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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A Firing Cannon: Bilateral Lower Limb Ischemia as a Manifestation of Cardiac Myxoma. - Elbayomi, Mohamed; Groß, Raphael; Presheet, Pathare; Agaimy, Abbas; May, Mattias; Wayend, Micheal; Heim, Christian (Thoracic and Cardiovascular Surgeon Reports, 2024)
Background Cardiac myxomas are the most common primary cardiac neoplasms. Case Description We present a case of a middle-aged lady with cardiac myxoma in her left atrium awaiting semi-elective surgery. During the preoperative period, the patient presented emergently with acute bilateral lower limb ischemia. This lady was fortunate to have these emboli fired towards a tissue with ischemia tolerance capacity. If these emboli had been directed toward the central nervous system, this patient would have experienced devastating complications and even death. Conclusion This presentation opens the debate on the timing of surgical intervention in myxoma patients.
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A floating collagen matrix triggers ring formation and stemness characteristics in human colorectal cancer organoids - Wimmers, Daniel; Hübner, Kerstin; Dale, Trevor; Papargyriou, Aristeidis; Reichert, Maximilian; Hartmann, Arndt; Schneider-Stock, Regine (Pathology Research and Practice, 2025)
Intestinal organoids reflect the 3D structure and function of their original tissues. Organoid are typically cultured in Matrigel, an extracellular matrix (ECM) mimicking the basement membrane, which is suitable for epithelial cells but does not accurately mimic the tumour microenvironment of colorectal cancer (CRC). The ECM and particularly collagen type I is crucial for CRC progression and invasiveness. Given that efforts to examine CRC organoid invasion in a more physiologically relevant ECM have been limited, we used a floating collagen type I matrix (FC) to study organoid invasion in three patient-derived CRC organoid lines. In FC gel, organoids contract, align, and fuse into macroscopic ring structures, initiating minor branch formation and invasion fronts, phenomena unique for the collagen ECM and otherwise not observed in Matrigel-grown CRC organoids. In contrast to Matrigel, FC organoids showed basal extrusion with improper actin localization, but without change in the organoid polarity. Moreover, small clusters of vital invading cells were observed. Gene expression analysis revealed that the organoids cultured in a FC matrix presented more epithelial and stem cell-like characteristics. This novel technique of cultivating CRC organoids in a FC matrix represents an in-vitro model for studying cancer organization and matrix remodelling with increased organoid stemness potential.
CRIS-Team Scopus Importer:2025-05-09
Keywords: Collagen I; Invasiveness; Matrigel; Ring structures; Stemness; TROP2

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

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

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

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

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

A humanized mouse identifies the bone marrow as a niche with low therapeutic IgG activity - Lux, Anja; Seeling, Michaela; Baerenwaldt, Anne; Lehmann, Birgit; Schwab, Inessa; Repp, Roland; Meidenbauer, Norbert; Mackensen, Andreas; Hartmann, Arndt; Heidkamp, Gordon Frederik; Dudziak, Diana; Nimmerjahn, Falk (Cell Reports, 2014)
Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG) activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fc? receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.
EVALuna2:6588

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

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

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

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

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

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

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

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

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

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

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

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

Analysis of androgen receptor mRNA expression in urothelial carcinoma of the bladder - Sikic, D.; Wirtz, R.; Wach, S.; Dyrskjot, L.; Erben, P.; Bolenz, C.; Breyer, J.; Otto, W.; Hoadley, K.; Lerner, S.; Eckstein, Markus; Hartmann, Arndt; et al. (2018)
EVALuna2:34064

