TY - JOUR A1 - Englbrecht, Matthias A1 - Alten, Rieke A1 - Aringer, Martin A1 - Baerwald, Christoph G. A1 - Burkhardt, Harald A1 - Eby, Nancy A1 - Flacke, Jan-Paul A1 - Fliedner, Gerhard A1 - Henkemeiner, Ulf A1 - Hofmann, Michael W. A1 - Kleinert, Stefan A1 - Kneitz, Christian A1 - Krüger, Klaus A1 - Pohl, Christoph A1 - Schett, Georg A1 - Schmalzing, Marc A1 - Tausche, Anne-Kathrin A1 - Tony, Hans-Peter A1 - Wendler, Jörg T1 - New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis – Implications from the prospective multicenter VADERA II study JF - PLoS ONE N2 - Objectives To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. Methods In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. Results In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. Conclusions Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. Clinical trial registration number This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483). Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227246 VL - 14 ER - TY - JOUR A1 - Canbay, Ali A1 - Kälsch, Julia A1 - Neumann, Ursula A1 - Rau, Monika A1 - Hohenester, Simon A1 - Baba, Hideo A. A1 - Rust, Christian A1 - Geier, Andreas A1 - Heider, Dominik A1 - Sowa, Jan-Peter T1 - Non-invasive assessment of NAFLD as systemic disease—A machine learning perspective JF - PLoS ONE N2 - Background & aims Current non-invasive scores for the assessment of severity of non-alcoholic fatty liver disease (NAFLD) and identification of patients with non-alcoholic steatohepatitis (NASH) have insufficient performance to be included in clinical routine. In the current study, we developed a novel machine learning approach to overcome the caveats of existing approaches. Methods Non-invasive parameters were selected by an ensemble feature selection (EFS) from a retrospectively collected training cohort of 164 obese individuals (age: 43.5±10.3y; BMI: 54.1±10.1kg/m2) to develop a model able to predict the histological assessed NAFLD activity score (NAS). The model was evaluated in an independent validation cohort (122 patients, age: 45.2±11.75y, BMI: 50.8±8.61kg/m2). Results EFS identified age, γGT, HbA1c, adiponectin, and M30 as being highly associated with NAFLD. The model reached a Spearman correlation coefficient with the NAS of 0.46 in the training cohort and was able to differentiate between NAFL (NAS≤4) and NASH (NAS>4) with an AUC of 0.73. In the independent validation cohort, an AUC of 0.7 was achieved for this separation. We further analyzed the potential of the new model for disease monitoring in an obese cohort of 38 patients under lifestyle intervention for one year. While all patients lost weight under intervention, increasing scores were observed in 15 patients. Increasing scores were associated with significantly lower absolute weight loss, lower reduction of waist circumference and basal metabolic rate. Conclusions A newly developed model (http://CHek.heiderlab.de) can predict presence or absence of NASH with reasonable performance. The new score could be used to detect NASH and monitor disease progression or therapy response to weight loss interventions. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222249 VL - 14 ER - TY - JOUR A1 - Ernst, Jochen A1 - Faller, Hermann A1 - Koch, Uwe A1 - Brähler, Elmar A1 - Härter, Martin A1 - Schulz, Holger A1 - Weis, Joachim A1 - Köhler, Norbert A1 - Hinz, Andreas A1 - Mehnert, Anja T1 - Doctor’s recommendations for psychosocial care: Frequency and predictors of recommendations and referrals JF - PLoS ONE N2 - Background A significant number of oncological patients are heavily burdened by psychosocial stress. Doctors recommending or referring their patients to psycho-oncologists in the course of routine consultations can positively influence psycho-oncological care. The aim of this study was to analyze the frequency and predictors of such recommendations and to examine the use of these services by patients. Methods 4,020 cancer patients (mean age 58 years; 51% women) were evaluated in a multicenter, cross-sectional study in Germany. Data was gathered about doctors’ referral practices, patients’ utilization of psycho-oncological care services, and disease-related symptoms. The PHQ-9 depression scale and the GAD-7 anxiety scale were used to measure psychological burden. Descriptive data analysis was conducted on the basis