Refine
Has Fulltext
- yes (95)
Is part of the Bibliography
- yes (95)
Year of publication
Document Type
- Journal article (95)
Language
- English (95) (remove)
Keywords
- multiple myeloma (23)
- Aspergillus (6)
- cytokines (5)
- Aspergillus fumigatus (4)
- T cells (4)
- allogeneic stem cell transplantation (4)
- fungal infection (4)
- immunotherapy (4)
- refractory (4)
- relapse (4)
- CXCR4 (3)
- NK cells (3)
- cancer (3)
- invasive aspergillosis (3)
- medicine (3)
- survival (3)
- 18F-FDG PET/CT (2)
- B cells (2)
- Bone marrow transplantation (2)
- CCL4 (2)
- COVID-19 (2)
- GVHD (2)
- Multiple myeloma (2)
- T cell (2)
- adaptive immunity (2)
- amplicon sequencing (2)
- aspergillus fumigatus (2)
- autologous transplantation (2)
- biomarker (2)
- cell staining (2)
- dendritic cells (2)
- extramedullary disease (2)
- galactomannan (2)
- immunoassay (2)
- inflammation (2)
- lenalidomide (2)
- leukemia (2)
- pomalidomide (2)
- quality of life (2)
- regulatory T cells (2)
- stem-cell transplantation (2)
- theranostics (2)
- transplantation (2)
- 11C-Methionine PET/CT (1)
- 68Ga-Pentixafor PET/CT (1)
- ABL gene (1)
- AKT-signaling (1)
- AML (1)
- Active disease (1)
- Acute lymphoblastic leukemia (1)
- Acute myeloid leukemia (1)
- Acute myeloid leukemia (AML) (1)
- Akt (1)
- Allogeneic stem cell transplantation (1)
- Allogeneic transplantation (1)
- Alpha therapy (1)
- Ascaris lumbricoides (1)
- Autoimmune diseases (1)
- B cell (1)
- B cell receptors (1)
- BCOR (1)
- BCORL1 (1)
- BRAF mutation (1)
- Bacteria (1)
- Bioluminescence (1)
- Bioluminescence imaging (1)
- Blood (1)
- Bone marrow cells (1)
- Bone marrow transplantantation (1)
- Bone-marrow-transplantation (1)
- C-X-C motif chemokine receptor 4 (1)
- CAPA (1)
- CAR T cell (1)
- CAR T cells (1)
- CAR-T-cell (1)
- CCL3 (1)
- CCL5 (1)
- CD11b+ myeloid cells (1)
- CD319 (1)
- CD38 (1)
- CD4(+) (1)
- CMV (1)
- CS1 (1)
- CXCR4/SDF-1 (1)
- Cancer genetics (1)
- Cancer risk factors (1)
- Cancer treatment (1)
- Candida albicans (1)
- Capicua transcriptional repressor (1)
- Chronic lymphoblastic leukemia (1)
- Chronic myeloid leukaemia (1)
- Chronic myeloid leukemia (1)
- Conditioning regimen (1)
- Dara-KDT-P(A)CE (1)
- Dendritische Zelle (1)
- Drug resistance (1)
- European experts (1)
- European group (1)
- Expression (1)
- Extramedullary disease (1)
- FDG (1)
- FDG PET/CT (1)
- Factor receptor (1)
- Fludarabine (1)
- Fludarabine-treosulfan (FT) (1)
- Fungal (1)
- Fusarium (1)
- GVL (1)
- Genome-wide association studies (1)
- Graft versus Tumor (1)
- Graft-versus-host disease (1)
- Graft-versus-leukemia (1)
- Gruppo-italiano (1)
- GvHD (1)
- HBV (1)
- HCV (1)
- HD (1)
- HIV (1)
- HLA antigens (1)
- HLA-E matching (1)
- HSTC outcome (1)
- Haematology (1)
- Hematopoietic stem cell transplantation (1)
- Hepatitis B virus (1)
- Hepatitis B virus reactivation (1)
- Herpes simplex virus (1)
- Hsp90 (1)
- Human immunodefiency virus (1)
- Immune receptor signaling (1)
- Infections (1)
- Infectious Diseases (1)
- Influenzae type B (1)
- Interleukin-2 (1)
- Invasive Aspergillosis (1)
- KRAS (1)
- Killer cell immunoglobulin-like receptors (1)
- LATE DEATHS (1)
- LPS (1)
- Late mortality (1)
- Low-dose acyclovir (1)
- Lymphomas (1)
- MAPKAPK2 (1)
- MEK/ERK-signaling (1)
- MIP-1β (1)
- MOR202 (1)
- MTB (1)
- MTX (1)
- MUST-Score (1)
- Medizin (1)
- Midollo-Osseo (1)
- Minor histocompatibility antigen mismatch transplantation (1)
- Molecularly targeted therapy (1)
- Multivariate analysis (1)
- Myeloma (1)
- NF-κB/NFAT reporter cells (1)
- NFkB-relatedgenes (1)
- NK-cells (1)
- PET (1)
- PET/CT (1)
- Pneumocystis-carinii-pneumonia (1)
- Pom‐PAD‐Dara (1)
- Prognostic scoring system (1)
- R-CHOP (1)
- RNA extraction (1)
- ROR1 (1)
- Regulatory-cells (1)
- Respiratory syncytial virus (1)
- Rheumatoid arthritis (1)
- Rhizopus (1)
- Risk factors (1)
- Ruxolitinib (1)
- SLAMF7 (1)
- Sibling donor (MSD) (1)
- Societe Francaise (1)
- Spleen (1)
- Stem cell transplantation (1)
- Suppression (1)
- Survival (1)
- T-cells (1)
- TNF (1)
- TNFR2 (1)
- TNFSF14 (1)
- TNFSF4 (1)
- TSLP (1)
- Thiotepa-busulfan-fludarabine (TBF) (1)
- Translational research (1)
- Tumor-necrosis-factor (1)
- Unrelated donor (UD) (1)
- Varicella-Zoster-Virus (1)
- Viral (1)
- [177Lu]PentixaTher (1)
- [68Ga]PentixaFor (1)
- [90Y]PentixaTher (1)
- \(^{11}\)C-methionine (1)
- actin (1)
- activation (1)
- acute Graft versus Host Disease (1)
- acute graft-versus-host disease (1)
- acute kidney injury (1)
