540 results on '"Ulrich Keilholz"'
Search Results
2. Impact of Smoking, Body Weight, Diabetes, Hypertension and Kidney Dysfunction on Survival in Pancreatic Cancer Patients—A Single Center Analysis of 2323 Patients within the Last Decade
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Christopher C. M. Neumann, François Schneider, Georg Hilfenhaus, Loredana Vecchione, Christian Benzing, Jana Ihlow, Uli Fehrenbach, Thomas Malinka, Ulrich Keilholz, Sebastian Stintzing, and Uwe Pelzer
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pancreatic cancer ,smoking ,body mass index ,hypertension ,diabetes ,kidney dysfunction ,insulin-therapy ,pancreatic enzyme replacement therapy ,General Medicine - Abstract
In addition to being risk factors for pancreatic cancer, parameters such as smoking, diabetes, or obesity might also act as potential prognostic factors for the survival of patients initially diagnosed with pancreatic cancer. By implementing one of the largest retrospective study cohorts of 2323 pancreatic adenocarcinoma (PDAC) patients treated at a single high-volume center, potential prognostic factors for survival were evaluated on the basis of 863 cases. Since parameters such as smoking, obesity, diabetes, and hypertension can cause severe chronic kidney dysfunction, the glomerular filtration rate was also considered. In the univariate analyses, albumin (p < 0.001), active smoking (p = 0.024), BMI (p = 0.018), and GFR (p = 0.002) were identified as metabolic prognostic markers for overall survival. In multivariate analyses, albumin (p < 0.001) and chronic kidney disease stage 2 (GFR < 90 mL/min/1.37 m2; p = 0.042) were identified as independent metabolic prognostic markers for survival. Smoking presented a nearly statistically significant independent prognostic factor for survival with a p-value of 0.052. In summary, low BMI, status of active smoking, and reduced kidney function at the time of diagnosis were associated with lower overall survival. No prognostic association could be observed for presence of diabetes or hypertension.
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- 2023
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3. preon: Fast and accurate entity normalization for drug names and cancer types in precision oncology
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Arik Ermshaus, Michael Piechotta, Gina Rüter, Ulrich Keilholz, Ulf Leser, and Manuela Benary
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MotivationIn precision oncology, clinicians are aiming to find the best treatment for any patient based on their molecular characterization. A major bottleneck is the annotation and evaluation of individual variants, for which usually a range of knowledge bases are manually screened. To incorporate and integrate the vast information of different databases, fast and accurate methods for harmonization are necessary.Summarypreon is a fast and accurate library for the normalization of drug names and cancer types in large-scale data integration.Availability and Implementationpreon is implemented in Python and freely available via the PyPI repository. Source code and gold standard data sets are available athttps://github.com/ermshaua/preon/.Contactmanuela.benary@bih-charite.deSupplementary informationSupplementary data are available online.
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- 2023
4. Inflammation-Based Prognostic Scores in Pancreatic Cancer Patients—A Single-Center Analysis of 1294 Patients within the Last Decade
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Christopher C. M. Neumann, François Schneider, Georg Hilfenhaus, Loredana Vecchione, Matthäus Felsenstein, Jana Ihlow, Dominik Geisel, Steffen Sander, Johann Pratschke, Sebastian Stintzing, Ulrich Keilholz, and Uwe Pelzer
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pancreatic cancer ,inflammatory biomarkers ,neutrophil to lymphocyte ratio (NLR) ,platelet to lymphocyte ratio (PLR) ,lymphocyte to monocyte ratio (LMR) ,CRP to albumin ratio (CAR) ,inflammatory benchmark index (IBI) ,Cancer Research ,Oncology - Abstract
Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer between 2009 and 2021 at our cancer center, inflammatory markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) were evaluated. We identified a new combined score, termed the inflammatory benchmark index (IBI). We performed univariate and multivariate overall survival analyses and identified optimal prognostic cut-off values for each parameter. In univariate analyses, advanced age (p < 0.001), gender (p < 0.001), tumor stage (p < 0.001), CA19-9 (p = 0.001), NLR (p = 0.001), LMR (p = 0.004), PLR (p = 0.004), CAR (p = 0.001) and IBI (p = 0.001) were identified as prognostic markers. In multivariate analyses advanced age (p < 0.001), gender (p = 0.001), tumor stage (p < 0.001), CA19-9 (p < 0.001), NLR (p = 0.001), LMR (p = 0.038), CAR (p < 0.001) and IBI (p < 0.001) were independent prognostic markers. These findings emphasize the impact of inflammation in pancreatic cancer, provide easily accessible prognostic values for the clinician, and may be useful as stratification parameters for trials aimed at patient inflammation or immune response.
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- 2023
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5. Supplementary Figures S1-S10 from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
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This file contains supplementary figures S1-S10.
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- 2023
6. Supplementary Tables S1-S7 from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
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This excel file contains supplementary tables S1-S7.
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- 2023
7. Supplementary Methods from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
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This file contains supplementary methods and references.
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- 2023
8. Data from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
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The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population.Significance:Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659
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- 2023
9. Data from Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment
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Ulrich Keilholz, Volker Budach, Thomas Gauler, Albrecht Stenzinger, Maren Knödler, Wilko Weichert, Konrad Klinghammer, and Ingeborg Tinhofer
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Purpose: Constitutive activation of epidermal growth factor receptor (EGFR) as a result of gene amplification, mutation, or overexpression of its ligands has been associated with response to EGFR targeting strategies. The role of these molecular mechanisms for the responsiveness of squamous cell carcinoma of the head and neck (SCCHN) to cetuximab-containing regimens remains unknown.Experimental Design: Tumor biopsies from 47 patients, enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel, were analyzed by immunohistochemistry for expression of EGFR, its deletion variant III (EGFRvIII) and its ligand amphiregulin (AREG). The relation between expression levels and disease control rate (DCR) was evaluated by logistic regression. Association between expression levels, progression-free survival (PFS), and overall survival (OS) was determined by Kaplan–Meier analysis, log-rank test, and uni- and multivariate Cox regression analysis.Results: High expression of EGFR, EGFRvIII, and AREG was detected in 73%, 17%, and 45% of SCCHN cases, respectively. Expression levels of EGFR had no impact on PFS or OS. High expression levels of EGFRvIII were significantly associated with reduced DCR and shortened PFS (HR: 3.3, P = 0.005) but not with OS. Patients with high AREG expression in tumor cells had significantly shortened OS (HR: 2.2, P = 0.002) and PFS (HR 2.2, P = 0.019) compared with patients with low expression score. Multivariate Cox analysis revealed an independent association of AREG and EGFRvIII with PFS but only AREG was an independent prognosticator of OS.Conclusions: High EGFRvIII and AREG expression levels identify SCCHN patients who are less likely to benefit from combination treatment with cetuximab and docetaxel. Clin Cancer Res; 17(15); 5197–204. ©2011 AACR.
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- 2023
10. Supplementary Figure 1 from Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment
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Ulrich Keilholz, Volker Budach, Thomas Gauler, Albrecht Stenzinger, Maren Knödler, Wilko Weichert, Konrad Klinghammer, and Ingeborg Tinhofer
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PDF file - 70K
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- 2023
11. Profile of the Multicenter Cohort of the German Cancer Consortium’s Clinical Communication Platform
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Daniel Maier, Jörg Janne Vehreschild, Barbara Uhl, Sandra Meyer, Karin Berger-Thürmel, Melanie Boerries, Rickmer Braren, Viktor Grünwald, Boris Hadaschik, Stefan Palm, Susanne Singer, Martin Stuschke, David Juárez, Pierre Delpy, Mohamed Lambarki, Michael Hummel, Cäcilia Engels, Stefanie Andreas, Nicola Gökbuget, Kristina Ihrig, Susen Burock, Dietmar Keune, Angelika Eggert, Ulrich Keilholz, Hagen Schulz, Daniel Büttner, Steffen Löck, Mechthild Krause, Mirko Esins, Frank Ressing, Martin Schuler, Christian Brandts, Daniel P. Brucker, Gabriele Husmann, Thomas Oellerich, Patrick Metzger, Frederik Voigt, Anna L. Illert, Matthias Theobald, Thomas Kindler, Ursula Sudhof, Achim Reckmann, Felix Schwinghammer, Daniel Nasseh, Wilko Weichert, Michael von Bergwelt-Baildon, Michael Bitzer, Nisar Malek, Öznur Öner, Klaus Schulze-Osthoff, Stefan Bartels, Jörg Haier, Raimund Ammann, Anja Franziska Schmidt, Bernd Guenther, Melanie Janning, Bernd Kasper, Sonja Loges, Stephan Stilgenbauer, Peter Kuhn, Eugen Tausch, Silvana Runow, Alexander Kerscher, Michael Neumann, Martin Breu, Martin Lablans, and Hubert Serve
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Epidemiology ,Medizin - Abstract
Treatment concepts in oncology are becoming increasingly personalized and diverse. Successively, changes in standards of care mandate continuous monitoring of patient pathways and clinical outcomes based on large, representative real-world data. The German Cancer Consortium’s (DKTK) Clinical Communication Platform (CCP) provides such opportunity. Connecting fourteen university hospital-based cancer centers, the CCP relies on a federated IT-infrastructure sourcing data from facility-based cancer registry units and biobanks. Federated analyses resulted in a cohort of 600,915 patients, out of which 232,991 were incident since 2013 and for which a comprehensive documentation is available. Next to demographic data (i.e., age at diagnosis: 2.0% 0–20 years, 8.3% 21–40 years, 30.9% 41–60 years, 50.1% 61–80 years, 8.8% 81 + years; and gender: 45.2% female, 54.7% male, 0.1% other) and diagnoses (five most frequent tumor origins: 22,523 prostate, 18,409 breast, 15,575 lung, 13,964 skin/malignant melanoma, 9,005 brain), the cohort dataset contains information about therapeutic interventions and response assessments and is connected to 287,883 liquid and tissue biosamples. Focusing on diagnoses and therapy-sequences, showcase analyses of diagnosis-specific sub-cohorts (pancreas, larynx, kidney, thyroid gland) demonstrate the analytical opportunities offered by the cohort’s data. Due to its data granularity and size, the cohort is a potential catalyst for translational cancer research. It provides rapid access to comprehensive patient groups and may improve the understanding of the clinical course of various (even rare) malignancies. Therefore, the cohort may serve as a decisions-making tool for clinical trial design and contributes to the evaluation of scientific findings under real-world conditions.
