482 results on '"Ulrich Keilholz"'
Search Results
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
- Subjects
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.
- Published
- 2022
19. Klassische Zytostatika-Gruppierungen
- Author
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Christoph Ritter, Susen Burock, and Ulrich Keilholz
- Published
- 2022
20. 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)
- Subjects
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.
- Published
- 2020
21. 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.
- Published
- 2019
22. 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
- Subjects
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.
- Published
- 2021
23. 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
- Subjects
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.
- Published
- 2021
24. 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
- Subjects
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.
- Published
- 2021
25. Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis
- Author
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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
26. 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
27. Peritoneal metastasis of colorectal cancer (pmCRC): identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models
- Author
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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
28. Unresolved questions regarding the promise of the TPEx regimen - Authors' reply
- Author
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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
29. 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
- Author
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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
- Subjects
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.
- Published
- 2021
30. 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
- Subjects
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.
- Published
- 2018
31. 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.
- Published
- 2021
32. RNA-Sequencing of Long-Term Label-Retaining Colon Cancer Stem Cells Identifies Novel Regulators of Quiescence
- Author
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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.
- Published
- 2021
33. 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.
- Published
- 2021
34. RNA sequencing of long-term label-retaining colon cancer stem cells identifies novel regulators of quiescence
- Author
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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
- Published
- 2020
35. Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for
- Author
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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
36. Adressen
- Author
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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
- Published
- 2020
37. Tumoren der Haut
- Author
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Ulrich Keilholz
- Published
- 2020
38. Gynäkologische Tumoren
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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, 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
- Published
- 2020
39. Cetuximab, Docetaxel and Cisplatin as First-Line Treatment in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Results of the GORTEC 2014-01 TPExtreme Randomized Trial
- Author
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Joël Guigay, Anne Aupérin, Jerome Fayette, Esma Saada-Bouzid, Cédrik Lafond, Miren Taberna, Lionnel Geoffrois, Laurent Martin, Olivier Capitain, Didier Cupissol, Hélène Castanie, Damien Vansteene, Philippe Schafhausen, Alison Johnson, Caroline Even, Christian Sire, Sophie Duplomb, Camille Evrard, Jean-Pierre Delord, Brigitte Laguerre, Sylvie Zanetta, Cécile Chevassus, Aldéric Fraslin, Fanny Louat, Laura Sinigaglia, Ulrich Keilholz, Jean Bourhis, Ricard Mesia, and GORTEC, AIO, TTCC, UniCancer H& Group
- Subjects
medicine.medical_specialty ,Performance status ,Cetuximab ,business.industry ,Head and neck cancer ,medicine.disease ,law.invention ,Regimen ,Randomized controlled trial ,Quality of life ,law ,Internal medicine ,medicine ,Clinical endpoint ,Adverse effect ,business ,medicine.drug - Abstract
Background: After promising results from TPEx phase II trial in first line recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), this trial compared the TPEx regimen (docetaxel-platinum-cetuximab) to the standard EXTREME regimen. Methods: Patients with R/M HNSCC unsuitable for curative treatment were randomized between TPEx (four cycles docetaxel-cisplatin-cetuximab followed by cetuximab maintenance 500 mg/m² every two weeks) and EXTREME (six cycles 5FU-cisplatin-cetuximab followed by weekly cetuximab 250 mg/m² maintenance). Main inclusion criteria were patients fit for cisplatin, performance status (PS) ≤1, creatinine clearance >60ml/min, and age
- Published
- 2020
40. Information, communication, and cancer patients’ trust in the physician: what challenges do we have to face in an era of precision cancer medicine?
