TY - JOUR A1 - Saraceni, Francesco A1 - Labopin, Myriam A1 - Brecht, Arne A1 - Kröger, Nicolaus A1 - Eder, Matthias A1 - Tischer, Johanna A1 - Labussiere-Wallet, Helene A1 - Einsele, Hermann A1 - Beelen, Dietrich A1 - Bunjes, Donald A1 - Niederwieser, Dietger A1 - Bochtler, Tilman A1 - Savani, Bipin N. A1 - Mohty, Mohamad A1 - Nagler, Arnon T1 - Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) JF - Journal of Hematology & Oncology N2 - Background Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p=0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p=0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p=0.01; p=0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III-IV aGVHD (p=0.02) and cGVHD (p=0.006), with no influence on relapse. Conclusions In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk. KW - Acute myeloid leukemia (AML) KW - Active disease KW - Allogeneic transplantation KW - Sibling donor (MSD) KW - Unrelated donor (UD) KW - Conditioning regimen KW - Fludarabine-treosulfan (FT) KW - Thiotepa-busulfan-fludarabine (TBF) KW - Fludarabine KW - intermediate dose Ara-C KW - amsacrine KW - total body irradiation/busulfan KW - cyclophosphamide (FLAMSA) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227345 VL - 12 IS - 44 ER - TY - JOUR A1 - San-Miguel, Jesus F. A1 - Einsele, Hermann A1 - Moreau, Philippe T1 - The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective JF - Advances in Therapy N2 - Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway. In August 2015, the European Commission authorized panobinostat for use in combination with bortezomib and dexamethasone for the treatment of relapsed or relapsed and refractory multiple myeloma (MM) in patients who have received aeyen2 prior regimens including bortezomib and an immunomodulatory drug. In January 2016, the National Institute for Health and Care Excellence recommended panobinostat for use in the same combination and patient population. The authorization and recommendation were based on results from the pivotal phase 3 PANORAMA 1 (NCT01023308) clinical trial, which demonstrated an improvement in median progression-free survival of 7.8 months for the three-drug combination compared with placebo plus bortezomib and dexamethasone in this patient population. This review will discuss the current treatment landscape for relapsed/refractory MM, the mechanism of action of panobinostat, clinical data supporting the European authorization, concerns about safety and strategies for mitigating toxicity, and how panobinostat fits into the current MM landscape in Europe. KW - multiple myeloma KW - oncology KW - panobinostat KW - relapsed and refractory KW - daratumumab monotherapy KW - relapsed Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186840 VL - 33 IS - 11 ER - TY - JOUR A1 - Rydzek, Julian A1 - Nerreter, Thomas A1 - Peng, Haiyong A1 - Jutz, Sabrina A1 - Leitner, Judith A1 - Steinberger, Peter A1 - Einsele, Hermann A1 - Rader, Christoph A1 - Hudecek, Michael T1 - Chimeric Antigen Receptor Library Screening Using a Novel NF-kappa B/NFAT Reporter Cell Platform JF - Molecular Therapy N2 - Chimeric antigen receptor (CAR)-T cell immunotherapy is under intense preclinical and clinical investigation, and it involves a rapidly increasing portfolio of novel target antigens and CAR designs. We established a platform that enables rapid and high-throughput CAR-screening campaigns with reporter cells derived from the T cell lymphoma line Jurkat. Reporter cells were equipped with nuclear factor kappa B (NF kappa B) and nuclear factor of activated T cells (NFAT) reporter genes that generate a duplex output of enhanced CFP (ECFP) and EGFP, respectively. As a proof of concept, we modified reporter cells with CD19-specific and ROR1-specific CARs, and we detected high-level reporter signals that allowed distinguishing functional from non-functional CAR constructs. The reporter data were highly reproducible, and the time required for completing each testing campaign was substantially shorter with reporter cells (6 days) compared to primary CAR-T cells (21 days). We challenged the reporter platform to a large-scale screening campaign on a ROR1-CAR library, and we showed that reporter cells retrieved a functional CAR variant that was present with a frequency of only 6 in 1.05 x 10(6). The data illustrate the potential to implement this reporter platform into the preclinical development path of novel CAR-T cell products and to inform and accelerate the selection of lead CAR candidates for clinical translation. KW - NF-κB/NFAT reporter cells KW - chimeric antigen receptor KW - library screening KW - cancer immunotherapy KW - ROR1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227193 VL - 27 IS - 2 ER - TY - JOUR A1 - Robin, Marie A1 - de Wreede, Liesbeth C. A1 - Wolschke, Christine A1 - Schetelig, Johannes A1 - Eikema, Diderik-Jan A1 - Van Lint, Maria Teresa A1 - Knelange, Nina Simone A1 - Beelen, Dietrich A1 - Brecht, Arne A1 - Niederwieser, Dietger A1 - Vitek, Antonin A1 - Bethge, Wolfgang A1 - Arnold, Renate A1 - Finke, Jürgen A1 - Volin, Liisa A1 - Yakoub-Agha, Ibrahim A1 - Nagler, Arnon A1 - Poiré, Xavier A1 - Einsele, Hermann A1 - Chevallier, Patrice A1 - Holler, Ernst A1 - Ljungman, Per A1 - Robinson, Stephen A1 - Radujkovic, Alekxandar A1 - McLornan, Donal A1 - Chalandon, Yves A1 - Kröger, Nicolaus T1 - Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis JF - Haematologica N2 - Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events Aoccur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64% (60-68%) and overall survival was 74% (71-78%) at ten years; results were better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients aged <45 years and 33% (13-53%) in patients aged >= 65 years. The main cause of death was relapse of the primary disease. Graft-versus-host disease (GvHD) before two years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GvHD disease prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at two years. However, the occurrence of late complications, including late relapses, infectious complications and secondary malignancies, highlights the importance of screening and monitoring of long-term survivors. KW - Prognostic scoring system KW - Societe Francaise KW - Gruppo-italiano KW - European group KW - Late mortality KW - Midollo-Osseo KW - LATE DEATHS KW - Survival KW - Blood KW - Ruxolitinib Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226386 VL - 104 IS - 9 ER - TY - JOUR A1 - Riedel, Simone S. A1 - Mottok, Anja A1 - Brede, Christian A1 - Bäuerlein, Carina A. A1 - Jordán Garrote, Ana Laura A1 - Ritz, Miriam A1 - Mattenheimer, Katharina A1 - Rosenwald, Andreas A1 - Einsele, Hermann A1 - Bogen, Bjarne A1 - Beilhack, Andreas T1 - Non-Invasive Imaging Provides Spatiotemporal Information on Disease Progression and Response to Therapy in a Murine Model of Multiple Myeloma N2 - Background: Multiple myeloma (MM) is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy. Material and Methods: A mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM) that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI). Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology. Results: Strong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase+ cells expressed CXCR4 and high levels of CD44 and a4b1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells. Conclusions: This study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring the effects of different treatment regimens. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77978 ER - TY - JOUR A1 - Rasche, Leo A1 - Duell, Johannes A1 - Morgner, Charlotte A1 - Chatterjee, Manik A1 - Hensel, Frank A1 - Rosenwald, Andreas A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Brändlein, Stephanie T1 - The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78 JF - PLoS ONE N2 - In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM. KW - cytotoxicity KW - apoptosis KW - immunohistochemistry techniques KW - enzyme-linked immunoassays KW - multiple myeloma KW - cell staining KW - cell binding KW - complement system Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130125 VL - 8 IS - 5 ER - TY - JOUR A1 - Proetel, Ulrike A1 - Pletsch, Nadine A1 - Lauseker, Michael A1 - Müller, Martin C. A1 - Hanfstein, Benjamin A1 - Krause, Stefan W. A1 - Kalmanti, Lida A1 - Schreiber, Annette A1 - Heim, Dominik A1 - Baerlocher, Gabriela M. A1 - Hofmann, Wolf-Karsten A1 - Lange, Elisabeth A1 - Einsele, Hermann A1 - Wernli, Martin A1 - Kremers, Stephan A1 - Schlag, Rudolf A1 - Müller, Lothar A1 - Hänel, Mathias A1 - Link, Hartmut A1 - Hertenstein, Bernd A1 - Pfirrmann, Markus A1 - Hochhaus, Andreas A1 - Hasford, Joerg A1 - Hehlmann, Rüdiger A1 - Saußele, Susanne T1 - Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV JF - Annals of Hematology N2 - The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874 KW - chronic myeloid leukemia KW - older patients KW - different imatinib dose regimens KW - early applied higher imatinib dosages Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121574 SN - 0939-5555 VL - 93 IS - 7 ER - TY - JOUR A1 - Philipp-Abbrederis, Kathrin A1 - Herrmann, Ken A1 - Knop, Stefan A1 - Schottelius, Margret A1 - Eiber, Matthias A1 - Lückerath, Katharina A1 - Pietschmann, Elke A1 - Habringer, Stefan A1 - Gerngroß, Carlos A1 - Franke, Katharina A1 - Rudelius, Martina A1 - Schirbel, Andreas A1 - Lapa, Constantin A1 - Schwamborn, Kristina A1 - Steidle, Sabine A1 - Hartmann, Elena A1 - Rosenwald, Andreas A1 - Kropf, Saskia A1 - Beer, Ambros J A1 - Peschel, Christian A1 - Einsele, Hermann A1 - Buck, Andreas K A1 - Schwaiger, Markus A1 - Götze, Katharina A1 - Wester, Hans-Jürgen A1 - Keller, Ulrich T1 - In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma JF - EMBO Molecular Medicine N2 - CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination andpoor prognosis. We evaluated the novel CXCR4 probe [\(^{68}\)Ga]Pentixafor for invivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [\(^{68}\)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [\(^{68}\)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [\(^{18}\)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34\(^{+}\) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [\(^{68}\)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases. KW - FDG PET/CT KW - cells KW - CXCR4/SDF-1 KW - CXCR4 KW - multiple myeloma KW - positron emission tomography KW - chemokine receptor KW - in vivo imaging KW - malignancies KW - involvement KW - microenvironment KW - survival KW - cancer KW - autologous transplantation KW - bone disease Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148738 VL - 7 IS - 4 ER - TY - JOUR A1 - Page, Lukas A1 - Wallstabe, Julia A1 - Lother, Jasmin A1 - Bauser, Maximilian A1 - Kniemeyer, Olaf A1 - Strobel, Lea A1 - Voltersen, Vera A1 - Teutschbein, Janka A1 - Hortschansky, Peter A1 - Morton, Charles Oliver A1 - Brakhage, Axel A. A1 - Topp, Max A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Loeffler, Juergen T1 - CcpA- and Shm2-Pulsed Myeloid Dendritic Cells Induce T-Cell Activation and Enhance the Neutrophilic Oxidative Burst Response to Aspergillus fumigatus JF - Frontiers in Immunology N2 - Aspergillus fumigatus causes life-threatening opportunistic infections in immunocompromised patients. As therapeutic outcomes of invasive aspergillosis (IA) are often unsatisfactory, the development of targeted immunotherapy remains an important goal. Linking the innate and adaptive immune system, dendritic cells are pivotal in anti-Aspergillus defense and have generated interest as a potential immunotherapeutic approach in IA. While monocyte-derived dendritic cells (moDCs) require ex vivo differentiation, antigen-pulsed primary myeloid dendritic cells (mDCs) may present a more immediate platform for immunotherapy. To that end, we compared the response patterns and cellular interactions of human primary mDCs and moDCs pulsed with an A. fumigatus lysate and two A. fumigatus proteins (CcpA and Shm2) in a serum-free, GMP-compliant medium. CcpA and Shm2 triggered significant upregulation of maturation markers in mDCs and, to a lesser extent, moDCs. Furthermore, both A. fumigatus proteins elicited the release of an array of key pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-8, and CCL3 from both DC populations. Compared to moDCs, CcpA- and Shm2-pulsed mDCs exhibited greater expression of MHC class II antigens and stimulated stronger proliferation and IFN-γ secretion from autologous CD4\(^+\) and CD8\(^+\) T-cells. Moreover, supernatants of CcpA- and Shm2-pulsed mDCs significantly enhanced the oxidative burst in allogeneic neutrophils co-cultured with A. fumigatus germ tubes. Taken together, our in vitro data suggest that ex vivo CcpA- and Shm2-pulsed primary mDCs have the potential to be developed into an immunotherapeutic approach to tackle IA. KW - antigens KW - dendritic cells KW - cytokines KW - host defense KW - immunotherapy KW - Aspergillus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239493 SN - 1664-3224 VL - 12 ER - TY - JOUR A1 - Neuchel, Christine A1 - Fürst, Daniel A1 - Niederwieser, Dietger A1 - Bunjes, Donald A1 - Tsamadou, Chrysanthi A1 - Wulf, Gerald A1 - Pfreundschuh, Michael A1 - Wagner, Eva A1 - Stuhler, Gernot A1 - Einsele, Hermann A1 - Schrezenmeier, Hubert A1 - Mytilineos, Joannis T1 - Impact of donor activating KIR genes on HSCT outcome in C1-ligand negative myeloid disease patients transplanted with unrelated donors - a retrospective study JF - PLOS One N2 - Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14–1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05–1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01–1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01–1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15–1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91–1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01–1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90–1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01–1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90–1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08–0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11–0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13–0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26–5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance. KW - Hematopoietic stem cell transplantation KW - Cancer risk factors KW - Multivariate analysis KW - Stem cell transplantation KW - T-cells KW - Bone marrow transplantation KW - NK-cells KW - Immune receptor signaling KW - Killer cell immunoglobulin-like receptors KW - Acute myeloid leukemia KW - Acute lymphoblastic leukemia KW - Chronic lymphoblastic leukemia KW - Chronic myeloid leukemia Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180995 VL - 12 IS - 1 ER - TY - JOUR A1 - Nerreter, Thomas A1 - Letschert, Sebastian A1 - Götz, Ralph A1 - Doose, Sören A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Sauer, Markus A1 - Hudecek, Michael T1 - Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T JF - Nature Communications N2 - Immunotherapy with chimeric antigen receptor-engineered T-cells (CAR-T) is under investigation in multiple myeloma. There are reports of myeloma remission after CD19 CAR-T therapy, although CD19 is hardly detectable on myeloma cells by flow cytometry (FC). We apply single molecule-sensitive direct stochastic optical reconstruction microscopy (dSTORM), and demonstrate CD19 expression on a fraction of myeloma cells (10.3–80%) in 10 out of 14 patients (density: 13–5,000 molecules per cell). In contrast, FC detects CD19 in only 2 of these 10 patients, on a smaller fraction of cells. Treatment with CD19 CAR-T in vitro results in elimination of CD19-positive myeloma cells, including those with <100 CD19 molecules per cell. Similar data are obtained by dSTORM analyses of CD20 expression on myeloma cells and CD20 CAR-T. These data establish a sensitivity threshold for CAR-T and illustrate how super-resolution microscopy can guide patient selection in immunotherapy to exploit ultra-low density antigens. KW - cancer imaging KW - cancer immunotherapy KW - imaging Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232258 