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- 2023
12. Treatment strategies in patients with gynecological sarcoma : Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1)
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Eva Roser, Philipp Harter, Dario Zocholl, Dominik Denschlag, Radoslav Chekerov, Pauline Wimberger, Christian Kurzeder, Annette Hasenburg, Mustafa-Zelal Muallem, Alexander Mustea, Guenter Emons, A G Zeimet, Felix Beck, Tjadina Arndt, Sara Y Brucker, Stefan Kommoss, Florian Heitz, Julia Welz, Eva-Katharina Egger, Matthias Kalder, Paul Buderath, Maximilian Klar, Christian Marth, Uwe Andreas Ulrich, Michael Weigel, Lea Traub, Christoph Anthuber, Hans Strauss, Lars Hanker, Theresa Link, Karol Kubiak, Badrig Melekian, Daniela Hornung, Martin Pölcher, Bjoern Lampe, Thomas Krauß, Ulrich Keilholz, Anne Flörcken, Klaus Pietzner, and Jalid Sehouli
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Oncology ,Medizin ,Obstetrics and Gynecology - Abstract
ObjectiveGynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study’s objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease.MethodsThe German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021.ResultsA total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy.ConclusionOur study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.
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- 2023
13. How to Standardize Molecular Profiling Programs for Routine Patient Care
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Ingeborg Tinhofer, Ulrich Keilholz, and Damian Rieke
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Management of patients with advanced cancer includes individualized treatment recommendations guided by molecular profiles. Refined complex molecular and immunological diagnostics are developed in parallel to the rapidly growing number of targeted therapies for defined genetic alterations and novel immunotherapies. For adequate counseling, patients are presented to Molecular Tumor Boards within the framework of precision oncology programs established at virtually all large cancer centers worldwide. The annotation and clinical interpretation of molecular pathology results are carried out by a multiprofessional team of experts formulating individualized treatment recommendations, taking also into account clinical characteristics. The process of annotation and clinical interpretation of molecular events in tumors also considers predictive factors defined in randomized studies as well as clinical judgement. All steps described above are not standardized, resulting in relevant heterogeneity in treatment recommendations among MTBs in different institutions.In this chapter, contemporary challenges will be discussed, including intratumoral heterogeneity, use of diverse molecular diagnostic systems with inherent differences in sensitivity and specificity of detecting genetic alterations; the yet insufficiently addressed need for harmonizing variant annotation and interpretation; and the currently rather intuitive inclusion of multiple further “soft” parameters; all of which may significantly contribute to the current heterogeneity of recommendations.
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- 2023
14. Therapie der bösartigen Speicheldrüsentumoren
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Damian T. Rieke, Ulrich Keilholz, Orlando Guntinas-Lichius, Tobias Ettl, and Carmen Stromberger
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Gynecology ,medicine.medical_specialty ,business.industry ,Head and neck surgery ,Medicine ,business - Abstract
Die malignen Speicheldrusentumoren sind eine extrem heterogene Gruppe seltener Tumoren mit groser klinischer, pathologischer und molekularbiologischer Variabilitat. Die chirurgische Resektion stellt in den meisten Fallen die Therapie der Wahl dar. Bei lokal fortgeschrittenen oder aggressiven malignen Tumoren ist haufig eine adjuvante Radiotherapie indiziert, die das Risiko fur ein Lokalrezidiv reduziert. Kontrovers diskutiert wird das Ausmas der Parotidektomie bei Karzinomen der Glandula parotis, insbesondere die Behandlung des N. facialis. Einigkeit herrscht weitestgehend daruber, diesen Nerv, wann immer moglich, zu erhalten, sofern nicht eine praoperative Parese oder eine offensichtliche intraoperative Tumorinfiltration einem Nervenerhalt entgegenstehen. Resezierte Anteile des N. facialis sollten moglichst sofort rekonstruiert werden. Die Chirurgie der von den kleinen Speicheldrusen ausgehenden Karzinome entspricht weitgehend dem Vorgehen bei Kopf-Hals-Plattenepithelkarzinomen. Bei adenoidzystischen Karzinomen ist aufgrund des perineuralen Wachstums und des haufigen Bezugs zur Schadelbasis eine R0-Resektion oft nicht zu erreichen, was die besondere Bedeutung der adjuvanten Radiotherapie bei dieser Entitat unterstreicht. Die Indikation der elektiven „neck dissection“ im cN0-Fall wird ebenfalls uneinheitlich gestellt. Wahrend einige Autoren die generelle Lymphknotenausraumung bei allen Karzinomen fordern, lautet der uberwiegende Konsens, eine elektive „neck dissection“ bei fortgeschrittener Tumorgrose, High-grade-Karzinomen und erhohtem Sicherheitsbedurfnis durchzufuhren. Die zunehmende Erkenntnis genomischer Alterationen und tumorspezifischer Signalwege eroffnet neue vielversprechende Moglichkeiten zielgerichteter molekularer Therapien im fortgeschrittenen Tumorstadium.
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- 2021
15. IC50: an unsuitable measure for large-sized prostate cancer spheroids in drug sensitivity evaluation
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Yipeng Xu, Gabriela Pachnikova, He Wang, Yaoyao Wu, Dorothea Przybilla, Reinhold Schäfer, Zihao Chen, Shaoxing Zhu, and Ulrich Keilholz
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Male ,Inhibitory Concentration 50 ,Cell Line, Tumor ,Humans ,Prostatic Neoplasms ,Antineoplastic Agents ,Docetaxel ,General Medicine - Abstract
Preclinical models of tumors have the potential to become valuable tools for commercial drug research and development, and 3D culture systems are gaining attraction in this area, including prostate cancer (PCa) research. However, nearly all 3D drug design and screening assessments are based on 2D experiments, indicating the limitations of 3D drug testing. To simulate the natural response of human cells to the drug, we detected the half-maximal inhibitory concentration (IC50) changes of 2D/3D LNCaP cells to the drug docetaxel and the sensitivity of different morphologies of 2D/3D LNCaP to docetaxel treatment. In contrast to 2D LNCaP cells, the evaluation of the susceptibility of LNCaP spheroids to treatment was more complicated. The fitness of IC50 curves of 2D and 3D tumor cell preclinical models differed significantly. IC50curves were unsuitable for large LNCaP spheroids. More evaluation indexes (e.g., maximal inhibition) and experiments (e.g., spheroids formation) should be explored and performed to systematically evaluate the susceptibility.
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- 2022
16. Multiplexed Quantification of Four Neuroblastoma DNA Targets in a Single Droplet Digital PCR Reaction
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Rasmus B. Linke, Karin Schmelz, Joern Toedling, Constantin Peitz, Angelika Eggert, Matthias Fischer, Clemens Messerschmidt, Maddalena Grimaldi, Hedwig E. Deubzer, Dieter Beule, Johannes H. Schulte, Marco Lodrini, Kathy Astrahantseff, Ulrich Keilholz, and Annika Sprüssel
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0301 basic medicine ,DNA Copy Number Variations ,Sensitivity and Specificity ,Pathology and Forensic Medicine ,Neuroblastoma ,03 medical and health sciences ,chemistry.chemical_compound ,Exon ,0302 clinical medicine ,Cell Line, Tumor ,Reference genes ,Blood plasma ,medicine ,Humans ,Anaplastic Lymphoma Kinase ,Digital polymerase chain reaction ,Liquid biopsy ,Alleles ,N-Myc Proto-Oncogene Protein ,Liquid Biopsy ,Reproducibility of Results ,Exons ,medicine.disease ,Molecular biology ,Data Accuracy ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Molecular Medicine ,Primer (molecular biology) ,Cell-Free Nucleic Acids ,Multiplex Polymerase Chain Reaction ,DNA - Abstract
The detection and characterization of cell-free DNA (cfDNA) in peripheral blood from neuroblastoma patients may serve as a minimally invasive approach to liquid biopsy. Major challenges in the analysis of cfDNA purified from blood samples are small sample volumes and low cfDNA concentrations. Droplet digital PCR (ddPCR) is a technology suitable for analyzing low levels of cfDNA. Reported here are two quadruplexed ddPCR assay protocols that reliably quantify MYCN and ALK copy numbers in a single reaction together with the two reference genes, NAGK and AFF3, and accurately estimate ALKF1174L (exon 23 position 3522, C>A) and ALKR1275Q (exon 25 position 3824, G>A) mutant allele fractions using cfDNA as input. The separation of positive and negative droplets was optimized for detecting two targets in each ddPCR fluorescence channel by the adjustment of the probe and primer concentrations of each target molecule. The quadruplexed assays were validated using a panel of 10 neuroblastoma cell lines and paired blood plasma and primary neuroblastoma samples from nine patients. Accuracy and sensitivity thresholds in quadruplexed assays corresponded well with those from the respective duplexed assays. Presented are two robust quadruplexed ddPCR protocols applicable in the routine clinical setting and that require only minimal plasma volumes for the assessment of MYCN and ALK oncogene status.
