188 results on '"Korinna Jöhrens"'
Search Results
2. Neurotrophic tyrosine receptor kinase gene fusions in adult and pediatric patients with solid tumors: a clinicogenomic biobank and record linkage study of expression frequency and patient characteristics from Finland
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Wei Zhang, Arndt A. Schmitz, Roosa E. Kallionpää, Merja Perälä, Niina Pitkänen, Mikko Tukiainen, Erika Alanne, Korinna Jöhrens, Renate Schulze-Rath, Bahman Farahmand, and Jihong Zong
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Clinicogenomic ,NTRK gene fusions ,solid tumors ,pediatrics ,epidemiology ,biobank ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers. Using the Auria Biobank in Finland, we aimed to identify and characterize patients with these gene fusions, and describe their clinical and tumor characteristics, treatments received, and outcomes. Material and methods: We evaluated pediatrics with any solid tumor type and adults with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), sarcoma, or salivary gland cancer. We determined tropomyosin receptor kinase (TRK) protein expression by pan-TRK immunohistochemistry (IHC) staining of tumor samples from the Auria Biobank, scored by a certified pathologist. NTRK gene fusion was confirmed by next generation sequencing (NGS). All 2,059 patients were followed-up starting 1 year before their cancer diagnosis. Results: Frequency of NTRK gene fusion tumors was 3.1% (4/127) in pediatrics, 0.7% (8/1,151) for CRC, 0.3% (1/288) for NSCLC, 0.9% (1/114) for salivary gland cancer, and 0% (0/379) for sarcoma. Among pediatrics there was one case each of fibrosarcoma (TPM3::NTRK1), Ewing’s sarcoma (LPPR1::NTRK2), primitive neuroectodermal tumor (DAB2IP::NTRK2), and papillary thyroid carcinoma (RAD51B::NTRK3). Among CRC patients, six harbored tumors with NTRK1 fusions (three fused with TPM3), one harbored a NTRK3::GABRG1 fusion, and the other a NTRK2::FXN/LPPR1 fusion. Microsatellite instability was higher in CRC patients with NTRK gene fusion tumors versus wild-type tumors (50.0% vs. 4.4%). Other detected fusions were SGCZ::NTRK3 (NSCLC) and ETV6::NTRK3 (salivary gland cancer). Four patients (three CRC, one NSCLC) received chemotherapy; one patient (with CRC) received radiotherapy. Conclusion: NTRK gene fusions are rare in adult CRC, NSCLC, salivary tumors, sarcoma, and pediatric solid tumors.
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- 2024
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3. Prognostic impact of the post-treatment T cell composition and spatial organization in soft tissue sarcoma patients treated with neoadjuvant hyperthermic radio(chemo)therapy
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Luise Rupp, Antonia Resag, Vlatko Potkrajcic, Verena Warm, Rebekka Wehner, Korinna Jöhrens, Hans Bösmüller, Franziska Eckert, and Marc Schmitz
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soft tissue sarcoma ,immune microenvironment ,T cells ,immune modulation ,radiotherapy ,chemotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Soft tissue sarcomas (STS) form a heterogeneous group of tumors sharing a mesenchymal origin. Despite good local control of the disease, the occurrence of distant metastases often limits survival of STS patients with localized, high-risk tumors of the extremities. Accumulating evidence suggests a central role for the tumor immune microenvironment in determining the clinical outcome and response to therapy. Thus, it has been reported that STS patients with a high immune signature and especially presence of B cells and tertiary lymphoid structures display improved overall survival and response to checkpoint inhibitor treatment. Here, we explored the effect of curative multimodal therapy on the T cell landscape of STS using multiplex immunohistochemistry. We analyzed the phenotype, frequency, and spatial distribution of STS-infiltrating CD8+ T cells by staining for CD8, 4-1BB, Granzyme B, Ki67, PD-1, and LAG-3 as well as CD3+ T helper cells using a panel consisting of CD3, T-bet, GATA3, RORγT, FoxP3, and Ki67. All patients received neoadjuvant radiotherapy plus locoregional hyperthermia with or without chemotherapy. While the treatment-naïve biopsy sample allows an analysis of baseline T cell infiltration levels, both intra- and peritumoral areas of the matched resected tissue were analyzed to assess composition and spatial distribution of the T cell compartment and its therapeutic modulation. Generally, post-treatment tissues displayed lower frequencies of CD3+ and CD8+ T cells. Association with clinical data revealed that higher post-treatment frequencies of peritumoral and intratumoral CD3+ T cells and intratumoral PD-1+ CD8+ T cells were significantly associated with improved disease-free survival (DFS), while these densities had no prognostic significance in the biopsy. Upon spatial analysis, a high ratio of intratumoral to peritumoral CD8+ T cells emerged as an independent prognostic marker for longer DFS. These results indicate that the STS T cell landscape is altered by multimodal therapy and may influence the clinical outcome of patients. An enhanced understanding of the STS immune architecture and its modulation by neoadjuvant therapy may pave the way towards novel treatment modalities and improve the long-term clinical outcome of STS patients.
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- 2023
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4. Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations
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Jan-Niklas Eckardt, Friedrich Stölzel, Desiree Kunadt, Christoph Röllig, Sebastian Stasik, Lisa Wagenführ, Korinna Jöhrens, Friederike Kuithan, Alwin Krämer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H. Brümmendorf, Ralph Naumann, Björn Steffen, Volker Kunzmann, Hermann Einsele, Markus Schaich, Andreas Burchert, Andreas Neubauer, Kerstin Schäfer-Eckart, Christoph Schliemann, Stefan W. Krause, Regina Herbst, Mathias Hänel, Maher Hanoun, Ulrich Kaiser, Martin Kaufmann, Zdenek Rácil, Jiri Mayer, Frank Kroschinsky, Wolfgang E. Berdel, Gerhard Ehninger, Hubert Serve, Carsten Müller-Tidow, Uwe Platzbecker, Claudia D. Baldus, Johannes Schetelig, Martin Bornhäuser, Christian Thiede, and Jan Moritz Middeke
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Acute myeloid leukemia ,Extramedullary ,Leukemia cutis ,Chloroma ,Myeloid sarcoma ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed. Methods We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM. Results AML patients with EM presented with significantly higher counts of white blood cells (p
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- 2022
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5. The Challenge to the Pathologist of PD-L1 Expression in Tumor Cells of Non-Small-Cell Lung Cancer—An Overview
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Korinna Jöhrens and Josef Rüschoff
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PD-L1 ,CTA ,LDT ,preanalytics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In recent years, the treatment of non-small-cell lung cancer (NSCLC) has been fundamentally changed by immunotherapy where the immune system is reactivated using anti-programmed cell death protein 1/programmed death ligand 1 (PD1/PD-L1) checkpoint inhibition. With this, the immunohistological detection of PD-L1 has become one of the most important predictive biomarkers, leading pathologists to play a central role in the immuno-oncological therapy decisions. This has brought them the challenge of requiring the knowledge of relevant checkpoint inhibitors (CI), different PD-L1 scores and cut-offs as well as the choice of the right tissues and controls. Their involvement is also required in the careful validation of both clinical trial assays (CTAs) and laboratory developed tests (LDTs), in addition to the internal and external quality assessment and the interpretation and scoring of the staining based on specialist training. After the training of tumor proportion score (TPS) scoring in NSCLC, pathologists show a high level of concordance, with some variation between different cut-offs. Since not all patients benefit from immunotherapy, further research is needed to validate new predictive markers and optimize existing ones. In this context, these studies focus on a combination of PD-L1 and molecular signatures.
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- 2021
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6. Perturbations of mesenchymal stromal cells after allogeneic hematopoietic cell transplantation predispose for bone marrow graft-versus-host-disease
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Thomas Krüger, Rebekka Wehner, Maik Herbig, Martin Kräter, Michael Kramer, Jan Moritz Middeke, Friedrich Stölzel, Catrin List, Katharina Egger-Heidrich, Raphael Teipel, Uta Oelschlägel, Martin Wermke, Helena Jambor, Manja Wobus, Johannes Schetelig, Korinna Jöhrens, Torsten Tonn, Julien Subburayalu, Marc Schmitz, Martin Bornhauser, and Malte von Bonin
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mesenchymal stromal cells ,allogeneic hematopoietic stem cell transplantation ,graft-versus-host-disease ,alloreactivity ,bone marrow niche ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Functional impairment of the bone marrow (BM) niche has been suggested as a major reason for prolonged cytopenia and secondary graft failure after allogeneic hematopoietic cell transplantation (alloHCT). Because mesenchymal stromal cells (MSCs) serve as multipotent progenitors for several niche components in the BM, they might play a key role in this process. We used collagenase digested trephine biopsies to directly quantify MSCs in 73 patients before (n = 18) and/or after alloHCT (n = 65). For the first time, we demonstrate that acute graft-versus-host disease (aGvHD, n = 39) is associated with a significant decrease in MSC numbers. MSC reduction can be observed even before the clinical onset of aGvHD (n = 10). Assessing MSCs instantly after biopsy collection revealed phenotypic and functional differences depending on the occurrence of aGvHD. These differences vanished during ex vivo expansion. The MSC endotypes observed revealed an enhanced population of donor-derived classical dendritic cells type 1 and alloreactive T cells as the causing agent for compartmental inflammation and MSC damage before clinical onset of aGvHD was ascertained. In conclusion, MSCs endotypes may constitute a predisposing conductor of alloreactivity after alloHCT preceding the clinical diagnosis of aGvHD.
