The most common cause of death in patients with acute myeloid leukemia (AML) who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) is AML relapse. Therefore, additive therapies ...post allo-HSCT have significant potential to prevent relapse. Natural killer (NK)-cell-based immunotherapies can be incorporated into the therapeutic armamentarium for the eradication of AML cells post allo-HSCT. In recent studies, NK cell-based immunotherapies, the use of adoptive NK cells, NK cells in combination with cytokines, immune checkpoint inhibitors, bispecific and trispecific killer cell engagers, and chimeric antigen receptor-engineered NK cells have all shown antitumor activity in AML patients. In this review, we will discuss the current strategies with these NK cell-based immunotherapies as possible therapies to cure AML patients post allo-HSCT. Additionally, we will discuss various means of immune escape in order to further understand the mechanism of NK cell-based immunotherapies against AML.
Inflammatory cytokines play a role in hematopoiesis and development of myelodysplastic syndromes (MDS). Although increased serum levels of inflammatory cytokines are associated with poor survival in ...MDS patients, clinical management does not include assessment of inflammation. We investigated the significance of inflammation in MDS using serum C-reactive protein (CRP) levels, an indicator of the degree of systemic inflammation that can be used in routine practice. We hypothesized that serum CRP levels can be used to further classify low-risk MDS. We conducted a retrospective analysis of 90 patients with low-risk MDS, defined by the international prognostic scoring system (IPSS). We examined the prognostic relevance of CRP and known prognostic factors at diagnosis. Increased serum CRP (≥ 0.58 mg/dL) was associated with poor survival (hazard ratio HR: 17.63, 95% confidence interval CI 5.83–53.28,
P
< 0.001) both overall and among the 73 patients with low-risk MDS as defined by the revised IPSS (HR: 28.05, 95% CI 6.15–128.04,
P
< 0.001). Increased CRP might predict poor prognosis and serum CRP levels can indicate clonal hematopoiesis and non-hematological comorbidity in patients with low-risk MDS.
Hemotropic mycoplasmas are common pathogens in animals, but it remains unclear what role these pathogens play in human infections. We report clinical and biologic characterization of Candidatus ...Mycoplasma haemohominis infection in a 42-year-old man in Japan. The patient had severe hemophagocytic syndrome 1 month after an accidental needlestick injury. Metagenomic deep sequencing identified Candidatus M. haemohominis and determined its draft genome for an isolate from serum of the patient. A high copy number of the Candidatus M. haemohominis genome was detected in serum and bone marrow samples. Electron microscopy examination showed morphologic characteristics of Candidatus M. haemohominis. Levofloxacin monotherapy induced resistance caused by a gyrase A gene mutation in the quinolone resistance-determining region, but a combination treatment with moxifloxacin and minocycline was effective. We identified Candidatus M. haemohominis in a patient who had life-threatening symptoms related to multiple organ infection. Human infection with this mycoplasma might occur more frequently than has been generally recognized.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hemophagocytic lymphohistiocytosis (HLH) is an uncontrolled hyperinflammatory disorder driven by an overactive immune system that results in high mortality. Post-transplant-associated hemophagocytic ...lymphohistiocytosis (PT-HLH) is a type of secondary HLH that occurs following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical features of PT-HLH remain unclear and diagnostic and prognostic tools have not yet been established. Here, we retrospectively evaluated the clinical manifestations and outcomes of PT-HLH in 94 patients who underwent allo-HSCT. According to our PT-HLH criteria (hyperferritinemia and increased macrophage count in bone marrow), PT-HLH occurred in 12 patients (12.8%). The PT-HLH patients showed splenomegaly (
P
= .001), a higher risk of engraftment failure (
P
= .013), and an increased percentage of macrophages and hemophagocytes in bone marrow aspirates (
P
= .0009 and
P
= .0006, respectively). Moreover, univariate and multivariate analyses revealed that the survival rate was lower in PT-HLH patients than non-PT-HLH patients (
P
= .0017 and
P
= .034, respectively). This study defines the clinical features of PT-HLH and PT-HLH criteria that could be useful tools for diagnosing PT-HLH.
Although follicular lymphoma (FL) is a pathological entity characterized by relatively uniform histological and molecular findings, its clinical course is highly variable. Establishment of ...therapeutic strategies based on a simple and practical prognostic model is important. C-reactive protein (CRP) is an adverse prognostic marker for various tumors and aggressive lymphomas. However, the significance of serum CRP levels as a prognostic index in low-grade lymphomas, such as FL, has not been thoroughly investigated. We retrospectively analyzed the relationship between serum CRP levels at diagnosis and the prognosis in patients with FL (
n
= 61) undergoing rituximab-containing chemotherapy. Elevated CRP levels showed a significant association with elevated fibrinogen (
P
= 0.002) in univariate analysis. Patients with higher CRP levels (> 5 mg/L) had a significantly shorter progression-free survival in multivariate analysis (
P
= 0.044). We concluded that serum CRP levels are important in prognostic stratification of patients with FL.