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- 2020
17. Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer
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Ulrich Keller, Andreas E. Albers, Raik Otto, Jan-Dirk Raguse, Jens Hoffmann, Theresa Eder, Konrad Klinghammer, Andreas M. Kaufmann, Ulrich Keilholz, Ingeborg Tinhofer, and Oliver Politz
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0301 basic medicine ,Cancer Research ,copanlisib ,HPV ,head and neck squamous cell carcinoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gene expression ,cetuximab ,medicine ,neoplasms ,PI3K/AKT/mTOR pathway ,Copanlisib ,Cetuximab ,patient-derived xenograft model ,business.industry ,Head and neck cancer ,medicine.disease ,Head and neck squamous-cell carcinoma ,Clinical trial ,Gene expression profiling ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,business ,medicine.drug ,Research Paper - Abstract
Despite recent advances, the treatment of head and neck squamous cell carcinoma (HNSCC) remains an area of high unmet medical need. HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target particularly in cetuximab-resistant tumors. Here, we explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft (PDX) models with known HPV and PI3K mutational status and available data on cetuximab sensitivity. Treatment with copanlisib alone resulted in moderate antitumor activity with 12/33 PDX models showing either tumor stabilization or regression. Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models (21/33), and the effect was particularly pronounced in cetuximab-resistant tumors (14/16). While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity evaluated through gene expression profiling showed a positive correlation with response to copanlisib. Together, these data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling as a potential biomarker for predicting treatment responses.
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- 2020
18. Liquid Biopsy in Colorectal Cancer: Quo Vadis? Implementation of Liquid Biopsies in Routine Clinical Patient Care in Two German Comprehensive Cancer Centers
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Laura E. Fischer, Sebastian Stintzing, Volker Heinemann, Ulrich Keilholz, Dietmar Keune, Claudia Vollbrecht, Thomas Burmeister, Andreas Kind, Lena Weiss, David Horst, Thomas Kirchner, Frederick Klauschen, Andreas Jung, Christoph Benedikt Westphalen, and Ivan Jelas
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Cancer Research ,Oncology - Abstract
ObjectivesThe use of liquid biopsies (LB) in patients with solid malignancies enables comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) and has the potential to guide therapy stratification and support disease monitoring. To examine clinical uptake of LB in a real-world setting, LB implementation was analyzed at two German cancer centers (LMU Munich and Charité - Universitätsmedizin Berlin) between 2017 and 2021, with focus on colorectal cancer (CRC) patients.MethodsIn this retrospective analysis, all patients who received a LB between January 2017 and December 2021 as part of routine clinical management were included. To provide adequate context, we collected disease characteristics and technical specifications of the LB methods applied. Additionally, we examined the concordance of RAS status in tumor tissue and LB. Finally, we discuss the potential of LB as a diagnostic tool to drive personalized treatment in CRC patients and how to implement LB in clinical routine.ResultsIn total, our cohort included 86 CRC patients and 161 LB conducted in these patients between 2017 and 2021. In 59 patients, comparison between tissue-based and liquid-based molecular diagnostics, revealed a divergence in 23 (39%) of the evaluable samples.ConclusionOur real-world data analysis indicates that the possibilities of LB are not yet exploited in everyday clinical practice. Currently, the variety of methods and lack of standardization, as well as restricted reimbursement for liquid based CGP hinder the use of LB in clinical routine. To overcome these issues, prospective clinical trials are needed to provide evidence driving the implementation of LB into the management of CRC patients and to support their implementation into clinical guidelines.
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- 2022
19. Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards
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Damian T. Rieke, Till de Bortoli, Peter Horak, Mario Lamping, Manuela Benary, Ivan Jelas, Gina Rüter, Johannes Berger, Marit Zettwitz, Niklas Kagelmann, Andreas Kind, Falk Fabian, Dieter Beule, Hanno Glimm, Benedikt Brors, Albrecht Stenzinger, Stefan Fröhling, and Ulrich Keilholz
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Nucleotides ,Neoplasms ,Humans ,High-Throughput Nucleotide Sequencing ,Feasibility Studies ,RNA ,General Medicine ,Technology Platforms ,Precision Medicine ,Poly(ADP-ribose) Polymerase Inhibitors ,Protein-Tyrosine Kinases ,Retrospective Studies - Abstract
Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. Methods High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0–1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. Results A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician’s choice. Conclusions Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts.
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- 2022
20. Gene expression-based prediction of pazopanib efficacy in sarcoma
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Christoph E. Heilig, Andreas Laßmann, Sadaf S. Mughal, Andreas Mock, Sebastian Pirmann, Veronica Teleanu, Marcus Renner, Carolin Andresen, Bruno C. Köhler, Bogac Aybey, Sebastian Bauer, Jens T. Siveke, Rainer Hamacher, Gunnar Folprecht, Stephan Richter, Evelin Schröck, Christian H. Brandts, Marit Ahrens, Peter Hohenberger, Gerlinde Egerer, Thomas Kindler, Melanie Boerries, Anna L. Illert, Nikolas von Bubnoff, Leonidas Apostolidis, Philipp J. Jost, C. Benedikt Westphalen, Wilko Weichert, Ulrich Keilholz, Frederick Klauschen, Katja Beck, Ulrike Winter, Daniela Richter, Lino Möhrmann, Michael Bitzer, Klaus Schulze-Osthoff, Benedikt Brors, Gunhild Mechtersheimer, Simon Kreutzfeldt, Christoph Heining, Daniel B. Lipka, Albrecht Stenzinger, Richard F. Schlenk, Peter Horak, Hanno Glimm, Daniel Hübschmann, and Stefan Fröhling
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Cancer Research ,Sulfonamides ,Young Adult ,Indazoles ,Pyrimidines ,Oncology ,Medizin ,Gene Expression ,Humans ,Sarcoma ,Soft Tissue Neoplasms ,Prospective Studies - Abstract
The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p lt; 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.
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- 2022
21. Evaluation of JQ1 Combined With Docetaxel for the Treatment of Prostate Cancer Cells in 2D- and 3D-Culture Systems
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Yipeng Xu, Gabriela Pachnikova, Dorothea Przybilla, Reinhold Schäfer, Yingying Cui, Dan Zhou, Zihao Chen, An Zhao, and Ulrich Keilholz
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Pharmacology ,Combination Treatment ,3D Culture Spheroid ,Prostate Cancer ,JQ1 ,Pharmacology (medical) ,Docetaxel ,Therapeutics. Pharmacology ,RM1-950 ,urologic and male genital diseases - Abstract
Introduction: Prostate cancer (PCa) is dependent on coupled androgen-androgen receptor (AR) signaling for growth and progression. Significant efforts have been made in this research field, as hormonal therapies have greatly improved the survival of patients with metastatic PCa (mPCa). The drug treatment agent JQ1, which potently abrogates bromodomain 4 (BRD4) localization to the AR target loci and therefore significantly impairs AR-mediated gene transcription, is a potent therapeutic option for patients with advanced PCa. In this study, we aimed to investigate the inhibitory effect of JQ1 combined with docetaxel on PCa cells in vitro for the first time. Furthermore, the 3D spheroid culture system was modeled to more accurately simulate the response of PCa cells to drugs.Methods: We established and measured 3D LNCaP spheroids in vitro in order to evaluate the susceptibility of 2D- and 3D-cultured LNCaP cells exposed to the same anti-cancer drug.Results: We demonstrated that JQ1 was an effective drug for promoting cell inhibition after docetaxel treatment in 2D- and 3D- cultured LNCaP cells. Inhibition of 3D cultured formation in the combined treatment group was significantly higher than that in docetaxel or JQ1 alone. Under the same conditions of drug solubility, the drug resistance of 3D spheroids was significantly higher than that of 2D cells. Moreover, dmax and lg volume were suitable parameters for LNCaP cells/spheroid size displaying and evaluating cell viability.Conclusion: 3D cultured spheroids of PCa are an effective tool for studying PCa drug trials. JQ1 combined with docetaxel may be an effective treatment for advanced PCa. This combination therapy strategy deserves further evaluation in clinical trials.
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- 2022
22. Biomarker-driven therapies for metastatic uveal melanoma: A prospective precision oncology feasibility study
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Serge Leyvraz, Frank Konietschke, Caroline Peuker, Moritz Schütte, Thomas Kessler, Sebastian Ochsenreither, Marc Ditzhaus, Erin D. Sprünken, Gina Dörpholz, Mario Lamping, Damian T. Rieke, Konrad Klinghammer, Susen Burock, Claas Ulrich, Gabriela Poch, Reinhold Schäfer, Frederick Klauschen, Antonia Joussen, Marie-Laure Yaspo, and Ulrich Keilholz
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Uveal Neoplasms ,Cancer Research ,Nivolumab ,Oncology ,Biomarkers, Tumor ,Feasibility Studies ,Humans ,Neoplasms, Second Primary ,Prospective Studies ,Precision Medicine ,Melanoma - Abstract
Targeted therapies for metastatic uveal melanoma have shown limited benefit in biomarker-unselected populations. The Treat20 Plus study prospectively evaluated the feasibility of a precision oncology strategy in routine clinical practice.Fresh biopsies were analyzed by high-throughput genomics (whole-genome, whole-exome, and RNA sequencing). A multidisciplinary molecular and immunologic tumor board (MiTB) made individualized treatment recommendations based on identified molecular aberrations, patient situation, drug, and clinical trial availability. Therapy selection was at the discretion of the treating physician. The primary endpoint was the feasibility of the precision oncology clinical program.Molecular analyses were available for 39/45 patients (87%). The MiTB provided treatment recommendations for 40/45 patients (89%), of whom 27/45 (60%) received ≥1 matched therapy. First-line matched therapies included MEK inhibitors (n = 15), MET inhibitors (n = 10), sorafenib (n = 1), and nivolumab (n = 1). The best response to first-line matched therapy was partial response in one patient (nivolumab based on tumor mutational burden), mixed response in two patients, and stable disease in 12 patients for a clinical benefit of 56%. The matched therapy population had a median progression-free survival and overall survival of 3.3 and 13.9 months, respectively. The growth modulation index with matched therapy was1.33 in 6/17 patients (35%) with prior systemic therapy, suggesting clinical benefit.A precision oncology approach was feasible for patients with metastatic uveal melanoma, with 60% receiving a therapy matched to identify molecular aberrations. The clinical benefit after checkpoint inhibitors highlights the value of tumor mutational burden testing.