- Author
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C. Benedikt Westphalen, Anne Letsch, Theresia Pichler, Ute Goerling, Philipp J. Jost, Amy Rohrmoser, Mario Lamping, Kristina Riedmann, Volker Heinemann, Peter Herschbach, and Ulrich Keilholz
- Subjects
Adult ,Male ,Information transfer ,Visual analogue scale ,Pain medicine ,Face (sociological concept) ,Information needs ,Molecular diagnostic ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Information ,medicine ,Humans ,Precision Medicine ,Qualitative Research ,Aged ,0303 health sciences ,Physician-Patient Relations ,Whole Genome Sequencing ,business.industry ,Nursing research ,Communication ,030305 genetics & heredity ,Cancer ,Middle Aged ,medicine.disease ,ddc ,Oncology ,030220 oncology & carcinogenesis ,Female ,Original Article ,Medical emergency ,business ,Precision cancer medicine ,Qualitative research - Abstract
Purpose Despite promising achievements in precision cancer medicine (PCM), participating patients are still faced with manifold uncertainties, especially regarding a potential treatment benefit of molecular diagnostics (MD). Hence, MD poses considerable challenges for patient information and communication. To meet these challenges, healthcare professionals need to gain deeper insight into patients’ subjective experiences. Therefore, this qualitative study examined information aspects of MD programs in cancer patients. Methods In two German Comprehensive Cancer Centers, 30 cancer patients undergoing MD participated in semi-structured interviews on information transfer and information needs regarding MD. Additionally, patients provided sociodemographic and medical data and indicated their subjective level of information (visual analogue scale, VAS, 0–10). Results On average patients had high levels of information (mean = 7, median = 8); nevertheless 20% (n = 6) showed an information level below 5 points. Qualitative analysis revealed that patients show limited understanding of the complex background of MD and have uncertainties regarding their personal benefit. Further, patients described unmet information needs. Existential threat in awaiting the results was experienced as burdensome. To withstand the strains of their situation, patients emphasized the importance of trusting their physician. Conclusion The challenges in PCM consist in providing unambiguous information, especially concerning treatment benefit, and providing guidance and support. Therefore, psycho-oncology needs to develop guidelines for adequate patient communication in order to help healthcare providers and cancer patients to handle these challenges in the developing field of PCM.
- Published
- 2019
41. Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells
- Author
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Johannes Haybaeck, Andreas Steffen, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Christian R. A. Regenbrecht, Nicole Golob-Schwarzl, Reinhold Schäfer, Caroline Schweiger, Hans Lehrach, Joseph L. Regan, David Henderson, Martin Lange, and Dominik Mumberg
- Subjects
0301 basic medicine ,animal structures ,Colorectal cancer ,Mice, Nude ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,HHAT ,Cancer stem cell ,medicine ,Animals ,Humans ,Hedgehog Proteins ,Autocrine signalling ,lcsh:QH301-705.5 ,Wnt Signaling Pathway ,Hedgehog ,Wnt signaling pathway ,Cancer ,medicine.disease ,Hedgehog signaling pathway ,3. Good health ,Patched-1 Receptor ,030104 developmental biology ,lcsh:Biology (General) ,Colonic Neoplasms ,embryonic structures ,Neoplastic Stem Cells ,Cancer research ,Female - Abstract
Summary: Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs). To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH)-positive CSCs. Canonical GLI-dependent Hedgehog signaling is a negative regulator of WNT signaling in normal intestine and intestinal tumors. Here, we show that Hedgehog signaling in colon CSCs is autocrine SHH-dependent, non-canonical PTCH1 dependent, and GLI independent. In addition, using small-molecule inhibitors and RNAi against SHH-palmitoylating Hedgehog acyltransferase (HHAT), we demonstrate that non-canonical Hedgehog signaling is a positive regulator of WNT signaling and required for colon CSC survival. : Colon cancer is a heterogeneous tumor driven by a subpopulation(s) of therapy-resistant cancer stem cells (CSCs). Regan et al. use 3D culture models to demonstrate that CSC survival is regulated by non-canonical, SHH-dependent, PTCH1-dependent Hedgehog signaling, which acts as a positive regulator of WNT signaling to block CSC differentiation. Keywords: WNT pathway, non-canonical Hedgehog signaling, cancer stem cell, colon cancer, cancer organoid, PTCH1, HHAT, SHH