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

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

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

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

Anamnese, pathologische Originalbefunde, Therapie bezogene Parameter und Krankheitsverlauf: retrospektive Analyse von klinisch basierten Faktoren für die Prognose des tumorspezifischen Überlebens von 378 Patienten mit pT1-Harnblasenkarzinom - Breyer, J.; Otto, Wolfgang; Hartmann, Arndt; Bumes, B.; Bruendl, J.; Gierth, M.; Bertz, Simone; Denzinger, Stefan; Burger, M.; Lausenmeyer, E. M. (Aktuelle Urologie, 2015)
Urothelial carcinoma of the bladder (UBC) at stage pT1 is a heterogenous disease. Established criteria for prognosis prediction are not suitable for every patient. Choosing the right therapeutic strategy for the individual patient thus remains a challenge. The aim of the present study was to identify clinical parameters regarding cancer-specific survival (CSS) in patients with pT1 UBC.A retrospective analysis of clinical parameters of all patients with a pT1 UBC between 1989 and 2012 from a single centre was performed. Treatment consisted of transurethral resection, second resection followed by initially bladder sparing treatment. Anamnestic data, histopathological reports and clinical course were assessed with CSS being defined as primary endpoint. Kaplan-Meier analysis, uni- and multivariate analysis were performed using SPSS (Version 22, IBM).378 patients (78% male, median age 72 years) were included, median follow-up was 35 months. Pathological stage pT1G3 (66 vs. 91%, p<0.001), lack of instillation therapy (66 vs. 83%, p<0.001), presence of a second malignoma (41 vs. 77%, p=0,004), diagnosis after 2000 (75 vs. 76%, p=0,018) and tumour progress (42 vs. 85%, p<0.001) were associated with a worse CSS in univariate and Kaplan-Meier analysis. Multivariate analysis revealed the presence of a second malignoma (HR 2.267; CI 95% 1.143-4.497, p=0.019), pathological stage pT1G3 at initial diagnosis (HR 4.567; CI 95% 2.040-10.22, p<0.001) and tumour progress (HR 3.742; CI 95% 1.544-9.069, p=0.003) as independent negative predictors of CSS. Instillation therapy was a prognostic factor for improved CSS (HR 0.368; CI 95% 0.212-0.638, p<0.001).The present study identified the presence of a second malignoma, pathological stage pT1G3 and tumour progress as negative predictive factors for CSS. Maintenance instillation therapy after reresection was associated with an improved CSS.
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Anatomical locations in the oral cavity where surgical resections of oral squamous cell carcinomas are associated with a close or positive margin-a retrospective study - Kerker, Florian; Adler, Werner; Brunner, Kathrin; Moest, Tobias; Wurm, Matthias; Nkenke, Emeka; Neukam, Friedrich Wilhelm; von Wilmowsky, Cornelius (Clinical Oral Investigations, 2018)
OBJECTIVES: This study aimed to identify anatomical areas where resections of oral squamous cell carcinomas (OSCC) are significantly associated with close or positive margins. MATERIALS AND METHODS: This retrospective study included 330 patients with a primary OSCC from 2010 to 2015. Patient and tumour data were categorised into three groups by R-status (R0 [clear], ≥ 5 mm, 185 patients [56.06%]; R1 [positive], < 1 mm, 24 patients [7.27%]; and R0 [close], 1-5 mm, 121 patients [36.67%]). RESULTS: Areas where resections were significantly associated with close or positive margins were the hard palate (p < 0.001), buccal mucosa (p = 0.03), floor of the mouth (p = 0.004), lower alveolar ridge (p = 0.01), retromolar triangle (p = 0.005), and dorsal tongue (p = 0.02). CONCLUSIONS: Anatomical areas were identified in the oral cavity where it is challenging to resect OSCCs with an adequate safety margin. CLINICAL RELEVANCE: These results may enable surgeons to achieve a postulated safe distance during tumour resection, leading to a survival benefit for patients.
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Androgen Receptor mRNA Expression in Urothelial Carcinoma of the Bladder: A Retrospective Analysis of Two Independent Cohorts - Sikic, Danijel; Wirtz, Ralph M.; Wach, Sven; Dyrskjot, Lars; Erben, Philipp; Bolenz, Christian; Breyer, Johannes; Otte, Wolfgang; Hoadley, Katherine A.; Lerner, Seth P.; Eckstein, Markus; Hartmann, Arndt; et al. (Translational Oncology, 2019)
INTRODUCTION: Gender-specific differences have led to the androgen receptor (AR) being considered a possible factor in the pathophysiology of urothelial carcinoma of the bladder (UCB), but the exact role remains unclear. MATERIALS AND METHODS: The association of AR mRNA expression with clinicopathological features was retrospectively analyzed in two previously described cohorts. The first cohort consisted of 41 patients with all stages of UCB treated at Aarhus University Hospital, Denmark. The second cohort consisted of 323 patients with muscle-invasive bladder cancer (MIBC) accumulated by the Cancer Genome Atlas (TCGA) Research Network. RESULTS: AR mRNA expression is significantly higher in non-muscle-invasive bladder cancer (NMIBC) when compared to MIBC (P = .0004), with no relevant changes within the different stages of MIBC. AR mRNA expression was significantly associated with TCGA molecular subtypes (P < .0001). In the total cohort, there was no association between AR expression and gender (P = .23). When analyzed separately, females showed a significantly worse disease-free (P = .03) and overall survival (P = .02) when expressing AR mRNA above median level, while the same was not observed for men. Multivariable Cox's regression analyses revealed AR mRNA expression to be an independent prognostic marker for disease-free survival in women (P = .007). CONCLUSIONS: AR mRNA expression is significantly higher in NMIBC than in MIBC, while high AR mRNA expression is associated with worse survival in females with MIBC. Further studies need to investigate the gender-specific role of AR in UCB.
CRIS-Team WoS Importer:2019-03-22

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

Angioleiomyoma of the Sinonasal Tract: Analysis of 16 Cases and Review of the Literature - Agaimy, Abbas; Michal, Michael; Thompson, Lester D.R.; Michal, Michal (Head and Neck Pathology, 2015)
Angioleiomyoma (ALM; synonyms: angiomyoma, vascular leiomyoma) is an uncommon benign tumor of skin and subcutaneous tissue. Most arise in the extremities (90 %). Head and neck ALMs are uncommon ( 10 % of all ALMs) and those arising beneath the sinonasal tract mucosa are very rare (<1 %) with 38 cases reported so far. We herein analyzed 16 cases identified from our routine and consultation files. Patients included seven females and nine males aged 25-82 years (mean 58; median 62). Symptoms were intermittent nasal obstruction, sinusitis, recurrent epistaxis, and a slow-growing mass. Fifteen lesions originated within different regions of the nasal cavity and one lesion was detected incidentally in an ethmoid sinus sample. Size range was 6-25 mm (mean 11). Histologically, all lesions were well circumscribed but non-encapsulated and most (12/16) were of the compact solid type superficially mimicking conventional leiomyoma but contained numerous compressed muscular veins. The remainder were of venous (2) and cavernous (2) type. Variable amounts of mature fat were observed in four cases (25 %). Atypia, necrosis, and mitotic activity were absent. Immunohistochemistry showed consistent expression of smooth muscle actin (12/12), h-caldesmon (9/9), muscle-specific actin (4/4), variable expression of desmin (11/14) and CD56 (4/6), and absence of HMB45 expression (0/11). The covering mucosa was ulcerated in 6 cases and showed squamous metaplasia in one case. There were no recurrences after local excision. Submucosal sinonasal ALMs are rare benign tumors similar to their reported cutaneous counterparts with frequent adipocytic differentiation. They should be distinguished from renal-type angiomyolipoma. Simple excision is curative.
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Angiosarcoma arising in association with vascular Dacron grafts and orthopedic joint prostheses: clinicopathologic, immunohistochemical, and molecular study - Agaimy, Abbas; Ben-Izhak, Ofer; Lorey, Thomas; Scharpf, Marcus; Rubin, Brian P. (Annals of Diagnostic Pathology, 2016)
Angiosarcoma may rarely arise near an inert foreign body material including vascular grafts and metal joint prostheses. Sixteen such cases have been reported since 1972 but mostly in the radiologic or surgical literature without detailed histologic or molecular analyses. We herein describe the clinicopathologic and molecular features of 2 new cases and reanalyzed 3 previously reported cases of angiosarcoma that developed in association with Dacron grafts for vascular repair (n=3) or related to orthopedic metal prostheses for joint replacement (n=2). All patients were men aged 50 to 84 years (median, 71 years). Mean time to development of angiosarcoma was 9years (range, 4.6-17 years). Symptoms were recurrent bleeding/loosening of prosthesis for suspected infection (in the joint prosthesis cases) and fatigue, weight loss, and abdominal symptoms in the Dacron-associated cases. Four patients died of disease within 1 to 24 months (mean, 8 months). One patient was alive after radical surgery, radiochemotherapy, and embolization of pulmonary metastases (17months). Histologically, all tumors were high-grade epithelioid neoplasms with a predominant solid growth pattern and variable vasoformation. All tumors expressed CD31, ERG, FLI-1, and variably pancytokeratin (diffuse in 3 cases), but none expressed D2-40, MDM2, or CDK4. Fluorescence in situ hybridization analysis revealed no MDM2 or CDK4 alterations. MYC was expressed in all cases, but only 1 case was MYC amplified by fluorescence in situ hybridization. Angiosarcomas are exceedingly rare fatal complications of long-standing metal and Dacron prostheses. Awareness of their morphology and frequent cytokeratin expression is necessary to avoid misdiagnosis as metastatic carcinoma. Limited awareness of their existence explains delayed clinical diagnosis in most of cases. Absence of MDM2/CDK4 alterations underlines their distinction from intimal-type sarcomas.
EVALuna2:6695

Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy - Naschberger, Elisabeth; Croner, Roland S.; Merkel, Susanne; Dimmler, Arno; Tripal, Philipp; Amann, Kerstin Ute; Kremmer, Elisabeth; Brueckl, Wolfgang M.; Papadopoulos, Thomas; Hohenadl, Christine; Hohenberger, Werner; Stürzl, Michael (International Journal of Cancer, 2008)
Angiogenesis and inflammation are the 2 major stroma reactions in colorectal carcinoma (CRC). Guanylate binding protein-1 (GBP-1) is a key mediator of angiostatic effects of inflammation. Therefore, we hypothesized that GBP-1 may be a biomarker of intrinsic angiostasis associated with an improved outcome in CRC patients. GBP-1 was strongly expressed in endothelial cells and immune cells in the desmoplastic stroma of 32% of CRC as determined by immunohistochemical investigation of 388 sporadic CRC. Cancer-related 5-year survival was highly significant (p < 0.001) increased (16.2%) in patients with GBP-1-positive CRC. Multivariate analysis showed that GBP-1 is an independent prognostic factor indicating a reduction of the relative risk of cancer-related death by the half (p = 0.032). A comparative transcriptome analysis (22,215 probe sets) of GBP-1-positive (n = 12) and -negative (n = 12) tumors showed that particularly IFN-γ-induced genes including the major antiangiogenic chemokines CXCL9, CXCL10 and CXCL11 were coexpressed with GBP-1. Altogether our findings indicated that GBP-1 may be a novel biomarker and an active component of a Th-1-like angiostatic immune reaction in CRC. This reaction may affect patient's response to antiangiogenic therapy and the identification of such tumors may provide a novel criterion for patient selection. Moreover, the induction of a Th-1-like angiostatic immune reaction may be a promising approach for the clinical treatment of CRC. © 2008 Wiley-Liss, Inc.
Created from Fastlane, Scopus look-up
Keywords: Angiogenesis; Colorectal carcinoma; Guanylate binding protein-1; Inflammation; Interferon-γ

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Association between mammographic density and pregnancies relative to age and BMI: a breast cancer case-only analysis - Hack, Carolin; Emons, Julius; Jud, Sebastian; Heusinger, Katharina; Adler, Werner; Gaß, Paul; Haeberle, Lothar; Heindl, Felix; Hein, Alexander; Schulz-Wendtland, Rüdiger; Uder, Michael; Hartmann, Arndt; et al. (Breast Cancer Research and Treatment, 2017)
Percentage mammographic density (PMD) is a major risk factor for breast cancer (BC). It is strongly associated with body mass index (BMI) and age, which are themselves risk factors for breast cancer. This analysis investigated the association between the number of full-term pregnancies and PMD in different subgroups relative to age and BMI.Patients were identified in the breast cancer database of the University Breast Center for Franconia. A total of 2410 patients were identified, for whom information on parity, age, and BMI, and a mammogram from the time of first diagnosis were available for assessing PMD. Linear regression analyses were conducted to investigate the influence on PMD of the number of full-term pregnancies (FTPs), age, BMI, and interaction terms between them.As in previous studies, age, number of FTPs, and BMI were found to be associated with PMD in the expected direction. However, including the respective interaction terms improved the prediction of PMD even further. Specifically, the association between PMD and the number of FTPs differed in young patients under the age of 45 (mean decrease of 0.37 PMD units per pregnancy) from the association in older age groups (mean decrease between 2.29 and 2.39 PMD units). BMI did not alter the association between PMD and the number of FTPs.The effect of pregnancies on mammographic density does not appear to become apparent before the age of menopause. The mechanism that drives the effect of pregnancies on mammographic density appears to be counter-regulated by other influences on mammographic density in younger patients.
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Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment - Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Keeman, Renske; Canisius, Sander; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Auer, Paul L.; Augustinsson, Annelie; Freeman, Laura E. Beane; et al. (BREAST CANCER RES, 2021)
Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
CRIS-Team WoS Importer:2021-09-03