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- 2022
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7. Long-Term Mixed Chimerism After Ex Vivo/In Vivo T Cell-Depleted Allogeneic Hematopoietic Cell Transplantation in Patients With Myeloid Neoplasms
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Leo Ruhnke, Friedrich Stölzel, Uta Oelschlägel, Malte von Bonin, Katja Sockel, Jan Moritz Middeke, Christoph Röllig, Korinna Jöhrens, Johannes Schetelig, Christian Thiede, and Martin Bornhäuser
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chimerism ,mixed donor chimerism ,allogeneic hematopoietic cell transplantation ,myeloid neoplasms ,AML ,CML ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In patients who have undergone allogeneic hematopoietic cell transplantation (HCT), myeloid mixed donor chimerism (MC) is a risk factor for disease relapse. In contrast, several studies found favorable outcome in patients with lymphoid MC. Thus far, most studies evaluating MC focused on a short-term follow-up period. Here, we report the first case series of long-term survivors with MC. We screened 1,346 patients having undergone HCT for myeloid neoplasms at our center from 1996 to 2016; 443 patients with data on total peripheral blood mononuclear cells (PBMC)/CD4+/CD34+ short tandem repeat (STR) donor chimerism (DC) and follow-up ≥24 months post-HCT were included. We identified 10 patients with long-term MC (PBMC DC
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- 2021
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8. Influence of Systemic Therapy on the Expression and Activity of Selected STAT Proteins in Prostate Cancer Tissue
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Celina Ebersbach, Alicia-Marie K. Beier, Pia Hönscheid, Christian Sperling, Korinna Jöhrens, Gustavo B. Baretton, Christian Thomas, Ulrich Sommer, Angelika Borkowetz, and Holger H. H. Erb
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STAT3 ,STAT5 ,STAT6 ,androgen deprivation therapy ,novel hormonal therapy ,chemotherapy ,Science - Abstract
Signal Transducer and Activator of Transcription (STAT) proteins have been identified as drivers of prostate cancer (PCa) progression and development of aggressive castration-resistant phenotypes. In particular, STAT3, 5, and 6 have been linked to resistance to androgen receptor inhibition and metastasis in in vitro and in vivo models. This descriptive study aimed to validate these preclinical data in tissue obtained from patients with PCa before and while under androgen-deprivation therapy. Therefore, STAT3, 5, and 6 expressions and activity were assessed by immunohistochemistry. The data revealed that STAT3 and 5 changed in PCa. However, there was no relationship between expression and survival. Moreover, due to the heterogeneous nature of PCa, the preclinical results could not be transferred congruently to the patient’s material. A pilot study with a longitudinal patient cohort could also show this heterogeneous influence of systemic therapy on STAT3, 5, and 6 expressions and activity. Even if the main mechanisms were validated, these data demonstrate the urge for better patient-near preclinical models. Therefore, these data reflect the need for investigations of STAT proteins in a longitudinal patient cohort to identify factors responsible for the diverse influence of system therapy on STAT expression.
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- 2022
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9. Prognosis of patients with malignant mesothelioma by expression of programmed cell death 1 ligand 1 and mesothelin in a contemporary cohort in Finland
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David Vizcaya, Bahman Farahmand, Annette O. Walter, Christoph Kneip, Korinna Jöhrens, Mikko Tukiainen, and Arndt A. Schmitz
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Mesothelioma ,Prognosis ,Biomarkers ,Disease progression ,Programmed cell death 1 ligand 1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Objectives: We aimed to describe mesothelin (MSLN) and programmed cell death 1 ligand 1 (PD-L1) tumour overexpression amongst patients with malignant mesothelioma (MM), and their associations with survival, amongst a cohort of patients with MM in Finland. Methods: Between 2004 and 2017, 91 adults with histologically confirmed MM were identified from the Auria Biobank in Finland and followed-up using linked data from electronic health records and national statistics. Biomarker content in tumour cell membranes was determined using automated Immunohistochemistry on histological sections. Stained tumour sections were scored for MSLN and PD-L1 intensity. Adjusted associations between MSLN/PD-L1 co-expression and mortality were evaluated by estimating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression. Results: Biomarker overexpression occurred in 52 patients for MSLN and 34 patients for PD-L1 and was associated with tumour histology and certain comorbidities. Fifteen per cent of patients had a tumour that overexpressed both biomarkers; r =-0.244, p-value: 0.02. Compared with MSLN+/PD-L1+ patients, HRs (95% CIs) for death were 4.18 (1.71–10.23) for MSLN-/PD-L1+ patients, 3.03 (1.35–6.77) for MSLN-/PD-L1- patients, and 2.13 (0.97–4.67) for MSLN+/PD-L1- patients. Conclusions: Both MSLN and PD-L1 markers were independent prognostic indicators in patients with MM. Overexpression of MSLN was associated with longer survival; yet their combined expression gave a better indication of survival. The risk of death was four times higher amongst MSLN-/PD-L1+ patients than in MSLN+/PD-L1+ patients.
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- 2020
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10. Impact of Androgen Receptor Activity on Prostate-Specific Membrane Antigen Expression in Prostate Cancer Cells
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Ulrich Sommer, Tiziana Siciliano, Celina Ebersbach, Alicia-Marie K. Beier, Matthias B. Stope, Korinna Jöhrens, Gustavo B. Baretton, Angelika Borkowetz, Christian Thomas, and Holger H. H. Erb
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FOLH1 ,AR ,PCa ,antiandrogen ,androgen deprivation therapy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Prostate-specific membrane antigen (PSMA) is an essential molecular regulator of prostate cancer (PCa) progression coded by the FOLH1 gene. The PSMA protein has become an important factor in metastatic PCa diagnosis and radioligand therapy. However, low PSMA expression is suggested to be a resistance mechanism to PSMA-based imaging and therapy. Clinical studies revealed that androgen receptor (AR) inhibition increases PSMA expression. The mechanism has not yet been elucidated. Therefore, this study investigated the effect of activation and inhibition of androgen signaling on PSMA expression levels in vitro and compared these findings with PSMA levels in PCa patients receiving systemic therapy. To this end, LAPC4, LNCaP, and C4-2 PCa cells were treated with various concentrations of the synthetic androgen R1881 and antiandrogens. Changes in FOLH1 mRNA were determined using qPCR. Open access databases were used for ChIP-Seq and tissue expression analysis. Changes in PSMA protein were determined using western blot. For PSMA staining in patients’ specimens, immunohistochemistry (IHC) was performed. Results revealed that treatment with the synthetic androgen R1881 led to decreased FOLH1 mRNA and PSMA protein. This effect was partially reversed by antiandrogen treatment. However, AR ChIP-Seq analysis revealed no canonical AR binding sites in the regulatory elements of the FOLH1 gene. IHC analysis indicated that androgen deprivation only resulted in increased PSMA expression in patients with low PSMA levels. The data demonstrate that AR activation and inhibition affects PSMA protein levels via a possible non-canonical mechanism. Moreover, analysis of PCa tissue reveals that low PSMA expression rates may be mandatory to increase PSMA by androgen deprivation.
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- 2022
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11. Dynamics of the Intratumoral Immune Response during Progression of High-Grade Serous Ovarian Cancer
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Mandy Stanske, Stephan Wienert, Dan Cacsire Castillo-Tong, Caroline Kreuzinger, Ignace Vergote, Sandrijne Lambrechts, Hani Gabra, Charlie Gourley, Ram N. Ganapathi, Ivonne Kolaschinski, Jan Budczies, Jalid Sehouli, Ilary Ruscito, Carsten Denkert, Hagen Kulbe, Wolfgang Schmitt, Korinna Jöhrens, Ioana Braicu, and Silvia Darb-Esfahani
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
PURPOSE: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression of HGSOC. EXPERIMENTAL DESIGN: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project. RESULTS: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P
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- 2018
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12. Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol
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Janin Henkel, Charles Dominic Coleman, Anne Schraplau, Korinna Jöhrens, Daniela Weber, José Pedro Castro, Martin Hugo, Tim Julius Schulz, Stephanie Krämer, Annette Schürmann, and Gerhard Paul Püschel
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Therapeutics. Pharmacology ,RM1-950 ,Biochemistry ,QD415-436 - Abstract
Abstract Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru- and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
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- 2017
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13. Characterization of the tumor immune micromilieu and its interference with outcome after concurrent chemoradiation in patients with oropharyngeal carcinomas
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Anne-Kathrin Hess, Korinna Jöhrens, Andre Zakarneh, Panagiotis Balermpas, Jens Von Der Grün, Claus Rödel, Wilko Weichert, Michael Hummel, Ulrich Keilholz, Volker Budach, and Ingeborg Tinhofer
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immune signature ,prediction score ,prognostic biomarker ,radiochemotherapy ,head neck cancer ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Intra-tumoral CD8 + T-cell infiltration in squamous cell carcinoma of the head and neck (HNSCC) has previously been linked to the efficacy of cisplatin-based chemoradiation (CDDP-CRTX) and immune checkpoint inhibitor (ICI) monotherapy. Further detailed characterization of the tumor immune-micromilieu and its influence on outcome may guide the development of CRTX-ICI combinations. Methods: Comprehensive immune transcriptome analysis was applied to a training set of tumor specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients treated with CDDP-CRTX in the ARO-0401 phase III study (n = 33). A composite immune signature risk score (ISRS) for survival prediction was developed, and subsequently validated in two independent OPSCC cohorts treated with either CDDP-CRTX (n = 36) or mitomycin-based CRTX (MMC-CRTX, n = 31). Further validation of the ISRS was performed in the OPSCC subset (n = 79) of the TCGA HNSCC cohort. Potential interference between immune signatures and HPV status was evaluated in multivariate Cox regression models. Results: Significant differences according to the 3-y OS status in the abundance of tumor-infiltrating T- and B-cells, and the expression levels of 51 immune-related genes were observed. A risk score based on 13 differentially expressed genes involved in cytokine signaling, T-cell effector functions and the TNFR pathway was established as robust predictive factor of OS. Its predictive power was superior to the 6-gene interferon-gamma signature of ICI efficacy and independent of the HPV status. Conclusions: This study further elucidates the complex interaction of the tumor immune microenvironment with the efficacy of CDDP-CRTX in OPSCC. The results suggest immune markers for selection of patients treated with CRTX-ICI combinations.