of subgroup comparisons and multivariable analysis was done using binary logistical regression. Results 21.9% of the respondents reported having been given a recommendation or referral for psycho-oncological care by a doctor within the course of their cancer diagnosis and treatment. This comprises 29.5% of the patients identified by screening as being psychologically burdened. Nearly half of the patients who received a recommendation or referral (49.8%) acted on it. Predictors for seeking out psycho-oncological care included: patient desire (OR = 2.0), previous experience with psycho-oncological care (OR = 1.59), and female gender (OR = 1.57). Multivariable analysis indicated that patients’ level of psychological burden (depression, anxiety) had no effect on whether doctors gave them a recommendation or referral. Conclusions Along with examining the degree to which patients are burdened (e.g. using screening instruments), determining whether or not patients would like to receive psycho-oncological care is an important aspect of improving referral practices and, by extension, will allow important progress in the field of psycho-oncological care to be made. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227265 VL - 13 ER - TY - JOUR A1 - Musto, Pellegrino A1 - Engelhardt, Monika A1 - Caers, Jo A1 - Bolli, Niccolo' A1 - Kaiser, Martin A1 - van de Donk, Niels A1 - Terpos, Evangelos A1 - Broijl, Annemiek A1 - de Larrea, Carlos Fernández A1 - Gay, Francesca A1 - Goldschmidt, Hartmut A1 - Hajek, Roman A1 - Vangsted, Annette Juul A1 - Zamagni, Elena A1 - Zweegman, Sonja A1 - Cavo, Michele A1 - Dimopoulos, Meletios A1 - Einsele, Hermann A1 - Ludwig, Heinz A1 - Barosi, Giovanni A1 - Boccadoro, Mario A1 - Mateos, Maria-Victoria A1 - Sonneveld, Pieter A1 - San Miguel, Jesus T1 - 2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr. Jekyll and Mr. Hyde JF - Haematologica N2 - According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of “monoclonal gammopathy of undetermined significance-like”, in which patients never progress during their lifetimes, to “early multiple myeloma”, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a “split personality” makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371372 VL - 106 ER - TY - JOUR A1 - Maulana, Tengku Ibrahim A1 - Kromidas, Elena A1 - Wallstabe, Lars A1 - Cipriano, Madalena A1 - Alb, Miriam A1 - Zaupa, Cécile A1 - Hudecek, Michael A1 - Fogal, Birgit A1 - Loskill, Peter T1 - Immunocompetent cancer-on-chip models to assess immuno-oncology therapy JF - Advanced Drug Delivery Reviews N2 - The advances in cancer immunotherapy come with several obstacles, limiting its widespread use and benefits so far only to a small subset of patients. One of the underlying challenges remains to be the lack of representative nonclinical models that translate to human immunity and are able to predict clinical efficacy and safety outcomes. In recent years, immunocompetent Cancer-on-Chip models emerge as an alternative human-based platform that enables the integration and manipulation of complex tumor microenvironment. In this review, we discuss novel opportunities offered by Cancer-on-Chip models to advance (mechanistic) immuno-oncology research, ranging from design flexibility to multimodal analysis approaches. We then exemplify their (potential) applications for the research and development of adoptive cell therapy, immune checkpoint therapy, cytokine therapy, oncolytic virus, and cancer vaccines. KW - tumor-on-chip KW - microphysiological systems KW - immunotherapy KW - in vitro models KW - adoptive cell therapy KW - immune checkpoint inhibitor KW - cytokine therapy KW - oncolytic viruses KW - cancer vaccine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370493 VL - 173 ER - TY - JOUR A1 - Mateos, Maria-Victoria A1 - Dimopoulos, Meletios A. A1 - Cavo, Michele A1 - Suzuki, Kenshi A1 - Knop, Stefan A1 - Doyen, Chantal A1 - Lucio, Paulo A1 - Nagy, Zsolt A1 - Pour, Ludek A1 - Grosicki, Sebastian A1 - Crepaldi, Andre A1 - Liberati, Anna Marina A1 - Campbell, Philip A1 - Yoon, Sung-Soo A1 - Iosava, Genadi A1 - Fujisaki, Tomoaki A1 - Garg, Mamta A1 - Iida, Shinsuke A1 - Bladé, Joan A1 - Ukropec, Jon A1 - Pei, Huiling A1 - Van Rampelbergh, Rian A1 - Kudva, Anupa A1 - Qi, Ming A1 - San-Miguel, Jesus T1 - Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE JF - Clinical Lymphoma, Myeloma & Leukemia N2 - Background In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status. Patients and Methods Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients. Results Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%). Conclusion Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status. KW - CD38 KW - clinical study KW - efficacy KW - frail KW - monoclonal antibody Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370456 VL - 21 ER - TY - JOUR A1 - Luu, Maik A1 - Riester, Zeno A1 - Baldrich, Adrian A1 - Reichardt, Nicole A1 - Yuille, Samantha A1 - Busetti, Alessandro A1 - Klein, Matthias A1 - Wempe, Anne A1 - Leister, Hanna A1 - Raifer, Hartmann A1 - Picard, Felix A1 - Muhammad, Khalid A1 - Ohl, Kim A1 - Romero, Rossana A1 - Fischer, Florence A1 - Bauer, Christian A. A1 - Huber, Magdalena A1 - Gress, Thomas M. A1 - Lauth, Matthias A1 - Danhof, Sophia A1 - Bopp, Tobias A1 - Nerreter, Thomas A1 - Mulder, Imke E. A1 - Steinhoff, Ulrich A1 - Hudecek, Michael A1 - Visekruna, Alexander T1 - Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer JF - Nature Communications N2 - Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy. KW - tumour immunology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-309332 VL - 12 ER - TY - JOUR A1 - Lock, Johan F A1 - Reimer, Stanislaus A1 - Pietryga, Sebastian A1 - Jakubietz, Rafael A1 - Flemming, Sven A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Seyfried, Florian T1 - Managing esophagocutaneous fistula after secondary gastric pull-up: A case report JF - World Journal of Gastroenterology N2 - Background Gastric pull-up (GPU) procedures may be complicated by leaks, fistulas, or stenoses. These complications are usually managed by endoscopy, but in extreme cases multidisciplinary management including reoperation may be necessary. Here, we report a combined endoscopic and surgical approach to manage a failed secondary GPU procedure. Case summary A 70-year-old male with treatment-refractory cervical esophagocutaneous fistula with stenotic remnant esophagus after secondary GPU was transferred to our tertiary hospital. Local and systemic infection originating from the infected fistula was resolved by endoscopy. Hence, elective esophageal reconstruction with free-jejunal interposition was performed with no subsequent adverse events. Conclusion A multidisciplinary approach involving interventional endoscopists and surgeons successfully managed severe complications arising from a cervical esophago-cutaneous fistula after GPU. Endoscopic treatment may have lowered the perioperative risk to promote primary wound healing after free-jejunal graft interposition. KW - esophageal fistula KW - gastric fistula KW - esophageal stenosis KW - esophageal perforation KW - endoscopic vacuum therapy KW - free-jejunal graft KW - autogenous jejunum transplantation KW - case report Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369417 VL - 27 ER - TY - JOUR A1 - Liebers, Nora A1 - Duell, Johannes A1 - Fitzgerald, Donnacha A1 - Kerkhoff, Andrea A1 - Noerenberg, Daniel A1 - Kaebisch, Eva A1 - Acker, Fabian A1 - Fuhrmann, Stephan A1 - Leng, Corinna A1 - Welslau, Manfred A1 - Chemnitz, Jens A1 - Middeke, Jan-Moritz A1 - Weber, Thomas A1 - Holtick, Udo A1 - Trappe, Ralf A1 - Pfannes, Roald A1 - Liersch, Ruediger A1 - Spoer, Christian A1 - Fuxius, Stefan A1 - Gebauer, Niklas A1 - Caillé, Léandra A1 - Geer, Thomas A1 - Koenecke, Christian A1 - Keller, Ulrich A1 - Claus, Rainer A1 - Mougiakakos, Dimitrios A1 - Mayer, Stephanie A1 - Huettmann, Andreas A1 - Pott, Christiane A1 - Trummer, Arne A1 - Wulf, Gerald A1 - Brunnberg, Uta A1 - Bullinger, Lars A1 - Hess, Georg A1 - Mueller-Tidow, Carsten A1 - Glass, Bertram A1 - Lenz, Georg A1 - Dreger, Peter A1 - Dietrich, Sascha T1 - Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas JF - Blood Advances N2 - The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369173 VL - 5 ER - TY - JOUR A1 - Leich, Ellen A1 - Schreder, Martin A1 - Pischimarov, Jordan A1 - Stühmer, Thorsten A1 - Steinbrunn, Torsten A1 - Rudelius, Martina A1 - Brünnert, Daniela A1 - Chatterjee, Manik A1 - Langer, Christian A1 - Keppler, Sarah A1 - Heredia-Guerrero, Sofia Catalina A1 - Einsele, Hermann A1 - Knop, Stefan A1 - Bargou, Ralf Christian A1 - Rosenwald, Andreas T1 - Novel molecular subgroups