408 results on '"Eva Wardelmann"'
Search Results
2. Deep learning identifies histopathologic changes in bladder cancers associated with smoke exposure status.
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Okyaz Eminaga, Hubert Lau, Eugene Shkolyar, Eva Wardelmann, and Mahmoud Abbas
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Medicine ,Science - Abstract
Smoke exposure is associated with bladder cancer (BC). However, little is known about whether the histologic changes of BC can predict the status of smoke exposure. Given this knowledge gap, the current study investigated the potential association between histology images and smoke exposure status. A total of 483 whole-slide histology images of 285 unique cases of BC were available from multiple centers for BC diagnosis. A deep learning model was developed to predict the smoke exposure status and externally validated on BC cases. The development set consisted of 66 cases from two centers. The external validation consisted of 94 cases from remaining centers for patients who either never smoked cigarettes or were active smokers at the time of diagnosis. The threshold for binary categorization was fixed to the median confidence score (65) of the development set. On external validation, AUC was used to assess the randomness of predicted smoke status; we utilized latent feature presentation to determine common histologic patterns for smoke exposure status and mixed effect logistic regression models determined the parameter independence from BC grade, gender, time to diagnosis, and age at diagnosis. We used 2,000-times bootstrap resampling to estimate the 95% Confidence Interval (CI) on the external validation set. The results showed an AUC of 0.67 (95% CI: 0.58-0.76), indicating non-randomness of model classification, with a specificity of 51.2% and sensitivity of 82.2%. Multivariate analyses revealed that our model provided an independent predictor for smoke exposure status derived from histology images, with an odds ratio of 1.710 (95% CI: 1.148-2.54). Common histologic patterns of BC were found in active or never smokers. In conclusion, deep learning reveals histopathologic features of BC that are predictive of smoke exposure and, therefore, may provide valuable information regarding smoke exposure status.
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- 2024
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3. Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer
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Zoltán Pethő, Karolina Najder, Stephanie Beel, Benedikt Fels, Ilka Neumann, Sandra Schimmelpfennig, Sarah Sargin, Maria Wolters, Klavs Grantins, Eva Wardelmann, Miso Mitkovski, Andrea Oeckinghaus, and Albrecht Schwab
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Metabolism ,Oncology ,Medicine - Abstract
Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH was sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding, focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially altered the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreased when mice received the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifted from granulocyte rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.
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- 2023
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4. Health related Quality of Life over time in German sarcoma patients. An analysis of associated factors - results of the PROSa study
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Martin Eichler, Leopold Hentschel, Susanne Singer, Beate Hornemann, Stephan Richter, Christine Hofbauer, Peter Hohenberger, Bernd Kasper, Dimosthenis Andreou, Daniel Pink, Jens Jakob, Robert Grützmann, Stephen Fung, Eva Wardelmann, Karin Arndt, Kerstin Hermes-Moll, Olaf Schoffer, Marius Fried, Helena K. Jambor, Jürgen Weitz, Klaus-Dieter Schaser, Martin Bornhäuser, Jochen Schmitt, and Markus K. Schuler
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sarcoma ,GIST ,health-related quality of life ,patient reported outcomes ,EORTC QLQ-C30 ,longitudinal observational cohort ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
IntroductionSarcomas are rare cancers and very heterogeneous in their location, histological subtype, and treatment. Health-Related Quality of Life (HRQoL) of sarcoma patients has rarely been investigated in longitudinal studies.MethodsHere, we assessed adult sarcoma patients and survivors between September 2017 and February 2020, and followed-up for one year in 39 study centers in Germany. Follow-up time points were 6 (t1) and 12 months (t2) after inclusion. We used a standardized, validated questionnaire (the European Organisation for Research and Treatment of Cancer Quality of Life Core Instrument (EORTC QLQ-C30) and explored predictors of HRQoL in two populations (all patients (Analysis 1), patients in ongoing complete remission (Analysis 2)) using generalized linear mixed models.ResultsIn total we included up to 1111 patients at baseline (915 at t1, and 847 at t2), thereof 387 participants were in complete remission at baseline (334 at t1, and 200 at t2). When analyzing all patients, HRQoL differed with regard to tumor locations: patients with sarcoma in lower extremities reported lower HRQoL values than patients with sarcomas in the upper extremities. Treatment which included radiotherapy and/or systemic therapy was associated with lower HRQoL. For patients in complete remission, smoking was associated with worse HRQoL-outcomes. In both analyses, bone sarcomas were associated with the worst HRQoL values. Being female, in the age group 55-
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- 2023
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5. Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
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Ruth Berthold, Ilka Isfort, Cihan Erkut, Lorena Heinst, Inga Grünewald, Eva Wardelmann, Thomas Kindler, Pierre Åman, Thomas G. P. Grünewald, Florencia Cidre-Aranaz, Marcel Trautmann, Stefan Fröhling, Claudia Scholl, and Wolfgang Hartmann
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation. As the fusion protein represents a therapeutically challenging target, a profound understanding of MLS biology is elementary to uncover FUS-DDIT3-dependent molecular vulnerabilities. Recently, a specific reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was detected in MLS; however, details on the molecular mechanism of FUS-DDIT3-dependent YAP1 activation, and YAP1´s precise mode of action remain unclear. In elaborate in vitro studies, employing RNA interference-based approaches, small-molecule inhibitors, and stimulation experiments with IGF-II, we show that FUS-DDIT3-driven IGF-IR/PI3K/AKT signaling promotes stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co-localization of FUS-DDIT3 and YAP1/TEAD in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS-DDIT3 and YAP1 co-regulate oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In adipogenic differentiation assays, we show that YAP1 critically contributes to FUS-DDIT3-mediated adipogenic differentiation arrest. Taken together, our study provides mechanistic insights into a complex FUS-DDIT3-driven network involving IGF-IR/PI3K/AKT signals acting on Hippo/YAP1, and uncovers substantial cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS.
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- 2022
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6. Genomic characterization of small cell carcinomas of the uterine cervix
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Anne M. Schultheis, Ino deBruijn, Pier Selenica, Gabriel S. Macedo, Edaise M. daSilva, Salvatore Piscuoglio, Achim A. Jungbluth, Kay J. Park, David S. Klimstra, Eva Wardelmann, Wolfgang Hartmann, Claus Dieter Gerharz, Mareike vonPetersdorff, Reinhard Buettner, Jorge S. Reis‐Filho, and Britta Weigelt
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HPV ,mutational signatures ,neuroendocrine ,small cell carcinoma ,uterine cervix ,whole‐exome sequencing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its histology and poor survival rate. Here, we sought to define the genetic underpinning of SCCs of the uterine cervix and compare their mutational profiles with those of human papillomavirus (HPV)‐positive head and neck squamous cell carcinomas, HPV‐positive cervical carcinomas, and SCLCs using publicly available data. Using a combination of whole‐exome and targeted massively parallel sequencing, we found that the nine uterine cervix SCCs, which were HPV18‐positive (n = 8) or HPV16‐positive (n = 1), harbored a low mutation burden, few copy number alterations, and other than TP53 in two cases no recurrently mutated genes. The majority of mutations were likely passenger missense mutations, and only few affected previously described cancer‐related genes. Using RNA‐sequencing, we identified putative viral integration sites on 18q12.3 and on 8p22 in two SCCs of the uterine cervix. The overall nonsilent mutation rate of uterine cervix SCCs was significantly lower than that of SCLCs, HPV‐driven cervical adeno‐ and squamous cell carcinomas, or HPV‐positive head and neck squamous cell carcinomas. Unlike SCLCs, which are reported to harbor almost universal TP53 and RB1 mutations and a dominant tobacco smoke‐related signature 4, uterine cervix SCCs rarely harbored mutations affecting these genes (2/9, 22% TP53; 0% RB1) and displayed a dominant aging (67%) or APOBEC mutational signature (17%), akin to HPV‐driven cancers, including cervical adeno‐ and squamous cell carcinomas and head and neck squamous cell carcinomas. Taken together, in contrast to SCLCs, which are characterized by highly recurrent TP53 and RB1 alterations, uterine cervix SCCs were positive for HPV leading to inactivation of the suppressors p53 and RB, suggesting that these SCCs are convergent phenotypes.