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- 2019
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14. Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH
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Janin Henkel, Katja Buchheim-Dieckow, José P. Castro, Thomas Laeger, Kristina Wardelmann, André Kleinridders, Korinna Jöhrens, and Gerhard P. Püschel
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nafld ,nash ,endurance exercise ,fgf21 ,glucose intolerance ,cholesterol ,oxidative stress ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production.
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- 2019
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15. PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma
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Jan Budczies, Gunhild Mechtersheimer, Carsten Denkert, Frederick Klauschen, Sadaf S. Mughal, Priya Chudasama, Michael Bockmayr, Korinna Jöhrens, Volker Endris, Amelie Lier, Felix Lasitschka, Roland Penzel, Manfred Dietel, Benedikt Brors, Stefan Gröschel, Hanno Glimm, Peter Schirmacher, Marcus Renner, Stefan Fröhling, and Albrecht Stenzinger
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amplification ,cd274 ,immune checkpoint inhibition ,pd-l1 ,soft-tissue sarcoma ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Soft-tissue sarcomas (STS) are rare malignancies that account for 1% of adult cancers and comprise more than 50 entities. Current therapeutic options for advanced-stage STS are limited. Immune checkpoint inhibitors targeting the PD-1/PD-L1 signaling axis are being explored as new treatment modality in STS; however, the determinants of response to these agents are largely unknown. Using the sarcoma data set of The Cancer Genome Altas (TCGA) and an independent cohort of untreated high-grade STS, we analyzed DNA copy number status and mRNA expression of PD-L1 in a total of 335 STS cases. Copy number gains (CNG) were detected in 54 TCGA cases (21.1%), of which 21 (8.2%) harbored focal PD-L1 CNG and that were most prevalent in myxofibrosarcoma (35%) and undifferentiated pleomorphic sarcoma (34%). In the untreated high-grade STS cohort, we detected CNG in six cases (7.6%). Analysis of co-amplified genes identified a 5.6-Mb core region comprising 27 genes, including JAK2. Patients with PD-L1 CNG had higher PD-L1 expression compared with STS without CNG (fold change, 1.8; p = 0.02), an effect that was most pronounced in the setting of focal PD-L1 CNG (fold change, 3.0; p = 0.0027). STS with PD-L1 CNG showed a significantly higher mutational load compared with tumors with a diploid PD-L1 locus (median number of mutated genes; 58 vs. 40; p = 3.6E-06), and PD-L1 CNG were associated with inferior survival (HR = 1.82; p = 0.025). In contrast, T-cell infiltrates quantified by mRNA expression of CD3Z were associated with improved survival (HR = 0.88; p = 0.024) and consequently influenced the prognostic power of PD-L1 CNG, with low CD3Z levels conferring poor survival in cases with PD-L1 CNG (HR = 1.8; p = 0.049). These data demonstrate that PD-L1 GNG and elevated expression of PD-L1 occur in a substantial proportion of STS, have prognostic impact that is modulated by T-cell infiltrates, and thus warrant investigation as response predictors for immune checkpoint inhibition.
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- 2017
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16. Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol
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Janin Henkel, Eugenia Alfine, Juliana Saín, Korinna Jöhrens, Daniela Weber, José P. Castro, Jeannette König, Christin Stuhlmann, Madita Vahrenbrink, Wenke Jonas, André Kleinridders, and Gerhard P. Püschel
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NASH ,non-alcoholic fatty liver disease (NAFLD) ,cholesterol ,PUFA ,inflammation ,oxidative stress ,Nutrition. Foods and food supply ,TX341-641 - Abstract
While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.
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- 2018
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17. The EndoPredict Gene-Expression Assay in Clinical Practice - Performance and Impact on Clinical Decisions.
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Berit Maria Müller, Elke Keil, Annika Lehmann, Klaus-Jürgen Winzer, Christiane Richter-Ehrenstein, Judith Prinzler, Nikola Bangemann, Angela Reles, Sylvia Stadie, Winfried Schoenegg, Jan Eucker, Marcus Schmidt, Frank Lippek, Korinna Jöhrens, Stefan Pahl, Bruno Valentin Sinn, Jan Budczies, Manfred Dietel, and Carsten Denkert
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Medicine ,Science - Abstract
The validated EndoPredict assay is a novel tool to predict the risk of metastases of patients with estrogen receptor positive, HER2 negative breast cancer treated with endocrine therapy alone. It has been designed to integrate genomic and clinical information and includes clinico-pathological factors such as tumor size and nodal status. The test is feasible in a decentral setting in molecular pathology laboratories. In this project, we investigated the performance of this test in clinical practice, and performed a retrospective evaluation of its impact on treatment decisions in breast cancer. During one year, EndoPredict assays from 167 patients could be successfully performed. For retrospective evaluation of treatment decisions, a questionnaire was sent to the clinical partner. Regarding the molecular EP class, samples from 56 patients (33.5%) had a low-risk, whereas 111 patients (66.5%) showed a high-risk gene profile. After integration of the clinicopathological factors the combined clinical and molecular score (EPclin) resulted in a low-risk group of 77 patients (46.4%), while 89 (53.6%) had a high risk EPclin score. The EPclin-based estimated median 10-year-risk for metastases with endocrine therapy alone was 11% for the whole cohort. The median handling time averaged three days (range: 0 to 11 days), 59.3% of the tests could be performed in three or less than three days. Comparison of pre- and post-test therapy decisions showed a change of therapy in 37.7% of patients. 16 patients (12.3%) had a change to an additional chemotherapy while 25.4% of patients (n = 33) changed to an endocrine therapy alone. In 73 patients (56.2%) no change of therapy resulted. In 6.1% of patients (n = 8), the patients did not agree to the recommendation of the tumor board. Our results show that the EndoPredict assay could be routinely performed in decentral molecular pathology laboratories and the results markedly change treatment decisions.
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- 2013
- Full Text
- View/download PDF
18. Update on quality assurance in neuropathology: Summary of the round robin trials on TERT promoter mutation, H3-3A mutation, 1p/19q codeletion, and KIAA1549::BRAF fusion testing in Germany in 2020 and 2021
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Sandra Pohl, Lora Dimitrova, Maja Grassow-Narlik, Korinna Jöhrens, Till Acker, Hildegard Dohmen, Jochen Herms, Mario Dorostkar, Christian Hartmann, Martin Hasselblatt, Manuela Neumann, Guido Reifenberger, Jörg Felsberg, Ulrich Schüller, Saida Zoubaa, Julia Lorenz, Tanja Rothhammer-Hampl, Katrin Mauch-Mücke, and Markus J. Riemenschneider
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Neurology ,Neurology (clinical) ,General Medicine ,Pathology and Forensic Medicine - Published
- 2023
19. Ringversuche – ein zentrales Mittel der externen Qualitätssicherung
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Korinna Jöhrens, Maja Grassow, Gustavo Baretton, and Florian Sperling
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- 2022
20. supplementary file 3 from Multilayered Omics-Based Analysis of a Head and Neck Cancer Model of Cisplatin Resistance Reveals Intratumoral Heterogeneity and Treatment-Induced Clonal Selection
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Ingeborg Tinhofer, Volker Budach, Korinna Jöhrens, Seval Türkmen, Michael Bockmayr, Frederick Klauschen, Denise Treue, Robert Konschak, Tanja Pilz, Theresa Eder, and Franziska Niehr
- Abstract
Differentially expressed phosphopeptides associated with a CDDP-resistant phenotype
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- 2023
21. supplementary file 2 from Multilayered Omics-Based Analysis of a Head and Neck Cancer Model of Cisplatin Resistance Reveals Intratumoral Heterogeneity and Treatment-Induced Clonal Selection
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Ingeborg Tinhofer, Volker Budach, Korinna Jöhrens, Seval Türkmen, Michael Bockmayr, Frederick Klauschen, Denise Treue, Robert Konschak, Tanja Pilz, Theresa Eder, and Franziska Niehr
- Abstract
Top-50 features associated with the CDDP-sensitive and -resistant phenotypes
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- 2023
22. supplementary file 1 from Multilayered Omics-Based Analysis of a Head and Neck Cancer Model of Cisplatin Resistance Reveals Intratumoral Heterogeneity and Treatment-Induced Clonal Selection
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Ingeborg Tinhofer, Volker Budach, Korinna Jöhrens, Seval Türkmen, Michael Bockmayr, Frederick Klauschen, Denise Treue, Robert Konschak, Tanja Pilz, Theresa Eder, and Franziska Niehr
- Abstract
List of 327 genes covered by tNGS
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- 2023
23. supplementary information from Multilayered Omics-Based Analysis of a Head and Neck Cancer Model of Cisplatin Resistance Reveals Intratumoral Heterogeneity and Treatment-Induced Clonal Selection
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Ingeborg Tinhofer, Volker Budach, Korinna Jöhrens, Seval Türkmen, Michael Bockmayr, Frederick Klauschen, Denise Treue, Robert Konschak, Tanja Pilz, Theresa Eder, and Franziska Niehr
- Abstract
supplementary information
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- 2023
24. Data from Multilayered Omics-Based Analysis of a Head and Neck Cancer Model of Cisplatin Resistance Reveals Intratumoral Heterogeneity and Treatment-Induced Clonal Selection
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Ingeborg Tinhofer, Volker Budach, Korinna Jöhrens, Seval Türkmen, Michael Bockmayr, Frederick Klauschen, Denise Treue, Robert Konschak, Tanja Pilz, Theresa Eder, and Franziska Niehr
- Abstract
Purpose: Platinum-based drugs, in particular cisplatin (cis-diamminedichloridoplatinum(II), CDDP), are used for treatment of squamous cell carcinoma of the head and neck (SCCHN). Despite initial responses, CDDP treatment often results in chemoresistance, leading to therapeutic failure. The role of primary resistance at subclonal level and treatment-induced clonal selection in the development of CDDP resistance remains unknown.Experimental Design: By applying targeted next-generation sequencing, fluorescence in situ hybridization, microarray-based transcriptome, and mass spectrometry-based phosphoproteome analysis to the CDDP-sensitive SCCHN cell line FaDu, a CDDP-resistant subline, and single-cell derived subclones, the molecular basis of CDDP resistance was elucidated. The causal relationship between molecular features and resistant phenotypes was determined by siRNA-based gene silencing. The clinical relevance of molecular findings was validated in patients with SCCHN with recurrence after CDDP-based chemoradiation and the TCGA SCCHN dataset.Results: Evidence of primary resistance at clonal level and clonal selection by long-term CDDP treatment was established in the FaDu model. Resistance was associated with aneuploidy of chromosome 17, increased TP53 copy-numbers and overexpression of the gain-of-function (GOF) mutant variant p53R248L. siRNA-mediated knockdown established a causal relationship between mutant p53R248L and CDDP resistance. Resistant clones were also characterized by increased activity of the PI3K–AKT–mTOR pathway. The poor prognostic value of GOF TP53 variants and mTOR pathway upregulation was confirmed in the TCGA SCCHN cohort.Conclusions: Our study demonstrates a link of intratumoral heterogeneity and clonal evolution as important mechanisms of drug resistance in SCCHN and establishes mutant GOF TP53 variants and the PI3K/mTOR pathway as molecular targets for treatment optimization. Clin Cancer Res; 24(1); 158–68. ©2017 AACR.