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- 2022
23. Cancer care in German centers of excellence during the first 2 years of the COVID-19 pandemic
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Volker Arndt, Daniela Doege, Stefan Fröhling, Peter Albers, Hana Algül, Ralf Bargou, Carsten Bokemeyer, Martin Bornhäuser, Christian H. Brandts, Peter Brossart, Sara Yvonne Brucker, Tim H. Brümmendorf, Hartmut Döhner, Norbert Gattermann, Michael Hallek, Volker Heinemann, Ulrich Keilholz, Thomas Kindler, Cornelia von Levetzow, Florian Lordick, Ulf Peter Neumann, Christoph Peters, Dirk Schadendorf, Stephan Stilgenbauer, Thomas Zander, Daniel Zips, Delia Braun, Thomas Seufferlein, Gerd Nettekoven, and Michael Baumann
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Cancer Research ,Oncology ,Medizin ,General Medicine - Abstract
Journal of cancer research and clinical oncology (2022). doi:10.1007/s00432-022-04407-1, Published by Springer, Berlin
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- 2022
- Full Text
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24. Klassische Zytostatika-Gruppierungen
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Christoph Ritter, Susen Burock, and Ulrich Keilholz
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- 2022
25. Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group ‘Molecular Diagnostics and Therapy’
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C. Benedikt Westphalen, Carsten Bokemeyer, Reinhard Büttner, Stefan Fröhling, Verena I. Gaidzik, Hanno Glimm, Ulrich T. Hacker, Volker Heinemann, Anna L. Illert, Ulrich Keilholz, Thomas Kindler, Martin Kirschner, Bastian Schilling, Jens T. Siveke, Thomas Schroeder, Verena Tischler, Sebastian Wagner, Wilko Weichert, Daniel Zips, Sonja Loges, Ralf Bargou (Würzburg), Hendrik Bläker (Leipzig), Melanie Börries (Freiburg), Christian Brandts (Frankfurt), Nikolas von Bubnoff (Lübeck), Melanie Demes (Frankfurt), Alexander Desuki (Mainz), Hartmut Döhner (Ulm), Justus Duyster (Freiburg), Nadine Gaisa (Aachen), Annkristin Heine (Bonn), Christoph Heining (Dresden), Peter Horak (Heidelberg), Ivan Jelas (Berlin), Philipp J. Jost (München), Andreas Jung (München), Thomas Kirchner (München), Frederick Klauschen (Berlin), Simon Kreutzfeldt (Heidelberg), Jörg Kumbrink (München), Volker Kunzmann (Würzburg), Silke Lassmann (Freiburg), Klaus Metzeler (München), Peter Möller (Ulm), Nadina Ortiz-Brüchle (Aachen), Claudia Paret (Mainz), Natalie Pelusi (Bonn), Christoph Peters (Freiburg), Nicole Pfarr (München), Daniela Richter (Dresden), Kristina Riedmann (München), Damian Rieke (Berlin), Christoph Ritzel (Mainz), Dirk Schadendorf (Essen), Hans-Ulrich Schildhaus (Essen), Hubert Schorle (Bonn), Thomas Seufferlein (Ulm), Ronald Simon (Hamburg), Albrecht Stenzinger (Heidelberg), Ghazaleh Tabatabai (Tübingen), Janna-Lisa Velthaus (Hamburg), Martin Werner (Freiburg), Peter J. Wild (Frankfurt), Jürgen Wolf (Köln), Schadendorf, Dirk (Beitragende*r), and Schildhaus, Hans-Ulrich (Beitragende*r)
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0301 basic medicine ,Cancer Research ,Collaborative strategy ,Consensus ,Delphi Technique ,Computer science ,Medizin ,Antineoplastic Agents ,Computer-assisted web interviewing ,03 medical and health sciences ,0302 clinical medicine ,Cancer Medicine ,Predictive Value of Tests ,Germany ,Neoplasms ,Humans ,Profiling (information science) ,Molecular Targeted Therapy ,Precision Medicine ,Task force ,Molecular diagnostics ,Precision medicine ,Engineering management ,030104 developmental biology ,Molecular Diagnostic Techniques ,Oncology ,Conceptual framework ,Research Design ,030220 oncology & carcinogenesis - Abstract
Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force 'Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality.
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- 2020
26. Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts
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Teresa Amaral, Claus Garbe, Alexander M.M. Eggermont, Lucie Heinzerling, Anja Gesierich, Dirk Schadendorf, Christos C. Zouboulis, Ulrike Leiter, Thomas Eigentler, Jochen Utikal, Felix Kiecker, Alessandro Testori, Cord Sunderkötter, Uwe Wollina, Peter Martus, Ulrich Keilholz, Ulrike Keim, Axel Hauschild, Thomas Tüting, Stefan Suciu, and Rudolf Stadler
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Medizin ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Original Reports ,medicine ,Humans ,Stage III melanoma ,030212 general & internal medicine ,Survival rate ,Melanoma ,Aged ,Neoplasm Staging ,business.industry ,Follow up studies ,Cancer ,Middle Aged ,medicine.disease ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,business ,Cohort study ,Follow-Up Studies - Abstract
PURPOSE Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma. PATIENTS AND METHODS The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data. RESULTS For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data. CONCLUSION The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.
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- 2020
27. Cancer testis antigen Cyclin A1 harbors several HLA-A*02:01-restricted T cell epitopes, which are presented and recognized in vivo
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Anne Letsch, Annika Nelde, Petra Quass, Sabrina Urban, Antonia Busse, Sebastian Ochsenreither, Ulrich Keilholz, Anja Tatjana Teck, Heiko Schuster, and Juliane S. Walz
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Cancer Research ,T cell ,Immunology ,Human leukocyte antigen ,Epitope ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,MHC class I ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,HLA immunopeptidome ,Ovarian carcinoma ,030304 developmental biology ,0303 health sciences ,Acute myeloid leukemia ,biology ,Chemistry ,Molecular biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Original Article ,Cyclin A1 ,CD8+ T cell ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,CD8 - Abstract
Cyclin A1 is a promising antigen for T cell therapy being selectively expressed in high-grade ovarian cancer (OC) and acute myeloid leukemia (AML) stem cells. For adoptive T cell therapy, a single epitope has to be selected, with high affinity to MHC class I and adequate processing and presentation by malignant cells to trigger full activation of specific T cells. In silico prediction with three algorithms indicated 13 peptides of Cyclin A1 9 to 11 amino acids of length to have high affinity to HLA-A*02:01. Ten of them proved to be affine in an HLA stabilization assay using TAP-deficient T2 cells. Their immunogenicity was assessed by repetitive stimulation of CD8+ T cells from two healthy donors with single-peptide-pulsed dendritic cells or monocytes. Intracellular cytokine staining quantified the enrichment of peptide-specific functional T cells. Seven peptides were immunogenic, three of them against both donors. Specific cell lines were cloned and used in killing assays to demonstrate recognition of endogenous Cyclin A1 in the HLA-A*02:01-positive AML cell line THP-1. Immunopeptidome analysis based on direct isolation of HLA-presented peptides by mass spectrometry of primary AML and OC samples identified four naturally presented epitopes of Cyclin A1. The immunopeptidome of HeLa cells transfected with Cyclin A1 and HLA-A*02:01 revealed six Cyclin A1-derived HLA ligands. Epitope p410–420 showed high affinity to HLA-A*02:01 and immunogenicity in both donors. It proved to be naturally presented on primary AML blast and provoked spontaneous functional response of T cells from treatment naïve OC and, therefore, warrants further development for clinical application.
