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Patient-derived xenograft (PDX) models have emerged as versatile preclinical platforms for investigation of functional pathomechanisms in myelodysplastic syndromes (MDS) and other myeloid neoplasms. However, despite increasingly improved methodology, engraftment efficiencies frequently remain low. Humanized three-dimensional scaffold models (ossicle xenotransplantation models) in immunocompromised mice have recently been found to enable improved engraftment rates of healthy and malignant human hematopoiesis. We therefore interrogated the feasibility of using four different three-dimensional ossicle-based PDX models for application with primary MDS samples. In a fully standardized comparison, we evaluated scaffold materials such as Gelfoam, extracellular matrix (ECM), and human or xenogenous bone substance in comparison to intrafemoral (IF) co-injection of bone marrow (BM)-derived mesenchymal stromal cells (MSCs) and CD34

Zusammenfassung Ziel der Studie Mobbing am Arbeitsplatz gilt als interpersoneller Stressfaktor. Beruflicher Stress und mentale Gesundheit bei Ärztinnen und Ärzten rücken zunehmend in den Fokus der Öffentlichkeit. Inwiefern Mobbing dabei eine Rolle spielt ist noch kaum untersucht. Die Studie soll daher Daten zu Prävalenz von Mobbing unter KlinikärztInnen in Deutschland und möglichen Zusammenhängen mit beruflichem Stress und mentaler Gesundheit liefern. Methoden Im Rahmen zweier Querschnittstudien wurden 692 KlinikärztInnen des Fachgebietes Psychiatrie/Psychotherapie (P/PT) und 667 KlinikärztInnen der Intensivmedizin (IM) auf Kongressen befragt. Zum Einsatz kamen standardisierte Fragebögen zu Mobbingerfahrung, Berufsstress und mentaler Gesundheit (Einzelitem aus dem COPSOQ, BDI-II, ERI, MBI). Ergebnisse Mobbing erlebten 4,6% (N=61) der Befragten. In der Tendenz sind IM und Frauen häufiger betroffen (nicht signifikant) und es zeigten sich Korrelationen mit Berufsstress (ERI), Overcommitment (OC), Emotionaler Erschöpfung (MBI) und Depressivität (BDI-II). Schlussfolgerung Unsere Daten an einer großen Kohorte von Ärztinnen und Ärzten in Fachgebieten mit unterschiedlichem Belastungsprofil zeigen, dass ein nicht unerheblicher Anteil von Mobbing betroffen ist und Mobbing in Zusammenhang mit dem Erleben von Berufsstress sowie Beeinträchtigungen der mentalen Gesundheit stehen. Daraus lassen sich Implikationen zu institutionellen und individuellen Präventions- und Unterstützungsangeboten ableiten.

Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

COVID-19 in patients with hematological diseases is associated with a high mortality. Moreover, preventive vaccination demonstrated reduced efficacy and the knowledge on influencing factors is limited. In this single-center study, antibody levels of the SARS-CoV-2 spike protein were measured ≥ 2 weeks after 2nd COVID-19 vaccination with a concentration ≥ 0.8 U/mL considered positive. Between July and October 2021, in a total of 373 patients (median age 64 years, 44% women) with myeloid neoplasms (n = 214, 57%), lymphoid neoplasms (n = 124, n = 33%), and other diseases (n = 35, 10%), vaccination was performed with BNT162b2 (BioNTech), mRNA-1273 (Moderna), ChADOx1 (AstraZeneca), or a combination. A total of 229 patients (61%) were on active therapy within 3 months prior vaccination and 144 patients (39%) were previously treated or treatment naïve. Vaccination-related antibody response was negative in 56/373 patients (15%): in 39/124 patients with lymphoid neoplasms, 13/214 with myeloid neoplasms, and 4/35 with other diseases. Active treatment per se was not correlated with negative response. However, rituximab and BTK inhibitor treatment were correlated significantly with a negative vaccination response, whereas younger age and chronic myeloid leukemia (CML) disease were associated with positive response. In addition, 5 of 6 patients with myeloproliferative neoplasm (MPN) and negative vaccination response were on active treatment with ruxolitinib. In conclusion, a remarkable percentage of patients with hematological diseases had no response after 2nd COVID-19 vaccination. Multivariable analysis revealed important factors associated with response to vaccination. The results may serve as a guide for better protection and surveillance in this vulnerable patient cohort.