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- 2023
25. Tomoelastography by multifrequency wave number recovery from time-harmonic propagating shear waves.
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Heiko Tzschätzsch, Jing Guo, Florian Dittmann 0002, Sebastian Hirsch, Eric Barnhill, Korinna Jöhrens, Jürgen Braun, and Ingolf Sack
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- 2016
- Full Text
- View/download PDF
26. Routineuntersuchungen der Pathologie für die Therapie mit modernen Medikamenten
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Korinna Jöhrens, Almuth Forberger, Pauline Wimberger, and Josef Rüschoff
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Oncology - Published
- 2022
27. MSI testing
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Markus Tiemann, Sabine Merkelbach-Bruse, Hendrik Bläker, Josef Rüschoff, Doris Mayr, Wolfgang Dietmaier, Reinhard Büttner, Korinna Jöhrens, Arndt Hartmann, Ruth Knüchel, Manfred Dietel, Lars-Christian Horn, Wilko Weichert, Katharina Tiemann, Peter Schirmacher, Gustavo Baretton, Hans-Ulrich Schildhaus, and Thomas Kirchner
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medicine.medical_specialty ,business.industry ,Colorectal cancer ,Immune checkpoint inhibitors ,Microsatellite instability ,Nice ,Pembrolizumab ,medicine.disease ,Pathology and Forensic Medicine ,Documentation ,Medicine ,Medical physics ,Stage (cooking) ,business ,Quality assurance ,computer ,computer.programming_language - Abstract
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 first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
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- 2021
28. Human glycoprotein-2 expressed in Brunner glands - A putative autoimmune target and link between Crohn's and coeliac disease
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Dirk Roggenbuck, Alexander Goihl, Mandy Sowa, Steffi Lopens, Stefan Rödiger, Peter Schierack, Karsten Conrad, Ulrich Sommer, Korinna Jöhrens, Robert Grützmann, Dirk Reinhold, and Martin W. Laass
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Immunology ,Immunology and Allergy - Abstract
Glycoprotein 2 (GP2) is an autoantigen in Crohn's (CD) and coeliac disease (CeD). We assessed GP2-isoform (GP2
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- 2022
29. Course and outcome of chilblain‐like acral lesions during <scp>COVID</scp> ‐19 pandemic
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Kristin Blau, Sophia Lehr, Roland Aschoff, Suzan Al Gburi, Normi Brück, Maria Chapsa, Anja Schnabel, Susanne Abraham, Korinna Jöhrens, Stefan Beissert, and Claudia Günther
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Chilblains ,Infectious Diseases ,SARS-CoV-2 ,Humans ,COVID-19 ,Dermatology ,Toes ,Pandemics - Published
- 2022
30. MSI testing : What is new? What should be considered?
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Josef Rüschoff, Manfred Dietel, Reinhard Büttner, Doris Mayr, Korinna Jöhrens, Hendrik Bläker, Arndt Hartmann, Markus Tiemann, Sabine Merkelbach-Bruse, Ruth Knüchel, Peter Schirmacher, Wilko Weichert, Wolfgang Dietmaier, Katharina Tiemann, Gustavo Baretton, Thomas Kirchner, Lars-Christian Horn, and Hans-Ulrich Schildhaus
- Subjects
0301 basic medicine ,Treatment response ,medicine.medical_specialty ,business.industry ,Immune checkpoint inhibitors ,Medizin ,Microsatellite instability ,Nice ,Pembrolizumab ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Documentation ,030220 oncology & carcinogenesis ,medicine ,Medical physics ,Stage (cooking) ,business ,Quality assurance ,computer ,computer.programming_language - Abstract
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 first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
- Published
- 2021
31. Prevalence, Clinical and Molecular Features, and Prognostic Value of Tetraploidy/Near-Tetraploidy in Patients with Acute Myeloid Leukemia
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Leo Ruhnke, Julia Frimmel, Christoph Röllig, Brigitte Mohr, Heidi Altmann, David Poitz, Sven Zukunft, Katrin Schranz, Sebastian Vosberg, Karsten Spiekermann, Michael von Bergwelt, Edgar Jost, Sabine Dressler, Kerstin Schäfer-Eckart, Triantafyllos Chavakis, Daniela Aust, Korinna Jöhrens, Gustavo Baretton, Martin Bornhäuser, Philipp A. Greif, Friedrich Stölzel, Sylvia Herold, and Lisa Wagenführ
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
32. [Interlaboratory comparisons-a central means of external quality assurance]
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Korinna, Jöhrens, Maja, Grassow, Gustavo, Baretton, and Florian, Sperling
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Quality Assurance, Health Care ,Humans ,Accreditation - Abstract
The precise performance of immunohistochemical and molecular examinations of diagnostic and predictive markers is essential for the further therapy of patients. Due to the increasing number of biomarkers and their detection at the immunohistochemical and molecular level in patient tissue, the pathology has a direct influence on the therapy of patients, which increases the value of external quality assurance (EQA). In pathology, various forms are available for this purpose, such as proficiency tests. The standards of both the certification and accreditation procedures of pathology require regular participation in EQA and a statement on the EQA policy of the institutes. The quality of an EQA depends on the scientific concept, the adequate selection of material, the evaluation concept, and the communication of results.Die präzise Durchführung immunhistologischer und molekularer Untersuchungen diagnostischer und prädiktiver Marker ist für die weitere Therapie der Patienten essenziell. Bedingt durch die steigende Anzahl von Biomarkern und deren Nachweis auf immunhistochemischer und molekularer Ebene am Patientengewebe nimmt die Pathologie direkten Einfluss auf die Therapie der Patienten, wodurch die externe Qualitätssicherung an Wertigkeit gewinnt. In der Pathologie stehen hierfür verschiedene Formen, wie z. B. Ringversuche (RV), zur Verfügung. Dabei fordern sowohl die Normen der Zertifizierungs- als auch der Akkreditierungsverfahren der Pathologie eine regelmäßige Teilnahme an RV und eine Stellungnahme zur RV-Politik der Institute. Die Qualität eines Ringversuches ist abhängig von dem wissenschaftlichen Konzept, der adäquaten Auswahl des Material, des Auswertekonzeptes und der Ergebnismitteilung.
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- 2022
33. Prognostic value of regulatory T cells and T helper 17 cells in high grade serous ovarian carcinoma
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Sofya Marchenko, Iris Piwonski, Inga Hoffmann, Bruno Valentin Sinn, Catarina Alisa Kunze, Nanna Monjé, Jonathan Pohl, Hagen Kulbe, Wolfgang Daniel Schmitt, Sylvia Darb-Esfahani, Elena Ioana Braicu, Ann-Christin von Brünneck, Jalid Sehouli, Carsten Denkert, David Horst, Korinna Jöhrens, and Eliane Tabea Taube
- Subjects
Cancer Research ,Oncology ,General Medicine - Abstract
Purpose In recent years the tumor microenvironment and its interaction with the tumor has emerged into research focus with increased attention to the composition of Tumor-infiltrating lymphocytes. We wanted to quantify the composition of Regulatory T cells (Tregs) and T helper 17 cells (Th17 cells) and their prognostic impact in high-grade serous tubo-ovarian carcinoma. Methods Tregs and Th17 cells were determined by immunohistochemical analysis of CD25 FoxP3 and RORγt, respectively on tissue microarrays of a cohort of 222 patients with reviewed histology and available clinical data. Expression was analyzed with Qupath for quantification and integration with clinical data enabled calculation of prognostic impact. For validation FOXP3 and RORC mRNA expression levels from 502 patients with HGSC in publicly available datasets were evaluated. Results An average percentage of 0.93 Tregs and of 0.06 Th17 cells was detected per cells in overall tissue. Optimal cut-offs were determined and higher Tregs were associated with a better overall survival in stroma (p = 0.006), tumor area (p = 0.0012) and overall tissue (p = 0.02). After accounting for well-known prognostic factors age at diagnosis, residual tumor and FIGO stage, this association remained significant for stromal Tregs with overall survival (p = 0.02). Survival analysis for Th17 cells revealed no significant association with survival rates. Moreover, lower Th17/Treg ratios had a positive impact on patient overall survival (p = 0.025 tumor, p = 0.049 stroma and p = 0.016 overall tissue). Conclusion Our results outline a positive prognostic effect for higher Tregs but not for Th17 in high grade serous tubo-ovarian carcinoma.