- Published
- 2017
42. Should cT2 esophageal cancer get neoadjuvant treatment before surgery?
- Author
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Peter C. Thuss-Patience, Loredana Vecchione, and Ulrich Keilholz
- Subjects
Pulmonary and Respiratory Medicine ,Cisplatin ,medicine.medical_specialty ,Preoperative Therapy ,business.industry ,Esophageal cancer ,medicine.disease ,law.invention ,Surgery ,03 medical and health sciences ,Editorial ,0302 clinical medicine ,Randomized controlled trial ,Neoadjuvant treatment ,law ,030220 oncology & carcinogenesis ,Medicine ,030211 gastroenterology & hepatology ,Stage (cooking) ,business ,Chemoradiotherapy ,Pathologic Complete Remission ,medicine.drug - Abstract
In recent years treatment options for esophageal cancer were expanding as randomized trials have shown a beneficial effect of preoperative chemotherapy and of chemoradiotherapy (1-7). However, it is unclear whether early stage cancers also benefit from preoperative therapy since the number of patients included in such randomized trials is small (8-10). In a more recently published randomized trial, Mariette et al. (11) investigated the benefit of preoperative chemoradiotherapy in stage I and II esophageal carcinomas. A total of 195 patients were randomized between primary surgery and preoperative chemoradiotherapy (cisplatin/5- FU +45 Gy), followed by surgery. Despite of a significant downstaging and a pathologic complete remission (pCR) in 33.3% of cases in the chemoradiotherapy group, no improvement of neither R0 resection rate nor overall survival were observed. Moreover, there was no difference in postoperative complications but there was an increase in hospital mortality in the chemoradiotherapy group (11.1% vs. 3.4%), which may have affected the overall outcome of the trial. Due to these results neoadjuvant treatment for T2 esophageal cancer remains highly controversial.
- Published
- 2017
43. Basal subtype is predictive for response to cetuximab treatment in patient-derived xenografts of squamous cell head and neck cancer
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Iduna Fichtner, Jan-Dirk Raguse, Konrad Klinghammer, Ulf Leser, Raik Otto, Ulrich Keilholz, Ingeborg Tinhofer, Andreas E. Albers, and Jens Hoffmann
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Targeted therapy ,03 medical and health sciences ,Basal (phylogenetics) ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Gene expression ,medicine ,Everolimus ,Cetuximab ,business.industry ,Head and neck cancer ,medicine.disease ,Carboplatin ,030104 developmental biology ,Docetaxel ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient-derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, everolimus, cis- or carboplatin and 5-fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after 3 weeks of treatment (RTV). Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs. BA 0.78 (MS vs. BA, unpaired t-test, p 0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient-derived xenografts.
