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Morphology Matters: A Critical Reappraisal of the Clinical Relevance of Morphologic Criteria From the 2019 WHO Classification in a Large Colorectal Cancer Cohort Comprising 1004 Cases.

Moritz Jesinghaus, Maxime Schmitt, Corinna Lang, Marianne Reiser, Alexander Scheiter, Björn Konukiewitz, Katja Steiger, Miguel Silva, Markus Tschurtschenthaler, Sebastian Lange, Sebastian Foersch, Karl F Becker, Dieter Saur, Helmut Friess, Kathrin Halfter, Jutta Engel, Melanie Boxberg, Nicole Pfarr, Dirk Wilhelm, Wilko Weichert,

The 2019 World Health Organization (WHO) classification of colorectal carcinoma (CRC) profoundly reclassified CRC subtypes and introduces tumor budding as a second major grading criterion, while condensing conventional grade into a 2-tiered system. So far it remains largely unexplored how these parameters interact with each other and whether they truly ... Read more >>

Am J Surg Pathol (The American journal of surgical pathology)
[2021, 45(7):969-978]

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[MSI testing : What is new? What should be considered? German version].

Josef Rüschoff, Gustavo Baretton, Hendrik Bläker, Wolfgang Dietmaier, Manfred Dietel, Arndt Hartmann, Lars-Christian Horn, Korinna Jöhrens, Thomas Kirchner, Ruth Knüchel, Doris Mayr, Sabine Merkelbach-Bruse, Hans-Ulrich Schildhaus, Peter Schirmacher, Markus Tiemann, Katharina Tiemann, Wilko Weichert, Reinhard Büttner,

Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD‑1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for ... Read more >>

Pathologe (Der Pathologe)
[2021, :]

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Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers.

Peter Horak, Christoph Heining, Simon Kreutzfeldt, Barbara Hutter, Andreas Mock, Jennifer Hullein, Martina Frohlich, Sebastian Uhrig, Arne Jahn, Andreas Rump, Laura Gieldon, Lino Mohrmann, Dorothea Hanf, Veronica Teleanu, Christoph E Heilig, Daniel B Lipka, Michael Allgauer, Leo Ruhnke, Andreas Lassmann, Volker Endris, Olaf Neumann, Roland Penzel, Katja Beck, Daniela Richter, Ulrike Winter, Stephan Wolf, Katrin Pfutze, Christina Georg, Bettina Meissburger, Ivo Buchhalter, Marinela Augustin, Walter E Aulitzky, Peter Hohenberger, Matthias Kroiss, Peter Schirmacher, Richard F Schlenk, Ulrich Keilholz, Frederick Klauschen, Gunnar Folprecht, Sebastian Bauer, Jens Thomas Siveke, Christian H Brandts, Thomas Kindler, Melanie Boerries, Anna L Illert, Nikolas von Bubnoff, Philipp J Jost, Karsten Spiekermann, Michael Bitzer, Klaus Schulze-Osthoff, Christof von Kalle, Barbara Klink, Benedikt Brors, Albrecht Stenzinger, Evelin Schrock, Daniel Hubschmann, Wilko Weichert, Hanno Glimm, Stefan Frohling,

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 ... Read more >>

Cancer Discov (Cancer discovery)
[2021, :]

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uPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils.

Bernd Uhl, Laura A Mittmann, Julian Dominik, Roman Hennel, Bojan Smiljanov, Florian Haring, Johanna B Schaubächer, Constanze Braun, Lena Padovan, Robert Pick, Martin Canis, Christian Schulz, Matthias Mack, Ewgenija Gutjahr, Peter Sinn, Jörg Heil, Katja Steiger, Sandip M Kanse, Wilko Weichert, Markus Sperandio, Kirsten Lauber, Fritz Krombach, Christoph A Reichel,

High intratumoral levels of urokinase-type plasminogen activator (uPA)-plasminogen activator inhibitor-1 (PAI-1) heteromers predict impaired survival and treatment response in early breast cancer. The pathogenetic role of this protein complex remains obscure. Here, we demonstrate that heteromerization of uPA and PAI-1 multiplies the potential of the single proteins to attract pro-tumorigenic ... Read more >>

EMBO Mol Med (EMBO molecular medicine)
[2021, 13(6):e13110]

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Corrigendum to "Biomarker testing in non-small cell lung cancer in routine care: Analysis of the first 3,717 patients in the German prospective, observational, nation-wide CRISP registry (AIO-TRK-0315)" [Lung Cancer 152 (2021) 174-184].