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- 2022
34. Abstract 926: Genomics-based personalized oncology of advanced thymic epithelial tumors
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Lino Möhrmann, Lysann Rostock, Małgorzata Oleś, Arne Jahn, Marie Arlt, Nagarajan Paramasivam, Korinna Jöhrens, Luise Rupp, Marc Schmitz, Daniela Richter, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Jennifer Hüllein, Elena E. Wolf, Dorothea Hanf, Laura Gieldon, Simon Kreutzfeldt, Christoph E. Heilig, Veronica Teleanu, Daniel B. Lipka, Andreas Mock, Ivan Jelas, Damian T. Rieke, Marcel Wiesweg, Melanie Boerries, Anna L. Illert, Alexander Desuki, Thomas Kindler, Angela M. Krackhardt, C. Benedikt Westphalen, Heidrun Grosch, Leonidas Apostolidis, Albrecht Stenzinger, Irina A. Kerle, Christoph Heining, Daniel Hübschmann, Evelin Schröck, Stefan Fröhling, and Hanno Glimm
- Subjects
Cancer Research ,Oncology - Abstract
Introduction: Thymic epithelial tumors (TETs) are very rare. Thymoma A and AB have a better prognosis than more aggressive thymoma B, thymic carcinoma (TC) and neuroendocrine tumors of the thymus (NET). While previous efforts such as TCGA have mainly characterized thymomas (Radovich et al., Cancer Cell 2018), the molecular landscape of TCs and NETs is still elusive. Patients and Methods: Between 03/2014 and 07/2020, we enrolled 44 TET patients (27 TCs, 11 thymomas, 6 NETs) in a prospective observational study (MASTER) conducted by the National Center for Tumor Diseases (NCT) Heidelberg, NCT Dresden and the German Cancer Consortium (DKTK). MASTER applied whole genome/exome sequencing (WGS, n=22; WES, n=22), transcriptome (n=40) and germline analysis to inform therapy recommendations by a dedicated molecular tumor board (MTB). We systematically gathered follow-up data to evaluate outcome and compared progression-free survival (PFS) of the first treatment according to an MTB recommendation (PFS2) to the last prior systemic treatment (PFS1) in each patient (PFS ratio). Results: Tumor mutational burden (TMB) was low (median=0.99 mutations/Mb, range 0.08-3.48) but higher than in TCGA (p 6 months and a PFS ratio > 1.3. The best outcome was achieved using imatinib in a patient with a KIT mutation (p.W557R). After progression, the MTB recommended ponatinib based on a secondary KIT mutation (p.V654A). The patient was still on ponatinib when the observation period ended. Conclusion: We demonstrate that comprehensive molecular analysis provides clinically relevant information in a subgroup of TET patients. Thymoma, TCs, and NETs present with different molecular characteristics. Distinction between immunologically hot and cold TCs may have value for risk stratification and therapeutic strategies. PARP inhibition could be a potential new treatment option in a small subgroup of TETs. Molecular testing of KIT, germline analysis and genetic counseling should be recommended for all patients with advanced TETs. Citation Format: Lino Möhrmann, Lysann Rostock, Małgorzata Oleś, Arne Jahn, Marie Arlt, Nagarajan Paramasivam, Korinna Jöhrens, Luise Rupp, Marc Schmitz, Daniela Richter, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Jennifer Hüllein, Elena E. Wolf, Dorothea Hanf, Laura Gieldon, Simon Kreutzfeldt, Christoph E. Heilig, Veronica Teleanu, Daniel B. Lipka, Andreas Mock, Ivan Jelas, Damian T. Rieke, Marcel Wiesweg, Melanie Boerries, Anna L. Illert, Alexander Desuki, Thomas Kindler, Angela M. Krackhardt, C. Benedikt Westphalen, Heidrun Grosch, Leonidas Apostolidis, Albrecht Stenzinger, Irina A. Kerle, Christoph Heining, Daniel Hübschmann, Evelin Schröck, Stefan Fröhling, Hanno Glimm. Genomics-based personalized oncology of advanced thymic epithelial tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 926.
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- 2023
35. Abstract 925: NTRK gene fusion in adults and pediatrics with solid tumors: a record linkage study of expression frequency and patient characteristics using the Auria Biobank in Finland
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Wei Zhang, Merja Perälä, Roosa E. Kallionpää, Niina Pitkänen, Korinna Jöhrens, Renate Schulze-Rath, Arndt A Schmitz, Helen Guo, and Jihong Zong
- Subjects
Cancer Research ,Oncology - Abstract
Introduction: Selective tropomyosin receptor kinase (TRK) inhibitors are targeted therapies for patients with solid tumors harboring a neurotrophic-receptor tyrosine kinase (NTRK) gene fusion. Estimates of the frequency of NTRK gene fusions and knowledge about characteristics of affected patients from population-based settings are limited. Methods: This was a retrospective cohort study using archival tissue samples from patients with histologically-confirmed solid tumors identified from the Auria Biobank in the Turku region of Finland (January 2005-December 2019). We evaluated all solid tumor types in pediatrics, and selected tumor types in adults (colorectal cancer [CRC], non-small cell-lung cancer [NSCLC], sarcoma, and salivary/parotid cancer). Expression of TRK protein was determined by pan-TRK immunohistochemistry (IHC) staining of tumor samples scored by a certified pathologist. NTRK gene fusion including fusion partners was then confirmed by next generation sequencing (NGS). Patients’ demographics, clinical characteristics, and survival status were determined through linkage to hospital electronic health records and the national vital statistics database; patients were followed from 1 year before cancer diagnosis until the end of follow-up/death. Results: NTRK gene fusion frequency and descriptions of patient and tumor characteristics are shown in the Table. The number of patients confirmed as NTRK positive after NGS as a proportion of those deemed NTRK positive after IHC staining was 80% (8/10) for CRC, 5% (1/21) for NSCLC, 6% (1/18) for salivary/parotid cancer, 0% (0/21) for sarcoma, and 25% (4/16) for pediatric solid tumors. Conclusions: This study shows that NTRK gene fusions are rare in adult CRC, NSCLC, parotid/salivary tumors, sarcoma, and pediatric solid tumors. Frequency of NTRK gene fusion in pediatric and select adult solid tumors, and characteristics of NTR NTRK gene fusion-positive NTRK gene fusion subtypes Fusion partners Median age (category) at diagnosis (years) Sex Tumor details Treatment/follow-up status Adults CRC (N=1151) 8 (0.7%) NTRK1 (n=6) NTRK2 (n=1) NTRK3 (n=1) NTRK1: TPM3 (n=3), LMNA (n=1), TPR (n=1), IRF2BP2 (n=1) NTRK2*: FXN (n=1), LPPR1 (n=1) NTRK3: GABRG1 (n=1) *In a single patient with two tumor samples NTRK2 was identified in both samples, but the fusion partner (and other genomic co-alterations) were different between the two samples. 60-69 3 male, 5 female All were grade 2-3 ECOG score 1 (n=4)† MSI: abnormal (n=4), normal (n=1), missing (n=1) †ECOG score was missing for the remaining patients. Chemotherapy: n=3 Radiotherapy: n=1 All alive at end of follow-up (range, 0.3-11.5 years) Sarcoma (N=379) 0 (0.0%) - - - - - - NSCLC (N=288) 1 (0.3%) NTRK3 (n=1) SGCZ (n=1) 60-69 Female Stage IVA, grade II, ECOG score 1 Chemotherapy but not radiotherapy Alive at 0.6 years‘ follow-up Salivary/parotid (N=114) 1 (0.9%) NTRK3 (n=1) ETV6 (n=1) 60-69 Male Salivary cancer, stage 1, T2N0M0 ECOG score was missing No chemotherapy/radiotherapy Alive after 13.9 years‘ follow-up Fibrosarcoma (n=1) Primitive neuroectodermal cancer (n=1) Ewing’s sarcoma (n=1) Papillary thyroid cancer (n=1) Pediatric solid tumors (N=127) 4 (3.1%) NTRK1 (n=1) NTRK2 (n=2) NTRK3 (n=1) NTRK1: TPM3 (n=1) NTRK2: DAB2IP (n=1), LPPR1 (n=1) NTRK3: RAD51B (n=1) NTRK1-TPM3; male, age category‡ 2-11 years, tumor stage unknown, no chemotherapy/radiotherapy. Alive at 15.1 years‘ follow-up. ‡According to US FDA age categories for pediatrics. NTRK2-DAB2IP; male, age category‡ 2-11 years, Grade III tumor, received both chemo- and radiotherapy. Died - survival time 0.9 years. ‡According to US FDA age categories for pediatrics. NTRK2-LPPR1; male, age category‡ 12-18 years, stage IV tumor, received both chemo- and radiotherapy. Died - survival time 1.1 years. ‡According to US FDA age categories for pediatrics. NTRK3-RAD51B; female, age category‡ 12-18 years, tumor stage unknown, no chemotherapy/radiotherapy. Alive at 7.4 years‘ follow-up. ‡According to US FDA age categories for pediatrics. Citation Format: Wei Zhang, Merja Perälä, Roosa E. Kallionpää, Niina Pitkänen, Korinna Jöhrens, Renate Schulze-Rath, Arndt A Schmitz, Helen Guo, Jihong Zong. NTRK gene fusion in adults and pediatrics with solid tumors: a record linkage study of expression frequency and patient characteristics using the Auria Biobank in Finland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 925.