- Published
- 2017
44. Expression of guanylyl cyclase C in tissue samples and the circulation of rectal cancer patients
- Author
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Yu-ping Zhu, Hai-Xing Ju, Dechuan Li, Guoping Cheng, Meucci Stefano, Ulrich Keilholz, Yong Liu, and Jun Qian
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,Pathology ,medicine.medical_specialty ,Colorectal cancer ,overall survival ,Rectum ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Stage (cooking) ,guanylyl cyclase C ,rectal cancer ,disease free survival ,Survival rate ,Aged ,Aged, 80 and over ,tumor metastasis ,Rectal Neoplasms ,business.industry ,Cancer ,Guanylate cyclase 2C ,Middle Aged ,Neoplastic Cells, Circulating ,Prognosis ,medicine.disease ,Survival Rate ,030104 developmental biology ,medicine.anatomical_structure ,Case-Control Studies ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,business ,Receptors, Atrial Natriuretic Factor ,Follow-Up Studies ,Research Paper - Abstract
// Yong Liu 1, 3 , Guoping Cheng 2 , Jun Qian 1 , HaiXing Ju 1 , YuPing Zhu 1 , Meucci Stefano 3 , Ulrich Keilholz 3 and DeChuan Li 1 1 Surgical Department of Colorectal Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China 2 Pathology Department, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China 3 Charite Comprehensive Cancer Center, Berlin, Germany Correspondence to: Yong Liu, email: liuyong@zjcc.org.cn Keywords: guanylyl cyclase C, rectal cancer, tumor metastasis, disease free survival, overall survival Received: December 10, 2016 Accepted: February 17, 2017 Published: March 21, 2017 ABSTRACT Guanylyl cyclase C (GCC) is a transmembrane surface receptor restricted to intestinal epithelial cells, from the duodenum to the rectum. We compared GCC expression in tumors and normal rectal tissues, and investigated the relation between GCC expression and metastasis and long-term survival of rectal cancer patients. Based on the UICC classification, 42 rectal cancer patients in this study were classified as stage I, 48 patients as stage II, and 90 patients as stage III. Overexpression of GCC was observed in 80 rectal tumors as compared to matched normal tissues, where no strong staining of GCC was observed. An association between GCC mRNA in the circulation and tumor emboli in vessels, CK20 mRNA, distant organ metastasis, and survival status was observed in 100 rectal cancer patients. Univariate Cox regression analysis indicated that tumor emboli in vessels, lymph node metastasis, mesenteric root lymph node metastasis and GCC mRNA correlated with 5-year disease-free survival (DFS); while lymph node metastasis, GCC mRNA, and CK20 mRNA strongly correlated with 5-year overall survival (OS). In a multivariate Cox regression model, GCC mRNA level and mesenteric root lymph node metastasis associated with DFS, while GCC mRNA levels associated with OS. Quantification of GCC expression in circulation is a valuable biomarker for assessing tumor burden and predicting outcome in rectal cancer patients.
- Published
- 2017
45. Zweite Interimsanalyse der multizentrischen NOGGO – Expression V – Umfrage zu den Erwartungen und Wünschen von Patientinnen mit gynäkologischen Malignomen und mit und ohne Migrationshintergrund
- Author
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U Torsten, Desislava Dimitrova, Radoslav Chekerov, G. Oskay-Özcelik, Konrad Neumann, E Yüksel, B Naghavi, J-U Blohmer, Ulrich Keilholz, Matthias David, C Kronenberger, Jalid Sehouli, Elena-Ioana Braicu, and I Blau
- Subjects
Maternity and Midwifery ,Obstetrics and Gynecology - Published
- 2017
46. VIST - a Variant-Information Search Tool for precision oncology
- Author
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Reinhold Schäfer, David Luis Wiegandt, Damian T. Rieke, Jurica Ševa, Julian Götze, Johannes Starlinger, Patrick Jähnichen, Ulrich Keilholz, Steffen Pallarz, Ulf Leser, Madeleine Kittner, and Mario Lamping
- Subjects
Computer science ,Documentation ,Biomedical information retrieval ,lcsh:Computer applications to medicine. Medical informatics ,computer.software_genre ,Biochemistry ,Ranking (information retrieval) ,User-Computer Interface ,Document classification ,03 medical and health sciences ,Search engine ,0302 clinical medicine ,Structural Biology ,Blueprint ,Neoplasms ,Humans ,Precision Medicine ,Document retrieval ,lcsh:QH301-705.5 ,Molecular Biology ,030304 developmental biology ,Internet ,0303 health sciences ,Focus (computing) ,Information retrieval ,Applied Mathematics ,Document triage ,Personalized oncology ,Computer Science Applications ,Search Engine ,Databases as Topic ,lcsh:Biology (General) ,Clinical relevance ,030220 oncology & carcinogenesis ,Vector space model ,lcsh:R858-859.7 ,User interface ,computer ,Algorithms ,Research Article - Abstract