- acute leukemia (AL) (1)
- acute lymphoblastic leukaemia (1)
- acute lymphoblastic leukemia (1)
- acute myeloid leukaemia (1)
- acute myeloid leukemia (1)
- acute myeloid-leukemia (1)
- adoptive cell therapy (1)
- adoptive transfer (1)
- adrenocortical carcinoma (1)
- agonist (1)
- alloSCT patients (1)
- allogeneic hematopoietic stem cell transplantation (1)
- alloreactive T cells (1)
- alveolar epithelium (1)
- amsacrine (1)
- antigen loss (1)
- antigens (1)
- apoptosis (1)
- artificial intelligence (1)
- aspergillosis (1)
- bacterial infection (1)
- beta-D-glucan (1)
- biophosphonate (1)
- bispecific antobodies (1)
- blinatumomab (1)
- blinatumoman (1)
- bone disease (1)
- bone marrow transplantation (1)
- bone remineralization (1)
- bone-disease (1)
- bone-mineral density (1)
- bortezomib (1)
- bortezomib plus dxamethasone (1)
- breakpoint (1)
- bridge-to-transplant (1)
- bronchoalveolar lavage fluid (1)
- cancer care (1)
- cancer immunotherapy (1)
- cancer treatment (1)
- carfilzomib (1)
- caspase-3 (1)
- cell binding (1)
- cells (1)
- cereblon expression (1)
- chemokine receptor (1)
- chemokines (1)
- chimeric antigen receptor (1)
- chronic myelogenous leukemia (1)
- chronic myeloid leukemia (1)
- chronic phase (1)
- clinical trial (1)
- combination therapy (1)
- complement system (1)
- computed tomography (1)
- consensus statement (1)
- corticosteroids (1)
- corticosteroids and cyclophosphamide (1)
- cyclophosphamide (FLAMSA) (1)
- cytogenetic response (1)
- cytotoxicity (1)
- daratumumab (1)
- daratumumab monotherapy (1)
- denritic cells (1)
- depression (1)
- diagnostics (1)
- different imatinib dose regimens (1)
- disorders (1)
- donor-cell leukemia (1)
- downstream (1)
- early applied higher imatinib dosages (1)
- elderly patients (1)
- elotuzumab (1)
- enal impairment (1)
- endoradiotherapy (1)
- enzyme-linked immunoassays (1)
- erythropoiesis-stimulating agents (1)
- fungal host response (1)
- fungal molecular diagnostics (1)
- fungi (1)
- galectin-2 (1)
- gene expression (1)
- gene expression data (1)
- gene regulation (1)
- gene regulation in immune cells (1)
- gene therapy (1)
- genetic polymorphisms (1)
- genetic susceptibility (1)
- granulocytes (1)
- group consensus statement (1)
- haploidentical γδ T lymphocytes (1)
- health care (1)
- hematologic malignancies (1)
- hematological malignancies (1)
- hematology (1)
- hematopoietic (1)
- hematopoietic cell transplantation (1)
- hematopoietic stem cell transplantation (1)
- hematopoietic stem cell transplantation (HSCT) (1)
- host defense (1)
- host response (1)
- human biomarker (1)
- human cytomegalovirus (HCMV) (1)
- human leukocyte antigen-E (HLA-E) (1)
- humans (1)
- hybrid messenger RNA (1)
- hypersensitivity (1)
- immune cell recruitment (1)
- immune cells (1)
- immune control (1)
- immune impairment (1)
- immune receptors (1)
- immune reconstitution (1)
- immune response (1)
- immunohistochemistry techniques (1)
- in vitro model (1)
- in vivo cell expansion (1)
- in vivo imaging (1)
- incidence (1)
- individual mind state (1)
- induction regimen (1)
- infectious diseases (1)
- infusion (1)
- inhibition (1)
- innate immune response (1)
- innate immunity (1)
- interaction (1)
- intermediate dose Ara-C (1)
- invasive fungal infections (1)
- invasive pulmonary aspergillosis (1)
- involvement (1)
- isoforms (1)
- kidney (1)
- library screening (1)
- life-threatening side-effects (1)
- lifestyle habits (1)
- loss-of-function (1)
- lymphoma (1)
- mAb engineering (1)
- malignancies (1)
- malignant transformation (1)
- malnutrition (1)
- management (1)
- mantle cell lymphoma (1)
- marrow plasma cells (1)
- matrix metallopeptidase-1 (1)
- mebendazole (1)
- mechanism (1)
- metastasis (1)
- microenvironment (1)
- mismatch (1)
- mold exposure (1)
- monoclonal antibody (1)
- monoclonal gammopathy (1)
- monocytes (1)
- mortality (1)
- motivational level (1)
- mouse models (1)
- mucormycosis (1)
- multiparameter flow-cytometry (1)
- multiparameter flow-cytpmetry (1)
- multiparametric flow cytometry (1)
- multiplicity of infection (1)
- murine model (1)
- mycophenolic acid (1)
- natural killer cell (1)
- natural killer cells (1)
- natural language processing (1)
- network (1)
- newly-diagnosed myeloma (1)
- no correlation (1)
- novel therapies (1)
- nutritional counseling (1)
- nutritional medical needs (1)
- nutritional risk screening (1)
- obinutuzumab (1)
- observational (1)
- older patients (1)
- oncology (1)
- oncology outpatients (1)
