68 research outputs found
Current Treatment Options in CLL
After impressive developments in recent years with the rise of new targeted agents,
chemoimmunotherapy (CIT) only plays a minor role in the treatment of patients with chronic
lymphocytic leukemia (CLL). Inhibitors of the Bruton tyrosine kinase (BTK), such as ibrutinib or
more recently acalabrutinib, are highly effective, even in poor-risk or chemo-refractory patients.
Venetoclax, an inhibitor of the anti-apoptotic BCL2 protein and, to a lesser extent, phosphoinositide-3
kinase (PI3K) delta inhibitors, add to the armamentarium of targeted agents for the treatment of
CLL. Furthermore, anti-CD20 monoclonal antibodies are used very successfully either alone or in
combination with BTK, BCL2 or PI3K inhibitors. Despite these advances, there is still an ongoing
pursuit for new therapeutic approaches in the treatment of CLL. An even bigger challenge poses the
determination of the optimal combination and sequence of those drugs. Here, we give an overview
of current treatment options in CLL, weighing the advantages and disadvantages of each approach
in the light of different clinical settings
Management of Extranodal Marginal Zone Lymphoma: Present and Upcoming Perspectives
Extranodal marginal zone lymphoma (EMZL) encompasses a subgroup of non-Hodgkin
lymphomas that often present with localized involvement and may manifest in a diversity of organs
and tissues. EMZL pathogenesis is in some cases linked to chronic inflammation/infection, which may
impose additional diagnostic and clinical challenges. The most studied and established connection
is the presence of Helicobacter pylori in gastric EMZL. Due to its heterogeneity of presentation and
intricate pathological features, treatment can be complex, and staging systems are decisive for the
choice of therapy. Nevertheless, there is no consensus regarding the most suitable staging system,
and recommendations vary among different countries. As a rule of thumb, in limited stages, a local
therapy with surgery or radiation is the preferred option, and it is potentially curative. Of note,
eradicating the causal agent may be an important step of treatment, especially in gastric EMZL,
in which Helicobacter pylori eradication remains the first-line therapy for the majority of patients.
In patients with more advanced stages, watch-and-wait is a valuable option, especially amongst
those without clear indications for systemic therapy, and it may be carried on for several years. If
watch-and-wait is not an option, systemic therapy may be needed. Even though several agents
have been tested as monotherapy or in combination in recent years, there is no consensus regarding
the first-line therapy, and decisions can vary depending on individual factors, such as age, clinical
performance and stage. This review aims to discuss the several aspects of EMZL, including genetic
milieu, pathogenesis and staging systems, that may influence the choice of therapy. In addition, we
present a summary of evidence of several systemic therapies, compare different recommendations
worldwide and discuss future perspectives and novelties in its therapy
Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma
To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper--glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach
Vitamin D Enhances Immune Effector Pathways of NK Cells Thus Providing a Mechanistic Explanation for the Increased Effectiveness of Therapeutic Monoclonal Antibodies
Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive
significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin
D deficiency; this is especially true for female patients. We have already been able to show that vitamin
D increases the antibody-dependent cytotoxicity (ADCC) of NK cells in a sex-dependent manner,
but it is unclear how vitamin D makes NK cells more efficient. Methods: Healthy individuals with
vitamin D deficiency were supplemented with vitamin D to sufficient levels. NK cells were isolated
from blood samples before and after vitamin D saturation. For transcriptome analysis, we used
the Affymetrix Gene-Chip 2.0™. Gene expression analysis as well as supervised and unsupervised
pathway analysis were performed. Results: Among others the “NK cell-associated cytotoxicity
pathway” increased after vitamin D substitution. Five IFN-α subtypes (2, 4, 6, 7 and 10) and IFN-κ
were more highly expressed and are mainly responsible in these pathways. In contrast, the pathway
“interferon-gamma response”, as well as other sets in cytokine production and chemotaxis showed a
reduction. Toll-like receptor genes (TLR-8, TLR-7, TLR-2) were downregulated and, therefore, are
responsible for the decline of these pathways. The same could be shown for the “ubiquitin-ligase”
pathway. Conclusions: Increased expression of several IFN-α subtypes may explain the increased
ADCC of NK cells in vitamin D-replenished and otherwise healthy subjects. Other regulators of
interferon production and ADCC are compensatory upregulated in compensation, such as Toll-like
receptors and those of the ubiquitin ligase, and normalize after vitamin D substitution
VEGFR2 and VEGFA polymorphisms are not associated with an inferior prognosis in Caucasian patients with aggressive B-cell lymphoma
Purpose
Previous published data showed an impact of single‐nucleotide polymorphisms in the VEGF A and VEGFR2 genes on the survival of patients with various malignancies, among others diffuse large B‐cell lymphoma (DLBCL).