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- 2020
28. Cancer patients' expectations when undergoing extensive molecular diagnostics—A qualitative study
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Anne Letsch, Volker Heinemann, C. Benedikt Westphalen, Amy Rohrmoser, Theresia Pichler, Ulrich Keilholz, Ute Goerling, and Peter Herschbach
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Adult ,Male ,medicine.medical_specialty ,Palliative care ,Attitude of Health Personnel ,precision medicine ,hope ,Psycho-oncology ,Experimental and Cognitive Psychology ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Surveys and Questionnaires ,Humans ,cancer ,Medicine ,Medical history ,030212 general & internal medicine ,Pathology, Molecular ,Neoplasm Staging ,Oncologists ,Motivation ,Physician-Patient Relations ,palliative care ,business.industry ,Middle Aged ,Precision medicine ,Psychiatry and Mental health ,Distress ,Oncology ,whole-genome sequencing ,030220 oncology & carcinogenesis ,Family medicine ,psycho-oncology ,Female ,Thematic analysis ,business ,Psychosocial ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,qualitative research ,Qualitative research - Abstract
Objective: Precision cancer medicine (PCM) aims at identifying tumor-driving molecular characteristics to improve therapy. Despite early successes for some cancers, the approach faces manifold challenges. Patients undergoing extensive molecular diagnostics (MD) may hope for personal benefit, although chances are small. In order to offer suitable support to this group, health-care professionals need to gain insight into patients' experience. Thus, this study sought to explore the expectations of cancer patients undergoing MD of their tumor. Methods: In two German Comprehensive Cancer Centers, 30 patients with advanced-stage cancer who had exhausted conventional treatment and had consented to extensive, research-oriented MD (whole-genome sequencing n = 24, panel sequencing n = 6) participated in semi-structured interviews. Following thematic content analysis by Kuckartz, the interview transcripts were coded for expectations of MD participation and topics closely related. Moreover, patients completed questionnaires on their sociodemographic characteristics, medical history, and psychosocial distress. Results: Patients reported to be expecting (a) an improvement of their treatment, (b) a contribution to research, and/or (c) additional insight to their own cancer. Further, they described to feel individually appreciated and to have a reason to maintain hope for cure or recovery by participating in MD. Conclusions: Molecular diagnostics participation led patients to feel treated in a more ���personalized��� way, allowing them a greater sense of control in their situation of severe illness. Oncologists and psycho-oncologists need to ensure comprehensive information and empathetic support for patients undergoing extensive MD to balance their expectations and actual chances of clinical benefit.
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- 2019
29. Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis
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Benedikt Kortüm, Harikrishnan Radhakrishnan, Fabian Zincke, Christoph Sachse, Susen Burock, Ulrich Keilholz, Mathias Dahlmann, Wolfgang Walther, Gunnar Dittmar, Dennis Kobelt, and Ulrike Stein
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Cancer Research ,Rectal Neoplasms ,Gene Expression Regulation, Neoplastic ,Colonic Neoplasms ,Genetics ,Trans-Activators ,Humans ,Niclosamide ,S100 Calcium-Binding Protein A4 ,Amino Acids ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Colorectal Neoplasms ,Molecular Biology ,beta Catenin - Abstract
Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.
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- 2021
30. Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data
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Theresia Conrad, Johannes Haybaeck, Marie-Laure Yaspo, Marlen Keil, Michael Becker, Jens Hoffmann, Ulrich Keilholz, Moritz Schütte, and Hans Lehrach
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Oncology ,Drug ,Cancer Research ,medicine.medical_specialty ,drug combinations ,Bevacizumab ,Colorectal cancer ,medicine.medical_treatment ,Systems biology ,media_common.quotation_subject ,Article ,Internal medicine ,medicine ,RC254-282 ,media_common ,Chemotherapy ,Cetuximab ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,personalized treatment ,Oxaliplatin ,colon cancer ,Irinotecan ,business ,medicine.drug - Abstract
Simple Summary This experimental preclinical study developed a strategy to identify signatures for the personalized treatment of colon cancer focusing on target-specific drug combinations. Tumor growth inhibition was analyzed in a preclinical phase II study using 25 patient-derived xenograft models (PDX) treated with drug combinations blocking alternatively activated oncogenic pathways. Results reveal an improved response by combinatorial treatment in some defined molecular subgroups and potential alternative treatment options in KRAS- and BRAF-mutated colon cancer. Abstract The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Background for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs.
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- 2021
31. Fear of prognosis? How anxiety, coping, and expected burden impact the decision to have cytogenetic assessment in uveal melanoma patients
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Johannes Gollrad, Nevenka Korpusik, Christopher Rabsahl, Dirk Boehmer, Angela Besserer, Ulrike Grittner, Alexander Boeker, Ulrich Keilholz, Antonia Joussen, Volker Budach, and Ute Goerling
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Uveal Neoplasms ,Oncology ,Adaptation, Psychological ,Cytogenetic Analysis ,Humans ,Fear ,Anxiety ,Prognosis ,Melanoma - Abstract
Background Cytogenetic testing (CGT) in uveal melanoma patients reveals prognostic information about the individual risk of developing distant metastasis with dismal prognosis. There is currently no medical intervention strategy with proven effect on the prognosis, rendering the result of the cytogenetic testing purely informative. We explored patients’ socio-demographic backgrounds, psychological preconditions, coping strategies, external influences, and concerns about “knowing their fate” to study their possible interactions with decision-making for CGT. Methods Uveal melanoma patients were asked to complete questionnaires on their interest in undergoing CGT for prognostication and the factors influencing their decision. Data were collected on socio-demographics, baseline anxiety (GAD-7), depression (PHQ-9), coping strategies (Brief COPE), and assumed future concerns regarding the CGT result. Data were analyzed by using multiple ordinal logistic regression and exploring estimated marginal effects. Results Questionnaires were returned by 121 of 131 (92.4%) patients. Fifty-two patients (43%) had no interest in CGT, 34 (28.1%) were undecided, and 35 (28.9%) were interested. We observed no significant differences regarding age, sex, partnership, education, occupation, baseline anxiety, or depression. Decision-making favoring CGT was influenced by the treating physicians, internet resources, and level of baseline anxiety. Patients were likely to reject CGT when they worried that “knowing the result will have an unintended influence” on their life. Conclusion Decision-making about CGT for prognostication in uveal melanoma is burdensome to many patients and in general not guided by medical advice regarding further treatment and screening procedures. The psychological impact of the decision is therefore unique and requires careful support by psycho-oncologists considering the patient’s fears and expectations.
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- 2021
32. Avelumab for platinum-ineligible/refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck: phase Ib results from the JAVELIN Solid Tumor trial
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Patrick Schöffski, Alain C. Mita, Ani Sarkis Balmanoukian, Marcis Bajars, Amaury Daste, Christophe Le Tourneau, Sanjay Goel, Michael S. Gordon, Hans Juergen Grote, Ulrich Keilholz, Keun Wook Lee, Martin Gutierrez, Manish R. Patel, Dongli Zhou, Damien Vansteene, Deborah J. Wong, Joël Guigay, and Nicolas Penel
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Avelumab ,Antineoplastic Agents, Immunological ,head and neck neoplasms ,Refractory ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Neoplasm Metastasis ,Adverse effect ,RC254-282 ,Aged ,Pharmacology ,Clinical/Translational Cancer Immunotherapy ,Chemotherapy ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,Middle Aged ,Oncology ,Response Evaluation Criteria in Solid Tumors ,Cohort ,Molecular Medicine ,Chills ,Female ,immunotherapy ,medicine.symptom ,business ,medicine.drug - Abstract
BackgroundRecurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004).MethodsEligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety.ResultsBetween April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0–6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths.ConclusionAvelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.
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- 2021
33. Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis
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Joseph L. Regan, Dirk Schumacher, Stephanie Staudte, Andreas Steffen, Ralf Lesche, Joern Toedling, Thibaud Jourdan, Johannes Haybaeck, Nicole Golob-Schwarzl, Dominik Mumberg, David Henderson, Balázs Győrffy, Christian R.A. Regenbrecht, Ulrich Keilholz, Reinhold Schäfer, and Martin Lange
- Subjects
Multidisciplinary - Published
- 2022
34. Corrigendum to 'Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group ‘Molecular Diagnostics and Therapy’' [European Journal of Cancer 135 (2020) 1-7]
- Author