- ontology (1)
- outcomes research (1)
- outreach (1)
- panobinostat (1)
- participation in clinical trials (1)
- pathogen-associated molecular patterns (1)
- pathophysiology (1)
- pathway (1)
- patient access (1)
- pattern (1)
- pattern recognition receptors (1)
- pediatric (1)
- phosphatidylinositol 3-kinase/Akt (1)
- phosphorylation (1)
- plasma cells (1)
- polymerase-chain-reaktion (1)
- population-based cohort (1)
- positron emission tomography (1)
- precision medicine (1)
- precision oncology (1)
- prediction (1)
- probe-based real-time PCR (1)
- progression (1)
- public health (1)
- radiogenomics (1)
- randomized controlled trial (1)
- randomized phase-3 trial (1)
- rare SNP (1)
- real life setting (1)
- real world data (1)
- real world evidence (1)
- real-time PCR (1)
- receptor tyrosine kinases (1)
- recombinant-human-erythropoietin (1)
- relapsed (1)
- relapsed and refractory (1)
- renal failure (1)
- respiratory virus (1)
- risk stratification (1)
- salvage (1)
- serum biomarkers (1)
- serum retention (1)
- significance MGUS (1)
- sirolimus (1)
- smoldering multiple-myeloma (1)
- smoldering myeloma (1)
- stem cell transplantation (1)
- stimulation (1)
- stress (1)
- susceptibility (1)
- symptom burden (1)
- term-follow-up (1)
- thalidomide maintenance (1)
- therapy (1)
- total body irradiation/busulfan (1)
- toxicity (1)
- transcripts (1)
- transient regulatory T-cell targeting (1)
- translational research (1)
- tumor‐specific antigen (1)
- tumour immunology (1)
- undetermined significance MGUS (1)
- venetoclax (1)
- venous thromboembolic disease (1)
- viral infection (1)
- virus (1)
- virus-specific T-cell (1)
- whole-body imaging (1)
- zoledonic acid (1)
Institute
- Medizinische Klinik und Poliklinik II (93)
- Pathologisches Institut (12)
- Klinik und Poliklinik für Nuklearmedizin (8)
- Institut für Hygiene und Mikrobiologie (7)
- Institut für Virologie und Immunbiologie (6)
- Theodor-Boveri-Institut für Biowissenschaften (6)
- Kinderklinik und Poliklinik (5)
- Medizinische Klinik und Poliklinik I (5)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (4)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (4)
Sonstige beteiligte Institutionen
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany (1)
- Mildred Scheel Early Career Center (1)
- University of Bari Medical School, Bari, Italy (1)
EU-Project number / Contract (GA) number
- 733297 (2)
- 754658 (2)
- 037602 (1)
- 19-COP-0031 (1)
- 2016 FGR 0053 (1)
- 260338 (1)
- 847507 (1)
- 853988 (1)
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.
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.
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.
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.
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.
A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.
(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.
The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs. 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48–0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs. 18%, P=0.005; HR=0.40, CI 95%=0.22–0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post–transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs.
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.
This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV\(_{mean}\)) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV\(_{mean}\) of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR\(_{mean}\)) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR\(_{mean}\) in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR\(_{max}\) of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.
Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools.
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.
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.
Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.
Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity.
Methods
Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems.
Results
STAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD.
Conclusions
NewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.
The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA.
Current limitations and perspectives of chimeric antigen receptor-T-cells in acute myeloid leukemia
(2021)
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.
Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.
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.