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- 2023
36. Rediscussing the Role of Traditional Risk Factors in Young Adults With Oral Squamous Cell Carcinoma
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Jan-Dirk Raguse, Norbert Neckel, Daniel Troeltzsch, Christian Doll, Korinna Jöhrens, Jonas Wüster, Max Heiland, Steffen Koerdt, Marco Michael, and Konrad Neumann
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Treatment results ,Young Adult ,Risk Factors ,Internal medicine ,Humans ,Medicine ,Basal cell ,Young adult ,Survival analysis ,business.industry ,Case-control study ,General Medicine ,Prognosis ,Survival Analysis ,Organ damage ,stomatognathic diseases ,Young age ,Oncology ,Risk indicator ,Case-Control Studies ,Carcinoma, Squamous Cell ,Female ,Mouth Neoplasms ,business - Abstract
Background/aim The current literature conjectures that oral squamous cell carcinoma (OSCC) in younger patients is an entirely separate entity with a different risk profile. We aimed to uncover the potential risk factors of OSCC and evaluated the long-term outcome in such patients. Patients and methods This hospital-based case-control study included 40 patients with OSCC and 40 controls under the age of 46 years. Survival was analyzed via Kaplan-Meier estimates, including a follow-up of up to 24.3 years. Results The patients with OSCC were prone to smoking and drinking heavily and even suffered secondary organ damage to the lungs and the liver at this young age. Early diagnosed as well as surgically treated patients had superior 5-year recurrence-free and overall survival. Conclusion Young patients with OSCC were found to have a traditional risk profile. Secondary organ damage to the liver and the lungs might be considered as a risk indicator. The meticulous screening of every age group with this risk profile is key to early diagnosis and acceptable treatment results.
- Published
- 2020
37. Qualitätssicherung in der diagnostischen In-situ-Hybridisierung – Erfahrungen der QuIP
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H Kreipe, Albrecht Stenzinger, A Forberger, Korinna Jöhrens, Philipp Jurmeister, Reinhard von Wasielewski, Manfred Dietel, and Josephine Fischer
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0301 basic medicine ,Gynecology ,03 medical and health sciences ,medicine.medical_specialty ,030104 developmental biology ,0302 clinical medicine ,business.industry ,030220 oncology & carcinogenesis ,medicine ,business ,Pathology and Forensic Medicine - Abstract
Die „Qualitatssicherung-Initiative Pathologie“ (QuIP) bietet den Pathologen die Moglichkeit, die methodischen Ablaufe der immunhistologischen und molekularen Diagnostik ergebnisorientiert uberprufen und zertifizieren zu lassen. Fur die In-situ-Hybridisierungs- (ISH-)Diagnostik wurden 2019 5 Ringversuche angeboten, 2 wiederkehrende (HER2-ISH-Magenkarzinome und HER2-ISH-Mammakarzinome) sowie 3 prototypische (ROS1-NSCLC, ALK1-NSCLC, NTRK). Dabei richten sich die angebotenen RV nach der Entwicklung in der Diagnostik und der Bedeutung der therapeutischen Relevanz, die mit den abzufragenden Molekulen und der damit einhergehenden Methoden verbunden ist. Die Ergebnisse der RV zeigten 2019 eine Sensitivitat von mindestens 94,4 % und eine Spezifitat von mindestens 96,6 % sowie einer Erfolgsquote von 85–99 %. Dies spricht fur einen hohen Qualitatsstandard der RV und der teilnehmenden Institute
- Published
- 2020
38. Role of endurance training in diet-induced steatohepatitis in rats
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Janin Henkel-Oberländer, Katja Buchheim-Dieckow, JosèP. Castro, Thomas Laeger, Korinna Jöhrens, and GerhardP. Püschel
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- 2022
39. A novel 2-metagene signature to identify high-risk HNSCC patients amongst those who are clinically at intermediate risk and are treated with PORT
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Shivaprasad, Patil, Annett, Linge, Hannah, Hiepe, Marianne, Grosser, Fabian, Lohaus, Volker, Gudziol, Max, Kemper, Alexander, Nowak, Dominik, Haim, Inge, Tinhofer, Volker, Budach, Maja, Guberina, Martin, Stuschke, Panagiotis, Balermpas, Jens von der, Grün, Henning, Schäfer, Anca-Ligia, Grosu, Amir, Abdollahi, Jürgen, Debus, Ute, Ganswindt, Claus, Belka, Steffi, Pigorsch, Stephanie E, Combs, Simon, Boeke, Daniel, Zips, Korinna, Jöhrens, Gustavo B, Baretton, Michael, Baumann, Mechthild, Krause, Steffen, Löck, and On Behalf Of The Dktk-Rog
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Cancer Research ,Article ,head and neck squamous cell carcinoma ,gene signature ,postoperative radiotherapy ,postoperative radiochemotherapy ,propensity score matching ,Oncology ,Gene Signature ,Head And Neck Squamous Cell Carcinoma ,Postoperative Radiochemotherapy ,Postoperative Radiotherapy ,Propensity Score Matching ,Medizin ,ddc - Abstract
(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.
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- 2022
40. Epstein–Barr virus infection patterns in nodular lymphocyte‐predominant Hodgkin lymphoma
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Elena Gerhard‐Hartmann, Korinna Jöhrens, Lisa‐Marie Schinagl, Alberto Zamó, Andreas Rosenwald, Ioannis Anagnostopoulos, and Mathias Rosenfeldt
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Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Histology ,Humans ,Ki-1 Antigen ,General Medicine ,Lymphocytes ,ddc:610 ,Reed-Sternberg Cells ,Hodgkin Disease ,Pathology and Forensic Medicine - Abstract
Aims To investigate Epstein‐Barr virus (EBV) latency types in 19 cases of EBV‐positive nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL), as such information is currently incomplete. Methods and results Immunohistochemistry (IHC) for CD20, CD79a, PAX5, OCT2, CD30, CD15, CD3 and programmed cell death protein 1 was performed. For EBV detection, in‐situ hybridisation (ISH) for EBV‐encoded RNA (EBER) was employed combined with IHC for EBV‐encoded latent membrane protein (LMP)‐1, EBV‐encoded nuclear antigen (EBNA)‐2, and EBV‐encoded BZLF1. In 95% of the cases, neoplastic cells with features of Hodgkin and Reed–Sternberg (HRS) cells were present, mostly showing expression of CD30. In all cases, the B‐cell phenotype was largely intact, and delineation from classic Hodgkin lymphoma (CHL) was further supported by myocyte enhancer factor 2B (MEF2B) detection. All tumour cells were EBER‐positive except in two cases. EBV latency type II was most frequent (89%) and type I was rare. Cases with latency type I were CD30‐negative. Five cases contained some BZLF1‐positive and/or EBNA‐2‐positive bystander lymphocytes. Conclusions As HRS morphology of neoplastic cells and CD30 expression are frequent features of EBV‐positive NLPHL, preservation of the B‐cell transcription programme, MEF2B expression combined with NLPHL‐typical architecture and background composition facilitate distinction from CHL. EBER ISH is the method of choice to identify these cases. The majority present with EBV latency type II, and only rare cases present with latency type I, which can be associated with missing CD30 expression. The presence of occasional bystander lymphocytes expressing BZLF1 and/or EBNA‐2 and the partial EBV infection of neoplastic cells in some cases could indicate that EBV is either not primarily involved or is only a transient driver in the pathogenesis of EBV‐positive NLPHL.
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- 2022
41. Assessment of gene expressions from squamous cell carcinoma of the head and neck to predict radiochemotherapy-related xerostomia and dysphagia
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Noorazrul Yahya, Annett Linge, Karoline Leger, Till Maile, Max Kemper, Dominik Haim, Korinna Jöhrens, Esther G. C. Troost, Mechthild Krause, and Steffen Löck
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Squamous Cell Carcinoma of Head and Neck ,dysphagia ,Gene Expression ,Chemoradiotherapy ,Hematology ,General Medicine ,Xerostomia ,stomatognathic diseases ,Oncology ,stomatognathic system ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,otorhinolaryngologic diseases ,Humans ,Parotid Gland ,gene expressions ,head and neck cancer ,Radiology, Nuclear Medicine and imaging ,Radiotherapy, Intensity-Modulated ,Deglutition Disorders ,xerostomia ,radiotherapy - Abstract
Purpose: We tested the hypothesis that gene expressions from biopsies of locally advanced head and neck squamous cell carcinoma (HNSCC) patients can supplement dose-volume parameters to predict dysphagia and xerostomia following primary radiochemotherapy (RCTx). Material and methods: A panel of 178 genes previously related to radiochemosensitivity of HNSCC was considered for nanoString analysis based on tumour biopsies of 90 patients with locally advanced HNSCC treated by primary RCTx. Dose-volume parameters were extracted from the parotid, subman- dibular glands, oral cavity, larynx, buccal mucosa, and lips. Normal tissue complication probability (NTCP) models were developed for acute, late, and for the improvement of xerostomia grade ≥2 and dysphagia grade ≥3 using a cross-validation-based least absolute shrinkage and selection operator (LASSO) approach combined with stepwise logistic regression for feature selection. The final signatures were included in a logistic regression model with optimism correction. Performance was assessed by the area under the receiver operating characteristic curve (AUC). Results: NTCP models for acute and late xerostomia and the improvement of dysphagia resulted in optimism-corrected AUC values of 0.84, 0.76, and 0.70, respectively. The minimum dose to the contra-lateral parotid was selected for both acute and late xerostomia and the minimum dose to the larynx was selected for dysphagia improvement. For the xerostomia endpoints, the following gene expressions were selected: RPA2 (cellular response to DNA damage), TCF3 (salivary gland cells development), GBE1 (glycogen storage and regulation), and MAPK3 (regulation of cellular processes). No gene expression features were selected for the prediction of dysphagia. Conclusion: This hypothesis-generating study showed the potential of improving NTCP models using gene expression data for HNSCC patients. The presented models require independent validation before potential application in clinical practice.