within the context of receptor tyrosine kinase and adhesion signalling in multiple myeloma JF - Blood Cancer Journal N2 - No abstract available. KW - cancer genetics KW - cancer genomics KW - cancer therapy KW - myeloma KW - translational research Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363410 VL - 11 ER - TY - JOUR A1 - Lauruschkat, Chris D. A1 - Page, Lukas A1 - Etter, Sonja A1 - Weis, Philipp A1 - Gamon, Florian A1 - Kraus, Sabrina A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Loeffler, Juergen T1 - T-Cell Immune Surveillance in Allogenic Stem Cell Transplant Recipients: Are Whole Blood–Based Assays Ready to Challenge ELISPOT? JF - Open Forum Infectious Diseases N2 - We compared the feasibility of 4 cytomegalovirus (CMV)- and Aspergillus-reactive T-cell immunoassay protocols in allogenic stem cell transplant recipients. While enzyme-linked immunospot performed best overall, logistically advantageous whole blood–based assays performed comparably in patients with less severe lymphocytopenia. CMV-induced interferon-gamma responses correlated strongly across all protocols and showed high concordance with serology. KW - immunoassay KW - biomarker KW - aspergillosis KW - cytomegalovirus KW - T cells KW - cytokines KW - flow cytometry KW - ELISPOT Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363164 VL - 8 ER - TY - JOUR A1 - Giles, James A. A1 - Greenhalgh, Andrew D. A1 - Denes, Adam A1 - Nieswandt, Bernhard A1 - Coutts, Graham A1 - McColl, Barry W. A1 - Allan, Stuart M. T1 - Neutrophil infiltration to the brain is platelet-dependent, and is reversed by blockade of platelet GPIbα JF - Immunology N2 - Neutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non-microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue-specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up-regulation of CXCL-1 (2·4-fold) and CCL5 (1·4-fold) acting as a compensatory mechanism in platelet-reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44%) in platelet-mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury. KW - brain KW - inflammation KW - neuroinflammation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233048 VL - 154 ER - TY - JOUR A1 - Duell, Johannes A1 - Lammers, Philip E. A1 - Djuretic, Ivana A1 - Chunyk, Allison G. A1 - Alekar, Shilpa A1 - Jacobs, Ira A1 - Gill, Saar T1 - Bispecific Antibodies in the Treatment of Hematologic Malignancies JF - Clinical Pharmacology & Therapeutics N2 - Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226392 VL - 106 ER - TY - JOUR A1 - Kampf, Thomas A1 - Reiter, Theresa A1 - Bauer, Wolfgang Rudolf T1 - An analytical model which determines the apparent T1 for Modified Look-Locker Inversion Recovery – Analysis of the longitudinal relaxation under the influence of discontinuous balanced (classical MOLLI) and spoiled gradient echo readouts JF - Zeitschrift für Medizinische Physik N2 - Quantitative nuclear magnetic resonance imaging (MRI) shifts more and more into the focus of clinical research. Especially determination of relaxation times without/and with contrast agents becomes the foundation of tissue characterization, e.g. in cardiac MRI for myocardial fibrosis. Techniques which assess longitudinal relaxation times rely on repetitive application of readout modules, which are interrupted by free relaxation periods, e.g. the Modified Look-Locker Inversion Recovery = MOLLI sequence. These discontinuous sequences reveal an apparent relaxation time, and, by techniques extrapolated from continuous readout sequences, a putative real T1 is determined. What is missing is a rigorous analysis of the dependence of the apparent relaxation time on its real partner, readout sequence parameters and biological parameters as heart rate. This is provided in this paper for the discontinuous balanced steady state free precession (bSSFP) and spoiled gradient echo readouts. It turns out that the apparent longitudinal relaxation rate is the time average of the relaxation rates during the readout module, and free relaxation period. Knowing the heart rate our results vice versa allow to determine the real T1 from its measured apparent partner. T2 - Ein analytisches Modell, das die apparente T1 Zeit für Modfied Look-Locker Inversion Recovery bestimmt-Analyse der longitudinalen Relaxation unter dem Einfluss diskontinuierlicher balanced (klassische