Bullying in the workplace is considered an interpersonal stress factor. Occupational stress and mental health among physicians is increasingly becoming the focus of public attention. The extent to which mobbing plays a role in this has hardly been investigated yet. The aim of this study is to provide data on the prevalence of bullying among hospital physicians in Germany and possible correlations with occupational stress and mental health.Within the framework of two cross-sectional studies, 692 hospital physicians in the field of psychiatry/psychotherapy (P/PT) and 667 hospital physicians in intensive care (IM) were interviewed at conferences. Standardized questionnaires on mobbing experience, occupational stress and mental health (single item from COPSOQ, BDI-II, ERI, MBI) were used.Bullying was experienced by 4.6% (n=61) of the respondents. IM and women physicians were more often affected (not significant) and correlations with occupational stress (ERI), overcommitment (OC), emotional exhaustion (MBI) and depression (BDI-II) were found.Our data on a large cohort of physicians in specialties with different exposure profiles show that a relevant proportion is affected by bullying and that bullying is related to the experience of occupational stress as well as mental health impairments. From this, implications for institutional and individual prevention and support services can be derived.Mobbing am Arbeitsplatz gilt als interpersoneller Stressfaktor. Beruflicher Stress und mentale Gesundheit bei Ärztinnen und Ärzten rücken zunehmend in den Fokus der Öffentlichkeit. Inwiefern Mobbing dabei eine Rolle spielt ist noch kaum untersucht. Die Studie soll daher Daten zu Prävalenz von Mobbing unter KlinikärztInnen in Deutschland und möglichen Zusammenhängen mit beruflichem Stress und mentaler Gesundheit liefern.Im Rahmen zweier Querschnittstudien wurden 692 KlinikärztInnen des Fachgebietes Psychiatrie/Psychotherapie (P/PT) und 667 KlinikärztInnen der Intensivmedizin (IM) auf Kongressen befragt. Zum Einsatz kamen standardisierte Fragebögen zu Mobbingerfahrung, Berufsstress und mentaler Gesundheit (Einzelitem aus dem COPSOQ, BDI-II, ERI, MBI).Mobbing erlebten 4,6% (N=61) der Befragten. In der Tendenz sind IM und Frauen häufiger betroffen (nicht signifikant) und es zeigten sich Korrelationen mit Berufsstress (ERI), Overcommitment (OC), Emotionaler Erschöpfung (MBI) und Depressivität (BDI-II).Unsere Daten an einer großen Kohorte von Ärztinnen und Ärzten in Fachgebieten mit unterschiedlichem Belastungsprofil zeigen, dass ein nicht unerheblicher Anteil von Mobbing betroffen ist und Mobbing in Zusammenhang mit dem Erleben von Berufsstress sowie Beeinträchtigungen der mentalen Gesundheit stehen. Daraus lassen sich Implikationen zu institutionellen und individuellen Präventions- und Unterstützungsangeboten ableiten.

The hypomethylating agent 5-azacytidine (5-Aza) is a standard-of-care for patients with higher-risk myelodysplastic syndromes (MDS). Although an initial response is induced in approximately 50% of 5-Aza treated patients, subsequent relapse is almost certain. Recently, inhibitors of anti-apoptotic BCL-2 protein family members have shown therapeutic potential in acute myeloid leukemia (AML) and higher-risk MDS. Alvocidib (Alv), a CDK9 inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has shown anti-leukemic effects in a phase 1 study of patients with AML (Lee DJ et al, Expert Opin Investig Drugs 2019; Zeidner JF et al, Leuk Res 2015). A phase 1b/2 study with Alv and 5-Aza or decitabine in higher-risk patients with MDS was recently completed (NCT03593915); however, biomarkers for response to the Alv and 5-Aza combination are not well characterized. To identify potential biomarkers of response, we performed a comprehensive in vitro assessment of Alv and 5-Aza combination using a clinically well-characterized cohort of n=45 higher-risk patients with MDS and n=11 healthy controls (HC). CD34+ cells were purified from bone marrow (BM) aspirates using positive selection with MACS beads. CD34+ cells of HC were obtained from femur head replacement surgery bone specimens. After 4 days of expansion in SFEM II medium containing StemSpan Myeloid Expansion Supplement, cells were treated with 5-Aza for 48h, Alv for 24h or their combination (5-Aza for 48h followed by Alv for 24h). Cell viability was determined using CellTiter-Glo (CTG) and Annexin-V apoptosis assays. MCL-1 dependency of MDS samples was assessed using MS1 peptide-based assay. Recurrent myeloid neoplasia mutations in 67 genes were assessed in BM mononuclear cells using NGS panel deep sequencing. The combination of 5-Aza+Alv had an additive cytotoxic effect on CD34+ MDS cells in CTG assay (median cell viability = 74%, 73.8% and 55% for 5-Aza, Alv and combination respectively, p Citation Format: Vladimir Ryabov, Nanni Schmitt, Qingyu Xu, Alexander Streuer, Johann-Christoph Jann, Alina Wein, Eva Altrock, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Ahmed Jawhar, Ali Darwich, Patrick Wuchter, Christel Weiss, Georgia Metzgeroth, Jason M. Foulks, Laurenz Steiner, Mohamad Jawhar, Wolf-Karsten Hofmann, Daniel Nowak. Mutations in the ASXL1 and ZRSR2 genes are associated with the response to the combination of alvocidib and 5-azacytidine in higher-risk myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6257.