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- 2022
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7. Complete Metabolic Response to Combined Immune Checkpoint Inhibition after Progression of Metastatic Colorectal Cancer on Pembrolizumab: A Case Report
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Carolin Krekeler, Klaus Wethmar, Jan-Henrik Mikesch, Andrea Kerkhoff, Kerstin Menck, Georg Lenz, Hans-Ulrich Schildhaus, Michael Wessolly, Matthias W. Hoffmann, Andreas Pascher, Inga Asmus, Eva Wardelmann, and Annalen Bleckmann
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immune checkpoint inhibition ,nivolumab ,ipilimumab ,microsatellite instability ,metastatic colorectal cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
DNA mismatch repair deficient (dMMR) and microsatellite instable (MSI) metastatic colorectal cancer (mCRC) can be successfully treated with FDA- and EMA-approved immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab (as single agents targeting the anti-programmed cell death protein-1 (PD-1)) or combinations of a PD-1 inhibitor with ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-targeting antibody. The best treatment strategy beyond progression on single-agent ICI therapy remains unclear. Here, we present the case of a 63-year-old male with Lynch-syndrome-associated, microsatellite instability-high (MSI-H) mCRC who achieved a rapid normalization of his tumor markers and a complete metabolic remission (CMR), currently lasting for ten months, on sequential ICI treatment with the combination of nivolumab and ipilimumab followed by nivolumab maintenance therapy after progression on single-agent anti-PD-1 ICI therapy. The therapy was well-tolerated, and no immune-related adverse events occurred. To the best of our knowledge, this is the first case of a sustained metabolic complete remission in an MSI-H mCRC patient initially progressing on single-agent anti-PD-1 therapy. Thus, dMMR mCRC patients might benefit from sequential immune checkpoint regimens even with long-term responses. However, further sophistication of clinical algorithms for treatment beyond progression on single-agent ICI therapy in MSI-mCRC is urgently needed.
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- 2023
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8. Sarcoma classification by DNA methylation profiling
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Christian Koelsche, Daniel Schrimpf, Damian Stichel, Martin Sill, Felix Sahm, David E. Reuss, Mirjam Blattner, Barbara Worst, Christoph E. Heilig, Katja Beck, Peter Horak, Simon Kreutzfeldt, Elke Paff, Sebastian Stark, Pascal Johann, Florian Selt, Jonas Ecker, Dominik Sturm, Kristian W. Pajtler, Annekathrin Reinhardt, Annika K. Wefers, Philipp Sievers, Azadeh Ebrahimi, Abigail Suwala, Francisco Fernández-Klett, Belén Casalini, Andrey Korshunov, Volker Hovestadt, Felix K. F. Kommoss, Mark Kriegsmann, Matthias Schick, Melanie Bewerunge-Hudler, Till Milde, Olaf Witt, Andreas E. Kulozik, Marcel Kool, Laura Romero-Pérez, Thomas G. P. Grünewald, Thomas Kirchner, Wolfgang Wick, Michael Platten, Andreas Unterberg, Matthias Uhl, Amir Abdollahi, Jürgen Debus, Burkhard Lehner, Christian Thomas, Martin Hasselblatt, Werner Paulus, Christian Hartmann, Ori Staszewski, Marco Prinz, Jürgen Hench, Stephan Frank, Yvonne M. H. Versleijen-Jonkers, Marije E. Weidema, Thomas Mentzel, Klaus Griewank, Enrique de Álava, Juan Díaz Martín, Miguel A. Idoate Gastearena, Kenneth Tou-En Chang, Sharon Yin Yee Low, Adrian Cuevas-Bourdier, Michel Mittelbronn, Martin Mynarek, Stefan Rutkowski, Ulrich Schüller, Viktor F. Mautner, Jens Schittenhelm, Jonathan Serrano, Matija Snuderl, Reinhard Büttner, Thomas Klingebiel, Rolf Buslei, Manfred Gessler, Pieter Wesseling, Winand N. M. Dinjens, Sebastian Brandner, Zane Jaunmuktane, Iben Lyskjær, Peter Schirmacher, Albrecht Stenzinger, Benedikt Brors, Hanno Glimm, Christoph Heining, Oscar M. Tirado, Miguel Sáinz-Jaspeado, Jaume Mora, Javier Alonso, Xavier Garcia del Muro, Sebastian Moran, Manel Esteller, Jamal K. Benhamida, Marc Ladanyi, Eva Wardelmann, Cristina Antonescu, Adrienne Flanagan, Uta Dirksen, Peter Hohenberger, Daniel Baumhoer, Wolfgang Hartmann, Christian Vokuhl, Uta Flucke, Iver Petersen, Gunhild Mechtersheimer, David Capper, David T. W. Jones, Stefan Fröhling, Stefan M. Pfister, and Andreas von Deimling
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Science - Abstract
Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.
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- 2021
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9. Analysis of drug sensitivity of human high-grade osteosarcoma in a chick chorioallantoic membrane (CAM) model: a proof of principle study
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Wiebke K. Guder, Wolfgang Hartmann, Marcel Trautmann, Jendrik Hardes, Eva Wardelmann, Maurice Balke, and Arne Streitbürger
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Chorioallantoic membrane model ,CAM ,Osteosarcoma ,Primary cell culture ,Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Objective Multi-agent chemotherapy is an important pillar in treatment of high-grade osteosarcoma. In an effort to improve patient survival, it is imperative to determine the effectiveness of new substances. The objective of this study was to investigate whether the chick chorioallantoic membrane (CAM) model can be used to analyze drug sensitivity in high-grade osteosarcoma. Results Spare biopsy tissue from five patients diagnosed with high-grade osteosarcoma was transferred into non-immortalized primary cell culture. After a pre-incubation period of 10 days, fertilized chick eggs were inoculated with primary tumor cells suspended in extracellular matrix gel. On day 16, treatment with 20 µmol/l doxorubicin (n = 4) or 25 µl of culture medium (n = 6) was performed for 24 h. CAM membranes were documented macroscopically, harvested and examined histologically. Transfer of biopsy specimens into primary cell culture was successful in all cases. 50% (n = 10) of eggs died after inoculation with tumor cells and before application of doxorubicin. No deaths occurred after application of doxorubicin. Histological examination found a response to doxorubicin in all four specimens. Based upon these results, the CAM model represents a promising preclinical alternative to animal experiments to determine drug sensitivity of osteosarcoma cells. Further research with regard to other substances and dosages appear justified.
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- 2020
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10. κB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis
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Stephanie Beel, Lina Kolloch, Lisa H. Apken, Lara Jürgens, Andrea Bolle, Nadine Sudhof, Sankar Ghosh, Eva Wardelmann, Michael Meisterernst, Konrad Steinestel, and Andrea Oeckinghaus
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Science - Abstract
The molecular mechanisms of acinar-to-ductal metaplasia (ADM) in the course of pancreatitis and cancer development are unclear. Here, the authors show that loss of κB-Ras and consequent Ral activation promotes tumour initiation and progression through persistent ADM and enhanced cell proliferation
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- 2020
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11. Impact of Adjuvant Radiation Therapy in Patients With Male Breast Cancer: A Multicenter International Analysis
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Daniel Rolf, MD, Khaled Elsayad, MD, Mohamed A.M. Meheissen, MD, Yasser Elkerm, MD, Carl Opitz, MD, Isabel Radke, MD, Anne Bremer, MD, Anne Hülskamp, MD, Rasha Elsaka, MD, Horeya M. Ismail, MD, Essam Elfaham, MD, Abdelsalam Attia Ismail, MD, Hazem Elmansy, MD, Eva Wardelmann, PhD, Amr Abdelaziz Elsaid, MD, Barbara Krause-Bergmann, MD, Joke Tio, MD, Hans Theodor Eich, PhD, and Oliver Micke, PhD
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Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Purpose: Breast cancer in men accounts for approximately 1% of all breast cancers. Breast cancer trials have routinely excluded men. The aim of this analysis was to determine the effect of different treatment factors, in particular, postoperative radiation therapy (RT) on long-term outcomes. Methods and Materials: Seventy-one patients with male breast cancer treated in 5 closely cooperating institutions between 2003 and 2019 were analyzed. Results: Almost all patients (95%) underwent surgical resection. Forty-two patients (59%) received chemotherapy, and 59 (83%) received adjuvant hormonal therapy. Of the 71 patients, 52 (73%) were treated with RT. The rate of recurrence was 20% in the whole cohort, with a locoregional recurrence rate of 3%. In the entire group, the 5-year local control (LC) was 95%, whereas 5-year progression-free survival (PFS) and 5-year overall survival (OS) were 62% and 96%, respectively. There was a lower rate of relapses after adjuvant RT (19% vs 32%, P = .05) without in-field relapse after postoperative RT (0%) versus 10% in patients without RT (P = .02). In the multivariate analysis performed, hormonal therapy administration was found to have a possible significant effect on LC and PFS. Administration of adjuvant RT and stage affect PFS. In patients who received RT, there were no grade 3 or 4 acute toxicities. Conclusions: Adjuvant RT is an effective and safe treatment for male breast cancer patients with no infield relapses and better PFS. Hormonal therapy administration was found to have a possible effect on LC and PFS.