Background Diagnosis and treatment decisions in cancer increasingly depend on a detailed analysis of the mutational status of a patient’s genome. This analysis relies on previously published information regarding the association of variations to disease progression and possible interventions. Clinicians to a large degree use biomedical search engines to obtain such information; however, the vast majority of scientific publications focus on basic science and have no direct clinical impact. We develop the Variant-Information Search Tool (VIST), a search engine designed for the targeted search of clinically relevant publications given an oncological mutation profile. Results VIST indexes all PubMed abstracts and content from ClinicalTrials.gov. It applies advanced text mining to identify mentions of genes, variants and drugs and uses machine learning based scoring to judge the clinical relevance of indexed abstracts. Its functionality is available through a fast and intuitive web interface. We perform several evaluations, showing that VIST’s ranking is superior to that of PubMed or a pure vector space model with regard to the clinical relevance of a document’s content. Conclusion Different user groups search repositories of scientific publications with different intentions. This diversity is not adequately reflected in the standard search engines, often leading to poor performance in specialized settings. We develop a search engine for the specific case of finding documents that are clinically relevant in the course of cancer treatment. We believe that the architecture of our engine, heavily relying on machine learning algorithms, can also act as a blueprint for search engines in other, equally specific domains. VIST is freely available at https://vist.informatik.hu-berlin.de/ Electronic supplementary material The online version of this article (10.1186/s12859-019-2958-3) contains supplementary material, which is available to authorized users.
- Published
- 2019
47. Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial
- Author
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Janice M. Mehnert, Sebastian Bauer, Lucjan Wyrwicz, Kevin M. Chin, Anja von Heydebreck, Ulrich Keilholz, Donald Gravenor, Manish R. Patel, John Nemunaitis, Vijay Kasturi, Keun Wook Lee, Hugues Bourgeois, Matthew H. Taylor, and James L. Gulley
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Skin Neoplasms ,Medizin ,Immune checkpoint inhibitor ,Gastroenterology ,B7-H1 Antigen ,Avelumab ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Immunology and Allergy ,030212 general & internal medicine ,Melanoma ,Aged, 80 and over ,Merkel cell carcinoma ,Antibodies, Monoclonal ,Ocular melanoma ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Primary tumor ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Chills ,medicine.symptom ,Cutaneous melanoma ,Research Article ,medicine.drug ,PD-L1 ,Adult ,medicine.medical_specialty ,Immunology ,Ocular Melanoma ,Ipilimumab ,Antibodies, Monoclonal, Humanized ,lcsh:RC254-282 ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Stage IIIC ,Adverse effect ,Aged ,Pharmacology ,business.industry ,Eye Neoplasms ,medicine.disease ,Survival Analysis ,Clinical trial ,030104 developmental biology ,business - Abstract
191 Background: Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is approved for the treatment of metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma progressed on platinum therapy (US). Here, we report phase 1b data for avelumab in a cohort of patients (pts) with previously treated metastatic melanoma. Methods: Pts with unresectable stage IIIC or IV melanoma progressed after ≥1 line of therapy for metastatic disease received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs; NCI CTCAE v4.0). Results: As of Dec 31, 2016, 51 pts were treated and followed for a median of 24.2 mo (range 16.1–31.5). Median age was 64 y (range 31–84). Site of primary tumor was cutaneous (n = 28, 54.9%), ocular (n = 16, 31.4%), mucosal (n = 2, 3.9%), or unknown (n = 5, 9.8%). Pts had received a median of 2 prior lines of therapy for advanced disease (range 0–4), including ipilimumab (n = 26, 51.0%). Confirmed ORR was 21.6% (95% CI 11.3–35.3), with complete response in 7.8% and partial response in 13.7%. In pts with cutaneous melanoma, ORR was 28.6% (95% CI 13.2–48.7). There were no objective responses in pts with ocular melanoma; however, 7 pts (43.8%) had stable disease. In pts with ≤1 (n = 25), 2 (n = 17), or ≥3 (n = 9) prior lines, ORR was 36.0% (95% CI 18.0–57.5), 11.8% (95% CI 1.5–36.4), and 0% (95% CI 0–33.6), respectively. Antitumor activity by PD-L1 status will be presented. Median duration of response was not estimable (NE) (95% CI 2.6 mo–NE). Median PFS was 3.1 mo (95% CI 1.4–6.3) and the 6-mo PFS rate was 39.2% (95% CI 25.2–52.9). Median OS was 18.5 mo (95% CI 9.3–NE) and the 12-mo OS rate was 62.3% (95% CI 46.9–74.4). 39 pts (76.5%) had a treatment-related (TR)AE, most commonly infusion-related reaction (25.5%), fatigue (17.6%), and chills (11.8%). 4 pts (7.8%) had a grade ≥3 TRAE. 5 pts (9.8%) had an immune-related AE; all were grade 1/2. No treatment-related deaths occurred. Conclusions: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in pts with previously treated metastatic melanoma. Clinical trial information: NCT01772004.