VL - 10 ER - TY - JOUR A1 - Munawar, Umair A1 - Zhou, Xiang A1 - Prommersberger, Sabrina A1 - Nerreter, Silvia A1 - Vogt, Cornelia A1 - Steinhardt, Maximilian J. A1 - Truger, Marietta A1 - Mersi, Julia A1 - Teufel, Eva A1 - Han, Seungbin A1 - Haertle, Larissa A1 - Banholzer, Nicole A1 - Eiring, Patrick A1 - Danhof, Sophia A1 - Navarro-Aguadero, Miguel Angel A1 - Fernandez-Martin, Adrian A1 - Ortiz-Ruiz, Alejandra A1 - Barrio, Santiago A1 - Gallardo, Miguel A1 - Valeri, Antonio A1 - Castellano, Eva A1 - Raab, Peter A1 - Rudert, Maximilian A1 - Haferlach, Claudia A1 - Sauer, Markus A1 - Hudecek, Michael A1 - Martinez-Lopez, J. A1 - Waldschmidt, Johannes A1 - Einsele, Hermann A1 - Rasche, Leo A1 - Kortüm, K. Martin T1 - Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma JF - Communications Biology N2 - The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM. KW - immunotherapy KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357609 VL - 6 ER - TY - JOUR A1 - Mueller-Loebnitz, Christoph A1 - Ostermann, Helmut A1 - Franzke, Anke A1 - Loeffler, Juergen A1 - Uharek, Lutz A1 - Topp, Max A1 - Einsele, Hermann T1 - Immunological Aspects of Candida and Aspergillus Systemic Fungal Infections JF - Interdisciplinary Perspectives on Infectious Diseases N2 - Patients with allogeneic stem cell transplantation (SCT) have a high risk of invasive fungal infections (IFIs) even after neutrophil regeneration. Immunological aspects might play a very important role in the IFI development in these patients. Some data are available supporting the identification of high-risk patients with IFI for example patients receiving stem cells fromTLR4 haplotype S4 positive donors. Key defense mechanisms against IFI include the activation of neutrophils, the phagocytosis of germinating conidia by dendritic cells, and the fight of the cells of the innate immunity such as monocytes and natural killer cells against germlings and hyphae. Furthermore, immunosuppressive drugs interact with immune effector cells influencing the specific fungal immune defense and antimycotic drugs might interact with immune response. Based on the current knowledge on immunological mechanism in Aspergillus fumigatus, the first approaches of an immunotherapy using human T cells are in development. This might be an option for the future of aspergillosis patients having a poor prognosis with conventional treatment. KW - Infectious Diseases Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129327 IS - ID 102934 ER - TY - JOUR A1 - Morton, Charles Oliver A1 - Fliesser, Mirjam A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Bauer, Ruth A1 - Kneitz, Susanne A1 - Hope, William A1 - Rogers, Thomas Richard A1 - Einsele, Hermann A1 - Löffler, Jürgen T1 - Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface N2 - The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA. KW - aspergillus fumigatus KW - gene expression KW - immune receptors KW - immune response KW - denritic cells KW - B cell receptors KW - gene regulation KW - RNA extraction Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112893 ER - TY - JOUR A1 - Morton, Charles O. A1 - Varga, John J. A1 - Hornbach, Anke A1 - Mezger, Markus A1 - Sennefelder, Helga A1 - Kneitz, Susanne A1 - Kurzai, Oliver A1 - Krappmann, Sven A1 - Einsele, Hermann A1 - Nierman, William C. A1 - Rogers, Thomas R. A1 - Loeffler, Juergen T1 - The Temporal Dynamics of Differential Gene Expression in Aspergillus fumigatus Interacting with Human Immature Dendritic Cells In Vitro N2 - No abstract avDendritic cells (DC) are the most important antigen presenting cells and play a pivotal role in host immunity to infectious agents by acting as a bridge between the innate and adaptive immune systems. Monocyte-derived immature DCs (iDC) were infected with viable resting conidia of Aspergillus fumigatus (Af293) for 12 hours at an MOI of 5; cells were sampled every three hours. RNA was extracted from both organisms at each time point and hybridised to microarrays. iDC cell death increased at 6 h in the presence of A. fumigatus which coincided with fungal germ tube emergence; .80% of conidia were associated with iDC. Over the time course A. fumigatus differentially regulated 210 genes, FunCat analysis indicated significant up-regulation of genes involved in fermentation, drug transport, pathogenesis and response to oxidative stress. Genes related to cytotoxicity were differentially regulated but the gliotoxin biosynthesis genes were down regulated over the time course, while Aspf1 was up-regulated at 9 h and 12 h. There was an up-regulation of genes in the subtelomeric regions of the genome as the interaction progressed. The genes up-regulated by iDC in the presence of A. fumigatus indicated that they were producing a pro-inflammatory response which was consistent with previous transcriptome studies of iDC interacting with A. fumigatus germ tubes. This study shows that A. fumigatus adapts to phagocytosis by iDCs by utilising genes that allow it to survive the interaction rather than just up-regulation of specific virulence genes. KW - Dendritische Zelle Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68958 ER - TY - JOUR A1 - Mitchell, Jonathan S. A1 - Li, Ni A1 - Weinhold, Niels A1 - Försti, Asta A1 - Ali, Mina A1 - van Duin, Mark A1 - Thorleifsson, Gudmar A1 - Johnson, David C. A1 - Chen, Bowang A1 - Halvarsson, Britt-Marie A1 - Gudbjartsson, Daniel F. A1 - Kuiper, Rowan A1 - Stephens, Owen W. A1 - Bertsch, Uta A1 - Broderick, Peter A1 - Campo, Chiara A1 - Einsele, Hermann A1 - Gregory, Walter A. A1 - Gullberg, Urban A1 - Henrion, Marc A1 - Hillengass, Jens A1 - Hoffmann, Per A1 - Jackson, Graham H. A1 - Johnsson, Ellinor A1 - Jöud, Magnus A1 - Kristinsson, Sigurdur Y. A1 - Lenhoff, Stig A1 - Lenive, Oleg A1 - Mellqvist, Ulf-Henrik A1 - Migliorini, Gabriele A1 - Nahi, Hareth A1 - Nelander, Sven A1 - Nickel, Jolanta A1 - Nöthen, Markus M. A1 - Rafnar, Thorunn A1 - Ross, Fiona M. A1 - da Silva Filho, Miguel Inacio A1 - Swaminathan, Bhairavi A1 - Thomsen, Hauke A1 - Turesson, Ingemar A1 - Vangsted, Annette A1 - Vogel, Ulla A1 - Waage, Anders A1 - Walker, Brian A. A1 - Wihlborg, Anna-Karin A1 - Broyl, Annemiek A1 - Davies, Faith E. A1 - Thorsteinsdottir, Unnur A1 - Langer, Christian A1 - Hansson, Markus A1 - Kaiser, Martin A1 - Sonneveld, Pieter A1 - Stefansson, Kari A1 - Morgan, Gareth J. A1 - Goldschmidt, Hartmut A1 - Hemminki, Kari A1 - Nilsson, Björn A1 - Houlston, Richard S. T1 - Genome-wide association study identifies multiple susceptibility loci for multiple myeloma JF - Nature Communications N2 - Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development. KW - Cancer genetics KW - Genome-wide association studies KW - Myeloma Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165983 VL - 7 ER - TY - JOUR A1 - Maucher, Marius A1 - Srour, Micha A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Hudecek, Michael A1 - Yakoub-Agha, Ibrahim T1 - Current limitations and perspectives of chimeric antigen receptor-T-cells in acute myeloid leukemia JF - Cancers N2 - Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them. KW - AML KW - CAR-T-cell KW - hematology KW - gene therapy KW - adoptive cell therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252180 SN - 2072-6694 VL - 13 IS - 24 ER - TY - JOUR A1 - Marischen, Lothar A1 - Englert, Anne A1 - Schmitt, Anna-Lena A1 - Einsele, Hermann A1 - Loeffler, Juergen T1 - Human NK cells adapt their immune response towards increasing multiplicities of infection of Aspergillus fumigatus JF - BMC Immunology N2 - Background: The saprophytic fungus Aspergillus fumigatus reproduces by generation of conidia, which are spread by airflow throughout nature. Since humans are inhaling certain amounts of spores every day, the (innate) immune system is constantly challenged. Even though macrophages and neutrophils carry the main burden, also NK cells are regarded to contribute to the antifungal immune response. While NK cells reveal a low frequency, expression and release of immunomodulatory molecules seem to be a natural way of their involvement. Results: In this study we show, that NK cells secrete chemokines such as CCL3/MIP-1α, CCL4/MIP-1β and CCL5/RANTES early on after stimulation with Aspergillus fumigatus and, in addition, adjust the concentration of chemokines released to the multiplicity of infection of Aspergillus fumigatus. Conclusions: These results further corroborate the relevance of NK cells within the antifungal immune response, which is regarded to be more and more important in the development and outcome of invasive aspergillosis in immunocompromised patients after hematopoietic stem cell transplantation. Additionally, the correlation between the multiplicity of infection and the expression and release of chemokines shown here may be useful in further studies for the quantification and/or surveillance of the NK cell involvement in antifungal immune responses. KW - Aspergillus fumigatus KW - aspergillosis KW - NK cells KW - chemokines KW - CCL4 KW - multiplicity of infection KW - MIP-1β Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176331 VL - 19 IS - 39 ER - TY - JOUR A1 - Lüke, Florian A1 - Haller, Florian A1 - Utpatel, Kirsten A1 - Krebs, Markus A1 - Meidenbauer, Norbert A1 - Scheiter, Alexander A1 - Spoerl, Silvia A1 - Heudobler, Daniel A1 - Sparrer, Daniela A1 - Kaiser, Ulrich A1 - Keil, Felix A1 - Schubart, Christoph A1 - Tögel, Lars A1 - Einhell, Sabine A1 - Dietmaier, Wolfgang A1 - Huss, Ralf A1 - Dintner, Sebastian A1 - Sommer, Sebastian A1 - Jordan, Frank A1 - Goebeler, Maria-Elisabeth A1 - Metz, Michaela A1 - Haake, Diana A1 - Scheytt, Mithun A1 - Gerhard-Hartmann, Elena A1 - Maurus, Katja A1 - Brändlein, Stephanie A1 - Rosenwald, Andreas A1 - Hartmann, Arndt A1 - Märkl, Bruno A1 - Einsele, Hermann A1 - Mackensen, Andreas A1 - Herr, Wolfgang A1 - Kunzmann, Volker A1 - Bargou, Ralf A1 - Beckmann, Matthias W. A1 - Pukrop, Tobias A1 - Trepel, Martin A1 - Evert, Matthias A1 - Claus, Rainer A1 - Kerscher, Alexander T1 - Identification of disparities in personalized cancer care — a joint approach of the German WERA consortium JF - Cancers N2 - (1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy. KW - precision oncology KW - MTB KW - patient access KW - cancer care KW - outreach KW - real world data KW - outcomes research Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290311 SN - 2072-6694 VL - 14 IS - 20 ER - TY - JOUR A1 - Lupiañez, Carmen B. A1 - Villaescusa, Maria T. A1 - Carvalho, Agostinho A1 - Springer, Jan A1 - Lackner, Michaela A1 - Sánchez-Maldonado, José M. A1 - Canet, Luz M. A1 - Cunha, Cristina A1 - Segura-Catena, Joana A1 - Alcazar-Fuoli, Laura A1 - Solano, Carlos A1 - Fianchi, Luana A1 - Pagano, Livio A1 - Potenza, Leonardo A1 - Aguado, José M. A1 - Luppi, Mario A1 - Cuenca-Estrella, Manuel A1 - Lass-Flörl, Cornelia A1 - Einsele, Hermann A1 - Vázquez, Lourdes A1 - Ríos-Tamayo, Rafael A1 - Loeffler, Jürgen A1 - Jurado, Manuel A1 - Sainz, Juan T1 - Common Genetic Polymorphisms within NF kappa B-Related Genes and the Risk of Developing Invasive Aspergillosis JF - Frontiers in Microbiology N2 - Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25–31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA. KW - Invasive Aspergillosis KW - genetic polymorphisms KW - susceptibility KW - NFkB-relatedgenes KW - interaction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165209 VL - 7 IS - 1243 ER - TY - JOUR A1 - Ludwig, Heinz A1 - Delforge, Michel A1 - Facon, Thierry A1 - Einsele, Hermann A1 - Gay, Francesca A1 - Moreau, Philippe A1 - Avet-Loiseau, Hervé A1 - Boccadoro, Mario A1 - Hajek, Roman A1 - Mohty, Mohamad A1 - Cavo, Michele A1 - Dimopoulos, Meletios A A1 - San-Miguel, Jesús F A1 - Terpos, Evangelos A1 - Zweegman, Sonja A1 - Garderet, Laurent A1 - Mateos, María-Victoria A1 - Cook, Gordon A1 - Leleu, Xavier A1 - Goldschmidt, Hartmut A1 - Jackson, Graham A1 - Kaiser, Martin A1 - Weisel, Katja A1 - van de Donk, Niels W. C. J. A1 - Waage, Anders A1 - Beksac, Meral A1 - Mellqvist, Ulf H. A1 - Engelhardt, Monika A1 - Caers, Jo A1 - Driessen, Christoph A1 - Bladé, Joan A1 - Sonneveld, Pieter T1 - Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network JF - Leukemia N2 - During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events. KW - disease prevention KW - myeloma Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237338 VL - 32 ER - TY - JOUR A1 - Luber, Verena A1 - Lutz, Mathias A1 - Thiede, Christian A1 - Haferlach, Claudia A1 - Dürk, Heinz Albert A1 - Einsele, Hermann A1 - Grigoleit, Götz Ulrich A1 - Mielke, Stephan T1 - Donor-cell leukemia with novel genetic features 2 years after sex-mismatched T cell-depleted haploidentical stem cell transplantation JF - Annals of Hematology N2 - No abstract available. KW - donor-cell leukemia Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232596 SN - 0939-5555 VL - 99 ER - TY - JOUR A1 - Luber, Verena A1 - Lutz, Mathias A1 - Abele-Horn, Marianne A1 - Einsele, Hermann A1 - Grigoleit, Götz Ulrich A1 - Mielke, Stephan T1 - Excretion of Ascaris lumbricoides following reduced‐intensity allogeneic hematopoietic stem cell transplantation and consecutive treatment with mebendazole JF - Transplant Infectious Disease N2 - Here, we present the unique case of a 51‐year‐old German patient with multiple myeloma excreting Ascaris lumbricoides in his stool five weeks after allogeneic hematopoietic stem cell transplantation. Stool analysis remained negative for the presence of eggs, and there was no eosinophilia in the peripheral blood at any time around stem cell transplantation. The patient was commenced on a three‐day treatment with mebendazole, which was well tolerated. No serious interactions with the concomitant post‐transplant medication or negative effects on the hematopoiesis were observed, and the myeloma still is in complete remission. To our knowledge, this is the first report on excretion of A lumbricoides in the context of allogeneic stem cell transplantation. The case is remarkable with view to the fact that the parasite has supposedly survived all courses of myeloma treatment including autologous and allogeneic conditioning. Parasitosis with A lumbricoides has a worldwide prevalence of about a billion and is extremely rare in northern Europe. Possibly the patient got infected during a trip to Egypt years before multiple myeloma was diagnosed. KW - sirolimus KW - mycophenolic acid KW - multiple myeloma KW - mebendazole KW - hematopoietic stem cell transplantation KW - Ascaris lumbricoides Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219608 SN - 1399-3062 VL - 22 IS - 1 ER - TY - JOUR A1 - Loda, Sophia A1 - Krebs, Jonathan A1 - Danhof, Sophia A1 - Schreder, Martin A1 - Solimando, Antonio G. A1 - Strifler, Susanne A1 - Rasche, Leo A1 - Kortüm, Martin A1 - Kerscher, Alexander A1 - Knop, Stefan A1 - Puppe, Frank A1 - Einsele, Hermann A1 - Bittrich, Max T1 - Exploration of artificial intelligence use with ARIES in multiple myeloma research JF - Journal of Clinical Medicine N2 - Background: Natural language processing (NLP) is a powerful tool supporting the generation of Real-World Evidence (RWE). There is no NLP system that enables the extensive querying of parameters specific to multiple myeloma (MM) out of unstructured medical reports. We therefore created a MM-specific ontology to accelerate the information extraction (IE) out of unstructured text. Methods: Our MM ontology consists of extensive MM-specific and hierarchically structured attributes and values. We implemented “A Rule-based Information Extraction System” (ARIES) that uses this ontology. We evaluated ARIES on 200 randomly selected medical reports of patients diagnosed with MM. Results: Our system achieved a high F1-Score of 0.92 on the evaluation dataset with a precision of 0.87 and recall of 0.98. Conclusions: Our rule-based IE system enables the comprehensive querying of medical reports. The IE accelerates the extraction of data and enables clinicians to faster generate RWE on hematological issues. RWE helps clinicians to make decisions in an evidence-based manner. Our tool easily accelerates the integration of research evidence into everyday clinical practice. KW - natural language processing KW - ontology KW - artificial intelligence KW - multiple myeloma KW - real world evidence Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197231 SN - 2077-0383 VL - 8 IS - 7 ER - TY - JOUR A1 - Leonhardt, Jonas A1 - Winkler, Marcela A1 - Kollikowski, Anne A1 - Schiffmann, Lisa A1 - Quenzer, Anne A1 - Einsele, Hermann A1 - Löffler, Claudia T1 - Mind–body-medicine in oncology—from patient needs to tailored programs and interventions BT - a cross-sectional study JF - Frontiers in Psychology N2 - Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior. Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts. Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.” Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept. KW - lifestyle habits KW - symptom burden KW - individual mind state KW - motivational level KW - stress Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321970 SN - 1664-1078 VL - 14 ER - TY - JOUR A1 - Lauruschkat, Chris David A1 - Muchsin, Ihsan A1 - Rein, Alice A1 - Erhard, Florian A1 - Grathwohl, Denise A1 - Dölken, Lars A1 - Köchel, Carolin A1 - Falk, Christine Susanne A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Grigoleit, Götz Ulrich A1 - Kraus, Sabrina T1 - CD4+ T cells are the major predictor of HCMV control in allogeneic stem cell transplant recipients on letermovir prophylaxis JF - Frontiers in Immunology N2 - Introduction Human cytomegalovirus (HCMV) causes significant morbidity and mortality in allogeneic stem cell transplant (alloSCT) recipients. Recently, antiviral letermovir prophylaxis during the first 100 days after alloSCT replaced PCR-guided preemptive therapy as the primary standard of care for HCMV reactivations. Here, we compared NK-cell and T-cell reconstitution in alloSCT recipients receiving preemptive therapy or letermovir prophylaxis in order to identify potential biomarkers predicting prolonged and symptomatic HCMV reactivation. Methods To that end, the NK-cell and T-cell repertoire of alloSCT recipients managed with preemptive therapy (n=32) or letermovir prophylaxis (n=24) was characterized by flow cytometry on days +30, +60, +90 and +120 after alloSCT. Additionally, background-corrected HCMV-specific T-helper (CD4+IFNγ+) and cytotoxic (CD8+IFNγ+CD107a+) T cells were quantified after pp65 stimulation. Results Compared to preemptive therapy, letermovir prophylaxis prevented HCMV reactivation and decreased HCMV peak viral loads until days +120 and +365. Letermovir prophylaxis resulted in decreased T-cell numbers but increased NK-cell numbers. Interestingly, despite the inhibition of HCMV, we found high numbers of “memory-like” (CD56dimFcεRIγ- and/or CD159c+) NK cells and an expansion of HCMV-specific CD4+ and CD8+ T cells in letermovir recipients. We further compared immunological readouts in patients on letermovir prophylaxis with non/short-term HCMV reactivation (NSTR) and prolonged/symptomatic HCMV reactivation (long-term HCMV reactivation, LTR). Median HCMV-specific CD4+ T-cell frequencies were significantly higher in NSTR patients (day +60, 0.35 % vs. 0.00 % CD4+IFNγ+/CD4+ cells, p=0.018) than in patients with LTR, whereas patients with LTR had significantly higher median regulatory T-cell (Treg) frequencies (day +90, 2.2 % vs. 6.2 % CD4+CD25+CD127dim/CD4+ cells, p=0.019). ROC analysis confirmed low HCMV specific CD4+ (AUC on day +60: 0.813, p=0.019) and high Treg frequencies (AUC on day +90: 0.847, p=0.021) as significant predictors of prolonged and symptomatic HCMV reactivation. Discussion Taken together, letermovir prophylaxis delays HCMV reactivation and alters NK- and T-cell reconstitution. High numbers of HCMV-specific CD4+ T cells and low numbers of Tregs seem to be pivotal to suppress post-alloSCT HCMV reactivation during letermovir prophylaxis. Administration of more advanced immunoassays that include Treg signature cytokines might contribute to the identification of patients at high-risk for long-term and symptomatic HCMV reactivation who might benefit from prolonged administration of letermovir. KW - human cytomegalovirus (HCMV) KW - viral infection KW - allogeneic stem cell transplantation KW - T cells KW - NK cells Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-316982 VL - 14 ER - TY - JOUR A1 - Lauruschkat, Chris D. A1 - Page, Lukas A1 - White, P. Lewis A1 - Etter, Sonja A1 - Davies, Helen E. A1 - Duckers, Jamie A1 - Ebel, Frank A1 - Schnack, Elisabeth A1 - Backx, Matthijs A1 - Dragan, Mariola A1 - Schlegel, Nicolas A1 - Kniemeyer, Olaf A1 - Brakhage, Axel A. A1 - Einsele, Hermann A1 - Loeffler, Juergen A1 - Wurster, Sebastian T1 - Development of a simple and robust whole blood assay with dual co-stimulation to quantify the release of T-cellular signature cytokines in response to Aspergillus fumigatus antigens JF - Journal of Fungi N2 - Deeper understanding of mold-induced cytokine signatures could promote advances in the diagnosis and treatment of invasive mycoses and mold-associated hypersensitivity syndromes. Currently, most T-cellular immunoassays in medical mycology require the isolation of mononuclear cells and have limited robustness and practicability, hampering their broader applicability in clinical practice. Therefore, we developed a simple, cost-efficient whole blood (WB) assay with dual α-CD28 and α-CD49d co-stimulation to quantify cytokine secretion in response to Aspergillus fumigatus antigens. Dual co-stimulation strongly enhanced A. fumigatus-induced release of T-cellular signature cytokines detectable by enzyme-linked immunosorbent assay (ELISA) or a multiplex cytokine assay. Furthermore, T-cell-dependent activation and cytokine response of innate immune cells was captured by the assay. The protocol consistently showed little technical variation and high robustness to pre-analytic delays of up to 8 h. Stimulation with an A. fumigatus lysate elicited at least 7-fold greater median concentrations of key T-helper cell signature cytokines, including IL-17 and the type 2 T-helper cell cytokines IL-4 and IL-5 in WB samples from patients with Aspergillus-associated lung pathologies versus patients with non-mold-related lung diseases, suggesting high discriminatory power of the assay. These results position WB-ELISA with dual co-stimulation as a simple, accurate, and robust immunoassay for translational applications, encouraging further evaluation as a platform to monitor host immunity to opportunistic pathogens. KW - immunoassay KW - biomarker KW - Aspergillus KW - cytokines KW - inflammation KW - adaptive immunity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241025 SN - 2309-608X VL - 7 IS - 6 ER - TY - JOUR A1 - Lauruschkat, Chris D. A1 - Etter, Sonja A1 - Schnack, Elisabeth A1 - Ebel, Frank A1 - Schäuble, Sascha A1 - Page, Lukas A1 - Rümens, Dana A1 - Dragan, Mariola A1 - Schlegel, Nicolas A1 - Panagiotou, Gianni A1 - Kniemeyer, Olaf A1 - Brakhage, Axel A. A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Loeffler, Juergen T1 - Chronic occupational mold exposure drives expansion of Aspergillus-reactive type 1 and type 2 T-helper cell responses JF - Journal of Fungi N2 - Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses. KW - mold exposure KW - immunoassay KW - biomarker KW - Aspergillus KW - cytokines KW - inflammation KW - adaptive immunity KW - hypersensitivity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245202 SN - 2309-608X VL - 7 IS - 9 ER - TY - JOUR A1 - Lapa, Constantin A1 - Herrmann, Ken A1 - Schirbel, Andreas A1 - Hänscheid, Heribert A1 - Lückerath, Katharina A1 - Schottelius, Margret A1 - Kircher, Malte A1 - Werner, Rudolf A. A1 - Schreder, Martin A1 - Samnick, Samuel A1 - Kropf, Saskia A1 - Knop, Stefan A1 - Buck, Andreas K. A1 - Einsele, Hermann A1 - Wester, Hans-Juergen A1 - Kortüm, K. Martin T1 - CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma JF - Theranostics N2 - C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted. KW - medicine KW - multiple myeloma KW - PET KW - CXCR4 KW - theranostics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172095 VL - 7 IS - 6 ER - TY - JOUR A1 - Lapa, Constantin A1 - Garcia-Velloso, Maria