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- 2020
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12. Focal adhesion kinase confers pro‐migratory and antiapoptotic properties and is a potential therapeutic target in Ewing sarcoma
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Konrad Steinestel, Marcel Trautmann, Esther‐Pia Jansen, Uta Dirksen, Jan Rehkämper, Jan‐Henrik Mikesch, Julia S. Gerke, Martin F. Orth, Giuseppina Sannino, Maria‐Francisca Arteaga, Claudia Rossig, Eva Wardelmann, Thomas G. P. Grünewald, and Wolfgang Hartmann
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cytoskeleton ,Ewing sarcoma ,focal adhesion kinase ,metastasis ,migration ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Oncogenesis of Ewing sarcoma (EwS), the second most common malignant bone tumor of childhood and adolescence, is dependent on the expression of chimeric EWSR1‐ETS fusion oncogenes, most often EWSR1‐FLI1 (E/F). E/F expression leads to dysregulation of focal adhesions (FAs) enhancing the migratory capacity of EwS cells. Here, we show that, in EwS cell lines and tissue samples, focal adhesion kinase (FAK) is expressed and phosphorylated at Y397 in an E/F‐dependent way involving Ezrin. Employing different EwS cell lines as in vitro models, we found that key malignant properties of E/F are mediated via substrate‐independent autophosphorylation of FAK on Y397. This phosphorylation results in enhanced FA formation, Rho‐dependent cell migration, and impaired caspase‐3‐mediated apoptosis in vitro. Conversely, treatment with the FAK inhibitor 15 (1,2,4,5‐benzenetetraamine tetrahydrochloride (Y15) enhanced caspase‐mediated apoptosis and EwS cell migration, independent from the respective EWSR1‐ETS fusion type, mimicking an anoikis‐like phenotype and paralleling the effects of FAK siRNA knockdown. Our findings were confirmed in vivo using an avian chorioallantoic membrane model and provide a first rationale for the therapeutic use of FAK inhibitors to impair metastatic dissemination of EwS.
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- 2020
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13. Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML
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Thomas Oellerich, Constanze Schneider, Dominique Thomas, Kirsten M. Knecht, Olga Buzovetsky, Lars Kaderali, Christoph Schliemann, Hanibal Bohnenberger, Linus Angenendt, Wolfgang Hartmann, Eva Wardelmann, Tamara Rothenburger, Sebastian Mohr, Sebastian Scheich, Federico Comoglio, Anne Wilke, Philipp Ströbel, Hubert Serve, Martin Michaelis, Nerea Ferreirós, Gerd Geisslinger, Yong Xiong, Oliver T. Keppler, and Jindrich Cinatl
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Science - Abstract
In acute myeloid leukemia, hypomethylating agents decitabine and azacytidine are used interchangeably. Here, the authors show that the major metabolite of decitabine, but not azacytidine, is subject to SAMHD1 inactivation, highlighting SAMHD1 as a potential biomarker and therapeutic target
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- 2019
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14. Overexpression and Tyr421-phosphorylation of cortactin is induced by three-dimensional spheroid culturing and contributes to migration and invasion of pancreatic ductal adenocarcinoma (PDAC) cells
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Katharina Stock, Rebekka Borrink, Jan-Henrik Mikesch, Anna Hansmeier, Jan Rehkämper, Marcel Trautmann, Eva Wardelmann, Wolfgang Hartmann, Jan Sperveslage, and Konrad Steinestel
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Pancreatic ductal adenocarcinoma ,Cortactin ,Tumor cell migration and invasion ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background The nucleation-promoting factor cortactin is expressed and promotes tumor progression and metastasis in various cancers. However, little is known about the biological role of cortactin in the progression of pancreatic ductal adenocarcinoma (PDAC). Methods Cortactin and phosphorylated cortactin (Y421) were investigated immunohistochemically in 66 PDAC tumor specimens. To examine the functional role of cortactin in PDAC, we modulated cortactin expression by establishing two cortactin knockout cell lines (Panc-1 and BxPC-3) with CRISPR/Cas9 technique. Cortactin knockout was verified by immunoblotting and immunofluorescence microscopy and functional effects were determined by cell migration and invasion assays. A proteomic screening approach was performed to elucidate potential binding partners of cortactin. Results Immunohistochemically, we observed higher cortactin expression and Tyr421-phosphorylation in PDAC metastases compared to primary tumor tissues. In PDAC cell lines Panc-1 and BxPC-3, knockdown of cortactin impaired migration and invasion, while cell proliferation was not affected. Three-dimensional spheroid culturing as a model for collective cell migration enhanced cortactin expression and Tyr421-phosphorylation. The activation of cortactin as well as the migratory capacity of PDAC cells could significantly be reduced by dasatinib, a Src family kinase inhibitor. Finally, we identified gelsolin as a novel protein interaction partner of cortactin in PDAC. Conclusion Our data provides evidence that cohesive cell migration induces cortactin expression and phosphorylation as a prerequisite for the gain of an invasive, pro-migratory phenotype in PDAC that can effectively be targeted with dasatinib.
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- 2019
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15. Aminopeptidase N (CD13): Expression, Prognostic Impact, and Use as Therapeutic Target for Tissue Factor Induced Tumor Vascular Infarction in Soft Tissue Sarcoma
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Torsten Kessler, Ariane Baumeier, Caroline Brand, Michael Grau, Linus Angenendt, Saliha Harrach, Ursula Stalmann, Lars Henning Schmidt, Georg Gosheger, Jendrik Hardes, Dimosthenis Andreou, Johannes Dreischalück, Georg Lenz, Eva Wardelmann, Rolf M. Mesters, Christian Schwöppe, Wolfgang E. Berdel, Wolfgang Hartmann, and Christoph Schliemann
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Aminopeptidase N (CD13) is expressed on tumor vasculature and tumor cells. It represents a candidate for targeted therapy, e.g., by truncated tissue factor (tTF)-NGR, binding to CD13, and causing tumor vascular thrombosis. We analyzed CD13 expression by immunohistochemistry in 97 patients with STS who were treated by wide resection and uniform chemo-radio-chemotherapy. Using a semiquantitative score with four intensity levels, CD13 was expressed by tumor vasculature, or tumor cells, or both (composite value, intensity scores 1-3) in 93.9% of the STS. In 49.5% tumor cells, in 48.5% vascular/perivascular cells, and in 58.8%, composite value showed strong intensity score 3 staining. Leiomyosarcoma and synovial sarcoma showed low expression; fibrosarcoma and undifferentiated pleomorphic sarcoma showed high expression. We found a significant prognostic impact of CD13, as high expression in tumor cells or vascular/perivascular cells correlated with better relapse-free survival and overall survival. CD13 retained prognostic significance in multivariable analyses. Systemic tTF-NGR resulted in significant growth reduction of CD13-positive human HT1080 sarcoma cell line xenografts. Our results recommend further investigation of tTF-NGR in STS patients. CD13 might be a suitable predictive biomarker for patient selection.