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

Association of molecular subtypes with breast cancer risk factors: a case-only analysis - Rauh, Claudia; Gaß, Paul; Heusinger, Katharina; Haeberle, Lothar; Jud, Sebastian; Hein, Alexander; Löhberg, Christian; Lux, Michael P.; Wachter, David; Heimrich, Jutta; Strehl, Johanna D.; Haller, Florian; et al. (European Journal of Cancer Prevention, 2015)
As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case-case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients' charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern.
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Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial - Kitz, Julia; Fokas, Emmanouil; Beissbarth, Tim; Stroebel, Philipp; Wittekind, Christian; Hartmann, Arndt; Rueschoff, Josef; Papadopoulos, Thomas; Roesler, Elisabeth; Ortloff-Kittredge, Peter; Kania, Ulrich; Schlitt, Hans; et al. (JAMA Surgery, 2018)
Importance: Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.. Objective: In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Design, Setting, and Participants: The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010. Interventions: Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy. Main Outcomes and Measures: The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model. Results: Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002). Conclusions and Relevance: This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.
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Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression, and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts - Bahlinger, Veronika; Branz, Annalena; Strissel, Pamela; Strick, Reiner; Lange, Fabienne; Geppert, Carol-Immanuel; Klümper, Niklas; Hölzel, Michael; Wach, Sven; Taubert, Helge; Sikic, Danijel; Wullich, Bernd; et al. (Histopathology, 2024)
Aims: Treatment options for advanced urothelial carcinoma (aUC) rapidly evolved: besides immunomodulative therapeutic options and inhibitors targeting Fibroblast growth factor receptor (FGFR) alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved. However, little is known about the associations of specific aUC properties and the surface target expression of TROP2 and NECTIN-4. Our aim was to characterize associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 protein and gene expression with morphomolecular and clinicopathological characteristics of aUC in two large independent cohorts. Methods and results: The TCGA BLCA (n = 405) and the CCC-EMN (n = 247) cohorts were retrospectively analysed. TROP2/TACSTD2 and NECTIN-4/NECTIN-4 are highly expressed at the protein and transcript level in aUC, and their expression status did not correlate with patient survival in both cohorts. NECTIN-4/NECTIN-4 expression was higher in luminal tumours and reduced in squamous aUCs. NECTIN-4 was negative in 10.6% of samples, and 18.4% of samples had low expression (H-score <15). The TROP2 negativity rate amounted to 6.5%. TACSTD2 and NECTIN-4 expression was reduced in neuroendocrine-like and/or protein-based double-negative tumours. TROP2- and NECTIN-4-negative tumours included one sarcomatoid and four neuroendocrine aUC. FGFR3 alterations and PD-L1 expression on tumour and immune cells did not associate with TROP2 or NECTIN-4 expression. Conclusions: TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression, thus representing a suitable target for ADC treatment in the majority of aUC. The expression loss was associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC.
CRIS-Team Scopus Importer:2024-01-19
Keywords: Advanced urothelial carcinoma; membranous expression; NECTIN-4/NECTIN-4; TACSTD2/TROP2; treatment options

A Standard Mammography Unit - Standard 3D Ultrasound Probe Fusion Prototype: First Results - Schulz-Wendtland, Rüdiger; Jud, Sebastian; Fasching, Peter; Hartmann, Arndt; Radicke, Marcus; Rauh, Claudia; Uder, Michael; Wunderle, Marius; Gaß, Paul; Langemann, Hanna; Beckmann, Matthias; Emons, Julius (Geburtshilfe und Frauenheilkunde, 2017)
The combination of different imaging modalities through the use of fusion devices promises significant diagnostic improvement for breast pathology. The aim of this study was to evaluate image quality and clinical feasibility of a prototype fusion device (fusion prototype) constructed from a standard tomosynthesis mammography unit and a standard 3D ultrasound probe using a new method of breast compression.Imaging was performed on 5 mastectomy specimens from patients with confirmed DCIS or invasive carcinoma (BI-RADS ((TM)) 6). For the preclinical fusion prototype an ABVS system ultrasound probe from an Acuson S2000 was integrated into a MAMMOMAT Inspiration (both Siemens Healthcare Ltd) and, with the aid of a newly developed compression plate, digital mammogram and automated 3D ultrasound images were obtained.The quality of digital mammogram images produced by the fusion prototype was comparable to those produced using conventional compression. The newly developed compression plate did not influence the applied x-ray dose. The method was not more labour intensive or time-consuming than conventional mammography. From the technical perspective, fusion of the two modalities was achievable.In this study, using only a few mastectomy specimens, the fusion of an automated 3D ultrasound machine with a standard mammography unit delivered images of comparable quality to conventional mammography. The device allows simultaneous ultrasound - the second important imaging modality in complementary breast diagnostics - without increasing examination time or requiring additional staff.
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Asymmetric Omphalopagus in a Triplet after In Vitro Fertilization: A Rare Case of Conjoined Twinning - Jabari, Samir; Carbon, Roman; Besendörfer, Manuel; Hartmann, Arndt; Rompel, Oliver; Hoerning, Andre; Söder, Stephan (Case Reports in Pediatrics, 2018)
Introduction: Asymmetric omphalopagus is a rare situation of conjoined twinning, in which a grossly defective twin is attached to the thorax and upper abdomen of the main twin. We describe a case of an asymmetric omphalopagus accompanied by a normal triplet after assisted reproductive technology (ART) and tried to further characterize the all aspects of the conjoined twins. Case Presentation: Perioperative diagnostic imaging was carried out followed by an autopsy to evaluate all aspects of the parasite accompanied by histological, immunohistochemical, and molecular biological evaluation. The parasite had well-developed lower extremities as well as upper extremities with a cleft hand syndrome. The sex was nondeterminable, but DNA fingerprinting revealed that both parasite and autosite are monozygotic, so are females. There was no sign of any axial skeleton or central nervous system. We found a rudimentary rectum with a nonpervious anus, a kidney, ureter, urinary bladder, and a blind-ending urethra. The blood supply of the parasite was connected to the vessel system of the autosite. Conclusions: To our knowledge, only two cases of parasitic omphalopagus after ART have been described to date. Altogether, 52 cases have been reported, and in most of them, the parasites were successfully separated.
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ATF2 loss promotes 5-FU resistance in colon cancer cells via activation of the ATR-Chk1 damage response pathway - Yang, Hao; Hübner, Kerstin; Hampel, Chuanpit; Erlenbach-Wünsch, Katharina; Selvamani, Selva Babu; Shukla, Vikas; Geppert, Carol-Immanuel; Hartmann, Arndt; Mahadevan, Vijayalakshmi; Schneider-Stock, Regine (BMC Cancer, 2023)
Background: The role of ATF2 in colon cancer (CC) is controversial. Recently, we reported that low ATF2 expression is characteristic of highly invasive tumors, suggesting that ATF2 might also be involved in therapy resistance. 5-Fluorouracil (5-FU) is the best-known chemotherapeutic drug for CC, but drug resistance affects its curative effect. To date, the role of ATF2 in the 5-FU response remains elusive. Methods/Results: For our study, we had available HCT116 cells (wild-type p53) and HT29 colon tumor cells (mutant p53) and their corresponding CRISPR‒Cas9-generated ATF2-KO clones. We observed that loss of ATF2 triggered dose- and time-dependent 5-FU resistance in HCT116 cells by activating the DNA damage response (DDR) pathway with high p-ATRThr1989 and p-Chk1Ser317 levels accompanied by an increase in the DNA damage marker γ-H2AX in vitro and in vivo using the chicken chorioallantoic membrane (CAM) model. Chk1 inhibitor studies causally displayed the link between DDR and drug resistance. There were contradictory findings in HT29 ATF2-KO cells upon 5-FU exposure with low p-Chk1Ser317 levels, strong apoptosis induction, but no effects on DNA damage. In ATF2-silenced HCT116 p53−/− cells, 5-FU did not activate the DDR pathway. Co-immunoprecipitation and proximity ligation assays revealed that upon 5-FU treatment, ATF2 binds to ATR to prevent Chk1 phosphorylation. Indeed, in silico modelling showed reduced ATR-Chk1 binding when ATF2 was docked into the complex. Conclusions: We demonstrated a novel ATF2 scaffold function involved in the DDR pathway. ATF2-negative cells are highly resistant due to effective ATR/Chk1 DNA damage repair. Mutant p53 seems to overwrite the tumor suppressor function of ATF2.
CRIS-Team Scopus Importer:2023-06-30
Keywords: ATR kinase; CAM model; DDR; DNA repair; γ-H2AX