Aberrant expression of the interleukin-3 receptor alpha chain (IL3RA or CD123) is frequently observed in patients with a subset of leukemic disorders, including acute myeloid leukemia (AML), ...particularly in leukemia stem cells. We analyzed the relationships between immunohistochemical (IHC) expression, including that of CD123, and clinical outcomes. This study involved a retrospective analysis of 48 patients diagnosed with de novo AML (M0–M5,
n
= 48) at our hospital between February 2008 and September 2015. Among patients with de novo AML, CD123 expression was associated with a failure to achieve complete response (CR) to initial induction chemotherapy (
P
= 0.044) and poor overall survival (OS) (
P
= 0.036). This is the first study using IHC to demonstrate that CD123 expression is associated with a poor CR rate and poor OS in de novo AML patients. These results support previous reports using flow cytometry (FCM). CD123 expression may thus be useful for assessing AML patients’ prognoses. At the time of diagnosis, CD123 expression analysis using IHC may represent a clinically useful assessment for de novo AML patients.
Chromosomal translocation t(8;21)(q22;q22) which leads to generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in about 10% of acute myelogenous leukemia (AML). To uncover somatic ...mutations that cooperate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in-depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid hyperplasia, splenomegaly, extramedullary hematopoiesis and poor reconstitution ability in transplantation models. Parallel analyses of young and >1-year old Asxl2-deficient mice revealed age-dependent perturbations affecting not only myeloid and erythroid differentiation but also maturation of lymphoid cells. Overall, these findings establish a critical role of ASXL2 in maintaining steady state hematopoiesis and provide insights into how its loss primes expansion of myeloid cells.
The refined disease risk index (R-DRI) is a well-designed prognostic parameter that is based on only the disease type and status and is used for stratifying patients undergoing allogeneic ...hematopoietic stem cell transplantation (allo HSCT) into 4 risk groups. However, the application of the R-DRI for rare diseases has remained unclear.
We evaluated 135 patients who underwent allo HSCT for hematological malignancies including rare diseases, such as acute leukemia of ambiguous lineage, acute T-cell leukemia/lymphoma, extranodal natural killer T-cell lymphoma, and lymphoblastic lymphoma, at our institute.
According to the R-DRI, overall survival (OS) and progression-free survival at 2 years for patients with the low, intermediate, high, and very high groups were 66.7% and 66.7%, 60.8% and 56.0%, 27.1% and 23.7%, and 5.9% and 5.1%, respectively (P < .0001 and P < .0001, respectively). OS showed no significant difference between B-cell non-Hodgkin lymphoma (B-NHL) and T-cell non-Hodgkin lymphoma (T-NHL) (P = .71). Moreover, OS at 1 year was 80%, 14.3%, 60%, and 0% for the intermediate risk group, the very high-risk group of B-NHL, the intermediate risk group, and the high-risk group of T-NHL, respectively (P = .035).
We showed the applicability of the R-DRI for hematological malignancies, including rare disorders. However, we suggest that T-NHL patients may be better to be assigned between the nodal group and the extranodal group in the R-DRI.
Cells with monocyte/macrophage lineage expressing receptor activator of NF-κB (RANK) differentiate into osteoclasts following stimulation with the RANK ligand (RANKL). Cell adhesion signaling is also ...required for osteoclast differentiation from precursors. However, details of the mechanism by which cell adhesion signals induce osteoclast differentiation have not been fully elucidated. To investigate the participation of cell adhesion signaling in osteoclast differentiation, mouse bone marrow-derived macrophages (BMMs) were used as osteoclast precursors, and cultured on either plastic cell culture dishes (adherent condition) or the top surface of semisolid methylcellulose gel loaded in culture tubes (non-adherent condition). BMMs cultured under the adherent condition differentiated into osteoclasts in response to RANKL stimulation. However, under the non-adherent condition, the efficiency of osteoclast differentiation was markedly reduced even in the presence of RANKL. These BMMs retained macrophage characteristics including phagocytic function and gene expression profile. Lipopolysaccharide (LPS) and tumor necrosis factor -αTNF-α activated the NF-κB-mediated signaling pathways under both the adherent and non-adherent conditions, while RANKL activated the pathways only under the adherent condition. BMMs highly expressed RANK mRNA and protein under the adherent condition as compared to the non-adherent condition. Also, BMMs transferred from the adherent to non-adherent condition showed downregulated RANK expression within 24 hours. In contrast, transferring those from the non-adherent to adherent condition significantly increased the level of RANK expression. Moreover, interruption of cell adhesion signaling by echistatin, an RGD-containing disintegrin, decreased RANK expression in BMMs, while forced expression of either RANK or TNFR-associated factor 6 (TRAF6) in BMMs induced their differentiation into osteoclasts even under the non-adherent condition. These results suggest that cell adhesion signaling regulates RANK expression in osteoclast precursors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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