J. A1 - Lückerath, Katharina A1 - Samnick, Samuel A1 - Schreder, Martin A1 - Otero, Paula Rodriguez A1 - Schmid, Jan-Stefan A1 - Herrmann, Ken A1 - Knop, Stefan A1 - Buck, Andreas K. A1 - Einsele, Hermann A1 - San-Miguel, Jesus A1 - Kortüm, Klaus Martin T1 - \(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions JF - Theranostics N2 - \(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM. KW - medicine KW - PET/CT KW - \(^{11}\)C-methionine KW - multiple myeloma KW - FDG Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172038 VL - 7 IS - 11 ER - TY - JOUR A1 - Kouhestani, Dina A1 - Geis, Maria A1 - Alsouri, Saed A1 - Bumm, Thomas G. P. A1 - Einsele, Hermann A1 - Sauer, Markus A1 - Stuhler, Gernot T1 - Variant signaling topology at the cancer cell–T-cell interface induced by a two-component T-cell engager JF - Cellular & Molecular Immunology N2 - No abstract available. KW - immunotherapy KW - tumour immunology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241189 VL - 18 ER - TY - JOUR A1 - Keppler, Sarah A1 - Weißbach, Susann A1 - Langer, Christian A1 - Knop, Stefan A1 - Pischimarov, Jordan A1 - Kull, Miriam A1 - Stühmer, Thorsten A1 - Steinbrunn, Torsten A1 - Bargou, Ralf A1 - Einsele, Hermann A1 - Rosenwald, Andreas A1 - Leich, Ellen T1 - Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma JF - Oncotarget N2 - Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the “Deutsche Studiengruppe Multiples Myelom”. Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significantly lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors. KW - multiple myeloma KW - rare SNP KW - amplicon sequencing KW - receptor tyrosine kinases Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177840 VL - 7 IS - 25 ER - TY - JOUR A1 - Kalleda, Natarajaswamy A1 - Amich, Jorge A1 - Arslan, Berkan A1 - Poreddy, Spoorthi A1 - Mattenheimer, Katharina A1 - Mokhtari, Zeinab A1 - Einsele, Hermann A1 - Brock, Matthias A1 - Heinze, Katrin Gertrud A1 - Beilhack, Andreas T1 - Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens JF - Frontiers in Microbiology N2 - Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4\(^+\) or CD8\(^+\) T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b\(^+\) myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b\(^+\) myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. KW - corticosteroids and cyclophosphamide KW - aspergillus fumigatus KW - CD11b+ myeloid cells KW - immune cell recruitment Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165368 VL - 7 IS - 1107 ER - TY - JOUR A1 - Jendretzki, Julia A1 - Henniger, Dorothea A1 - Schiffmann, Lisa A1 - Wolz, Constanze A1 - Kollikowski, Anne A1 - Meining, Alexander A1 - Einsele, Hermann A1 - Winkler, Marcela A1 - Löffler, Claudia T1 - Every fifth patient suffered a high nutritional risk — Results of a prospective patient survey in an oncological outpatient center JF - Frontiers in Nutrition N2 - Introduction Malnutrition in cancer patients often remains undetected and underestimated in clinical practice despite studies revealing prevalences from 20 to 70%. Therefore, this study aimed to identify patient groups exposed to an increased nutritional risk in a university oncological outpatient center. Methods Between May 2017 and January 2018 we screened oncological patients there using the malnutrition universal screening tool (MUST). Qualitative data were collected by a questionnaire to learn about patients’ individual information needs and changes in patients’ diets and stressful personal nutrition restrictions. Results We included 311 patients with various cancers. 20.3% (n = 63) were found to be at high risk of malnutrition, 16.4% (n = 51) at moderate risk despite a mean body mass index (BMI) of 26.5 ± 4.7 kg/m2. The average age was 62.7 (± 11.8) with equal gender distribution (52% women, n = 162). In 94.8% (n = 295) unintended weight loss led to MUST scoring. Patients with gastrointestinal tumors (25%, n = 78) and patients >65 years (22%, n = 68) were at higher risk. Furthermore, there was a significant association between surgery or chemotherapy within six months before survey and a MUST score ≥2 (OR = 3.6). Taste changes, dysphagia, and appetite loss were also particular risk factors (OR = 2.3–3.2). Young, female and normal-weight patients showed most interest in nutrition in cancer. However, only 38% (n = 118) had a nutritional counseling. Conclusion This study confirms that using the MUST score is a valid screening procedure to identify outpatients at risk of developing malnutrition. Here one in five was at high risk, but only 1% would have been detected by BMI alone. Therefore, an ongoing screening procedure with meaningful parameters should be urgently implemented into the clinical routine of cancer outpatients as recommended in international guidelines. KW - nutritional risk screening KW - malnutrition KW - nutritional counseling KW - oncology outpatients KW - MUST-Score KW - nutritional medical needs Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311284 SN - 2296-861X VL - 9 ER - TY - JOUR A1 - Hose, Dorothea A1 - Schreder, Martin A1 - Hefner, Jochen A1 - Bittrich, Max A1 - Danhof, Sophia A1 - Strifler, Susanne A1 - Krauth, Maria-Theresa A1 - Schoder, Renate A1 - Gisslinger, Bettina A1 - Einsele, Hermann A1 - Gisslinger, Heinz A1 - Knop, Stefan T1 - Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers JF - Journal of Cancer Research and Clinical Oncology N2 - Background The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited. Purpose To analyze the efficacy and safety of elo/pom/dex in a “real world” cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna. Findings We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia. Conclusion Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide. KW - multiple myeloma KW - elotuzumab KW - SLAMF7 KW - pomalidomide KW - lenalidomide Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235762 SN - 0171-5216 VL - 147 ER - TY - JOUR A1 - Hirsch, Hans H. A1 - Martino, Rodrigo A1 - Ward, Katherine N. A1 - Boeckh, Michael A1 - Einsele, Hermann A1 - Ljungman, Per T1 - Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for Diagnosis and Treatment of Human Respiratory Syncytial Virus, Parainfluenza Virus, Metapneumovirus, Rhinovirus, and Coronavirus JF - Clinical Infectious Diseases N2 - Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus. KW - hematopoietic KW - leukemia KW - transplantation KW - respiratory virus KW - bone marrow transplantation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124758 VL - 56 IS - 2 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Müller, Kerstin A1 - Notz, Quirin A1 - Hübsch, Martha A1 - Haas, Kirsten A1 - Horn, Anna A1 - Schmidt, Julia A1 - Heuschmann, Peter A1 - Maschmann, Jens A1 - Frosch, Matthias A1 - Deckert, Jürgen A1 - Einsele, Hermann A1 - Ertl, Georg A1 - Frantz, Stefan A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients JF - Scientific Reports N2 - Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19. KW - health care KW - public health KW - quality of life Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357174 VL - 13 ER - TY - JOUR A1 - Hellmann, Anna-Maria A1 - Lother, Jasmin A1 - Wurster, Sebastian A1 - Lutz, Manfred B. A1 - Schmitt, Anna Lena A1 - Morton, Charles Oliver A1 - Eyrich, Matthias A1 - Czakai, Kristin A1 - Einsele, Hermann A1 - Loeffler, Juergen T1 - Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus JF - Frontiers in Immunology N2 - Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus. However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus. For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus. Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host–pathogen interaction studies. KW - murine model KW - humans KW - Aspergillus fumigatus KW - innate immune response KW - fungal infection Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169926 VL - 8 IS - 1716 ER - TY - JOUR A1 - Hausmann, Stefan A1 - Brandt, Evelyn A1 - Köchel, Carolin A1 - Einsele, Hermann A1 - Bargou, Ralf C. A1 - Seggewiss-Bernhardt, Ruth A1 - Stühmer, Thorsten T1 - Loss of serum and glucocorticoid-regulated kinase 3 (SGK3) does not affect proliferation and survival of multiple myeloma cell lines JF - PLoS ONE N2 - Multiple myeloma (MM) is a generally fatal plasma cell cancer that often shows activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway. Targeted pharmacologic therapies, however, have not yet progressed beyond the clinical trial stage, and given the complexity of the PI3K/Akt signalling system (e.g. multiple protein isoforms, diverse feedback regulation mechanisms, strong variability between patients) it is mandatory to characterise its ramifications in order to better guide informed decisions about the best therapeutic approaches. Here we explore whether serum and glucocorticoid-regulated kinase 3 (SGK3), a potential downstream effector of PI3K, plays a role in oncogenic signalling in MM cells-either in concert with or independent of Akt. SGK3 was expressed in all MM cell lines and in all primary MM samples tested. Four MM cell lines representing a broad range of intrinsic Akt activation (very strong: MM. 1s, moderate: L 363 and JJN-3, absent: AMO-1) were chosen to test the effects of transient SGK3 knockdown alone and in combination with pharmacological inhibition of Akt, PI3K-p110\(\alpha\), or in the context of serum starvation. Although the electroporation protocol led to strong SGK3 depletion for at least 5 days its absence had no substantial effect on the activation status of potential downstream substrates, or on the survival, viability or proliferation of MM cells in all experimental contexts tested. We conclude that it is unlikely that SGK3 plays a significant role for oncogenic signalling in multiple myeloma. KW - Akt KW - phosphorylation KW - downstream KW - mechanism KW - pathway KW - isoforms KW - activation KW - cancer KW - inhibition KW - phosphatidylinositol 3-kinase/Akt Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148708 VL - 10 IS - 4 ER - TY - JOUR A1 - Hanfstein, Benjamin A1 - Lauseker, Michael A1 - Hehlmann, Rüdiger A1 - Saussele, Susanne A1 - Erben, Philipp A1 - Dietz, Christian A1 - Fabarius, Alice A1 - Proetel, Ulrike A1 - Schnittger, Susanne A1 - Haferlach, Claudia A1 - Krause, Stefan W. A1 - Schubert, Jörg A1 - Einsele, Hermann A1 - Hänel, Mathias A1 - Dengler, Jolanta A1 - Falge, Christiane A1 - Kanz, Lothar A1 - Neubauer, Andreas A1 - Kneba, Michael A1 - Stengelmann, Frank A1 - Pfreundschuh, Michael A1 - Waller, Cornelius F. A1 - Spiekerman, Karsten A1 - Baerlocher, Gabriela M. A1 - Pfirrmann, Markus A1 - Hasford, Joerg A1 - Hofmann, Wolf-Karsten A1 - Hochhaus, Andreas A1 - Müller, Martin C. T1 - Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib JF - Haematologica N2 - The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 x 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 x 109/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier: 00055874) KW - chronic myelogenous leukemia KW - polymerase-chain-reaktion KW - hybrid messenger RNA KW - chronic phase KW - cytogenetic response KW - no correlation KW - ABL gene KW - transcripts KW - breakpoint KW - survival Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115476 SN - 1592-8721 VL - 99 IS - 9 ER - TY - JOUR A1 - Gründahl, Marie A1 - Wacker, Beate A1 - Einsele, Hermann A1 - Heinz, Werner J. T1 - Invasive fungal diseases in patients with new diagnosed acute lymphoblastic leukaemia JF - Mycoses N2 - Background Patients with acute leukaemia have a high incidence of fungal infections. This has primarily been shown in acute myeloid leukaemia and is different for acute lymphoblastic leukaemia. Until now no benefit of mould active prophylaxis has been demonstrated in the latter population. Methods In this retrospective single‐centre study, we analysed the incidence, clinical relevance, and outcome of invasive fungal diseases (IFD) as well as the impact of antifungal prophylaxis for the first 100 days following the primary diagnosis of acute lymphoblastic leukaemia. Results In 58 patients a high rate of proven, probable, and possible fungal infections could be demonstrated with a 3.4%, 8.6%, and 17.2% likelihood, respectively. The incidence might be even higher, as nearly 40% of all patients had no prolonged neutropenia for more than 10 days, excluding those from the European Organization of Research and Treatment of cancer and the Mycoses Study Group criteria for probable invasive fungal disease. The diagnosed fungal diseases had an impact on the duration of hospitalisation, which was 13 days longer for patients with proven/probable IFD compared to patients with no signs of fungal infection. Use of antifungal prophylaxis did not significantly affect the risk of fungal infection. Conclusion Patients with acute lymphoblastic leukaemia are at high risk of acquiring an invasive fungal disease. Appropriate criteria to define fungal infections, especially in this population, and strategies to reduce the risk of infection, including antifungal prophylaxis, need to be further evaluated. KW - acute lymphoblastic leukaemia KW - fungal infection KW - galactomannan KW - incidence KW - mortality Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217844 VL - 63 IS - 10 SP - 1101 EP - 1106 ER - TY - JOUR A1 - Grunz, Jan-Peter A1 - Kunz, Andreas Steven A1 - Baumann, Freerk T. A1 - Hasenclever, Dirk A1 - Sieren, Malte Maria A1 - Heldmann, Stefan A1 - Bley, Thorsten Alexander A1 - Einsele, Hermann A1 - Knop, Stefan A1 - Jundt, Franziska T1 - Assessing osteolytic lesion size on sequential CT scans is a reliable study endpoint for bone remineralization in newly diagnosed multiple myeloma JF - Cancers N2 - Multiple myeloma (MM) frequently induces persisting osteolytic manifestations despite hematologic treatment response. This study aimed to establish a biometrically valid study endpoint for bone remineralization through quantitative and qualitative analyses in sequential CT scans. Twenty patients (seven women, 58 ± 8 years) with newly diagnosed MM received standardized induction therapy comprising the anti-SLAMF7 antibody elotuzumab, carfilzomib, lenalidomide, and dexamethasone (E-KRd). All patients underwent whole-body low-dose CT scans before and after six cycles of E-KRd. Two radiologists independently recorded osteolytic lesion sizes, as well as the presence of cortical destruction, pathologic fractures, rim and trabecular sclerosis. Bland–Altman analyses and Krippendorff’s α were employed to assess inter-reader reliability, which was high for lesion size measurement (standard error 1.2 mm) and all qualitative criteria assessed (α ≥ 0.74). After six cycles of E-KRd induction, osteolytic lesion size decreased by 22% (p < 0.001). While lesion size response did not correlate with the initial lesion size at baseline imaging (Pearson’s r = 0.144), logistic regression analysis revealed that the majority of responding osteolyses exhibited trabecular sclerosis (p < 0.001). The sum of osteolytic lesion sizes on sequential CT scans defines a reliable study endpoint to characterize bone remineralization. Patient level response is strongly associated with the presence of trabecular sclerosis. KW - multiple myeloma KW - bone remineralization KW - computed tomography KW - whole-body imaging Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-362526 SN - 2072-6694 VL - 15 IS - 15 ER - TY - JOUR A1 - Garitano-Trojaola, Andoni A1 - Sancho, Ana A1 - Götz, Ralph A1 - Eiring, Patrick A1 - Walz, Susanne A1 - Jetani, Hardikkumar A1 - Gil-Pulido, Jesus A1 - Da Via, Matteo Claudio A1 - Teufel, Eva A1 - Rhodes, Nadine A1 - Haertle, Larissa A1 - Arellano-Viera, Estibaliz A1 - Tibes, Raoul A1 - Rosenwald, Andreas A1 - Rasche, Leo A1 - Hudecek, Michael A1 - Sauer, Markus A1 - Groll, Jürgen A1 - Einsele, Hermann A1 - Kraus, Sabrina A1 - Kortüm, Martin K. T1 - Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia JF - Communications Biology N2 - The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML. KW - actin KW - acute myeloid leukaemia Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260709 VL - 4 IS - 1 ER - TY - JOUR A1 - Fuji, Shigeo A1 - Kapp, Markus A1 - Einsele, Hermann T1 - Monitoring of Pathogen-Specific T-Cell Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation JF - Frontiers in Immunology N2 - The clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) has been significantly improved during the last decades with regard to the reduction in organ failure, infection, and severe acute graft-versus-host disease. However, severe complications due to infectious diseases are still one of the major causes of morbidity and mortality after allogeneic HSCT, in particular in patients receiving haploidentical HSCT or cord blood transplant due to a slow and often incomplete immune reconstitution. In order to improve the immune control of pathogens without an increased risk of alloreactivity, adoptive immunotherapy using highly enriched pathogen-specificT cells offers a promising approach. In order to identify patients who are at high risk for infectious diseases, several monitoring assays have been developed with potential for the guidance of immunosuppressive drugs and adoptive immunotherapy in clinical practice. In this article, we aim to give a comprehensive overview regarding current developments of T-cell monitoring techniques focusing on T cells against viruses and fungi. In particular, we will focus on rather simple, fast, non-labor-intensive, cellular assays which could be integrated in routine clinical screening approaches. KW - immune reconstitution KW - virus KW - fungi KW - T cell KW - allogeneic stem cell transplantation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129250 VL - 4 IS - 276 ER - TY - JOUR A1 - Fuji, Shigeo A1 - Kapp, Markus A1 - Einsele, Hermann T1 - Alloreactivity of virus-specific T cells: possible implication of graft-versus-host disease and graft-versus-leukemia effects JF - Frontiers in Immunology N2 - Immune reconstitution of functional virus-specific T cells after allogeneic hematopoietic stem cell transplantation (HSCT) has been intensively investigated. However, the possible role of crossreactivity of these virus-specific T cells against allogeneic targets is still unclear. Theoretically, as in the field of organ transplantation, virus-specific T cells possess crossreactivity potential after allogeneic HSCT. Such crossreactivity is assumed to play a role in graft-versus-host disease and graft-versus-leukemia effects. In this article, we aim to give a comprehensive overview of current understanding about crossreactivity of virus-specific T cells. KW - mismatch KW - allogeneic stem cell transplantation KW - GVHD KW - HLA antigens KW - GVL KW - virus-specific T-cell Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129260 VL - 4 IS - 330 ER - TY - JOUR A1 - Fuj, Shigeo A1 - Kapp, Markus A1 - Einsele, Hermann T1 - Possible Implication of Bacterial Infection in Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation JF - Frontiers in Oncology N2 - Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T-cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT. KW - pathogen-associated molecular patterns KW - LPS KW - GVHD KW - bacterial infection KW - allogeneic hematopoietic stem cell transplantation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120674 SN - 2234-943X VL - 4 IS - 89 ER - TY - JOUR A1 - Fischer, Julia A1 - Knop, Stefan A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Keller, Daniela A1 - Löffler, Claudia T1 - The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: a prospective observational study JF - BMC Cancer N2 - Background Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions. Methods In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy. Results In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL. Conclusion This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept. KW - multiple myeloma KW - quality of life KW - participation in clinical trials KW - depression KW - observational Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300435 VL - 22 ER - TY - JOUR A1 - Engelhardt, Monika A1 - Terpos, Evangelos A1 - Kleber, Martina A1 - Gay, Francesca A1 - Wäsch, Ralph A1 - Morgan, Gareth A1 - Cavo, Michele A1 - van de Donk, Niels A1 - Beilhack, Andreas A1 - Bruno, Benedetto A1 - Johnsen, Hans Erik A1 - Hajek, Roman A1 - Driessen, Christoph A1 - Ludwig, Heinz A1 - Beksac, Meral A1 - Boccadoro, Mario A1 - Straka, Christian A1 - Brighen, Sara A1 - Gramatzki, Martin A1 - Larocca, Alessandra A1 - Lokhorst, Henk A1 - Magarotto, Valeria A1 - Morabito, Fortunato A1 - Dimopoulos, Meletios A. A1 - Einsele, Hermann A1 - Sonneveld, Pieter A1 - Palumbo, Antonio T1 - European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma JF - Haematologica N2 - Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high-versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B). KW - undetermined significance MGUS KW - stem-cell transplantation KW - multiparameter flow-cytpmetry KW - bortezomib plus dxamethasone KW - monoclonal gammopathy KW - randomized phase-3 trial KW - elderly patients KW - thalidomide maintenance KW - cereblon expression KW - autologous transplantation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117477 VL - 99 IS - 2 ER - TY - JOUR A1 - Einsele, Hermann A1 - Borghaei, Hossein A1 - Orlowski, Robert Z. A1 - Subklewe, Marion A1 - Roboz, Gail J. A1 - Zugmaier, Gerhard A1 - Kufer, Peter A1 - Iskander, Karim A1 - Kantarjian, Hagop M. T1 - The BiTE (Bispecific T‐Cell Engager) Platform: Development and Future Potential of a Targeted Immuno‐Oncology Therapy Across Tumor Types JF - Cancer N2 - Immuno‐oncology therapies engage the immune system to treat cancer. BiTE (bispecific T‐cell engager) technology is a targeted immuno‐oncology platform that connects patients' own T cells to malignant cells. The modular nature of BiTE technology facilitates the generation of molecules against tumor‐specific antigens, allowing off‐the‐shelf immuno‐oncotherapy. Blinatumomab was the first approved canonical BiTE molecule and targets CD19 surface antigens on B cells, making blinatumomab largely independent of genetic alterations or intracellular escape mechanisms. Additional BiTE molecules in development target other hematologic malignancies (eg, multiple myeloma, acute myeloid leukemia, and B‐cell non‐Hodgkin lymphoma) and solid tumors (eg, prostate cancer, glioblastoma, gastric cancer, and small‐cell lung cancer). BiTE molecules with an extended half‐life relative to the canonical BiTE molecules are also being developed. Advances in immuno‐oncology made with BiTE technology could substantially improve the treatment of hematologic and solid tumors and offer enhanced activity in combination with other treatments. KW - B cell KW - blinatumomab KW - hematologic malignancies KW - T cell KW - tumor‐specific antigen Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215426 VL - 126 IS - 14 SP - 3192 EP - 3201 ER - TY - JOUR A1 - Eckardt, Jan-Niklas A1 - Stasik, Sebastian A1 - Kramer, Michael A1 - Röllig, Christoph A1 - Krämer, Alwin A1 - Scholl, Sebastian A1 - Hochhaus, Andreas A1 - Crysandt, Martina A1 - Brümmendorf, Tim H. A1 - Naumann, Ralph A1 - Steffen, Björn A1 - Kunzmann, Volker A1 - Einsele, Hermann A1 - Schaich, Markus A1 - Burchert, Andreas A1 - Neubauer, Andreas A1 - Schäfer-Eckart, Kerstin A1 - Schliemann, Christoph A1 - Krause, Stefan W. A1 - Herbst, Regina A1 - Hänel, Mathias A1 - Frickhofen, Norbert A1 - Noppeney, Richard A1 - Kaiser, Ulrich A1 - Baldus, Claudia D. A1 - Kaufmann, Martin A1 - Rácil, Zdenek A1 - Platzbecker, Uwe A1 - Berdel, Wolfgang E. A1 - Mayer, Jiří A1 - Serve, Hubert A1 - Müller-Tidow, Carsten A1 - Ehninger, Gerhard A1 - Stölzel, Friedrich A1 - Kroschinsky, Frank A1 - Schetelig, Johannes A1 - Bornhäuser, Martin A1 - Thiede, Christian A1 - Middeke, Jan Moritz T1 - Loss-of-function mutations of BCOR are an independent marker of adverse outcomes in intensively treated patients with acute myeloid leukemia JF - Cancers N2 - Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation. KW - acute myeloid leukemia KW - BCOR KW - BCORL1 KW - loss-of-function KW - risk stratification KW - survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236735 SN - 2072-6694 VL - 13 IS - 9 ER -