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C. Benedikt Westphalen, Carsten Bokemeyer, Reinhard Büttner, Stefan Fröhling, Verena I. Gaidzik, Hanno Glimm, Ulrich T. Hacker, Volker Heinemann, Anna L. Illert, Ulrich Keilholz, Thomas Kindler, Martin Kirschner, Bastian Schilling, Jens T. Siveke, Thomas Schroeder, Verena Tischler, Sebastian Wagner, Wilko Weichert, Daniel Zips, Sonja Loges, Ralf Bargou (Würzburg), Hendrik Bläker (Leipzig), Melanie Börries (Freiburg), Christian Brandts (Frankfurt), Nikolas von Bubnoff (Freiburg), Melanie Demes (Frankfurt), Alexander Desuki (Mainz), Hartmut Döhner (Ulm), Justus Duyster (Freiburg), Nadine Gaisa (Aachen), Annkristin Heine (Bonn), Christoph Heining (Dresden), Peter Horak (Heidelberg), Ivan Jelas (Berlin), Philipp J. Jost (München), Andreas Jung (München), Thomas Kirchner (München), Frederick Klauschen (Berlin), Simon Kreutzfeldt (Heidelberg), Jörg Kumbrink (München), Volker Kunzmann (Würzburg), Silke Lassmann (Freiburg), Klaus Metzeler (München), Peter Möller (Ulm), Nadina Ortiz-Brüchle (Aachen), Claudia Paret (Mainz), Natalie Pelusi (Bonn), Christoph Peters (Freiburg), Nicole Pfarr (München), Daniela Richter (Dresden), Kristina Riedmann (München), Damian Rieke (Berlin), Christoph Ritzel (Mainz), Dirk Schadendorf (Essen), Hans-Ulrich Schildhaus (Essen), Hubert Schorle (Bonn), Thomas Seufferlein (Ulm), Ronald Simon (Hamburg), Albrecht Stenzinger (Heidelberg), Ghazaleh Tabatabai (Tübingen), Janna-Lisa Velthaus (Hamburg), Martin Werner (Freiburg), Peter J. Wild (Frankfurt), and Jürgen Wolf (Köln)
- Subjects
Cancer Research ,Oncology - Published
- 2022
35. Peritoneal metastasis of colorectal cancer (pmCRC): identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models
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Beate Rau, Guido Gambara, Lena Wedeken, Safak Gül-Klein, Eva Pachmayr, Jens Hoffmann, Ulrike Stein, Bernadette Brzezicha, Andreas Brandl, Mathias Dahlmann, Oliver Popp, Alina Pflaume, Ulrich Keilholz, Christian R. A. Regenbrecht, Philipp Mertins, Caroline Schweiger-Eisbacher, Margarita Mokritzkij, and Wolfgang Walther
- Subjects
Cancer Research ,Peritoneal metastasis ,Matching (statistics) ,Colorectal cancer ,Biology ,In Vitro Techniques ,Translational Research, Biomedical ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Precision Medicine ,Letter to the Editor ,RC254-282 ,Peritoneal Neoplasms ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Genomics ,medicine.disease ,Prognosis ,Disease Models, Animal ,Oncology ,Cancer research ,Molecular Medicine ,Identification (biology) ,Technology Platforms ,Colorectal Neoplasms - Published
- 2021
36. Unresolved questions regarding the promise of the TPEx regimen - Authors' reply
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Joël Guigay, Ricard Mesia, Aldéric Fraslin, A. Auperin, Ulrich Keilholz, and Jean Bourhis
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Oncology ,Cisplatin ,medicine.medical_specialty ,Cetuximab ,business.industry ,MEDLINE ,Docetaxel ,Regimen ,Text mining ,Fluorouracil ,Internal medicine ,medicine ,Humans ,business ,medicine.drug ,Platinum - Published
- 2021
37. A randomized phase II study comparing the efficacy and safety of the glyco-optimized anti-EGFR antibody tomuzotuximab against cetuximab in patients with recurrent and/or metastatic squamous cell cancer of the head and neck - the RESGEX study
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P. Debourdeau, A. Kawecki, Sebastian Ochsenreither, G. Folprecht, Sylvie Rottey, H. Baumeister, Ulrich Keilholz, J. Lavernia, I. Ahrens-fath, B. Dietrich, A. Zurlo, Konrad Klinghammer, Andreas Dietz, J. Fayette, A. Jacobs, and P. Schafhausen
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medicine.medical_specialty ,Cancer Research ,FUCOSE ,tomuzotuximab ,Palliative care ,CARCINOMA ,medicine.medical_treatment ,IGG1 ,Phases of clinical research ,Cetuximab ,Gastroenterology ,HNSCC ,Internal medicine ,cetuximab ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Medicine and Health Sciences ,Humans ,POLYMORPHISMS ,Original Research ,Chemotherapy ,palliative care ,business.industry ,Head and neck cancer ,Hazard ratio ,Epithelial Cells ,CHEMOTHERAPY ,medicine.disease ,OPEN-LABEL ,Head and neck squamous-cell carcinoma ,HNC ,Oncology ,Fluorouracil ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,FC-GAMMA-RIIIA ,head and neck cancer ,Neoplasm Recurrence, Local ,business ,ADCC ,medicine.drug - Abstract
Background The aim of the RESGEX study was to compare the efficacy and safety of the anti-epidermal growth factor receptor (anti-EGFR) antibody tomuzotuximab against cetuximab both in combination with chemotherapy in patients with recurrent and/or metastatic squamous cell cancer of the head and neck in the first-line treatment. Patients and methods In this phase II trial 240 patients were equally randomized for six cycles to receive either tomuzotuximab (initial dose 990 mg then 720 mg) weekly and cisplatin 100 mg/m2 and fluorouracil (5-FU; 1000 mg/m2/day, days 1-4) every 3 weeks or cetuximab (400 mg/m2 subsequent 250 mg/m2) weekly with the same chemotherapeutic backbone followed by antibody maintenance treatment. The primary endpoint was progression-free survival. Results Median progression-free survival was 6.5 months [95% confidence interval (CI) 5.9-7.9 months] in the tomuzotuximab group and 6.2 months (95% CI 5.8-7.3 months) in the cetuximab group (P = 0.86). The median overall survival (OS) estimate was 11.6 months (95% CI 9.5-17.2 months) in the tomuzotuximab group and 13.8 months (95% CI 12.3-16.4 months) in the cetuximab group (P = 0.96). In an exploratory analysis a small subgroup of p16-positive patients had a significantly longer OS compared with p16-negative patients (hazard ratio 1.860, 95% CI 1.09-3.16, P = 0.02). Conclusions The glyco-engineered antibody tomuzotuximab failed to demonstrate improved efficacy with a chemotherapeutic backbone in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. It remains a so far unanswered question whether such antibody would partner better with different drugs such as checkpoint inhibitors., Highlights • Tomuzotuximab has a potential higher antibody-dependent cell cytotoxicity than other EGFR-directed antibodies. • Comparison of two anti-EGFR antibodies combined with chemotherapy in patients with squamous cell cancer of head and neck. • Efficacy, safety, and tolerability of tomuzotuximab and cetuximab in combination with chemotherapy were similar.
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- 2021
38. Development and validation of a nomogram to predict recurrence and melanoma-specific mortality in patients with negative sentinel lymph nodes
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Tamar Nijsten, Alexander M.M. Eggermont, D. van Klaveren, Dirk J. Grünhagen, Cees Verhoef, Piotr Rutkowski, D. Verver, Viola Franke, A.C.J. van Akkooi, Ulrich Keilholz, Surgery, and Dermatology
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Male ,Oncology ,medicine.medical_specialty ,Skin Neoplasms ,Sentinel lymph node ,030230 surgery ,Breslow Thickness ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Adjuvant therapy ,Humans ,Medicine ,Melanoma ,Aged ,Retrospective Studies ,business.industry ,Proportional hazards model ,Original Articles ,Middle Aged ,Nomogram ,Prognosis ,medicine.disease ,Clinical trial ,Nomograms ,Lymphatic Metastasis ,Cohort ,Female ,Original Article ,Surgery ,Neoplasm Recurrence, Local ,Sentinel Lymph Node ,business - Abstract
Background Patients with melanoma and negative sentinel nodes (SNs) have varying outcomes, dependent on several prognostic factors. Considering all these factors in a prediction model might aid in identifying patients who could benefit from a personalized treatment strategy. The objective was to construct and validate a nomogram for recurrence and melanoma‐specific mortality (MSM) in patients with melanoma and negative SNs. Methods A total of 3220 patients with negative SNs were identified from a cohort of 4124 patients from four EORTC Melanoma Group centres who underwent sentinel lymph node biopsy. Prognostic factors for recurrence and MSM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c‐index) and calibration in cross‐validation across the four centres. A nomogram was developed for graphical presentation. Results There were 3180 eligible patients. The final prediction model for recurrence and the calibrated model for MSM included three independent prognostic factors: ulceration, anatomical location and Breslow thickness. The c‐index was 0·74 for recurrence and 0·76 for the calibrated MSM model. Cross‐validation across the four centres showed reasonable model performance. A nomogram was developed based on these models. One‐third of the patients had a 5‐year recurrence probability of 8·2 per cent or less, and one‐third had a recurrence probability of 23·0 per cent or more. Conclusion A nomogram for predicting recurrence and MSM in patients with melanoma and negative SNs was constructed and validated. It could provide personalized estimates useful for tailoring surveillance strategies (reduce or increase intensity), and selection of patients for adjuvant therapy or clinical trials., Could personalize care
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- 2019
39. Comparison of Treatment Recommendations by Molecular Tumor Boards Worldwide
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Christophe Le Tourneau, Mark E. Burkard, Serge Leyvraz, Marissa Schuh, Damian T. Rieke, Ulrich Keilholz, Mario Lamping, Neus Baste, and Klaus H. Metzeler
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,business.industry ,Treatment options ,Genomic biomarkers ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Genomic information ,Medical physics ,business - Abstract
Purpose Precision oncology holds the promise of improving patient outcome. It is based on the idea that the testing of genomic biomarkers can lead to the recommendation of a treatment option tailored to the specific patient. To derive treatment recommendations from molecular profiles, interdisciplinary molecular tumor boards (MTBs) have been established recently in many academic institutions. The recommendation process in MTBs, however, has not been well defined, which limits applicability to larger clinical trials and patient populations. Methods We created four fictional patients on the basis of recent real cases with genomic information on mutations, fusions, copy numbers, and gene expression. We identified 29 tumor boards from nine countries worldwide and asked them to provide treatment recommendations for the sample patients. In addition, a questionnaire regarding the setup and methods used by MTBs was circulated. Results Five MTBs from four countries provided treatment recommendations and answered the questionnaire. For one patient, three tumor board treatment recommendations were identical, and two tumor boards had identical treatment strategies for the other three patients. There was heterogeneity in the interpretation of tumor and germline aberrations as well as in standards of prioritization. Conclusion Differences in the interpretation and recommendation process contribute to heterogeneity in MTB recommendations. Additional comparative analyses of recommendations could help improve rational decision making and lead to standardization.