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- 2018
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16. Strengthening health data on a rare and heterogeneous disease: sarcoma incidence and histological subtypes in Germany
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Meike Ressing, Eva Wardelmann, Peter Hohenberger, Jens Jakob, Bernd Kasper, Katharina Emrich, Andrea Eberle, Maria Blettner, and Sylke Ruth Zeissig
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Sarcoma ,Incidence ,Histology ,Germany ,Gastrointestinal Stromal tumours ,Topography, Medical ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background The population-based incidence of sarcoma and its histological subtypes in Germany is unknown. Up-to-date information on a disease with an incidence comparable to other cancer entities is of high public health relevance. The aim of this study was to determine this incidence and to detect significant changes in incidence trends using data from German epidemiological cancer registries. Methods Pooled data from the German Centre for Cancer Registry Data with a primary diagnosis occurring in 2013 were used. To date, this is the latest data on cancer incidence available for Germany. All German cancer registries with sufficient completeness were included (10 out of 11), covering a population of 70.0 million people, representing 87% of the German population. All malignant sarcomas according to the RARECARE Project and the WHO classification 2002 were considered for analysis and, above all, gastrointestinal stromal tumours (GIST) of uncertain behaviour. Sensitivity analysis was performed excluding certain histologies. Results The analysis included 3404 cases in men and 3442 cases in women diagnosed in 2013. The age adjusted sarcoma incidence (European standard) was 7.4 (men) and 6.6 (women) per 100,000 inhabitants. About 70% of sarcomas were soft tissue sarcomas, about 22% GIST, and about 9% bone sarcomas. The most common histological subtypes besides GIST were fibrosarcomas (14%) and liposarcomas (12%) in men and complex mixed and stromal neoplasms (22%), non-uterine leiomysarcomas (10%) and fibrosarcomas (9%) in women. Considering the trend for the years of diagnosis 2004 to 2013, there was a significant increase in incidence for GIST while the incidence of soft tissue sarcomas (only men) as well as of bone sarcoma stayed constant over time. As to soft tissue sarcoma in women, the incidence stayed constant up to the year 2009 and significantly decreased afterwards. Conclusion This study is the first detailed analysis of a German-wide population-based sarcoma incidence showing results comparable to the incidence detected in the RARECARE Project.
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- 2018
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17. Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis
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Miriam Stölting, Christiane Geyer, Anne Helfen, Anke Hahnenkamp, Marco V. Usai, Eva Wardelmann, Michael T. Kuhlmann, Moritz Wildgruber, and Carsten Höltke
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atherosclerosis ,endothelin system ,molecular imaging ,ApoE-KnockOut ,carotid endarterectomy ,fluorescence imaging ,Biology (General) ,QH301-705.5 - Abstract
Cardiovascular disease remains the most frequent cause of death worldwide. Atherosclerosis, an underlying cause of cardiovascular disease, is an inflammatory disorder associated with endothelial dysfunction. The endothelin system plays a crucial role in the pathogenesis of endothelial dysfunction and is involved in the development of atherosclerosis. We aimed to reveal the expression levels of the endothelin-A receptor (ETAR) in the course of atherogenesis to reveal possible time frames for targeted imaging and interventions. We used the ApoE−/− mice model and human specimens and evaluated ETAR expression by quantitative rtPCR (qPCR), histology and fluorescence molecular imaging. We found a significant upregulation of ETAR after 22 weeks of high-fat diet in the aortae of ApoE−/− mice. With regard to translation to human disease, we applied the fluorescent probe to fresh explants of human carotid and femoral artery specimens. The findings were correlated with qPCR and histology. While ETAR is upregulated during the progression of early atherosclerosis in the ApoE−/− mouse model, we found that ETAR expression is substantially reduced in advanced human atherosclerotic plaques. Moreover, those expression changes were clearly depicted by fluorescence imaging using our in-house designed ETAR-Cy 5.5 probe confirming its specificity and potential use in future studies.
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- 2020
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18. Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment.
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Michaela Angelika Ihle, Sebastian Huss, Wiebke Jeske, Wolfgang Hartmann, Sabine Merkelbach-Bruse, Hans-Ulrich Schildhaus, Reinhard Büttner, Harri Sihto, Kirsten Sundby Hall, Mikael Eriksson, Peter Reichardt, Heikki Joensuu, and Eva Wardelmann
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Medicine ,Science - Abstract
Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.
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- 2018
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19. Downregulation of PIK3CA via antibody-esiRNA-complexes suppresses human xenograft tumor growth.
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Nicole Bäumer, Jan Rehkämper, Neele Appel, Lisa Terheyden, Wolfgang Hartmann, Eva Wardelmann, Frank Buchholz, Carsten Müller-Tidow, Wolfgang E Berdel, and Sebastian Bäumer
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Medicine ,Science - Abstract
Precision cancer therapy requires on the one hand detailed knowledge about a tumor's driver oncogenes and on the other hand an effective targeted therapy that specifically inhibits these oncogenes. While the determination of genomic landscape of a tumor has reached a very precise level, the respective therapy options are scarce. The application of small inhibitory (si) RNAs is a promising field of investigation. Here, we present the effective in vivo-treatment of colorectal cancer (CRC) xenograft tumors with antibody-complexed, endoribonuclease-prepared small inhibitory (esi)RNAs. We chose heterogeneous endoribonuclease-prepared siRNA pools (esiRNAs) against the frequently mutated genes PIK3CA and KRAS and coupled them to the anti-EGFR antibody cetuximab, which was internalized specifically into the tumor cells. esiRNA pools have been shown to exhibit superior specificity in target gene knockdown compared to classic siRNAs. We identified a significant decrease in tumor growth upon this treatment due to decreased tumor cell proliferation. The ex vivo-analysis of the xenograft CRC tumors revealed the expected downregulation of the intended direct targets PIK3CA and KRAS on protein level. Moreover, known downstream targets for EGFR signaling such as p-ERK, p-AKT, and c-MYC were decreased as well. We therefore propose the use of antibody-esiRNA complexes as a novel experimental treatment option against key components of the EGFR signaling cascade.
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- 2018
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20. Adjuvant chemotherapy-Radiotherapy-Chemotherapy sandwich protocol in resectable soft tissue sarcoma: An updated single-center analysis of 104 cases.
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Christoph Schliemann, Andrea Kerkhoff, Paula Hesse, Sebastian Bröckling, Jendrik Hardes, Arne Streitbürger, Dimosthenis Andreou, Georg Gosheger, Sandra Elges, Eva Wardelmann, Wolfgang Hartmann, Rolf Mesters, Georg Lenz, Normann Willich, Jan Kriz, Hans Eich, Wolfgang E Berdel, and Torsten Kessler
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Medicine ,Science - Abstract
Adjuvant therapy of local soft tissue sarcomas (STS) after wide surgical excision still is a topic under controversial scientific debate. In this single center report we have offered an adjuvant "sandwich" therapy protocol consisting of 4 cycles of doxorubicin (75 mg/m2 i.v. over 1 h on day 1) followed by ifosfamide (5 g/m2 i.v. over 24 h starting on day 1) and local radiotherapy scheduled between chemotherapy cycles 2 and 3 to 104 consecutive patients after wide surgical excision (R0) of histologically proven high-grade STS. After a mean follow-up of 39 months (range 5-194 months) relapse free survival (RFS) at 2 and 5 years was 68.1% (95% CI, 58.5-77.7%) and 61.2% (95% CI, 50.4-71.6%). When analyzing the 82 STS cases of the extremities only 2- and 5-year RFS was 74.0% (95% CI, 64.0-84.0%) and 65.3% (95% CI, 53.7-76.9%). By intent-to-treat analysis, the overall survival (OS) at 2 years was 87.3% (95% CI, 80.5-94.1%) and 75.6% (95% CI, 65.2-86.0%) at 5 years, while OS for STS of the extremities only cohort was 90.5% (95% CI, 83.7-97.3%) and 79.0% (95% CI, 68.4-89.6%), respectively. Tolerability of the treatment was good. This analysis demonstrates the feasibility of adjuvant chemoradiotherapy and reflects the results of the long lasting intensive multidisciplinary team approach at our "high-volume" sarcoma center. The long-term survival in our patients is among the highest reported and the low local and distant recurrence rate in high-risk STS is at least comparable to the published data.
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- 2018
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21. Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer.
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Lars Henning Schmidt, Birthe Heitkötter, Arik B Schulze, Christoph Schliemann, Konrad Steinestel, Marcel Trautmann, Alessandro Marra, Ludger Hillejan, Michael Mohr, Georg Evers, Eva Wardelmann, Kambiz Rahbar, Dennis Görlich, Georg Lenz, Wolfgang E Berdel, Wolfgang Hartmann, Rainer Wiewrodt, and Sebastian Huss
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Medicine ,Science - Abstract
PSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC).Immunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated.PSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases.Here, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option.