Frank Griesinger, Wilfried Eberhardt, Arnd Nusch, Marcel Reiser, Mark-Oliver Zahn, Christoph Maintz, Christiane Bernhardt, Christoph Losem, Albrecht Stenzinger, Lukas C Heukamp, Reinhard Büttner, Norbert Marschner, Martina Jänicke, Annette Fleitz, Lisa Spring, Jörg Sahlmann, Aysun Karatas, Annette Hipper, Wilko Weichert, Monika Heilmann, Parvis Sadjadian, Wolfgang Gleiber, Christian Grah, Cornelius F Waller, Martin Reck, Achim Rittmeyer, Petros Christopoulos, Martin Sebastian, Michael Thomas, ,

Lung Cancer (Lung cancer (Amsterdam, Netherlands))
[2021, 157:167]

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[Predictive diagnostics for checkpoint inhibitors].

Hans-Ulrich Schildhaus, Wilko Weichert,

Checkpoint inhibitors have revolutionized oncological treatment in many cancers and added a new immuno-oncological treatment pillar to the medicinal arsenal of conventional and molecularly targeted therapies. In monotherapy and in combination therapies, however, not all patients respond equally well, even in generally responsive tumor entities. Therefore, since the introduction of these ... Read more >>

Pathologe (Der Pathologe)
[2021, :]

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Implementation of Mass Spectrometry Imaging in Pathology: Advances and Challenges.

Juliana Pereira Lopes Gonçalves, Christine Bollwein, Wilko Weichert, Kristina Schwamborn,

Mass spectrometry imaging (MSI) combines the excellence in molecular characterization of mass spectrometry with microscopic imaging capabilities of hematoxylin- and eosin-stained samples, enabling the precise location of several analytes in the tissue. Especially in the field of pathology, MSI may have an impactful role in tumor diagnosis, biomarker identification, prognostic ... Read more >>

Clin Lab Med (Clinics in laboratory medicine)
[2021, 41(2):173-184]

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The Chemokine CX3CL1 Improves Trastuzumab Efficacy in HER2 Low-Expressing Cancer In Vitro and In Vivo.

Tobias F Dreyer, Sabine Kuhn, Christoph Stange, Nadine Heithorst, Daniela Schilling, Jil Jelsma, Wolfgang Sievert, Stefanie Seitz, Stefan Stangl, Alexander Hapfelmeier, Aurelia Noske, Anja K Wege, Wilko Weichert, Jürgen Ruland, Manfred Schmitt, Julia Dorn, Marion Kiechle, Ute Reuning, Viktor Magdolen, Gabriele Multhoff, Holger Bronger,

A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2<sup>+</sup>) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC ... Read more >>

Cancer Immunol Res (Cancer immunology research)
[2021, :]

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Prediction of Tumor Cellularity in Resectable PDAC from Preoperative Computed Tomography Imaging.

Friederike Jungmann, Georgios A Kaissis, Sebastian Ziegelmayer, Felix Harder, Clara Schilling, Hsi-Yu Yen, Katja Steiger, Wilko Weichert, Rebekka Schirren, Ishan Ekin Demir, Helmut Friess, Markus R Makowski, Rickmer F Braren, Fabian K Lohöfer,

<h4>Background</h4>PDAC remains a tumor entity with poor prognosis and a 5-year survival rate below 10%. Recent research has revealed invasive biomarkers, such as distinct molecular subtypes, predictive for therapy response and patient survival. Non-invasive prediction of individual patient outcome however remains an unresolved task.<h4>Methods</h4>Discrete cellularity regions of PDAC resection specimen ... Read more >>

Cancers (Basel) (Cancers)
[2021, 13(9):]

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Conventional and semi-automatic histopathological analysis of tumor cell content for multigene sequencing of lung adenocarcinoma.

Daniel Kazdal, Eugen Rempel, Cristiano Oliveira, Michael Allgäuer, Alexander Harms, Kerstin Singer, Elke Kohlwes, Steffen Ormanns, Ludger Fink, Jörg Kriegsmann, Michael Leichsenring, Katharina Kriegsmann, Fabian Stögbauer, Luca Tavernar, Jonas Leichsenring, Anna-Lena Volckmar, Rémi Longuespée, Hauke Winter, Martin Eichhorn, Claus Peter Heußel, Felix Herth, Petros Christopoulos, Martin Reck, Thomas Muley, Wilko Weichert, Jan Budczies, Michael Thomas, Solange Peters, Arne Warth, Peter Schirmacher, Albrecht Stenzinger, Mark Kriegsmann,

<h4>Background</h4>Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated ... Read more >>

Transl Lung Cancer Res (Translational lung cancer research)
[2021, 10(4):1666-1678]

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PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer.