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- 2018
40. Variant information systems for precision oncology
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Johannes Starlinger, Christine Sers, Jurica Ševa, Ulrich Keilholz, Ulf Leser, Steffen Pallarz, and Damian T. Rieke
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0301 basic medicine ,Computer science ,Health Informatics ,computer.software_genre ,Medical Oncology ,lcsh:Computer applications to medicine. Medical informatics ,Health informatics ,Set (abstract data type) ,03 medical and health sciences ,Information system ,Humans ,Medical Informatics Applications ,Precision Medicine ,Variant information system ,Data model ,business.industry ,Health Policy ,Aggregate (data warehouse) ,Genetic Variation ,Genomics ,Pipeline (software) ,Data science ,3. Good health ,Computer Science Applications ,030104 developmental biology ,Relational model ,Genomic variant data integration ,lcsh:R858-859.7 ,Molecular cancer therapy ,business ,computer ,Data integration ,Research Article - Abstract
Background The decreasing cost of obtaining high-quality calls of genomic variants and the increasing availability of clinically relevant data on such variants are important drivers for personalized oncology. To allow rational genome-based decisions in diagnosis and treatment, clinicians need intuitive access to up-to-date and comprehensive variant information, encompassing, for instance, prevalence in populations and diseases, functional impact at the molecular level, associations to druggable targets, or results from clinical trials. In practice, collecting such comprehensive information on genomic variants is difficult since the underlying data is dispersed over a multitude of distributed, heterogeneous, sometimes conflicting, and quickly evolving data sources. To work efficiently, clinicians require powerful Variant Information Systems (VIS) which automatically collect and aggregate available evidences from such data sources without suppressing existing uncertainty. Methods We address the most important cornerstones of modeling a VIS: We take from emerging community standards regarding the necessary breadth of variant information and procedures for their clinical assessment, long standing experience in implementing biomedical databases and information systems, our own clinical record of diagnosis and treatment of cancer patients based on molecular profiles, and extensive literature review to derive a set of design principles along which we develop a relational data model for variant level data. In addition, we characterize a number of public variant data sources, and describe a data integration pipeline to integrate their data into a VIS. Results We provide a number of contributions that are fundamental to the design and implementation of a comprehensive, operational VIS. In particular, we (a) present a relational data model to accurately reflect data extracted from public databases relevant for clinical variant interpretation, (b) introduce a fault tolerant and performant integration pipeline for public variant data sources, and (c) offer recommendations regarding a number of intricate challenges encountered when integrating variant data for clincal interpretation. Conclusion The analysis of requirements for representation of variant level data in an operational data model, together with the implementation-ready relational data model presented here, and the instructional description of methods to acquire comprehensive information to fill it, are an important step towards variant information systems for genomic medicine. Electronic supplementary material The online version of this article (10.1186/s12911-018-0665-z) contains supplementary material, which is available to authorized users.
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- 2018
41. NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?-Case series and review of the literature
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Jana K. Striefler, Claudia Vollbrecht, Annika Kurreck, Jobst C. von Einem, Hiroki Osumi, Arndt Stahler, Loredana Vecchione, Sebastian Stintzing, Andreas Kind, Dominik Paul Modest, Annabel Helga Sophie Alig, Ivan Jelas, and Ulrich Keilholz
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Male ,Cancer Research ,Colorectal cancer ,medicine.medical_treatment ,Reversion ,medicine.disease_cause ,Circulating Tumor DNA ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Panitumumab ,Humans ,Liquid biopsy ,Neoplasm Metastasis ,Chemotherapy ,Cetuximab ,business.industry ,Middle Aged ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,ras Proteins ,Female ,KRAS ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
Upfront KRAS and NRAS gene testing (‘RAS’) is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent ‘NeoRAS wild-type’ phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies.
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- 2021
42. RNA-Sequencing of Long-Term Label-Retaining Colon Cancer Stem Cells Identifies Novel Regulators of Quiescence
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Balazs Gyorffy, Johannes Haybaeck, Martin Lange, Joern Toedling, Reinhold Schäfer, Stephanie Staudte, David Henderson, Christian R.A. Regenbrecht, Ulrich Keilholz, Joseph L Regan, Thibaud Jourdan, Ralf Lesche, Dirk Schumacher, Dominik Mumberg, and Andreas Steffen
- Subjects
0303 health sciences ,education.field_of_study ,Colorectal cancer ,Population ,Cell ,Wnt signaling pathway ,Cell cycle ,Biology ,medicine.disease ,Hedgehog signaling pathway ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Cancer stem cell ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Stem cell ,education ,030304 developmental biology - Abstract
SUMMARYRecent data suggests that colon tumors contain a subpopulation of therapy resistant quiescent cancer stem cells (qCSCs) that are the source of relapse following treatment. Here, using colon cancer patient-derived organoids (PDOs) and xenograft (PDX) models, we identify a rare population of long-term label-retaining (PKH26Positive) qCSCs that can re-enter the cell cycle to generate new tumors. RNA-sequencing analyses demonstrated that these cells are enriched for stem cell associated gene sets such as Wnt and hedgehog signaling, epithelial-to-mesenchymal transition (EMT), embryonic development, tissue development and p53 pathway but have downregulated expression of genes associated with cell cycle, transcription, biosynthesis and metabolism. Furthermore, qCSCs are enriched for p53 interacting negative regulators of cell cycle, includingAKAP12, CD82, CDKN1A, FHL2, GPX3, KIAA0247, LCN2, TFF2, UNC5BandZMAT3, that we show are indicators of poor prognosis and may be targeted for qCSC abolition. Interestingly, CD82, KIAA0247 and UNC5B proteins localize to the cell surface and may therefore be potential markers for the prospective isolation of qCSCs. These data support the temporal inhibition of p53 signaling for the elimination of qCSCs and prevention of relapse in colorectal cancer.
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- 2021
43. Identification of a Nervous System Gene Expression Signature in Colon Cancer Stem Cells Reveals a Role for Neural Crest RegulatorsEGR2andSOX2in Tumorigenesis
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Thibaud Jourdan, Joern Toedling, Joseph L. Regan, Johannes Haybaeck, Dirk Schumacher, David Henderson, Dominik Mumberg, Christian R.A. Regenbrecht, Ralf Lesche, Reinhold Schäfer, Balázs Győrffy, Stephanie Staudte, Ulrich Keilholz, Andreas Steffen, Martin Lange, and Nicole Golob-Schwarzl
- Subjects
0303 health sciences ,HOXA4 ,Neural crest ,Biology ,medicine.disease_cause ,Embryonic stem cell ,Neural stem cell ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,SOX2 ,Cancer stem cell ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Stem cell ,Carcinogenesis ,030304 developmental biology - Abstract
SUMMARYRecent data support a hierarchical model of colon cancer driven by a population of cancer stem cells (CSCs). Greater understanding of the mechanisms that regulate CSCs may therefore lead to more effective treatments. Serial limiting dilution xenotransplantation assays of colon cancer patient-derived tumors demonstrated ALDHPositivecells to be enriched for tumorigenic self-renewing CSCs. In order to identify CSC modulators, we performed RNA-sequencing analysis of ALDHPositiveCSCs from a panel of colon cancer patient-derived organoids (PDOs) and xenografts (PDXs). These studies demonstrated CSCs to be enriched for embryonic and neural development gene sets. Functional analyses of genes differentially expressed in both ALDHPositivePDO and PDX CSCs demonstrated the neural crest stem cell (NCSC) regulator and wound response geneEGR2to be required for CSC tumorigenicity and to control expression of homeobox superfamily embryonic master transcriptional regulatorHOXgenes and the embryonic and neural stem cell regulatorSOX2. In addition, we identifyEGR2,HOXA2,HOXA4,HOXA5,HOXA7,HOXB2,HOXB3and the tumor suppressorATOH1as new prognostic biomarkers in colorectal cancer.
