pT1. In NMIBC expression of ESR1, ERBB2 and MKI67 are significantly different between stage and grade. This potentially provides objective parameters for pathological evaluation.
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ETV6 Gene Rearrangements Characterize a Morphologically Distinct Subset of Sinonasal Low-grade Non-intestinal-type Adenocarcinoma: A Novel Translocation-associated Carcinoma Restricted to the Sinonasal Tract - Andreasen, Simon; Skálová, Alena; Agaimy, Abbas; Bishop, Justin A.; Laco, Jan; Leivo, Ilmo; Franchi, Alessandro; Larsen, Stine R.; Erentaite, Daiva; Ulhøi, Benedicte P.; von Buchwald, Christian; Melchior, Linea C.; et al. (American Journal of Surgical Pathology, 2017)
Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease.
EVALuna2:6881

Europe-side external quality assessment (EQA) of RNA based testing of ER, PR, HER2 and Ki67 in invasive breast cancer - Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Stöhr, Robert; Beckmann, Matthias; Zentgraf, M.; Rübner, Matthias; Hübner, Hanna; Fischer, J.; Guerini Rocco, E.; Viale, G.; Cayre, A.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-06-26

Evaluation of a Hybrid Capture–Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes - Kroeze, Leonie I.; de Voer, Richarda M.; Kamping, Eveline J.; von Rhein, Daniel; Jansen, Erik A.M.; Hermsen, Mandy J.W.; Barberis, Massimo C.P.; Botling, Johan; Garrido-Martin, Eva M.; Haller, Florian; Lacroix, Ludovic; Maes, Brigitte; et al. (Journal of Molecular Diagnostics, 2020)
Stratification of patients for targeted and immune-based therapies requires extensive genomic profiling that enables sensitive detection of clinically relevant variants and interrogation of biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI). Detection of single and multiple nucleotide variants, copy number variants, MSI, and TMB was evaluated using a commercially available next-generation sequencing panel containing 523 cancer-related genes (1.94 megabases). Analysis of formalin-fixed, paraffin-embedded tissue sections and cytologic material from 45 tumor samples showed that all previously known MSI-positive samples (n = 7), amplifications (n = 9), and pathogenic variants (n = 59) could be detected. TMB and MSI scores showed high intralaboratory and interlaboratory reproducibility (eight samples tested in 11 laboratories). For reliable TMB analysis, 20 ng DNA was shown to be sufficient, even for relatively poor-quality samples. A minimum of 20% neoplastic cells was required to minimize variations in TMB values induced by chromosomal instability or tumor heterogeneity. Subsequent analysis of 58 consecutive lung cancer samples in a diagnostic setting was successful and revealed sufficient somatic mutations to generate mutational signatures in 14 cases. In conclusion, the 523-gene assay can be applied for evaluation of multiple DNA-based biomarkers relevant for treatment selection.
CRIS-Team Scopus Importer:2020-06-02

Evaluation of different diagnostic methods for identification of FGFR alteration in advanced urothelial carcinomas: Proficiency results based on multiple RNA extraction kits and mutation detection methods - Weyerer, Veronika; Stöhr, Robert; Juette, H.; Wirtz, R.; Eckstein, Markus; Roghmann, F.; Breyer, J.; Porubsky, S.; Sikic, D.; Bolenz, C.; Kriegmair, M. C.; Hartmann, Arndt; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Evaluation of endocervical curettage (ECC) in colposcopy for detecting cervical intraepithelial lesions - Behrens, Annika; Dietl, Anna; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Mehlhorn, Grit; Koch, Martin C.; Schulmeyer, Carla; Seibold, Anja; Gaß, Paul; et al. (Archives of Gynecology and Obstetrics, 2024)
Purpose: Diagnostic challenges in colposcopy arise especially in women aged 50 or older, with postmenopausal status and transformation zone type 3 (TZ3). Endocervical curettage (ECC) is a valuable tool for diagnosing intracervical lesions. The aim of this retrospective analysis was to evaluate the use of ECC in colposcopy for detecting cervical intraepithelial lesions. Methods: A retrospective study was carried out of colposcopies performed in the certified Dysplasia Unit at Erlangen University Hospital between July 2016 and June 2023. Pap and human papillomavirus (HPV) results were correlated with the histologic findings via ECC, obtained during examinations or surgery. The primary outcome was the rate of accuracy between the colposcopic and histologic findings with regard to cytology, age of patients, and type of transformation zone (TZ). Results: A total of 429 colposcopies in 413 women with histologic samples obtained via ECC were included in the final analysis. In all, 355 women had TZ3. Among patients with TZ3, evidence of high-grade lesions and invasive carcinoma was also found in women with normal or low-grade abnormal cytology. For patients with normal colposcopic findings, cervical intraepithelial neoplasia (CIN) 2 and CIN 3/adenocarcinoma in situ (AIS) were found in 56 patients (16%), and invasive carcinoma was found in four patients (0.1%). Conclusion: This analysis suggests that ECC is a valuable tool in the diagnosis of cervical intraepithelial neoplasia, especially for patients who present with a normal colposcopy of the cervix and vagina but have either recurrent abnormal cytologic findings or high-grade abnormal cytology indicating CIN 2 +.
CRIS-Team Scopus Importer:2024-11-08
Keywords: Cervical cancer; Cervical cancer screening assessment; Cervical intraepithelial neoplasia; Colposcopy; Cytology; Endocervical curettage