Background: In general, patients with hematological diseases are predisposed to develop infections. Severe COVID-19 infection associated with high mortality is more likely in these patient cohorts compared to the general population. Due to immune defects related to the primary disease and/or to immunosuppressive treatment regimes, vaccination efficacy may be reduced in patients with hematological diseases. So far, data on this area are limited. Aim: To evaluate vaccination-related antibody response to BNT162b2, mRNA-1273, and ChADOx1 in patients with hematological disorders. Patients and methods: In this interim analysis of a prospective, observational single-center study, we report antibody levels at least 2 weeks after COVID-19 vaccination. A FDA/CE approved electrochemiluminescent assay (ECLIA) (Elecsys®, Roche, Mannheim, Germany) was used to quantify antibodies, pan Ig (including IgG) against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The assay has a measurement range of 0.4 to 250 U/mL, with a concentration ≥0.8 U/ml considered as positive. Data were analyzed for patients without detection of anti-N (nucleocapsid) SARS-CoV-2 antibody (i.e., without having passed SARS-CoV-2 infection). All tests were performed according to the manufacturer's instructions in an accredited laboratory at the University Hospital Mannheim. Results: Between February 2021 and July 2021, a total of 175 patients with hematological diseases were included in this study. The median age was 66 years (range 21-90 years), and 81 (46.3%) were female. The antibody levels were measured at least 14 days (median, 58 days) after the 2 nd vaccination. The patients were vaccinated with BNT162b2 (BioNTech, n=134), mRNA-1273 (Moderna, n=19), ChADOx1 (AstraZeneca, n=12), or got the first vaccination with BNT162b2 and the second with ChADOx1 (n=10). Overall, 145/175 (82.9%) were diagnosed with a malignant hematological disease (myeloid neoplasms, n=108; lymphoid neoplasms, n=37) and 30/175 with a non-malignant hematological disease (autoimmune disease, n=24; benign, n=6). 124 patients (70.1%) were on active therapy, and 51 patients (29.1%) were previously treated or treatment naïve. Correlation to specific therapies is ongoing and will be presented. In general, vaccination-related antibody response was positive (≥0.8 U/mL) in 148/175 (84.6%) patients with a median level of 208.6 U/mL (range 0.8-250.00) and negative ( In myeloid neoplasms, patients with classical myeloproliferative neoplasm (MPN) had the highest negative result for antibodies with 4/7 (57.1%) followed by myelodysplastic syndrome (MDS) 2/7 (28.6%). Interestingly, all patients with chronic myeloid leukemia (CML) had a measurable immune response. In lymphoid neoplasms, patients with low-grade non-hodgkin lymphoma (NHL) (predominately chronic lymphocytic leukemia, CLL) had the highest negative antibody result 13/16 (81.3%) followed by high-grade NHL 4/8 (50%; predominately diffuse large b-cell lymphoma, DLBCL). In non-malignant hematological diseases, only patients with autoimmune diseases had a negative result. Conclusion: A remarkable group of patients with hematological disease were measured with no or low immune response after 2 nd COVID-vaccination, especially those with low-grade NHL, MDS and autoimmune disease. It seems that the percentage of patients with MPN and low response is less critical. No problems appeared in CML patients. Further explorations are needed with focus on potential risk of COVID infections despite full vaccination: The potential of 3 rd booster vaccination should be explored within clinical trials. Disclosures Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Kreil: Novartis: Research Funding. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Jawhar: Takeda: Honoraria, Other: Travel support; Blueprint Medicines: Honoraria; Stemline: Consultancy, Honoraria; Celgene: Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.