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- 2021
44. Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Albrecht Stenzinger, Ivo Buchhalter, Peter Hohenberger, Sebastian Bauer, Ulrich Keilholz, Andreas Mock, Daniel B. Lipka, Benedikt Brors, Michael Allgäuer, Andreas Rump, Stephan Wolf, Melanie Boerries, Klaus Schulze-Osthoff, Gunnar Folprecht, Katrin Pfütze, Christof von Kalle, Christian Brandts, Michael Bitzer, Laura Gieldon, Arne Jahn, Peter Schirmacher, Olaf Neumann, Matthias Kroiss, Barbara Klink, Daniela Richter, Sebastian Uhrig, Peter Horak, Ulrike Winter, Nikolas von Bubnoff, Barbara Hutter, Walter E. Aulitzky, Wilko Weichert, Jennifer Hüllein, Philipp J. Jost, Veronica Teleanu, Thomas Kindler, Leo Ruhnke, Martina Fröhlich, Christoph E. Heilig, Katja Beck, Karsten Spiekermann, Volker Endris, Evelin Schröck, Frederick Klauschen, Dorothea Hanf, Simon Kreutzfeldt, Daniel Hübschmann, Jens T. Siveke, Bettina Meißburger, Lino Möhrmann, Richard F. Schlenk, Andreas Laßmann, Anna Lena Illert, Roland Penzel, Christina Geörg, Christoph Heining, Marinela Augustin, and Hanno Glimm
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Genetic counseling ,MEDLINE ,Medizin ,Cancer ,medicine.disease ,Clinical trial ,Transcriptome ,Internal medicine ,Medicine ,Clinical significance ,Observational study ,business ,Exome - Abstract
The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. Significance: Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677. This article is highlighted in the In This Issue feature, p. 2659
- Published
- 2021
45. RNA sequencing of long-term label-retaining colon cancer stem cells identifies novel regulators of quiescence
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Dirk Schumacher, Martin Lange, Dominik Mumberg, Balázs Győrffy, Ulrich Keilholz, Johannes Haybaeck, Ralf Lesche, Stephanie Staudte, Thibaud Jourdan, Joern Toedling, Joseph L. Regan, Reinhold Schäfer, Andreas Steffen, David Henderson, and Christian R.A. Regenbrecht
- Subjects
0301 basic medicine ,Colorectal cancer ,Science ,02 engineering and technology ,Biology ,Quiescence ,Article ,Transcriptome ,03 medical and health sciences ,Cancer stem cell ,Organoid ,medicine ,Transcriptomics ,Gene ,Multidisciplinary ,Cancer stem cells ,RNA ,Cell cycle ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,Colon cancer ,p53 signaling ,Organoids ,030104 developmental biology ,Cancer research ,Stem cell ,0210 nano-technology - Abstract
Summary Recent data suggest that therapy-resistant quiescent cancer stem cells (qCSCs) are the source of relapse in colon cancer. Here, using colon cancer patient-derived organoids and xenografts, we identify rare long-term label-retaining qCSCs that can re-enter the cell cycle to generate new tumors. RNA sequencing analyses demonstrated that these cells display the molecular hallmarks of quiescent tissue stem cells, including expression of p53 signaling genes, and are enriched for transcripts common to damage-induced quiescent revival stem cells of the regenerating intestine. In addition, we identify negative regulators of cell cycle, downstream of p53, that we show are indicators of poor prognosis and may be targeted for qCSC abolition in both p53 wild-type and mutant tumors. These data support the temporal inhibition of downstream targets of p53 signaling, in combination with standard-of-care treatments, for the elimination of qCSCs and prevention of relapse in colon cancer., Graphical Abstract, Highlights • Colon tumors contain therapy-resistant quiescent cancer stem cells (qCSCs) • qCSC gene expression mirrors that of quiescent stem cells of the regenerating gut • qCSCs are enriched for p53 signaling genes • qCSC elimination may be achieved by inhibiting downstream targets of p53 signaling, Cancer stem cells ; Quiescence; Organoids; Colon cancer; p53 signaling; Transcriptomics
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- 2020
46. Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for
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Joseph L, Regan, Dirk, Schumacher, Stephanie, Staudte, Andreas, Steffen, Ralf, Lesche, Joern, Toedling, Thibaud, Jourdan, Johannes, Haybaeck, Nicole, Golob-Schwarzl, Dominik, Mumberg, David, Henderson, Balázs, Győrffy, Christian R A, Regenbrecht, Ulrich, Keilholz, Reinhold, Schäfer, and Martin, Lange
- Abstract
Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDH
- Published
- 2020
47. ESMO consensus conference recommendations on the management of locoregional melanoma
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Iwona Lugowska, C. Gaudy-Marqueste, J.-J. Grob, Marco Donia, Paul Nathan, Bart Neyns, Mark B. Faries, Piotr Rutkowski, A.C.J. van Akkooi, Vernon K. Sondak, Bastian Schilling, Andrew J. Hayes, Christoph Hoeller, Ulrich Keilholz, P.A. Ascierto, J.B.A.G. Haanen, Matthias Guckenberger, Vanna Chiarion Sileni, C. Lebb, R. Dummer, C. Blank, H.A. Tawbi, Olivier Michielin, M. Mandal, Paul Lorigan, S. Puig, Helen Gogas, C. Robert, A. Testori, Roger Olofsson Bagge, Ivan Marquez-Rodas, A. Arance, Faculty of Arts and Philosophy, Clinical sciences, Medical Oncology, Laboratory for Medical and Molecular Oncology, and Laboratory of Molecullar and Cellular Therapy
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0301 basic medicine ,medicine.medical_specialty ,Skin Neoplasms ,Consensus ,business.industry ,Melanoma ,Skin Neoplasms/therapy ,Consensus conference ,Hematology ,medicine.disease ,medical oncology ,Melanoma/therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Humans ,Medical physics ,business ,Netherlands - Abstract
The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
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- 2020
48. [Interdisciplinary recommendations for the treatment of advanced metastatic renal cell carcinoma]
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Kurt, Miller, Lothar, Bergmann, Christian, Doehn, Viktor, Grünwald, Jürgen E, Gschwend, Philipp, Ivanyi, Ulrich, Keilholz, and Markus A, Kuczyk
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Axitinib ,Sunitinib ,Humans ,Antineoplastic Agents ,Carcinoma, Renal Cell ,Kidney Neoplasms - Abstract
Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved. A median overall survival of more than two years is a realistic goal. Immunotherapy combinations with checkpoint inhibitors or checkpoint inhibitors and the tyrosine kinase inhibitor axitinib are new first-line options.Sunitinib, pazopanib, tivozanib and the combination of bevacizumab + interferon alpha are approved for first-line therapy regardless of the progression risk score. The use of both the combination of nivolumab + ipilimumab and cabozantinib is restricted to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with sunitinib. Temsirolimus is only approved for high-risk patients.Sunitinib and pazopanib can also be applied as second-line options - for pazopanib the use is restricted to the event of cytokine failure. Nivolumab and cabozantinib demonstrated superior overall survival compared with everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second-line and further settings. Everolimus has been replaced in the second-line setting by these new options.The question regarding the optimal sequence is still unanswered.The purpose of an interdisciplinary expert meeting was to debate which criteria should influence treatment. The members discussed several aspects of treating patients with advanced or metastatic RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.Die Prognose von Patienten mit metastasiertem Nierenzellkarzinom (mRCC) hat sich dank neuer Therapien deutlich verbessert. Überlebenszeiten von mehr als zweieinhalb Jahren sind realistisch. Immuntherapiekombinationen mit Checkpoint-Inhibitoren (CPI) oder dem Tyrosinkinaseinhibitor Axitinib sind neue Standards in der Erstlinientherapie und haben die Monotherapie mit Tyrosinkinase-Inhibitoren weitgehend verdrängt.Für die Erstlinientherapie des mRCC sind Ipilimumab + Nivolumab (intermediäres und hoges Risiko) und Pembrolizumab + Axitinib sowie Avelumab + Axitinib für alle Risikogruppen zugelassen. Darüber hinaus stehen Sunitinib, Pazopanib, Tivozanib, Cabozantinib (intermediäres und hohes Risiko), die Kombination Bevacizumab + Interferon-alpha sowie Temsirolimus (hohes Risiko) zur Verfügung.Sunitinib und Pazopanib haben eine Zulassung auch für die Zweitlinientherapie – bei Pazopanib gilt diese für den Einsatz nach Zytokinen. Für Nivolumab und Cabozantinib wurde in der Zweitlinientherapie ein signifikanter Überlebensvorteil gegenüber Everolimus gezeigt. Die Kombination Lenvatinib + Everolimus sowie Axitinib sind weitere für die Zweitlinie zugelassene Substanzen. Everolimus als Monotherapie ist durch die neuen Optionen in der Zweitlinie abgelöst worden.Die Frage nach der optimalen Sequenztherapie muss aufgrund des Einzugs von CPI in die Erstlinie neu diskutiert werden, da die meisten Optionen nach Versagen einer VEGF-gerichteten TKI-Therapie geprüft wurden. Solange hierzu keine validen Studien oder Biomarker vorliegen, müssen andere Kriterien für die Therapieentscheidung herangezogen werden.Ziel eines interdisziplinären RCC-Expertengesprächs war es, gemeinsame Therapieempfehlungen auf Basis der aktuell publizierten Daten und der eigenen klinischen Erfahrung für den Praxisalltag abzuleiten. Die Ergebnisse werden in dieser Publikation vorgestellt.
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- 2020
49. The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node-positive melanoma without the need for completion lymph node dissection
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Ulrike Leiter, Astrid A M van der Veldt, Cornelis Verhoef, David van Klaveren, D. Verver, Dirk J. Grünhagen, Alexander M.M. Eggermont, Caroline Robert, Alexander C.J. van Akkooi, Barbara L. van Leeuwen, Barry W.E.M. Powell, Piotr Rutkowski, Rudolf Stadler, Ulrich Keilholz, Claus Garbe, A Rekkas, Alessandro Testori, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Surgery, Public Health, and Medical Oncology
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,CUTANEOUS MELANOMA ,MULTICENTER ,Nomogram ,0302 clinical medicine ,Risk Factors ,INTERFERON-ALPHA-2B ,Prospective Studies ,Prospective cohort study ,Lymph node ,Melanoma ,Middle Aged ,Sentinel node ,Prognosis ,RESECTED STAGE-III ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,TUMOR BURDEN ,BIOPSY ,SURVIVAL ,Female ,Sentinel lymph node ,Adult ,medicine.medical_specialty ,ADJUVANT THERAPY ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Adjuvant therapy ,Humans ,INTERVAL ,Aged ,Proportional hazards model ,business.industry ,IPILIMUMAB ,medicine.disease ,Nomograms ,030104 developmental biology ,Lymph Node Excision ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
PURPOSE: Based on recent advances in the management of patients with sentinel node (SN)-positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM).METHODS: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation.RESULTS: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of CONCLUSIONS: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making.
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- 2020
50. Adressen
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Kurt Possinger, Anne C. Regierer, Jan Eucker, Annette Dieing, Bernd Flath, Gunnar Folprecht, Michael Geißler, Florian Heidel, Erhard Hiller, Andreas Hochhaus, Kai Hübel, Henning Jann, Christian Jehn, Ulrich Keilholz, Konrad Klinghammer, Wolfgang Knauf, Hans-Jochem Kolb, Hannes Kroenlein, Anne Sophie Kubasch, Diana Lüftner, Matthias Möhlig, Ralph Naumann, Helmut Oettle, null Oettle, null Mayer, Ulrich-Frank Pape, Uwe Platzbecker, Andreas Rank, Peter Reichardt, Oliver Rick, Damian Rieke, Hanno Riess, Markus Ruhnke, Markus Schaich, Andreas Schalhorn, Ann-Kristin Schmälter, Alexander Schmittel, Christian Scholz, Hubert Schrezenmeier, Carsten-Oliver Schulz, Dorothee Speiser, and Bertram Wiedenmann
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- 2020
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