73 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
Advances in Lymphoma Molecular Diagnostics
Lymphomas encompass a diverse group of malignant lymphoid neoplasms. Over recent
years much scientific effort has been undertaken to identify and understand molecular changes
in lymphomas, resulting in a wide range of genetic alterations that have been reported across
all types of lymphomas. As many of these changes are now incorporated into the World Health
Organization’s defined criteria for the diagnostic evaluation of patients with lymphoid neoplasms,
their accurate identification is crucial. Even if many alterations are not routinely evaluated in daily
clinical practice, they may still have implications in risk stratification, treatment, prognosis or disease
monitoring. Moreover, some alterations can be used for targeted treatment. Therefore, these advances
in lymphoma molecular diagnostics in some cases have led to changes in treatment algorithms. Here,
we give an overview of and discuss advances in molecular techniques in current clinical practice, as
well as highlight some of them in a clinical context
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
Cytotoxic Efficiency of Human CD8+ T Cell Memory Subtypes
Immunological memory is important to protect humans against recurring diseases.
Memory CD8+ T cells are required for quick expansion into effector cells but also
provide immediate cytotoxicity against their targets. Whereas many functions of the two
main cytotoxic subtypes, effector memory CD8+ T cells (TEM) and central memory CD8+ T
cells (TCM), are well defined, single TEM and TCM cell cytotoxicity has not been quantified.
To quantify cytotoxic efficiency of TEM and TCM, we developed a FRET-based single cell
fluorescent assay with NALM6 target cells which allows analysis of target cell apoptosis,
secondary necrosis following apoptosis, and primary necrosis after TEM- or TCM-target cell
contact. Both, single cell and population cytotoxicity assays reveal a higher cytotoxic
efficiency of TEM compared to TCM, as quantified by target cell apoptosis and secondary
necrosis. Perforin, granzyme B, FasL, but not TRAIL expression are higher in TEM
compared to TCM. Higher perforin levels (likely in combination with higher granzyme
levels) mediate higher cytotoxic efficiency of TEM compared to TCM. Both, TEM and TCM
need the same time to find their targets, however contact time between CTL and target,
time to induce apoptosis, and time to induce secondary necrosis are all shorter for TEM. In
addition, immune synapse formation in TEM appears to be slightly more efficient than in
TCM. Defining and quantifying single TEM and TCM cytotoxicity and the respective
mechanisms is important to optimize future subset-based immune therapies
Dual-Energy Computed Tomography in Stroke Imaging : Value of a New Image Acquisition Technique for Ischemia Detection after Mechanical Thrombectomy
OBJECTIVE: To assess if a new dual-energy computed tomography (DECT) technique enables an improved visualization of ischemic brain tissue after mechanical thrombectomy in acute stroke patients.
MATERIAL AND METHODS: The DECT head scans with a new sequential technique (TwinSpiral DECT) were performed in 41 patients with ischemic stroke after endovascular thrombectomy and were retrospectively included. Standard mixed and virtual non-contrast (VNC) images were reconstructed. Infarct visibility and image noise were assessed qualitatively by two readers using a 4-point Likert scale. Quantitative Hounsfield units (HU) were used to assess density differences of ischemic brain tissue versus healthy tissue on the non-affected contralateral hemisphere.
RESULTS: Infarct visibility was significantly better in VNC compared to mixed images for both readers R1 (VNC: median 1 (range 1-3), mixed: median 2 (range 1-4), p < 0.05) and R2 (VNC: median 2 (range 1-3), mixed: 2 (range 1-4), p < 0.05). Qualitative image noise was significantly higher in VNC compared to mixed images for both readers R1 (VNC: median 3, mixed: 2) and R2 (VNC: median 2, mixed: 1, p < 0.05, each). Mean HU were significantly different between the infarcted tissue and the reference healthy brain tissue on the contralateral hemisphere in VNC (infarct 24 ± 3) and mixed images (infarct 33 ± 5, p < 0.05, each). The mean HU difference between ischemia and reference in VNC images (mean 8 ± 3) was significantly higher (p < 0.05) compared to the mean HU difference in mixed images (mean 5 ± 4).
CONCLUSION: TwinSpiral DECT allows an improved qualitative and quantitative visualization of ischemic brain tissue in ischemic stroke patients after endovascular treatment
Progranulin antibodies entertain a proinflammatory environment in a subgroup of patients with psoriatic arthritis
Psoriatic arthritis (PsA) is a distinctive inflammatory arthritis which may typically develop in a subgroup of individuals suffering from psoriasis. We recently described progranulin autoantibodies (PGRN-Abs) in the sera of patients with different autoimmune diseases including seronegative polyarthritis. In the present study we investigated the occurrence of PGRN-Abs in PsA.PGRN-Abs were determined in 260 patients with PsA, 100 patients with psoriasis without arthritic manifestations (PsC) and 97 healthy controls using a recently described ELISA. PGRN plasma levels were determined from subgroups by a commercially available ELISA-kit. Possible functional effects of PGRN-antibodies were analysed in vitro by tumour necrosis factor (TNF)-α mediated cytotoxicity assays using WEHI-S and HT1080 cells.PGRN-Abs were detected with relevant titres in 50/260 (19.23%) patients with PsA, but in 0/100 patients with psoriasis without arthritic manifestations (P = 0.0001). All PGRN-Abs belonged to immunoglobulin G (IgG). PGRN-Abs were significantly more frequent in PsA patients with enthesitis or dactylitis. PGRN-Abs were also more frequent in PsA patients receiving treatment with TNF-α-blockers than in patients treated without TNF-α-blockers (20.8% versus 17.4%; P = 0.016). PGRN plasma levels were significantly lower in PGRN-Ab-positive patients with PsA than in healthy controls and patients with psoriasis without arthritic manifestations (P < 0.001), indicating a neutralizing effect of PGRN-Abs. Moreover cytotoxicity assays comparing PGRN-antibody positive with negative sera from matched patients with PsA, clearly showed a proinflammatory effect of PGRN antibodies.Neutralizing PGRN-Abs occur with relevant titres in a subgroup of patients with PsA, but not in patients without arthritic manifestations (PsC). PGRN-Ab-positive patients had more frequent enthesitis or dactylitis. TNF-α-induced cytotoxicity assays demonstrated that the protective effects of progranulin were inhibited by serum containing PGRN-Abs. This suggests that PGRN-Ab might not only be useful as a diagnostic and prognostic marker, but may provide a proinflammatory environment in a subgroup of patients with PsA
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