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- 2022
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42. MEDB-34. A very rare case: medulloblastoma relapse with bone marrow infiltration in a toddler
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Claudia Zinke, Gudrun Fleischhack, Julia Hauer, Björn Sönke Lange, Jenny Dörnemann, Gabriele Hahn, Gabriele Schackert, Kristin Gurtner, Matthias Meinhardt, Korinna Jöhrens, and Ralf Knöfler
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Cancer Research ,Oncology ,Medizin ,Neurology (clinical) - Abstract
We report about a female toddler congenitally deaf and diagnosed with a non-metastatic desmoplastic medulloblastoma (SHH activated, TP53-wt, variant in LDB1 gene). No tumor predisposition syndrome was found. After complete tumor resection the patient was treated according to I-HIT-MED-Guidance protocol. Five months later an asymptomatic localised relapse (same histology, PTEN frameshift deletion, TERT mutation, LDB1 mutation) detected by routine MRI was treated by complete resection, craniospinal irradiation and an antiangiogenic regimen adapted from the MEMMAT scheme including fenofibrate, thalidomide, celecoxib, topotecan, temozolomide, bevacizumab and intraventricular cytarabine. Before start of systemic treatment blood cell counts were normal. In the second cycle we had to interrupt chemotherapy due to a leukopenia while continuing the antiangiogenic treatment. In order to avoid relevant bone marrow toxicity chemotherapy doses were reduced. Nevertheless we had to stop the fourth cycle because of a severe pancytopenia. Same time the girl presented with fever, neck and leg pain. A full blood count showed: hemoglobin 6.92 g/dl, leukocytes 640/µl, platelets 8,000/µl. Suspecting an infection supported by the presence of a high CrP value of 230 mg/l the patient was treated with i.v. antibiotics. MRI showed an unspecific retropharyngeal soft tissue augmentation, a pleural effusion and high T2 signals in multiple vertebral bodies but no central tumor relapse. The bone marrow diagnostics revealed a diffuse medulloblastoma cell infiltration with the known PTEN frameshift deletion and LDB1 mutation. The liquor was tumor-cell free. We report on an extremely rare case of an early local relapse of desmoplastic medulloblastoma progressing to a diffuse bone marrow infiltration in a toddler. The girl died due to therapy resistance 9 weeks after bone marrow relapse. It remains unclear whether the fatal course was related to the hereditary deafness syndrome and the molecular alterations of the tumor.
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- 2022
43. The Immune Contexture of Liposarcoma and Its Clinical Implications
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Antonia Resag, Giulia Toffanin, Iva Benešová, Luise Müller, Vlatko Potkrajcic, Andrej Ozaniak, Robert Lischke, Jirina Bartunkova, Antonio Rosato, Korinna Jöhrens, Franziska Eckert, Zuzana Strizova, and Marc Schmitz
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Cancer Research ,Oncology ,immune architecture ,immunotherapy ,liposarcoma - Abstract
Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.
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- 2022
44. Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)
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Stephan Kreher, Lukas Kenner, Kathrin D Wurster, Olaf Merkel, Nikolai Schleussner, Arjan Diepstra, Reiner Siebert, Bernd Gillissen, Ioannis Anagnostopoulos, Mariantonia Costanza, Selina Glaser, Björn Lamprecht, Arturo Molina, Karl Köchert, Harald Stein, Korinna Jöhrens, Michael Hummel, Martin Janz, Stephan Mathas, and Stem Cell Aging Leukemia and Lymphoma (SALL)
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Cancer Research ,C-Met ,CD74 ,TUMOR-CELLS ,Major histocompatibility complex ,SURFACE EXPRESSION ,ALK translocation ,Article ,T cell lymphoma ,T-Zell-Lymphom ,ACTIVATION ,PATHWAY ,invariant chain ,chemistry.chemical_compound ,immune system diseases ,hemic and lymphatic diseases ,PERIPHERAL T-CELL ,medicine ,Anaplastic lymphoma kinase ,T-cell lymphoma ,Cytotoxic T cell ,ddc:610 ,INVARIANT CHAIN CD74 ,MHC-II ,Anaplastic large-cell lymphoma ,Invariante Kette ,RC254-282 ,Crizotinib ,MIF ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Lymphoma ,Oncology ,chemistry ,Cancer research ,SURVIVAL ,C-MET ,HODGKIN ,DDC 610 / Medicine & health ,medicine.drug - Abstract
In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2, 5)(p23, q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL. Key pathogenic events in ALK-negative (ALK−) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK+ and ALK− ALCL and predisposes for occurrence of t(2, 5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK+ ALCL or of CD95 death-receptor signaling in ALK− ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.
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- 2021
45. [Detection of BRAF V600E mutation in metastatic colorectal carcinoma : A QuIP round robin test]
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Korinna, Jöhrens, Josephine, Fischer, Markus, Möbs, Klaus, Junker, Jutta, Kirfel, Sven, Perner, Silke, Laßmann, Martin, Werner, Vanessa, Borgmann, Hendrik, Bläker, and Michael, Hummel
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Proto-Oncogene Proteins B-raf ,Mutation ,Antibodies, Monoclonal ,Humans ,Precision Medicine ,Colorectal Neoplasms - Abstract
Round robin testing is an important instrument for quality assurance. Increasingly, this also applies to the results of molecular diagnostics in pathology, which directly influence therapy decisions in precision oncology. In metastatic colorectal carcinoma (mCRC), the focus has been on detecting KRAS and NRAS mutations, whose absence allows therapy with EGFR blocking antibodies. Recently, BRAF has been added as another predictive marker, since mCRC patients with BRAF V600E mutation benefit significantly from treatment with encorafenib (a BRAF inhibitor) in combination with cetuximab (anti-EGFR antibody) after systemic therapy. Due to the approval of this treatment in 2020, it is a pre-requisite that BRAF V600E mutation detection in diagnostic pathologies is reliably performed. Therefore, this round robin test with BRAF V600E testing either by immunohistochemistry or molecular methods was performed. The round robin test results demonstrate that molecular BRAF V600E detection is currently clearly superior to immunohistochemical detection.Ringversuche sind ein wichtiges Instrument zur Qualitätssicherung. Dies betrifft in zunehmendem Maße auch die molekulare Diagnostik in der Pathologie, von deren Ergebnissen Therapieentscheidungen in der Präzisionsonkologie direkt abhängen. Beim metastasierten kolorektalen Karzinom (mKRK) stand bisher der Nachweis von KRAS-und NRAS-Mutationen im Vordergrund, deren Abwesenheit eine Therapie mit EGFR-blockierenden Antikörpern ermöglicht. Nun ist BRAF als weiterer prädiktiver Marker hinzugekommen, da mKRK Patienten mit einer BRAF-V600E-Mutation nach systemischer Vortherapie von einer Behandlung mit Encorafenib (einem BRAF-Inhibitor) in Kombination mit Cetuximab (Anti-EGFR-Antikörper) profitieren. Aufgrund der 2020 erfolgten Zulassung für diese Behandlung ist es wichtig, dass der diagnostische Nachweis einer BRAF-V600E-Mutation zuverlässig in den Pathologien durchgeführt werden kann. Daher wurde dieser Ringversuch durchgeführt, bei dem der Nachweis der BRAF-V600E-Mutation entweder mittels Immunhistochemie oder molekularer Verfahren erfolgen konnte. Die Ergebnisse des Ringversuchs belegen eindeutig, dass derzeit die molekulare BRAF-V600E-Bestimmung dem immunhistologischen Nachweis überlegen ist.
- Published
- 2021
46. MSI testing : What's new? What should be considered?
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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, and Reinhard, Büttner
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Neoplasms ,Humans ,Female ,Microsatellite Instability ,Prognosis ,DNA Mismatch Repair ,Immune Checkpoint Inhibitors ,Immunohistochemistry - Abstract
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 first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.Aufgrund neuer Studiendaten mit Immuncheckpoint-Inhibitoren (ICI) gewinnt der Nachweis einer hochgradigen Mikrosatelliteninstabilität (MSI-H) bzw. der zugrunde liegenden Mismatch-Repair-Protein-Defizienz (dMMR) nun auch zur Prädiktion von Therapieansprechen zunehmend an Bedeutung. Aktuell wurde von der Europäischen Medizinischen Agentur (EMA) erstmals ein PD-1-ICI (Pembrolizumab) für die Erstlinientherapie des fortgeschrittenen (Stadium IV) dMMR/MSI‑H kolorektalen Karzinoms (KRK) zugelassen. Weitere Indikationen, wie z. B. für das metastastasierte dMMR/MSI-H-Endometriumkarzinom (EK) in der Zweitlinientherapie (Dostarlimab) sind bereits gefolgt, andere werden noch im laufenden Jahr 2021 erwartet. Dies erfordert eine Neubewertung der Frage nach der optimalen Testung in der Routinediagnostik. Auf Basis einer Abwägung von Stärken und Schwächen der in der Breite zur Verfügung stehenden Methoden (Immunhistochemie und PCR) wird ein Testalgorithmus vorgeschlagen, der qualitätsgesichert eine zuverlässige und kosteneffektive dMMR/MSI-H-Testung erlaubt. Für das KRK und EK ist damit analog internationaler Empfehlungen (NICE, NCCN) eine Testung bereits bei der Primärdiagnose möglich. Somit wird der Kliniker von vornherein in die Lage versetzt, neben den prädiktiven auch die prognostischen und prädispositionsbedingten Implikationen eines solchen Tests bei der Beratung von Patienten und Erarbeitung von Therapieempfehlungen zu berücksichtigen. Als Grundlage der Qualitätssicherung wird die Teilnahme an Ringversuchen und eine fortlaufende Ergebnisdokumentation (z. B. QuIP-Monitor) empfohlen.