Lucia Liotta, Sebastian Lange, H Carlo Maurer, Kenneth P Olive, Rickmer Braren, Nicole Pfarr, Sebastian Burger, Alexander Muckenhuber, Moritz Jesinghaus, Katja Steiger, Wilko Weichert, Helmut Friess, Roland Schmid, Hana Algül, Philipp J Jost, Juliane Ramser, Christine Fischer, Anne S Quante, Maximilian Reichert, Michael Quante,

BACKGROUNDPancreatic cancer is one of the deadliest cancers, with low long-term survival rates. Despite recent advances in treatment, it is important to identify and screen high-risk individuals for cancer prevention. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are related to an increased risk and ... Read more >>

JCI Insight (JCI insight)
[2021, 6(8):]

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Publisher Correction: LifeTime and improving European healthcare through cell-based interceptive medicine.

Nikolaus Rajewsky, Geneviève Almouzni, Stanislaw A Gorski, Stein Aerts, Ido Amit, Michela G Bertero, Christoph Bock, Annelien L Bredenoord, Giacomo Cavalli, Susanna Chiocca, Hans Clevers, Bart De Strooper, Angelika Eggert, Jan Ellenberg, Xosé M Fernández, Marek Figlerowicz, Susan M Gasser, Norbert Hubner, Jørgen Kjems, Jürgen A Knoblich, Grietje Krabbe, Peter Lichter, Sten Linnarsson, Jean-Christophe Marine, John C Marioni, Marc A Marti-Renom, Mihai G Netea, Dörthe Nickel, Marcelo Nollmann, Halina R Novak, Helen Parkinson, Stefano Piccolo, Inês Pinheiro, Ana Pombo, Christian Popp, Wolf Reik, Sergio Roman-Roman, Philip Rosenstiel, Joachim L Schultze, Oliver Stegle, Amos Tanay, Giuseppe Testa, Dimitris Thanos, Fabian J Theis, Maria-Elena Torres-Padilla, Alfonso Valencia, Céline Vallot, Alexander van Oudenaarden, Marie Vidal, Thierry Voet, ,

Nature (Nature)
[2021, 592(7852):E8]

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Sexual Difference Matters: Females with High Microsatellite Instability Show Increased Survival after Neoadjuvant Chemotherapy in Gastric Cancer.

Meike Kohlruss, Katja Ott, Bianca Grosser, Moritz Jesinghaus, Julia Slotta-Huspenina, Alexander Novotny, Alexander Hapfelmeier, Thomas Schmidt, Matthias M Gaida, Wilko Weichert, Gisela Keller,

We aimed to investigate patients with gastric/gastro-esophageal adenocarcinomas for sex- and age-specific differences regarding overall survival (OS) and response to neoadjuvant chemotherapy (CTx) under consideration of tumor specific molecular subtypes. Overall, 717 patients were analyzed, including 426 patients treated with and 291 treated without neoadjuvant CTx. Microsatellite instability (MSI) and ... Read more >>

Cancers (Basel) (Cancers)
[2021, 13(5):]

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Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors - An analysis of 2765 patients from neoadjuvant clinical trials.

Sonia L Villegas, Valentina Nekljudova, Nicole Pfarr, Jutta Engel, Michael Untch, Simone Schrodi, Frank Holms, Hans U Ulmer, Peter A Fasching, Karsten E Weber, Christian Albig, Clemens Heinrichs, Frederik Marmé, Arndt Hartmann, Claus Hanusch, Wolfgang D Schmitt, Jens Huober, Bianca Lederer, Marion van Mackelenbergh, Hans Tesch, Christian Jackisch, Mahdi Rezai, Peter Sinn, Bruno V Sinn, John Hackmann, Marion Kiechle, Andreas Schneeweiss, Wilko Weichert, Carsten Denkert, Sibylle Loibl,

<h4>Aim</h4>To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC.<h4>Methods</h4>We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1-9%) and strong-positive (ER or PR ... Read more >>

Eur J Cancer (European journal of cancer (Oxford, England : 1990))
[2021, 148:159-170]

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Detection of gene fusions using targeted next-generation sequencing: a comparative evaluation.