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

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

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

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

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

Atypical Fibroxanthoma - Histological Diagnosis, Immunohistochemical Markers and Concepts of Therapy - Koch, Michael; Freundl, Anne J.; Agaimy, Abbas; Kiesewetter, Franklin; Kuenzel, Julian; Cicha, Iwona; Alexiou, Christoph (Anticancer Research, 2015)
Atypical fibroxanthoma (AFX) is an uncommon, rapidly growing cutaneous neoplasm of uncertain histogenesis. Thus far, there are no guidelines for diagnosis and therapy of this tumor.We included 18 patients with 21 AFX, and 2,912 patients with a total of 2,939 AFX cited in the literature between 1962 and 2014.In our cohort, excision with safety margin was performed in 100% of primary tumors. Local recurrences were observed in 25% of primary tumors and parotid metastases in 5%. Ten-year disease-specific survival was 100%. The literature research yielded 280 relevant publications. Over 90% of the reported cases were negative for cytokeratins, S100, desmin and human melanoma black 45 (HMB-45). Recurrent AFX was reported in 7.6% and metastasizing AFX in 2.75% cases. No significant differences in the recurrence and survival rates following wide local excision versus Mohs microsurgery were observed. Twenty-year disease-specific survival rate was 97.8%.A well-selected panel of immunohistochemical markers is necessary to establish AFX diagnosis with sufficient certainty. Adequately treated, AFX has an excellent prognosis, but long-term follow-up is recommended due to the potential for aggressive behavior.
EVALuna2:6738

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

Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With Ipilimumab - Uslu, Ugur; Agaimy, Abbas; Hundorfean, Gheorghe; Harrer, Thomas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2015)
Ipilimumab, a humanized CTLA-4 antibody, improves overall survival in patients with metastatic melanoma. However, immune-related adverse effects occur in about 65% of ipilimumab-treated patients and have to be adequately managed. A 55-year-old patient developed grade 3 autoimmune colitis 7 weeks after initiation of ipilimumab treatment and subsequently hepatitis with grade 3 elevation of transaminases and ?-glutamyl transferase. Colitis manifested with up to 18 watery and bloody stools per day and severe attacks of abdominal pain. After exclusion of infectious causes, immunosuppression with corticosteroids was initiated. Because of recurrent abdominal pain, spontaneous perforation of the colon had to be excluded. Elevated liver function tests (grade 3 CTCAE) occurred and differential diagnosis included immune-mediated, toxic, and viral hepatitis. It is interesting to note that, not an immune-mediated but a cytomegalovirus-induced hepatitis was diagnosed by serum blood tests and liver biopsy and was subsequently successfully treated. Careful elaboration of the patient under immunotherapy was essential as further immunosuppression mandatory for autoimmune hepatitis would have worsened the viral hepatitis. In conclusion, cytomegalovirus reactivation should be included in the differential in patients under immunotherapy with checkpoint inhibitors and has to be considered as a cause for morbidity.
EVALuna2:1966

Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis - Voskens, Caroline; Stoica, Diane; Rosenberg, Marita; Vitali, Francesco; Zundler, Sebastian; Ganslmayer, Marion; Knott, Heike; Wiesinger, Manuel; Wunder, Jutta; Kummer, Mirko; Siegmund, Britta; Schnoy, Elisabeth; et al. (Gut, 2022)
Objective Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.
CRIS-Team WoS Importer:2022-04-29

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Biological predictors of radiosensitivity in head and neck squamous cell carcinoma - Fiedler, Mathias; Weber, Florian; Hautmann, Matthias G.; Haubner, Frank; Reichert, Torsten E.; Klingelhoeffer, Christoph; Schreml, Stephan; Meier, Johannes K.; Hartmann, Arndt; Ettl, Tobias (Clinical Oral Investigations, 2018)
OBJECTIVES: The aim of this study is to investigate the influence of prognostic biomarkers on radiosensitivity and survival of advanced head and neck squamous cell carcinomas treated by primary (chemo)radiation. MATERIAL AND METHODS: The clinicopathological data and immunohistochemical staining of p16, c-Met, survivin, PD-1, and PD-L1 of 82 primarily (chemo)irradiated patients with head and neck squamous cell carcinoma were analyzed. Associations with local and locoregional radiation response, overall survival (OS), disease-free (DFS), and disease-specific survival (DSS) were assessed. RESULTS: Complete tumor response was associated with increased patient age (p = 0.007), N0-status (p = 0.022), M0-status (p = 0.007), and p16-positivity (p = 0.022). High PD-L1 was associated with M0-status (p = 0.026) and indicated tumor response to irradiation (p = 0.057); survivin expression showed higher rates of response failure (p = 0.073). Low PD-1 was associated with increased T-stage (p = 0.029) and local recurrence (p = 0.014). High PD-1 was strongly correlated with PD-L1-positive tumor infiltrating lymphocytes (p < 0.001). Low PD-L1 showed a significant correlation with high c-Met expression (p = 0.01). Significant predictors for unfavorable univariate survival were incomplete tumor response (DSS, p < 0.001), single radiotherapy (DSS, p = 0.002), M1-status (DSS, p < 0.001), decreased radiation dose (DSS, p = 0.014), high survivin (DSS, p = 0.045), and high c-Met (OS, p < 0.05). Survivin and c-Met also showed prognostic significance in multivariate survival analysis. CONCLUSIONS: P16 and PD-L1 indicate radiosensitivity, whereas survivin and c-Met implicate radioresistance in primarily (chemo)irradiated head and neck squamous cell carcinomas. The role of the PD-1/PD-L1 immune checkpoints in radiation response and survival merits further investigation. CLINICAL RELEVANCE: The findings may improve patient-specific therapy according to individual tumor characteristics.
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Biomarkers of precancerous colorectal cancer stages identified by transcriptome profiling - Siskova, Anna; Vymetalkova, Veronika; Vodicka, Pavel; Ferrero, Giulio; Naccarati, Alessio; Hampel, Chuanpit; Schneider-Stock, Regine (CANCER RESEARCH, 2022)
CRIS-Team WoS Importer:2023-04-07

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

Biphasic papillary renal cell carcinoma is a rare morphological variant with frequent multifocality: a study of 28 cases - Trpkov, Kiril; Athanazio, Daniel; Magi-Galluzzi, Cristina; Yilmaz, Helene; Clouston, David; Agaimy, Abbas; Williamson, Sean R.; Brimo, Fadi; Lopez, Jose I.; Ulamec, Monika; Rioux-Leclercq, Nathalie; Kassem, Maysoun; et al. (Histopathology, 2018)
AIMS: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC. METHODS AND RESULTS: We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39-86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34βE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes). CONCLUSIONS: Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal.
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Biphasic Squamoid Alveolar Renal Cell Carcinoma: A Distinctive Subtype of Papillary Renal Cell Carcinoma? - Hes, Ondrej; Condom Mundo, Enric; Peckova, Kvetoslava; Lopez, Jose I.; Martinek, Petr; Vanecek, Tomas; Falconieri, Giovanni; Agaimy, Abbas; Davidson, Whitney; Petersson, Fredrik; Bulimbasic, Stela; Damjanov, Ivan; et al. (American Journal of Surgical Pathology, 2016)
Biphasic squamoid alveolar renal cell carcinoma (BSARCC) has been recently described as a distinct neoplasm. Twenty-one cases from 12 institutions were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization. Tumors were removed from 11 male and 10 female patients, whose age ranged from 53 to 79 years. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9/21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. aCGH (confirmed by fluorescence in situ hybridization) in 5 analyzable cases revealed multiple numerical chromosomal changes including gains of chromosomes 7 and 17 in all cases. These changes were further disclosed in 6 additional cases, which were unsuitable for aCGH. We conclude that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All BSARCCs expressed CK7, EMA, vimentin, and cyclin D1. Antibody to cyclin D1 showed a unique and previously not recognized pattern of immunohistochemical staining. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to papillary RCC. Some BSARCCs were clinically aggressive, but their prognosis could not be predicted from currently available data. Present microscopic, immunohistochemical, and molecular genetic data strongly support the view that BSARCC is a distinctive and peculiar morphologic variant of papillary RCC.
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Bladder tumor subtype commitment occurs in carcinoma in-situ driven by key signaling pathways including ECM remodeling - Wullweber, Adrian; Strick, Reiner; Lange, Fabienne; Sikic, Danijel; Taubert, Helge; Wach, Sven; Wullich, Bernd; Bertz, Simone; Weyerer, Veronika; Stöhr, Robert; Breyer, J.; Burger, M.; et al. (EUROPEAN UROLOGY, 2021)
CRIS-Team WoS Importer:2021-08-20