Evaluation of FGFR Alteration Status in Urothelial Tumors - Bahlinger, Veronika; Eckstein, Markus; Hartmann, Arndt; Stöhr, Robert (Urothelial Carcinoma - Methods and Protocols, 2023)
FGFR alterations in urothelial carcinoma are key driver alterations of tumorigenesis and are long recognized. In 2019 the Food and Drug Administration (FDA) approved the first pan-FGFR inhibitor, as the first specific targeted therapy in urothelial carcinoma. To receive the drug, alteration testing is required, and only alteration carriers can profit of this new agent. Due to this clinical need of detection and analysis of FGFR, here we describe two distinct and specific analytical methodologies: the SNaPshot analysis of nine FGFR3 point mutations and the QIAGEN therascreen® FGFR RGQ RT-PCR Kit, the FDA-approved companion diagnostic kit.
CRIS-Team Scopus Importer:2023-07-21
Keywords: FGFR testing; Inhibitor; QIAGEN therascreen; SNaPshot analysis; Targeted therapy; Urothelial carcinoma

Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma - Mikuteit, Marie; Zschäbitz, Stefanie; Stoehr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Ströbel, Philipp; Becker, Frank; Wülfing, Christian; Barth, Peter; Stöckle, Michael; et al. (Urologia Internationalis, 2023)
Introduction: Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. Methods: The patients' sample collection is a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. Results: In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas- groups did not significantly differ in any tumor or patient characteristics. Conclusion: Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.
CRIS-Team Scopus Importer:2023-08-11

Evaluation of Nectin-4 and Trop-2: Implications for Patient Outcomes and Therapy in Penile Cancer - Mink, Jan Niklas; Eckstein, Markus; Khalmurzaev, Oybek; Pryalukhin, Alexey; Geppert, Carol-Immanuel; Lohse, Stefan; Bende, Kristóf; Lobo, João; Henrique, Rui; Loertzer, Hagen; Steffens, Joachim; Jerónimo, Carmen; et al. (Modern Pathology, 2025)
Metastatic penile cancer (PC) continues to have a poor prognosis because of inadequate treatment options. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates (ADCs) that have significantly improved the prognosis of several other tumor types and are, therefore, promising candidates for the successful treatment of metastatic PC. We examined the expression of ADC targets Nectin-4 and Trop-2 in an international multicenter cohort of 203 PC patients both in the primary tumor and in metastases. In addition, we evaluated their prognostic values. Either intermediate or high Nectin-4 membrane expression was found in 28.0% of primary tumors and 18.8% of metastases. The expression in primary tumor decreased significantly with increasing T stage (P ≤ .001). It did not correlate with human papillomavirus status (P = .307) and was not associated with metastasis-free survival, cancer-specific survival, or overall survival. Nectin-4 expression levels at the tumor front and in metastases were significantly associated with each other (P = .005). Trop-2 was detected on the membrane of almost all samples with intermediate or high expression (primary tumor, 98.1%; metastasis, 100%). It was not associated with metastasis-free survival, cancer-specific survival, or overall survival. The expression at tumor front was significantly increased in human papillomavirus–positive tumors (P = .005). Neither Nectin-4 nor Trop-2 was found to be of prognostic value in PC. Enfortumab vedotin therapy seems promising for selected patients with high Nectin-4 expression, which should be confirmed in PC metastases before treatment is considered. Trop-2 is highly expressed in almost all PCs, and therefore, it is a very interesting potential target for sacituzumab govitecan therapy. Both ADCs warrant investigation in clinical trials focusing on PC.
CRIS-Team Scopus Importer:2025-05-23
Keywords: antibody-drug conjugate; immunohistochemistry; Nectin-4; penile squamous cell carcinoma; Trop-2

EVALUATION OF OPTOACOUSTIC IMAGING FOR ANALYSIS OF PLACENTAL VILLOUS VASCULARIZATION - Hübner, Hanna; Knieling, Ferdinand; Faschingbauer, Florian; Rübner, Matthias; Kehl, Sven; Beckmann, Matthias; Rascher, Wolfgang; Hartner, Andrea; Fahlbusch, Fabian (2018)
EVALuna2:208000