Carina Heydt, Christina B Wölwer, Oscar Velazquez Camacho, Svenja Wagener-Ryczek, Roberto Pappesch, Janna Siemanowski, Jan Rehker, Florian Haller, Abbas Agaimy, Karl Worm, Thomas Herold, Nicole Pfarr, Wilko Weichert, Thomas Kirchner, Andreas Jung, Jörg Kumbrink, Wolfgang Goering, Irene Esposito, Reinhard Buettner, Axel M Hillmer, Sabine Merkelbach-Bruse,

<h4>Background</h4>Gene fusions represent promising targets for cancer therapy in lung cancer. Reliable detection of multiple gene fusions is therefore essential.<h4>Methods</h4>Five commercially available parallel sequencing assays were evaluated for their ability to detect gene fusions in eight cell lines and 18 FFPE tissue samples carrying a variety of known gene fusions. ... Read more >>

BMC Med Genomics (BMC medical genomics)
[2021, 14(1):62]

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Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.

Alexander M Betzler, Lahiri K Nanduri, Barbara Hissa, Linda Blickensdörfer, Michael H Muders, Janine Roy, Moritz Jesinghaus, Katja Steiger, Wilko Weichert, Matthias Kloor, Barbara Klink, Michael Schroeder, Massimiliano Mazzone, Jürgen Weitz, Christoph Reissfelder, Nuh N Rahbari, Sebastian Schölch,

<h4>Background</h4>Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, ... Read more >>

Cancers (Basel) (Cancers)
[2021, 13(4):]

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Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia.

Begüm Alankus, Veronika Ecker, Nathalie Vahl, Martina Braun, Wilko Weichert, Stephan Macher-Göppinger, Torben Gehring, Tanja Neumayer, Thorsten Zenz, Maike Buchner, Jürgen Ruland,

Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell-intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma-derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK ... Read more >>

J Exp Med (The Journal of experimental medicine)
[2021, 218(2):]

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[Diagnosis and therapy of tumors with NTRK gene fusion].

Albrecht Stenzinger, Cornelis M van Tilburg, Ghazaleh Tabatabai, Florian Länger, Norbert Graf, Frank Griesinger, Lukas C Heukamp, Michael Hummel, Thomas Klingebiel, Simone Hettmer, Christian Vokuhl, Sabine Merkelbach-Bruse, Friedrich Overkamp, Peter Reichardt, Monika Scheer, Wilko Weichert, C Benedikt Westphalen, Carsten Bokemeyer, Philipp Ivanyi, Sonja Loges, Peter Schirmacher, Bernhard Wörmann, Stefan Bielack, Thomas T W Seufferlein,

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or ... Read more >>

Pathologe (Der Pathologe)
[2021, 42(1):103-115]

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KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315).

Martin Sebastian, Wilfried E E Eberhardt, Petra Hoffknecht, Martin Metzenmacher, Thomas Wehler, Konrad Kokowski, Jürgen Alt, Wolfgang Schütte, Reinhard Büttner, Lukas C Heukamp, Albrecht Stenzinger, Martina Jänicke, Annette Fleitz, Stefan Zacharias, Stephanie Dille, Annette Hipper, Marlen Sandberg, Wilko Weichert, Matthias Groschek, Eyck von der Heyde, Jacqueline Rauh, Tobias Dechow, Michael Thomas, Frank Griesinger, ,

<h4>Objectives</h4>After decades of unsuccessful efforts in inhibiting KRAS, promising clinical data targeting the mutation subtype G12C emerge. Since little is known about outcome with standard treatment of patients with G12C mutated non-small cell lung cancer (NSCLC), we analyzed a large, representative, real-world cohort from Germany.<h4>Patients and methods</h4>A total of 1039 ... Read more >>

Lung Cancer (Lung cancer (Amsterdam, Netherlands))
[2021, 154:51-61]

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Spatial and temporal plasticity of neoantigen-specific T-cell responses bases on characteristics associated to antigen and TCR

Eva Bräunlein, Gaia Lupoli, Esam Abualrous, Niklas de Andrade Krätzig, Dario Gosmann, Franziska Füchsl, Lukas Wietbrock, Sebastian Lange, Thomas Engleitner, Huan Lan, Stefan Audehm, Manuel Effenberger, Melanie Boxberg, Katja Steiger, Yinshui Chang, Kai Yu, Cigdem Atay, Florian Bassermann, Wilko Weichert, Dirk Busch, Roland Rad, Christian Freund, Iris Antes, Angela Krackhardt,

Neoantigens derived from somatic mutations have been demonstrated to correlate with therapeutic responses mediated by treatment with immune checkpoint inhibitors. Neoantigens are therefore highly attractive targets for the development of personalized medicine approaches although their quality and associated immune responses is not yet well understood. In a case study of ... Read more >>

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Positionspapier der DRG, DGNR, GPR, DeGIR, ÖRG und DGP zur Nutzung klinischer Daten für wissenschaftliche Zwecke.