- Published
- 2021
47. Immunhistochemische Analyse von Bcl‐2, nukleärem S100A4, MITF und Ki67 zur Risikostratifizierung von Melanomen im Frühstadium – ein kombinierter immunhistochemischer Score
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Korinna Jöhrens, C Treese, Michael Bockmayr, Ulrike Stein, Manfred Dietel, Maximilian von Laffert, Frederick Klauschen, Philipp Jurmeister, Dido Lenze, Wolfgang Ch. Marsch, Franziska Friedling, and Eckhard Fiedler
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Gynecology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,business.industry ,medicine ,Dermatology ,business - Abstract
Hintergrund und zielsetzung Patienten mit malignen Melanomen im Fruhstadium haben ein unterschiedliches Gesamtuberleben. Derzeit existieren keine etablierten prognostischen Marker. Unser Ziel war es, zu einem besseren Verstandnis der potenziell prognostischen immunhistochemischen Marker fur die Risikostratifizierung beizutragen. Patienten und methoden 161 operativ entfernte maligne Melanome (Stadien pT1 und pT2) wurden immunhistochemisch auf die Expression von 20 verschiedenen Proteinen untersucht. Die Ergebnisse wurden mit dem Gesamtuberleben korreliert. Die Kohorte wurde randomisiert in eine Entdeckungs- und eine Validierungskohorte aufgeteilt. Ergebnisse Eine hohe Bcl-2-Expression, eine hohe nukleare S100A4-Expression und ein Ki67-Proliferationsindex von ≥ 20 % waren mit einem kurzeren Gesamtuberleben assoziiert. Eine starke MITF-Immunreaktivitat erwies sich als pradiktiv fur eine gute Prognose. Die Kombination dieser vier Marker ergab einen Multimarker-Score mit signifikantem prognostischem Wert in der multivariaten Uberlebensanalyse (HR: 3,704; 95 %-KI 1,484-9,246; p = 0,005). Zusatzlich gelang es mit dem Score, drei prognostische Gruppen zu identifizieren: eine Niedrigrisikogruppe mit sehr guten Gesamtuberlebensraten (Funf-Jahres-Uberlebensrate 100 %), eine Gruppe mit mittlerem Risiko (Funf-Jahres-Uberlebensrate 81,8 %) und eine Hochrisikogruppe (Funf-Jahres-Uberlebensrate 52,6 %). Der prognostische Aussagewert bestatigte sich in der Validierungskohorte. Schlussfolgerungen Die kombinierte immunhistochemische Analyse von Bcl-2, nuklearem S100A4, Ki67 und MITF konnte zu einer besseren Risikostratifizierung bei Patienten mit malignen Melanomen im Fruhstadium beitragen.
- Published
- 2019
48. Treatment options for critical size defects - Comparison of different materials in a calvaria split model in sheep
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Jan Oliver Voss, Svenja Kasselmann, Steffen Koerdt, Carsten Rendenbach, Heilwig Fischer, Korinna Jöhrens, Marcus Czabanka, Katharina Schmidt-Bleek, Georg N. Duda, Max Heiland, and Jan-Dirk Raguse
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Titanium ,Sheep ,Bone Substitutes ,Skull ,Bone Cements ,Animals ,Polymethyl Methacrylate ,Female ,Polyethylenes - Abstract
Bone defects of the craniofacial skeleton are often associated with aesthetic and functional impairment as well as loss of protection to intra- and extracranial structures. Solid titanium plates and individually adapted bone cements have been the materials of choice, but may lead to foreign-body reactions and insufficient osseointegration. In contrast, porous scaffolds are thought to exhibit osteoconductive properties to support bone ingrowth. Here, we analyse in critical size defects of the calvaria in sheep whether different bone replacement materials may overcome those remaining challenges. In a critical size defect model, bilateral 20 × 20 × 5-mm craniectomies were performed on either side of the sagittal sinus in 24 adult female blackheaded sheep. Bony defects were randomised to one of five different bone replacement materials (BRMs): titanium scaffold, biodegradable poly(d,l-lactic acid) calcium carbonate scaffold (PDLLA/CC), polyethylene 1 (0.71 mm mean pore size) or 2 (0.515 mm mean pore size) scaffolds and polymethyl methacrylate (PMMA)-based bone cement block. Empty controls (n = 3) served as references. To evaluate bone growth over time, three different fluorochromes were administered at different time points. At 3, 6 and 12 months after surgery, animals were sacrificed and the BRMs and surrounding bone analysed by micro-CT and histomorphometry. The empty control group verified that the calvaria defect in this study was a reliable critical size defect model. Bone formation in vivo was detectable in all BRMs after 12 months by micro-CT and histomorphometric analysis, except for the non-porous PMMA group. A maximum of bone formation was detected in the 12-months group for titanium and PDLLA/CC. Bone formation in PDLLA/CC starts to increase rapidly between 6 and 12 months, as the BRM resorbs over time. Contact between bone and BRM influenced bone formation inside the BRM. Empty controls exhibited bone formation solely at the periphery. Overall, porous BRMs offered bone integration to different extent over 12 months in the tested calvaria defect model. Titanium and PDLLA/CC scaffolds showed remarkable osseointegration properties by micro-CT and histomorphometric analysis. PDLLA/CC scaffolds degraded over time without major residues. Pore size influenced bone ingrowth in polyethylene, emphasising the importance of porous scaffold structure.
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- 2022
49. Qualitätssicherung in der dMMR- und MSI-Diagnostik
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Josef Rüschoff, Josephine Fischer, Korinna Jöhrens, Manfred Dietel, Wolfgang Dietmaier, and Kirsten Utpatel
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0301 basic medicine ,Gynecology ,03 medical and health sciences ,medicine.medical_specialty ,030104 developmental biology ,0302 clinical medicine ,business.industry ,030220 oncology & carcinogenesis ,medicine ,business ,Pathology and Forensic Medicine - Abstract
Mismatch-Repair-Defizienz (dMMR) und Mikrosatelliteninstabilitat (MSI) haben nicht nur bei kolorektalen Karzinomen, sondern auch bei Karzinomen anderer Entitaten (Endometrium, Gallenwege, Pankreas) eine therapeutische Relevanz. Um die Kenntnisse und gute technische Qualitat, die fur die adaquate Durchfuhrung der entsprechenden Analysen notig sind, in den Instituten gewahrleisten zu konnen, bietet die „Die Qualitatssicherung-Initiative Pathologie“ seit Jahren Ringversuche (RV) an. Dabei hat sich gezeigt, dass beim dMMR-RV verschiedene Antikorperklone von unterschiedlichen Herstellern bis auf leichte Schwankungen vergleichbare Ergebnisse bei immunhistologischen Untersuchungen liefern. Die Schwierigkeit liegt hier eher im Farbeprotokoll (Intensitat der Farbung) und der Interpretation der Farbeergebnisse. Der molekularpathologische MSI-RV zeigt uber die letzten 3 Jahre einen positiven Trend auf hohem Qualitatsniveau. Die Erfolgsraten steigerten sich von 89 (2018) auf 97 % (2019/20). Die Wahl der Assays, ob kommerziell oder In-house-Tests, mit den dazu vorgesehenen Cut-Offs hat in den ausgewahlten Ringversuchsproben keinen signifikanten Einfluss auf das Bestehen des RV gezeigt.
- Published
- 2021
50. Status quo of ALK testing in lung cancer: results of an EQA scheme based on in-situ hybridization, immunohistochemistry, and RNA/DNA sequencing
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Volker Endris, Thomas Kirchner, Philipp Jurmeister, Daniela Aust, Claudia Vollbrecht, Reinhard Büttner, Roland Penzel, Jens Neumann, Sabine Merkelbach-Bruse, Peter Schirmacher, Michael Hummel, Annette Fisseler-Eckhoff, Manfred Dietel, Maximilian von Laffert, Albrecht Stenzinger, Korinna Jöhrens, Wolfram Jochum, Regulo Rodriguez, Hans Kreipe, Anke Behnke, Danny Jonigk, and David Horst
- Subjects
0301 basic medicine ,Oncology ,Laboratory Proficiency Testing ,Lung Neoplasms ,Translocation, Genetic ,chemistry.chemical_compound ,Anaplastic lymphoma kinase ,0302 clinical medicine ,Non-small cell lung cancer ,Round robin ,hemic and lymphatic diseases ,Carcinoma, Non-Small-Cell Lung ,Germany ,In Situ Hybridization ,Observer Variation ,High-Throughput Nucleotide Sequencing ,General Medicine ,Immunohistochemistry ,External quality assessment ,030220 oncology & carcinogenesis ,Original Article ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,medicine.medical_specialty ,Concordance ,In situ hybridization ,DNA sequencing ,Pathology and Forensic Medicine ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Lung cancer ,Molecular Biology ,business.industry ,Sequence Analysis, RNA ,RNA ,Reproducibility of Results ,Cell Biology ,Sequence Analysis, DNA ,medicine.disease ,030104 developmental biology ,chemistry ,Next-generation sequencing ,business ,DNA - Abstract
With this external quality assessment (EQA) scheme, we aim to investigate the diagnostic performance of the currently available methods for the detection of ALK alterations in non-small cell lung cancer on a national scale, namely, in situ hybridization (ISH), immunohistochemistry (IHC), and RNA/DNA sequencing (NGS). The EQA scheme cohort consisted of ten specimens, including four ALK positive and six ALK negative samples, which were thoroughly pretested using IHC, ISH, and RNA/DNA NGS. Unstained tumor sections were provided to the 57 participants, and the results were retrieved via an online questionnaire. ISH was used by 29, IHC by 38, and RNA/DNA sequencing by 19 participants. Twenty-eight institutions (97%) passed the ring trial using ISH, 33 (87%) by using IHC, and 18 (95%) by using NGS. The highest sensitivity and interrater agreement (Fleiss ‘ kappa) was observed for RNA/DNA sequencing (99%, 0.975), followed by ISH (94%, 0.898) and IHC (92%, 0.888). However, the proportion of samples that were not evaluable due to bad tissue quality was also higher for RNA/DNA sequencing (4%) compared with ISH (0.7%) and IHC (0.5%). While all three methods produced reliable results between the different institutions, the highest sensitivity and concordance were observed for RNA/DNA sequencing. These findings encourage the broad implementation of this method in routine diagnostic, although the application might be limited by technical capacity, economical restrictions, and tissue quality of formalin-fixed samples. Supplementary Information The online version contains supplementary material available at 10.1007/s00428-021-03106-5.
- Published
- 2021
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