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- 2017
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22. Correction: Potential therapeutic impact of CD13 expression in non-small cell lung cancer.
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Lars Henning Schmidt, Caroline Brand, Janine Stucke-Ring, Christoph Schliemann, Torsten Kessler, Saliha Harrach, Michael Mohr, Dennis Görlich, Alessandro Marra, Ludger Hillejan, Carsten Müller-Tidow, Georg Lenz, Eva Wardelmann, Rainer Wiewrodt, Wolfgang E Berdel, Christian Schwöppe, and Wolfgang Hartmann
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0177146.].
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- 2017
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23. Potential therapeutic impact of CD13 expression in non-small cell lung cancer.
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Lars Henning Schmidt, Caroline Brand, Janine Stucke-Ring, Christoph Schliemann, Torsten Kessler, Saliha Harrach, Michael Mohr, Dennis Görlich, Alessandro Marra, Ludger Hillejan, Carsten Müller-Tidow, Georg Lenz, Eva Wardelmann, Rainer Wiewrodt, Wolfgang E Berdel, Christian Schwöppe, and Wolfgang Hartmann
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Medicine ,Science - Abstract
Aminopeptidase N (CD13) is a zinc-binding protease that has functional effects on both cancerogenesis and tumor angiogenesis. Since CD13 is an antigen suitable for molecular targeted therapies (e.g. tTF-NGR induced tumor vascular infarction), we evaluated its impact in NSCLC patients, and tested the effects of the CD13-targeted fusion protein tTF-NGR (truncated tissue factor (tTF) containing the NGR motif: asparagine-glycine-arginine) in vivo in nude mice.Expression of both CD13 and CD31 was studied in 270 NSCLC patients by immunohistochemistry. Clinical correlations and prognostic effects of the expression profiles were analyzed using univariate and multivariate analyses. In addition, a microarray-based analysis on the basis of the KM plotter database was performed. The in vivo effects of the CD13-targeted fusion protein tTF-NGR on tumor growth were tested in CD1 nude mice carrying A549 lung carcinoma xenotransplants.CD13 expression in tumor endothelial and vessel associated stromal cells was found in 15% of the investigated samples, while expression in tumor cells was observed in 7%. Although no significant prognostic impact was observed in the full NSCLC study cohort, both univariate and multivariate models identified vascular CD13 protein expression to correlate with poor overall survival in stage III and pN2+ NSCLC patients. Microarray-based mRNA analysis for either adenocarcinomas or squamous cell carcinomas did not reveal any significant effect. However, the analysis of CD13 mRNA expression for all lung cancer histologies demonstrated a positive prognostic effect. In vivo, systemic application of CD13-targeted tissue factor tTF-NGR significantly reduced CD13+ A549 tumor growth in nude mice.Our results contribute a data basis for prioritizing clinical testing of tTF-NGR and other antitumor molecules targeted by NGR-peptides in NSCLC. Because CD13 expression in NSCLC tissues was found only in a specific subset of NSCLC patients, rigorous pre-therapeutic testing will help to select patients for these studies.
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- 2017
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24. PD-1 and PD-L1 Expression in NSCLC Indicate a Favorable Prognosis in Defined Subgroups.
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Lars Henning Schmidt, Andreas Kümmel, Dennis Görlich, Michael Mohr, Sebastian Bröckling, Jan Henrik Mikesch, Inga Grünewald, Alessandro Marra, Anne M Schultheis, Eva Wardelmann, Carsten Müller-Tidow, Tilmann Spieker, Christoph Schliemann, Wolfgang E Berdel, Rainer Wiewrodt, and Wolfgang Hartmann
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Medicine ,Science - Abstract
Immunotherapy can become a crucial therapeutic option to improve prognosis for lung cancer patients. First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ligand PD-L1 have shown promising results in several solid tumors. However, in lung cancer the diagnostic, prognostic and predictive value of these immunologic factors remains unclear.The impact of both factors was evaluated in a study collective of 321 clinically well-annotated patients with non-small lung cancer (NSCLC) using immunohistochemistry.PD-1 expression by tumor infiltrating lymphocytes (TILs) was found in 22%, whereas tumor cell associated PD-L1 expression was observed in 24% of the NSCLC tumors. In Fisher's exact test a positive correlation was found for PD-L1 and Bcl-xl protein expression (p = 0.013). Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010). These observations were confirmed by multivariate cox regression models.One major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC, with increased tumor size, with a positive lymph node status and NSCLC patients who received adjuvant therapies. This study provides first data for immune-context related risk stratification of NSCLC patients. Further studies are necessary both to confirm this observation and to evaluate the predictive value of PD-1 and PD-L1 in NSCLC in the context of PD-1 inhibition.
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- 2015
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25. MET gene copy number alterations and expression of MET and hepatocyte growth factor are potential biomarkers in angiosarcomas and undifferentiated pleomorphic sarcomas.
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Katja Schmitz, Hartmut Koeppen, Elke Binot, Jana Fassunke, Helen Künstlinger, Michaela A Ihle, Carina Heydt, Eva Wardelmann, Reinhard Büttner, Sabine Merkelbach-Bruse, Josef Rüschoff, and Hans-Ulrich Schildhaus
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Medicine ,Science - Abstract
Soft tissue sarcomas are a heterogeneous group of tumors with many different subtypes. In 2014 an estimated 12,020 newly diagnosed cases and 4,740 soft tissue sarcoma related deaths can be expected in the United States. Many soft tissue sarcomas are associated with poor prognosis and therapeutic options are often limited. The evolution of precision medicine has not yet fully reached the clinical treatment of sarcomas since therapeutically tractable genetic changes have not been comprehensively studied so far. We analyzed a total of 484 adult-type malignant mesenchymal tumors by MET fluorescence in situ hybridization and MET and hepatocyte growth factor immunohistochemistry. Eleven different entities were included, among them the most common and clinically relevant subtypes and tumors with specific translocations or complex genetic changes. MET protein expression was observed in 2.6% of the cases, all of which were either undifferentiated pleomorphic sarcomas or angiosarcomas, showing positivity rates of 14% and 17%, respectively. 6% of the tumors showed hepatocyte growth factor overexpression, mainly seen in undifferentiated pleomorphic sarcomas and angiosarcomas, but also in clear cell sarcomas, malignant peripheral nerve sheath tumors, leiomyosarcomas and gastrointestinal stromal tumors. MET and hepatocyte growth factor overexpression were significantly correlated and may suggest an autocrine activation in these tumors. MET FISH amplification and copy number gain were present in 4% of the tumors (15/413). Two samples, both undifferentiated pleomorphic sarcomas, fulfilled the criteria for high level amplification of MET, one undifferentiated pleomorphic sarcoma reached an intermediate level copy number gain, and 12 samples of different subtypes were categorized as low level copy number gains for MET. Our findings indicate that angiosarcomas and undifferentiated pleomorphic sarcomas rather than other frequent adult-type sarcomas should be enrolled in screening programs for clinical trials with MET inhibitors. The screening methods should include both in situ hybridization and immunohistochemistry.
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- 2015
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26. Regulators of Actin Dynamics in Gastrointestinal Tract Tumors
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Konrad Steinestel, Eva Wardelmann, Wolfgang Hartmann, and Inga Grünewald
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Reorganization of the actin cytoskeleton underlies cell migration in a wide variety of physiological and pathological processes, such as embryonic development, wound healing, and tumor cell invasion. It has been shown that actin assembly and disassembly are precisely regulated by intracellular signaling cascades that respond to changes in the cell microenvironment, ligand binding to surface receptors, or oncogenic transformation of the cell. Actin-nucleating and actin-depolymerizing (ANFs/ADFs) and nucleation-promoting factors (NPFs) regulate cytoskeletal dynamics at the leading edge of migrating cells, thereby modulating cell shape; these proteins facilitate cellular movement and mediate degradation of the surrounding extracellular matrix by secretion of lytic proteases, thus eliminating barriers for tumor cell invasion. Accordingly, expression and activity of these actin-binding proteins have been linked to enhanced metastasis and poor prognosis in a variety of malignancies. In this review, we will summarize what is known about expression patterns and the functional role of actin regulators in gastrointestinal tumors and evaluate first pharmacological approaches to prevent invasion and metastatic dissemination of malignant cells.
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- 2015
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27. Loss of the keratin cytoskeleton is not sufficient to induce epithelial mesenchymal transition in a novel KRAS driven sporadic lung cancer mouse model.