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

BLU-285-the breakthrough in treatment of patients with aggressive systemic mastocytosis and gastrointestinal stromal tumor - Schneider-Stock, Regine (Annals of Translational Medicine, 2018)
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Bone Tissue Engineering Under Xenogeneic-Free Conditions in a Large Animal Model as a Basis for Early Clinical Applicability - Weigand, Annika; Beier, Justus; Schmid, Rafael; Knorr, Thomas; Kilian, David; Goetzl, Rebekka; Gerber, Thomas; Horch, Raymund E.; Boos, Anja (Tissue Engineering: Parts A, B, and C, 2017)
For decades, researchers have been developing a range of promising strategies in bone tissue engineering with the aim of producing a significant clinical benefit over existing therapies. However, a major problem concerns the traditional use of xenogeneic substances for the expansion of cells, which complicates direct clinical transfer. The study's aim was to establish a totally autologous sheep model as a basis for further preclinical studies and future clinical application. Ovine mesenchymal stromal cells (MSC) were cultivated in different concentrations (0%, 2%, 5%, 10%, and 25%) of either autologous serum (AS) or fetal calf serum (FCS). With an increase of serum concentration, enhanced metabolic activity and proliferation could be observed. There were minor differences between MSC cultivated in AS or FCS, comparing gene and protein expression of osteogenic and stem cell markers, morphology, and osteogenic differentiation. MSC implanted subcutaneously in the sheep model, together with a nanostructured bone substitute, either in stable block or moldable putty form, induced similar vascularization and remodeling of the bone substitute irrespective of cultivation of MSC in AS or FCS and osteogenic differentiation. The bone substitute in block form together with MSC proved particularly advantageous in the induction of ectopic bone formation compared to the cell-free control and putty form. It could be demonstrated that AS is suitable for replacement of FCS for cultivation of ovine MSC for bone tissue engineering purposes. Substantial progress has been made in the development of a strictly xenogeneic-free preclinical animal model to bring future clinical application of bone tissue engineering strategies within reach.
EVALuna2:32847

BRAF mutation testing in melanoma: results from a German observational multicenter study - Hartmann, Arndt; Schirmacher, Peter; Sterlacci, William; Koch, Winfried; Liesenfeld, David B.; Schif, Birgit; Garbe, Claus (Virchows Archiv, 2019)
Quality control of BRAF mutation testing methods used in routine practice is crucial for optimal treatment selection. In this prospective study, we assessed the impact of patient/sample characteristics on BRAF mutation testing results in patients with melanoma, during clinical practice. Data were collected on routine testing practices and documented mutation status in patients with melanoma stages IIIB, IIIC, or IV across 28 diagnostic pathology centers in Germany. Patient/sample data collected included: patient age, location of primary melanoma and metastases, origin of sample, melanoma subtype, and quality of tissue. Statistical influence of patient/sample characteristics on BRAF mutation rate was assessed using multiple logistic regression analyses and statistical models developed to predict the probability of BRAF mutations for individual patient cohorts. Data/samples from 642 patients with melanoma were analyzed. BRAF mutations were documented in 241/642 patients (37.5%). The primary statistical model to predict BRAF mutation rates included: age (continuous), origin of sample, method of mutation analysis, and quality of tissue. Analyses of post hoc collected data identified major deviations between documented mutation rates included in this study vs. routinely recorded mutation rates for three centers. When samples from these centers were excluded, the influence of testing method was no longer statistically significant. The final model included patient age, origin of sample (including metastasis location), and quality of tissue. Once validated in an independent population, this type of model could allow pathology centers to compare the performance of their testing methods with what would be expected based on patient, tumor, and sample characteristics.
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Branchioma: immunohistochemical and molecular genetic study of 23 cases highlighting frequent loss of retinoblastoma 1 immunoexpression - Bradová, Martina; Thompson, Lester D.R.; Hyrcza, Martin; Vaněček, Tomáš; Grossman, Petr; Michal, Michael; Hájková, Veronika; Taheri, Touraj; Rupp, Niels; Suster, David; Lakhani, Sunil; Nikolov, Dimitar Hadži; et al. (Virchows Archiv, 2023)
Branchioma is an uncommon benign neoplasm with an adult male predominance, typically occurring in the lower neck region. Different names have been used for this entity in the past (ectopic hamartomatous thymoma, branchial anlage mixed tumor, thymic anlage tumor, biphenotypic branchioma), but currently, the term branchioma has been widely accepted. Branchioma is composed of endodermal and mesodermal lineage derivatives, in particular epithelial islands, spindle cells, and mature adipose tissue without preexistent thymic tissue or evidence of thymic differentiation. Twenty-three branchiomas were evaluated morphologically. Eighteen cases with sufficient tissue were assessed by immunohistochemistry, next-generation sequencing (NGS) using the Illumina Oncology TS500 panel, and fluorescence in situ hybridization (FISH) using an RB1 dual-color probe. All cases showed a biphasic morphology of epithelial and spindle cells with intermingled fatty tissue. Carcinoma arising in branchioma was detected in three cases. The neoplastic cells showed strong AE1/3 immunolabeling (100%), while the spindle cells expressed CD34, p63, and SMA (100%); AR was detected in 40–100% of nuclei (mean, 47%) in 14 cases. Rb1 showed nuclear loss in ≥ 95% of neoplastic cells in 16 cases (89%), while two cases revealed retained expression in 10–20% of tumor cell nuclei. NGS revealed a variable spectrum of likely pathogenic variants (n = 5) or variants of unknown clinical significance (n = 6). Loss of Rb1 was detected by FISH in two cases. Recent developments support branchioma as a true neoplasm, most likely derived from the rudimental embryological structures of endoderm and mesoderm. Frequent Rb1 loss by immunohistochemistry and heterozygous deletion by FISH is a real pitfall and potential confusion with other Rb1-deficient head and neck neoplasms (i.e., spindle cell lipoma), especially in small biopsy specimens.
CRIS-Team Scopus Importer:2023-11-24
Keywords: And neck; Branchioma; CD34; Ectopic hamartomatous thymoma; Head; RET; Retinoblastoma 1