Christiane Kuhl, Peter Walter, Claus Zimmer, Hans-Joachim Mentzel, Peter Reimer, Klaus A Hausegger, Gustavo Baretton, Ralf-Thorsten Hoffmann, Walter Heindel, Christoph Düber, Michael Uder, Konstantin Nikolaou, Gerald Antoch, , , , , , , ,

Rofo (RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin)
[2021, 193(4):381-387]

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The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations.

Barbara Willvonseder, Fabian Stögbauer, Katja Steiger, Moritz Jesinghaus, Peer-Hendrik Kuhn, Christine Brambs, Jutta Engel, Holger Bronger, Georg Philipp Schmidt, Bernhard Haller, Wilko Weichert, Gisela Keller, Aurelia Noske, Nicole Pfarr, Melanie Boxberg,

<h4>Objective</h4>POLE-mutant, microsatellite-instable (MSI), p53-mutant and non-specific molecular profile (NSMP) are TCGA-defined molecular subgroups of endometrial cancer (EC). Hypothesizing that morphology and tumor immunology might differ depending on molecular background concerning composition and prognostic impact, we aimed to comprehensively interconnect morphologic, immunologic and molecular data.<h4>Methods</h4>TCGA-defined molecular groups were determined by immunohistochemistry ... Read more >>

Cancer Immunol Immunother (Cancer immunology, immunotherapy : CII)
[2021, 70(6):1679-1689]

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A multicentre analytical comparison study of inter-reader and inter-assay agreement of four programmed death-ligand 1 immunohistochemistry assays for scoring in triple-negative breast cancer.

Aurelia Noske, Johannes U Ammann, Daniel-Christoph Wagner, Carsten Denkert, Annette Lebeau, Peter Sinn, Hans-Heinrich Kreipe, Ulrich Sommer, Gustavo Baretton, Katja Steiger, Marion Kiechle, Stefanie Hieke-Schulz, Mike Flores, Wilfried Roth, Wilko Weichert,

<h4>Aims</h4>Studies in various cancer types have demonstrated discordance between results from different programmed death-ligand 1 (PD-L1) assays. Here, we compare the reproducibility and analytical concordance of four clinically developed assays for assessing PD-L1-positivity in tumour-infiltrating immune cells in the tumour area (PD-L1-IC-positivity) in triple-negative breast cancer (TNBC).<h4>Methods and results</h4>Primary TNBC ... Read more >>

Histopathology (Histopathology)
[2021, 78(4):567-577]

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[Impact of the novel in vitro diagnostic regulation (IVDR) of the European Union on pathology laboratories. What's important?]

Albrecht Stenzinger, Wilko Weichert,

In 2022 the new in vitro diagnostic regulation (IVDR) of the European Union will come into full effect. This complex regulatory framework aims at a stricter regulation and monitoring of industrial diagnostic assay production. The IVDR defines many new methodological requirements and includes an additional entirely new focus on the clinical ... Read more >>

Pathologe (Der Pathologe)
[2020, 41(Suppl 2):129-133]

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Circulating Interleukin-4 Is Associated with a Systemic T Cell Response against Tumor-Associated Antigens in Treatment-Naïve Patients with Resectable Non-Small-Cell Lung Cancer.

Seyer Safi, Yoshikane Yamauchi, Hans Hoffmann, Wilko Weichert, Philipp J Jost, Hauke Winter, Thomas Muley, Philipp Beckhove,

Spontaneous T cell responses to tumor-associated antigens (TAs) in the peripheral blood of patients with non-small-cell lung cancer (NSCLC) may be relevant for postoperative survival. However, the conditions underlying these T cell responses remain unclear. We quantified the levels of 27 cytokines in the peripheral blood and tumor tissues from ... Read more >>

Cancers (Basel) (Cancers)
[2020, 12(12):]

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