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Katharina König, Lydia Meder, Cornelia Kröger, Linda Diehl, Alexandra Florin, Ursula Rommerscheidt-Fuss, Philip Kahl, Eva Wardelmann, Thomas M Magin, Reinhard Buettner, and Lukas C Heukamp
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Medicine ,Science - Abstract
Epithelial-to-mesenchymal transition (EMT), the phenotypical change of cells from an epithelial to a mesenchymal type, is thought to be a key event in invasion and metastasis of adenocarcinomas. These changes involve loss of keratin expression as well as loss of cell polarity and adhesion. We here aimed to determine whether the loss of keratin expression itself drives increased invasion and metastasis in adenocarcinomas and whether keratin loss leads to the phenotypic changes associated with EMT. Therefore, we employed a recently described murine model in which conditional deletion of the Keratin cluster II by Cre-recombinase leads to the loss of the entire keratinmultiprotein family. These mice were crossed into a newly generated Cre-recombinase inducible KRAS-driven murine lung cancer model to examine the effect of keratin loss on morphology, invasion and metastasis as well as expression of EMT related genes in the resulting tumors. We here clearly show that loss of a functional keratin cytoskeleton did not significantly alter tumor morphology or biology in terms of invasion, metastasis, proliferation or tumor burden and did not lead to induction of EMT. Further, tumor cells did not induce synchronously expression of vimentin, which is often seen in EMT, to compensate for keratin loss. In summary, our data suggest that changes in cell shape and migration that underlie EMT are dependent on changes in signaling pathways that cause secondary changes in keratin expression and organization. Thus, we conclude that loss of the keratin cytoskeleton per se is not sufficient to causally drive EMT in this tumor model.
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- 2013
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28. KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial
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Heikki Joensuu, Eva Wardelmann, Mikael Eriksson, Annette Reichardt, Kirsten Sundby Hall, Jochen Schütte, Silke Cameron, Peter Hohenberger, Harri Sihto, Philipp J. Jost, Lars H. Lindner, Sebastian Bauer, Bengt Nilsson, Raija Kallio, Tommi Pesonen, and Peter Reichardt
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Cancer Research ,Oncology - Abstract
Purpose: Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib. Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses. Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15–0.72; P = 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31–0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib. Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
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- 2023
29. Interdependence of SS18-SSX–driven YAP1 and β-Catenin Activation in Synovial Sarcoma
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Ilka Isfort, Ruth Berthold, Lorena Heinst, Eva Wardelmann, Olle Larsson, Marcel Trautmann, and Wolfgang Hartmann
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Cancer Research ,Oncology ,Molecular Biology - Abstract
Synovial sarcoma, a rare malignant soft tissue tumor, is characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives synovial sarcoma pathogenesis by integrating into the BAF complex and dysregulating gene transcription. Because previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional coregulators YAP1/TAZ and β-catenin, respectively, this study examined a potential interdependence between these essential effector proteins in synovial sarcoma. In a large cohort of synovial sarcoma tissue specimens, IHC analyses revealed a substantial subset of synovial sarcoma with concurrent nuclear accumulation of YAP1/TAZ and β-catenin. In vitro, small-molecule inhibitor treatment, RNAi-mediated knockdown, and vector-based overexpression assays demonstrated that YAP1, TAZ, and β-catenin transcriptional activity is not only stimulated by the SS18-SSX fusion protein, but that they also mutually enhance each other's activation. These analyses showed the highest cooperative effect with overexpression of YAP1 in combination with β-catenin. Coimmunoprecipitation experiments detected nuclear interactions between YAP1, β-catenin, and the SS18-SSX fusion protein, the latter being an integral part of the BAF complex. Disruption of BAF complex assembly affected the coregulation of YAP1 and β-catenin, indicating that this chromatin remodeling complex plays a crucial role for interdependent YAP1 and β-catenin activation in synovial sarcoma cells. Implications: This study provides deeper insights into synovial sarcoma tumor biology demonstrating a mutual dependence between YAP1/TAZ and β-catenin transcriptional activity and a complex interplay with the SS18-SSX fusion protein within the BAF complex.
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- 2023
30. Efficacy of Multimodality Approach in Patients With Recurrent Head and Neck Squamous Cell Carcinoma
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PASCALE ALICIA HOELL, KHALED ELSAYAD, HENDRIK BERSSENBRUEGGE, DOMINIK HERING, CHRISTOPHER KITTEL, JOHANNES KLEINHEINZ, ANNALEN BLECKMANN, GEORG EVERS, EVA WARDELMANN, CLAUDIA RUDACK, and HANS THEODOR EICH
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Cancer Research ,Oncology ,General Medicine - Published
- 2023
31. Controversies in the management of patients with soft tissue sarcoma: Recommendations of the Conference on State of Science in Sarcoma 2022
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Christian Rothermundt, Dimosthenis Andreou, Jean-Yves Blay, Thomas Brodowicz, Ingrid M.E. Desar, Palma Dileo, Hans Gelderblom, Rick Haas, Jens Jakob, Robin L. Jones, Ian Judson, Wolfgang G. Kunz, Berndadette Liegl-Atzwanger, Lars H. Lindner, Christina Messiou, Aisha B. Miah, Peter Reichardt, Joanna Szkandera, Winette T.A. van der Graaf, Winan J. van Houdt, Eva Wardelmann, Silvia Hofer, Thomas Barth, Sebastian Bauer, Veronika Blum, Beata Bode, Sylvie Bonvalot, Judith Bovee, Petra Braam, Jean Martin Broto, Angelo Dei Tos, Dominik Denschlag, Ingrid Desar, Antonia Digklia, Uta Dirksen, Thomas Douchy, Florence Duffaud, Mikael Eriksson, Stefan Fröhling, Alessandro Gronchi, Jenrik Hardes, Wolfgang Hartmann, Peter Hohenberger, Daphne Hompes, Paul Huang, Antoine Italiano, Robin Jones, Günter Köhler, Attila Kollàr, Fatime Krasniqi, Stijn Krol, Wolfgang Kunz, Franel Le Grange, Cécile Le Pechoux, Alexandre LeCesne, Andreas Leithner, Bernadette Liegl-Atzwanger, Lars Lindner, Gunhild Mechtersheimer, Aisha Miah, Daniel Pink, Cleo Romagosa, Piotr Rutkowski, Akmel Safwat, Claudia Sangalli, Khin Thway, Per-Ulf Tunn, Winette Van der Graaf, Winan Van Houdt, Ralph Zachariah, Sander Botter, Thomas Cerny, and Hompes, Daphne
- Subjects
Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14] ,Cancer Research ,All institutes and research themes of the Radboud University Medical Center ,Oncology ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Owing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence.During the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma. We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022.Sixty-two European sarcoma experts participated in the survey. Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus.In this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS.
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- 2023
32. Comprehensive molecular profiling of sarcomas in adolescent and young adult patients
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Marie Morfouace, Peter Horak, Simon Kreutzfeldt, Aleksandra Stevovic, Teresa de Rojas, Evgeniya Denisova, Barbara Hutter, Francisco Bautista, Júlio Oliveira, Anne-Sophie Defachelles, Jeff White, Bernd Kasper, Matthias Preusser, Vassilis Golfinopoulos, Stefan Pfister, Winette Van der Graaf, Eva Wardelmann, Patrick Shenjere, Stefan Fröhling, Martin G. McCabe, and Medical Oncology
- Subjects
Europe ,Young Adult ,Cancer Research ,Adolescent ,Oncology ,SDG 3 - Good Health and Well-being ,Exome Sequencing ,Humans ,Sarcoma ,Soft Tissue Neoplasms ,Prognosis - Abstract
Background: Adolescent and young adult (AYA) patients with cancer are poorly recruited to molecularly targeted trials and have not witnessed the advances in cancer treatment and survival seen in other age groups. We report here a pan-European proof-of-concept study to identify actionable alterations in some of the worst prognosis AYA cancers: bone and soft tissue sarcomas. Design: Patients aged 12–29 years with newly diagnosed or recurrent, intermediate or high-grade bone and soft tissue sarcomas were recruited from six European countries. Pathological diagnoses were centrally reviewed. Formalin-fixed tissues were analysed by whole exome sequencing, methylation profiling and RNA sequencing and were discussed in a multidisciplinary, international molecular tumour board. Results: Of 71 patients recruited, 48 (median 20 years, range 12–28) met eligibility criteria. Central pathological review confirmed, modified and re-classified the diagnosis in 41, 3, and 4 cases, respectively. Median turnaround time to discussion at molecular tumour board was 8.4 weeks. whole exome sequencing (n = 48), methylation profiling (n = 44, 85%) and RNA sequencing (n = 24, 50%) led to therapeutic recommendations for 81% patients, including 4 with germ line alterations. The most common were for agents targeted towards tyrosine kinases (n = 20 recommendations), DNA repair (n = 18) and the PI3K/mTOR/AKT pathway (n = 15). Recommendations were generally based on weak evidence such as activity in a different tumour type (n = 68, 61%), reflecting the dearth of relevant molecular clinical trial data in the same tumour type. Conclusions: We demonstrate here that comprehensive molecular profiling of AYA patients' samples is feasible and deliverable in a European programme.