- Published
- 2019
48. Mutational load and mutational patterns in relation to age in head and neck cancer
- Author
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Ingeborg Tinhofer, Oliva A. Ebner, Stefano Meucci, and Ulrich Keilholz
- Subjects
Adult ,0301 basic medicine ,Oncology ,Aging ,medicine.medical_specialty ,medicine.medical_treatment ,head and neck squamous cell carcinoma ,Bioinformatics ,Cohort Studies ,Young Adult ,03 medical and health sciences ,Research Paper: Gerotarget (Focus on Aging) ,0302 clinical medicine ,Gene Frequency ,Internal medicine ,genomics ,medicine ,Humans ,Genetic Predisposition to Disease ,Young adult ,Allele frequency ,Aged ,Aged, 80 and over ,Gerotarget ,business.industry ,Head and neck cancer ,Age Factors ,HPV infection ,Cancer ,sequencing ,Middle Aged ,medicine.disease ,Head and neck squamous-cell carcinoma ,Radiation therapy ,stomatognathic diseases ,030104 developmental biology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Mutation ,Carcinoma, Squamous Cell ,somatic mutations ,business ,Signal Transduction ,Cohort study - Abstract
// Stefano Meucci 1 , Ulrich Keilholz 1 , Ingeborg Tinhofer 2 and Oliva A. Ebner 1 1 Charite Comprehensive Cancer Center, Charite University Hospital, Chariteplatz, Berlin, Germany 2 Department of Radiation Oncology and Radiotherapy, Charite University Hospital Berlin, Translational Radiation Oncology Research Laboratory, Chariteplatz, Berlin, Germany Correspondence to: Ulrich Keilholz, email: // Stefano Meucci, email: // Keywords : head and neck squamous cell carcinoma; aging; somatic mutations; sequencing; genomics; Gerotarget Received : December 21, 2015 Accepted : July 23, 2016 Published : August 16, 2016 Abstract Head and neck squamous cell carcinoma (HNSCC) is a cancer with well-defined tumor causes such as HPV infection, smoking and drinking. Using The Cancer Genome Atlas (TCGA) HNSCC cohort we systematically studied the mutational load as well as patterns related to patient age in HNSCC. To obtain a homogenous set we excluded all patients with HPV infection as well as wild type TP53. We found that the overall mutational load is higher in patients of old age. Through unsupervised hierarchical clustering, we detected distinct mutational clusters in very young as well as very old patients. In the group of old patients, we identified four enriched pathways (“Axon Guidance”, “ECM-Receptor Interaction”, “Focal Adhesion” and “Notch Signaling”) that are only sporadically mutated in the other age groups. Our findings indicate that the four pathways regulate cell motility, tumor invasion and angiogenesis supposedly leading to less aggressive tumors in older age patients. Importantly, we did not see a strict pattern of genes always mutated in older age but rather an accumulation of mutations in the same pathways. Our study provides indications of age-dependent differences in mutational backgrounds of tumors that might be relevant for treatment approaches of HNSCCs patients.