MOLLI) und spoiled gradient echo readouts KW - longitudinal relaxation KW - T1 KW - T2 KW - Lock Locker KW - MOLLI KW - balanced steady state free precession KW - spoiled gradient echo Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325498 VL - 28 ER - TY - JOUR A1 - Hoenigl, Martin A1 - Orasch, Thomas A1 - Faserl, Klaus A1 - Prattes, Juergen A1 - Loeffler, Juergen A1 - Springer, Jan A1 - Gsaller, Fabio A1 - Reischies, Frederike A1 - Duettmann, Wiebke A1 - Raggam, Reinhard B. A1 - Lindner, Herbert A1 - Haas, Hubertus T1 - Triacetylfusarinine C: A urine biomarker for diagnosis of invasive aspergillosis JF - Journal of Infection N2 - Objectives Early diagnosis of invasive aspergillosis (IA) remains challenging, with available diagnostics being limited by inadequate sensitivities and specificities. Triacetylfusarinine C, a fungal siderophore that has been shown to accumulate in urine in animal models, is a potential new biomarker for diagnosis of IA. Methods We developed a method allowing absolute and matrix-independent mass spectrometric quantification of TAFC. Urine TAFC, normalized to creatinine, was determined in 44 samples from 24 patients with underlying hematologic malignancies and probable, possible or no IA according to current EORTC/MSG criteria and compared to other established biomarkers measured in urine and same-day blood samples. Results TAFC/creatinine sensitivity, specificity, positive and negative likelihood ratio for probable versus no IA (cut-off ≥ 3) were 0.86, 0.88, 6.86, 0.16 per patient. Conclusion For the first time, we provide proof for the occurrence of TAFC in human urine. TAFC/creatinine index determination in urine showed promising results for diagnosis of IA offering the advantages of non-invasive sampling. Sensitivity and specificity were similar as reported for GM determination in serum and bronchoalveolar lavage, the gold standard mycological criterion for IA diagnosis. KW - aspergillosis KW - biomarker KW - diagnosis KW - siderophore KW - urine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320939 VL - 78 ER - TY - JOUR A1 - Estes, Chris A1 - Anstee, Quentin M. A1 - Arias-Loste, Maria Teresa A1 - Bantel, Heike A1 - Bellentani, Stefano A1 - Caballeria, Joan A1 - Colombo, Massimo A1 - Craxi, Antonio A1 - Crespo, Javier A1 - Day, Christopher P. A1 - Eguchi, Yuichiro A1 - Geier, Andreas A1 - Kondili, Loreta A. A1 - Kroy, Daniela C. A1 - Lazarus, Jeffrey V. A1 - Loomba, Rohit A1 - Manns, Michael P. A1 - Marchesini, Giulio A1 - Nakajima, Atsushi A1 - Negro, Francesco A1 - Petta, Salvatore A1 - Ratziu, Vlad A1 - Romero-Gomez, Manuel A1 - Sanyal, Arun A1 - Schattenberg, Jörn M. A1 - Tacke, Frank A1 - Tanaka, Junko A1 - Trautwein, Christian A1 - Wei, Lai A1 - Zeuzem, Stefan A1 - Ravazi, Homie T1 - Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030 JF - Journal of Hepatology N2 - Background & Aims Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. Methods A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. Results If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0–30%), between 2016–2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15–56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population. Conclusions NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. Lay summary Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years. KW - burden of disease KW - cardiovascular disease KW - health care resource utilization KW - metabolic syndrome KW - NAFLD KW - NASH KW - cirrhosis KW - HCC KW - diabetes mellitus KW - obesity Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227286 VL - 69 ER - TY - JOUR A1 - Heimann, Sebastian M. A1 - Penack, Olaf A1 - Heinz, Werner J. A1 - Rachow, Tobias A1 - Egerer, Gerlinde A1 - Kessel, Johanna A1 - Claßen, Annika Y. A1 - Vehreschild, Jörg Janne T1 - Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals JF - International Journal of Infectious Diseases N2 - Objectives Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. Methods We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. Results Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD. Conclusions Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species. KW - invasive fungal infection KW - neutropenia KW - posaconazole serum level KW - clinical effectiveness KW - high-risk patient Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319567 