- Published
- 2023
33. Molekularpathologie bei ausgewählten Weichgewebssarkomen: diagnostisch und therapeutisch relevante Aberrationen
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Eva Wardelmann, Anna Kuntze, and Wolfgang Hartmann
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- 2022
34. Abdominelle Weichgewebstumoren
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Eva Wardelmann, Anna Kuntze, Marcel Trautmann, and Wolfgang Hartmann
- Abstract
ZusammenfassungGastrointestinale Stromatumoren sind mit einer Inzidenz von 10–15 Fällen pro 1 Mio. Einwohner in Deutschland die häufigsten mesenchymalen Tumoren im Abdominalbereich. Ihre eindeutige Identifikation und Charakterisierung ist für betroffene Personen prognostisch und therapeutisch von großer Bedeutung. Ebenso wichtig ist aber auch die klare Abgrenzung anderer mesenchymaler Neoplasien, zu denen leiomyomatöse, neurogene, adipozytäre und fibroblastäre Tumoren gehören. Zudem wächst die Zahl der translokationspositiven Entitäten, die sich nur mit entsprechenden molekularen Methoden eindeutig diagnostizieren lassen. Ziel dieses Beitrags ist es, für deren sichere Identifikation praktische Hinweise zu geben. Eine mögliche Referenzpathologie kann die Diagnosefindung unterstützen.
- Published
- 2022
35. Eröffnungsrede der Tagungspräsidentin
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Eva Wardelmann
- Published
- 2022
36. SS18-SSX drives CREB activation in synovial sarcoma
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Magdalene Cyra, Miriam Schulte, Ruth Berthold, Lorena Heinst, Esther-Pia Jansen, Inga Grünewald, Sandra Elges, Olle Larsson, Christoph Schliemann, Konrad Steinestel, Susanne Hafner, Thomas Simmet, Eva Wardelmann, Sareetha Kailayangiri, Claudia Rossig, Ilka Isfort, Marcel Trautmann, and Wolfgang Hartmann
- Subjects
Mice ,Sarcoma, Synovial ,Cancer Research ,Oncogene Proteins, Fusion ,Oncology ,Carcinogenesis ,Cell Line, Tumor ,Animals ,Humans ,Molecular Medicine ,Apoptosis ,General Medicine - Abstract
Purpose Synovial sarcoma (SySa) is a rare soft tissue tumor characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein represents the major driver of the disease, acting as aberrant transcriptional dysregulator. Oncogenic mechanisms whereby SS18-SSX mediates sarcomagenesis are incompletely understood, and strategies to selectively target SySa cells remain elusive. Based on results of Phospho-Kinase screening arrays, we here investigate the functional and therapeutic relevance of the transcription factor CREB in SySa tumorigenesis. Methods Immunohistochemistry of phosphorylated CREB and its downstream targets (Rb, Cyclin D1, PCNA, Bcl-xL and Bcl-2) was performed in a large cohort of SySa. Functional aspects of CREB activity, including SS18-SSX driven circuits involved in CREB activation, were analyzed in vitro employing five SySa cell lines and a mesenchymal stem cell model. CREB mediated transcriptional activity was modulated by RNAi-mediated knockdown and small molecule inhibitors (666-15, KG-501, NASTRp and Ro 31-8220). Anti-proliferative effects of the CREB inhibitor 666-15 were tested in SySa avian chorioallantoic membrane and murine xenograft models in vivo. Results We show that CREB is phosphorylated and activated in SySa, accompanied by downstream target expression. Human mesenchymal stem cells engineered to express SS18-SSX promote CREB expression and phosphorylation. Conversely, RNAi-mediated knockdown of SS18-SSX impairs CREB phosphorylation in SySa cells. Inhibition of CREB activity reduces downstream target expression, accompanied by suppression of SySa cell proliferation and induction of apoptosis invitro and in vivo. Conclusion In conclusion, our data underline an essential role of CREB in SySa tumorigenesis and provides evidence for molecular targeted therapies.
- Published
- 2022
37. Supplementary Table S1 from KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial
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Peter Reichardt, Tommi Pesonen, Raija Kallio, Bengt Nilsson, Sebastian Bauer, Lars H. Lindner, Philipp J. Jost, Harri Sihto, Peter Hohenberger, Silke Cameron, Jochen Schütte, Kirsten Sundby Hall, Annette Reichardt, Mikael Eriksson, Eva Wardelmann, and Heikki Joensuu
- Abstract
Representativeness of Study Participants
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- 2023
38. Study Protocol from KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial
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Peter Reichardt, Tommi Pesonen, Raija Kallio, Bengt Nilsson, Sebastian Bauer, Lars H. Lindner, Philipp J. Jost, Harri Sihto, Peter Hohenberger, Silke Cameron, Jochen Schütte, Kirsten Sundby Hall, Annette Reichardt, Mikael Eriksson, Eva Wardelmann, and Heikki Joensuu
- Abstract
Study protocol
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- 2023
39. Data from KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial
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Peter Reichardt, Tommi Pesonen, Raija Kallio, Bengt Nilsson, Sebastian Bauer, Lars H. Lindner, Philipp J. Jost, Harri Sihto, Peter Hohenberger, Silke Cameron, Jochen Schütte, Kirsten Sundby Hall, Annette Reichardt, Mikael Eriksson, Eva Wardelmann, and Heikki Joensuu
- Abstract
Purpose:Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib.Patients and Methods:The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses.Results:During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15–0.72; P = 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31–0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib.Conclusions:Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
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- 2023
40. Supplementary Figure S2 from KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial
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Peter Reichardt, Tommi Pesonen, Raija Kallio, Bengt Nilsson, Sebastian Bauer, Lars H. Lindner, Philipp J. Jost, Harri Sihto, Peter Hohenberger, Silke Cameron, Jochen Schütte, Kirsten Sundby Hall, Annette Reichardt, Mikael Eriksson, Eva Wardelmann, and Heikki Joensuu
- Abstract
Kaplan-Meier estimates of recurrence-free survival of patients with KIT exon 11 substitution mutation (A) and patients with KIT exon 9 mutation (B). The 5-year and 10-year survival rates are shown. Censored patients are indicated with a bar
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- 2023
41. Figure S3 from Interdependence of SS18-SSX–driven YAP1 and β-Catenin Activation in Synovial Sarcoma
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Wolfgang Hartmann, Marcel Trautmann, Olle Larsson, Eva Wardelmann, Lorena Heinst, Ruth Berthold, and Ilka Isfort
- Abstract
Figure S3 shows a reciprocal regulation of YAP1/TAZ-TEAD and β-catenin-TCF in SySa cells via luciferase assays.