Patients and Methods
We investigated the role of four VEGF‐A and two VEGFR‐2 gene polymorphisms on the outcome of 273 patients with diffuse large B‐cell lymphoma who were treated with R‐CHOP within a prospective, randomized trial of the German High‐Grade Non‐Hodgkin Lymphoma Study Group (DSHNHL). The genomic DNA samples were analyzed using commercial DNA Probes (Applied Biosystems, USA) to detect single‐nucleotide polymorphisms in the VEGF A rs699947, rs1570360, rs2010963, rs3025039 and rs1870377, and rs2305948 in the VEGFR2 receptor. Hundred healthy blood donors served as a control.
Results
There was no difference between the SNP allele frequencies in lymphoma patients compared to the control group for all investigated SNPs. None of the investigated SNPs was significantly associated with EFS or OS. After adjusting for the International Prognostic Index risk factors in a multivariate analysis, these results could be confirmed.
Conclusion
Single‐nucleotide polymorphisms of the VEGF and VEGFR2 were not associated with a worse outcome in Caucasian patients with DLBCL
Increased B-cell activity with consumption of activated monocytes in severe COVID-19 patients
The pathogenesis of autoimmune complications triggered by SARS-CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID-19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T-cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4+T, CD8+T-lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8-cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1
Effects of face masks on performance and cardiorespiratory response in well-trained athletes
Background
During the COVID-19 pandemic, compulsory masks became an integral part of outdoor sports such as jogging in crowded areas (e.g. city parks) as well as indoor sports in gyms and sports centers. This study, therefore, aimed to investigate the effects of medical face masks on performance and cardiorespiratory parameters in athletes.
Methods
In a randomized, cross-over design, 16 well-trained athletes (age 27 ± 7 years, peak oxygen consumption 56.2 ± 5.6 ml kg−1 min−1, maximum performance 5.1 ± 0.5 Watt kg−1) underwent three stepwise incremental exercise tests to exhaustion without mask (NM), with surgical mask (SM) and FFP2 mask (FFP2). Cardiorespiratory and metabolic responses were monitored by spiroergometry and blood lactate (BLa) testing throughout the tests.
Results
There was a large effect of masks on performance with a significant reduction of maximum performance with SM (355 ± 41 Watt) and FFP2 (364 ± 43 Watt) compared to NM (377 ± 40 Watt), respectively (p < 0.001; ηp2 = 0.50). A large interaction effect with a reduction of both oxygen consumption (p < 0.001; ηp2 = 0.34) and minute ventilation (p < 0.001; ηp2 = 0.39) was observed. At the termination of the test with SM 11 of 16 subjects reported acute dyspnea from the suction of the wet and deformed mask. No difference in performance was observed at the individual anaerobic threshold (p = 0.90).
Conclusion
Both SM and to a lesser extent FFP2 were associated with reduced maximum performance, minute ventilation, and oxygen consumption. For strenuous anaerobic exercise, an FFP2 mask may be preferred over an SM
Comparison of Circular and Parallel-Plated Membrane Lungs for Extracorporeal Carbon Dioxide Elimination
Extracorporeal carbon dioxide removal (ECCO2R) is an important technique to treat critical lung diseases such as exacerbated chronic obstructive pulmonary disease (COPD) and mild or
moderate acute respiratory distress syndrome (ARDS). This study applies our previously presented
ECCO2R mock circuit to compare the CO2 removal capacity of circular versus parallel-plated membrane lungs at different sweep gas flow rates (0.5, 2, 4, 6 L/min) and blood flow rates (0.3 L/min,
0.9 L/min). For both designs, two low-flow polypropylene membrane lungs (Medos Hilte 1000,
Quadrox-i Neonatal) and two mid-flow polymethylpentene membrane lungs (Novalung Minilung,
Quadrox-iD Pediatric) were compared. While the parallel-plated Quadrox-iD Pediatric achieved the
overall highest CO2 removal rates under medium and high sweep gas flow rates, the two circular
membrane lungs performed relatively better at the lowest gas flow rate of 0.5 L/min. The low-flow
Hilite 1000, although overall better than the Quadrox i-Neonatal, had the most significant advantage
at a gas flow of 0.5 L/min. Moreover, the circular Minilung, despite being significantly less efficient
than the Quadrox-iD Pediatric at medium and high sweep gas flow rates, did not show a significantly
worse CO2 removal rate at a gas flow of 0.5 L/min but rather a slight advantage. We suggest that
circular membrane lungs have an advantage at low sweep gas flow rates due to reduced shunting as
a result of their fiber orientation. Efficiency for such low gas flow scenarios might be relevant for
possible future portable ECCO2R devices
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