Evaluation of Potential Targeted Therapy and Molecular Subtype in Large Nested Variant of Urothelial Carcinoma (LNUC) - Weyerer, Veronika; Eckstein, Markus; Comperat, Eva; Juette, Hendrik; Gaisa, Nadine; Allory, Yves; Stoehr, Robert; Wullich, Bernd; Roupret, Morgan; Hartmann, Arndt; Bertz, Simone (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Evaluation of Prognostic Parameters to Identify Aggressive Penile Carcinomas - Mink, Jan Niklas; Khalmurzaev, Oybek; Pryalukhin, Alexey; Geppert, Carol-Immanuel; Lohse, Stefan; Bende, Kristóf; Lobo, João; Henrique, Rui; Loertzer, Hagen; Steffens, Joachim; Jerónimo, Carmen; Wunderlich, Heiko; et al. (Cancers, 2023)
Background: Advanced penile carcinoma is characterized by poor prognosis. Most data on prognostic factors are based on small study cohorts, and even meta-analyses are limited in patient numbers. Therefore, there is still a lack of evidence for clinical decisions. In addition, the most recent TNM classification is questionable; in line with previous studies, we found that it has not improved prognosis estimation. Methods: We evaluated 297 patients from Germany, Russia, and Portugal. Tissue samples from 233 patients were re-analyzed by two experienced pathologists. HPV status, p16, and histopathological parameters were evaluated for all patients. Results: Advanced lymph node metastases (N2, N3) were highly significantly associated with reductions in metastasis-free (MFS), cancer-specific (CS), and overall survival (OS) rates (p = <0.001), while lymphovascular invasion was a significant parameter for reduced CS and OS (p = 0.005; p = 0.007). Concerning the primary tumor stage, a significant difference in MFS was found only between pT1b and pT1a (p = 0.017), whereas CS and OS did not significantly differ between T categories. In patients without lymph node metastasis at the time of primary diagnosis, lymphovascular invasion was a significant prognostic parameter for lower MFS (p = 0.032). Histological subtypes differed in prognosis, with the worst outcome in basaloid carcinomas, but without statistical significance. HPV status was not associated with prognosis, either in the total cohort or in the usual type alone. Conclusion: Lymphatic involvement has the highest impact on prognosis in penile cancer, whereas HPV status alone is not suitable as a prognostic parameter. The pT1b stage, which includes grading, as well as lymphovascular and perineural invasion in the T stage, seems questionable; a revision of the TNM classification is therefore required.
CRIS-Team Scopus Importer:2023-10-20
Keywords: histological subtype; HPV; p16; penile cancer; prognosis

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study - Koebel, M.; Madore, J.; Ramus, S. J.; Clarke, B. A.; Pharoah, P. D. P.; Deen, S.; Bowtell, D. D.; Odunsi, K.; Menon, U.; Morrison, C.; Lele, S.; Bshara, W.; et al. (British Journal of Cancer, 2014)
Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.
EVALuna2:6660

EWSR1::ATF1 fusions characterize a group of extra-abdominal epithelioid and round cell mesenchymal neoplasms, phenotypically overlapping with sclerosing epithelioid fibrosarcomas, and intra-abdominal FET::CREB fusion neoplasms - Rekhi, Bharat; Dermawan, Josephine K.; Fritchie, Karen J.; Zimpfer, Annette; Mohammad, Tareq M.; Ali, Fatima S.; Nandy, Koushik; Zou, Youran; Stöhr, Robert; Agaimy, Abbas (Virchows Archiv, 2024)
With the increasing use of next generation sequencing in soft tissue pathology, particularly in neoplasms not fitting any World Health Organization (WHO) category, the spectrum of EWSR1 fusion-associated soft tissue neoplasms has been expanding significantly. Although recurrent EWSR1::ATF1 fusions were initially limited to a triad of mesenchymal neoplasms including clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma and malignant gastrointestinal neuroectodermal tumor (MGNET), this family has been expanding. We herein describe 4 unclassified extra-abdominal soft tissue (n = 3) and bone (n = 1) neoplasms displaying epithelioid and round cell morphology and carrying an EWSR1::ATF1 fusion. Affected were 3 males and 1 female aged 20–56 years. All primary tumors were extra-abdominal and deep-seated (chest wall, mediastinum, deltoid, and parapharyngeal soft tissue). Their size ranged 4.4–7.5 cm (median, 6.2). One patient presented with constitutional symptoms. Surgery with (2) or without (1) neo/adjuvant therapy was the treatment. At last follow-up (8–21 months), 2 patients developed progressive disease (1 recurrence; 1 distant metastasis). The immunophenotype of these tumors is potentially misleading with variable expression of EMA (2 of 3), pankeratin (2 of 4), synaptophysin (2 of 3), MUC4 (1 of 3), and ALK (1 of 3). All tumors were negative for S100 and SOX10. These observations point to the existence of heretofore under-recognized group of epithelioid and round cell neoplasms of soft tissue and bone, driven by EWSR1::ATF1 fusions, but distinct from established EWSR1::ATF1-associated soft tissue entities. Their overall morphology and immunophenotype recapitulate that of the emerging EWSR1/FUS::CREB fusion associated intra-abdominal epithelioid/round cell neoplasms. Our cases point to a potentially aggressive clinical behavior. Recognizing this tumor type is mandatory to delineate any inherent biological and/or therapeutic distinctness from other, better-known sarcomas in the differential diagnosis including sclerosing epithelioid fibrosarcoma.
CRIS-Team Scopus Importer:2024-07-26
Keywords: Ewing sarcoma; Genetic landscape; Mimics; Precision medicine; Profiling; Targeted next-generation sequencing