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

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients - Wunderle, Marius; Gaß, Paul; Häberle, Lothar; Flesch, Vivien M.; Rauh, Claudia; Bani, Mayada; Hack, Carolin; Schrauder, Michael G.; Jud, Sebastian; Emons, Julius; Erber, Ramona; Ekici, Arif Bülent; et al. (Breast Cancer Research and Treatment, 2018)
PURPOSE: BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy. METHODS: Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival. RESULTS: Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as "ypT0; ypN0" was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26-4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status. CONCLUSIONS: BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.
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Breast cancer risk - From genetics to molecular understanding of pathogenesis - Fasching, Peter; Ekici, Arif Bülent; Wachter, David Lukas; Hein, Alexander; Bayer, Christian M.; Häberle, Lothar; Löhberg, Christian; Schneider, Michael; Jud, Sebastian; Heusinger, K.; Rübner, Matthias; Rauh, Claudia; et al. (Geburtshilfe und Frauenheilkunde, 2013)
Several advancements over the last decade have triggered the developments in the field of breast cancer risk research. One of them is the availability of the human genome sequence along with cheap genotyping possibilities. Another is the globalization of research, which has led to the growth of research collaboration into large international consortia that facilitate the pooling of clinical and genotype data of hundreds of thousands of patients and healthy control individuals. This review concerns with the recent developments in breast cancer risk research and focuses on the discovery of new genetic breast cancer risk factors and their meaning in the context of established non-genetic risk factors. Finally the clinical application is highly dependent on the accuracy of breast cancer risk prediction models, not only for all breast cancer patients, but also for molecular subtypes, preferably for those which are associated with an unfavorable prognosis. Recently risk prediction incorporates all possible risk factors, which include epidemiological risk factors, mammographic density and genetic risk factors. © Georg Thieme Verlag KG Stuttgart• New York•.
CRIS-Team Scopus Importer:2021-07-19
Keywords: BRCA; breast cancer risk; gene-environment interaction; genetic risk factors; prediction models

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

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

Breast Tumor Analysis Using Shifted-Excitation Raman Difference Spectroscopy (SERDS) - Gebrekidan, Medhanie; Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Emons, Julius; Beckmann, Matthias; Bräuer, Andreas (Technology in Cancer Research & Treatment, 2018)
We used a shifted-excitation Raman difference spectroscopy method for the ex vivo classification of resected and formalin-fixed breast tissue samples as normal (healthy) tissue, fibroadenoma, or invasive carcinoma. We analyzed 8 tissue samples containing invasive carcinoma that were surrounded by normal tissue and 3 tissue samples with fibroadenoma only. We made various measurement sites on various tissue samples, in total 240 measurements for each type of tissue. Although the acquired raw spectra contain enough information to clearly differentiate between normal and tumor (fibroadenoma and invasive carcinoma) tissue, the differentiation between fibroadenoma and invasive carcinoma was possible only after the shifted-excitation Raman difference spectroscopy isolation of pure Raman spectra from the heavily fluorescence interfered raw spectra. We used 784 and 785 nm as excitation wavelengths for the shifted-excitation Raman difference spectroscopy method. The differences in the obtained pure Raman spectra are assigned to the different chemical compositions of normal breast tissue, fibroadenoma, and invasive breast carcinoma. Principal component analysis and linear discriminant analysis showed excellent classification results in the Raman shift range between 1000 and 1800 cm-1. Invasive breast carcinoma was identified with 99.15% sensitivity, and the absence of invasive carcinoma was identified with 90.40% specificity. Tumor tissue in tumor-containing tissue was identified with 100% sensitivity, and the absence of tumor in no-tumor containing tissue was identified with 100% specificity. As gold standard for the determination of the sensitivity and the specificity, we considered the conventional histopathological classification. In summary, shifted-excitation Raman difference spectroscopy could be potentially very useful to support histopathological diagnosis in breast pathology.
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Breast Tumor Cell Survival and Morphology in a Brain-like Extracellular Matrix Depends on Matrix Composition and Mechanical Properties - Türker, Esra; Andrade Mier, Mateo S.; Faber, Jessica; Padilla Padilla, Selma J.; Murenu, Nicoletta; Stahlhut, Philipp; Lang, Gregor; Lamberger, Zan; Weigelt, Jeanette; Schaefer, Natascha; Tessmar, Jörg; Strissel, Pamela; et al. (Advanced Biology, 2024)
Triple-negative breast cancer (TNBC) is the most invasive type of breast cancer with high risk of brain metastasis. To better understand interactions between breast tumors with the brain extracellular matrix (ECM), a 3D cell culture model is implemented using a thiolated hyaluronic acid (HA-SH) based hydrogel. The latter is used as HA represents a major component of brain ECM. Melt-electrowritten (MEW) scaffolds of box- and triangular-shaped polycaprolactone (PCL) micro-fibers for hydrogel reinforcement are utilized. Two different molecular weight HA-SH materials (230 and 420 kDa) are used with elastic moduli of 148 ± 34 Pa (soft) and 1274 ± 440 Pa (stiff). Both hydrogels demonstrate similar porosities. The different molecular weight of HA-SH, however, significantly changes mechanical properties, e.g., stiffness, nonlinearity, and hysteresis. The breast tumor cell line MDA-MB-231 forms mainly multicellular aggregates in both HA-SH hydrogels but sustains high viability (75%). Supplementation of HA-SH hydrogels with ECM components does not affect gene expression but improves cell viability and impacts cellular distribution and morphology. The presence of other brain cell types further support numerous cell–cell interactions with tumor cells. In summary, the present 3D cell culture model represents a novel tool establishing a disease cell culture model in a systematic way.
CRIS-Team Scopus Importer:2024-07-19
Keywords: breast tumor cells; co-cultures; hyaluronic acid; Matrigel; PCL scaffolds

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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