VL - 83 ER - TY - JOUR A1 - Mueller, Dolores A1 - Jung, Kathrin A1 - Winter, Manuel A1 - Rogoll, Dorothee A1 - Melcher, Ralph A1 - Kulozik, Ulrich A1 - Schwarz, Karin A1 - Richling, Elke T1 - Encapsulation of anthocyanins from bilberries – Effects on bioavailability and intestinal accessibility in humans JF - Food Chemistry N2 - Anthocyanins are flavonoids that have been suggested to provide beneficial health effects. The biological activity of anthocyanins is influenced by their pharmacokinetic properties, but anthocyanins are associated with limited bioavailability in humans. In the presented study, we investigated how the encapsulation of bilberry extract (BE), a source of anthocyanins, with either whey protein or citrus pectin influences the bioavailability and intestinal accessibility of anthocyanins in humans. We performed an intervention study that analyzed anthocyanins and their degradation products in the urine, plasma, and ileal effluent of healthy volunteers and ileostomists (subjects without an intact colon). We were able to show, that whey protein encapsulation modulated short-term bioavailability and that citrus pectin encapsulation increased intestinal accessibility during passage through the small intestine and modulated the formation of the degradation product phloroglucinol aldehyde (PGAL) in human plasma. KW - anthocyanins KW - encapsulation KW - human intervention KW - bioavailability KW - phloroglucinol aldehyde Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224247 VL - 248 ER - TY - JOUR A1 - Stein, Anthony S. A1 - Kantarjian, Hagop A1 - Gökbuget, Nicola A1 - Bargou, Ralf A1 - Litzow, Mark R. A1 - Rambaldi, Alessandro A1 - Ribera, Josep-Maria A1 - Zhang, Alicia A1 - Zimmerman, Zachary A1 - Zugmaier, Gerhard A1 - Topp, Max S. T1 - Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation JF - Biology of Blood and Marrow Transplantation N2 - Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population. KW - blinatumomab KW - Philadelphia chromosome-negative B precursor ALL KW - efficacy KW - safety KW - allogeneic hematopoietic stem cell transplantation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239510 VL - 25 ER - TY - JOUR A1 - Weiss, Esther A1 - Ziegler, Sabrina A1 - Fliesser, Mirjam A1 - Schmitt, Anna-Lena A1 - Hünniger, Kerstin A1 - Kurzai, Oliver A1 - Morton, Charles-Oliver A1 - Einsele, Hermann A1 - Loeffler, Juergen T1 - First Insights in NK—DC Cross-Talk and the Importance of Soluble Factors During Infection With Aspergillus fumigatus JF - Frontiers in Cellular and Infection Microbiology N2 - Invasive aspergillosis (IA) is an infectious disease caused by the fungal pathogen Aspergillus fumigatus that mainly affects immunocompromised hosts. To investigate immune cell cross-talk during infection with A. fumigatus, we co-cultured natural killer (NK) cells and dendritic cells (DC) after stimulation with whole fungal structures, components of the fungal cell wall, fungal lysate or ligands for distinct fungal receptors. Both cell types showed activation after stimulation with fungal components and were able to transfer activation signals to the counterpart not stimulated cell type. Interestingly, DCs recognized a broader spectrum of fungal components and thereby initiated NK cell activation when those did not recognize fungal structures. These experiments highlighted the supportive function of DCs in NK cell activation. Furthermore, we focused on soluble DC mediated NK cell activation and showed that DCs stimulated with the TLR2/Dectin-1 ligand zymosan could maximally stimulate the expression of CD69 on NK cells. Thus, we investigated the influence of both receptors for zymosan, Dectin-1 and TLR2, which are highly expressed on DCs but show only minimal expression on NK cells. Specific focus was laid on the question whether Dectin-1 or TLR2 signaling in DCs is important for the secretion of soluble factors leading to NK cell activation. Our results show that Dectin-1 and TLR2 are negligible for NK cell activation. We conclude that besides Dectin-1 and TLR2 other receptors on DCs are able to compensate for the missing signal. KW - natural killer cells KW - dendritic cells KW - NK-DC cross-talk KW - Aspergillus fumigatus KW - soluble factors KW - innate immunity Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233565 VL - 8 ER -