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- 2023
42. Data from Interdependence of SS18-SSX–driven YAP1 and β-Catenin Activation in Synovial Sarcoma
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Wolfgang Hartmann, Marcel Trautmann, Olle Larsson, Eva Wardelmann, Lorena Heinst, Ruth Berthold, and Ilka Isfort
- Abstract
Synovial sarcoma, a rare malignant soft tissue tumor, is characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives synovial sarcoma pathogenesis by integrating into the BAF complex and dysregulating gene transcription. Because previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional coregulators YAP1/TAZ and β-catenin, respectively, this study examined a potential interdependence between these essential effector proteins in synovial sarcoma. In a large cohort of synovial sarcoma tissue specimens, IHC analyses revealed a substantial subset of synovial sarcoma with concurrent nuclear accumulation of YAP1/TAZ and β-catenin. In vitro, small-molecule inhibitor treatment, RNAi-mediated knockdown, and vector-based overexpression assays demonstrated that YAP1, TAZ, and β-catenin transcriptional activity is not only stimulated by the SS18-SSX fusion protein, but that they also mutually enhance each other's activation. These analyses showed the highest cooperative effect with overexpression of YAP1 in combination with β-catenin. Coimmunoprecipitation experiments detected nuclear interactions between YAP1, β-catenin, and the SS18-SSX fusion protein, the latter being an integral part of the BAF complex. Disruption of BAF complex assembly affected the coregulation of YAP1 and β-catenin, indicating that this chromatin remodeling complex plays a crucial role for interdependent YAP1 and β-catenin activation in synovial sarcoma cells.Implications:This study provides deeper insights into synovial sarcoma tumor biology demonstrating a mutual dependence between YAP1/TAZ and β-catenin transcriptional activity and a complex interplay with the SS18-SSX fusion protein within the BAF complex.
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- 2023
43. Data from KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors — TORC1/2 Inhibition as Salvage Strategy
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Sebastian Bauer, Jonathan A. Fletcher, Stefan Fröhling, Peter Hohenberger, Peter Horak, Benedikt Brors, Albrecht Stenzinger, Hanno Glimm, Hans-Ulrich Schildhaus, Thomas Herold, Stefanie Bertram, Karl Worm, Jürgen Treckmann, Eva Wardelmann, Wolfgang Hartmann, Marcel Trautmann, Adrian Marino-Enriquez, Susanne Grunewald, Michael C. Heinrich, Julia Ketzer, and Thomas Mühlenberg
- Abstract
Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of KIT or PDGFRA, favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of KIT secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients—adding further complexity to the scope of resistance. We collected genotyping data for KIT from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary KIT mutations (n = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates (NF1/2, PTEN, RAS, PIK3CA, TSC1/2, AKT, BRAF) potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in KIT, PTEN, KRAS, NF1, and TSC2. We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT–related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.
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- 2023
44. Data from Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
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Sebastian Bauer, Michael C. Heinrich, Daniel Rauh, Oleg Schmidt-Kittler, Stephen Miller, Paul Czodrowski, Sascha Jung, Jonathan A. Fletcher, Juergen Treckmann, Hans-Ulrich Schildhaus, Wolfgang Hartmann, Eva Wardelmann, Christiane Ehrt, Ajia Town, Johanna Falkenhorst, Jonas Lategahn, Thomas Mühlenberg, Lillian R. Klug, and Susanne Grunewald
- Abstract
Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of PDGFRA-mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance.Significance:Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST.This article is highlighted in the In This Issue feature, p. 1
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- 2023
45. Data from Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma
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Wolfgang Hartmann, Sebastian Huss, Eva Wardelmann, Pierre Åman, Jessica Becker, Thomas Simmet, Susanne Hafner, Claudia Rossig, Bianca Altvater, Konrad Steinestel, Inga Grünewald, Arne Krüger, Birte Jeiler, Ilka Isfort, Magdalene Cyra, and Marcel Trautmann
- Abstract
Myxoid liposarcoma (MLS) is an aggressive soft-tissue tumor characterized by a specific reciprocal t(12;16) translocation resulting in expression of the chimeric FUS–DDIT3 fusion protein, an oncogenic transcription factor. Similar to other translocation-associated sarcomas, MLS is characterized by a low frequency of somatic mutations, albeit a subset of MLS has previously been shown to be associated with activating PIK3CA mutations. This study was performed to assess the prevalence of PI3K/Akt signaling alterations in MLS and the potential of PI3K-directed therapeutic concepts. In a large cohort of MLS, key components of the PI3K/Akt signaling cascade were evaluated by next generation seqeuncing (NGS), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). In three MLS cell lines, PI3K activity was inhibited by RNAi and the small-molecule PI3K inhibitor BKM120 (buparlisib) in vitro. An MLS cell line–based avian chorioallantoic membrane model was applied for in vivo confirmation. In total, 26.8% of MLS cases displayed activating alterations in PI3K/Akt signaling components, with PIK3CA gain-of-function mutations representing the most prevalent finding (14.2%). IHC suggested PI3K/Akt activation in a far larger subgroup of MLS, implying alternative mechanisms of pathway activation. PI3K-directed therapeutic interference showed that MLS cell proliferation and viability significantly depended on PI3K-mediated signals in vitro and in vivo. Our preclinical study underlines the elementary role of PI3K/Akt signals in MLS tumorigenesis and provides a molecularly based rationale for a PI3K-targeted therapeutic approach which may be particularly effective in the subgroup of tumors carrying activating genetic alterations in PI3K/Akt signaling components.
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- 2023
46. Supplemental Methods and Supplemental Figures S1-S3 from KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors — TORC1/2 Inhibition as Salvage Strategy
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Sebastian Bauer, Jonathan A. Fletcher, Stefan Fröhling, Peter Hohenberger, Peter Horak, Benedikt Brors, Albrecht Stenzinger, Hanno Glimm, Hans-Ulrich Schildhaus, Thomas Herold, Stefanie Bertram, Karl Worm, Jürgen Treckmann, Eva Wardelmann, Wolfgang Hartmann, Marcel Trautmann, Adrian Marino-Enriquez, Susanne Grunewald, Michael C. Heinrich, Julia Ketzer, and Thomas Mühlenberg
- Abstract
Supplemental Methods; Supplemental Figure S1: Cancer-related mutations in the DKTK-Master patient cohort; Supplemental Figure S2: T1-PTEN cells were treated with increasing concentrations of approved KIT-inhibitors for 72h and analyzed by SRB assay; Supplemental Figure S3: Dose-combination studies with sapanisertib
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- 2023
47. Supplementary Data from Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
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Sebastian Bauer, Michael C. Heinrich, Daniel Rauh, Oleg Schmidt-Kittler, Stephen Miller, Paul Czodrowski, Sascha Jung, Jonathan A. Fletcher, Juergen Treckmann, Hans-Ulrich Schildhaus, Wolfgang Hartmann, Eva Wardelmann, Christiane Ehrt, Ajia Town, Johanna Falkenhorst, Jonas Lategahn, Thomas Mühlenberg, Lillian R. Klug, and Susanne Grunewald
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Contains: Supplemental Figures 1-7; Supplemental Tables 1 -3; Supplemental Methods
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- 2023
48. Supplementary Table S1, Supplementary Table S2, Supplementary Table S3 from Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma
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Wolfgang Hartmann, Sebastian Huss, Eva Wardelmann, Pierre Åman, Jessica Becker, Thomas Simmet, Susanne Hafner, Claudia Rossig, Bianca Altvater, Konrad Steinestel, Inga Grünewald, Arne Krüger, Birte Jeiler, Ilka Isfort, Magdalene Cyra, and Marcel Trautmann
- Abstract
Supplementary Table S1: Clinicopathological characteristics of patients with myxoid liposarcoma (n=56) including semi-quantitative immunohistochemistry and mutational analyses results. Supplemental Table S2: Gene list. Supplementary Table S3: In silico tools to predict the deleterious impact of gene variants detected in myxoid liposarcoma.
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- 2023
49. Supplementary Figure S1 from Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma
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Wolfgang Hartmann, Sebastian Huss, Eva Wardelmann, Pierre Åman, Jessica Becker, Thomas Simmet, Susanne Hafner, Claudia Rossig, Bianca Altvater, Konrad Steinestel, Inga Grünewald, Arne Krüger, Birte Jeiler, Ilka Isfort, Magdalene Cyra, and Marcel Trautmann
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Supplementary Figure S1: In vitro and in vivo evaluation of PI3K suppression (LY294002) in myxoid liposarcoma cell lines.
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- 2023
50. Supplementary Table S2 from Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma
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Markus Metzler, Uta Dirksen, Heribert Juergens, Wolfgang Hartmann, Eva Wardelmann, Joerg Juengert, Benjamin Frey, Abbas Agaimy, Torsten Fritscher, Clarissa Gillmann, Tobias Bäuerle, Benedikt Steif, Julia Hellberg, and Manuela Krumbholz
- Abstract
Sequences of primers and probes used for quantification of genomic fusion sequences
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- 2023
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