Refine
Has Fulltext
- yes (103)
Is part of the Bibliography
- yes (103)
Year of publication
Document Type
- Journal article (103)
Language
- English (103) (remove)
Keywords
- multiple myeloma (23)
- Aspergillus (6)
- cytokines (6)
- Aspergillus fumigatus (5)
- T cells (5)
- allogeneic stem cell transplantation (4)
- fungal infection (4)
- immunotherapy (4)
- refractory (4)
- relapse (4)
- CXCR4 (3)
- NK cells (3)
- biomarker (3)
- cancer (3)
- dendritic cells (3)
- immunoassay (3)
- invasive aspergillosis (3)
- medicine (3)
- myeloma (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)
- aspergillosis (2)
- aspergillus fumigatus (2)
- autologous transplantation (2)
- cancer genetics (2)
- cancer genomics (2)
- cancer immunotherapy (2)
- cell staining (2)
- extramedullary disease (2)
- galactomannan (2)
- inflammation (2)
- innate immunity (2)
- lenalidomide (2)
- leukemia (2)
- natural killer cells (2)
- pomalidomide (2)
- quality of life (2)
- regulatory T cells (2)
- stem-cell transplantation (2)
- theranostics (2)
- translational research (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)
- ELISPOT (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-DC cross-talk (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)
- 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 imaging (1)
- cancer therapy (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)
- cytomegalovirus (1)
- cytotoxicity (1)
- daratumumab (1)
- daratumumab monotherapy (1)
- denritic cells (1)
- depression (1)
- diagnostics (1)
- different imatinib dose regimens (1)
- disease prevention (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)
- flow cytometry (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)
- imaging (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)
- 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 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 factors (1)
- risk stratification (1)
- salvage (1)
- serum biomarkers (1)
- serum retention (1)
- significance MGUS (1)
- sirolimus (1)
- smoldering multiple-myeloma (1)
- smoldering myeloma (1)
- soluble factors (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)
- 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 (101)
- Pathologisches Institut (13)
- Institut für Hygiene und Mikrobiologie (8)
- Klinik und Poliklinik für Nuklearmedizin (8)
- Theodor-Boveri-Institut für Biowissenschaften (7)
- Institut für Virologie und Immunbiologie (6)
- Kinderklinik und Poliklinik (5)
- Medizinische Klinik und Poliklinik I (5)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (4)
- Comprehensive Cancer Center Mainfranken (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
- 037602 (2)
- 733297 (2)
- 754658 (2)
- 19-COP-0031 (1)
- 2016 FGR 0053 (1)
- 260338 (1)
- 847507 (1)
- 853988 (1)
Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874
Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T-cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT.
Unlike induced \(Foxp3^+\) regulatory T cells (\(Foxp3^+\) \(iT_{reg}\)) that have been shown to play an essential role in the development of protective immunity to the ubiquitous mold Aspergillus fumigatus, type-(1)-regulatory T cells (Tr1) cells have, thus far, not been implicated in this process. Here, we evaluated the role of Tr1 cells specific for an epitope derived from the cell wall glucanase Crf-1 of A. fumigatus (Crf-1/p41) in antifungal immunity. We identified Crf-1/p41-specific latent-associated \(peptide^+\) Tr1 cells in healthy humans and mice after vaccination with Crf-1/p41+zymosan. These cells produced high amounts of interleukin (IL)-10 and suppressed the expansion of antigen-specific T cells in vitro and in vivo. In mice, in vivo differentiation of Tr1 cells was dependent on the presence of the aryl hydrocarbon receptor, c-Maf and IL-27. Moreover, in comparison to Tr1 cells, \(Foxp3^+\) \(iT_{reg}\) that recognize the same epitope were induced in an interferon gamma-type inflammatory environment and more potently suppressed innate immune cell activities. Overall, our data show that Tr1 cells are involved in the maintenance of antifungal immune homeostasis, and most likely play a distinct, yet complementary, role compared with \(Foxp3^+\) \(iT_{reg}\).
The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 x 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 x 109/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier: 00055874)
Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenstrom's macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance.
Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high-versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).
Background: The primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical gamma delta T lymphocytes.
Methods: Patients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS (R) device according to the manufacturer's instructions. On average, patients received 2.17 x 10(6)/kg (range 0.9-3.48) γδ T cells with <1% CD4-or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m(2) day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0x10(6) IU/m(2) IL-2 on day +1 until day +6 for the induction of gamma delta T cell proliferation in vivo.
Results: This resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment.
Conclusion: This pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases.
The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.
European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications
(2015)
The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin < 10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).