- Published
- 2016
49. Prevalence and associated survival of high-risk HPV-related adenoid cystic carcinoma of the salivary glands
- Author
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Veit Maria Hofmann, Michael Hummel, Andreas E. Albers, Andreas M. Kaufmann, Ulrich Keilholz, Chao Chen, Georgios Tzamalis, and Xu Qian
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Adolescent ,Adenoid cystic carcinoma ,Kaplan-Meier Estimate ,Disease ,Biology ,Malignancy ,Disease-Free Survival ,Salivary Glands ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Carcinoma ,Humans ,Neoplasm Metastasis ,Papillomaviridae ,Pathological ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,Aged, 80 and over ,HPV infection ,Middle Aged ,Salivary Gland Neoplasms ,medicine.disease ,Carcinoma, Adenoid Cystic ,Molecular medicine ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Ki-67 Antigen ,030104 developmental biology ,030220 oncology & carcinogenesis ,Resection margin ,Female ,Tumor Suppressor Protein p53 - Abstract
Adenoid cystic carcinoma (SACC) is a rare malignancy, but a frequent subtype in minor and major salivary glands. The molecular alterations or biomarkers that underlie its development and progression as well as therapy outcomes are poorly characterized. The main study goal was to investigate reliable biomarkers and patient-related factors that may have impact on recurrence and long-term survival of SACC. The prevalence of human papilloma virus (HPV) in SACC was determined by HPV-DNA genotyping and p16 immunostaining. Epithelial growth factor receptor (EGFR), p53 and Ki-67 expression were also evaluated. Twenty-eight (42%) of 67 patients were HPV-DNA positive. Kaplan-Meier analysis indicated that SACC patients with metastases (P=0.03) had a poor overall survival (OS) and a shorter recurrence-free survival (P
- Published
- 2016
50. Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients
- Author
-
Kurt Miller, Anastasia Dielmann, Anika Nonnenmacher, Anne Letsch, Antonia Busse, and Ulrich Keilholz
- Subjects
Adult ,Male ,Sorafenib ,TBX21 ,Cancer Research ,CD3 ,Immunology ,Eomesodermin ,Biology ,Immunophenotyping ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,T-Lymphocyte Subsets ,medicine ,Humans ,Immunology and Allergy ,RNA, Messenger ,Neoplasm Metastasis ,Carcinoma, Renal Cell ,Transcription factor ,Aged ,Neoplasm Staging ,Middle Aged ,Prognosis ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,Killer Cells, Natural ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,T-Box Domain Proteins ,Memory T cell ,030215 immunology ,medicine.drug - Abstract
T-box transcription factors, T-box expressed in T cells (T-bet) encoded by Tbx21 and Eomesodermin (Eomes), drive the differentiation of effector/memory T cell lineages and NK cells. The aim of the study was to determine the prognostic influence of the expression of these transcription factors in peripheral blood (pB) in a cohort of 41 metastatic (m) RCC patients before receiving sorafenib treatment and to analyze their association with the immunophenotype in pB. In contrast to Tbx21, in the multivariate analysis including clinical features, Eomes mRNA expression was identified as an independent good prognostic factor for progression-free survival (PFS, p = 0.042) and overall survival (OS, p = 0.001) in addition to a favorable ECOG performance status (p = 0.01 and p = 0.008, respectively). Eomes expression correlated positively not only with expression of Tbx21 and TGFβ1 mRNA, but also with mRNA expression of the activation marker ICOS, and with in vivo activated HLA-DR(+) T cells. Eomes expression was negatively associated with TNFα-producing T cells. On protein level, Eomes was mainly expressed by CD56(+)CD3(-) NK cells in pB. In conclusion, we identified a higher Eomes mRNA expression as an independent good prognostic factor for OS and PFS in mRCC patients treated with sorafenib.
- Published
- 2016
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